HK40005117A - Intranasal lower dosage strength testosterone gel formulations and use thereof for treating anorgasmia or hypoactive sexual desire disorder - Google Patents

Description

Intranasal lower dosage strength testosterone gel formulations and their use for treating anorgasmia or hypoactive sexual desire disorders

The application is a divisional application of Chinese patent application with application number 201280034554.2, application date of 2012, 5 and 14, and invented as 'testosterone gel preparation with lower dosage strength in nose and application thereof for treating anorgasmia or hyposexuality disease'.

Technical Field

The present invention relates to lower dose strength intranasal testosterone gels for providing intranasal delivery of testosterone to females, and to intranasal treatment methods for treating females suffering from anorgasmia and/or Hypoactive Sexual Desire Disorder (HSDD). In particular, the present invention relates to improved methods and lower dose strength intranasal testosterone gel formulations for the treatment of female anorgasmia and/or HSDD. The invention also relates to a system for intranasally dispensing precise doses of such gels at optimal anatomic locations within each nostril of a female such that an effective amount of testosterone is deposited within each nostril at the optimal anatomic location, thereby effectively treating female anorgasmia and/or HSDD.

Background

Reduction of endogenous steroid hormone levels in humans often leads to various undesirable clinical symptoms. For example, low testosterone levels (hypogonadism) in men can lead to clinical symptoms including impotence, lack of sexual arousal, muscle weakness, and osteoporosis. Similarly, in women, a decrease in testosterone and/or estrogen levels can lead to female sexual disorders, which include clinical symptoms such as lack of sexual drive, lack of arousal or pleasure, decreased energy levels or fatigue with bradykinesia, depressed mood or depression, decreased well-being, insomnia, allergies, decreased vaginal lubrication and osteoporosis. Moreover, a decrease in estrogen and/or progesterone levels in women, as observed during menopause, often leads to clinical symptoms including hot flashes, night sweats, vaginal atrophy, decreased libido, and osteoporosis.

Testosterone was once considered to be an androgen, but it is also synthesized in small amounts in women, mainly by the ovaries and adrenal glands. The physiological functions of testosterone in women include, among others, development of pubic and axillary hair, libido; affecting bone density and muscle tone, libido and overall vitality and psychological well-being. Testosterone plasma concentrations in premenstrual women typically fluctuate during the menstrual cycle, with total testosterone plasma concentrations typically being between about 15ng/dL and about 65 ng/dL. However, in the years that menopause is walked through, circulating testosterone levels begin to decline, which is generally thought to be due to age-related reductions in ovarian and adrenal secretions. Generally, testosterone levels in testosterone deficient women are less than about 20-25ng/dL, while testosterone levels in ovariectomized women are less than about 10 ng/dL.

In a national health and social life survey of 1,700 women aged 18-59, 43% acknowledge certain types of Female Sexual Dysfunction (FSD). For example, see Laumann et al, Sexual dysfunction in the United states: predictors and predictors; JAMA,281:537-544 (1999).

Hypoactive Sexual Desire Disorder (HSDD), the most common female sexual problem, is a condition characterized by a lack or absence of sexual fantasy and desire for sexual activity, which results in significant distress or difficulty in personal relationships. Sexual dysfunction is neither attributable to additional psychiatric disorders nor caused by direct physiological effects on substances (i.e. drug abuse) or by general medical conditions.

Anorgasmia, the second most commonly reported female sexual problem, is believed to be persistent or delayed or absent recurrence of orgasm following the period of normal sexual arousal, resulting in significant distress or difficulty in personal relationships. When female sexual activity is not accompanied by the release of a high quality orgasm, the sexual activity can become a nuisance or a task rather than a satisfying, intimate experience. This can also lead to indirect diminished interest and/or difficulties with human relations.

Hypoactive sexual desire disorder and anorgasmia affect millions of women in the united states.

Sexual response is a complex and finely regulated process that can be perturbed at various time points in the reproductive life cycle (prenatal and postpartum, perimenopausal and postamenorrhea), which may be responsible for the reported high prevalence of neutral dysfunction in the general healthy female population. See, for example, Laumann et al, supra.

It is hypothesized that testosterone has a central and secondary role in sexual function. The surgically-induced decline in postmenopausal androgen levels has supported the hypothesis that: that is, a decrease in testosterone levels is associated with decreased libido. Testosterone, the primary circulating androgen in a woman, is a naturally occurring steroid. In women, androgens originate from three sources: adrenal, ovarian and peripheral transition. Androgens are secreted by the ovary and adrenal glands. In contrast to the sudden drop in estrogen during menopause, serum androgen levels gradually decrease as women age, primarily due to the decreased production of adrenal androgen precursors. For example, see Goldstat et al, transgenic testosterone therapy wells-bening, mood, and dsextrinsic function in pre-nonpausal mouse; menopause,10(5): 390-. As mentioned above, this may be due to a decline in ovarian and adrenal function with age.

Recent lateral studies in women 18-75 years of age have shown that total and free testosterone levels decline significantly with age from early childbearing. Unlike naturally occurring menopause, women who undergo bilateral ovariectomy experience a significant decline in testosterone production, with levels as much as 50%.

Testosterone is reported to play a role in mood, body composition and bone mineral density, and has a central and secondary role in sexual function. For example, see Davis et al, android replacement in women: a communition; menopause, J Clin Endocrinol Metab,84(6):1886-1891 (1999); and Goldstat et al, supra. In the periphery, nitric oxide requires testosterone to stimulate vascular congestion to engorge clitoral tissue and lubricate the vagina during sexual arousal.

Recent studies have shown that testosterone is effective in increasing the number of sexual satisfaction events, increasing libido and reducing personal distress in women undergoing bilateral ovariectomy and hysterectomy of HSDD.

The core effects of testosterone are not well characterized. Testosterone stimulation involves a stimulation and reward system, including dopamine release in various brain structures of sexual desire. In rats, testosterone was found to stimulate dopamine release in the central anterior region of the anterior inferior colliculus under basal conditions and sexual stimulation. For example, see Halaris A.: Neurochemical aspects of the sexualresponse cycle; CNS spectra, 9:211-216 (2003). fMRI studies in healthy women of different ages showed testosterone level dependent modulation of tonsil activity, indicating that age-related decreases in androgen levels contribute to a decrease in tonsil reactivity. In addition, it has been reported that decreased tonsil reactivity in older women can be restored to the level of younger women by intranasal exogenous testosterone. For example, see van Wigen et al, Testosterone in createsamyla reactivity in middle-formed, from to a young adultwood level; neuropsychropharmacology, Feb:34(3)539-547 (2009).

Loeser reported in 1940 the use of androgens to enhance female libido. Some young married women previously thought to be "stiff" themselves were observed by Salmon (1942) to be able to experience a "significant increase in sexual satisfaction, eventually ending with orgasm" after testosterone propionate injection. The effect gradually disappeared within a few weeks after the injection was stopped. For example, see Traish et al, Testosterone therapy in women with gynecomology and Sexual disorders, atriumph of clinical endoronilogy from 1938to 2008; j Sex Med 4:609-619 (2009). In the 80's of the 20 th century, the role of androgens in maintaining sexual function was studied in ovariectomized women. For example, see Sherwin et al, The role of an alkane in The maintenance of a basic functional in an oven programmed book; psychosmatic Medicine,49: 397-. In a three (3) month prospective open study on 44 women, a study by Sherwin et al, monthly injections of estrogen and testosterone were reported to increase libido, the rate of sexual arousal, and the number of fantasy. Higher rates of sexual intercourse and orgasm in women treated with androgens and estrogens compared to controls have also been reported in Sherwin et al.

Over the past 20 years, post-menopausal women with HSDD have been subjected to more than 80 studies with exogenous testosterone, either by oral, transdermal, sublingual or parenteral (parental) routes of administration, with or without concurrent estrogen therapy, which purported to observe an increase in libido, arousal, frequency of satisfactory sexual activity, pleasure and responsiveness to some extent. See, Traish et al, supra, 2009.

There is a fresh study of low libido premenstrual women. Goldstat et al, supra, apparently studied the effects of transdermal testosterone therapy on the appearance of hypoactive gonadal (eugonadal), well-being, mood and sexual function in women before amenorrhea. Testosterone treatment resulted in a statistically significant improvement in the overall mental health index, the sabbatatsberg sexual self-rating scale and the overall score of the becker depression questionnaire when compared to placebo. These effects were found when the average total testosterone level was at the low end of the normal range before treatment and at the high end of the normal range during treatment. However, testosterone treatment had a clear effect on orgasm at different levels of the sabbatarberg libido scale. This study shows that while most previous studies with testosterone have addressed the decline in libido in women after amenorrhea, it is also particularly important for women to have overall sexual well-being and orgasm before amenorrhea.

Yincui sandIs a testosterone sustained-release transdermal patch.Indicated for the treatment of Hypoactive Sexual Desire Disorder (HSDD) in bilateral ovariectomized and hysterectomized (surgically induced menopausal) women receiving concurrent estrogen treatment. Utilization in post-menopausal women with HSDDClinical studies conducted have shown an increase in sexual desire and satisfaction events, with mild androgenic skin effects as a major safety concern. See, for example, Shifresn et al: transdermal testosterone transaction in a mouse with modulatedA sexual functional after oophorotomy; n Eng N Med 343(10), 682-688 (2000); branstein et al, Safety and efficiency of a stortionone batch for the treatment of a latent sexualreception order in a qualitative mental routine, an random plated-controlled batch; arch Intern Med,165(14), 1582-; butter et al, Testosterone Patch for low sexual positioning in experimental mental women, arandomized real; obstet Gynecol, 105(5Pt 1):944-952 (2005); simon et al, Testosterone batch in organisms sequential activity and device in a qualitative zymophyusal boiler with a hydrolytic sequential device; j Clin EndocrinolMetab,90(9)5226-5233 (2005); davis et al, efficiency and safety of a template for the treatment of a reactive sequential destination recorder in a biochemical engineering of an alpha randomised, placbo-controlled project; menopause,13(3): 387-; and Shifront et al, a template for the transaction of a passive default order in a native mental world from the interface 1 student; menopause,143:770-779 (2006).

LibiGel is a gel formulation of testosterone that is applied to the upper arms of women. Treatment with LibiGel reportedly increases the number of satisfaction events compared to baseline and placebo treated individuals. Effective doses of LibiGel have also been reported to produce blood levels of testosterone within the normal range for premenstrual women. For example, seewww.libigel.org。

Is a blend of vegetable oil and extract comprising: borage seed oil, evening primrose oil, angelica sinensis extract, Coleus Forskohlii (Coleus Forskohlii) extract, theobromine, antioxidants { ascorbyl palmitate (vitamin C), tocopherol (vitamin E) }; and perfumes (U.S.6,737,084), which may benefit some women with anorgasmia. In the measurement of female sexual desire, arousal and sexual satisfaction,significant improvements have been shown. For example, seewww.zestra.com。

ArginMax^TMIs a mixture of L-arginine, ginseng, ginkgo biloba, terbinafine, calcium and iron. ArginMax for female^TMIs especially formulated for women. It contains calcium and iron to help alleviate fatigue problems specific to women. American ginseng in male products has been replaced by Terna, an aromatic herb that helps to calm anxiety and induce relaxation of the mind. ArginMax for females^TMProviding 100% vitamin A, C, E and the RDA of the B complex vitamin. ArginMax^TMThe female experience is safely enhanced by improving circulation. Adequate blood flow is critical for female arousal, hyperemia, and lubrication. For example, seewww.arginimax.com。

In view of the fact that the united states and millions of women worldwide suffer from HSDD and anorgasmia, there is a real and urgent need for effective medical treatments that can treat these diseases so that the quality of life of these individuals can be improved. One therapeutic goal of such treatment to address this urgent need may be to restore testosterone levels in women to young adult levels or at least to the natural pre-menopausal state in an effort to alleviate symptoms typically associated with HSDD and/or anorgasmia that may result from testosterone deficiency.

Disclosure of Invention

The present invention overcomes the limitations and disadvantages associated with treating anorgasmia and/or HDDD with available therapies through the discovery of a novel lower dosage strength nasal testosterone gel and method of use for treating HSDD and/or anorgasmia. In particular, the present invention overcomes the limitations and disadvantages of currently available options for administering testosterone through the discovery of new and improved lower dose strength testosterone gel formulations, specifically designed for intranasal administration, to deliver a therapeutically effective amount of testosterone to treat women suffering from and/or having been diagnosed with HSDD and/or anorgasmia.

The term "therapeutically effective amount" means an amount of testosterone sufficient to cause a therapeutic or prophylactic effect for use in testosterone replacement or supplementation therapy to treat female sexual dysfunction ("FSD"), i.e., hypoactive sexual desire disorder ("HSDD") and/or female orgasmic disorder ("anorgasmia").

Thus, in general, the present invention provides new and improved substantially less irritating lower dose strength testosterone gel formulations formulated with testosterone in the range of between about 0.10% to about 1.5% by weight for nasal administration to deliver a therapeutically effective amount of testosterone to effectively treat anorgasmia and/or HSDD.

The present invention also relates to a novel method for nasal administration of nasal testosterone gels. In general, the novel methods involve the local deposition of intranasal testosterone gels into the nasal cavity of each nostril over the period of dose validity (dose life) to deliver a therapeutically effective amount of testosterone, e.g., from about 150 mcg/nostril to about 600 mcg/nostril per application, for providing sustained effective brain and/or blood levels of testosterone for testosterone replacement or supplemental therapy, particularly for effectively treating women in need of testosterone treatment anorgasmia and/or HSDD.

According to the novel method of the invention, intranasal testosterone gel is deposited locally on the outer lateral wall (opposite the nasal septum) within the nasal cavity of each nostril, preferably in about the middle to about the upper portion (opposite the nasal septum) of the outer lateral wall, just below the cartilaginous portion of the outer lateral wall within the nasal cavity of each nostril. Once gel deposition is complete within each nostril of the nose, the exterior of the nose is gently and carefully squeezed and/or rubbed by the subject so that the deposited gel remains in contact with the mucous membranes within the nasal cavity to provide sustained release of testosterone over the life of the dose. Typical testosterone gels deposited by nasal application are administered in amounts of between about 50 to about 150 microliters per nostril, preferably about 100 microliters per nostril.

During practice of the methods of the invention, between about 50 microliters and about 150 microliters of the lower dosage strength testosterone gels of the invention are applied to each nostril of a subject once or twice a day, e.g., for one, two, three, four, or more consecutive weeks, or for two, three, four, five, or six consecutive weeks or more, or intermittently applied, such as once every other day or once, twice, or three times a week, or once or twice in the same day as needed, to treat HSDD and/or anorgasmia.

While the present invention has identified what are believed to be the preferred concentrations of intranasal testosterone gel formulations, times of daily application, duration of treatment, nasal methods, and pre-filled multi-dose applicator systems, it should be understood by those skilled in the art that the present invention contemplates any effective low dose testosterone concentrations in intranasal gel formulations that deliver an effective amount of testosterone, i.e., between about 0.10% and about 1.5% by weight and any number of applications/day, week, month, or year that are effective in treating anorgasmia and/or HSDD without causing undesirable testosterone therapy limiting reactions or associated adverse events, as described herein.

Accordingly, the present invention provides a new and improved treatment for anorgasmia and/or HSDD, wherein nasal administration of the low dose strength testosterone gel formulation of the present invention provides: (1) rapid delivery of testosterone due to systemic and blood brain barrier entry of highly permeable nasal tissue into the brain; (2) the effect is quick; (3) avoid first pass metabolism of the liver; (4) ease of application to enhance sexual experience; (5) avoidance of irritation from transdermal administration, in particular, no exposure to contact, no migration from topical gels, and no local sensitivity from topical patch products; and (6) a more pleasant mode of administration compared to injections and buccal or sublingual tablets.

In other words, the present invention provides new and improved anorgasmia and/or HSDD treatments that (a) are easy and convenient to apply according to a specified treatment regimen or as needed, (b) rapidly deliver a therapeutically effective amount of testosterone, thereby duly improving female sexual function, (c) provide for simple application, (d) reduce side effects associated with existing exogenous systemic testosterone therapies, (e) avoid local sensitivity associated with existing topical gels and topical patches, and (f) eliminate the need for invasive and painful testosterone injections.

In one embodiment, the present invention provides a number of surprising advantages over anorgasmia and currently available therapies for HSDD. For example, the present invention provides (1) a rapid increase in plasma testosterone levels (e.g., an increase in plasma testosterone to a level of at least about 0.4ng/ml within about 15 minutes immediately after nasal administration of a testosterone gel formulation of the present invention); (2) a sustained increase in plasma testosterone levels (e.g., an increase in plasma testosterone levels is maintained in the subject for at least about 6 hours following nasal administration of a testosterone gel formulation of the invention); and (3) administration immediately within about 100 minutes after administrationThe maximum level of plasma testosterone is higher thereafter (e.g., compared to the maximum level of plasma testosterone)To at least about 0.7ng/ml compared to about 0.1 ng/ml).

As shown in figure 1, the improved testosterone gel formulation of the present invention provides advantages over currently available therapies for the treatment of anorgasmia and HSDD. For example, the testosterone gel formulations of the present invention, comprising about 0.6% testosterone by weight of the gel formulation, are administered intranasally to a subject. In contrast, byThe patch treated control subjects received testosterone doses of about 2100-2800 mcg/day up to about 3.5-4.5 times the testosterone doses received by women treated with the lower dose strength testosterone gels of the invention (i.e., about 600, 1800, or 2400 mcg/day for 0.15%, 0.45%, and 0.6% testosterone gels of the invention, respectively, or about 600, 1200, or 1800 mcg/day for 0.24%, 0.48%, or 0.72% testosterone gels of the invention, respectively). Importantly, withThe patches differ in that testosterone levels return to baseline (at least for 0.15% and 0.45% of the gel formulations of the invention) after about 12 hours after treatment with the lower dose strength testosterone gel of the invention.

A andthe comparative unique drug metabolism profile is shown in figure 1. The improved 0.6% testosterone gel formulation for nasal administration of the present invention provides a plasma testosterone concentration following nasal administration, wherein (a) a plasma testosterone level of at least about 0.4ng/ml is achieved; (b) achieving a plasma testosterone level of at least about 0.7 ng/ml; (c) achieving an increase in plasma testosterone levels within at least about 10 minutes after nasal administration to a subject; (d) achieving a plasma testosterone level of at least about 0.4ng/ml and maintaining for at least about 6 hours immediately after nasal administration to a subject; (e) achieving a plasma testosterone level of at least about 0.3ng/ml and for at least about 13 hours immediately after nasal administration to a subject; and (f) achieves a plasma testosterone level of at least about 0.7ng/ml within about 100 minutes immediately after nasal administration to a subject (see fig. 1).

On the contrary, in useAfter treatment, as shown in figure 1, until administrationThe plasma testosterone level is increased at least about 3 hours later. Even then, it is not until at least about 6.5 hours after administrationPlasma testosterone concentrations of at least about 0.4ng/ml were observed in treated subjects. Until applicationAfter about 12 hours, use is observedMaximum plasma testosterone levels in treated subjects (only about 0.68 ng/ml).

Thus, after nasal administration, an improved testosterone (0.6%) gel formulation of the present invention for nasal administration provides one or more of the following plasma testosterone concentrations:

(a) less than an hour after administration, a plasma testosterone concentration of at least about 0.4 ng/ml;

(b) less than about 100 minutes after administration, a plasma testosterone concentration of at least about 0.7 ng/ml;

(c) an increase in plasma testosterone concentration for at least about 10 minutes following nasal administration to a subject;

(d) (ii) a plasma testosterone concentration of at least about 0.4ng/ml immediately after nasal administration to a subject, wherein said increase is achieved and maintained for at least about 6 hours;

(e) achieving a plasma testosterone level of at least about 0.3ng/ml and for at least about 13 hours immediately after nasal administration to a subject; and/or

(f) A plasma testosterone concentration of at least about 0.7ng/ml was achieved within about 100 minutes immediately after nasal administration to a subject (see fig. 1).

Thus, as shown in FIG. 1, the present invention overcomes and utilizes currently available therapies, for exampleCertain limitations associated with the treatment of anorgasmia and/or HSDD, and address the current medical need for (1) pharmaceutical formulations that are convenient, easy and prudent to administer; (2) a fast acting formulation that timely ameliorates female sexual dysfunction; (3) reduced incidence of application site reactions; (4) the preparation has little side effect; and (5) formulations which may be in accordance with a prescribed treatment regimen orApplied as required; therapeutic anorgasmia and/or HSDD.

A safety study was also conducted in accordance with the present invention as reported in example 11, wherein women were treated intranasally with a 0.72% testosterone gel of the present invention (administered at about 1200 mcg/dose), t.i.d. (three times a day), for two consecutive days, and on the third consecutive day, qd, with the result that the total daily dose of testosterone was about 3600 mcg/day on the first two days and about 1200mcg on the third consecutive day. As shown in example 11, the intranasal testosterone gel of the present invention is believed to be safe and well tolerated.

Important elements of the novel intranasal testosterone gels according to the invention include: (a) a therapeutically effective amount of testosterone, (b) a solvent, (c) a wetting agent, and (d) a viscosity increasing agent. The improved lower dosage strength testosterone gel formulations of the present invention can be formulated with the following amounts of testosterone: between about 0.10% and about 1.5% by weight, such as about 0.15%, 0.24%, 0.45%, 0.48%, 0.6% and 0.72%, and more preferably, between about 0.24% and 0.72%. Exemplary nasally administered testosterone gel formulations contemplated by the present invention include:

(a) 0.15% testosterone, 91.85% castor oil, 4.0% oleoyl polyoxylglyceride, and 4% colloidal silicon dioxide;

(b) 0.24% testosterone, 91.76% castor oil, 4.0% oleoyl polyoxylglyceride, and 4% colloidal silicon dioxide;

(c) 0.45% testosterone, 91.55% castor oil, 4.0% oleoyl polyoxylglyceride, and 4% colloidal silicon dioxide;

(d) 0.48% testosterone, 91.52% castor oil, 4.0% oleoyl polyoxylglyceride, and 4% colloidal silicon dioxide;

(e) 0.6% testosterone, 91.4% castor oil, 4.0% oleoyl polyoxylglyceride, and 4% colloidal silicon dioxide; and

(f) 0.72% testosterone, 91.28% castor oil, 4.0% oleoyl polyoxylglyceride, and 4% colloidal silicon dioxide.

Thus, the improved testosterone gel formulations for nasal administration of the present invention may further comprise any pharmaceutically acceptable carriers, excipients and/or other active ingredients.

In addition, the present invention contemplates testosterone gel formulations for nasal administration that: methods of equivalence or bioequivalence, such as the methods of drug metabolism, microdialysis, in vitro and in vivo methods, and/or clinical endpoints described herein, are shown without regard to selection, and are pharmaceutically equivalent, therapeutically equivalent, bioequivalent, and/or interchangeable.

Thus, the present invention contemplates testosterone gel formulations for nasal administration that are bioequivalent, pharmaceutically equivalent and/or therapeutically equivalent, particularly testosterone gel formulations for nasal administration that are 0.15% testosterone by weight of the gel formulation, 0.24% testosterone by weight of the gel formulation, 0.45% testosterone by weight of the gel formulation, 0.48% testosterone by weight of the gel formulation, 0.6% testosterone by weight of the gel formulation and 0.72% testosterone by weight of the gel formulation when therapeutic anorgasmia and/or HSDD are administered intranasally according to the present therapy. Thus, the present invention contemplates: (a) a pharmaceutically equivalent testosterone gel formulation for nasal administration containing the same amount of testosterone in the same dosage form; (b) a bioequivalent testosterone gel formulation for nasal administration that is chemically equivalent and that results in similar bioavailability when administered to the same individual in the same dosage regimen; (c) a therapeutically equivalent testosterone gel formulation for nasal administration that provides substantially the same efficacy and/or toxicity when administered to the same individual in the same dosage regimen; and (d) the interchangeable testosterone gel formulations for nasal administration of the present invention which are pharmaceutically, bioequivalent and therapeutically equivalent.

While the intranasal testosterone gel of the present invention is the preferred pharmaceutical formulation when practicing the novel method of the present invention, it is to be understood that the novel topical intranasal gel formulation and method of the present invention also contemplates nasally administering any suitable active ingredient, alone or in combination with testosterone or other active ingredients, such as neurosteroids or sex hormones (e.g., androgens and progestins such as testosterone, estradiol, oestrogen, estrone, progesterone, and the like), neurotransmitters (e.g., acetylcholine, epinephrine, norepinephrine, dopaminergic, 5-hydroxytryptamine, melatonin, histamine, glutamate, gamma-aminobutyric acid, aspartate, glycine, adenosine, ATP, GTP, oxytocin, vasopressin, endorphin, nitric oxide, pregnenolone, and the like), in any suitable pharmaceutical formulation, such as a liquid, cream, ointment, salve, or gel, Prostaglandins, benzodiazepines, such as diazepam (diazepam), midazolam, lorazepam, and the like, and PDEF inhibitors, such as sildenafil (sildenafil), tadalafil (tadalafil), vardenafil (vardenafil), and the like. Examples of additional topical formulations for practicing the novel method according to the present invention include topical nasal formulations disclosed in the following documents: for example, U.S. patent nos. 5,578,588, 5,756,071, and 5,756,071 and U.S. patent publication nos. 2005/0100564, 2007/0149454, and 2009/0227550, all of which are incorporated by reference herein in their entirety.

The present invention also relates to packaged pharmaceuticals comprising the novel and improved testosterone gel formulations of the present invention for nasal administration. For example, the present invention contemplates pre-filled single or multi-dose applicator systems for nasal administration to strategically and uniquely deposit nasal testosterone gels in preferred locations within the nasal cavity to implement the novel methods and teachings of the present invention. In general, the applicator system of the present invention is, for example, an airless fluid, dip-tube (dip-tube) fluid dispensing system, pump, syringe, or any other system suitable for practicing the methods of the present invention. The applicator system or pump includes, for example, a chamber pre-filled with a single or multiple doses of intranasal testosterone gel of the present invention, which is closed by an actuator (activator) nozzle or cap. The actuator nozzle may include an outlet channel and a tip, wherein the actuator nozzle is shaped to conform to the inner surface of a user's nares to (a) continuously deliver a uniform dosage amount of the intranasal testosterone gel of the present invention within the nasal cavity during nasal application, and (b) an indicated location deposited within each of the patient's nares, as contemplated by the novel methods and teachings of the present invention. Examples of prefilled multi-dose applicator systems include, for example, (a) COMOD systems available from Ursatec, Verpackung-GmbH, schillerstr.4,66606st.wendel, germany, (b) Albion or digital airless applicator systems available from airless systems, RD 14927380Charleval, france or 250North Route 303 Congers, NY 10950 (see, e.g., fig. 39), (c) nasal applicators, from Neopac, The Tube, Hoffmann Neopac AG, Burgdorfstrasse 22, Postfach,3672 obendiessbach, switzerland, or (d) syringes as described in The examples herein below.

It will be appreciated by those skilled in the art that the amount of testosterone in the lower dose strength intranasal testosterone gel of the present invention that is therapeutically effective in a particular situation will depend on: dosage regimen, site of application, specific gel formulation, dose viability and condition being treated. Thus, it is generally impractical to determine a particular amount to be administered herein; however, it is believed that one skilled in the art will be able to determine the appropriate therapeutically effective amount based on the guidance provided herein, information available in the art to which testosterone replacement therapy pertains, and routine testing.

It should also be understood that the above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The specification further illustrates the illustrative embodiments. Guidance is provided at several places in the specification by way of examples, which examples can be applied in various combinations. In each instance, the instances serve only as representative group(s), and should not be construed as exclusive instances.

Drawings

The patent or application file contains at least one drawing executed in color. The patent or patent application publication with the accompanying color drawing will be provided by the office upon request and payment of the necessary fee.

The above and other objects, advantages and features of the invention and the manner of attaining them will become more apparent by considering the following detailed description of the invention in conjunction with the accompanying drawings and examples illustrating embodiments thereof, wherein:

FIG. 1 showsIn contrast, the effect of a single dose of the testosterone nasal gel formulation of the invention (0.6% testosterone by weight of the gel formulation) on plasma testosterone levels in subjects diagnosed with HSDD (triangles-100 microliters of the 0.6% testosterone nasal gel formulation of the invention per nostril; squares-)；

FIG. 2 showsIn contrast, the effect of the testosterone nasal gel formulation of the invention (0.6% testosterone by weight of the gel formulation) on plasma testosterone levels in subjects diagnosed with anorgasmia after a fifth dose once every 12 hours (TBS-2 line-0.6% testosterone nasal gel formulation of the invention (100 mcl. times.2); solid line-)；

Figure 3 shows the effect of the testosterone nasal gel formulations of the invention (0.15, 0.45 and 0.6% testosterone by weight of the gel formulation) on plasma testosterone levels in subjects diagnosed with HSDD after the first and fifth once every 12 hours dose compared to the emerald sand R single dose;

FIG. 4 showsIn contrast, the effect of the testosterone nasal gel formulation of the invention on plasma testosterone levels in subjects diagnosed with HSDD on day zero (open triangles) and day three (dose of 0.6% testosterone by weight of the gel formulation 5-filled squares) (0.6% squares-The hollow square zeroth-third antenna of (1);

FIG. 5 is a reproduction of FIG. 1 but with first and third day 0.6% testosterone gels andthe comparison data of (1);

FIG. 6 is a first and third day 0.6% testosterone gel andcomparative data for treatment studies with HSDD;

FIG. 7 showsEffect of single dose compared, testosterone nasal gel formulations of the invention (0.15, 0.45 and 0.6% testosterone by weight of the gel formulation) on plasma testosterone levels in subjects diagnosed with anorgasmia after the first and fifth doses once every 12 hours;

fig. 8 shows the effect of the testosterone nasal gel formulation of the invention after the first and fifth once every 12 hours doses (on Day three, 0.45% testosterone by weight of the gel formulation (Med Day 1) and on Day zero and Day three 0.6% testosterone by weight of the gel formulation (ano));

figure 9 shows the cumulative effect of the testosterone nasal gel formulations of the invention (0.15, 0.45 and 0.6% testosterone by weight of the gel formulation) on plasma testosterone levels in subjects diagnosed with HSDD or anorgasmia at time (0) prior to once every two days dose of testosterone gel;

FIG. 10 (same as 12, except AUC Cavg and Cmax are tabulated) comparison(Note-becauseNot approved for anorgasmia, not evaluated in this study);

FIG. 11 shows a nasal gel formulation of testosterone (0.15%, 0.45% or 0.6% testosterone by weight of the gel formulation) or placebo (anorgasmia) or a diagnosis diagnosed with anorgasmia or HSDD of the present invention(HSDD) trough data for the subject treated;

FIG. 12 shows mean concentration profiles of testosterone for the first (AUC _0-12) and last dose (AUC _48-60) TBS-2 treatment. Boxplots show median (thick solid line), interquartile range (box), and extremum (line (whisker)). The horizontal gray solid line represents the median C _ mean from 48 to 60hrs during treatment with delphinium odoratum, and the horizontal dashed line represents the minimum and maximum C _ mean from 48-60hrs during treatment with delphinium odoratum;

fig. 13 shows AFSDQ scores at 30 minutes (left) and 4.5 hours (right) post-dose. White bars start at time; the solid bar ends with time. Group from left to right: ANOR placebo, ANOR low, ANOR medium, ANOR high, HSDD masa (only at 30 min), HSDD low, HSDD medium, HSDD high;

FIG. 14 relates to mean testosterone levels in women with anorgasmia after TBS-2 high, TBS-2 medium and TBS-2 low dose administration or placebo administration (0-12 hours). In this study of drug metabolism, three different dosage strengths of TBS-2 testosterone bioadhesive gel formulations of the present invention were administered intranasally to a mixed group of 12 women with impaired health and sexual pleasure as described in example 9. As shown in FIG. 14, three different testosterone bioadhesive gel formulations of the invention (by weight of the gel formulation) were compared over a 2 hour period following the single application of each TBS-2 formulation or placebo to each of 12 women0.15%, 0.45% and 0.6% testosterone, as reported in examples 1-5). The total testosterone dose intensity administered is 1.2mg (0.6-0.6 mg/100 μ l/nostril), 0.9mg (0.45-0.45 mg/100 μ l/nostril) or 0.3mg (0.15-0.15 mg/100 μ l/nostril). After administration, testosterone serum levels were measured and compared. As shown in figure 14, after single dose administration, the C of testosterone was at each of the three dose strengths_maxAnd C_avgDoes not exceed normal testosterone serum levels in women (3-80 ng/dL);

fig. 15 depicts a study design (example 10) in which 56 anorgasmic women participated in a shock stimulation study (VTS) involving three different testosterone bioadhesive gel formulations of the present invention, namely, 0.15%, 0.45% and 0.6% testosterone by weight of the gel formulation, as reported in examples 1-5;

FIG. 16 depicts the orgasm results of the VTS study of example 10, in which the number of orgasms achieved during the treatment phase and post-treatment phase are compared;

figure 17 depicts the results of the sexual response of the example 10VTS study for three different testosterone bioadhesive gel formulations of the present invention compared to placebo, namely, 0.15%, 0.45% and 0.6% testosterone by weight of the gel formulation, as reported in examples 1-5;

figure 18 depicts VTS ascending score of the example 10VTS study for three different testosterone bioadhesive gel formulations of the present invention, i.e., 0.15%, 0.45%, and 0.6% testosterone by weight of the gel formulation, as compared to placebo, as reported in examples 1-5;

figure 19 depicts Mean Corrected (Mean Corrected) free testosterone concentrations (single dose group);

figure 20 depicts mean corrected total testosterone concentrations (single dose group);

figure 21 depicts mean corrected dihydrotestosterone concentrations (single dose group);

figure 22 depicts mean corrected estradiol concentrations (single dose group);

figure 23 depicts mean corrected SHBG concentrations (single dose group);

figure 24 depicts mean observed free testosterone concentrations (single dose group);

figure 25 depicts mean observed total testosterone concentrations (single dose group);

figure 26 depicts the mean observed dihydrotestosterone concentrations (single dose population);

figure 27 depicts mean observed estradiol concentrations (single dose group);

figure 28 depicts mean observed SHBG concentrations (single dose group);

figure 29 depicts mean free testosterone plasma concentrations (multi-dose group);

figure 30 depicts mean total testosterone plasma concentrations (multi-dose group);

figure 31 depicts mean dihydrotestosterone plasma concentrations (multi-dose group);

figure 32 depicts mean estradiol plasma concentrations (multiple dose group);

figure 33 depicts mean SHBG plasma concentrations (multiple dose group);

FIG. 34 depicts Spaghetti concentration profiles (multiple dose groups) with mean values of free testosterone plasma concentrations;

figure 35 describes the Spaghetti concentration curve (multiple dose group) with mean values of total testosterone plasma concentration;

FIG. 36 depicts Spaghetti concentration curves (multiple dose groups) with mean values of dihydrotestosterone plasma concentrations;

FIG. 37 depicts Spaghetti concentration curves (multiple dose groups) with mean values of estradiol plasma concentrations;

figure 38 depicts the Spaghetti concentration curve (multiple dose group) with the mean of SHBG plasma concentrations; and

FIG. 39 depicts an inter-nasal applicator contemplated by the present invention and used in accordance with the present invention.

FIG. 40 depicts a flow chart of a manufacturing process.

Detailed Description

By way of illustration and to provide a more complete understanding of the present invention and many of the advantages that result therefrom, the following detailed description and examples are given which relate to the novel lower dosage strength intranasal testosterone gels, devices for use and methods of the present invention.

I. Definition of

As used in this specification and the appended claims, the singular forms "a", "an", and "the" are used interchangeably and are intended to include the plural forms as well, and fall within the scope of each meaning unless the context clearly indicates otherwise. Also, as used herein, "and/or" refers to and includes any and all possible combinations of one or more of the listed items, as well as the absence of a combination, when interpreted in the alternative ("or").

As used herein, "at least one" is intended to mean "one or more" of the listed elements.

The singular forms are intended to include the plural forms and, where appropriate, are also used interchangeably herein and are to be within the scope of each meaning unless otherwise specifically indicated.

Unless otherwise indicated, all capitalized and non-capitalized forms of the terms fall within the scope of each meaning.

Unless otherwise indicated, it is to be understood that all numbers expressing quantities, ratios, and numerical properties of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about".

All parts, percentages, ratios, etc. herein are by weight unless otherwise indicated.

As used herein, "bioequivalence" or "bioequivalence" refers to a testosterone gel formulation or pharmaceutical product administered nasally that is pharmaceutically equivalent and that has a similarity in bioavailability (rate and extent of absorption) to the extent that following administration in the same molar dose or amount: that is, their therapeutic effects with respect to safety and efficacy are substantially the same. In other words, "bioequivalence" or "bioequivalence" means that there is no significant difference in the rate and extent at which testosterone can be utilized from such a formulation at the site of onset of testosterone when administered at the same molar dose under similar conditions, e.g., the rate at which testosterone can leave such a formulation and the rate at which testosterone can be absorbed or utilized at the site of onset of the influential anorgasmia and/or HSDD. In other words, there is a high similarity in bioavailability for the two testosterone gel formulation drug products of the same molar dose for nasal administration (belonging to the same galenic form), the same molar dose being less likely to produce clinically relevant differences in therapeutic efficacy or adverse effects or both. The terms "bioequivalence" and "pharmaceutical equivalence" and "therapeutic equivalence" are also used herein as defined and/or applied by (a) the FDA, (b) federal regulations ("c.f.r.") (federal regulatory set), article 21, (c) Health Canada (Health Canada), european medicines Agency (EMEA), and/or (e) Japanese minimum of Health and welfare (japan department of Health and welfare). Thus, it should be understood that the present invention contemplates testosterone gel formulations or pharmaceutical products for nasal administration that are bioequivalent to other testosterone gel formulations or pharmaceutical products of the present invention for nasal administration. By way of example, according to the present invention, a first testosterone gel formulation or pharmaceutical product for nasal administration is bioequivalent to a second testosterone gel formulation or pharmaceutical product for nasal administration when the measurement of at least one drug metabolism parameter(s), such as Cmax, Tmax, AUC, etc., of the first testosterone gel formulation or pharmaceutical product for nasal administration does not vary by more than about ± 25% as compared to the measurement of the same drug metabolism parameter of the second testosterone gel formulation or pharmaceutical product for nasal administration of the present invention.

As used herein, "bioavailability" or "bioeffective" generally means the rate and extent of testosterone absorption into the systemic circulation, and more specifically, means a rate or measurement intended to reflect the rate and extent at which testosterone is available at or from the site of action and is available at the site of action. In other words and by way of example, as reflected by the time-concentration profile of testosterone in the systemic circulation, the extent and rate of testosterone absorption from the lower dose strength gel formulations of the present invention for nasal administration.

As used herein, the term "pharmaceutically equivalent" or "pharmaceutically equivalent" refers to a testosterone gel formulation or a pharmaceutical product of the present invention for nasal administration that contains the same amount of testosterone in the same dosage form, but does not necessarily contain the same inactive ingredients for the same route of administration, and meets the same or equivalent pharmacopoeia (compendial) or other applicable criteria of identity, strength, quality and purity, including potency, and, where applicable, content uniformity and/or stability. Thus, it should be understood that the present invention contemplates testosterone gel formulations or pharmaceutical products for nasal administration that are pharmaceutically equivalent to other testosterone gel formulations or pharmaceutical products for nasal administration used in accordance with the present invention.

As used herein, "therapeutic equivalence" or "therapeutically equivalent" means those testosterone gel formulations or pharmaceutical products for nasal administration that (a) will produce the same clinical effect and safety when using a testosterone pharmaceutical product to treat anorgasmia or HSDD according to the present invention, and (b) are pharmaceutically equivalent, e.g., they contain testosterone in the same dosage form, they have the same route of administration; and they have the same testosterone intensity. In other words, therapeutic equivalence means that a chemically equivalent lower dose strength testosterone formulation of the invention (i.e., containing the same amount of testosterone in the same dosage form when administered to the same individual in the same dosing regimen) will provide substantially the same efficacy and toxicity.

As used herein, "testosterone gel formulation for nasal administration" means a formulation comprising testosterone in combination with a solvent, a wetting agent, and a viscosity increasing agent.

As used herein, "increase" in reference to plasma testosterone levels also means that plasma testosterone levels are 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 500, 1000, or 10,000 times or more higher in a subject treated with a testosterone gel formulation for nasal administration of the present invention compared to plasma testosterone levels in a subject before treatment.

As used herein, "plasma testosterone level" means the level of testosterone in the plasma of a subject. Plasma testosterone levels are determined by methods known in the art.

As used herein, "diagnosis" or "prognosis" refers to the use of information (e.g., biological or chemical information from biological samples, signs and symptoms, physical examination results, psychological examination results, etc.) to predict the most likely outcome, schedule, and/or response of a particular treatment for a given disease, disorder, or condition based on comparison of common symptoms, signs, family history lines, or other data relevant to consideration of the patient's health condition, or the confirmation of a subject's affliction, e.g., suffering from anorgasmia and/or HSDD.

According to some embodiments, a "subject" is an individual whose signs and symptoms, physical examination results, and/or psychological examination results are to be determined and recorded in connection with the individual's condition (i.e., disease or condition state) and/or response to a drug candidate or treatment.

As used herein, a "subject" is preferably, but not necessarily limited to, a human subject. The subject may be male or female, and is preferably female, and may belong to any ethnic group or race, including but not limited to caucasian, african american, african, asian, Hispanic (Hispanic), indian, and the like. As used herein, a subject may also include animals, particularly mammals, such as canines, felines, bovines, caprines (caprines), equines, ovines (ovines), porcines, rodents (e.g., rats and mice), lagomorphs, primates (including non-human primates), and the like, which may be treated or screened according to the methods of the invention for veterinary or pharmaceutical drug development purposes. According to some embodiments of the invention, the subject comprises a patient, human or otherwise in need of treatment for anorgasmia and/or HSDD.

As used herein, "treatment" includes any drug, drug product, method, procedure, lifestyle change, or other modification introduced in an attempt to affect a particular aspect of the subject's health (i.e., related to a particular disease, disorder, or condition).

As used herein, "drug" or "drug substance" refers to an active ingredient, such as a chemical entity or a biological entity or a combination of chemical entities and/or biological entities, which is suitable for administration to a subject for (a) treatment of anorgasmia and/or (b) treatment of HSDD. According to the invention, the drug or drug substance is testosterone or a pharmaceutically acceptable salt or ester thereof.

As used herein, the term "pharmaceutical product" is synonymous with the terms "drug," medicament, "" therapeutic intervention, "or" pharmaceutical product. More preferably, the pharmaceutical product is approved by a governmental agency for use in accordance with the methods of the invention. According to the invention, the pharmaceutical product is an intranasal gel formulated with a pharmaceutical substance, i.e. testosterone.

"disease," "disorder," and "condition" are generally recognized in the art and indicate the presence of signs and/or symptoms in an individual or patient that is generally identified as abnormal and/or undesirable. The disease or condition may be diagnosed and classified based on pathological changes. The Disease or condition may be selected from standard textbooks such as Harrison's Principles of Internal Medicine (Harrison's Internal sciences), 1997, or Robbins Pathology Basis of Disease (Robin Pathology base), 1998.

As used herein, "diagnosing" or "identifying a patient or subject with anorgasmia or HSDD" refers to the process of determining whether an individual has anorgasmia or HSDD.

As used herein, "control subject" means a subject that has not been diagnosed with anorgasmia and/or HSDD and/or does not exhibit any detectable symptoms associated with these diseases. By "control subject" is also meant a subject that is not in developing anorgasmia and/or HSDD, as described herein.

II.Disease and disorder

Anorgasmia syndrome

Anorgasmia is a type of sexual dysfunction in which a person is unable to regularly achieve orgasm, even with adequate stimulation. In men, this condition often involves delayed ejaculation. Anorgasmia can often lead to sexual frustration. Anorgasmia is far more prevalent in women than in men, and is especially rare in young men. Anorgasmia is a very common occurrence in women affecting one fifth of the women worldwide.

This condition is sometimes classified as psychosis. However, it can also be caused by medical problems such as diabetic neuropathy, multiple sclerosis, genital deformities, complications from genital surgery, pelvic trauma (such as that caused by a drop from a pole of a climbing rack, bicycle or gymnastic balance), hormonal imbalance, total hysterectomy, spinal cord injury, cauda equina syndrome, uterine embolism, childbirth trauma (vaginal laceration caused by the use of forceps or suction or large or unclosed vulvotomy), vulvodynia, and cardiovascular disease.

As proposed by Meston et al, the general definition of orgasm in women is as follows:

"[ A ] the altered state of consciousness produced by the variable, transient peak sensation of intense pleasure, usually accompanied by involuntary, rhythmic contractions of the striated muscles around the pelvic cavity, often accompanied by simultaneous uterine and anal contractions and myotonia of the solution-induced vascular congestion (sometimes only partially), usually accompanied by well-being and satisfactory production. "

Diagnostic and Statistical Manual of Mental Disorders, 4 th edition, text revision (DSM-IV-TR) defines the female orgasm disorder (FOD, previously depressed female orgasm) as persistent or recurrent delayed or absent orgasm following the normal period of sexual arousal.

The type or intensity of the stimulus that triggers orgasm in women varies widely among women. Thus, the diagnosis of orgasmic female disorders according to DSM-IV-TR is based on the following 3 criteria:

standard a: the clinician must judge that orgasm is less than reasonable for her age, she receives sexual experience and adequate sexual stimulation.

Standard B: the confusion must result in significant distress or interpersonal difficulties.

Standard C: additional disorders of axis I (in addition to additional sexual dysfunction) do not cause orgasmic disorders more than female orgasmic disorders, and orgasmic disorders are not exclusively due to direct physiological effects on the substance (e.g. drug abuse, medication) or general medical conditions.

In DSM-IV-TR, female orgasmic disorder discriminators include the following:

terminal or acquired

Prevalence or situation

Due to psychological factors or combined factors

The existence of a normal sexual impulse phase is a necessary condition for female orgasm. In other words, if there is no orgasm after a period of decreased desire for sexual activity, then it may be more appropriate to diagnose conditions such as hypoactive sexual desire disorder, sexual aversion disorder (sexual aversion disorder) or female sexual arousal disorder, respectively, if the reduction in sexual desire is followed by a period of decreased sexual activity, even though anorgasmia is a common end result.

Many physical and psychological factors of anorgasmia have been identified.

They include the following:

sexual abuse (sexual abuse) or sexual aggressive rape (sexual rap) history

Fun and boring in sexual activity

Certain prescription drugs, including fluoxetine (baryzarine), paroxetine (Paxil) and sertraline (seroline, Zoloft)

Hormonal disorders, hormonal changes due to menopause and chronic diseases affecting general health and sexual interest

Medical conditions that affect the neural supply to the pelvic cavity (such as multiple sclerosis, diabetic neuropathy and spinal cord injury)

Negative attitude of pertinence (usually known in childhood or adolescence)

Photophobia or embarrassment what type of stimulation is best required

Conflict or lack of emotional intimacy in relationships

Physical factors

Many diseases, physical changes and medications can intervene in orgasm:

·medical diseases.Any disease may affect the individual libido of the moiety, including diabetes and neurological diseases such as multiple sclerosis. Orgasm can also be affected by gynecological procedures, such as hysterectomy or cancer surgery. In addition, lack of orgasm is often accompanied by other sexual problems, such as pain during intercourse.

·And (4) performing drug therapy.Many prescriptions and non-prescriptions can be usedIntervene in orgasm. This includes blood pressure medications, antihistamines and antidepressants-especially selective 5-hydroxytryptamine reuptake inhibitors (SSRIs). In men, SSRIs can actually cause anorgasmia and inability to achieve sufficient erection for satisfactory sexual activity (erectile dysfunction) at the same time.

·Alcohol and drugs.One glass of wine can make you feel more, but too much alcohol can limit you' ability to reach climax; the same is true for street drugs.

·Aging process.As one ages, the normal changes in anatomy, hormones, nervous system, and circulatory system can affect libido. The estrogen decline that occurs during the transition phase of menopause can be a particularly noticeable enemy of orgasm. Lower levels of this female hormone can reduce clitoral, nipple and skin sensation and prevent blood flow to the vagina and clitoris, which can delay or completely interrupt orgasm. However, anorgasmia is not limited to older women. Moreover, many women show that sexual activity becomes more desirable with age.

Psychological factors

Many psychological factors play a role in the ability to achieve orgasm, including:

mental health problems, such as anxiety or depression

Operational anxiety (Performance anxiety)

Pressure and economic pressure

Cultural and religious beliefs

Fear of pregnancy or sexually transmitted diseases

Embarrassment

Self-blame for enjoying sexual experience

Problem of relationship

Many couples who experience problems other than hermaphroditic relationships will also experience hermaphroditic problems. These prominent problems include:

lack of connection to spouse

Unresolved conflicts or quarries

Poor communication of sexual needs and preferences

Loyalty or credit

A common cause of paradoxical anorgasmia in men and women is the use of antidepressants, especially selective 5-hydroxytryptamine reuptake inhibitors (SSRIs). post-SSRI sexual dysfunction (PSSD) is the name given to the reported iatrogenic sexual dysfunction due to prior use of SSRI antidepressants. Although anorgasmia is reported as an inaccurate side effect of SSRIs, it is estimated that 15-50% of users of this medication are affected by the condition. The chemical tricyclodecanolamine has been shown to slow SSRI-induced anorgasmia in some but not all humans.

Another cause of anorgasmia is opiate addiction, especially to heroin.

Difficulty with orgasm is reported in about 15% of women, and orgasm has never been reached in as many as 10% of women in the united states. Many women with orgasm regularity reach orgasm only about 50-70% of the time.

The main symptoms of anorgasmia are inability to experience orgasm or long delay in achieving orgasm. Different types of anorgasmia have been identified.

Primary anorgasmia

Primary anorgasmia is a condition in which an individual never experiences orgasm. This is significantly more common in women, although it may occur in men who lack the gladipudendal (bulbocavernosal) reflex.

Women with this condition can sometimes achieve relatively low levels of sexual arousal. Contusion, restlessness, pelvic pain or pelvic heaviness may occur due to vascular congestion.

Sometimes, there may be no obvious reason why it is difficult to obtain orgasm. In such cases, female reports cannot achieve orgasm even if they have a body-paste, skilled partners, sufficient time and privacy and do not present medical problems that would affect sexual satisfaction. It should be noted that the interests and skills of the partner of the individual are not closely related to the level of comfort implicit in the female. Thus, a female anorgasmia with its partner warm enough and clever should not be considered a clinical puzzle.

Some social theorists believe that failure to achieve orgasm may be related to a residual psychosocial understanding that female sexual desire is 'wrong', and this stems from depression in the victoria age. It is believed that this view may discourage some women-perhaps those who grow in a more depressed environment-from experiencing a natural and healthy feeling of sex. Although these proposals have a certain position in academic social theory, they have not been scientifically determined. Thus, an idea such as this may be an element of treatment as one of many considerations, but the clinical practice of the responsible person should not be guided or informed on the basis thereof.

Primary male anorgasmia is more common in circumcised men than intact men. As many men age, they lose their ability to achieve orgasm even though they still ejaculate. Orgasmic pleasure decreases in older men.

Secondary anorgasmia

Secondary anorgasmia is the loss of the ability to have orgasm. In particular, individuals once had orgasm, but now have difficulty reaching orgasm. The cause may be alcoholism, depression, sadness, pelvic surgery (such as total hysterectomy) or injury, certain medications, disease, estrogen loss associated with menopause, or an event that violates the patient's sexual valence system.

Secondary anorgasmia is approximately 50% in men undergoing prostatectomy; approximately 80% of radical prostatectomy men. This is a serious adverse outcome, since radical prostatectomy is often given to young men who are expected to survive for more than 10 years. At older ages, the prostate is less likely to grow in the rest of the life. This is usually caused by damage to the primary nerve serving the penile region, which passes near the prostate. Removing the prostate frequency impairs or even completely removes these nerves, making sexual counterstrain unreasonably difficult.

Because of the presence of these nerves in the prostate, surgeons performing sex-resetting procedures on patients who switch from males to females avoid removing the prostate. This leaves nerves that then lead to the new formation of the clitoris and reduces the probability that the patient will not respond to clitoral stimulation after surgery. In addition, by leaving the prostate in the patient, the surgeon positions it close to the newly formed vaginal wall, which can potentially increase irritation during vaginal intercourse after surgery.

Paradoxical anorgasmia

In some situations people with orgasm are not necessarily orgasm in other situations. This means that an individual is only able to achieve orgasm in certain circumstances, such as in oral sex or masturbation. This is common in women. In fact, about 80% of women experience orgasm by stimulating the clitoris.

A person may have a orgasm by one type of stimulus rather than another, a person may reach a orgasm with one partner rather than another, or only in certain situations or only in situations of a certain type or amount of pari-mutuel play. These common differences are within the range of normal expression and should not be considered problematic.

Factors that may affect whether an individual is orgasmic include fatigue, emotional concerns, stress on sexual activity when he or she is not interested, or sexual dysfunction of the partner. In the relatively common example of female sexual anorgasmia during penile-vaginal intercourse, some sexual therapists recommend that couples incorporate manual or vibrator stimulation during intercourse, or that use the upper position of the female, as it may allow greater stimulation of the clitoris by the penis or pubic symphysis, or both, and it allows the female to better control movement.

Generalized anorgasmia

This means that the individual cannot sexually orgasm in any situation with any partner.

Random anorgasmia

Some people want climax, but in rare cases meet their proper or desired feelings.

Prevention of

Sexual health attitude, and education regarding sexual stimuli and responses will minimize problems.

Couples that explicitly communicate their sexual needs with expectations-either through language or not-will experience less orgasmic disorders.

It is also important to recognize that: sexual response is a complex coordination of thought and body, and both need to function well to allow orgasm to occur.

Symptoms and signs

Symptoms of orgasmic disorders are inability to achieve orgasm, taking longer to achieve orgasm than desired, or simply having unsatisfactory orgasm.

Symptoms and tests

Complete medical history and physical examinations need to be completed, but the results are almost always normal. If the problem starts after the start of medication, it should be discussed in relation to the physician who started the medication. An expert qualified in sexual therapy may be helpful.

Treatment of

Treatment may involve education, cognitive behavior therapy, orgasm by addressing pleasurable stimuli and educated masturbation.

Most women require clitoral stimulation to achieve orgasm. It may be necessary to incorporate this into sexual activity. If this does not solve the problem, teaching a woman to masturbation may help her understand what she needs to become sexually exciting.

It would be helpful to practice a range of activities that communicate, stimulate more effectively, and enjoy. If the relationship difficulties have an impact, treatment may include communication training and relationship improvement efforts.

Medical problems, new drug therapies, or untreated depression may require evaluation and treatment to improve orgasmic disorders.

These needs are addressed as part of the treatment plan if other sexual dysfunction (such as lack of interest and pain in intercourse) occurs simultaneously.

HSDD

Hypoactive Sexual Desire Disorder (HSDD) is considered sexual dysfunction and is listed under the sexual and sex discriminating disorder of DSM-IV. It was first included in DSM-III under the name of libido-inhibiting disorders, but renamed in DSM-III-R.

HSDD is characterized by a lack or absence of sexual fantasy and desire for sexual activity over a period of time. It must cause significant distress or interpersonal difficulties and not be primarily caused by another psychiatric condition (i.e., depression), medication (legal or illegal), or some other medical condition, in order to be considered a condition.

There are various subtypes. HSDD may be general (usually lack libido) or circumstantial (still libido, but lack libido for the current partner), and it may be acquired (HSDD starting after the normal sexual function phase) or lifelong (individual always has no/low libido).

In the early versions of DSM, only two sexual dysfunctions were listed: frigidity (for females) and impotence (for males).

In 1970, Masters and Johnson published their book Human SexualInadequacy (Human sexual dysfunction) describing sexual dysfunction, although these included only those involving genital function, such as premature ejaculation and impotence in men, and anorgasmia and vaginismus in women. Prior to the studies by Masters and Johnson, female orgasm was postulated to originate primarily from vaginal rather than clitoral stimulation. Therefore, the allegedist advocates that "frigidity" is "defined by men as inability of women to achieve a orgasm of vaginal nature".

After this book, sexual therapy was increasing in the 70 s of the 20 th century. Reports of low sexual desire by sexually treating experts have been reported at least in 1972, but they were not classified as specific disorders until 1977. In that year, the sexually treating experts Helen singer kaplan and hard Lief propose, independently of each other, establishing specific categories for persons with low or no libido. Lief names it "inhibiting sexual desire" and Kaplan names it "Hypoactive SexualDesure". The main causes of this are that previous models of sexual therapy assume a certain level of interest for an individual partner, and that problems are caused only by abnormal functioning or lack of functional or operational anxiety of the genitalia, but treatments based on these problems are ineffective for persons who are not sexually active for their partner. The next year, 1978, where both Lief and Kaplan together proposed the disease to the APA working group as DSM III, both Kaplan and Lief being members of the APA working group. Diagnostic conclusions about Inhibited Sexual Desire (ISD) were added to DSM when third edition was published in 1980.

To understand this diagnostic conclusion, it is important to recognize the social context it creates. In some cultures, low libido may be considered normal, while high libido is problematic. In other cultures, this may be the opposite. Some cultural efforts have suppressed libido. Other cultures try to motivate it. The concept of "normal" sexual desire level is culture dependent and rarely value neutral. In the 70's of the 20 th century, there was a strong cultural thought that sexuality was good for you, and "more is better". In this context, persons who have not been interested in sex, who may not have previously regarded this as a problem, are more likely to consider this to be a situation that needs to be fixed. They may have been perceived to be distracted by mainstream thought regarding libido, and increasingly people suffer from low libido to therapists. It is in this context that the diagnostic result of ISD is produced.

In DSM-III revision (DSM-III-R), published in 1987, ISDs are subdivided into two classes: hyposexuality and Sexual Aversion Disorder (SAD). The former is lack of interest and the latter is aversion to sexual fear. In addition to this subdivision, one reason for the change is that the committee involved in revising DMS-III-R psychosocial diseases believes that the term "inhibitory" indicates psychomotor etiology (i.e., a sexual desire condition exists, but the individual suppresses their own interest for some reason). The term "hyposexuality" is more difficult to handle, but more neutral as to cause. DSM-III-R estimates that about 20% of the population suffers from HSDD. In DSM-IV (1994), a criterion was added that the diagnostic conclusion requires "significant distress or difficulty in personal relationship".

Reason for

Low libido is not equal to HSDD because low libido leads to significant annoyance and prerequisites for human involvement and because low libido is not primarily caused by additional disorders in DSM or by general medical problems, it is difficult to specify what causes HSDD. Instead, it is easier to describe what causes low libido.

In men, there are theoretically more types of HSDD/hypolibido, and men are usually diagnosed with only one of the three subtypes.

Terminal/generalized nature：

The male has little or no desire for sexual stimulation (by partner or alone) and never.

Availability/situation：

Men have had sexual interest on their present partner before, but are now lacking in sexual interest, but have had a desire for sexual stimulation (i.e., alone or by someone other than their present partner).

Acquired/generalized：

Men have had sexual interest previously with their current partner, but lack sexual interest with sexual activity-either with partner or alone.

Although it is sometimes difficult to distinguish between these types, they do not necessarily have the same etiology. The reason for the terminal/generalized HSDD is unknown. In the case of acquired/generalized hyposexuality, possible causes include various medical/health problems, mental problems, low levels of testosterone or high levels of prolactin. One theory holds that libido is controlled by a balance between inhibitory and excitatory factors. This is thought to be expressed by neurotransmitters in selective brain regions. Thus, decreased libido may be due to an imbalance between neurotransmitters having excitatory activity, such as dopamine and norepinephrine, and neurotransmitters having inhibitory activity, such as 5-hydroxytryptamine. Low libido can also be a side effect of various medications. In the case of acquired/adventure HSDD, possible causes include difficulty in closeness, relationship problems, sexual addiction and chronic disease of male partners. Evidence of these is also under discussion. Some of the purported reasons for low sexual desire are based on empirical evidence. However, some are based only on clinical observations. In many cases, the cause of HSDD is simply unknown.

Several factors are believed to be possible causes of HSDD in women. As with men, HSDD can be caused by various medical problems, psychiatric problems (such as mood disorders) or increased amounts of prolactin. Other hormones are believed to be involved. In addition, factors such as relationship problems or stress are believed to be a possible cause of decreased sexual desire in women.

III.Testosterone

The steroid hormone testosterone is the active ingredient in the testosterone gel formulation of the present invention. The production of pharmaceutical substances does not pose a potential risk to humans; the synthetic route is well characterized.

Table 1: testosterone nomenclature

Structural formula (I)

Molecular formula

C₁₉H₂₈O₂

Relative molecular mass

288.4

The physicochemical properties of testosterone are listed in table 2.

Table 2: general Properties of Testosterone

The testosterone used in the testosterone gel formulations of the present invention appears as white or micro-emulsion white crystals or crystalline powder. It is readily soluble in methanol and ethanol, soluble in acetone and isopropanol, and insoluble in n-heptane. It is also considered insoluble in water (S)_20℃＝2.41×10^-2g/L±0.04×10^-2g/L); its n-octanol/water partition coefficient (log P by HPLC)_OW) It was 2.84. Solubility of Testosterone in oil in meatAssay was 0.8% in isopropyl myristate, 0.5% in peanut oil, 0.6% in soybean oil, 0.5% in corn oil, 0.7% in cottonseed oil and up to 4% in castor oil.

Since testosterone is sufficiently dissolved in the formulation of the present invention, the physical characteristics of the drug substance do not affect the performance of the drug product, the testosterone gel formulation of the present invention. However, the manufacturability of the testosterone gel formulations of the present invention is influenced by the testosterone particle size. The solubility of the drug substance in the matrix is particularly advantageous when particle sizes of 50% to 25 microns, 90% to 50 microns are used.

In formulating the intranasal testosterone gel of the present invention according to the present invention, the testosterone drug may be in the form of, for example, crystalline, amorphous, micronized, non-micronized, powder, small particle, or large particle. Exemplary ranges for testosterone particle size include from about 0.5 microns to about 200 microns. Preferably, the testosterone has a particle size ranging from about 5 microns to about 100 microns and the form of testosterone is crystalline or amorphous or non-micronized or micronized. Preferably, the testosterone is in crystalline or amorphous micronized form.

The molecular structure of testosterone does not contain functional groups that can be protonated or deprotonated at physiological pH-ranges. Thus, testosterone is considered to be a neutral molecule, which has no pKa value in the range of 1-14. Since it is neutral, testosterone is compatible with excipients.

Pharmaceutical product

The testosterone gel formulations of the present invention are viscous thixotropic oil-based formulations containing a testosterone solution intended for intranasal application. The non-irritating formulation is designed to adhere to the inside of the nose. In addition, it acts as a control matrix, thus allowing drug delivery to be maintained through the nasal mucosa.

Other pharmaceutically inactive ingredients in testosterone intranasal gels are castor oil USP, oleoyl macrogolglyceride (EP) and colloidal silicon dioxide NF. None of these excipients are of human or animal origin. All excipients are well known and listed in the FDA issued list of approved drug products "no active ingredients".

According to the Handbook of Pharmaceutical Additives, oleoyl polyoxylglycerides are used as hydrophilic oils for topical, injectable and nasal formulations. In FDA approved medical products, they are used as co-emulsifiers in topical creams/lotions/creams and vaginal creams/creams. In France, the excipients are approved for nasal preparations, such as "Rhino-Sulforgan" (Laboratoire Jolly-Jatel, France; containing 10% oleoyl polyoxylglycerides) and "Huile Gomenolee 2%" (Laboratoire GomLe nol, France; containing 10% oleoyl polyoxylglycerides). Thus, like castor oil, oleoyl polyoxylglycerides can be inferred to be suitable for routes of application where safety and tolerability are most important (e.g., injectable formulations and nasal or vaginal formulations).

Oleoyl macrogolglycerides are also known as Labrafil M1944 CS, almond oil PEG-6 ester, Peglicol-5-oleate, mixtures of glycerides and polyvinyl esters. Castor oil is used as a solvent for the testosterone gel formulation of the present invention, which is a fixed oil. Such oils have the advantage of being non-volatile or diffusive (compared to essential oils or liquid paraffin) but have the disadvantage of being hydrophobic. The nasal mucosa contains 95-97% water. In the absence of oleoyl macrogolglycerides, castor oil containing the active ingredient forms a non-interactive layer on the mucosa. To achieve sufficient contact between the castor oil layer and the mucous membrane, a hydrophilic oleoyl macrogol glyceride oil is added to the formulation to form an emulsion between the castor oil and the mucous membrane fluid.

Oleoyl polyglycolyglycerides are used in the semi-solid in a concentration range of about 3 to 20%, depending on the application. The amount of oleoyl macrogolglycerides in the testosterone gel formulation of the invention is high enough to allow better contact of the carrier oil with the mucosa, and low enough to have minimal effect on the amount of testosterone that can be incorporated into the carrier oil. It was found that the advantageous concentration of oleoyl macrogolglyceride in the testosterone gel formulation of the invention was 4% of the formulation.

According to the "Handbook of Pharmaceutical Additives", colloidal silica is used as oil adsorbent, heat stabilizer and gelling agent. In FDA-approved pharmaceutical products, they are used in dental gels, sublingual tablets, intracervical gels, suppositories, vaginal creams/tablets/tampons and capsules for inhalation. Furthermore, it was used as an excipient in "transdermal testosterone with adhesive (Testoderm)" (Alza Corporation, approved in 1996) testosterone transdermal patches. Thus, it can be concluded that colloidal silica is suitable for the most important application routes of safety and tolerability (e.g. inhalants, endocervical, vaginal or rectal formulations).

For clinical trial supply, testosterone intranasal gel was provided in a unit dose syringe, which consisted of: a syringe body made of polypropylene, a plunger molded from polyethylene, and a syringe cap made of high density polyethylene. The syringe was wrapped in aluminum foil as a secondary package. Syringe capacity (125mg) totaled 0.10 to 1.5 mg of testosterone.

The oil in the testosterone gel formulation of the present invention is thickened with colloidal silicon dioxide, which acts as a gel former. This compound is commonly used to thicken oil gels.

The contemplated dosage form of the testosterone gel formulation of the invention is semi-solid, rather than liquid. The formulation was thickened with colloidal silica. It is believed that the colloidal silica contributes to the thixotropic nature of the gel, facilitating drug delivery to the nostrils.

Colloidal silica is generally an inert substance that is well tolerated as an excipient in mucosal applications such as suppositories. Colloidal silica is typically used in these formulations at concentrations ranging from about 0.5 to 10%. The concentration of colloidal silica in the testosterone gel formulation of the invention is sufficiently high to effect gel formation, but at a level that minimally affects the incorporation of testosterone into the carrier oil.

Preferably, the viscosity of the intranasal testosterone gel of the present invention is generally in the range of between about 3,000cps and about 27,000 cps. However, it will be understood by those skilled in the art that while the above viscosity ranges are believed to be the preferred viscosity ranges, any suitable viscosity or viscosity range that does not defeat the purpose of the invention is contemplated.

A detailed description of some of the testosterone gel formulations of the present invention is shown in table 3.

Table 3: compositions of the Testosterone gel formulations of the invention

The testosterone gel formulations of the present invention are stored at room temperature (20-25 ℃ or 68 to 77F.). See also example 11. Temperature excursions of 15 to 30 ℃ or 59 to 86 ° f are permissible for the testosterone gel formulations of the invention. The stability data available to date is convincing to support a 24-month shelf life. The unit dose syringe is selected for the primary packaging of clinical substances for this clinical trial to allow ease of administration, to allow for multiple doses and consistency of delivered dose by varying the fill volume. The syringe consists of a syringe body, a plunger and a syringe cap. The syringe body is molded from polypropylene, the plunger is molded from polyethylene and the cap is HDPE. These syringes are designed and manufactured to deliver sterile and non-sterile solutions, liquids and gels in low volumes. To protect further from the environment (i.e., exposure to dirt, light, moisture, and oxygen), the syringes are packaged in foil laminated overwrap bags.

The syringe and cap are designed for use in a clinical setting and meet the requirements of EU Medical Devices Directive 93/42/EEC (EU Medical Devices Directive 93/42/EEC) revised on day 14/6 1993. Since the container closure is only intended for this part of the clinical procedure, no additional studies have been conducted on syringes and syringe components. See also example 11 and figure 39.

For the further protection element, the two syringes are contained in a secondary package consisting of an aluminium foil pouch. Two syringes were packaged in aluminum foil bags, and each bag was sealed.

The pouch consisted of a flexible, 3-layer-foil-laminate of a) polyester, 12 microns, b) aluminum, 12 microns and c) polyethylene, 75 microns. It is manufactured by Floeter Flexibles GmbH and supplied under the name "CLIMAPAC II 12-12-75".

Procter&Transdermal therapeutic system developed by Gamble contains testosterone as the active substance for the treatment of HSDD (SD)). 4 clinical control studies (phase II b 2, phase III 2) were performed.

In the case of synchronous estrogen therapy, the 300 μ g testosterone transdermal system is effective in treating HSDD in surgically menopausal women. Women receiving testosterone experienced increased frequency of satisfactory sexual activity, increased libido and reduced distress compared to women receiving placebo. Improvements were also seen at other efficacy endpoints (i.e., arousal, pleasure, orgasm, responsiveness, self-impression, attention). Testosterone serum levels increased to, but not beyond, the physiological range of premenstrual women.

Overall, therapeutic benefit was seen at the earliest 4 weeks, with the greatest effect of overall satisfaction events and libido seen at approximately 12 weeks. The beneficial effect is maintained for the remainder of the 24-week drug life. At week 24, the test results showed that, compared to placebo,significantly increasing the frequency (p) of total satisfaction events<0.05) and also experience a significantly greater increase in the PSFS (female sexual function curve) libido and a significantly greater decrease in personal distress (p) in placebo-administered patients<0.05)。Is approved in the European UnionHSDD for use in treating bilateral ovariectomy and hysterectomy in women receiving concurrent estrogen therapy.

Biosante developed a testosterone gel designed to be rapidly absorbed through the skin after once daily application to the upper arm, delivering testosterone evenly into the blood stream during treatment of HSDD. One phase II study has been conducted and two phase III studies are being conducted.

Phase II test results show that LibiGel significantly increased the number of satisfaction events by 238% (p <0.0001) compared to baseline; this increase was also significant compared to placebo (p < 0.05). In this study, an effective dose of LibiGel produced testosterone blood levels within the normal range for premenstrual women and had a safety profile similar to that observed in the placebo group. In addition, there were no serious adverse events and there were no abortions due to adverse events occurring in any of the subjects receiving the LibiGel.

IV.Dosage and mode of administration

The present invention provides a testosterone gel formulation for intranasal administration, wherein the formulation dosage is from about 0.15% testosterone by weight of said gel formulation to about 0.6% testosterone by weight of said gel formulation, e.g., 0.15% testosterone by weight of the gel formulation, 0.45% testosterone by weight of said gel formulation and 0.6% by weight of the gel formulation.

V.Applications of

The methods of the invention are useful for treating anorgasmia and/or HSDD in a subject diagnosed with one or both of these conditions. The invention also provides intranasal testosterone gel formulations that are useful for treating anorgasmia or HSDD in a subject diagnosed with one or both of these conditions.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Examples

Having now generally described the invention, the same will be more readily understood through reference to the following examples of the invention, which are provided by way of illustration and are not intended to be limiting of the invention unless otherwise specified.

The following examples are provided for illustrative purposes only and are not intended to limit the scope of what the inventors regard as their invention.

Example 1

Description and composition of Testosterone gel formulations of the invention

The composition of the three different concentrations of the drug product to be administered in this clinical trial is provided in the following table.

Description of the dosage forms

The testosterone gel formulations of the present invention are viscous thixotropic oil-based formulations containing dissolved testosterone and are intended for intranasal application. The pharmaceutical product is formulated with the following pharmacopoeia inactive ingredients: castor oil, oleoyl polyoxy-glycerides and colloidal silica.

Three different doses of the testosterone gel formulation of the present invention were administered intranasally: 0.15% w/w, 0.45% w/w and 0.6% w/w. An excess amount (over) was added to each syringe to form a gel that remained in the syringe after administration. This excess remained constant at 23. mu.l, regardless of the amount of gel in the syringe.

Lower dose strength intranasal testosterone formulations

Table 4: the ingredients, amounts, quality standards and functions of the 0.15% testosterone gel formulation of the invention

Table 5: the ingredients, amounts, quality standards and functions of the 0.45% testosterone gel formulation of the invention

Table 6: the ingredients, amounts, quality standards and functions of the 0.6% testosterone gel formulation of the invention

Container with a lid

The testosterone gel formulations of the present invention are provided in unit dose polypropylene syringes. Both syringes for each dose were packaged in protective aluminum foil bags.

Example 2

Intranasal testosterone gel formulations

The testosterone gel formulation of the invention, being a testosterone formulation in intranasal gel, is proposed for evaluating the drug metabolism and efficacy of three different doses of the testosterone gel formulation of the invention, compared in women with Hypoactive Sexual Desire Disorder (HSDD) and Secondary Anorgasmia (SA)And placebo with the testosterone gel formulation of the invention.

The active ingredient testosterone is from Bayer Schering.

Challenges with nasal delivery include:

larger particles than required for pulmonary administration (i.e. only particles >10 μm are heavy enough to avoid entry into the respiratory tract);

the concentration must be higher due to the smaller amount that can be applied;

rapid clearance of the therapeutic agent from the site of deposition, resulting in a shorter time available for absorption;

the potential for local tissue stimulation; and

limited formulation handling possibilities to alter the drug delivery profile.

Testosterone was indicated for the treatment of HSDD in women with bilateral ovariectomy and hysterectomy (surgically-induced menopause) who received simultaneous estrogen therapy. It is also indicated for the treatment of hormone replacement therapy in the treatment of male hypogonadism. Currently available options for administering testosterone are oral, buccal, injection, implantation and transdermal administration.

Intranasal testosterone (3.2%) gel-TBS-1 gel was developed for The treatment of male hypogonadism and has been administered to hypogonadism men in several clinical trials (Mattern, c. et al, 2008The aging male 11(4): 171-. Intranasal testosterone gels for women — testosterone gel formulations of the present invention were developed at concentrations ranging from about 0.15% to about 0.6% testosterone.

Example 3

Excess of

[ Hair dressing for hair growthGelatin preparation of Mingtongosterone]

No excess was added to the formulation. An excess amount is added to each syringe to form a gel that remains in the syringe after administration. This excess remained constant at 23. mu.l, regardless of the amount of gel in the syringe. The theoretical fill and dispense amounts of the testosterone gel formulations of the present invention are given below.

Example 4

Physicochemical and biological Properties

[ Testosterone gel formulations of the invention]

The viscosity of the testosterone gel formulations of the present invention ranges from 3,000 to 10,000mPa × sec. Viscosity is important because it helps the gel in the nasal cavity to maintain contact with the nasal mucosa. When the viscosity is less than about 3,000mPa × sec (i.e., 3,000 centipoise), the gel tends to be sucked out of the nasal cavity by gravity.

Example 5

Square material (Batch Formula)

[ Testosterone gel formulations of the invention]

Three different concentrations of the testosterone gel formulations of the invention-0.15%, 0.45% and 0.6% -were prepared for proposed clinical trials. The recipes for these batches are shown in table 5 below.

Table 5: the invention relates to a formula of 0.15%, 0.45% and 0.6% testosterone gel preparation, and the batch is 8kg

Example 6

Preparation process and process control

[ Testosterone gel formulations of the invention]

The material was prepared according to the preparation process flow diagram as described in fig. 40.

Mixed Components-Mass gels

A premix was prepared by mixing sufficient testosterone with part 1 of castor oil for 10 minutes using a propeller mixer.

Mixture I was prepared by adding the premix to the remaining castor oil and mixing for 60 minutes. The product temperature was maintained below 50 ℃ throughout the mixing process.

Oleoyl polyoxylglycerides are preheated to 40-50 ℃ and mixed for 10 minutes before being added to mixture I. This was identified as mixture II. It was mixed for 45 minutes while maintaining the product temperature below 50 ℃. Mixture II was then screened through a sieve to remove any undissolved testosterone aggregates.

Mixture III was prepared by adding colloidal silica to mixture II and mixing for 15 minutes while maintaining the product temperature below 50 ℃. Visual inspection was performed after this step to ensure that the gel was clear.

Upon completion of mixing, the gel was agitated and cooled to a product temperature below 30 ℃. The product was then discharged into a stainless steel drum and a large sample of the gel was taken for analytical testing.

Filling and packaging-clinical supply

After release of the final gel mixture by the quality control laboratory, the filling and packaging process is completed by filling a predetermined amount into the syringe and then applying the syringe cap. The two syringes are packaged into foil pouches.

The syringe was filled with a pipette, with the gel taken from the reservoir. The tip of the pipette is discarded after filling the syringe and applying the syringe cap. Each syringe is individually labeled.

After application of the label, the two syringes are packaged in a preformed foil pouch and the pouch is sealed. Each bag is labeled.

Example 7

Evaluation of Testosterone gel formulations of the invention in women with anorgasmia

In a study of women with anorgasmia, the drug metabolism and pharmacodynamic efficacy of the testosterone gel formulation of the invention were evaluated. The effect of testosterone gel formulations of the invention on the neutral stimulation of women with anorgasmia was also determined.

Patient population

An otherwise healthy female presenting with anorgasmia was evaluated for age 18 to 65 years. Sixteen (16) subjects were recruited.

Administration of drugs

Three doses of the testosterone gel formulations of the present invention were studied: 150 μ g, 450 μ g and 600 μ g per nostril. A total of 5 doses of the testosterone gel formulation of the invention were intranasally administered to women via BID. The placebo testosterone gel formulation of the present invention was administered as a control.

Duration of treatment

Test subjects received 5 doses of the testosterone gel formulation of the present invention over a three day period.

Terminal point

Primary end point:

plasma concentrations of total testosterone and dihydrotestosterone were measured using validated LC/MS. The following drug metabolism parameters were determined for all subjects:

determination of Cmin, Cmax, tmax, PTF and PTS for each dosing interval

AUC 0-tau and Cavg were calculated for each dosing interval.

Percentage of times within, below and above the physiological reference range of plasma testosterone and dihydrotestosterone

Secondary end point:

efficacy was determined by a set of computer and psychophysiological tests.

Monitoring safety according to the following parameters:

whole blood count at baseline and central off Visit (Close Out Visit).

Omicron clinical chemistry and urinalysis tests at baseline and central shutdown to evaluate selected endocrine parameters, renal function, liver function, skeletal/myocardial muscle injury, lipid abnormalities, and calcium homeostasis changes.

Omicron measurements of plasma testosterone, dihydrotestosterone, and various hormones were turned off at baseline, study period, and center.

Omicron adverse events.

Randomization

Subjects in the ANOR cohort were randomized to receive either a testosterone gel formulation of the invention (3 dose levels) or placebo. Randomization is assigned according to the following design.

LD (0.15%) -low dose; MD (0.45%) -medium dose; HD (0.6%) -high dose

Blind method

The study was both double-blind and open, depending on the treatment cohort. For the subjects in the ANOR group, the study was placebo-controlled and double-blind.

Dosage and dosage regimen

All subjects were administered five (5) occasions during the study either the testosterone gel formulation of the invention (0.15%, 0.45% or 0.6%) or a placebo of the testosterone gel formulation of the invention: the first day, at 2000 hours, the second day, at 800 and 2000 hours and the third day, at 800 and 2000 hours. Intranasal gels were administered to both nostrils (1 syringe (100 μ l amount) per nostril).

Packaging and labelling

Study medication consisted of a testosterone gel formulation of the present invention and a placebo gel and was packaged in a disposable syringe designed to expel 100 μ l of gel. Two syringes were packaged in foil pouches.

Treatment planning

Subjects were randomized into dosing regimens administered in a four day (three night) hospitalized patient treatment period and received either an intranasal testosterone gel formulation (3 dose levels) or placebo (ANOR) of the present invention according to the following design assignment:

a randomized protocol was generated for each study center, which would consist of four treated modules per group.

The study was a four day study. The study began with study drug administration between 2000 and 2100 hours on the first day (baseline). For plasma testosterone and dihydrotestosterone profiles, blood samples were drawn at-60, 0, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 and 480 minutes after the first and third day evening doses and at 0 and 60 minutes after administration after the second and third day morning doses.

PD tests (computer tests) were performed 30 minutes and 4.5 hours after the next morning dose (psychophysiological tests) and 30 minutes after the third morning dose for subjects assigned to three testosterone gel formulations or placebo gels of the arm (arm) of the invention. The subject experienced a practical psychophysiological period prior to the first administration.

Because repeated nocturnal bleeding during the first night is not expected to allow the subject to fall asleep well, the sequence of psychophysiological testing and computer testing is not balanced. Computer tests are expected to be more negatively affected by insufficient sleep than psychophysiological tests. Therefore, psychophysiological testing was performed the next day and computer testing was performed on the third day.

Adverse events were assessed and reported.

Patient selection and withdrawal

The subject in this study was a female with ANOR. Subjects are recruited from medical practice or general populations by advertising in local newspapers and additional information available from the web. Before scheduling the screening visit, the subject was asked a series of standardized questions by telephone to assess whether they might be appropriate for the study.

Inclusion criteria

Omicron, age 18-65 years.

Omicron is diagnosed as female orgasm disorder (anorgasmia) according to the DSM-IV standard. The current diseased phase must last at least 24 weeks at screening visit. The subtype should be generalized and not due to etiological factors (e.g., depression, alcoholism, surgery, injury) that would prevent a therapeutic response. HSDD is allowed as a co-morbid condition only after it begins with anorgasmia.

οBMI<35。

Omicron women must have an FSDS-R score of >11 at screening visit, while the FSFI score is < 26.55.

Women are in a stable relationship for at least 12 months, or single women, who use masturbation as the primary means of trying to achieve orgasm.

Omicron pre-and post-amenorrhea women-post-physiological and surgical amenorrhea women-estrogen/progestin replacement (low dose combined ET/P) for at least three (3) months before study entry or after amenorrhea women do not go onAnd ET/P substitution.

Omicron pre-amenorrhea heterosexual women will need to resort to a reliable method of contraception (i.e. the OCP or partner must use a condom).

Normal thyroid function, physiological prolactin concentration.

Normal ear, nose and throat examination.

Written informed consent is provided.

Exclusion criteria

Any other history of clinically relevant psychosis that may affect sexual function, risk patients for safety, or may affect compliance is assessed. This includes bipolar depression, psychotic disorders, severe anxiety, eating disorders, socially-compromised personality disorders, and the like.

Omicron before the screening visit the history of major depression is within six (6) months or the becker depression questionnaire II score is no less than 14.

A subject that satisfies DSM-IV criteria (APA) for the following diseases: sexual aversion disorder, substance-induced sexual dysfunction, dyspareunia (not caused by insufficient prodigious stimulation or moderation by lubricants), vaginismus, sexually transmitted disorders, paraplegia, or sexual dysfunction due to a general medical condition.

Omicron subject, who experiences dissonance in relation, as indicated by MMQ score > 20.

A subject suffering from known acute pelvic inflammation, urinary or vaginal infection/vaginitis, cervicitis, interstitial cystitis, vulvodynia, or significant vaginal atrophy.

Omicron subject who is nursing, or has been nursing within the last six (6) months prior to baseline visit.

Subjects who have become pregnant (passed the serum pregnancy test at screening visit), or have become pregnant within the last 12 months prior to baseline visit.

Omicron is treated with systemic glucocorticoids.

Omicron with sex steroid hormones, such as androgens, estrogens other than the low dose combination ET/P, or progesterone (e.g., anabolic steroids, DHEA, progesterone, etc.),(conjugated equine estrogens)).

Treatment with thyroid hormone (only for stable replacement therapy).

Any type of severe intermorbidity, especially liver, kidney or heart disease, any type of diabetes (subjects with antacids or treated hyperlipidemia or treated hypothyroidism will not be excluded if they are stable in their drug dose for at least six (6) months).

Omicron, history of nasal disorders (e.g., seasonal or perennial allergic rhinitis, atrophic rhinitis, polyposis, nasal mucosal decongestant abuse, clinically relevant septal deflection, recurrent nasal bleeding), or sleep apnea.

A subject having a history of: dementia or other neurodegenerative diseases, organic brain diseases, stroke, transient ischemic attacks, brain surgery, severe brain injury, multiple sclerosis, spinal cord injury, peripheral neuropathies and epilepsy (febrile seizures limited to childhood do not exclude subjects).

Cancer-not including basal cell carcinoma-history.

Omicron severe or multiple allergies, severe adverse drug reactions, or a history of leukopenia.

Omicron abnormal bleeding tendency or history of thrombophlebitis unrelated to venipuncture or intravenous cannulation.

Omicron DVT medical history.

Omicron hepatitis B medical history, positive hepatitis B surface antigen detection, hepatitis C medical history, positive hepatitis C antibody detection, HIV infection medical history or the presence of HIV antibodies.

Omicron recent history of severe sleep problems. The shift worker, prior to study enrollment, needs to have sufficient day and night rhythms for three weeks.

A regular drinker, more than three (3) units of ethanol per day (1 unit 300ml beer, 1 glass wine, 1 metric spirit).

-historical or current signs of alcoholism or abuse of any drug substance-legal or illegal; or positive urine and alcohol screening for drug abuse and alcohol.

It was difficult to abstain from OTC medication (except occasional paracetamol/aspirin) for the duration of the study.

Poor dependents, or subjects are unlikely to attend the study visit.

In this study, any drug was accepted as part of the study within 30 days of initial dose administration.

Omicron donated blood (typically 550ml) in a 12-week period prior to the initial study dose.

Treatment object

Research visit

Visit 1 (day 15) -screening subjects for inclusion and exclusion criteria:

pre-study screening was performed within two (2) weeks before treatment initiation. After the informed consent was actively signed and before enrollment, subjects were interviewed by a clinical investigator or his/her assigned physician who would receive medical, sexual and physical medical records, record demographic data, and conduct routine physical examinations including vital signs (blood pressure, resting heart rate, weight, and height).

Manage FSFI and FSDS-R as well as MMQ, BDI-II, IS, SIDI-II, and SESII-W.

Ear, nose and throat examinations were performed by ENT specialist doctors.

Venous blood was collected after overnight fasting for CBC (hemoglobin, hemoglobin A1c, hematocrit, MCV, MCHC, RBC, WBC and differential), clinical chemistry profile (Na/K, glucose, urea, creatinine, total bilirubin, albumin, calcium, phosphate, uric acid, LDL, HDL, triglycerides, AST, ALT, ALP, GGT and CK).

Venous blood samples were collected for estradiol, free testosterone (percent), follicle stimulating hormone, luteinizing hormone, prolactin, progesterone, sex hormone binding globulin, total testosterone and dehydroepiandrosterone sulfate.

Blood samples were obtained for TSH, total and free thyronine triiodide, total and free thyroxine.

Urine is collected for specific gravity, glucose, ketone, bilirubin, pH, urobilinogen, leukocytes, nitrite measurements.

Subjects, underwent hepatitis b, hepatitis c and HIV tests (hepatitis b surface antigen, hepatitis c antibody, HIV antibody in plasma).

Urine drug screening was performed against amphetamine, benzodiazepines, cannabinoids, cocaine, opiates, MDMA. Subjects with positive test results did not participate.

Will be screened for ethanol by breathalyzer.

Visit 2 (day one) -baseline onset, randomization, PK blood sampling and PD testing:

the subject was allowed to stay in the clinic for three nights in the afternoon.

Check-in to check for non-accepted medication (OTC and prescription), drugs, alcohol or cigarettes. Subjects were asked to abstain from alcohol for 48 hours before admission to the clinic. Alcohol consumption is strictly prohibited at any time during the overnight stay in the clinic. There was no restriction on food intake during blood collection for PK distribution.

Repeat urinalysis for the same drug abuse at screening.

Exclude pregnancy (if applicable) using a urine test.

Check vital signs (blood pressure, resting heart rate and body weight).

Draw blood for CBC, chemical profile, hormonal profile and pregnancy test.

Urine was collected for urinalysis and urine drug screening, with alcohol breath testing.

● Prior to administration and blood sampling, subjects underwent a psychophysiological familiarity test in which neutral and sexual activity films were displayed and VPAs recorded to familiarize with the test procedure and exposure to sexual stimulation of exposed bones. The data obtained were not used for analysis.

The venous cannula will be placed in the forearm vein and blood sampling will begin one hour prior to nighttime administration of the study drug.

Subjects were dosed at 2000 and 2100 hours.

Blood samples were drawn at-60, 0, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 and 480 minutes post-administration for measurement of plasma testosterone and dihydrotestosterone levels.

Randomization of treatment regimens in this visit.

Record the security assessment.

Subjects remained in the clinic overnight.

Visit 3 (next day) -PK blood sampling:

obtain vital signs.

Collection of hormone profiles.

Subjects were given study medication between 800 and 900 and between 2000 and 2100 hours (except takingOther than that). Blood samples were drawn at 0 and 60 minutes post-administration for measurement of plasma testosterone and dihydrotestosterone levels.

Psychophysiological tests were performed 30 minutes and 4.5 hours after morning dosing for subjects assigned to the three testosterone gel formulations or placebo gels of the arm of the invention.

Record the security assessment.

Subjects remained in the clinic overnight.

Visit 4 (third day) -PK blood sampling and PD testing:

obtain vital signs.

Collection of hormone profiles.

Between 800 and 900 and 2000 and 2100 hours, subjects were given study medication. Blood samples were drawn at 0 and 60 minutes after administration of the morning dose and at 0, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 and 480 minutes after administration of the evening dose for plasma testosterone and dihydrotestosterone levels.

For subjects assigned to the three testosterone gel formulations or placebo gels of the arm of the invention, computer tests were performed 30 minutes after morning dosing.

Record the security assessment.

Visit 5 (fourth day) -off-center off:

physical examination, including vital signs.

Venous blood was collected after overnight fasting for CBC (hemoglobin, hemoglobin A1c, hematocrit, MCV, MCHC, RBC, WBC and differential), clinical chemistry profile (Na/K, glucose, urea, creatinine, total bilirubin, albumin, calcium, phosphate, uric acid, LDL, HDL, triglycerides, AST, ALT, ALP, GGT and CK).

Appropriate blood samples were collected for estradiol, free testosterone (percent), follicle stimulating hormone, luteinizing hormone, prolactin, progesterone, sex hormone binding globulin, total testosterone and dehydroepiandrosterone sulfate.

Urine is collected for specific gravity, glucose, ketone, bilirubin, pH, urobilinogen, leukocytes, nitrite.

Record the security assessment.

Clinical evaluation

Screening and covariate questionnaires were used for clinical evaluation.

BDI

To index the current level of depression, 21-items of BDI-II (Beck, Steer, & Brown.1996), Dutch adaptation (Van der Does,2002) were managed. The overall BDI score ranged from 0-63, with higher scores indicating more depressive disorders.

MMQ

Maudsley Marital questingnaire (MMQ; crown, 1978) is a 20-item self-reporting tool that measures dissatisfaction with general relationships, sexual relationships, and with overall life. MMQ has shown good reliability and correctness. The netherlands version of MMQ was also found to be of satisfactory quality for psychometric measurements (Arrindell, Boelens, & lambert.1983). A higher score represents greater satisfaction.

FSFI

Female sexual function levels are assessed by female sexual function index (FSFI; Rosen, Brown, Heiman, et al, 2000).Is a self-administered questionnaire consisting of 19 questions. The components contain six domains: desire, arousal, lubrication, orgasm, satisfaction, and pain. The overall score ranged from 2-36, with lower scores representing poor sexual function. The FSFI psychometric quality is satisfactory (Wiegel, Meston,&rosen.2005). The intrinsic consistency and stability of FSFI was found to be satisfactory to good based on dutch samples consisting of approximately 350 women with or without sexual complaints. The ability of FSFI to distinguish between sexually functioning and dysfunctional women is outstanding, as is the ability to predict the presence or absence of complaints (ter Kuile, Brauer,&Laan, 2006)。

FSDS-R

the level of female personal distress due to sexual dysfunction is assessed by a revised female sexual distress scale: (Derogatis, Clayton, Lewis-D' Agostino, et al, 2008).

The items ask negative emotions and questions that were perplexing or causing distress over the past 30 days.(12-project version) reliabilitySexual and correctness have been evaluated in different samples of women with sexual function and sexual dysfunction. For theThe results show a one-dimensional factor structure, high intrinsic consistency and test-retest reliability. In each of its three confirmatory studies,both show a high degree of discrimination between sexual dysfunction and sexually functioning women. The results of the dutch sample support the one-dimensional structure of FSDS and its reliability and psychometric correctness (ter Kuile, Brauer,&laan, 2006). Additional questions (question 13) have been added to the acknowledgementThe problem relates to distress, especially those related to sexual desire. Indicating greatest horizontalityThe maximum total score is '52'.Both the total score and the individual question 13 scores were analyzed.

Covariate questionnaire

Sexual satisfaction Index (ISS)

Female sexual satisfaction levels were assessed by the sexual satisfaction index (ISS; Hudson, Harrison, & Crosscup.1981). The 25-item questionnaire required subjects to evaluate various aspects of their sexual relationships, resulting in a total score ranging between 0 and 100. A higher score corresponds to greater sexual satisfaction. This metric has been shown to have good face (face), convergence (convergent), and discrimination correctness for various samples. Example items are "i feel my partner enjoy our sexual life", "i think that sex is wonderful" and "my partner is very sexually exciting". For current research purposes, the ISS is translated into Dutch.

SDI-II

Female sexual desire levels are assessed by the sexual desire list-II (SDI-II; Spector, Carey, & steinberg.1996) SDI-II consists of two seven-item self-reporting scales, a two-entry sexual desire scale, which measures the individual's desire for sexual activity with a partner, and an individual sexual desire scale, which measures the individual's desire for autologous sexual activity, the two sub-components are essentially identical (Cronbach's α: the two-entry component is 0.86; the individual component is 0.96).

Sexual excitation/inhibition (SESII-W)

The female sexual suppression/excitement catalog (SESII-W; Graham, Sanders, & Milhausen.2006) was used to assess individual preferences for sexual excitement and sexual suppression. It consists of 36 items, involving either stimulation situations that affect sexual suppression and excitement or general statements about arousal ability and suppression. Instructions to ask women to report what the most typical reactions will now be or if the project is not suitable for them, they think they will do what reactions. Items were ranked according to the 4-point Like's rating Scale, from "strongly disagreeable" to "strongly agreeable". SESII-W has 8 lower order factors which in turn belong to (load on) two higher order factors-sexual excitement and sexual suppression. The questionnaire showed good test-retest reliability and convergence and discrimination correctness, and sexual excitation and sexual suppression appeared to be relatively independent factors. The list has been used in the netherlands, but the psychometric properties have not been studied.

Efficacy and drug efficacy test

Computer testing

Single target implicit association task (StIAT):

conform wigbold et al (2005), the stIAT used in this study was designed to assess the emotional association of subjects to sexual stimuli (filed by Brauer, van leewen, Janssen, et al). The object is instructed to classify the picture depicting the sexual act (i.e., the target stimulus) and the wording representing the "positive" or "negative" meaning (i.e., the attribute stimulus) into the appropriate upper category (i.e., "sex," "active," "negative") as quickly as possible by simply pressing the left or right answer key on the keyboard. These labels for these categories (sexual, active, passive) are continuously visible on the computer screen. The stIAT consists of practice and test modules (for a detailed method, see Greenwald, McGhee & schwartz. 1998). The test module consists of one 'inconsistent' and one 'consistent' module of the test. In the inconsistent module, "negative" and "positive" are mapped to a single key and "positive" is mapped to other keys, while in the consistent module "negative" and "positive" are mapped to the same key and "negative" is mapped to other keys. The difference in reaction time between the two test modules is assumed to correlate more strongly with positive or negative reactivity. Faster responses in the consistent modules (as compared to other modules) reflect a stronger connection between positive and negative, while faster responses in the inconsistent modules reflect a stronger connection between negative and positive. The object-property combinations of the common reply key (i.e., module commands) compete against the left or right key answer requirements. Each key module consists of 40 trials, where the answers are evenly divided over the two answer keys. The object class consists of example stimuli of 5 sexual images from the International emotional Picture System (IAPS; center for research on emotions and attention, 1995) with the following numbers: 4800. 4652, 4658, 4659, and 4672. The attribute categories consist of 20 generally positive and 20 generally negative terms (Dotsch & Wigboldus, 2008; Dotsch, Wigboldus, Langner, et al, 2008), reflecting a more comprehensive emotional association. The length and frequency of these words are controlled. The strength of stIAT in terms of correctness lies in the high efficiency size (size), since the dual opposite categories often result in slower reaction times (the classification decision requires effort, as there are several possibilities to consider).

Picture Association Task (PAT)

This task was developed by van Leeuwen and Macrae (2004), which initiates tasks based on emotion (e.g., Bargh, Chaiken, Govender, et al, 1992; Fazio, Sanbonmatsu, Powell, et al, 1986; Hermans, DeHouwer, & Eelen,1994) where target wording occurs after other wording or images that affect the classification of target wording. However, in PAT, the target word and the image appear at the same time. In PAT used in this study, subjects were presented with positive or negative words appended in neutral pictures or neutral pictures (filed by Brauer, van leewen, Janssen, etc.). Instructing them to classify the wording as positive or negative as soon as possible by pressing one of the two computer keys. The subject is also instructed to note words appearing on the screen and not to focus on background images, since these are not important for the task, and the category (sexy, neutral) to which the pictorial stimuli belong is not illustrated. Thus, PAT captures the unintentional impact of emotional value on picture background stimuli on task performance. The timing of choosing the correct answer to the word (positive or negative) is influenced by the match between the word valence and the background image (sexually or neutral) valence, thus indirectly revealing the subject picture valence. The wording category consists of 10 active words and 10 passive words. However, general active and passive terms (e.g., and flat, respect, war, hate) are selected for the stIAT, and the PAT consists of such active and passive terms: it applies to sexual situations but does not exclusively relate to sexual experience (e.g. pleasant, wonderful, dirty, nausea) to produce a conceptual overlap between word satisfaction and satisfaction triggered by sexual pictures. These terms were taken from an experimental study in the netherlands, where female subjects (N ═ 20) were asked to show how well each positive and negative term described a positive or negative situation, respectively, according to a 7-point leke component (Brauer & Laan, 2008). The wording appears in one of four random positions on the image to avoid expecting relevant answers and to ensure that the subject will move their eyes on the image. Sexual pictures were taken from another study on implicit associations to sexual stimuli in women with dyspareunia (Brauer, de Jong, Huijding et al, 2009). These pictures show various sexual acts (e.g., kissing, licking, oral sex, intercourse). On a per sexual picture basis, a control picture is generated by disorganizing sequential imagery (sexual images), leaving neutral stimuli behind. All pictures were normalized to 600 × 480 pixels and made the same brightness and contrast. Each stimulus remains on the screen until the subject makes a decision or until after 3,000 ms. After 10 practical trials, 80 experimental trials were presented. Each wording was randomly paired with a sexual picture and a neutral picture, resulting in four different combinations, each occurring 20 times: active words and sexual images, passive words and sexual images, active words and sexual images, passive words and sexual images. The order of trial presentation competes among subjects, and the response key mapping (i.e., active/passive or passive/active) competes among subjects. The computer records the accuracy and latency of each response. For correctness, PAT has the advantage that it is insensitive to possible explanation biases, since different stimulation classes need to be addressed at the same time, as in stIAT.

Point exploration task (DOT)

The point detection task (DOT) assesses attention preferences for sexual and neutral visual stimuli. In this task, two side-by-side images are displayed to the subject on the computer screen for 500 ms. When both images disappear, the target stimulus represented by a small dot appears at the position of one image. The object is required to indicate the position of a point (side). The average RTs is calculated for three classes: 1) neutral 2) neutral and neutral point 3) neutral and neutral point. The response time is faster when the point appears at the location of certain types of stimuli, which indicates a preference for attention for that type of stimulus.

Psychophysiological testing

Genital reaction (VPA)

The psychophysiological test consists of: evaluation of genital response (vaginal pulse amplitude) and targeted sexual arousal during sexual and self-induced sexual desire fantasy (3min), low intensity sexual desire movie clips (5min) and high intensity sexual desire movie clips (5min) (lan et al, in preparation). Sexual desire conditions are separated by different inter-stimulus intervals during which the subject completes the task of interest (a simple arithmetic problem) to allow return to baseline. The sexual stimulation test was preceded by an 8min neutral movie to establish baseline levels. VPA was measured using a vaginal photoplethysmograph developed by Bert Molenkamp (technical support of psychology, university of amsterdam) based on an instrument originally developed by Sintchak and Geer (1975). The mass production of the light source (3mm led, λ 620nm) and the optical sensor (Texas Instruments TSL250) at 100 led to almost equal electronic characteristics for all the photoplethysmographs used in this study. The signal conditioning amplifier separates the VPA from the DC component using a 12 dB/octave, 0.7-Hz filter. Additional filtering for VPA was 24 dB/octave, 0.4Hz high pass. The VPA signal was digitized at 100Hz by a Keithley KPCI3107A/D converter running on a Windows 2000PC system. The probe depth and light source direction were controlled by a device (9-x2-cm FDA-approved plexiglas plate) connected to the cable within 5cm of the optical sensor. The subject is instructed to insert the probe until the plate contacts its labia. The probe and plate were sterilized according to standard protocols.

Sexuality and emotion (SAQ).

Before and immediately after sexual desire stimulation, subjects filled out a questionnaire that measures sexual perception and emotion during sexual stimulation, consisting of 5 components: sexual arousal (Cronbach's α ═ 0.87), genital perception (Cronbach's α ═ 0.96), good colour (Cronbach's α ═ 0.73), positive emotion (Cronbach's α ═ 0.93), and negative emotion (Cronbach's α ═ 0.65), each question appeared after the next sentence: "i feel during movie", followed by description of positive, negative, physical or sexual experience, e.g., pleasure; fear; genitals pulse or beat; sexual arousal, component measures from 1 (not at all) to 7 (strongly).

Acute Female Sexual Desire (AFSDQ)

Subjects filled out an acute female libido questionnaire (Laan, Heiman, unpublished) before and after psychophysiological testing. The questionnaire assesses interest in sexual stimulation and has been shown to distinguish women with acquired HSDD from sexual-functional controls (Laan et al, in preparation).

Statistical method

Calculation of drug metabolism parameters

·C_min、C_maxAnd t_maxTaken from actual measurements. The values are determined relative to the time of testosterone administration in the treated subject.

The area under the concentration curve (AUC) was evaluated for the 0 to 24 hour time interval and the BID dosing interval using the trapezoidal theorem.

The testosterone gel formulation and placebo of the invention after the first evening dose and the testosterone gel formulation, placebo and placebo of the inventionPK assessment-AUC, total and free testosterone, DHT, estradiol, SHBG concentrations after the third day evening dose of the patch (which was applied on the first day). Analysis C_avg、C_min、C_max、t_max、 AUC_0-tPTF and PTS. C for a 12 hour period and τ is calculated at the appropriate time_avg. For takingThe subject of (1), was calculated for 24 hours.

The mean concentration (C) in the dosing interval was calculated from AUC using the following formula_avg)：C_avg＝AUC_0–τAnd/τ, where τ is the dosing interval.

Peak-to-valley fluctuation (PTF) and peak-to-valley steering (Swing) (PTS) are calculated as follows:

ο PTF＝(C_max-C_min)/C_avg

οPTS＝(C_max-C_min)/C_min

calculate the percentage of time plasma testosterone concentrations above, within and below the reference range of 10 to 70 ng/dl.

Statistical analysis of pharmacodynamic data

stIAT：

Incorrect responses were excluded from the analysis. In addition, RT shorter than 300ms or longer than 3000ms was excluded from the analysis. For the stIAT data, according to wigbold, Holland & van knipenberg (2005), because for each object, median reaction latency to correct reaction of property items in consistent and inconsistent modules is applied. After this, the median reaction times of the two test modules were subtracted from each other to obtain the stIAT effect (i.e. the stIAT effect is median (sexual/passive) -median (sexual/active)). The negative stIAT effect indicates a negative association with a relatively strong sexual stimulation.

The stIAT effect was analyzed by analysis of variance, treated by fixed factor, group (HSDD and SA) and by group interaction. Controls were calculated within the model.

PAT：

The median response latencies for correct responses were calculated from van Leeuwen and Macrae (2004). To correct for baseline responses to positive and negative words, a difference score is calculated by subtracting the RTs of the neutral words appended to the sexual picture from the positive words appended to the sexual picture. The same is true for negative words attached to neutral pictures and neutral pictures (i.e., neutral/positive RT and neutral/negative RT.

Two PAT variables (RT positive and RT negative) were analyzed by analysis of variance with fixed factor treatment, group (ANOR) and group by treatment. Controls were calculated within the model.

DOT：

For each subject, the difference between the average RT for class neutrality, where the point is below neutral, and the average RT for class neutrality, where the point is below neutral, is calculated to obtain the DOT effect (i.e., DOT effect-average neutrality of points below neutral). A higher DOT score indicates a relatively stronger concern for sexual stimulation.

DOT effects were analyzed by analysis of variance, by fixed factor treatment, by group (ANOR) and by group interaction treatment. Controls were calculated within the model.

VPA：

After VPA manual deletion, performed by a computer program developed by Bert Molenkamp (psychology technical support of the university of amsterdam), the peak-to-valley amplitude of each remaining pulse was calculated. VPA was averaged every 30 seconds in several cases: neutral movies (8min), self-induced sexual desire fantasy (3min), low-intensity sexual desire movie clips (5min), and high-intensity sexual desire movie clips (5 min). All conditions are provided twice: once 0.5 hours after administration of the nasal gel and once 4.5 hours after administration of the nasal gel.

VPA during sexual desire fantasy, low intensity movies and high intensity movies were analyzed separately and at different times (0.5 hours post-dosing and 4.5 hours post-dosing) to yield 6 analyses. VPA during the situation and time is analyzed with a mixed variance analysis model by fixed factor processing, group (ANOR), time, group by processing, processing by time, and random factor objects, and with the average VPA score during the neutral movie as covariate. Controls were calculated within the model.

SAQ：

For each of the five SAQ components, the average response during the condition and time of day was analyzed by analysis of variance with factor treatment, group (ANOR), group by treatment, with scores before sexual stimulation as covariates. Controls were calculated within the model.

AFSDQ：

ASFDQ scores after sexual stimulation during the time period were analyzed by analysis of variance with factor treatment, group (ANOR), group by treatment, and score before sexual stimulation as covariates. Controls were calculated within the model.

The data is logarithmically transformed if necessary to meet the requirements of analysis of variance. The results were inverted and reported as% change.

A graph of the least squares mean estimate over the treatment time is presented with error bars representing 95% confidence intervals for the upper and lower limits of the highest and lowest lines, respectively. The least squares means of the controls are tabulated.

If it is not feasible to perform an analysis according to the described model with the given data, the analysis is adjusted. If deemed useful, additional exploratory analysis is performed.

Statistical analysis of security data

And (4) presenting nasal tolerance data in a summary table. Statistical analysis will not be performed.

Vital signs and clinical laboratory parameters:

tables summarizing all laboratory test values and changes from baseline are presented for each treatment group. The clinical significance of these results was evaluated with the parameters at ± 20% of their reference ranges.

The results of this analysis are presented in FIGS. 1 and 4-6. Subsequent figures 3 and 9-11 compare the results between the effects of lower dose strength testosterone gel nasal formulations of the invention in subjects diagnosed with anorgasmia or HSDD.

Example 8

Evaluation of Testosterone nasal gel formulations of the invention in women with HSDD

The drug metabolism and pharmacodynamic efficacy of the testosterone gel formulations of the invention were evaluated in a study on women with HSDD. The effect of testosterone gel formulations of the invention on the neutral stimulation of women with HSDD was also determined.

Administration of drugs

Three doses of the testosterone gel formulations of the present invention were studied: 150 μ g, 450 μ g and 600 μ g per nostril. A total of 5 doses of the testosterone gel formulation of the invention were intranasally administered to women via BID.Patches (300 μ g testosterone) were administered as a control in HSDD cohorts.

Patient population

Otherwise healthy women presenting HSDD are evaluated for age 18 to 65 years. Sixteen (16) subjects were recruited per indication.

Duration of treatment

Test subjects received 5 doses of the testosterone gel formulation of the present invention over a three day period.

Terminal point

Primary end point:

plasma concentrations of total testosterone and dihydrotestosterone were measured using validated LC/MS. The following drug metabolism parameters were determined for all subjects:

determination of Cmin, Cmax, tmax, PTF and PTS for each dosing interval

AUC 0-tau and Cavg were calculated for each dosing interval.

Percentage of times within, below and above the physiological reference range of plasma testosterone and dihydrotestosterone

Secondary end point:

efficacy was determined by a set of computer and psychophysiological tests.

Monitoring safety according to the following parameters:

whole blood count at baseline and central off Visit (Close Out Visit).

Omicron clinical chemistry and urinalysis tests at baseline and central shutdown to evaluate selected endocrine parameters, renal function, liver function, skeletal/myocardial muscle injury, lipid abnormalities, and calcium homeostasis changes.

Omicron measurements of plasma testosterone, dihydrotestosterone, and various hormones were turned off at baseline, study period, and center.

Omicron adverse events

Randomization

Subjects in the HSDD cohort were randomized to receive testosterone gel formulations of the invention (3 dose levels) orA patch. Randomization is assigned according to the following design.

LD (0.15%) -low dose; MD (0.45%) -medium dose; HD (0.6%) -high dose

Blind method

This is both a double-blind and open study, depending on the treatment cohort. For the HSDD group, this was a partial release study, as blinding administration of intranasal versus patch administration was not feasible. The testosterone gel formulations of the invention were dosed blindly in the HSDD cohort.

Dosage and dosage regimen

Five (5) occasions during the three-quarters (75%) study of subjects in HSDD cohort were administered the testosterone gel formulation of the invention (0.15%, 0.45% or 0.6%): the first day at2000 hours, the second day, at 800 and 2000 hours and the third day, at 800 and 2000 hours. Intranasal gels were administered to both nostrils (1 syringe (100 μ l amount) per nostril). The first day, the remaining quarter (25%) of subjects were administered at 2000 hoursPatch, which will remain in the subject's lower abdomen during the study period. The patch was removed on day four and the subject was then discharged from the clinic.

Packaging and labelling

Study medication consisted of a testosterone gel formulation of the invention and a placebo gel of the testosterone gel formulation of the invention and was packaged in a disposable syringe designed to expel 100 μ l of gel. Two syringes were packaged in foil pouches. HSDD group Activity control-Remain in its original packaging from the manufacturer.

Treatment planning

The subjects were randomized into dosing regimens and received intranasal testosterone gel formulations of the invention (3 dose levels) or dispensed according to the following designPatch (HSDD), said dosing regimen being administered in a four day (three night) inpatient treatment phase:

a randomization protocol was generated for each study center, consisting of four treatment modules per group.

The study was a four day study. The study began with study drug administration between 2000 and 2100 hours on the first day (baseline). For plasma testosterone and dihydrotestosterone profiles, blood samples were drawn at-60, 0, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 and 480 minutes after the first and third day evening doses and at 0 and 60 minutes after administration (except for the delphinidin branches-no 60 minute morning draw on the second and third days) after the second and third day morning doses.

PD tests (computer tests) will be performed 30 minutes and 4.5 hours after the next morning dose (psychophysiological tests) and 30 minutes after the third morning dose for subjects assigned to the three testosterone gel formulations or placebo gels of the arm (arm) of the invention. The subject will experience a practical psychophysiological period prior to the first administration.

Because repeated nocturnal bleeding during the first night is not expected to allow the subject to fall asleep well, the sequence of psychophysiological testing and computer testing is not balanced. Computer tests are expected to be more negatively affected by insufficient sleep than psychophysiological tests. Therefore, psychophysiological testing was performed the next day and computer testing was performed on the third day. For being randomized toSubjects of the patch were subjected to psychophysiological testing between 800 and 900 hours on the third day, and then to computer testing between 1600 and 1700 hours in the afternoon on the third day.

Adverse events were assessed and reported.

Patient selection and withdrawal

The subject in this study was a female with HSDD. Subjects are recruited from medical practice or general populations by advertising in local newspapers and additional information available from the web. Before scheduling a screening visit, subjects were asked a series of standardized questions by telephone to assess whether they might be appropriate for the study.

Inclusion criteria

Female, up to 65 years old.

Post-menopausal women, initially diagnosed as HSDD at the screening visit, belonging to the generalized acquired category according to the DSM-IV criteria. The current disease stage must last at least 24 weeks at the screening visit. If co-morbid, secondary female sexual arousal disorder and/or female orgasmic disorder is permitted. This inclusion criterion was met only if HSDD started before female arousal and/or orgasmic female disorders and HSDD was more important to the subject at the discretion of the investigator.

·BMI<35。

Women must have an FSDS-R score >11 at screening visit, while the FSFI score < 26.55.

Women are in stable relationship for at least 12 months.

Female-estrogen/progesterone replacement (low dose combined ET/P) after physiological and surgical amenorrhea for at least three (3) months for study enrollment or no ET/P replacement after amenorrhea.

Normal thyroid function, physiological prolactin concentration.

Normal ear, nose and throat examination.

Provide written informed consent.

Exclusion criteria-HSDD

Any other clinically relevant psychiatric history that could affect sexual function, risk patient safety, or possibly affect compliance, as assessed by MINI. This includes bipolar depression, psychotic disorders, severe anxiety, eating disorders, socially-compromised personality disorders, and the like.

History of major depression within six (6) months prior to screening visit or a Becky Depression questionnaire II score ≧ 14.

A subject that meets DSM-IV criteria (APA) for the following diseases: sexual aversion disorder, substance-induced sexual dysfunction, dyspareunia (not caused by inadequate previous stimulus or alleviated by a lubricant), vaginismus, sexually-discriminating disorders, paraplegia, or sexual dysfunction due to a general medical condition.

A subject with a known acute pelvic inflammatory disease, urinary or vaginal infection/vaginitis, cervicitis, interstitial cystitis, vulvodynia, or marked vaginal atrophy.

Women, with dissonance of the relationship, as indicated by MMQ score > 20.

Treatment with systemic glucocorticoids.

With sex steroid hormones, such as androgens, estrogens or progestins other than low-dose combinations of ET/P (e.g., anabolic steroids, DHEA, beta-glucosidase, and beta-glucosidase,(conjugated equine estrogens)).

Treatment with thyroid hormones (only for stable replacement therapy).

Any type of severe intermorbidity, especially liver, kidney or heart disease, or any type of diabetes (subjects with antacids or with treated hyperlipidemia or treated hypothyroidism will not be excluded if they are stable in their drug dose for at least six months).

History of nasal disorders (e.g., seasonal or perennial allergic rhinitis, atrophic rhinitis, polyposis, nasal mucosal decongestant abuse, clinically relevant nasal septum deflection, recurrent nasal bleeding) or sleep apnea.

A subject with a history of: dementia or other neurodegenerative diseases, organic brain diseases, stroke, transient ischemic attacks, brain surgery, severe brain injury, multiple sclerosis, spinal cord injury, peripheral neuropathy and epilepsy (febrile seizures limited to childhood do not exclude subjects).

Cancer-excluding basal cell carcinoma-history.

A history of severe or multiple allergies, severe adverse drug reactions, or leukopenia.

Abnormal bleeding tendency or thrombophlebitis not associated with venipuncture or intravenous cannulation

The history of DVT.

History of hepatitis B, positive detection of hepatitis B surface antigen, history of hepatitis C, positive detection of hepatitis C antibody, history of HIV infection or presence of HIV antibody.

Recent history of severe sleep problems. The shift worker, prior to study enrollment, needs to have sufficient day and night rhythms for three weeks.

Regular drinkers, more than three (3) units of ethanol per day (1 to 300ml beer, 1 glass wine, 1 metric spirit).

Historical or current signs of alcohol abuse or abuse of any drug substance, legal or illegal; or positive urine and alcohol screening for drug abuse and alcohol.

Difficult to withdraw by OTC medication (except occasional paracetamol/aspirin) for the duration of the study.

Poor dependents, or subjects are unlikely to attend the study visit.

In this study, any drug was received within 30 days of initial dose administration as part of the study.

Donated blood (typically 550ml) in a 12 week period prior to the initial study dose.

Treatment object

Research visit

Visit 1 (day 15) -screening subjects for inclusion and exclusion criteria:

pre-study screening was performed within two (2) weeks before treatment initiation. After the informed consent was actively signed and before enrollment, subjects were interviewed by a clinical investigator or his/her assigned physician who received medical, sexual and physical medical records, recorded demographic data, and performed routine physical examinations including vital signs (blood pressure, resting heart rate, weight, and height).

Manage FSFI and FSDS-R as well as MMQ, BDI-II, IS, SIDI-II, and SESII-W.

Ear, nose and throat examinations were performed by ENT specialist doctors.

Venous blood was collected after overnight fasting for CBC (hemoglobin, hemoglobin A1c, hematocrit, MCV, MCHC, RBC, WBC, and differential), clinical chemistry profile (Na/K, glucose, urea, creatinine, total bilirubin, albumin, calcium, phosphate, uric acid, LDL, HDL, triglycerides, AST, ALT, ALP, GGT, and CK).

Venous blood samples were collected for estradiol, free testosterone (percent), follicle stimulating hormone, luteinizing hormone, prolactin, progesterone, sex hormone binding globulin, total testosterone and dehydroepiandrosterone sulfate.

Blood samples were obtained for TSH, total and free thyronine triiodide, total and free thyroxine.

Urine is collected for specific gravity, glucose, ketone, bilirubin, pH, urobilinogen, leukocytes, nitrite measurements.

Subjects also underwent hepatitis b, hepatitis c and HIV tests (hepatitis b surface antigen, hepatitis c antibody, HIV antibody in plasma).

Urine drug screening was performed against amphetamine, benzodiazepines, cannabinoids, cocaine, opiates, MDMA. Subjects with positive test results did not participate.

Screening for ethanol by breathalyzer.

Visit 2 (day one) -baseline onset, randomization, PK blood sampling and PD testing:

the subject was allowed to stay in the clinic for three nights in the afternoon.

Check-in to check for non-accepted medication (OTC and prescription), drugs, alcohol or cigarettes. Subjects were asked to abstain from alcohol for 48 hours before admission to the clinic. Alcohol consumption is strictly prohibited at any time during the overnight stay in the clinic. There was no restriction on food intake during blood collection for PK profiles.

Repeat urinalysis for the same drug abuse at screening.

Exclude pregnancy (if applicable) using a urine test.

Check vital signs (blood pressure, resting heart rate and body weight).

Draw blood for CBC, chemical profile, hormonal profile and pregnancy test.

Urine was collected for urinalysis and urine drug screening, with alcohol breath testing.

● Prior to administration and blood sampling, subjects underwent a psychophysiological familiarity test in which neutral and sexual activity films were displayed and VPAs recorded to familiarize with the test procedure and exposure to sexual stimulation of exposed bones. The data obtained were not used for analysis.

The venous cannula was placed in the forearm vein and blood sampling was initiated one hour prior to nighttime administration of study drug.

Subjects were dosed at 2000 and 2100 hours.

Blood samples were drawn at-60, 0, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 and 480 minutes post-administration for plasma testosterone and dihydrotestosterone levels.

Randomization of treatment regimens in this visit.

Record the security assessment.

Subjects remained in the clinic overnight.

Visit 3 (next day) -PK blood sampling:

obtain vital signs.

Collection of hormone profiles.

Subjects were given study medication between 800 and 900 and between 2000 and 2100 hours (except takingOther than that). Blood samples were drawn at 0 and 60 minutes post-administration for plasma testosterone and dihydrotestosterone levels. For takingThe object of (1), is extracted at time 0 between 800-.

Psychophysiological tests were performed 30 minutes and 4.5 hours after morning dosing for subjects assigned to the three testosterone gel formulations or placebo gels of the arm of the invention.

Record the security assessment.

Subjects remained in the clinic overnight.

Visit 4 (third day) -PK blood sampling and PD testing:

obtain vital signs.

Collection of hormone profiles.

Between 800 and 900 and 2000 and 2100 hours, subjects were given study medication (unless taken). 0 and 6 after administration of morning doseBlood samples were drawn for plasma testosterone and dihydrotestosterone levels at 0 minutes and at 0, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 and 480 minutes after administration of the evening dose. ReceivingThe subjects in the morning dose time 0 and all the time in the evening draw as if they received a new dose.

For subjects assigned to the three testosterone gel formulations or placebo gels of the arm of the invention, computer tests were performed 30 minutes after morning dosing. For randomization toThe female of the patch was subjected to psychophysiological testing between 800 and 900 hours on the third day. Computer testing was then performed between 1600 and 1700 hours in the afternoon on the third day.

Record the security assessment.

Visit 5 (fourth day) -off-center off:

physical examination, including vital signs.

Venous blood was collected after overnight fasting for CBC (hemoglobin, hemoglobin A1c, hematocrit, MCV, MCHC, RBC, WBC & differential), clinical chemistry profile (Na/K, glucose, urea, creatinine, total bilirubin, albumin, calcium, phosphate, uric acid, LDL, HDL, triglycerides, AST, ALT, ALP, GGT and CK).

Appropriate blood samples were collected for estradiol, free testosterone (percent), follicle stimulating hormone, luteinizing hormone, prolactin, progesterone, sex hormone binding globulin, total testosterone and dehydroepiandrosterone sulfate.

Urine is collected for specific gravity, glucose, ketone, bilirubin, pH, urobilinogen, leukocytes, nitrite.

·The patch is removed (when appropriate).

Record the security assessment.

Clinical evaluation

Screening and covariate questionnaires were used for clinical evaluation.

BDI

To index the current level of depression, 21-items of BDI-II (Beck, Steer, & Brown.1996), Dutch adaptation (Van der Does,2002) were managed. The overall BDI score ranged from 0-63, with higher scores indicating more depressive disorders.

MMQ

Maudsley Marital questingnaire (MMQ; crown, 1978) is a 20-item self-reporting tool that measures dissatisfaction with general relationships, sexual relationships, and with overall life. MMQ has shown good reliability and correctness. The netherlands version of MMQ was also found to be of satisfactory quality for psychometric measurements (Arrindell, Boelens, & lambert.1983). A higher score represents greater satisfaction.

FSFI

Female sexual function levels are assessed by female sexual function index (FSFI; Rosen, Brown, Heiman, et al, 2000).Is a self-administered questionnaire consisting of 19 questions. The components contain six domains: desire, arousal, lubrication, orgasm, satisfaction, and pain. The overall score ranged from 2-36, with lower scores representing poor sexual function. The FSFI psychometric quality is satisfactory (Wiegel, Meston,&rosen.2005). The intrinsic consistency and stability of FSFI was found to be due to Dutch samples consisting of approximately 350 women with or without sexual complaintsThe people satisfied well. The ability of FSFI to distinguish between sexually functioning and dysfunctional women is outstanding, as is the ability to predict the presence or absence of complaints (ter Kuile, Brauer,&Laan, 2006)。

FSDS-R

the level of female personal distress due to sexual dysfunction is assessed by a revised female sexual disturbance scale (Derogatis, Clayton, Lewis-D' Agostino, et al, 2008).

The items ask negative emotions and questions that were perplexing or causing distress over the past 30 days.The reliability and correctness of (12-project version) has been evaluated in different samples of women with sexual function and sexual dysfunction. For theThe results show a one-dimensional factor structure, high intrinsic consistency and test-retest reliability. In each of its three confirmatory studies,both show a high degree of discrimination between sexual dysfunction and sexually functioning women. The results of the dutch sample support the one-dimensional structure of FSDS and its reliability and psychometric correctness (ter Kuile, Brauer,&laan, 2006). Additional questions (question 13) have been added to the acknowledgementThe problem relates to distress, especially those related to sexual desire. Indicating greatest horizontalityThe maximum total score is '52'.Both the total score and the individual question 13 scores were analyzed.

Sexual satisfaction Index (ISS)

Female sexual satisfaction levels were assessed by the sexual satisfaction index (ISS; Hudson, Harrison, & Crosscup.1981). The 25-item questionnaire required subjects to evaluate various aspects of their sexual relationships, resulting in a total score ranging between 0 and 100. A higher score corresponds to greater sexual satisfaction. This metric has been shown to have good face (face), convergence (convergent), and discrimination correctness for various samples. Example items are "i feel my partner enjoy our sexual life", "i think that sex is wonderful" and "my partner is very sexually exciting". For the purposes of the present study, the ISS is translated into Dutch.

SDI-II

Female sexual desire levels are assessed by the sexual desire list-II (SDI-II; Spector, Carey, & steinberg.1996) SDI-II consists of two seven-item self-reporting scales, a two-entry sexual desire scale, which measures the individual's desire for sexual activity on a partner, and an individual sexual desire scale, which measures the individual's desire for sexual activity on an individual basis, the two sub-components are essentially identical (Cronbach's α: the two-entry component is 0.86; the individual component is 0.96).

Sexual excitation/inhibition (SESII-W)

The female sexual suppression/excitement catalog (SESII-W; Graham, Sanders, & Milhausen.2006) was used to assess individual preferences for sexual excitement and sexual suppression. It consists of 36 items, involving either stimulation situations that affect sexual suppression and excitement or general statements about arousal ability and suppression. Instructions to ask women to report what the most typical reactions will now be or if the project is not suitable for them, they think they will do what reactions. Items were ranked according to the 4-point Like's rating Scale, from "strongly disagreeable" to "strongly agreeable". SESII-W has 8 lower order factors, which in turn belong to the two higher order factors, sexual excitation and sexual suppression. The questionnaire showed good test-retest reliability and convergence and discrimination correctness, and sexual excitation and sexual suppression appeared to be relatively independent factors. The list has been used in the netherlands, but the psychometric properties have not been studied.

Potency pharmacokinetic testing

Computer testing

Single target implicit association task (StIAT):

conform wigbold et al (2005), the stIAT used in this study was designed to assess the emotional association of subjects to sexual stimuli (filed by Brauer, van leewen, Janssen, et al). The subject is instructed to classify the pictures depicting sexual activity (i.e., target stimuli) and the wording representing "positive" or "negative" meaning (i.e., attribute stimuli) into the appropriate upper categories (i.e., "sex," "positive," "negative") as quickly as possible by simply pressing the left or right answer keys on the keyboard. These labels for these categories (sexual, active, passive) are continuously visible on the computer screen. The stIAT consists of practice and test modules (for a detailed method, see Greenwald, McGhee & schwartz. 1998). The test module consists of one 'inconsistent' and one 'consistent' module of the test. In the inconsistent module, "negative" and "positive" are mapped to a single key and "positive" is mapped to other keys, while in the consistent module "negative" and "positive" are mapped to the same key and "negative" is mapped to other keys. The difference in reaction time between the two test modules is assumed to correlate more strongly with positive or negative reactivity. Faster responses in the consistent modules (as compared to other modules) reflect a stronger connection between positive and negative, while faster responses in the inconsistent modules reflect a stronger connection between negative and positive. The object-property combinations of the common reply key (i.e., module commands) compete against the left or right key answer requirements. Each key module consists of 40 trials, where the answers are evenly divided over the two answer keys. The object class consists of example stimuli of 5 sexual images from the International emotional Picture System (IAPS; center for research on emotions and attention, 1995) with the following numbers: 4800. 4652, 4658, 4659, and 4672. The attribute categories consist of 20 generally positive and 20 generally negative terms (Dotsch & Wigboldus, 2008; Dotsch, Wigboldus, Langner, et al, 2008), reflecting a more comprehensive emotional association. The length and frequency of these words are controlled. In terms of correctness, the amount of force of the stIAT lies in the efficient size (size), since the dual opposite categories often result in slower reaction times (the categorization decision requires effort, as there are several possibilities to consider).

Picture Association Task (PAT)

This task was developed by van Leeuwen and Macrae (2004), which initiates tasks based on emotion (e.g., Bargh, Chaiken, Govender, et al, 1992; Fazio, Sanbonmatsu, Powell, et al, 1986; Hermans, DeHouwer, & Eelen,1994) where target wording occurs after other wording or images that affect the classification of target wording. However, in PAT, the target word and the image appear at the same time. In PAT used in this study, subjects were presented with positive or negative words appended in neutral pictures or neutral pictures (filed by Brauer, van leewen, Janssen, etc.). Instructing them to classify the wording as positive or negative as soon as possible by pressing one of the two computer keys. The subject is also instructed to note the words appearing on the screen and not the background images, since these are not important for the task, and the category (sexual, neutral) to which the pictorial stimuli belong is not illustrated. Thus, PAT captures the unintentional impact of emotional value on picture background stimuli on task performance. The time to select the correct answer to the word (positive or negative) is influenced by the match between the word valence and the background image valence (neutral or neutral), thus indirectly revealing the subject picture valence. The wording category consists of 10 active words and 10 passive words. However, general positive and negative terms (e.g., peace, respect, war, hate) are selected for stIAT, and PAT consists of such positive and negative terms: it applies to sexual situations but does not exclusively relate to sexual experience (e.g. pleasant, wonderful, dirty, nausea) to produce a conceptual overlap between word satisfaction and satisfaction triggered by sexual pictures. These terms were taken from an experimental study in the netherlands, where female subjects (N ═ 20) were asked to show how well each positive and negative term described a positive or negative situation, respectively, according to a 7-point leke component (Brauer & Laan, 2008). The wording appears in one of four random positions on the image to avoid expecting relevant answers and to ensure that the subject will move their eyes on the image. Sexual pictures were taken from another study on implicit associations to sexual stimuli in women with dyspareunia (Brauer, de Jong, Huijding et al, 2009). These pictures show various sexual acts (e.g., kissing, licking, oral sex, intercourse). On a per sexual picture basis, a control picture is generated by disorganizing sequential imagery (sexual images), leaving neutral stimuli behind. All pictures were normalized to 600 × 480 pixels and made the same brightness and contrast. Each stimulus remains on the screen until the subject makes a decision or until after 3,000 ms. After 10 practical trials, 80 experimental trials were presented. Each spoken word was randomly paired with a neutral picture and a neutral picture, resulting in four different combinations, each occurring 20 times: positive words and sexual images, negative words and sexual images, positive words and neutral images, and negative words and neutral images. The order of trial presentation competed among subjects, and the answer key mapping (i.e., positive/negative or negative/positive) competed among subjects. The computer records the accuracy and latency of each answer. For correctness, PAT has the advantage that it is insensitive to possible explanation biases, since different stimulation classes need to be addressed at the same time, as in stIAT.

Point exploration task (DOT)

The point detection task (DOT) assesses attention preferences for sexual and neutral visual stimuli. In this task, two side-by-side images are displayed to the subject on the computer screen for 500 ms. When both images disappear, the target stimulus represented by a small dot appears at the position of one image. The object is required to indicate the position of a point (side). The average RTs is calculated for three classes: 1) neutral 2) neutral and neutral point 3) neutral and neutral point. The response time is faster when the point appears at the location of certain types of stimuli, which indicates a preference for attention for that type of stimulus.

Psychophysiological testing

Genital reaction (VPA)

The psychophysiological test consists of: evaluation of genital response (vaginal pulse amplitude) and targeted sexual arousal during sexual and self-induced sexual desire fantasy (3min), low intensity sexual desire movie clips (5min) and high intensity sexual desire movie clips (5min) (lan et al, in preparation). Sexual desire conditions are separated by different inter-stimulus intervals during which the subject completes the task of interest (a simple arithmetic problem) to allow return to baseline. The sexual stimulation test was preceded by an 8min neutral movie to establish baseline levels. VPA was measured using a vaginal photoplethysmograph developed by Bert Molenkamp (psychology technical support of the university of amsterdam) based on an instrument originally developed by Sintchak and Geer (1975). The mass production of the light source (3mm led, λ 620nm) and optical sensor (Texas Instruments TSL250) at 100 led to almost equal electronic characteristics for all photoplethysmographs used in this study. The signal conditioning amplifier separates the VPA from the dc component using a 12 dB/octave, 0.7-Hz filter. Additional filtering for VPA was 24 dB/octave, 0.4Hz high pass. The VPA signal was digitized at 100Hz by a Keithley KPCI3107A/D converter running on a Windows 2000PC system. The probe depth and light source direction were controlled by a device (9-x2-cm FDA-approved plexiglas plate) connected to the cable within 5cm of the optical sensor. The subject is instructed to insert the probe until the plate contacts its labia. The probe and plate were sterilized according to standard protocols.

Sexuality and emotion (SAQ).

Before and immediately after sexual desire stimulation, subjects filled out a questionnaire measuring the feelings of sex and emotion during sexual stimulation, consisting of 5 components: sexual arousal (Cronbach's α ═ 0.87), genital sensation (Cronbach's α ═ 0.96), good colour (Cronbach's α ═ 0.73), positive feelings (Cronbach's α ═ 0.93), and negative feelings (Cronbach's α ═ 0.65), each question appeared after the following sentence: "i felt during movie", after which positive, negative, body or sexual experiences are described, e.g. pleasure; genital pulsation or beating; sexual arousal, component measures from 1 (not at all) to 7 (intense).

Acute Female Sexual Desire (AFSDQ)

Subjects filled out an acute female libido questionnaire (Laan, Heiman, unpublished) before and after psychophysiological testing. The questionnaire assesses interest in sexual stimulation and has been shown to distinguish women with acquired HSDD from sexual-functional controls (Laan et al, in preparation).

Statistical method

Calculation of drug metabolism parameters

·C_min、C_maxAnd t_maxTaken from actual measurements. Measured relative to the time of testosterone administration in the treated subject.

Area under the concentration curve (AUC) was evaluated for the 0 to 24 hour time interval and BID dosing interval using the trapezoidal theorem.

The testosterone gel formulation and placebo of the invention after the first evening dose and the testosterone gel formulation, placebo and placebo of the inventionPK assessment-AUC, total and free testosterone, DHT, estradiol, SHBG concentrations after the third day evening dose of the patch (which was applied on the first day). Analysis C_avg、C_min、C_max、t_max、 AUC_0-tPTF and PTS. C for a 12 hour period and τ is calculated at the appropriate time_avg. For takingThe subject of (1), was calculated for 24 hours.

The mean concentration (C) in the dosing interval was calculated from AUC using the following formula_avg)：C_avg＝AUC_0–τAnd/τ, where τ is the dosing interval.

Peak-to-valley fluctuation (PTF) and peak-to-valley steering (PTS) are calculated as follows:

ο PTF＝(C_max-C_min)/C_avg

οPTS＝(C_max-C_min)/C_min

calculate the percentage of time plasma testosterone concentrations above, within and below the reference range of 10 to 70 ng/dl.

Statistical analysis of pharmacodynamic data

stIAT：

Incorrect responses were excluded from the analysis. In addition, RT shorter than 300ms or longer than 3000ms was excluded from the analysis. For the stIAT data, according to wigbold, Holland & van knipenberg (2005), because for each object, median reaction latency to correct reaction of property items in consistent and inconsistent modules is applied. After this, the median reaction times of the two test modules were subtracted from each other to obtain the stIAT effect (i.e. the stIAT effect is median (sexual/passive) -median (sexual/active)). The negative stIAT effect indicates a negative association with a relatively strong sexual stimulation.

The stIAT effect was analyzed by analysis of variance, treated by fixed factor, group (HSDD and SA) and by group interaction. Controls were calculated within the model.

PAT：

The median response latencies for correct responses were calculated from van Leeuwen and Macrae (2004). To correct for the baseline response to positive and negative words, a difference score is calculated by subtracting the RTs of the neutral words appended to the sexual picture from the positive words appended to the sexual picture. The same applies to the negative words appended to the neutral and neutral pictures (i.e., negative/positive RT-RT and negative/neutral auto-positive association of negative/positive).

Two PAT variables (RT positive and RT negative) were analyzed by analysis of variance with fixed factor treatment, group (ANOR) and group by treatment. Controls were calculated within the model.

DOT：

For each subject, the difference between the average RT for class neutrality, where the point is below neutral, and the average RT for class neutrality, where the point is below neutral, is calculated to obtain the DOT effect (i.e., DOT effect-average neutrality of points below neutral). A higher DOT score indicates a relatively stronger concern for sexual stimulation.

DOT effects were analyzed by analysis of variance, by fixed factor treatment, by group (ANOR) and by group interaction treatment. Controls were calculated within the model.

VPA：

After VPA manual deletion, performed by a computer program developed by Bert Molenkamp (psychology technical support of the university of amsterdam), the peak-to-valley amplitude of each remaining pulse was calculated. VPA was averaged every 30 seconds in several cases: neutral movies (8min), self-induced sexual desire fantasy (3min), low-intensity sexual desire movie clips (5min), and high-intensity sexual desire movie clips (5 min). All conditions are provided twice: once 0.5 hours after administration of the nasal gel and once 4.5 hours after administration of the nasal gel.

VPA during sexual desire fantasy, low intensity movies and high intensity movies were analyzed separately and at different times (0.5 hours post-dosing and 4.5 hours post-dosing) to yield 6 analyses. VPA during the situation and time is analyzed with a mixed variance analysis model by fixed factor processing, group (ANOR), time, group by processing, processing by time, and random factor objects, and with the average VPA score during the neutral movie as covariate. Controls were calculated within the model.

SAQ：

For each of the five SAQ components, the average response during the condition and time of day was analyzed by analysis of variance with factor treatment, group (ANOR), group by treatment, with scores before sexual stimulation as covariates. Controls were calculated within the model.

AFSDQ：

ASFDQ scores after sexual stimulation during the time period were analyzed by analysis of variance with factor treatment, group (ANOR), group by treatment, and score before sexual stimulation as covariates. Controls were calculated within the model.

The data is logarithmically transformed if necessary to meet the requirements of analysis of variance. The results were back-transformed and reported as% change.

A graph of the least squares mean estimate over the processing time is presented with error bars representing 95% confidence intervals for the upper and lower limits of the highest and lowest lines (profile), respectively. The least squares means of the controls are tabulated.

If it is not feasible to perform an analysis according to the described model with the given data, the analysis is adjusted. If deemed useful, additional exploratory analysis is performed.

Statistical analysis of security data

And (4) presenting nasal tolerance data in a summary table. Statistical analysis will not be performed.

Vital signs and clinical laboratory parameters:

tables summarizing all laboratory test values and changes from baseline are presented for each treatment group. The clinical significance of these results was evaluated with the parameters at ± 20% of their reference ranges.

The results of this analysis are presented in fig. 2, 3 and 7-8. Figures 3 and 9-11 show or compare the results between the effects of testosterone gel nasal formulations of the invention on subjects diagnosed with anorgasmia or HSDD.

Example 9

Drug metabolism ("PK") and drug efficacy ("PD") studies in 53 anorgasmic women and three different testosterone bioadhesive gel formulations of the invention (by weight of the gel formulation)0.15% -, 0.45% and 0.6% testosterone, as per example Examples 1 to 5 reported)

The target is as follows:

as shown in figure 14, the PK and PD studies evaluated serum testosterone drug metabolism profile and pharmacodynamic response, which measured vaginal pulse amplitude ("VPA") in women with anorgasmia compared to placebo after single dose administration of each of the testosterone bioadhesive gel formulations of the present invention (0.15% -, 0.45% and 0.6% testosterone by weight of the gel formulation, as reported in examples 1-5).

The method comprises the following steps:

a total of 12 women with anorgasmia (n-12) were included in the placebo and active comparator PK and PD studies. Each woman received four different single intranasal doses, 100 mul per nostril, on four different days, administered by unit dose syringe (i.e., each of the 12 women in this study received either a TBS-2 high dose (1.2 mg-0.6% testosterone-0.6 mg by weight/100 μ l/nostril), a TBS-2 medium dose (0.9 mg-0.45% testosterone-0.45 mg/100 μ l/nostril) or a TBS-2 low dose (0.3 mg-0.15% testosterone-0.15 mg/100 μ l/nostril) and a placebo TBS-2 (anorgasmia group), frequent PK serum samples were collected from each woman during the first 12 hours after intranasal dose administration.

As a result:

PK results show that plasma testosterone levels increase with increasing dose levels. See fig. 14. The mean plasma testosterone concentrations 0-12 hours after administration were: (a) TBS-2 high dose (1.2 mg-0.6% testosterone by weight-0.6 mg/100 μ Ι/nostril) -about 70ng/dL after about the first 100 minutes of administration, about 50ng/dL after about the first 250 minutes of administration, and about 40ng/dL after about 350 minutes of administration and thereafter; (b) TBS-2 medium dose (0.9 mg-0.45% testosterone by weight-0.45 mg/100 μ Ι/nostril) -about 55 ng/dL after about the first 25 minutes of administration, about 35ng/dL after about the first 250 minutes of administration, and about 35-30ng/dL after about 350 minutes of administration and thereafter; and (c) TBS-2 low dose (0.3 mg-0.15% testosterone by weight-0.15 mg/100 μ l/nostril) -about 28ng/dL after about the first 100 minutes of administration, about 23ng/dL after about the first 250 minutes of administration, and about 20ng/dL after and about 350 minutes of administration.

Testosterone C of Testosterone after Single dose administration, three TBS-2 dose strengths_maxAnd C_avgNone exceeded normal testosterone serum levels in women (3-80 ng/dL).

For all TBS-2 dose intensities, testosterone levels returned to baseline after single dose administration.

For the PD aspect of the study, there were favorable statistically significant differences in female VPA responses at 0.5 hours and 4.5 hours post-dosing for each of the control placebo TBS-2 dose strengths.

And (4) conclusion:

it is presently believed that the nasally applied testosterone bioadhesive gels of the present invention (i) can be administered independently when needed, i.e. on demand, (ii) have desirable safety, i.e. exhibit no androgen-related side effects, low testosterone drug loading and (iii) do not present the risk of testosterone transfer.

Example 10

Shaking stimulus study of 56 women with anorgasmia ('VTS')

The target is as follows:

single dose of high dose TBS-2(1.2 mg-0.6% testosterone by weight-0.6 mg/100 μ l/nostril as reported in examples 1-5) was evaluated for the effect on orgasm at 0.5, 2.0, 4.0 and 8.0 hours after dose administration in 56 women with anorgasmia. Other objectives of this study were to evaluate the time to achieve orgasm and the quality of orgasm after intranasal administration of TBS-2. In addition, the objective of this VTS study was to determine the effect of high doses of TBS-2 on arousal, well-being and genital irritation and to assess safety. See fig. 15.

The method comprises the following steps:

the VTS study was a single-center, randomized, single-blind, placebo-controlled, five-pronged parallel group study using shock stimulation in combination with visual stimulation (n-56). See fig. 15.

According to this VTS study protocol, each woman was administered an intranasal single high dose of TBS-2(1.2 mg-0.6% testosterone by weight-0.6 mg/100. mu.l/nostril).

The demographic characteristics of this VTS study are as follows, see fig. 15:

59 women randomized, 56 completed the study

All 3-bit exit-midway due to violation scheme

Mean age 27.8 years

87.5% Primary anorgasmia, 12.5% Secondary anorgasmia

All randomized subjects met the entry criteria for marital quality and depression

3% of patients (3 of 97) were excluded due to orgasm at visit 2

As a result:

as shown in figure 16, more women treated with high dose TBS-2 reported orgasm compared to placebo. In fact, women treated with high dose TBS-2 reported a total of 8 orgasms compared to those receiving placebo without orgasm during the post-4 week treatment period. With respect to the treatment period, women treated with high dose TBS-2 reported a total of 4 orgasms compared to those receiving placebo for 2 orgasms. See fig. 16.

Additional VTS findings and findings include:

the time to achieve orgasm after high dose TBS-2 administration ranged from 12.17 minutes to 18.22 minutes;

women given TBS-2 reported more pleasurable and stronger orgasm than those given placebo;

more TBS-2 women reported high arousal compared to placebo (83.3% versus 16.7%). See fig. 17 and 18;

TBS-2 women reported more libido (AFSDQ score). See also fig. 17 and 18;

for TBS-2, a positive response to stimulation is more pronounced. See FIG. 18;

as reported in example 9, there was a statistically significant difference (mean change from baseline) in VPA between TBS-2 high, medium and low doses and placebo;

increase in overall testosterone levels to the upper normal limit (average about 66.7 ng/dL);

mean free testosterone levels of about 6.35pg/mL (long-term treatment reaches about 3.1-4.0 pg/mL);

other findings-patient feedback

(a) Women prefer home environment

(i) The mind of experimenters about hospital environment makes the hospital environment distracted

(ii) Is still slightly tense due to the environment

(iii) Good environment of home

(iv) More relaxed at home

(v) Due to location, there is some limitation in activity

(b) Partner engagement is important for some women

(i) Will be better with real life partners

(ii) For his (partner) not being there to be creditable

(iii) It is better in the presence of male

Safety:

absence of serious adverse events

A total of 18 adverse events were reported

(i) Not severe and resolved at the end of the study

(ii)5 were not related to study medication

(iii)3 due to unknown etiology (probably related)

(iv) Independent of active treatment and adverse events

(v) Comparison of 19.1% TBS-2, placebo allows 50% of women to report adverse events

No differences in the results of endocrinology (SHBG, albumin, hemoglobin)

Conclusion

Sufficient clitoral stimulation alone is insufficient to treat anorgasmia

Data from examples 10 and 11 indicate the success of TBS-2 pharmacological intervention plus effective stimulation

TBS-2 data indicates a positive response between 2 and 8 hours after dosing

TBS-2 is thought to elicit and enhance a female sexual response when administered prn

TBS-2 is believed to maintain total and free testosterone levels within the normal range

TBS-2 was considered safe and no adverse events were observed as commonly observed with chronic testosterone treatment

Comfortable environment (home environment) and partner interaction may play a role in achieving orgasm

Example 11

1. Topic of questions

Intranasal Testosterone gel (TBS-2) at three dosage levelsOpen label, sheet in healthy premenstrual female subjects One and multiple applications

2. Summary of the invention

The primary objective was to assess the bioavailability of total testosterone by a drug metabolism (PK) profile obtained after single administration of TBS-2 at doses of 600 μ g, 1200 μ g and 1800 μ g for intranasal application and multiple administration of TBS-2 at 1200 μ g-three times a day (t.i.d.), for 3 days. TBS-2 is a bioadhesive intranasal testosterone gel.

The second objective was to assess the bioavailability of free testosterone, dihydrotestosterone, Sex Hormone Binding Globulin (SHBG) and estradiol, and to assess the safety of TBS-2, by a PK profile obtained after a single administration of TBS-2 at doses of 600 μ g (0.24%), 1200 μ g (0.48%) and 1800 μ g (0.72%) for intranasal application and multiple administrations of TBS-2 at 1200 μ g (0.72%) for three days (first two days t.i.d., and once in the morning on the third day).

A.Method of producing a composite material

This is a phase 1, single-center, randomized, open label parallel group study designed to evaluate the safety, tolerability, and PK of TBS-2 in women with normal healthy cycles. Subjects were randomly assigned to one of 3 treatment groups (group 1, group 2 or group 3) on a 1:1:1 basis at time period 1 and administered a single dose of intranasally applied TBS-2 at doses of 600 μ g, 1200 μ g or 1800 μ g (single doses of 300 μ g, 600 μ g and 900 μ g per nostril). At the end of period 1, a total of 8 subjects from these 3 cohorts were selected as samples, and subjects willing and able to continue the multi-dose portion of the study were selected to participate in period 2. In period 2, subjects were administered 1200 μ g TBS-2(600 μ g/nostril), t.i.d. for two days and once in the morning on the third day. Subjects were screened for eligibility up to 3 weeks prior to period 1 dosing (visit 1) and were admitted to a Clinical Research Unit (CRU) at 0700 hours the day prior to dosing (visit 2, day one). On the next day, subjects were administered a single dose of TBS-2, which remained in the CRU for 72 hours after dosing (fourth day) for safety monitoring and PK assessment. In period 2, subjects were admitted to the CRU at 0700 hours on the day of dosing (visit 3, day one). On days 1 and 2, TBS-2 was administered to the subjects at 0800 hours (+ -30 minutes), 1600 hours (+ -30 minutes), and 2400 hours (+ -30 minutes). On the third day, at 0800 hours (+ -30 minutes), TBS-2 was administered to the subjects.

In phase 1, blood samples for determination of baseline testosterone (free and total), SHBG, Dihydrotestosterone (DHT) and estradiol concentrations were collected on day 0745 hours first, then at 15, 30 and 45 minutes and at 1, 1.5, 2, 4,6, 8, 12, 16, 20 and 23.5 hours versus 0800 hour clock time. Blood samples for determination of testosterone (free and total), SHBG, dihydrotestosterone and estradiol plasma concentrations were collected during the restriction period, on the second day (15, 30 and 45 minutes and 1, 1.5, 2, 4,6, 8, 12, 16 and 20 hours post-administration) and on the third day (24, 32, 40 and 48 hours post-administration).

In phase 2, blood samples were collected at 0745 hours (i.e., 15 minutes prior to study drug administration) for baseline testosterone (free and total), SHBG, DHT and estradiol concentrations. Blood samples were collected for the determination of testosterone (free and total), SHBG, dihydrotestosterone and estradiol concentrations during the first day (predose [ 15 minutes prior to administration ] and at 1545 and 2345 hours), the second day (1545 and 2345 hours), the third day (15, 30 and 45 minutes and 1, 1.5, 2, 4,6, 8, 12, 16 and 20 hours) and the fourth day (24, 32, 40 and 48 hours) during the restraint period.

Other assessments performed in the study included monitoring of Adverse Events (AEs), clinical laboratory assessments (chemistry [ including hormone profiles ], hematology and urinalysis), vital sign assessments (systolic and diastolic blood pressure [ BP ], heart rate [ HR ], respiratory rate [ RR ] and body temperature), and physical examination. In addition, otorhinolaryngological examination results, 12-lead Electrocardiogram (ECG) readings, medical history and concurrent medication applications were recorded.

B.Number of objects (planned and analyzed))

Planning to be used: a total of 24 objects are scheduled for enrollment.

Registering: a total of 24 subjects were enrolled and randomly assigned to treatments in session 1: 8-bit objects in group 1, 8-bit objects in group 2, and 8-bit objects in group 3. A total of 8 subjects were taken from these 3 cohorts as samples, and subjects willing and able to continue the multi-dose portion of the study were selected to participate in period 2.

And (3) analysis: all 24 subjects were included in the security analysis and 24 subjects were included in the PK analysis.

C.Major criteria for diagnosis and enrollment

The study included healthy, normal-cycle premenstrual women between the ages of 18 and 40 years (including 18 and 40 years) with a Body Mass Index (BMI) of 18.5 to 35kg/m²(including 18.5 and 35kg/m²) Meeting all inclusion criteria and not meeting any exclusion criteria and providing informed consent.

D.Test product, dosage and administration mode, batch number

TBS-2 used in this study was an intranasal testosterone gel provided in a pre-filled dispenser with 0.24% testosterone gel, 300 μ g of testosterone per nostril (group 1), 0.48% testosterone gel, 600 μ g of testosterone per nostril (group 2[ single dose ] and multiple dose groups) and 0.72% testosterone gel, and 900 μ g of testosterone per nostril (group 3). TBS-2 drug substance combinations used in this study were IMP11008, IMP11009 and IMP 11010.

The composition of the three different concentrations of drug product to be used in this clinical trial is provided in the CMC section below and in table 3.2. p.1-1-3.

E.Duration of treatment

The study involved 1 session of cohorts 1, 2 and 3, and the duration of individual subjects from the start of screening until the study visit participation was approximately 25 days. The study included two periods, totaling 30 to 36 days for the multiple dose group.

F.Evaluation criteria

Safety: safety was assessed throughout the study, including monitoring AEs, clinical laboratory evaluations (chemistry [ including hormone profiles ], hematology and urinalysis), vital signs and 12-lead ECG. Physical and otorhinolaryngological examinations were performed and history and concurrent medication was recorded.

Drug metabolism: whole blood samples were collected at designated time points for determination of plasma concentrations of testosterone (free and total), SHBG, DHT and estradiol. The actual sampling time points were recorded and used for PK calculations. Testosterone (free and total), S, for all subjects were calculated by standard non-compartmental (standard non-compartmental) methods when data allowedDrug metabolism parameters of HBG, DHT and estradiol. PK parameters assessed for plasma concentrations of testosterone (free and total), SHBG, dihydrotestosterone and estradiol after single dose cohort (cohorts 1, 2 and 3) included the area under the plasma concentration time curve from time zero to the last measurable concentration time point (AUC)_0-t) Area under plasma concentration time curve from time zero to infinity (AUC)_0-∞) Maximum concentration observed after administration (C)_max) Observed with respect to the time of administration C_maxTime (t) of_max) Final cancellation rate constant (λ)_z) And elimination half-life (t)_1/2). PK parameters assessed for plasma testosterone (free and total), SHBG, dihydrotestosterone and estradiol concentrations after multiple dose cohort included the area under the concentration-time curve from time zero to dosing interval (AUC)_0—τWhere τ is 8 hours), C_max、t_maxMinimum concentration in dosing intervals during multiple dosing (C)_min) Predose concentration (C) measured immediately before the dose is at steady state_pd) Average steady state concentration (C)_avg) % peak-to-valley fluctuation (PTF) and% peak-to-valley diversion (PTS).

G.Statistical method

This study evaluated PK properties as well as TBS-2 safety and tolerability. No power calculations were performed. The sample size of the study was not determined based on statistical hypothesis testing. Based on typical early PK studies, groups of 8 subjects per group provided sufficient clinical information to reach the study goals. Data were summarized by using descriptive statistical analysis (sample size, mean, median, standard deviation [ SD ], minimum and maximum) for each safety variable in treatment groups and overall. The data for all visits during the study are presented in a data list.

Concentration-time data for 5 analytes (testosterone [ total and free ], SHBG, dihydrotestosterone, and estradiol) were determined by validated assays and PK parameters were calculated. The actual sampling time points are recorded and used to calculate the time actually elapsed from dose to sampling for PK calculations. Because each administration is to each nostril, the time of administration is the time of administration to the first nostril. After pre-dose administration prior to calculation of PK parameters, the baseline analyte concentration for the pre-24 hour dose profile was subtracted from the time-matched analyte concentration.

Individual PK parameters were evaluated for each subject profile in the PK cohort by using winnonlin (pharsight corporation) and displayed in a data list. By using descriptive statistical analysis (mean, SD,% coefficient of variation [ CV ]]Confidence Interval (CI), median, minimum and maximum) summary data and are shown by treatment groups. Geometric means are included for AUC and C_maxEvaluated, and included for some other PK parameters. By making use ofMedium Generalized Linear Model (GLM) program, parameter AUC for Natural Log (ln) transformation_0-t、AUC_0-∞、AUC_0-τ、C_avgAnd C_maxAnd for the unconverted parameter t_1/2And λ_zAnalysis of variance (ANOVA) was performed with a significance level of 0.05. Calculation of AUC by Using ANOVA residuals_0-t、AUC_0-∞、AUC_0-τAnd C_maxThe intra-subject CV of (a).

Dose linearity after single dose administration (period 1) in AUC_0-t、AUC_0-∞And C_maxThe natural log transformation was then evaluated.

The following period 1 comparisons were made for PK parameters:

comparison 1:600 μ g (0.24%) TBS-2 vs 1200 μ g 0.48% TBS-2;

comparison 2:600 μ g (0.24%) TBS-2 vs 1800 μ g 0.72% TBS-2;

comparison 3: 1200. mu.g (0.48%) TBS-2 vs 1800. mu.g 0.72% TBS-2.

3. List of charts

Table 91: study plan

Table 92: drug metabolism sample collection plan

Table 111: medical history (Single dose group)

FIG. 19: mean corrected free testosterone concentration (single dose group)

FIG. 20: mean corrected total testosterone concentration (single dose group)

FIG. 21: mean corrected dihydrotestosterone concentration (single dose group)

FIG. 22: mean corrected estradiol concentrations (single dose group)

FIG. 23: average corrected SHBG concentration (single dose group)

FIG. 24: mean observed free testosterone concentration (single dose group)

FIG. 25: average observed Total Testosterone concentration (Single dose group)

FIG. 26: average observed Dihydrotestosterone concentration (Single dose group)

FIG. 27 is a schematic view showing: mean observed estradiol concentrations (single dose group)

FIG. 28: average observed SHBG concentration (single dose group)

FIG. 29: mean free testosterone plasma concentration (multiple dose group)

FIG. 30: mean total testosterone plasma concentration (multiple dose group)

FIG. 31: mean dihydrotestosterone plasma concentration (multidose group)

FIG. 32: mean estradiol plasma concentration (multiple dose group)

FIG. 33: mean SHBG plasma concentration (multiple dose group)

FIG. 34: spaghetti concentration curves were plotted against the mean of free testosterone plasma concentrations (multiple dose groups)

FIG. 35: spaghetti concentration curves were plotted using the mean of total testosterone plasma concentrations (multiple dose group)

FIG. 36: spaghetti concentration curves were plotted using mean dihydrotestosterone plasma concentrations (multiple dose groups)

FIG. 37: spaghetti concentration curves were plotted using mean values of estradiol plasma concentrations (multiple dose groups)

FIG. 38: spaghetti concentration curves (multiple dose groups) were plotted using the mean values of SHBG plasma concentrations

Table 1122: free testosterone summary (Single dose group)

Table 1123: total testosterone summary (Single dose group)

Table 1124: dihydrotestosterone summary (Single dose group)

Table 1125: estradiol summary (Single dose group)

Table 1126: SHBG summary (Single dose group)

Table 1127: free testosterone summary for multiple dose profiles (multiple dose group)

Table 1128: free testosterone concentration at baseline (single dose group)

Table 1129: total Testosterone summary for multiple dose profiles (multiple dose group)

Table 1130: total testosterone concentration at baseline (single dose group)

Table 1131: summary of Dihydrotestosterone for multiple dose profiles (multiple dose group)

Table 1132: dihydrotestosterone concentration at baseline (single dose group)

Table 1133: estradiol summary of multiple dose profiles (multiple dose group)

Table 1134: estradiol concentrations at baseline (single dose group)

Table 1135: SHBG summary of multiple dose profiles (multiple dose group)

Table 1136: SHBG concentration at baseline (Single dose group)

Table 1137: dose proportionality analysis (single dose group)

Table 1138: analysis of variance of some drug metabolism parameters (single dose group)

Table 1139: results of paired t-test of the drug metabolism parameters AUC0-8 and AUC0-24 in subjects dosed with 1200. mu.g TBS-2 at time periods 1 and 2

Table 121: treatment of incidence of Emergency adverse events according to systemic organ Classification and preferred terminology (Single dose group)

Table 122: treatment of incidence of Emergency adverse events according to systemic organ Classification and preferred terminology (Multi-dose group)

Table 123: subjects with adverse reactions (single and multiple dose groups)

Table 124: subjects with post-dose neoisohemology laboratory evaluation results (single and multiple dose groups)

Table 125: subjects with post-dose neoisochemical laboratory evaluation (single and multiple dose groups)

Table 126: subjects with post-dose neoabnormal urinalysis laboratory evaluation (single and multiple dose cohorts)

Table 127: subjects with abnormal basic ear, nose and throat examination (single and multiple dose groups)

4. Glossary of abbreviations and terms

AE adverse events

ALT alanine aminotransferase

ANOVA analysis of variance

AST aspartate aminotransferase

AUC plasma concentration area under time Curve

AUC0- ∞ AUC from time zero to infinity

AUC0-t AUC from time zero to the last measurable concentration time point

AUC_0-τAUC from time zero to dosing interval (where τ is 8 hours) over a multi-dose period

AUC_0-8AUC from time zero to 8 hours over a single dose period

BMI body mass index

BP blood pressure

BUN blood urea nitrogen

Average steady state concentration of Cavg

CFR U.S. Federal regulations

CI confidence interval

CK creatine kinase

CL clearance

Maximum concentration observed after Cmax administration

Minimum concentration in dosing intervals during Cmin multiplex administration

ConcBase baseline concentration

ConcBC Baseline correction concentration

Active dose concentration of ConcBLQ corrected for BLQ

Pre-dose concentration of Cpd determined immediately before dose is at steady state

CRF case report form

CRU clinical research unit

Clinically significant for CS

Coefficient of variation of CV

DHT dihydrotestosterone

ECG electrocardiogram

eCRF electronic case report form

FDA food and drug administration

FSD female sexual dysfunction

Good clinical practice of GCP

GGT gamma-glutamyl transferase

GLM general Linear model

HBsAg hepatitis B surface antigen

HCV hepatitis C virus

HIV human immunodeficiency virus

HR heart rate

ICF informed consent

IRB ethical review committee

logarithmic for ln

Meddra-managed active medical dictionary

NCS not clinically significant

OTC over-the-counter

PD pharmacodynamic (pharmacodynamic)

Principal researchers of PI

Of PK drug metabolism (pharmacokinetic)

PTF% peak to valley fluctuation

PTS% peak to valley steering

RR respiratory rate

SAP statistical analysis plan

Standard deviation of SD

SHBG sex hormone-binding globulin

t1/2 elimination half-life

tmax time to Cmax observed for dosing time

VPA vaginal pulse amplitude

Lambdaz Final Elimination Rate constant

5. Ethics of

A. Ethical review board (IRB)

Each center was reviewed by the ethical review board (IRB) for both the study and any modifications. Any subsequent protocol modifications or informed consent revisions are approved by the IRB before any changes begin.

B. Ethical behavior of the study

The study was conducted according to ethical principles stemming from the declaration of helsinki and current Good Clinical Practice (GCP) and subject to local regulatory requirements and 21CFR 312.

C. Object information and unification

The format and content of the subject information sheet and Informed Consent Form (ICF) were agreed upon by the main investigators (PI), IRB and Trimel pharmaceuticals Corp (hereinafter referred to as Trimel). Written informed consent for each subject to participate in the study was obtained prior to any study-specific procedures. The PI of the research team or member qualified for medical use provides the subject with sufficient description for: study drug and treatment distribution patterns, possible risks and benefits, and compensation or available treatments in case of study-related injuries.

Subjects who agreed to participate in the study were signed up for ICF and dated. At the same time, the designated field worker also signs the ICF and notes the date. The original and all modified signed and dated ICFs remain at the research site and copies of these documents are provided to the subject.

6. Researcher and research management structure

The study was conducted at a study site in the united states. The PI at the study site is responsible for the correctness and accuracy of the data provided on the Case Report Form (CRF). The entrusting authority is allowed to complete the CRF, but the PI is responsible for accurate completion and requires signing the completed CRF, which is a true and correct reflection of the subject's participation in the study.

The PI sign-up agreement sign-up page for the research site. By signing on this page, the PI agrees to conduct the study according to the study protocol, but also to comply with the requirements relating to the clinical investigator's responsibility and all other requirements relating to the appropriate regulatory bodies.

7. Introduction to

TBS-2 was developed for use in the treatment of anorgasmia.

A.Background

Anorgasmia is the second most commonly reported female sexual problem following hypoactive sexual desire disorder. Global survey of sexual attitude and behavior 9000 female sexual questions aged 40 to 80 years (including 40 and 80 years) in 29 countries were evaluated. The prevalence of failure to achieve orgasm ranged from 17.7% (in northern europe) to 41.2% (in southeast asia). In the PRESIDE survey conducted on over 31,000 women, approximately 10% report low desire and distress, and nearly 5% report difficulty and distress in achieving orgasm. Anorgasmia is considered to be a persistent or delayed or non-existent recurrence of orgasm after the period of normal sexual arousal, resulting in significant distress or poor interpersonal relationships. When female sexual activity is not accompanied by the release of a high quality orgasm, the sexual activity can become a nuisance or task rather than a satisfying, intimate experience. This can also lead to indirect diminished interest and/or difficulties with human relations.

Testosterone, the major circulating androgen in women, is a naturally occurring steroid secreted by the ovaries and suprarenal glands. In contrast to the sudden decrease in estrogen during menopause, the serum levels of androgen decline as women age, primarily due to the decreased production of adrenal androgen precursors. Testosterone plays a role in mood regulation, body composition and bone mineral density and has a central and secondary role in sexual function. In the periphery, nitric oxide requires testosterone to stimulate vascular congestion to engorge clitoral tissue and lubricate the vagina during sexual arousal. Testosterone stimulation involves the stimulation and reward system, including dopamine release in the various brain structures of libido. In rats, testosterone was found to stimulate dopamine release in the medial preoptic area of the anterior hypothalamus under basal conditions and sexual stimulation.

Loeser first reported in 1940 the use of androgens to enhance female libido. Some young married women previously considered to be "stiff" themselves, by Salmon, were able to experience a "significant increase in sexual satisfaction" following testosterone propionate injection, eventually ending with a orgasm "that gradually disappeared within a few weeks after injection was stopped. In the 80's of the 20 th century, the role of androgens in maintaining sexual function was studied in ovariectomized women. In this 3 month prospective open study of 44 women, monthly injections of estrogen and testosterone increased libido, the rate of sexual arousal and the number of fantasy. Furthermore, the rate of sexual intercourse and orgasm was higher in women treated with androgen and estrogen compared to controls. Over the past 20 years, over 80 studies of women with hypoactive sexual desire disorders have been conducted with exogenous testosterone by oral, transdermal, sublingual or parenteral routes of administration, with or without concurrent estrogen therapy, resulting in increased libido, orgasm, arousal, frequency of satisfactory sexual activity, pleasure and responsiveness.

Trimel has developed an intranasal testosterone gel containing 0.24% to 0.72% testosterone with castor oil, oleoyl polyoxylglycerides and colloidal silicon dioxide as excipients. TBS-2 was applied as a dose evenly to each nostril. The formulation has many advantageous features including rapid absorption into the systemic circulation and rapid clearance, lack of first pass metabolism, avoidance of transfer from one person to another, and ease of application. In a study project dedicated to the study of testosterone effects, the next logical step was to investigate whether TBS-2, in the absence of other FSDs, had a direct effect on sexual function in general and anorgasmia in particular.

Two drug metabolism (PK)/drug efficacy (PD) studies have been conducted to evaluate the effect of testosterone on tonsil reactivity and the PD endpoint associated with sexual stimulation. The first PD study (CMO-nr:2004/144) investigated whether an age-related decline in androgen levels was associated with decreased tonsil activity and whether exogenous testosterone could restore tonsil activity. Increased testosterone levels are positively correlated with the upper cortical response and negatively correlated with the pre-orbital cortical response in the individual, which may reflect testosterone-induced changes in tonsillar regulation. These results support the modulatory effects of testosterone on affective cues, suggesting that testosterone contributes to the enhancement of the sensation necessary to trigger orgasm.

The second study (TBS-2-2010-01) evaluated the PK and sexual function PD of TBS-2 at 3 dose levels compared to testosterone patch and placebo. PK results indicate a horizontal increase in plasma testosterone with increasing dose levels. In the first PK series, the mean plasma testosterone concentration and the area under the plasma concentration-time curve (AUC) in the TBS-2 high-dose group reached the same level as the mean concentration and AUC of the testosterone patch in steady state. During the second PK series, the mean plasma testosterone concentration and AUC achieved levels in the TBS-2 high-dose group were higher than the mean plasma testosterone concentration and AUC in the testosterone patch group, but still within the upper limit of the normal physiological range. The efficacy of sexual function PD was explored by computer tasks evaluating the effect of testosterone on Vaginal Pulse Amplitude (VPA), subjective arousal questionnaires, and confirmation. In anorgasmia groups, there was a clear difference in the VPA response observed in women after testosterone administration. Women receiving TBS-2 (see examples 9 and 10 above) had stronger reactivity and subjective measures in genital response than women receiving testosterone patches.

The products studied in this study, TBS-2 of strength 0.24%, 0.48% and 0.72%, were bioadhesive intranasal testosterone gels. In contrast to transdermal administration (alexandrite, a testosterone transdermal patch that has been approved in the european union for the treatment of Hypoactive Sexual Desire Disorder (HSDD) in women receiving simultaneous estrogen treatment, bilateral ovariectomized and hysterectomized [ surgically induced menopause ], the application of bioadhesive TBS-2 via the nasal mucosa allows rapid absorption into the systemic circulation. Rapid onset and higher peak concentrations are hypothesized to be more effective in enhancing libido and orgasm, where lower total testosterone concentrations are required, thereby enhancing efficacy and reducing side effects. In addition, TBS-2 may demonstrate effective alleviation of anorgasmia in an "on demand" manner, thereby avoiding long-term testosterone exposure.

8. Object of study

A. Main object of

The main objective of this study was to assess the bioavailability of total testosterone by a PK profile obtained after single administration of TBS-2 at doses of 600 μ g, 1200 μ g and 1800 μ g for intranasal application and multiple administration of TBS-2 at 1200 μ g, three times a day (t.i.d.) the first two days, once in the morning the third day.

B. Second target

The second objective of this study was:

the second objective was to assess the bioavailability of free testosterone, Sex Hormone Binding Globulin (SHBG), Dihydrotestosterone (DHT) and estradiol by a PK profile obtained after single administration of TBS-2 at doses of 600 μ g, 1200 μ g and 1800 μ g for intranasal application and multiple administration of TBS-2 at 1200 μ g given three days (two days before, t.i.d., and once in the morning on the third day).

TBS-2 was evaluated for safety.

9. Study plan

A. General design and plan description

This is a phase 1, single-center, randomized, open label parallel group study performed in adult women with normal healthy cycles. Approximately 24 healthy adult females were enrolled. Subjects were randomly assigned to one of 3 treatment groups (group 1, group 2 or group 3) on a 1:1:1 basis at time period 1 and administered a single dose of intranasally applied TBS-2 at doses of 600 μ g, 1200 μ g or 1800 μ g (single doses of 300 μ g, 600 μ g and 900 μ g per nostril). At the end of period 1, a total of 8 subjects from these 3 cohorts were selected as samples, and subjects willing and able to continue the multi-dose portion of the study were selected to participate in period 2. In period 2, subjects were administered 1200 μ g TBS-2(600 μ g/nostril), t.i.d. for two days and once in the morning on the third day.

Subjects were screened for eligibility for participation up to 3 weeks prior to period 1 dosing (visit 1) and were admitted to a Clinical Research Unit (CRU) at 0700 hours the day prior to dosing (visit 2, day one) for baseline testosterone measurements. On the next day, subjects were administered a single dose of TBS-2, which remained in the CRU for 72 hours after dosing (fourth day) for safety monitoring and PK assessment. On day four, subjects were discharged from the clinic and subjects who did not continue to enter period 2 also underwent a central closure assessment. Depending on its period, the objects selected to participate in epoch 2 return to the CRU approximately 26 to 32 days after epoch 1 ends for visit 3 (epoch 2). In time period 2, subjects were admitted to the CRU at 0700 hours on the day of dosing (visit 3, day one). On days 1 and 2, TBS-2 was administered to the subjects at 0800 hours (+ -30 minutes), 1600 hours (+ -30 minutes), and 2400 hours (+ -30 minutes). On the third day, at 0800 hours, TBS-2 was administered to the subjects. Subjects remained in the CRU for 48 hours after the third day of dosing for safety monitoring and PK assessment. On the fifth day, subjects were released from the clinic.

In phase 1, blood samples for determination of baseline testosterone (free and total), SHBG, Dihydrotestosterone (DHT) and estradiol concentrations were collected on day 0745 hours first, then at 15, 30 and 45 minutes and at 1, 1.5, 2, 4,6, 8, 12, 16, 20 and 23.5 hours versus 0800 hour clock time. Blood samples were collected at the second day (15, 30 and 45 minutes and 1, 1.5, 2, 4,6, 8, 12, 16 and 20 hours post-administration) and third day (24, 32, 40 and 48 hours post-administration) for the determination of testosterone (free and total), SHBG, dihydrotestosterone and estradiol concentrations during the restriction period. In phase 2, blood samples were collected at 0745 hours (i.e., 15 minutes prior to study drug administration) for baseline serum testosterone concentrations. Blood samples were collected for determination of testosterone (free and total), SHBG, dihydrotestosterone and estradiol plasma concentrations during the confinement period on the first day (predose [ 15 minutes prior to administration ] and at 1545 and 2345 hours), the second day (1545 and 2345 hours), the third day (15, 30 and 45 minutes and 1, 1.5, 2, 4,6, 8, 12, 16 and 20 hours) and the fourth day (24, 32, 40 and 48 hours).

Other assessments performed in the study included monitoring of Adverse Events (AEs), clinical laboratory assessments (chemistry [ including hormone profiles ], hematology and urinalysis), vital sign assessments (systolic and diastolic blood pressure [ BP ], heart rate [ HR ], respiratory rate [ RR ] and body temperature), and physical examination. In addition, otorhinolaryngological examination results, 12-lead Electrocardiogram (ECG) readings, medical history and concurrent medication applications were recorded.

B. Discussion of study design and control group selection

This was a phase 1, single-center, randomized, open label parallel group study of TBS-2 performed in time 1 (single dose) 3 cohorts of subjects (cohorts 1, 2 and 3) and time 2 multiple dose cohorts. Approximately 24 healthy women will receive a single intranasal dose of TBS-2-600. mu.g, 1200. mu.g or 1800. mu.g-to assess the safety, tolerability and PK of TBS-2. In epoch 1, the subject is restrained for 4 days in the CRU and 5 days in the epoch.

C. Selection of study population

Inclusion criteria

A subject is eligible for enrollment if the following enrollment criteria are met:

1. female subjects, age between 18 and 40 years.

2. The subject, with menstrual cycle regularity, was between 26 and 32 days.

3. Women with fertility potential must agree to apply one of the following reliable methods of contraception before, during and until one month after the end of the study:

a. surgical contraception (tubal ligation).

b. The intrauterine device was placed at least three months prior to the study initiation.

c. Barrier contraception (partner application of condoms with spermicide).

d. Abstinence.

4. A subject who is negative for drug abuse, hepatitis b-surface antigen (HbsAg), hepatitis c, Human Immunodeficiency Virus (HIV), and pregnancy (serum β -HCG).

5. Subject having a Body Mass Index (BMI) of 18.5kg/m²And 35kg/m²Between (including 18.5 kg/m)²And 35kg/m²)。

6. The subject, ear, nose, throat (ENT) checked normal.

7. A subject, having a normal thyroid-stimulating hormone (TSH) value.

8. Subject, no clinically significant findings in physical examination, 12 lead ECG and vital signs.

9. The subject has normal thyroid function, physiological prolactin concentration.

10. Subjects whose clinical test values do not fall outside the acceptable range unless PI determines that they are not clinically significant.

11. The subject is able to understand and provide written informed consent.

12. Subjects, throughout the study period, were able to participate and were willing to comply with protocol requirements, as indicated by the signed ICF.

Exclusion criteria

Subjects were excluded from study participation if they met any of the following exclusion criteria:

1. a history of known hypersensitivity to testosterone (e.g., deltoid patch) and/or related drugs.

2. Known history of polycystic ovarian syndrome.

3. A known history of or presence of cardiac, pulmonary, gastrointestinal, endocrine, musculoskeletal, neurological, psychiatric, hematologic, reproductive, hepatic or renal disease, unless judged not to be clinically significant by PI or medical instructions.

4. There is a history of estrogen-sensitive tumors such as breast cancer or a known history thereof and/or any cancer, not including basal cell carcinoma.

5. A known history of frequently occurring, clinically significant acne.

6. Known history of hirsutism.

7. Nasal surgery, especially turbinate surgery, septal rhinoplasty, "rhinoplasty" or sinus surgery history.

8. A previous nasal fracture.

9. Active allergic reactions such as rhinitis, rhinorrhea and nasal congestion.

10. Mucosal inflammatory disorders, in particular pemphigus and sjogren's comprehensive aging.

11. Sinus tract diseases, in particular acute sinusitis, chronic sinusitis or allergic mycotic sinusitis.

12. A history of nasal disorders (e.g., polyposis, recurrent nasal bleeding [1 nasal bleed per month ], abuse of nasal mucosal decongestants), or sleep apnea.

13. Any form of intranasal drug delivery is used, especially nasal corticosteroids and nasal sprays containing oxymetazoline (e.g., dritan 12 hour nasal spray).

14. History of hepatitis B, positive HBsAg detection, history of hepatitis C, positive detection of hepatitis C antibody, history of HIV infection or presence of HIV antibody.

15. Any history of severe allergic reactions, including drugs, food, insect bites, environmental allergens, or any condition known to interfere with drug absorption, distribution, metabolism, or excretion.

16. Any history of drug abuse or alcohol abuse within 6 months of study drug administration, according to the Diagnostic and Statistical Manual of mental Disorders (fourth edition) criteria.

17. Current treatment with any hormone therapy in the first 12 months, treatment with drugs that interfere with testosterone metabolism within 30 days of study drug administration, and/or any other prescribed medication. Over the duration of the study, it was difficult to quit Over The Counter (OTC) medication applications.

18. Oral, transdermal and implant contraceptives were used within 30 days prior to study drug administration, or injections of long-acting contraceptives were used within one year prior to study drug administration.

19. Pregnancy or lactation signs.

20. Subjects, who were nursing or who had been nursing within 6 months prior to the screening visit.

21. Within 30 days prior to study drug administration, other study drugs were administered.

22. Blood donations were made within 56 days prior to study drug administration.

23. Any plasmapheresis program was engaged as a plasma provider within 7 days prior to the study.

24. Intolerance to venipuncture.

25. Abnormal bleeding tendency or history of thrombophlebitis not associated with venipuncture or intravenous cannulation.

26. History of deep vein thrombosis or coagulation disorders.

Removing a subject from treatment or assessment

Subjects withdrawn from the study after receiving the study medication are not replaced, for whatever reason they are withdrawn.

Subjects may prematurely discontinue the study for any of the following reasons:

apparently not following the study protocol and procedure.

Intermediately occurring diseases that intervene in the course of the study.

Intolerant AEs, including clinically significant abnormal test results, which appear to interfere with subject safety at the PI.

The primary investigator elected to withdraw from the study to be most beneficial to the subject.

D. Treatment of

Treatment of administration

Subjects were randomly assigned to one of 3 treatment groups (group 1, group 2 or group 3) on a 1:1:1 basis at time period 1 and administered a single dose of intranasally applied TBS-2 at doses of 600 μ g, 1200 μ g or 1800 μ g (single doses of 300 μ g, 600 μ g and 900 μ g per nostril). At the end of period 1, a total of 8 subjects from these 3 cohorts were selected as samples, and subjects willing and able to continue the multi-dose portion of the study were selected to participate in period 2. In period 2, subjects were administered 1200 μ g tbs-2(600 μ g/nostril), t.i.d. for two days and once in the morning on the third day.

Treatment 1: TBS-2 dispensers were pre-filled with 0.24% testosterone gel to deliver a single dose of 300 μ g testosterone per nostril for a total dose of 600 μ g given at 0800 hours (+ -30 minutes) on the second day of group 1 period 1.

Treatment 2: TBS-2 dispenser was pre-filled with 0.48% testosterone gel to deliver a single dose of 600 μ g testosterone per nostril for a total dose of 1200 μ g given at 0800 hours (+ -30 minutes) on day two of group 2 period 1.

Treatment 3: TBS-2 dispenser was pre-filled with 0.72% testosterone gel to deliver a single dose of 900 μ g testosterone per nostril for a total dose of 1800 μ g — administered at 0800 hours (+ -30 minutes) on day two of group 3 period 1.

Treatment 4: TBS-2 dispensers were pre-filled with 0.48% testosterone gel to deliver a single dose of 600 μ g testosterone per nostril for a total of 1200 μ g doses given daily at 0800 hours (+ -30 minutes), 1600 hours (+ -30 minutes), and 2400 hours (+ -30 minutes) on days 1 and 2 of period 2, and once at 0800 hours (+ -30 minutes) on the third morning of period 2 (multiple dose group).

Subjects were instructed to apply TBS-2 gel intranasally according to the correct procedure by using pre-filled dispensers. The study drug was self-administered at 0800 hours on day 1 and day 1, 2 and 3 of period 2. The study staff monitored TBS-2 self-administration. The subjects were instructed not to blow their nose or inhale immediately and within the first hour of study drug administration.

Identification of research products

The activity study drug was supplied in a pre-filled dispenser containing 0.24%, 0.48% or 0.72% TBS-2.

TBS-2 gel was packaged in pre-filled dispensers. A multi-dose dispenser is used to deposit the gel in the nasal cavity. The dispenser is a finger-actuated dispensing system designed to dispense 125 μ LTBS-2 gel into the nasal cavity from a non-pressurized container per actuation. The key components of a multi-dose dispenser include a barrel (barrel), a base, a pump and an actuator, which are constructed from polypropylene and a piston constructed from polyethylene. See fig. 39 and the lower CMC section.

All study drug cassettes and dispensers were labeled and supplied according to appropriate regulatory requirements. Eligible certified investigators prepared unit doses for study following a randomized protocol. Study drug is provided to the subject in a suitable unit dose foil pouch that clearly marks the amount of drug administered.

Study drug was stored in a safe location at controlled room temperature, 15 ℃ to 25 ℃ (59 ° f to 77 ° f). The storage site is a locked, limited-access room that only allows access by appropriate researchers.

PI or approved representatives (e.g., cooperative researchers) ensure that all study drugs are stored in a safe area under recommended storage conditions and in accordance with appropriate regulatory requirements.

At the completion or end of the study and upon receipt of book-based authorization for Trimel, all unused and/or partially used study medications are returned or proposed by Trimel for disposal at the study site.

Method for assigning objects to treatment groups

The randomization protocol was prepared by Premier Research (previous study) and provided to the PI at the CRU before the study began.

Subjects who met the enrollment criteria were randomly assigned to 3 treatment groups on a 1:1:1 basis.

Selection of dose in the study

Doses of 600 μ g, 1200 μ g and 1800 μ g were selected for this study based on clinical pharmacologic data, which is appropriate for the phase 1 study. Animal toxicology studies completed to date have not demonstrated any unusual or unexpected toxicity associated with TBS-2 exposure. Subjects were not expected to experience the side effects of TBS-2.

Selecting and timing doses for each subject

Study drug was administered the second day of period 1 (single dose). At time period 2 (multiple doses), study drug was administered on days 1 and 2, t.i.d., and on the third morning. Subjects were restrained in CRUs for 4 days in period 1 and 5 days in period 2.

Blind method

This is an open study; for treatment assignment, subjects were not blinded.

Previous and concurrent treatments

Treatment with any prescribed or non-prescribed drug therapy or with drugs that interfere with testosterone metabolism is prohibited within 30 days of study drug administration and until the final study visit. Any form of intranasal drug delivery, particularly nasal corticosteroids and oxymetazoline-containing nasal sprays (e.g., drisan 12 hour nasal spray) were prohibited until the final study visit. Current treatment by any hormone therapy is prohibited 12 months prior to study drug administration and until the final study visit. Oral, transdermal and implant contraceptives are also prohibited for 30 days prior to study drug administration, or long-acting contraceptive injections are administered within a year prior to study drug administration. In addition, administration of other study drugs was prohibited within 30 days prior to study drug administration. Illegal drugs are not allowed when the subject is enrolled in the study.

Throughout the study, PI may indicate any concurrent therapy deemed necessary to provide adequate supportive care. The PI informs any subject's sponsor (sponsor) whether to utilize medication within 30 days prior to the first day or whether to require concurrent medication in the study. The decision to allow the subject to enroll in the study or to take medication in the study is made jointly by the insurer and PI and is based on their view that: that is, the application of medication is unlikely to compromise the safety of the subject, or be based on interpretation of the study data. All medications taken within 30 days prior to administration and all concurrent treatments were recorded on the appropriate portion of the CRF.

Treatment compliance

Subjects receiving study drug doses were monitored by the investigator within 1 hour after dosing to ensure compliance with TBS-2 instructions. Subjects were restrained in CRUs for 4 days in period 1 and 5 days in period 2, and were closely monitored. A medication dispensing log is maintained. Drug metabolism results can be used to confirm compliance.

Study drug was administered the second day of period 1 (single dose). Study drug, t.i.d., was administered on days 1 and 2, and study drug was administered in the morning on the third day, in period 2 (multiple doses). Subjects were restrained in CRUs for 4 days in period 1 and 5 days in period 2.

E. Drug metabolism and safety variables

Assessed drug metabolism and safety measurements and flow charts

The study plan is shown in Table 9-1.

Appropriateness of measurement result

The measurements included in this study are typical for phase I single and multiple dose studies.

Drug metabolism drug concentration measurement

Whole blood samples were collected at various time points indicated in table 9-2 for the determination of testosterone (free and total), SHBG, dihydrotestosterone and estradiol concentrations. The date and time of collection is recorded on the CRF in the closest minutes. Obtaining a whole blood sample by direct venipuncture; for early time point PK sample collection, heparin fixation or IV indwelling catheters were allowed. The amount of plasma sample used for PK analysis for each subject was approximately 120mL for period 1 and 292mL for period.

Table 9-2: drug metabolism sample collection plan

Abbreviations: DHT ═ dihydrotestosterone; PK ═ drug metabolism; SHBG-sex hormone-binding globulin; t.i.d. three times daily

Note that: in period 1, administration occurred the next morning. In period 2, dosing occurred on days 1 and 2, t.i.d., and once in the morning on the third day.

Drug metabolism parameter assessment

Concentration-time data for 5 analytes [ testosterone (total and free), SHBG, dihydrotestosterone and estradiol ] were determined and PK parameters were calculated therefrom. The actual sampling time points were recorded and used to calculate the time actually elapsed from dose to sample for PK calculations. Because each administration is to each nostril, the time of administration is the time of administration to the first nostril. The concentration units for each of the 5 different analytes may be different, so the final concentration unit reflects the bioanalytical laboratory data reported for concentration. The units of PK parameters are derived from analyte concentration units. The baseline analyte concentration for the 24-hour pre-dose profile was subtracted from the reported analyte concentration prior to calculation of PK parameters.

The following PK parameters were calculated for PK characterization as single dose (groups 1, 2 and 3). The summary interval is the sample that begins and continues from the first administration to the last sample collected on the day of administration. PK parameters were assessed by standard methods utilized by the WinNonlin program and a short description is given below. The determination of the final elimination phase is more fully described in the WinNonlin file. Note that C_min、C_maxAnd t_maxValues taken from actual measurements-but in pair C_minAnd C_maxAfter baseline correction is performed.

The following PK parameters were calculated as multiple doses (multiple dose group):

additional exploratory analyses of PK parameters may also be performed, if necessary.

Security measurement

Safety measurements include monitoring of AEs, clinical laboratory evaluations (chemistry [ including hormone profiles ], hematology and urinalysis), vital signs and 12-lead ECG. In addition, physical and otorhinolaryngological examinations were performed, and a history of disease and concurrent medication was recorded. The security measurements were performed at the times specified in Table 9-1. PI followed all clinically significant abnormal findings after study drug treatment until resolution or return to baseline.

Adverse events

An AE is any unexpected, undesirable, unplanned clinical event that occurs in the form of signs, symptoms, disease, or laboratory or physiological observations in a person taking Trimel products involved in clinical studies, whatever the cause and effect. The pre-existing condition is a condition: it is present prior to study drug administration and is reported as part of the subject's medical history. A pre-existing condition is only reported as AE if the frequency, intensity, or characteristic of the pre-existing condition worsens during the study.

Laboratory abnormalities are not considered AEs unless they are associated with clinical signs or symptoms or require medical intervention. However, the following laboratory abnormalities (e.g., clinically significant changes detected in clinical chemistry [ including hormone profiles ], hematology, urinalysis) are considered AEs: independent of the underlying medical condition and the need for medical or surgical intervention, or to cause discontinuation or discontinuation of study medication.

All AEs judged to be clinically significant, including clinically significant laboratory abnormalities, were tracked until resolution or return to baseline.

F. Severity level

The severity of all AEs or SAEs was assessed by using the following scale components:

events that are slightly easily tolerated by subjects; brief or mild discomfort (typically <48 hours); no medical intervention/treatment is required.

Moderate events that can interfere with normal daily activities; some assistance may be required; no or minimal medical intervention/treatment is required.

An event that severely impedes the subject from performing their normal daily activities; some assistance is usually required; medical intervention/treatment, possibly hospitalization, is required.

When the severity of AEs changes more frequently than once a day, the maximum severity experienced that day is recorded. If the severity category changes within days, these changes are recorded separately (with the exact date of onset). AE severity is recorded in the appropriate portion of the AE page of the CRF. The assessment of severity is different from the "severe" assessment. Severe events may not meet severe criteria and severe events may be rated as mild.

G. Rating of causality

For each reported adverse reaction, PI was used to evaluate the relationship of this event to the study drug using the following components:

certainly there seems to be a reasonable time relationship with drug administration and withdrawal and it occurs again after the drug has re-worked.

There is likely to be a reasonable temporal relationship with drug administration.

There may appear to be a reasonable temporal relationship with drug administration, but there may be a reasonable correlation with other factors.

There is unlikely to be a plausible temporal relationship with drug administration.

It is not known that there is an adequate basis for determining associations with drug intake.

No correlation was associated with study drug administration.

H. Serious adverse events

PI classifies each AE as severe or not severe. A Severe Adverse Event (SAE) is defined as any AE occurring at any dose that results in any of the following outcomes:

death of^a

Endangering life^b

Requiring hospitalization or extending hospitalization

Resulting in permanent or marked disability/insufficiency^c

Cause congenital abnormalities/birth defects

Additionally, important medical events that may not result in death, life threatening, or require hospitalization may be considered SAE when they may jeopardize the subject based on proper medical judgment and may require medical or surgical intervention to prevent one of the outcomes listed above. For example: allergic bronchospasm requires intensive treatment in the emergency room or at home.

Note that:

a. death results rather than AE. In the case of death, the cause of death was noted as AE. The only example is "sudden death" without any known cause.

b. Life-threatening AEs include any adverse drug experience that appears to the PI to place the subject at direct risk of death-due to the reactions that occur. It does not include such reactions: if it occurs in a more severe form, death may result.

c. Disability is defined as a major disruption of an individual's ability to perform normal life functions.

Within 24 hours of the scene awareness event, all SAEs that led to death or life threatening, regardless of cause and effect, were reported to Trimel (or nominated). Duplicate products of the initial SAE report are received within one working day. All other SAEs or other events that can be reported to Trimel are sent to Trimel (or a designated person) within one working day. If there is any doubt as to whether the information constitutes an SAE, the information is treated as an SAE for the purposes of this study.

Clinical laboratory test

Clinical laboratory tests were performed according to the schedule provided in table 9-1.

Serum chemical evaluations include sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphate, uric acid, total bilirubin, albumin, aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), alkaline phosphatase, gamma-glutamyl transferase (GGT), Creatine Kinase (CK), and cholesterol and hormone profiles.

Hormone profiles include TSH, total and free thyronine triiodide, total and free thyroxine, FSH, prolactin and progesterone.

Hematological evaluations include white blood cell counts, hemoglobin, and hematocrit.

Urinalysis includes glucose, bilirubin, ketones, specific gravity, blood, pH, proteins, urobilinogen, nitrite, leukocytes and, if necessary, microscopy.

Upon screening and admission to the CRU, urine samples were obtained to test for drug abuse (cannabis, cocaine, opiates, amphetamines, phencyclidine, benzodiazepines, and barbiturates) and alcohol was tested by using the alcohol breath test.

HbsAg, anti-HCV and HIV tests were only performed at screening (visit 1).

Samples were analyzed by medthox Laboratories, inc.

Vital signs

Vital sign measurements include systolic and diastolic BP and HR, body temperature and RR. Vital sign assessments were performed at the times specified in table 9-1.

12-lead electrocardiogram

The standard 12 lead ECG was only performed at screening (visit 1).

Other security measures

The physical examination was performed at the time specified in Table 9-1.

At screening, ENT (ear, nose and throat) rhinoscopy was performed. Basic ENT (ear, nose and throat) examinations were performed at the times specified in table 9-1; the on-site physician examines the subject and identifies any clinically significant changes in the nasal mucosa at follow-up.

Concurrent medication was monitored throughout the study.

I. Data quality assurance

The study was monitored by trained experienced personnel on GCP. Clinical study auditors review study records to verify compliance with the protocol, accuracy, completeness, and consistency of the data; and compliance with local regulations when conducting clinical studies. Clinical auditors maintain regular contact with the site and have acquired medical records of the subject and other study-related records needed to verify enrollment in CRF.

The electronic crf (eCRF) was used for this study, which included as identifiers only the initial (initial) of the subject, the birthday, and the assigned subject number on the eCRF. The PI ensures availability and reliability of the source file from which the information on the eCRF originates, and is required to comply with the file retention procedures listed in the scheme. The accuracy of the case report table was reviewed and signed and dated by the PI.

J. Statistical methods and sample size determination

Statistical and analytical planning

The statistical methods proposed in the study protocol were replaced by those described in the Statistical Analysis Program (SAP). This study evaluated PK properties as well as TBS-2 safety and tolerability. No power calculations were performed. Data were summarized by descriptive statistical analysis (sample size, mean, median, standard deviation [ SD ], minimum and maximum) for each safety variable in treatment groups and overall. All interviewed data was shown in a data list during the study.

Concentration-time data for 5 analytes (testosterone [ total and free ], SHBG, dihydrotestosterone, and estradiol) were determined by validated assays and PK parameters were calculated. The actual sampling time points are recorded and used to calculate the time actually elapsed from dose to sampling for PK calculations. Because each administration is to each nostril, the time of administration is the time of administration to the first nostril. After pre-dose administration prior to calculation of PK parameters, the baseline analyte concentration for the pre-24 hour dose profile was subtracted from the time-matched analyte concentration.

Plasma TBS-2 concentration-time data were analyzed by using Phoenix WinNonlin (Pharsight Corporation). PK parameters (referring to drug metabolism parameter assessment) for testosterone (free and total), SHBG, DHT and estradiol for all subjects were calculated by standard non-compartmental methods, as data allows. Individual PK parameters were evaluated for each subject's profile in the PK population and displayed in a data list. Data were summarized by using descriptive statistical analysis (mean, SD,% coefficient of variation [ CV ], Confidence Interval (CI), median, minimum and maximum) and shown by treatment groups.

Including geometric means, for AUC and C_maxEvaluated, and included for some other PK parameters. By making use ofMedium Generalized Linear Model (GLM) program, parameters for Natural Log (ln) transformationAUC_0-t、 AUC_0-∞、AUC_0-τ、C_avgAnd C_maxAnd for the unconverted parameter t_1/2And λ_zAnalysis of variance (ANOVA) was performed at a significance level of 0.05. Calculation of AUC by Using ANOVA residuals_0-t、AUC_0-∞、AUC_0-τAnd C_maxThe intra-subject CV of (a).

Under the AUC_0-t、AUC_0-∞And C_maxAfter normalization to the administered dose, dose linearity after single dose administration was evaluated (period 1).

The following period 1 comparisons were made for PK parameters:

comparison 1: 600. mu.g 0.24% TBS-2 vs 1200. mu.g 0.48% TBS-2;

comparison 2: 600. mu.g 0.24% TBS-2 vs 1800. mu.g 0.72% TBS-2;

compare 3. mu.g 0.48% TBS-2 to 1800. mu.g 0.72% TBS-2.

Determining sample size

The sample size of the study was not determined based on statistical hypothesis testing. Based on typical early PK studies, a group of 8 subjects per cohort was sufficient to provide sufficient clinical information to meet the study objectives.

Interim analysis

No regular interim analysis was performed in this study. However, when concentration data is received from the bioanalytical laboratory after period 1 and again after period 2, the limit of the available data is reached by providing all PK TLFs using the planned sampling time instead of the actual planned sampling time. The primary PK analysis or quality control testing of the primary tables, lists and graphs is not completed in the interim analysis, and the testing of interim PK parameters is not completed in the interim analysis.

K. Changes in analysis under study or plan

There was a change in SAP for the PK data analysis of the detailed design plan after the first draft analysis was performed. These fall into the category of additional exploratory analysis of PK parameters provided in SAP.

The first analysis used SAP (corrected τ of 8 hours), but found that the elimination half-life could not be properly estimated throughout the 48 hour collection phase.

The pharmacokinetic advisor directs the PK analysis and makes changes to the PK analysis plan to best present PK results. In the final analysis, some additional PK parameters were added to the analysis and additional tests were performed.

The first round of advisory review required these to be added to the PK analysis:

1. the respective plots for 3 subjects receiving a 1200 μ g dose over two periods. The data included BLQ-corrected raw data curves from Bioanalyst for free, total and dihydrotestosterone. A total of 9 plots, with 3 plots for each of the 3 analytes.

2. AUC was recalculated from BLQ-corrected data from Bioanalyst (ConcBLQ)_0-8And AUC_0-24. These parameters were compared by ANOVA in the new table between epoch 1 and epoch 2. Only 3 subjects received 1200 μ g doses in period 1 (single dose) and period 2 (multiple dose). The ANOVA required was data for subjects receiving the 1200 μ g dose and for all 8 subjects.

The second round of advisor review requires the following. Both consultants review the PK portion of SAP and make the following comments.

1.AUC_0-8Or AUC_0-24An AUC is required that utilizes a baseline corrected for a single dose rather than a baseline corrected for multiple doses. Both are provided.

2. Required AUC_0-∞Limited to 24 hours, which is baseline for single dose correction.

3. At C₂₄Is reported as a single dose PK parameter.

4. Note the error in SAP, where τ was incorrectly assigned to 12 hours when it was 8 hours.

5. Requiring multiple doses of C₀And C₂₄Is added to the PK parameters.

6. Note that C_avgTo be administered on an 8 hour dosing interval (τ) basis.

10. Study object

A. Object arrangement

A total of 24 subjects were registered in epoch 1; each of the 8 objects was randomized into group 1, group 2, and group 3. All 24 subjects completed epoch 1.

After epoch 1, a total of 8 subjects continue to epoch 2. All 8 subjects completed epoch 2.

B. Deviation of the scheme

The protocol deviations reported in the study were small and not expected to affect the results of the study. A total of 6 subjects out of 24 (25.0%) had the following protocol deviations: missing vital sign assessments or PK blood draws were 2 or 3 minutes outside the window.

11. Drug metabolism evaluation

A. Data set of analysis

Single dose group: all subjects randomized and receiving at least 1 dose of TBS-2 in the study; 24 subjects (100%) were all included in the group (section 14.1, table 14.1.1 a).

Multiple dose cohorts: all subjects in the single dose group, selected for continuation of study period 2; 8 subjects (100%) were all included in the group (section 14.1, table 14.1.1 b).

B. Population and other baseline characteristics

Demographic data

The majority of subjects in epoch 1 were white (19 subjects out of 24 [ 79.2%]) Second, by percentage, is a black subject (4 subjects out of 24 [ 16.7%)]) And Indian americans or Alaska indigenous/white (1 out of 24 subjects [ 4.2%]). The number of similar subjects was not Hispanic descent or Hispanic Americans (13 of 24 subjects [ 54.2%]) And hispanic descendents or hispanic americans (11 of 24 subjects [ 45.8%]). The mean (SD) age was 29.8(5.86) years. The mean (SD) height was 161.02(6.667) cm, the weight was 66.36(11.378) kg and the BMI was 25.61(4.079) kg/m². Most subjects had a normal BMI (13 subjects out of 24 [ 54.2% ]]) Second, by percentage, is an overweight subject (7 out of 24 subjects [ 29.2%]) And obese subjects (4 of 24 subjects [ 16.7%])。

The majority of subjects in epoch 2 were white (5 of 8 subjects [ 62.5%]) Second, in percent, is a black subject (2 subjects out of 8 subjects [ 25.0%)]) And Indian americans or Alaska indigenous/white (1 out of 8 subjects [ 12.5%]). The number of similar subjects was not Hispanic descent or Hispanic Americans (5 of 8 subjects [ 62.5%]) And hispanic descendents or hispanic americans (3 of 8 subjects [ 37.5%]). The mean (SD) age was 30.3(6.48) years. Average (SD) height of 160.8 (3.99) cm, weight of 61.13(9.815) kg and BMI of 23.65(3.454) kg/m². Most subjects had a normal BMI (6 out of 8 subjects [ 75.0%)]) Second, by percentage, is an overweight subject (2 out of 8 subjects [ 25.0%]).

Base line characteristics

Medical history

The subject history reports reported at screening are summarized by the body system in table 11.1.

Currently active non-exclusive medical history conditions are reported by at least 10% of the subjects in total in the following body system: the nervous system (15 out of 24 subjects [ 62.5% ]), the genitourinary system (7 out of 24 subjects [ 29.2% ]), the cutaneous system (4 out of 24 subjects [ 16.7% ]), and allergic conditions (4 out of 24 subjects [ 16.7% ]).

TABLE 11-3 medical history (Single dose group)

Head, eye, ear, nose and throat.

D. Pre-and concurrent medication

No concurrent medication was reported in the study.

In total, 10 subjects reported prior medication. Most of the reported prior medications are over-the-counter analgesic or anti-inflammatory medications and multivitamins.

E. Measurement of treatment compliance

All subjects were observed at the study site during dosing, which followed study drug administration.

F. Tabulation of single object data

Drug metabolism analysis

In this study, there are 3 doses summarized for drug metabolism: the 3 doses are summarized for a single dose period, and the 1 dose is summarized for a multiple dose period. The single dose profile included the following doses of testosterone in separate groups: 600. 1200 and 1800 μ g, while the multi-dose period included only 1200 μ g testosterone doses. Each dose is summarized for free and total testosterone, dihydrotestosterone, estradiol and SHBG. There were 8 subjects per dose group.

Concentration results are shown first, followed by PK parameter results.

G. Concentration results

Period 1: single dose profile

After baseline correction, the mean concentration profiles for each of the 5 analytes are shown in the following figures. The free and total testosterone concentrations are shown graphically to show the most clear relationship between concentration and elevated testosterone dose (fig. 19 and fig. 20, respectively). The dihydrotestosterone analyte clearly distinguished between the 1800 μ g doses compared to the lower doses that did not clearly differ from each other (figure 21). This opposition was observed in estradiol concentrations, with the lowest dose being 600 μ g, clearly distinguished from the two higher doses that did not clearly differ from each other (fig. 22). SHBG concentrations did not clearly differentiate between testosterone doses administered (figure 23).

Free and total testosterone and, to a lesser extent, dihydrotestosterone concentrations were more clearly distinguished between baseline and active dose (fig. 24, 25 and 26, respectively). Post-dose curves for estradiol and SHBG concentrations overlapped with baseline concentrations for the same dose (fig. 27 and fig. 28, respectively).

Period 2: multiple dose profile

The mean values of free and total testosterone are plotted to show the most pronounced dose effect at the highest concentration upon administration and will plateau at about 12-16 hours. The concentration appears to return to baseline levels after 10 hours post-dose. The two graphs track so closely that the components appear to be non-overlapping once they are adjusted (fig. 19 and 20, respectively). The dihydrotestosterone concentration also indicated a peak upon administration, but was not as clear as in the case of free and total testosterone (figure 21). Small differences in estradiol and SHBG concentrations were observed over the observation period of the multiple dose profile, which could be attributed to the lack of a sharp increase in concentration when the dose was administered (fig. 32 and 33, respectively).

At 12 hours after the final dose, the free testosterone concentration of subjects 522-03 did not show a similar decrease compared to the other 7 subjects (fig. 34). The free testosterone concentration of subjects 522-03 was also the highest concentration after 12 hours, but not as different as the free testosterone concentration from the other 7 subjects (fig. 35). For dihydrotestosterone, estradiol and SHBG it is increasingly difficult to find-in this order-a dose-relationship where SHBG concentrations are essentially constant for each subject, but at different concentrations (fig. 36, 37 and 38, respectively).

H. Drug metabolism parameter assessment

Drug metabolism parameters were assessed by using the Phoenix WinNonlin version 6.2.

Period 1: single dose drug metabolism parameter assessment

All PK parameter assessments were performed at baseline corrected concentrations during the first 24 hours. PK parameters assessed for each individual from the single dose profile are shown in appendix 16.2, list 16.2.5.1.2a and summarized in section 14.2, table 14.4.2 a. The following tables (tables 11-22) show data for single dose PK parameters, but with SD and median omitted.

The profile of all 24 subjects assessed d λ z (final elimination rate) for free and total testosterone. Profile of only 12 subjects assessed d λ z for dihydrotestosterone, 11 assessed d λ z for estradiol and 9 assessed d λ z for SHBG. In the absence of λ z, the elimination half-life, t, cannot be calculated_1/2And AUC_0-∞。

Free testosterone

For free testosterone, mean C_maxThe dose administered was closely followed, indicating proportionality to the dose. Mean AUC_0-8Doses from 600 μ g to 1200 μ g were proportional (1.94 ratio compared to 2.00 dose ratio), but slightly lower for the 1800 μ g dose (3.55 ratio compared to 3.00 dose ratio). Other measures of AUC are less clearly related to dose and, unlike AUC_0-8That strongly indicates a proportional relationship with the dose. This is probably due to the increase in concentration resulting from the least significant dose in the first 8 hours, as seen in the figure. The az values are similar between doses.

Tables 11 to 22: free testosterone summary (Single dose group)

Total testosterone

Total testosterone C as all AUC measures_maxThe parameters increased with increasing dose. Lambda [ alpha ]_zThe measurements were similar between doses (tables 11-23).

Tables 11 to 23: total testosterone summary (Single dose group)

Dihydrotestosterone

Dihydrotestosterone PK parameters were missing some parameter values, and some overall profile was missing after baseline correction; there are only 18 of the 24 distributions, and λ z can only be evaluated in 12 of the 24 profiles. Average C_max、AUC_0-8And AUC_0-∞Values decreased from the 600 μ g dose to the 1200 μ g dose and then increased for the 1800 μ g dose. Other AUC measures showed increased exposure with increasing dose. Lambda [ alpha ]_zThe values were substantially similar for each dose (tables 11-24).

Tables 11 to 24: dihydrotestosterone summary (Single dose group)

Estradiol

C_maxThe estradiol PK parameters measured by AUC are similar for 1200 μ g and 1800 μ g doses, but always values less than the 600 μ g dose. For example, mean C compared to 1200 μ g and 1800 μ g doses, respectively_maxThe ratio was 0.61 and 0.64 for a 600 μ g dose. AUC_0-8Are 0.31 and 0.47, respectively, wherein ratios of 2.00 and 3.00 may indicate proportionality. Note also that N-8 for the 600 μ g dose, and 7 for the 1200 μ g and 1800 μ g doses. Lambda [ alpha ]_zThe values are similar (tables 11-25).

Tables 11 to 25: estradiol summary (Single dose group)

SHBG

SHBG C_maxAnd AUC_0-8、AUC_0-24And AUC_0-tThe values are similar for the 600 μ g and 1200 μ g doses. Lambda [ alpha ]_zIs not typical for many of these objects (tables 11-26).

Tables 11 to 26: SHBG summary (Single dose group)

I. Period 2: multi-dose drug metabolism parameter assessment

PK parameters assessed from the multi-dose profile for each individual are shown in appendix 16.2, list 16.2.5.1.2b and summary in section 14.2, table 14.4.2 b. The following table shows data for multi-dose PK parameters summarized in part 14.2, table 14.4.2b, but with SD and median omitted. All subjects received 7 doses of 1200 μ g testosterone.

Free testosterone

Since a 1200 μ g testosterone dose was used for the single and multiple dose periods of the study, it seems useful to compare its PK parameters. However, this may not be useful because single dose data is baseline corrected based data and multiple dose data is not. However, baseline concentration data for a single dose period may be reviewed in comparison to multiple dose data. Because the data in tables 11-28 are from baseline, the doses were not relevant, as all concentrations preceded the dose.

For all 3 dose groups, the minimum and maximum values observed during the multiple dose period were greater than the minimum and maximum values observed during the baseline period. This demonstrates that multiple administrations of testosterone increase the minimum and maximum free testosterone concentrations above baseline and provide the expected increase in free testosterone concentration after multiple administrations. (tables 11 to 27) and (tables 11 to 28).

AUC_0-8And AUC_0-τThis was consistent at 8 hours dosing intervals. AUC_0-24Hours span the last dose period of 8 hours, but also include the preceding 16 hours. The% PTF and% PTS are respectively represented by C_avgOr C_minPhase division time C_maxAnd C_minThe percentage difference between them.

Tables 11 to 27: free testosterone summary for multiple dose profiles (multiple dose group)

Tables 11 to 28: free testosterone concentration at baseline (single dose group)

Total testosterone

Total testosterone PK C after multiple administrations compared to the maximum testosterone concentration range observed at baseline between 41.10 and 58.00ng/dL_maxThe range is 85.80 to 242.00 ng/dL. C post-multiple dosing compared to the minimum range of total testosterone observed at baseline of 8.00 to 12.70ng/dL_minThe range is 25.20 to 79.50ng/dL total testosterone. C_maxAnd C_minBoth are indicative of testosterone dosing effects; for C_max2-to 4-fold effect and for C_min3 times the effect. (tables 11-29 and 11-30), however, this accumulation disappeared within 24 hours after the last application.

Tables 11 to 29: total Testosterone summary for multiple dose profiles (multiple dose group)

Tables 11 to 30: total testosterone concentration at baseline (single dose group)

Dihydrotestosterone

Dihydrotestosterone observations do not indicate much difference from baseline observations. Maximum dihydrotestosterone C for multiple dosing periods_max30.50ng/dL, comparable to 32.60C observed at baseline_maxAnd (4) comparing. Minimum C of multiple dose period_min6.32ng/dL, comparable to 5.02ng/dL observed at baseline. No testosterone administration effect was observed in this comparison of dihydrotestosterone concentrations to baseline (tables 11-31 and tables 11-32).

Tables 11 to 31: multidose profile dihydrotestosterone summary (multidose group)

Tables 11 to 32: dihydrotestosterone concentration at baseline (single dose group)

Estradiol

Estradiol C observed within 24 hours of baseline observation period_minThe concentration was 17.00pg/mL (24 subjects in a single dose period ranged from 17.00 to 20.90pg/mL), versus 12.70pg/mL in multiple dose periods (8 subjects)Subject range of 12.70 to 95.20pg/mL) comparable to the standard. Estradiol C_maxThe concentration was 122.00 at baseline and 145.00 at multi-dose. Although there were some differences in these concentrations, they were similar (tables 11-33 and tables 11-34).

Tables 11 to 33: estradiol summary of multiple dose profiles (multiple dose group)

Tables 11 to 34: estradiol concentrations at baseline (single dose group)

SHBG

SHBG C at baseline observation period_min15.30nmol/L, and C for a multiple dose period_minIt was 19.90 nmol/L. SHBG C_max137.00nmol/L, and C of multiple dose period_maxWas 100.00 nmol/L. The effect of testosterone administration on SHBG concentration was not significant (tables 11-35 and tables 11-36).

Tables 11 to 35: SHBG summary of multiple dose profiles (multiple dose group)

AUC_0-8Area under the plasma concentration time curve from time zero to 8 hours post-dose; AUC_0-24Area under the plasma concentration time curve from time zero to 24 hours post-administration; AUC_0-τArea under the concentration-time curve from time zero to dosing interval; c_maxMaximum concentration observed after dosing; c₀Maximum concentration at baseline; c_minMinimum concentration in the dosing interval during multiple dosing periods; c_avgMean steady state concentration；C₂₄Maximum concentration at 24 hours post-dose; coefficient of variation of CV ═ percent; geo mean value is geometric mean value; percent PTF-percent peak to valley fluctuation; % PTS is percent peak-to-valley steering; t is t_maxTime relative to the maximum concentration observed for the time of administration.

Tables 11 to 36: SHBG concentration at baseline (single dose group)

ConcBase-baseline concentration

J. Statistical testing of drug metabolism parameters

Dose proportionality analysis for single doses

Part 14.2, table 14.4.3 shows the dose proportionality analysis. Tables 11-37 are summarized from this table to show linear regression analysis of log transformed PK parameters.

Dose proportionality occurs when an increase in the administered dose is accompanied by a proportional increase in the exposure (PK parameter) metric. A linear regression model was fitted to each PK parameter of interest by using dose (600, 1200 and 1800 μ g) as predictor variable:

PK ═ slope + dose + intercept.

If the 95% confidence limit for the intercept includes 0, the dose proportionality assumption cannot be rejected.

AUC for free testosterone alone_0-24、AUC_0-8And AUC_0-tDose proportionality cannot be rejected.

Tables 11 to 37: dose proportionality analysis (single dose group)

AUC_0-8Area under the plasma concentration time curve from time zero to 8 hours post-dose; AUC_0-24Area under the plasma concentration time curve from time zero to 24 hours post-dose; AUC_0-tArea under the plasma concentration time curve from time zero to the last measurable concentration time point; AUC_0-∞Area under the plasma concentration time curve from time zero to infinity; c_maxMaximum concentration observed after dosing.

Dose pairwise test with analysis of variance

Tables 11-38 show pairwise comparisons of single dose PK parameters using ANOVA after dose normalization. The results found that AUC was measured in addition to free testosterone_0-24、AUC_0-8And AUC_0-tIn addition, there was a difference in the dose normalized values for all analytes for at least one of the 3 pairwise comparisons.

Tables 11 to 38: analysis of variance of some drug metabolism parameters (single dose group)

AUC_0-8Area under the plasma concentration time curve from time zero to 8 hours post-dose; AUC_0-24Area under the plasma concentration time curve from time zero to 24 hours post-dose; AUC_0-tArea under the plasma concentration time curve from time zero to the last measurable concentration time point; AUC_0-∞Area under the plasma concentration time curve from time zero to infinity; c_maxMaximum concentration observed after dosing; lambda [ alpha ]_zFinal elimination rate constant; t is t_1/2Elimination half-life

The coefficient of variation a is 100 × ANOVA residual (root mean square error)/PK parameter mean. Pairwise comparisons were from ANOVA models with dose as the class (category) variable and PK parameter estimates as the dependent variables.

Note that: AUC_0-8、AUC_0-∞、AUC_0-tAnd C_maxThe parameter values are all natural log transformed.

AUC from single to multiple doses_0-8And AUC_0-24Paired t-test comparison

There were 3 subjects participating in the 1200 μ g single and multiple dose period. AUC is calculated from free testosterone, total testosterone and dihydrotestosterone analyte concentrations_0-8And AUC_0-24Uncorrected parameters for comparison to uncorrected parameters for a multiple dose profile. Tables 11-39 AUC of free testosterone, total testosterone and dihydrotestosterone in these 3 subjects were compared by using paired t-test_0-8And AUC_0-24. Results of log-transformed comparisons are provided.

Tables 11 to 39: drug metabolism parameter AUC of subjects taking 1200. mu.g TBS-2 in time period 1 and time period 2_0-8And AUC_0-24Paired t test results of

AUC_0-8Area under the plasma concentration time curve from time zero to 8 hours; AUC_0-24Area under the plasma concentration time curve from time zero to 24 hours; PK is drug metabolism.

Comparison of both AUC measures of free testosterone at 95% CI includes zero difference, so equality between single and multi-dose AUC measures cannot be rejected. Total testosterone 95% CI vs AUC_0-8Rather than for AUC_0-24Including zero, so for AUC_0-8Rather than for AUC_0-24Equality cannot be rejected. In the analyte dihydrotestosterone, no 95% CI included zero, so equality was rejected for both AUCs.

Statistical and analytical problems

K. Adjustment of covariates

Not applicable.

L. processing of retired or missing data

To address missing or partial AEs and synchronize medication dates, the following rules apply:

1. for partial AEs and synchronous medication start dates, missing values were given if the year was unknown. The month and day of the first dose date if the month is unknown and the year matches the year of the first dose date; otherwise designated as january. (ii) a day due to the first dose date if the day is unknown and the month and year coincide with the month and year of the first dose date; otherwise "01" is given.

2. For partial AEs and synchronous medication end dates, missing values were given if the year was unknown. If month is unknown, 'December' is given. If the day is unknown, then the last day of the month is given.

After implementing the above rules, to determine whether an AE (or medication) lacking a start or stop date is pre-treatment or in/after treatment, the following strategy is applied:

1. if both the start and stop dates were missing, the most conservative approach was taken and the AE (or medication) was considered to be occurring (or concomitant) with the treatment.

2. If the start date is missing but the stop date is not missing and is after the study dose administration day, then the most conservative approach is taken and the AE (or medication) is considered to be occurring (or concomitant) in the treatment.

3. An AE (or medication) is considered pre-treatment (or prior) if the start date is absent but the stop date is absent and is on or before the day of study dose administration and after the date of informed consent signing.

4. If the start date is not missing but the stop date is missing, the most conservative approach is taken and medication is considered concomitant, whereas AE is defined by the start date.

Severity of missing AEs was assigned to maximum severity; the causal relationship of the missing study drug to AE is classified as "related".

Interim analysis and data monitoring

Interim analysis is discussed in the interim analysis section above.

Multi-centre study

Not applicable to

O. multiple comparison/diversity

A few pairwise comparisons were made, but type 1 error ratios were not adjusted because they were exploratory analyses.

Use of the subject "drug metabolism subset

All subjects were included in the PK analysis.

Activity-control study intended to show equivalence

Not applicable.

Inspection of subgroups

Not applicable.

Tabulation of individual response data

Not applicable.

Drug dose, drug concentration and response relationship

Not applicable.

Drug-drug and drug-disease interactions

Not applicable.

Comparison object (By-Subject) presentation

Not applicable.

Conclusion on drug metabolism

1. Single dose baseline corrected free and total testosterone concentrations had the most clear concentration versus increasing testosterone dose. The dihydrotestosterone analyte concentration provides a clear distinction between 1800 μ g doses compared to lower doses that are not clearly distinguishable from each other. Slight changes in estradiol concentrations were observed, with the lowest dose being 600 μ g, which was clearly distinguished from the two higher doses which were not clearly distinguished from each other. SHBG concentrations did not clearly distinguish between doses of testosterone administered.

2. Multiple dose concentrations were not baseline corrected, but had similar graphical evaluation results. The free and total testosterone concentrations most clearly show the increase in concentration due to the dose. A more modest increase in dihydrotestosterone concentration was observed upon administration, but a slight increase in estradiol and SHBG concentrations was observed upon administration. Testosterone accumulates 2-4 fold when BID is administered at these doses, but returns to baseline after 12-15 hours.

3. Drug metabolism parameters for single dose and multi-dose profiles are listed and summarized individually. A normal dose proportionality statistical test was performed for the single dose profile.

4. Examination of the single dose profile using linear regression in all 3 doses indicated that the free testosterone PK parameter AUC_0-8、AUC_0-24And AUC_0-tOnly the analyte parameters for which dose proportionality was not rejected.

5. Pairwise testing of dose for single dose profiles using ANOVA was consistent with linear regression and also showed free testosterone AUC_0-8、AUC_0-24And AUC_0-tThe parameters are only analyte parameters, which indicate that dose proportionality cannot be rejected for their comparison for one less dose.

6. Comparison of AUC using paired t-test of 3 subjects participating in Single and Multi-dose profiles at the same 1200. mu.g dose level_0-8And AUC_0-24. Two parameters for dihydrotestosterone and AUC of total testosterone_0-24Between uncorrected single and multiple dose profiles, etcEfficacy was rejected but equivalence between profiles was not rejected for any of the free testosterone parameters.

12. Evaluation of safety

A. Degree of exposure

Study drug administration was performed at the clinical site under the supervision of the investigator.

B. Adverse events

Summary of adverse events occurring during treatment

There were no deaths, SAEs or AEs leading to discontinuation in the study. Most TEAEs are in the following systemic organ classification: general disorders (nasal-related events) and conditions at the site of administration and respiratory, thoracic and mediastinal disorders. Most TEAEs were mildly severe and unlikely to be related or unrelated to study medication.

Presentation of adverse events occurring during treatment

The incidence of TEAE in time period 1 is shown in tables 12-1 and 12-2.

Table 12-1: incidence of adverse events in treatment according to systemic organ classification and preferred terminology (single dose group)

MedDRA ═ managing the active medical dictionary; TEAE ═ adverse events occurring in the treatment

Note that: subjects reporting more than 1 TEAE (systemic organ classification or preferred term) at each level were counted only once.

Table 12-2: incidence of adverse events in treatment according to systemic organ classification and preferred terminology (multiple dose cohort)

MedDRA ═ managing the active medical dictionary; TEAE ═ adverse events occurring in the treatment

Note that: subjects reporting more than 1 TEAE (systemic organ classification or preferred term) at each level were counted only once.

Adverse event analysis

Adverse events in epoch 1

In summary, 11 subjects out of 24 (45.8%) experienced at least one TEAE in epoch 1. Most subjects experienced the following TEAE: general disorders and application site disorders (experienced by 7 out of 24 subjects [ 29.2% ]) and respiratory, thoracic and mediastinal disorders (experienced by 5 out of 24 subjects [ 20.8% ]). TEAE experienced by more than 1 subject was ductal site erythema (experienced by 3 out of 24 subjects [ 12.5% ]) and ductal site hemorrhage, ductal site inflammation, dizziness and nasal congestion (experienced by 2 out of 24 subjects [ 8.3% ]). (Table 12-1).

Most of the TEAEs in period 1 were slightly severe. A total of 10 subjects out of 24 (41.7%) underwent mild TEAE. Only 1 subject out of 24 (4.2%) experienced moderate TEAE. Subjects 522-53 (group 2) experienced moderate severe headache and dizziness on the first day. Both TEAEs resolved without treatment the next day and were considered unlikely to be related to study drug.

In summary, 4 of 24 subjects (16.7%) experienced TEAE considered likely to be associated with study medication. A total of 3 subjects out of 24 (12.5%) had TEAEs considered unlikely to be relevant to study medication and 4 subjects out of 24 (16.7%) had TEAEs considered not relevant to study medication.

Adverse events in epoch 2

In summary, 4 of 8 subjects (50.0%) experienced at least one TEAE during epoch 2. General disease and site of administration disorders occurred in 2 of 8 subjects (25.0%). TEAE experienced by 1 subject out of 8 subjects (12.5%) was ductal site pain, ductal site phlebitis, dyspepsia, headache, and nasal pain, respectively. (Table 12-2).

Most TEAEs were mildly severe in period 2. In summary, 3 of 8 subjects (37.5%) experienced mild TEAE. Only 1 subject out of 8 (12.5%) experienced moderate TEAE. Subjects 522-29 experienced moderate severe headache exacerbations the next day. The TEAE resolved after two days without treatment and was seen as possibly related to study medication.

In summary, 2 of 8 subjects (25.0%) experienced a TEAE considered likely to be related to study medication, and 2 of 8 subjects (25.0%) experienced a TEAE considered unrelated to study medication.

Adverse reactions in periods 1 and 2

Adverse reactions (defined as TEAEs considered likely, likely or certainly relevant to study medication) in periods 1 and 2 are shown in tables 12-3.

A total of 6 subjects in the study experienced adverse reactions: in epoch 1, 4 subjects out of 24 (16.7%). And 2 of 8 subjects (25.0%) in epoch 2. All adverse reactions were considered to be likely related to study medication. Subjects 522-29 (period 2) had 2 adverse headache reactions, which were recorded as TEAE: mild headache, with an increased to moderate severity.

Tables 12 to 3: subjects with adverse reactions (single and multiple dose groups)

MedDRA ═ managing the active medical dictionary; TEAE ═ adverse events occurring in the treatment

a. Onset was calculated as [ onset date of epoch 1-treatment date +1] if onset occurred in epoch 1, or [ onset date of epoch 2-treatment date +1] if onset occurred in epoch 2, respectively.

b. Severity was graded by primary investigators as mild, moderate or severe.

Adverse events according to object list

Adverse events are listed in appendix 16.2, list 16.2.7.1, according to the subject. Adverse reactions in periods 1 and 2 (defined as TEAEs considered likely, likely or certainly relevant to study medication) are listed in appendix 16.2, list 16.2.7.4, by subject.

C. Death, other serious adverse events and other significant adverse events

There were no deaths, SAEs or AEs leading to discontinuation in the study.

D. Clinical laboratory evaluation

Evaluation of Each laboratory parameter

Laboratory values over time

The change in laboratory values over time was not calculated.

Single object variation

Subjects with abnormal test values not present at the time of screening are shown in tables 12-4 (hematology), tables 12-5 (chemistry) and tables 12-26 (urinalysis).

Tables 12 to 24: subjects with novel abnormal hematology laboratory assessments after dosing (single and multiple dose groups)

Tables 12 to 25: subjects with novel abnormal chemical laboratory evaluation results after dosing (single and multiple dose groups)

CK ═ creatine kinase; TSH (thyroid-stimulating hormone)

Tables 12 to 26: subjects with new abnormal urinalysis laboratory assessments after dosing (single and multiple dose groups)

Clinically significant abnormalities in individuals

No abnormal clinical laboratory results were recorded as TEAE.

E. Vital signs, physical examination, and other observations related to safety

Vital signs

No abnormal vital signs were PI reported or recorded as TEAE.

Physical examination

Three subjects had abnormal physical findings related to the site of venipuncture of the PK blood sample. None of these results were considered clinically significant.

Subject 522-35(1200 μ g) -phase 2, day 5: mild phlebitis of anterior left elbow

Subject 522-38(1200 μ g) -phase 2, day 5: tenderness/pain in the anterior left elbow region

Subjects 522-51(1200 μ g) -phase 1, day 4: mild tenderness in the left AC IV site

No other abnormal physical examination results were reported except those related to the veno-puncture site of the HEENT or PK blood samples.

Rhinoscopy

No ENT rhinoscopy findings were reported at screening (appendix 16.2, list 16.2.4.3.2).

In phase 1, two subjects had ENT exam findings on day four that were interpreted by PI as clinically significant: subject 522-37(600 μ g) had mild rhinorrhea, and subject 522-53(1200 μ g) had mild erythema on the mucosa of the left nostril.

All abnormal findings in the basic ENT examination are shown in tables 12-27.

Tables 11 to 27: subjects with abnormal basic ear, nose and throat examination (single and multiple dose groups)

CS is clinically significant; ENT ═ ear, nose, and throat; NCS is not clinically significant; TEAE ═ adverse events occurring in the treatment

a. TEAE of rhinorrhea (mild, possibly related to study medication) was reported the next day and resolved on day 5.

b. TEAE reporting nasal mucosal disorders (mild, possibly associated with study medication) on day three and in progress at study completion.

F. Safety conclusions

There were no deaths, SAEs or AEs leading to discontinuation in the study. Most TEAEs are in the following systemic organ classification: general and site of administration and respiratory, thoracic and mediastinal disorders (nasal-related events). Most TEAEs are mild in severity and are unlikely to be associated or unrelated to study medication.

In period 1, a total of 11 subjects (45.8%) out of 24 subjects underwent at least one TEAE. Those experienced by more than one subject were ductal site erythema (experienced by 3 of 24 subjects [ 12.5% ]) and ductal site hemorrhage, ductal site inflammation, dizziness and nasal congestion (experienced by 2 of 24 subjects each [ 8.3% ]).

Most TEAEs were mildly severe in period 1. A total of 10 subjects out of 24 (41.7%) underwent mild TEAE. Only 1 subject out of 24 (4.2%) experienced moderate TEAE. Subjects 522-53(1200 μ g) experienced moderate severe headache and dizziness on the first day. The next day, both TEAEs resolved without treatment and were considered unlikely to be related to study drug.

In period 2, a total of 4 subjects (50.0%) out of 8 subjects experienced at least one TEAE. General disease and site of administration disorders occurred in 2 of 8 subjects (25.0%). TEAE experienced by 1 of 8 subjects (12.5%) was ductal site pain, ductal site phlebitis, dyspepsia, headache and nasal pain, respectively.

Most TEAEs were mildly severe in period 2. In summary, 3 of 8 subjects (37.5%) experienced mild TEAE. Only 1 subject out of 8 (12.5%) experienced moderate TEAE. Subjects 522-29 experienced moderate severe headache exacerbations the next day. The TEAE resolved after two days without treatment and was considered likely to be relevant to the study drug.

A total of 6 subjects experienced adverse reactions in the study (defined as TEAEs considered likely, likely or certainly relevant to study medication); 4 subjects in epoch 1 and 2 subjects in epoch 2. All adverse reactions are considered to be likely related to study medication. Subjects 522-29 (period 2, 600 μ g) had 2 adverse headache reactions, which were recorded as TEAE: mild headache, with an increase in severity to moderate.

A total of 6 subjects experienced adverse reactions in the study: epoch 1, four of 24 subjects (16.7%), and two of epoch 2, 8 subjects (25.0%). All adverse events were considered to be possibly related to study medication. Subjects 522-29 (period 2) had 2 adverse headache reactions, which were recorded as TEAE: mild headache, with an increase in severity to moderate.

There is no TEAE associated with clinical laboratory tests or vital signs. On day four of phase 1, two subjects had ENT examination findings, which were interpreted by PI as clinically significant: subject 522-37(600 μ g) had mild rhinorrhea and subject 522-53(1200 μ g) had mild left nostril mucosal erythema.

CMC part

Testosterone lot 80402960 for clinical mass production was thoroughly tested by the applicant according to USP specifications.

The pharmaceutical product TBS-2 is an adhesive bioadhesive oil-based formulation containing dissolved testosterone, intended for intranasal application, for the treatment of female anorgasmia.

The medicine product is prepared by the following pharmacopoeia inactive ingredients: castor oil, oleoyl polyoxylglycerides, and colloidal silica. TBS-2 was provided in a white, non-aerosol, multi-dose, metering pump vessel. The containers were provided as cartridges (Albion 15ml) and pumps (VP39/140H), respectively, with lids attached. The container sleeve (closure) is made of a material acceptable for pharmaceutical applications. See fig. 39.

The container sleeve relies on air pressure and device design to deliver the required dose. When the actuator of the VP39/140 pump is depressed, the valve opens in the pump mechanism. This allows air pressure to act on the piston through the base of the Albion 15ml cartridge containing the gel, forcing it upwards. As a result, the gel is forced upward through the top of the device. The precise and concise amount of gel delivered is a function of the design of the VP39/140 pump. When actuation ceases, a spring in the pump mechanism closes the valve, preventing the action of air pressure on the piston and returning the actuator to its starting position.

The patient is instructed to place his or her finger on the pump of the actuator and to push the tip of the actuator forward until the finger on the pump reaches the bottom of the nose. The opening of the actuator tip must face the nasal mucosa. The patient depresses the pump and expels the gel into the nasal mucosa. Each administration consists of two actuations, one for each nostril.

The composition of the drug product to be used in this clinical trial at three different concentrations is provided in table 3.2. p.1-1-3.

Table 3.2. p.1-1: ingredient, quality standard and function-0.24% TBS-2 gel

Table 3.2. p.1-2: component, quality standard and function-0.48% TBS-2 gel

Table 3.2. p.1-3: ingredient, quality standard and function-0.72% TBS-2 gel

The study was completed according to the USP <51> antimicrobial efficacy test to determine the absence of microbial growth in the container closure system after filling and in use. The study was performed with 4.5% testosterone gel filled in a multi-dose dispenser.

Sixteen (16) multi-dose dispensers were tested in this study. Each multi-dose dispenser was inoculated with 0.05mL of a standardized microbial suspension (Candida albicans, Aspergillus brasiliensis, staphylococcus aureus, Pseudomonas aeruginosa) through the top of the piston. These microorganisms were chosen because they are the microorganisms recommended for use in nasal products by the USP <51> antimicrobial efficacy test. The theoretical concentration of organisms used for inoculation is between 100,000 and 1,000,000 microorganisms/mL. On the following 21 days, two actuations were performed daily for each multi-dose dispenser to reflect actual use (2 actuations correspond to up to 1 dose).

The inoculated dispensers were incubated upright at 20-25 ℃. After inoculation, each sample was examined on days 1, 7, 14 and 21. The study was performed within twenty-one (21) days. The first day time point was selected to evaluate the worst case scenario. Sample testing was performed after daily actuation. The gel remaining in the cartridge was detected for all time points. The plunger was removed and the remaining gel in the cartridge was further tested using a 10 gram sample to determine the number of test organisms present. Any observable change in the appearance (i.e., color, viscosity) of the sample is examined in these intervals. Each dispenser was discarded after sampling. The results are shown in Table 3.2. P.2.5-1.

Table 3.2. p.2.5-1: number of microorganisms surviving the test period

ND-not detected; no change in product appearance was observed at each time point during the test interval

Table 3.2. p.2.5-2: standard for testing microorganisms (Category 2)

In summary, the bacteria staphylococcus aureus and pseudomonas aeruginosa showed a decrease of not less than 2.0 from the initial count at 14 days, and no increase at 21 days from 14 days. The yeasts candida albicans and aspergillus brasiliensis showed no increase in counts initially calculated from days 14 and 21. Testosterone nasal gel packaged in a multi-dose dispenser meets the criteria for antimicrobial efficacy testing.

Three different concentrations of TBS-2 clinical material-0.24%, 0.48% and 0.72% were prepared for proposed clinical trials. The recipes for these batches are shown in Table 3.2. P.3.2-1.

Table 3.2. p.3.2-1: 100kg batches of 0.24%, 0.48% and 0.72% TBS-2 formulations

TBS-2 was tested for a large number of gels with the following specifications for batch release.

Table 3.2. p.5.1-1: TBS-2 Mass gel Specification

TBS1RC 4-17-hydroxyandrosta-4, 6-dien-3-one (Δ -6-testosterone);

EP impurity I TBS1RC 5-17-hydroxyandrost-4-en-3-one

(epitestosterone); EP impurity C

TBS-2 gels packaged in multi-dose dispensers were tested for the following specifications for batch release.

Table 3.2. p.5.1-2: TBS-2 gel format packaged in multi-dose dispenser

TBS1RC 4-17-hydroxyandrosta-4, 6-dien-3-one (Δ -6-testosterone);

EP impurity I TBS1RC 5-17-hydroxyandrost-4-en-3-one

(epitestosterone); EP impurity C

The delivered dose uniformity/USP was added as a release test to verify the performance of the dispenser. In addition, the analytical procedures for testing related compounds have been modified. The viscosity and water content of the gel were tested at release and used for informational purposes only. These analytical procedures are described in this section.

Ten individual cartridges were employed and tested for uniformity of dose delivered according to the method summarized in table 3.2. p.5.2.1.1-1. Each dispenser was filled 10 times by actuating the pump. The drug content of the first dose, i.e. actuations #11 and #12, and the last dose (10 doses, i.e. 20 actuations based on the label statement), i.e. actuations #29 and #30, were tested. The average of 10 doses (20 actuations) was reported.

Table 3.2. p.5.2.1.1-1: summary of chromatographic status of delivered dose uniformity

The finished product was analyzed by HPLC for the relevant compounds TBS1RC4 (impurity I/Δ -6-testosterone) and TBS1RC5 (impurity C/table testosterone), and for the unknown impurities according to the methods summarized in table 3.2. p.5.2.1.2-1.

Table 3.2. p.5.2.1.2-1: summary of chromatographic disorders for related Compound methods

TBS-2 viscosity was measured using a rotational viscometer. The results are reported, only for informational purposes.

Gel water content was determined using direct titration measurements according to USP method 1 a. The moisture content results are reported for informational purposes only.

The dose uniformity of the test and delivery has been added as a release test to verify the performance of the dispenser according to USP. In addition, the analytical procedures for testing related compounds have been modified. Validation of these analytical procedures is described in this section.

The dosage method of verification and delivery has been confirmed according to the parameters listed in table 3.2. p.5.3.1-1.

Table 3.2. p.5.3.1-1: verification and dose confirmation of delivery

Related compounds/degradation products by HPLC. The methods have been validated for the performance characteristics shown in tables 3.2.p.5.3.2-1 and 3.2. p.5.3.2-2.

Table 3.2. p.5.3.2-1: analytical confirmation by HPLC determination of related compounds

Table 3.2. p.5.3.2-2: analytical confirmation by HPLC determination of related compounds

It can be inferred that the analysis method satisfies the acceptance criteria described in the validation plan.

For the phase I experiment, three large gel batches of TBS-2 have been prepared and are summarized in Table 3.2. P.5.4-1. Batch analysis data for a number of gel batches IMP 11005, IMP 11006 and IMP11007 are shown in table 3.2.p.5.4-2, and batch analysis data for completed drug product batches IMP 11008, IMP 11009 and IMP 11010 are shown in table 3.2. p.5.4-3.

Table 3.2. p.5.4-1: description of TBS-2 batches

Net fill weight 10. g. + -. 1.0g

Table 3.2. p.5.4-2: batch analysis-TBS-2 Large gels, batches IMP 11005, IMP 11006 and IMP11007

TBS1RC 4-17-hydroxyandrosta-4, 6-dien-3-one (Δ -6-testosterone);

EP impurity I TBS1RC 5-17-hydroxyandrost-4-en-3-one

(epitestosterone); EP impurity C

BRT-below reported threshold

Table 3.2. p.5.4-3: batch analysis-TBS-2 completed product filled in Multi-dose Dispenser batches IMP 11008, IMP 11009 and IMP 11010

TBS1RC 4-17-hydroxyandrosta-4, 6-dien-3-one (Δ -6-testosterone);

EP impurity I TBS1RC 5-17-hydroxyandrost-4-en-3-one

(epitestosterone); EP impurity C

TAMC-total aerobic microbial count; TYMC-total combined yeast/mould count; BRT-below reported threshold

The only change to the previous specification was the uniformity of the dose delivered according to an additional test of USP to verify the performance of the dispenser. The following is a description of the test in the specification, where it is discussed in terms of its suitability for the intended use and judged against acceptable criteria.

The delivered dose of gel expelled from the nasal actuator is analyzed from the sample at the beginning and end of a single multi-dose dispenser for active content. Each dispenser was activated by actuating the pump 10 times. The drug content of the first dose, i.e., actuations #11 and #12, and the last dose (10 doses based on the label statement, i.e., 20 actuations), i.e., actuations #29 and #30, was measured using an indoor HPLC method to determine the amount of active ingredient delivered from the nasal actuator, expressed as a percentage of the label statement.

The delivered dose uniformity test showed uniformity in the dose per actuation and the total dose expelled from the nasal actuator (2 actuations) and was consistent with the label statement.

Proposed acceptance criteria are USP <601> based on delivered dose uniformity and nasal spray and inhalation solutions, suspensions and spray drug product guidelines-chemistry, preparation and control documents:

for more than 2 of 20 assays performed from 10 containers, the amount of active ingredient per assay does not exceed 80 to 120% of LC; no measurements exceeded 75 to 125% of the LC, and the average of each of the initial and final measurements did not exceed 85 to 115% of the LC.

TBS-2 was packaged in an Albion 15ml cartridge consisting of polypropylene with a VP39/140H pump and lid. The cartridge was filled with gel under vacuum using a vacuum system laboratory filling unit (airless systems, RD 149Charleval 27380, france) to effectively expel 125mg of gel.

The target fill weight for the Albion 15ml cartridge was 10.0. + -. 1.0 g.

For packaging ingredients, quality control measures are proposed. Material information on an Albion 15ml cartridge with VP39/140H pump and lid is provided in table 3.2. p.7-1. In addition to the supplier issuing the CoA, the container closure system was re-tested on receipt to meet the specifications summarized in Table 3.2. P.7-2. The CoA of the Albion 15ml cartridge Lot 10318UV12101 is provided in appendix 5. A diagram of a 15ml Albion vial and PMP VP39/140H 15Albion + digital actuator + cap 15ml round Albion is provided in fig. 39.

Table 3.2. p.7-1: albion 15ml Cartridge-Material information with VP39/140H Pump and lid

Table 3.2. p.7-2: albion 15ml cartridge-format with VP39/140H Pump and lid

Three clinical batches of TBS-2 (IMP 11005, IMP 11006 and IMP 11007) were prepared in bulk in GMP equipment. Each batch was then filled in a multi-dose dispenser as summarized in table 3.2. p.8.1.

Table 3.2. p.8.1: bulk gel and finished product batch

A large number of gels will be stored at real-time conditions 25 ± 2 ℃, 60 ± 5% RH and will be tested at the time intervals indicated in table 3.2.p.8.3. -2.

Table 3.2. p.8.3-2: stability schedules for TBS-2 batches IMP 11005, IMP 11006 and IMP11007

Table 3.2. p.8.1-3: TBS-2 stability study of Large gels test parameters and corresponding acceptance criteria

TBS1RC 4-17-hydroxyandrosta-4, 6-dien-3-one (Δ -6-testosterone);

EP impurity I TBS1RC 5-17-hydroxyandrost-4-en-3-one

(epitestosterone); EP impurity C

The multi-dose dispensers were stored in real-time storage (25 + -2 deg.C, 60 + -5% RH), intermediate time storage (30 + -2 deg.C, 65 + -5% RH) and early storage conditions (40 + -2 deg.C, 75 + -5% RH) and tested against the schedule shown in Table 3.2. P.8.1-4. Ten (10) dispensers will be analyzed at each time point.

Table 3.2. p.8.1-4: stability schedules for COMPLEO-completed products filled in multi-dose dispensers

The attributes used to confirm the quality of the finished product of TBS-2 and the corresponding acceptance criteria are listed in Table 3.2. P.8.1-5.

Table 3.2. p.8.1-5: stability study of TBS-2 completed products test parameters and corresponding acceptance criteria

After data generation, the stability study results will be evaluated for any trends and suggested shelf life. Room temperature, intermediate and early stability studies are ongoing and updated data is available upon request.

TBS-2 batches and finished product will be placed according to the stability program described in section 3.2. p.8.1. Providing a stability renewal material for utilization.

The 4.5% testosterone gel according to the invention was packaged in a consistent container closure system with an Albion 15ml cartridge composed of polypropylene and having a VP39/140H pump and cap. For the 4.5% gel, the qualitative (qualitative) formulation was the same as for the 0.24%, 0.48% and 0.72% gels, except for the proportions of castor oil and testosterone. Tables 3.2.P.8.3-1 and 3.2.P.8.3-2 provide supporting data for the stability of testosterone gels packaged in Albion 15ml cartridges composed of polypropylene with a VP39/140H pump and lid. This supporting data indicates that the gel packaged in the dispenser provides adequate protection for efficacy and purity, and is within accepted standards.

Table 3.2. p.8.3-1: stability data for 4.5% testosterone gel batch 1969 in multi-dose dispenser (25 ± 2 ℃, 60 ± 5% r.h., upright)

BRT-below reported threshold

Table 3.2. p.8.3-2: stability data for 4.5% testosterone gel batch 1969 in multi-dose dispenser (40 ± 2 ℃, 75 ± 5% r.h., upright)

BRT-below reported threshold

14. Discussion and general conclusions

A.Object summary

This is a phase 1, single-center, randomized, open label parallel group study of TBS-2 in 3 cohort subjects (cohorts 1, 2 and 3) in epoch 1 (single dose) and in multiple dose cohorts in epoch 2. A total of 24 healthy women received 600, 1200 or 1800 μ g TBS-2 intranasally to evaluate TBS-2 for safety, tolerability and PK.

B.Conclusion on drug metabolism

The results of the study showed free testosterone concentration and AUC_0-8、AUC_0-24And AUC_0-tThe parameters are dose proportional. Although the total testosterone concentration and parameters clearly embody the dose, the strongest dose proportionality relationship is with free testosterone. Dose proportionality was tested by linear regression and by pairwise dose parameter comparison, while both tests were ambiguous because free testosterone concentration was dose proportional. The other analyte concentrations were less dose-dependent and were in the following order: dihydrotestosterone has less variation to estradiol with minimal change to SHBG finally.

In addition, AUC for free testosterone_0-8And AUC_0-24Equivalence between single and multiple dose profiles was not rejected for any of the parameters, indicating that there was little, if any, accumulation of free testosterone after multiple administrations. However, the results are limited to receiving 1200 μ g of 3 objects on each profile. Single dose parameter calculations were performed for uncorrected concentrations of free testosterone, total testosterone and dihydrotestosterone for comparison to multiple dose parameters. The drug metabolism analysis was based on 5 endogenous analytes that had been reported in the normal range as well as the baseline range. The following table shows the normal range, the observed baseline range, and the baseline range broken by the dose cohort.

Comparison of these data for the normal range with the pooled (pooled) baseline range indicates that the pooled baseline range is outside the normal range for free testosterone (min and max), dihydrotestosterone (max), estradiol (min), and SHBG (min and max).

C.Safety conclusions

There were no deaths, SAEs or AEs leading to discontinuation in the study. Most TEAEs are in the following systemic organ classification: general disorders (nasal-related events) and disorders at the site of administration and respiratory, thoracic and mediastinal disorders. This was unexpected when performing venipuncture for PK blood sample extraction and intranasal study drug administration. Most TEAEs were mildly severe and unlikely to be related or unrelated to study medication.

TBS-2 was considered safe with respect to AE and vital signs, and well tolerated.

The disclosures of the patents, patent documents, articles, abstracts, and other publications cited herein are hereby incorporated by reference in their entirety as if each were individually incorporated. In case of conflict, the present specification, including definitions, will control. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope and spirit of the invention. The exemplary embodiments and examples are provided only as examples and are not intended to limit the scope of the present invention. The scope of the invention is limited only by the claims presented below.

Claims (166)

1. A lower dosage strength testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. between about 0.1% to about 1.5% testosterone by weight of the gel formulation; and

b. a pharmaceutically acceptable vehicle.

2. The testosterone gel formulation of any one of claim 2, wherein said gel formulation further comprises a solvent, a wetting agent, and a viscosity increasing agent.

3. The testosterone gel formulation of claim 2, wherein said solvent is castor oil.

4. The testosterone gel formulation of claim 2, wherein said wetting agent is oleoyl polyoxylglyceride.

5. The testosterone gel formulation of claim 2, wherein said viscosity increasing agent is colloidal silicon dioxide.

6. The testosterone gel formulation of any one of claims 1 or 2, wherein said gel formulation further comprises castor oil, oleoyl polyoxylglycerides, and colloidal silicon dioxide.

7. The testosterone gel formulation of any one of claims 1-6, wherein said gel formulation is a bioequivalent formulation.

8. The testosterone gel formulation of any one of claims 1-6, wherein said gel formulation is a pharmaceutically equivalent formulation.

9. The testosterone gel formulation of any one of claims 1-6, wherein said gel formulation is a therapeutically equivalent formulation.

10. A packaged pharmaceutical comprising:

(a) a lower dosage strength testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises between about 0.1% and 1.5% testosterone by weight; and

(b) instructions for using said testosterone gel formulation to treat anorgasmia.

11. A packaged pharmaceutical comprising:

(a) a lower dosage strength testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises between about 0.1% and 1.5% testosterone by weight; and

(b) instructions for using said testosterone gel formulation to treat Hypoactive Sexual Desire Disorder (HSDD).

12. The packaged pharmaceutical of claim 10 or 11, wherein said testosterone is present as a pharmaceutical composition comprising a therapeutically effective amount of testosterone or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.

13. The packaged pharmaceutical of claim 10 or 11, further comprising the step of identifying a subject in need of said pharmaceutical.

14. A method of treating anorgasmia comprising administering intranasally to a subject said gel formulation of any one of claims 1-9 to deliver a therapeutically effective amount of testosterone to effectively treat HSDD.

15. A method of treating Hypoactive Sexual Desire Disorder (HSDD), the method comprising administering intranasally to each nostril of a subject said gel formulation of any one of claims 1-9 to deliver a therapeutically effective amount of testosterone to effectively treat HSDD.

16. An intranasal method of treating a subject diagnosed with anorgasmia with a lower dosage strength testosterone gel formulation for nasal administration comprising between about 0.1% and 1.5% testosterone by weight of said gel formulation, comprising: applying the testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said anorgasmia.

17. The method of claim 16, wherein the subject receives the testosterone gel intranasally twice daily.

18. An intranasal method of treating a subject diagnosed with HSDD with a lower dose strength testosterone gel formulation for nasal administration comprising between about 0.1% and 1.5% testosterone by weight of said gel formulation, comprising: applying said testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said HSDD.

19. The method of claim 18, wherein said subject receives said testosterone gel intranasally twice daily.

20. The method of claim 18, wherein the lower dosage strength testosterone gel formulation comprises between about 0.24% and 0.72% testosterone by weight of said gel formulation.

21. The method of claim 18, wherein the lower dosage strength testosterone gel formulation comprises about 0.24% testosterone by weight of said gel formulation.

22. The method of claim 18, wherein the lower dosage strength testosterone gel formulation comprises about 0.48% testosterone by weight of said gel formulation.

23. The method of claim 18, wherein the lower dosage strength testosterone gel formulation comprises about 0.72% testosterone by weight of said gel formulation.

24. The lower dosage strength testosterone gel formulation of claim 1, wherein said lower dosage strength testosterone gel formulation comprises between about 0.24% and 0.72% testosterone by weight of said gel formulation.

25. The method of claim 1, wherein the lower dosage strength testosterone gel formulation comprises about 0.24% testosterone by weight of said gel formulation.

26. The method of claim 1, wherein the lower dosage strength testosterone gel formulation comprises about 0.48% testosterone by weight of said gel formulation.

27. The method of claim 1, wherein the lower dosage strength testosterone gel formulation comprises about 0.72% testosterone by weight of said gel formulation.

28. The packaged pharmaceutical of claim 10, wherein the lower dosage strength testosterone gel formulation comprises between about 0.24% and 0.72% testosterone by weight of said gel formulation.

29. The method of claim 10, wherein the lower dosage strength testosterone gel formulation comprises about 0.24% testosterone by weight of said gel formulation.

30. The method of claim 10, wherein the lower dosage strength testosterone gel formulation comprises about 0.48% testosterone by weight of said gel formulation.

31. The method of claim 10, wherein the lower dosage strength testosterone gel formulation comprises about 0.72% testosterone by weight of said gel formulation.

32. The packaged pharmaceutical of claim 11, wherein the lower dosage strength testosterone gel formulation comprises between about 0.24% and 0.72% testosterone by weight of said gel formulation.

33. The method of claim 11, wherein the lower dosage strength testosterone gel formulation comprises about 0.24% testosterone by weight of said gel formulation.

34. The method of claim 11, wherein the lower dosage strength testosterone gel formulation comprises about 0.48% testosterone by weight of said gel formulation.

35. The method of claim 11, wherein the lower dosage strength testosterone gel formulation comprises about 0.72% testosterone by weight of said gel formulation.

36. A testosterone gel formulation for nasal administration, wherein said gel formulation increases plasma testosterone levels to at least about 0.4ng/ml within about 10 minutes after direct nasal administration of said testosterone gel formulation to a subject.

37. A testosterone gel formulation for nasal administration, wherein said gel formulation increases plasma testosterone levels to at least about 0.7ng/ml within about 100 minutes after direct nasal administration of said testosterone gel formulation to a subject.

38. A testosterone gel formulation for nasal administration, wherein administration of said gel formulation elevates plasma testosterone levels for at least about 10 minutes after direct nasal administration of said testosterone gel formulation to a subject.

39. A testosterone gel formulation for nasal administration, wherein nasal administration of said formulation increases plasma testosterone levels to a level of at least about 0.3ng/ml, and wherein said increase is maintained in a subject for about 6 hours after nasal administration of said testosterone gel formulation to said subject.

40. A testosterone gel formulation for nasal administration, wherein nasal administration of said formulation to a subject increases plasma testosterone levels to at least about 0.4ng/ml, and wherein said increase is maintained for at least 6 hours after nasal administration to a subject.

41. A testosterone gel formulation for nasal administration, wherein nasal administration of said formulation to a subject increases plasma testosterone levels to at least 0.7ng/ml within about 60 minutes immediately after nasal administration of said testosterone gel formulation to a subject.

42. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. about 0.6% testosterone by weight of said gel formulation; and

b. a pharmaceutically acceptable vehicle.

43. The testosterone gel formulation of any one of claims 36-42, wherein said gel formulation further comprises a pharmaceutically acceptable vehicle.

44. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. testosterone; and

b. pharmaceutically acceptable vehicle

Wherein a plasma testosterone level of at least about 0.4ng/ml is maintained in the subject for about 6 hours immediately after nasal administration of the gel formulation to the subject.

45. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. testosterone; and

b. a pharmaceutically acceptable vehicle;

wherein a plasma testosterone level of at least about 0.7ng/ml is achieved in the subject within about 60 minutes immediately after nasal administration of the gel formulation to the subject.

46. The testosterone gel formulation of any one of claims 36-45, wherein said gel formulation further comprises a solvent, a wetting agent, and a viscosity increasing agent.

47. The testosterone gel formulation of claim 46, wherein said solvent is castor oil.

48. The testosterone gel formulation of claim 46, wherein said wetting agent is oleoyl polyoxylglyceride.

49. The testosterone gel formulation of claim 46, wherein said viscosity increasing agent is colloidal silicon dioxide.

50. The testosterone gel formulation of any one of claims 36-45, wherein said gel formulation further comprises castor oil, oleoyl polyoxylglycerides, and colloidal silicon dioxide.

51. The testosterone gel formulation of any one of claims 36-50, wherein said gel formulation is a bioequivalent formulation.

52. The testosterone gel formulation of any one of claims 36-50, wherein said gel formulation is a pharmaceutically equivalent formulation.

53. The testosterone gel formulation of any one of claims 36-50, wherein said gel formulation is a therapeutically equivalent formulation.

54. A packaged pharmaceutical comprising:

(a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 0.6% by weight; and

(b) instructions for using said testosterone gel formulation to treat anorgasmia.

55. A packaged pharmaceutical comprising:

(a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 0.6% by weight; and

(b) instructions for using said testosterone gel formulation to treat Hypoactive Sexual Desire Disorder (HSDD).

56. The packaged pharmaceutical of claim 54 or 55, wherein said testosterone is present as a pharmaceutical composition comprising a therapeutically effective amount of testosterone or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.

57. The packaged pharmaceutical of claim 54 or 55, further comprising the step of identifying a subject in need of said pharmaceutical.

58. A method of treating anorgasmia, comprising administering intranasally to each nostril of a subject said gel formulation of any one of claims 36-57 to deliver a therapeutically effective amount of testosterone to effectively treat anorgasmia.

59. A method of treating Hypoactive Sexual Desire Disorder (HSDD), said method comprising administering intranasally to each nostril of a subject said gel formulation of any one of claims 36-57 to deliver a therapeutically effective amount of testosterone to effectively treat HSDD.

60. An intranasal method of treating a subject suffering from or diagnosed with anorgasmia with a testosterone gel formulation for nasal administration comprising about 0.6% testosterone by weight of said gel formulation, said method comprising: applying the testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said anorgasmia.

61. The method of claim 60, wherein said subject receives said testosterone gel intranasally twice daily.

62. An intranasal method of treating a subject suffering from or diagnosed with HSDD with a testosterone gel formulation for nasal administration comprising about 0.6% testosterone by weight of said gel formulation, comprising: applying said testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said HSDD.

63. The method of claim 62, wherein said subject receives said testosterone gel intranasally twice daily.

64. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. about 0.72% testosterone by weight of said gel formulation; and

b. a pharmaceutically acceptable vehicle in the form of a pharmaceutically acceptable vehicle,

wherein the gel formulation increases plasma testosterone levels to at least about 0.4ng/ml within about 10 minutes after direct nasal administration of the testosterone gel formulation to a subject.

65. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. about 0.72% testosterone by weight of said gel formulation; and

b. a pharmaceutically acceptable vehicle in the form of a pharmaceutically acceptable vehicle,

wherein the gel formulation increases plasma testosterone levels to at least about 0.7ng/ml within about 100 minutes after direct nasal administration of the testosterone gel formulation to a subject.

66. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. about 0.72% testosterone by weight of said gel formulation; and

b. a pharmaceutically acceptable vehicle in the form of a pharmaceutically acceptable vehicle,

wherein administration of the gel formulation increases plasma testosterone levels for at least about 10 minutes after direct nasal administration of the testosterone gel formulation to a subject.

67. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. about 0.72% testosterone by weight of said gel formulation; and

b. a pharmaceutically acceptable vehicle in the form of a pharmaceutically acceptable vehicle,

wherein nasal administration of the formulation increases plasma testosterone levels to a level of at least about 0.3ng/ml immediately after nasal administration of the testosterone gel formulation to the subject, and wherein the increase is maintained in the subject for about 6 hours.

68. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. about 0.72% testosterone by weight of said gel formulation; and

b. a pharmaceutically acceptable vehicle in the form of a pharmaceutically acceptable vehicle,

wherein nasal administration of the formulation to a subject increases plasma testosterone levels to at least about 0.4ng/ml immediately after nasal administration to the subject, and wherein the increase is maintained for at least 6 hours.

69. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. about 0.72% testosterone by weight of said gel formulation; and

b. a pharmaceutically acceptable vehicle in the form of a pharmaceutically acceptable vehicle,

wherein nasal administration of the formulation to a subject increases plasma testosterone levels to at least 0.7ng/ml about 60 minutes immediately after nasal administration of the testosterone gel formulation to the subject.

70. The testosterone gel formulation of any one of claims 64-69, wherein said gel formulation further comprises a pharmaceutically acceptable vehicle.

71. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. about 0.72% testosterone; and

b. a pharmaceutically acceptable vehicle in the form of a pharmaceutically acceptable vehicle,

wherein a plasma testosterone level of at least about 0.4ng/ml is maintained in the subject for about 6 hours immediately after nasal administration of the gel formulation to the subject.

72. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. about 0.72% testosterone; and

b. a pharmaceutically acceptable vehicle;

wherein a plasma testosterone level of at least about 0.7ng/ml is achieved in the subject within about 60 minutes immediately after nasal administration of the gel formulation to the subject.

73. The testosterone gel formulation of any one of claims 63-72, wherein said gel formulation further comprises a solvent, a wetting agent, and a viscosity increasing agent.

74. The testosterone gel formulation of claim 73, wherein said solvent is castor oil.

75. The testosterone gel formulation of claim 73, wherein said wetting agent is oleoyl polyoxylglyceride.

76. The testosterone gel formulation of claim 73, wherein said viscosity increasing agent is colloidal silicon dioxide.

77. The testosterone gel formulation of any one of claims 64-72, wherein said gel formulation further comprises castor oil, oleoyl polyoxylglycerides, and colloidal silicon dioxide.

78. The testosterone gel formulation of any one of claims 64-77, wherein said gel formulation is a bioequivalent formulation.

79. The testosterone gel formulation of any one of claims 64-77, wherein said gel formulation is a pharmaceutically equivalent formulation.

80. The testosterone gel formulation of any one of claims 64-77, wherein said gel formulation is a therapeutically equivalent formulation.

81. A packaged pharmaceutical comprising:

(a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 0.72% by weight; and

(b) instructions for using said testosterone gel formulation to treat anorgasmia.

82. A packaged pharmaceutical comprising:

(a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 0.72% by weight; and

(b) instructions for using said testosterone gel formulation to treat Hypoactive Sexual Desire Disorder (HSDD).

83. The packaged pharmaceutical of claim 81 or 82, wherein said testosterone is present as a pharmaceutical composition comprising a therapeutically effective amount of testosterone or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.

84. The packaged pharmaceutical of claim 82 or 83, further comprising the step of identifying a subject in need of said pharmaceutical.

85. A method of treating anorgasmia, comprising administering intranasally to each nostril of a subject said gel formulation of any one of claims 64-84 to deliver a therapeutically effective amount of testosterone to effectively treat anorgasmia.

86. A method of treating Hypoactive Sexual Desire Disorder (HSDD), said method comprising administering intranasally to each nostril of a subject said gel formulation of any one of claims 29-49 to deliver a therapeutically effective amount of testosterone to effectively treat HSDD.

87. An intranasal method of treating a subject suffering from or diagnosed with anorgasmia with a testosterone gel formulation for nasal administration comprising about 0.72% testosterone by weight of said gel formulation, said method comprising: applying the testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said anorgasmia.

88. The method of claim 87, wherein said subject receives said testosterone gel intranasally twice daily.

89. An intranasal method of treating a subject suffering from or diagnosed with HSDD with a testosterone gel formulation for nasal administration comprising about 0.72% testosterone by weight of said gel formulation, comprising: applying said testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said HSDD.

90. The method of claim 89, wherein said subject receives said testosterone gel intranasally twice daily.

91. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. about 0.45% testosterone by weight of said gel formulation; and

b. a pharmaceutically acceptable vehicle.

92. The testosterone gel formulation of claim 91, wherein said gel formulation further comprises a solvent, a wetting agent, and a viscosity increasing agent.

93. The testosterone gel formulation of claim 92, wherein said solvent is castor oil.

94. The testosterone gel formulation of claim 93, wherein said wetting agent is oleoyl polyoxylglyceride.

95. The testosterone gel formulation of claim 93, wherein said viscosity increasing agent is colloidal silicon dioxide.

96. The testosterone gel formulation of any one of claims 91 or 92, wherein said gel formulation further comprises castor oil, oleoyl polyoxylglycerides, and colloidal silicon dioxide.

97. The testosterone gel formulation of any one of claims 91-96, wherein said gel formulation is a bioequivalent formulation.

98. The testosterone gel formulation of any one of claims 91-96, wherein said gel formulation is a pharmaceutically equivalent formulation.

99. The testosterone gel formulation of any one of claims 91-96, wherein said gel formulation is a therapeutically equivalent formulation.

100. A packaged pharmaceutical comprising:

(a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 0.45% by weight; and

(b) instructions for using said testosterone gel formulation to treat anorgasmia.

101. A packaged pharmaceutical comprising:

(a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 0.45% by weight; and

(b) instructions for using said testosterone gel formulation to treat Hypoactive Sexual Desire Disorder (HSDD).

102. The packaged pharmaceutical of claim 100 or 101, wherein said testosterone is present as a pharmaceutical composition comprising a therapeutically effective amount of testosterone or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.

103. The packaged pharmaceutical of claim 100 or 101, further comprising the step of identifying a subject in need of said pharmaceutical.

104. A method of treating anorgasmia comprising administering intranasally to a subject said gel formulation of any one of claims 91-99 to deliver a therapeutically effective amount of testosterone to effectively treat HSDD.

105. A method of treating Hypoactive Sexual Desire Disorder (HSDD), the method comprising administering intranasally to each nostril of a subject said gel formulation of any one of claims 1-9 to deliver a therapeutically effective amount of testosterone to effectively treat HSDD.

106. An intranasal method of treating a subject diagnosed with anorgasmia with a testosterone gel formulation for nasal administration comprising about 0.45% testosterone by weight of said gel formulation, said method comprising: applying the testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said anorgasmia.

107. The method of claim 106, wherein said subject receives said testosterone gel intranasally twice daily.

108. An intranasal method of treating a subject diagnosed with HSDD with a testosterone gel formulation for nasal administration comprising about 0.45% testosterone by weight of said gel formulation, comprising: applying said testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said HSDD.

109. The method of claim 108, wherein said subject receives said testosterone gel intranasally twice daily.

110. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. about 0.48% testosterone by weight of said gel formulation; and

b. a pharmaceutically acceptable vehicle.

111. The testosterone gel formulation of claim 110, wherein said gel formulation further comprises a solvent, a wetting agent, and a viscosity increasing agent.

112. The testosterone gel formulation of claim 111, wherein said solvent is castor oil.

113. The testosterone gel formulation of claim 112, wherein said wetting agent is oleoyl polyoxylglyceride.

114. The testosterone gel formulation of claim 112, wherein said viscosity increasing agent is colloidal silicon dioxide.

115. The testosterone gel formulation of any one of claims 100 or 111, wherein said gel formulation further comprises castor oil, oleoyl polyoxylglycerides, and colloidal silicon dioxide.

116. The testosterone gel formulation of any one of claims 110-115, wherein said gel formulation is a bioequivalent formulation.

117. The testosterone gel formulation of any one of claims 110-115, wherein said gel formulation is a pharmaceutically equivalent formulation.

118. The testosterone gel formulation of any one of claims 110-115, wherein said gel formulation is a therapeutically equivalent formulation.

119. A packaged pharmaceutical comprising:

(a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 0.48% by weight; and

(b) instructions for using said testosterone gel formulation to treat anorgasmia.

120. A packaged pharmaceutical comprising:

(a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 0.48% by weight; and

(b) instructions for using said testosterone gel formulation to treat Hypoactive Sexual Desire Disorder (HSDD).

121. The packaged pharmaceutical of claim 119 or 120, wherein said testosterone is present as a pharmaceutical composition comprising a therapeutically effective amount of testosterone or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.

122. The packaged pharmaceutical of claim 119 or 1200, further comprising the step of identifying a subject in need of said pharmaceutical.

123. A method of treating anorgasmia comprising administering intranasally to a subject said gel formulation of any one of claims 110-118 to deliver a therapeutically effective amount of testosterone to effectively treat HSDD.

124. A method of treating Hypoactive Sexual Desire Disorder (HSDD), the method comprising administering intranasally to each nostril of a subject the gel formulation of any one of claims 110-118 to deliver a therapeutically effective amount of testosterone to effectively treat HSDD.

125. An intranasal method of treating a subject diagnosed with anorgasmia with a testosterone gel formulation for nasal administration comprising about 0.48% testosterone by weight of said gel formulation, said method comprising: applying the testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said anorgasmia.

126. The method of claim 125, wherein said subject receives said testosterone gel intranasally twice daily.

127. An intranasal method of treating a subject diagnosed with HSDD with a testosterone gel formulation for nasal administration comprising about 0.48% testosterone by weight of said gel formulation, comprising: applying said testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said HSDD.

128. The method of claim 127, wherein said subject receives said testosterone gel intranasally twice daily.

129. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. about 0.15% testosterone by weight of said gel formulation; and

b. a pharmaceutically acceptable vehicle.

130. The testosterone gel formulation of claim 129, wherein said gel formulation further comprises a solvent, a wetting agent, and a viscosity increasing agent.

131. The testosterone gel formulation of claim 130, wherein said solvent is castor oil.

132. The testosterone gel formulation of claim 130, wherein said wetting agent is oleoyl polyoxylglyceride.

133. The testosterone gel formulation of claim 130, wherein said viscosity increasing agent is colloidal silicon dioxide.

134. The testosterone gel formulation of any one of claims 129 or 130, wherein said gel formulation further comprises castor oil, oleoyl polyoxylglycerides, and colloidal silicon dioxide.

135. The testosterone gel formulation of any one of claims 129 or 134, wherein said gel formulation is a bioequivalent formulation.

136. The testosterone gel formulation of any one of claims 129 or 134, wherein said gel formulation is a pharmaceutically equivalent formulation.

137. The testosterone gel formulation of any one of claims 129 or 134, wherein said gel formulation is a therapeutically equivalent formulation.

138. A packaged pharmaceutical comprising:

(a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 0.15% by weight; and

(b) instructions for using said testosterone gel formulation to treat anorgasmia.

139. A packaged pharmaceutical comprising:

(a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 0.15% by weight; and

(b) instructions for using said testosterone gel formulation to treat Hypoactive Sexual Desire Disorder (HSDD).

140. The packaged pharmaceutical of claim 138 or 139, wherein said testosterone is present as a pharmaceutical composition comprising a therapeutically effective amount of testosterone or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.

141. The packaged pharmaceutical of claim 138 or 139, further comprising the step of identifying a subject in need of said pharmaceutical.

142. A method of treating anorgasmia comprising administering intranasally to each nostril of a subject said gel formulation of any one of claims 129-137 to deliver a therapeutically effective amount of testosterone to effectively treat anorgasmia.

143. A method of treating Hypoactive Sexual Desire Disorder (HSDD), the method comprising administering intranasally to each nostril of a subject said gel formulation of any one of claims 1-9 to deliver a therapeutically effective amount of testosterone to effectively treat HSDD.

144. An intranasal method of treating a subject diagnosed with anorgasmia with a testosterone gel formulation for nasal administration comprising about 0.15% testosterone by weight of said gel formulation, said method comprising: applying the testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said anorgasmia.

145. The method of claim 144, wherein said subject receives said testosterone gel intranasally twice daily.

146. An intranasal method of treating a subject diagnosed with HSDD with a testosterone gel formulation for nasal administration comprising about 0.15% testosterone by weight of said gel formulation, comprising: applying said testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said HSDD.

147. The method of claim 146, wherein said subject receives said testosterone gel intranasally twice daily.

148. A testosterone gel formulation for nasal administration, said testosterone gel formulation comprising:

a. about 0.24% testosterone by weight of said gel formulation; and

b. a pharmaceutically acceptable vehicle.

149. The testosterone gel formulation of claim 148, wherein said gel formulation further comprises a solvent, a wetting agent, and a viscosity increasing agent.

150. The testosterone gel formulation of claim 149, wherein said solvent is castor oil.

151. The testosterone gel formulation of claim 150, wherein said wetting agent is oleoyl polyoxylglyceride.

152. The testosterone gel formulation of claim 150, wherein said viscosity increasing agent is colloidal silicon dioxide.

153. The testosterone gel formulation of any one of claims 148 or 149, wherein said gel formulation further comprises castor oil, oleoyl polyoxylglycerides, and colloidal silicon dioxide.

154. The testosterone gel formulation of any one of claims 148-153, wherein said gel formulation is a bioequivalent formulation.

155. The testosterone gel formulation of any one of claims 148-153, wherein said gel formulation is a pharmaceutically equivalent formulation.

156. The testosterone gel formulation of any one of claims 148-153, wherein said gel formulation is a therapeutically equivalent formulation.

157. A packaged pharmaceutical comprising:

(a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 0.24% by weight; and

(b) instructions for using said testosterone gel formulation to treat anorgasmia.

158. A packaged pharmaceutical comprising:

(a) a testosterone gel formulation for nasal administration or a pharmaceutically acceptable salt or prodrug thereof, wherein said gel formulation comprises about 0.24% by weight; and

(b) instructions for using said testosterone gel formulation to treat Hypoactive Sexual Desire Disorder (HSDD).

159. The packaged pharmaceutical of claim 157 or 158, wherein said testosterone is present as a pharmaceutical composition comprising a therapeutically effective amount of testosterone or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier.

160. The packaged pharmaceutical of claim 157 or 158, further comprising the step of identifying a subject in need of said pharmaceutical.

161. A method of treating anorgasmia comprising administering intranasally to a subject said gel formulation of any one of claims 148-156 to deliver a therapeutically effective amount of testosterone to effectively treat HSDD.

162. A method of treating Hypoactive Sexual Desire Disorder (HSDD), the method comprising administering intranasally to each nostril of a subject the gel formulation of any one of claims 148-156 to deliver a therapeutically effective amount of testosterone to effectively treat HSDD.

163. An intranasal method of treating a subject diagnosed with anorgasmia with a testosterone gel formulation for nasal administration comprising about 0.24% testosterone by weight of said gel formulation, said method comprising: applying the testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said anorgasmia.

164. The method of claim 163, wherein said subject receives said testosterone gel intranasally twice daily.

165. An intranasal method of treating a subject diagnosed with HSDD with a testosterone gel formulation for nasal administration comprising about 0.24% testosterone by weight of said gel formulation, comprising: applying said testosterone gel formulation to each nostril of said subject at least once a day to deliver an effective amount of testosterone to treat said HSDD.

166. The method of claim 165, wherein said subject receives said testosterone gel intranasally twice daily.