WO2017035619A1 - Nasal pharmaceutical testosterone formulation and kit designed as a card of unit nasal devices for the application of testosterone monodoses - Google Patents

Abstract

The invention relates to a nasal pharmaceutical testosterone formulation and of a series of devices that form a packaging card-shaped pharmaceutical kit for nasal administration of testosterone, the kit being formed by a plurality of therapeutically measured single doses or monodoses. The series of devices that form the pharmaceutical kit is characterised by a series of individual devices (1) containing a micronised testosterone gel formulation of high viscosity, with a low hormone dosage, providing to a female or male patient precisely measured and physiologically suitable testosterone unit doses. After use, the device is immediately discarded by the user, without residual hormone losses even during nasal administration, in view of the high viscosity of the formulation which, together with the air pumping device for the medicinal drug contained in the device, ensures the release of practically all the content of the device. Each device comprises a hollow chamber (2) containing the medicinal drug, and an air column zone that acts as a plunger to expel the volume of medicinal drug contained in the chamber (2). The air expulsion chamber (3) provides air compressed by the user inside the hollow chamber (2), which acts as compressed air when it is pressed through the neck (6) located between the hollow chamber (2) and the air chamber (3). Predetermined tearing lines (8 - 9 - 12) make it easier to remove each device from the packaging card before use.

Description

NASAL PHARMACEUTICAL FORMULATION OF TESTOSTERONE AND "CARTON" KIT OF UNITARY NASAL DEVICES FOR APPLICATION OF TESTOSTERONE MONODOSIS.

APPLICATION FIELD

This patent application is a set of devices comprising a device-shaped pharmaceutical kit for nasal testosterone administration consisting of a plurality of single dose single dose delivery devices. monodose, therapeutically measured.

 Each device is provided for the administration of a single dose of a testosterone formulation to an individual in need of hormone treatment, and after use is discarded.

 Each device releases an accurate volume amount of the testosterone formulation without leaving dead volume.

 To this end, the testosterone formulation is such that it allows the device to release an accurate and substantially total amount of the testosterone formulation contained therein, without leaving any remaining volume.

 More particularly, the patient is a female patient undergoing hormone replacement treatment in which a minimal daily dose of the hormone testosterone is administered for this purpose.

 In particular, the patient is also male and given an adequate minimum daily dose for the purpose of hormone replacement or supplementation.

 BACKGROUND OF THE INVENTION

Testosterone is usually thought of as a "male hormone" but is found in both men and women. women, although the amount of this hormone in the female body is usually about twenty (20) times lower than in men.

 Testosterone, the main androgen of the circulation, is responsible for the development and maintenance of male sexual characteristics and anabolic state of tissues. The physiology and pathophysiology of testosterone are well differentiated in men and women.

 Chemically testosterone is a spheroid hormone (formed from cholesterol).

 Specifically in women testosterone decreases slowly and progressively from the third decade and throughout life.

 The decline of this hormone can lead to a state of deficiency that is insidiously manifested by decreased sexual function, well-being, energy, loss of lean mass, white fat gain, and bone loss.

Before menopause testosterone in women is produced by the ovaries (25%) which are stimulated by LH and the adrenal or adrenal (25%). The remaining 50% is produced from peripheral conversion from androstenedione and DHEA (dehydroepiandrosterone).

After menopause the total production of testosterone drops dramatically in the ovaries but continues to be produced to a lesser extent by the adrenals.

 Testosterone deficiency can have serious consequences, both physical and mental, impairing a woman's health and libido. In special cases this deficiency is even more prominent, as in the case of ovarian removal due to pathologies or various physiological situations, such as:

 • menopause;

• adrenal insufficiency (suprarenal); • Use (current or previous) of hormonal contraceptives, mainly orally;

 • Excessive use of alcohol;

 • Surgical removal of ovaries - oophorectomy;

 · Partial failure of ovaries to produce

 testosterone;

 • Environmental xenoestrogens such as bisphenol. This substance is present in some types of plastics and when subjected to extreme temperatures blocks the receptors for testosterone;

• Medicines like some antidepressants and cholesterol lowering drugs; and

 • Excessive stress - Cortisol (stress hormone) blocks testosterone.

Testosterone hormone depletion can occur in both postmenopausal women, either natural or for surgical reasons, leading to a large population of women needing to have their hormone levels measured, such as just as they need to become users of some form of hormone replacement.

 This also occurs in women using hormonal contraceptives, where it is possible to find very low levels of testosterone, which can lead to significant decrease in libido, fatigue and difficulty in losing weight or gain lean mass.

 In addition, the contraceptive decreases the amount of free testosterone as it stimulates the production by the liver of a protein called sex hormone binding globulin (SHBG). This protein binds very strongly to testosterone, decreasing its active form, the free form.

Accordingly, it is an object of the present invention to provide a pharmaceutical form for the delivery of testosterone to an individual, such as a female patient in need of replacement of this hormone, so that its metabolism does not occur in the patient's liver.

 This situation occurs both in contraceptive pill users, and in women who undergo menopausal hormone replacement with oral and even injectable hormones.

 In general, the lack of testosterone in both the female and male populations can lead to a number of signs and symptoms that decrease the quality of life of patients with this type of hormone deficiency, including if:

 1. Difficulty reaching orgasm or decreasing its intensity;

 2. Decreased self-esteem and self-confidence;

 3. Lack of initiative and willingness to care;

 4. Increased body fat;

 5. Decreased skeletal muscle mass;

 6. decreased bone mass; and

 7. Lower muscle tone, weakness / tiredness;

 Lack of testosterone is associated with a number of physiological changes, among which we can mention:

 1. Increased sex hormone binding globulin (SHBG) if you take oral contraceptives or oral menopausal hormone replacement therapy;

 2. Decrease in good cholesterol or HDL;

 3. Decrease in total and free testosterone;

 4. Dramatic increase in FSH and LH in menopausal women; and

 5. Suppression of FSH and LH in pill users.

When the patient is male, and more particularly in the case of men who have lost their sexual interest and erectile ability, the use of testosterone replacement is the preferred approach. In humans, the lowest acceptable normal amount of total testosterone is 200 ng / dL [6.9 nmol / L]) and free testosterone is 40 ng / dL [1.8 nmol / L]). In women, the lowest acceptable normal amount of total testosterone is 20 ng / dL [6.9 nmol / L]) and free testosterone is 4 ng / dL [0.18 nmol / L]).

 Similarly, also for the female patient, the lack of testosterone is also basically supplied by hormone replacement with testosterone and other testosterone precursors such as DHEA.

 However, especially in women, hormone replacement should be done carefully because of the side effects associated with testosterone overdose.

Supraphysiological testosterone levels, generally greater than 100ng / dl, may lead to the appearance of masculinizing signs. The onset of hair and acne, or Adam's apple, clitoral enlargement, facial modification, excessive hair growth and acne, too much muscle mass, voice changes and menstrual changes are seen in women who use indiscriminate and uncontrolled of derivatives of this hormone, which in general use this hormone in much higher potency and in large unnatural amounts.

Therefore, it is a further object of the present invention to provide a device which is a set of packaged carton devices to form a pharmaceutical monodose device kit. testosterone for nasal administration, whose pharmaceutical form allows the administration of single-dose testosterone, measured at a dosage corresponding to physiological conditions, for the replacement of this hormone to a patient in need of such replacement. Testosterone deficiency is a relatively common pathological condition in both female and male populations [1-2]. The WHO, NIH, and FDA recommend that the primary goal of therapy is to replace deficient testosterone levels to levels as close to physiological concentrations as possible.

 Thus, it is another object of the present invention to provide testosterone to a patient in need of such supply at dosages as close as possible to physiological concentrations. This has led the inventors of the present invention to develop a device containing a suitable formulation for providing testosterone to such patients at metered doses without loss of content to ensure that the dosage provided is within the physiological conditions determined. by WHO.

 OF THE TECHNICAL PROBLEM TO BE SOLVED BY THE INVENTION

It is well known that many hormones, including testosterone, follow a circadian rhythm. In fact, many physiological functions in humans are organized in time as biological rhythms with different periods, and many drugs have different potencies and / or toxicities associated with their onset rhythm in the bloodstream and different biochemical and physiological processes [3].

 At the moment none of the available hormone replacement therapies are ideal.

The solutions which are currently being employed in hormone replacement therapies, on the other hand, are offered in pharmaceutical forms, which in one way or another have drawbacks, for example in the face of side effects because they are metabolized. in the liver, or even due to the patient's nonadherence to treatment. [0033] Intramuscular injection of testosterone shows large variations in circulating levels with often supraphysiological plasma concentrations, leading to overdose with its known adverse effects [4].

 Testosterone patches, another pharmaceutical form of medication used for hormone replacement, have a high rate of skin irritation [5,6].

Similarly, testosterone gels, despite being the most accepted hormone replacement medicine in the United States, are less irritating to human skin, but are not always considered convenient and may be at risk of gel transfer from one patient to another by skin-to-skin cross-contamination [7-13].

 Oral testosterone undecanoate formulations, however, need to be administered with a high fat meal and the absorption levels obtained are generally low [14-19]. Oral formulations are generally related to high levels of dihydrotestosterone because of the high levels of 5-reductase in the human intestine [20].

In view of this, it is a further object of the present invention to provide testosterone via a pharmaceutical form which does not present the drawbacks of the usual hormone replacement administration forms of hormones such as testosterone. To this end, a formulation provided in a nasal drug delivery device was developed to allow a patient to supply testosterone in a single dose, metered without causing skin irritation, not promoting overdose, not requiring fat supply for absorption and without the need for metabolism via the gastric as with oral forms of hormone supplementation of testosterone.

 The state of the art already informs us that nasal drug preparations can generate good levels of systemic absorption [21-23]. In addition, some researchers have found a good potential of this route for testosterone delivery in hormone replacement therapies, however, the duration of effective serum levels was very short, presenting a low ti / 2 (40-50 min) leading to peaks. early concentrations followed by disappearance in the blood [24-26].

 Nasal testosterone formulations must have an ideal viscosity so that it does not drip and is swallowed, becoming an undesirable oral route.

 Another interesting aspect of the nasal formulation in the case of testosterone is the emulsion presentation with an oily excipient which makes testosterone, due to its fat-soluble characteristic, more penetrable in the nasal mucosae. These two properties can further be enhanced by the addition of a surfactant. Thus, pharmacokinetic aspects such as Cmax, Ti / 2, and AUC∞ may be modulated by viscosity and water / oil emulsion ratio and surfactant adjuvants.

[004 1] Table 1 below proposes an analysis by the researchers of the present patent, based on current knowledge of the state of the art, in order to evaluate the most appropriate pharmaceutical form for the presentation of the formulation of their drug, using of the minimum dose required to produce the testosterone hormone replacement effectiveness achieved by the present invention.

Table 1 - Research of pharmaceutical forms Way Advantage Disadvantage Problems or archaeological advantages

 testosterone in this pharmaceutical form

Adhesive Maintains Low Adhesiveness Product Cost Daily Secretion To High Treatment, Demanding Testosterone Face Care Product

 by the organism, be visible and specific to the large non-discrete substance peaks but to the integral use of the constant shape of the constant adhesive device; patient; It will fix the easy episodes of skin product from penetrating the allergy to the user in order for the organism's substances to avoid contact with the adhesive path; sensitivity and skin detachment of the user's skin allergies; unexpected and place of application;

 difficulty in

 reuse

 of product

 cool;

 hard application

 in certain regions

 (in the testicles,

 for example . );

 Tablet Does not pass through Still in The regulation of the mouth of the liver (the test; rapid release of excess release of absorption Absorption is compressed and rapid irregular metabolism, may prolonged hepatic absorption may promote peak drug is to cause greater increase, but end efficacy

 prostate gland rapidly; infertility, proportional to impotence, liver cancer technology, and pancreatic drug technology); employed in

 tablet production;

 Tablet Does not go through the difficult preparation Oral liver; copy a don't have for certain

(daily secretion release continues compound) of testosterone

 testosterone;

 Injectable Doesn't Go Through Concentration Is More

 liver; very high us commonly used

Application between early days and over time

7 days and 21 even without passing days replacement by the liver, can hormone male, cause particularly excessive metabolism involving high in other tissues dosages and cause hormone increase; prostate solution, infertility drug, requiring impotence, solvents specific liver cancer;

 and pancreas No

 mimics secretion

 daily and

 hormonal variation

 it's big;

 Implant Does not pass through Does not mimic the Ineffective in the case of subcutaneous liver; daily secretion hormone replacement;

 Periodic exchange of testosterone,

 every eight because it keeps the

 months; same secretion

 hormonal time

 whole;

 Pill is taken by 0 number of high cost of oral orally, but pills is treatment, versus

(undecanoate does not go high (10 / day); efficacy in case of liver because it is Weaker replacement action

testosterone) absorbed by other hormonal than;

 bowel; methods, no

 fits in all

 cases;

 More discreet gel; There is not; Care for

 Easy to develop formula application; hypoallergenic and does not cause better allergies effect; systemic

 Does not pass through absorption by the liver skin; of the patient; there may be a risk of gel transfer from one patient to another by skin-to-skin cross contamination

Nasal drops Easy None; Easy way

 application; for greater development of forms

 adhesion to pharmaceuticals with treatment; better control of Do not go through the dosage;

 liver; Need to

 studies for the development of proper viscosity;

The use of testosterone and its derivatives is the subject of frequent studies to define the best pharmaceutical form for proper administration in view of the therapeutic target and the gender of the patient to be treated. Similarly, depending on the pharmaceutical form adopted, a specific formulation is developed for the appropriate absorption of the therapeutic substance combined with the preferred route of administration. As seen above, the administration of the hormone as a function of the desired therapeutic outcome has greater or lesser therapeutic effects, as well as side effects and greater or lesser patient adherence to treatment.

 For example, in hypogonadic men, the intramuscular route is the most common and least costly form of androgen replacement, but on the other hand, if employed more steadily and permanently, it may result in poor patient adherence. treatment.

 In the case of oral or sublingual administration of the drug, these androgens - testosterone and its derivatives have low bioavailability and large hepatic inactivation, except for the 17-alpha-alkylated androgens, such as methyltestosterone. absorbed but have higher hepatotoxicity.

 TECHNICAL STATE

It is well known in the prior art (Andrade, Gustavo Coutinho; CRM 806927 / RJ - "The History of Hormonal Replacement Therapy" - 2010) that among the testosterone derivatives available on the market for clinical use, propionate presents short duration of effect is commonly used for injectable use, requiring injections every 1 or 2 days, and is impractical for the patient for both single and constant use.

Similarly, as the state of the art represented by GB855716 published 7/12/1960, as well as US6495534 published 17/12/2002, both testosterone enanthate and cypionate exhibit longer absorption and duration, 10 to 14 days after intramuscular 200 mg application, while caproate and testosterone isocaproate are longer, 14 and 28 days, in use for male patients and by injection.

 The use of pharmaceutical forms of testosterone derivatives, on the other hand, when formulated in an oily vehicle, is already in common use in the prior art, particularly when the chosen form is injectable.

The choice of testosterone derivative to be used as an active ingredient is crucial to the achievement of the expected results, in view of the above stated objectives to be achieved by the present invention, to be packaged in the monodose device and for nasal application. .

The use of testosterone butyrate associated with oily vehicle is reported in GB729808 published 11/05/1955, such as sesame oil, also for injectable use.

 In the injectable form of testosterone, the use of oily vehicle undecanoate and aqueous vehicle testosterone buciclate are known, which may have an effective duration of 2 and 4 months, respectively, after a single IM (intramuscular) injection. ).

 Similarly, the association of active ingredients such as testosterone for emulsion administration is also known, and is also associated with fatty acids diluted in vegetable oil, as can be seen in US8372434 published 12/02/2013, which, however, has as its main objective an ophthalmic drug.

 Prolonged-release implants, as known in US5733565 published March 31, 1998, provide more stable testosterone levels for up to 6 months, but have complications such as extrusion, bleeding, and local infection in about 5% of users. .

Transdermal application of testosterone, either by patches or gel, is an attractive alternative because it provides more stable circulating testosterone levels and avoid pain at the application site.

 However, both the patch and the testosterone gel have a much higher final drug cost than injection. Scrotal patches require depilation and may cause deleterious effects on the prostate due to excessive increase in local DHT production. Non-scrotal adhesives have similar efficacy, are more practical and do not generate an excessive increase in DHT levels.

 However, in these types of devices, contact dermatitis can occur in up to 10% of users of these patches. Testosterone gel (1%) for daily application at doses of 5 to 10 g on shoulders, arms and / or abdomen has efficacy and the same problems presented similarly by adhesives.

 [0057] Testosterone use may be contraindicated in hypogonadic patients with prostate or breast carcinoma.

Testosterone replacement, in addition to the aforementioned side effects, especially when administered at supraphysiological doses, can cause water retention, gynecomastia, cholestatic jaundice, liver damage, acne, priapism, aggressive behavior, and increased hematocrit.

In view of such already well-known state-of-the-art problems and aiming to overcome them by providing a safe, effective hormone replacement drug for patients of both sexes in measured and physiologically doses As appropriate, the inventors of the present invention have developed a formulation employing bioidentical testosterone in micronized form as active agent.

[0060] According to Scolt T. Wepfer in his study RPH, FIACP, The Compunding Shoppe, Birminghan, Alabama "Hormonal Modulation with Bioidentical Hormones is a therapeutic breakthrough that allows for safe and effective clinical results. "

Classic and traditional hormone replacement therapy utilizes Synthetic hormones.

These substances have a different three-dimensional molecular structure than human hormones, so they do not occupy cell hormone receptors to the same perfection as bioidentical hormone, eliciting a not always adequate pharmacological therapeutic response.

Considering the aforementioned adversities that may occur in patients on hormone replacement therapy, obtaining a formulation to be administered that avoids the undesirable complications that may result from HRT therapies, the use of hormones that mimic the structure. Three-dimensional molecular, just as human hormones would be desirable.

When these substances are replaced and absorbed by the body, they are readily recognized by the cells and result in a physiological therapeutic response, ie producing the same physiological responses as the endogenous hormones in our body.

 Individual dosing that optimizes response and limits undesirable effects is possible when using bioidentical hormones, and the exact dose and most appropriate pharmaceutical form, such as the dermal form, may be formulated via the nasal route. An example of the use of bioidentical testosterone in hormone therapy using bioidentical hormones is seen in US7563565 published 21/07/2009.

 However, this document neither anticipates nor suggests the embodiment of the present invention employing bioidentical hormone monodose such as micronized testosterone.

The use in the formulation of the present invention of bioidentical testosterone in its micronized form, finely divided to a powder, is essential for increasing the solubility and bioavailability of the drug, notably in the preparation of the preferred formulation in view of its application via the nasal route. Preferably, the hormonal active agent of the present invention is presented as a particulate powder in an average particle diameter range of less than 5μπι obtained by laser diffraction.

Modern pharmacotechnics use particle size reduction of the active compound of formulations to obtain an increase in the specific surface of the powder, that is, the surface area to weight ratio. Both drug dissolution and absorption rates, content uniformity and stability of the pharmaceutical form are directly dependent on the degree of particle size variation, size distribution and interactions between solid surfaces.

 Better availability of poorly water-soluble drugs with retarding dissolution rate of the drug absorption process is achieved when they are administered as finely divided particles, such as micronized forms, for example.

The testosterone of the present invention in its micronized form has a high specific surface and thus dissolves with greater speed in the patient's medium of administration, which has as a differentiated technical effect with respect to known testosterone preparations of the state of the art. by promoting the absorption of the drug by passive diffusion.

However, if the adjuvants chosen for the preparation of the formulation are not suitable, even if the solids have adequate particle sizes, the dissolution rate of the drug may be affected.

Summary of the Invention

These are a set of devices, constituting a packaged pharmaceutical kit for nasal testosterone administration, formed from a plurality of therapeutically measured single dose single dose delivery devices.

 The set of devices constituting the pharmaceutical kit is characterized by a set of individual devices (1) containing low viscosity, high viscosity, micronized testosterone-based gel formulation to provide the a patient, whether female or male, precisely measured and physiologically appropriate unit doses of testosterone.

 [0074] The device after use is immediately discarded by the user without residual hormone losses even when administered via the nasal route, due to the high viscosity of the formulation coupled with the air pumping system of the drug contained in the device, ensures the release of virtually all of your content.

Each device is provided with a hollow chamber (2), where the medicine is packed, and an air column area that acts as a plunger to expel the volume of medicine contained in the chamber (2). Expulsion air chamber (3) provides user-pressurized air into the hollow chamber (2), which acts as compressed air in the face of passing through the neck (6) provided between the hollow chamber (2) and the inner tube (3). Tear lines (8 - 9 - 12) are provided to facilitate the removal of each device from the card for use.

 DESCRIPTION OF THE INVENTION

In the formulation of the present invention, in order to avoid the drawbacks of the art, for example making the hydrophobic formulation undesirable, since the chosen route of administration of the formulation of the present invention is nasal, the formulation was prepared as a gel using the semi-solid hormone. Other precautions have been observed so that particle size does not affect content uniformity since the testosterone dosage of the formulation of the present invention is significantly low, and thus tight control has been maintained in the preparation of the formulation, since such inconvenience would not occur as long as the interaction between the particles was ensured and the flow characteristics of the drug were maintained.

Also, in order to avoid the drawbacks of the art, the nasal formulation of the present invention employed micronized bioidentical testosterone, with a mean diameter of 5 μπι, employed in a gel preparation at a dosage of 0, 08% w / w 3.33% w / w, containing testosterone in appropriate doses according to the formulation for female or male use respectively.

 The formulation of the present invention is therefore provided for nasal delivery via a rigidly metered "ampoule" applicator device containing up to 200 mg of a micronized testosterone formulation.

 Gels are defined as semi-solid systems composed of dispersions of small inorganic particles or large organic molecules enclosed by a liquid.

 Nasal preparations are often used for the administration of drugs that need to be employed for both local and systemic effects.

In the present invention, the nasal route is the focus of interest because of the need to develop a non-oral and non-parenteral route for the absorption of biologically active testosterone from the formulation of the present invention. Testosterone, like other drugs, is subject to destruction by gastrointestinal fluids as it is intensely metabolized by the liver. Most testosterone-based medicines are now injected.

 The nasal route of administration for achieving systemic effects in certain drug preparations is known to be very satisfactory as the nasal mucosa is amenable to systemic absorption of certain non-peptide drugs, including testosterone.

The nose serves as an important barrier to the entry of bacteria into the lungs by acting as a protective mechanism of the organism. To this end, its surface is covered by a mucosa with a pH value between 5.5 and 6.5.

Because nasal tissue is highly vascularized, it becomes a suitable site for rapid and efficient systemic absorption. A major advantage of this absorption pathway is that it avoids first pass metabolism through the liver.

Thus, the nasal preparation of the present invention has been designed to maintain bioidentical pH levels to those of the nasal mucosa where the formulation of the present invention will be administered.

 Another essential feature that the formulation of the present invention had to take into account was that it was not irritating to the nasal mucosa, and mainly did not interfere with the ciliary movement that normally occurs in the nasal cavities, and would have as a function of driving the medicine for deeper airway regions for its full absorption.

 It is also an important condition of the formulation of the present invention for such medicament to have adequate osmolarity, viscosity and pH, preventing deleterious effects on the action of the nasal cilia.

Nasal gels, as the formulation of the present invention, are semi-solid preparations for nasal application and may be used to obtain local or systemic effect. Absorption of the drug is ensured to achieve the desired systemic effect of absorption of testosterone since the nose cavity has a capacity of approximately 20mL with a large surface area of about 180.00cm ² , The desired absorption is ensured by the micro villi located along the pseudo stratified columnar epithelial cells of the nasal mucosa.

 The formulation of the present invention is made from a reduced amount of micronized testosterone, preferably bioidentical testosterone, in dosage ranging from 0.05% w / w to 3.5% w / w, relative to the total weight of the gel formulation.

 The semisolid form of micronized testosterone is provided in powders of less than 5μπι.

 Excipients constituted to promote the reach of the gel form of the formulation such as at least one thickener, chosen from colloidal silicon dioxide, polyvinyl alcohol hydroxyethylcellulose, sodium carboxymethylcellulose, starch, and gelatin, are further employed.

 Preferably colloidal silicon dioxide is used which is already presented as a very fine amorphous submicroscopic powder, less than 15μπι promoting optimal aggregation to testosterone in its micronized form.

It acts as an adsorbent in the formulation and as a viscosity agent being employed in the range of 2 to 10% w / w of the formulation with this function, also acting to improve the flow property of the powders. More preferably, the chosen viscosity agent is employed in a range of 2.5 to 4% by weight with respect to the total weight of the formulation.

It also acts as a stabilizer in the gel formulation, dispensing the use of other substances to act with this stabilizing function. Since the pH of the nasal medium is aqueous and is in the pH range 5.5 to 6.5, the colloidal silicon dioxide viscosity agent whose pH according to USP 26 must be in the range 3 , 5 and 5,5 is effective in increasing the viscosity of the formulation when administered to the patient via the nasal route, which is particularly favorable for drug administration without loss of product dripping out of the user's nose.

 The viscosity of the formulation of the present invention is thus within a range of 30,000 to 150,000 mPa * s.

The formulation of the present invention further provides for the use of a surfactant chosen from benzalkonium chloride, oleoyl macrogolglycerides, nonoxynol 10 (nonionic surfactant), polysorbate 80, sodium lauryl sulfate. Nonoxynol-9 ("N-9") has been identified as particularly useful as it is used for intranasal administration of insulin. Of the surfactants in the indicated group, oleoyl macrogolglyceride is preferred because of its best suitability for a gel formulation.

The surfactant of the present invention is employed in amounts ranging from 3.5 to 4.5%, and more preferably 4% of the total formulation weight.

 An oily vehicle made up of vegetable oil is also envisaged for the better solubility of the hormone in an oily environment, while still considering that the more liquid formulation, such as an aqueous formulation, unlike the gel formulation. of the present invention, is more prone to runny nose of the user under nasal testosterone administration.

The vegetable oil employed as an oily or lipid carrier in the present invention may be one or a combination of oils selected from the group represented by cottonseed oil, sesame oil, castor oil, or castor oil; wheat germ oil, among others. Preferably castor oil or castor oil is chosen for its favorable performance in the gel formulation of the present invention in view of its high concentration of unsaturated fatty acids.

 In addition, its well-known antifungal and anti-inflammatory properties, and because it is odorless, elect it as the appropriate excipient for use in drug formulations to be administered by the nasal route.

[0105] Vegetable oil is employed in the present formulation in an amount ranging from 85 to 95%, and more specifically ranging from 88.67 to 93.42%,

 Considering that the amounts of hormones to be used in male and female populations differ, and since one of the purposes of the present invention was to provide a formulation to be administered to a male and / or female patient. In a female device, through a nasal device, two types of formulations were prepared for both sexes, by way of example and not limitation.

 [0107] Example 1 - Gel formulation to be packaged in a single dose nasal device for use by a female patient. 0.08% testosterone concentration.

Example IA - Gel formulation to be packaged in a single dose nasal device for employment by female patient. Testosterone concentration 0.16%.

 Example 1B - Gel formulation to be packaged in a single dose nasal device for use by a female patient. 0.32% testosterone concentration.

 [0110] Example 2 - Gel formulation to be packaged in a single dose nasal device for use by a male patient. Testosterone concentration at 3.33%.

 Presentation Quantity 17 kg

 Theoretical plastic container

 250 mg

 FORMULA

 Raw Material

 Formula for 17kg of product

 Micronized Testosterone 3, 33 566.67 g

 Oleoil 4.0 680.00 g

 Macrogolglyceride

 Silicon dioxide 4.0 680.00 g

 colloidal

castor oil 88, 67 15,073.33 g In both formulations the yield was in the range of 96 to 100%.

 In order to evaluate the effectiveness of the contribution of the excipients employed and the final viscosity adopted in the formulations of the present invention, the following tests were performed, the results of which are tabulated in Table 2.

[0113] These tests were aimed at verifying that the possible loss of the drug at the time of administration by the patient was as small as possible, so that the minimum therapeutic dosages of the drug would not be compromised in its efficacy in the treatment, in particular. any such losses. Table 2 - Effectiveness of the contribution of the excipients employed and the final viscosity adopted in the formulations of the present invention.

 Ampoule No. Mass of

 full ampoule dose

 1,258,145.8

 2,254,147.0

 3,243,144.8

 4 254 157.3

 5 258 157.4

 6 262 156.0

 7 254 153.1

 8 255 150.2

 9 252 153.6

 10 252 152.5

 11 256 158.5

 12 251 134.4

 13 254 128.9

 14 249 145.3

 15 239 136.1

 16 250 154.4

 17 243 136.1

 18 249 158.0

 19 249 154.7

 20 248 147.0

 21 260 149.5

 22 250 140.5

 23 256 152, 1

 24 249 148.1

 25 250 145, 1

 26 252 150, 1

 27 253 145.5

 28 251 154.5

 29 250 151.3

30 249 152.0 Average of

 251, 666667 148, 66

 pastas

[0114] Example 3 - Dose Release Measurement

 [0115] In this example, measurements of the dose delivered by the inhaler device with thirty independent uses of a pilot batch manufactured in holder FBM were taken.

FARM

 The graphs of Figures 5 and 6, relating to Table 2 of Example 3, show the variations in measurements taken from the mass of dispensed formulations versus the total mass of the devices containing the formulations contained in each of such devices, before and after. the dispensation.

More specifically, the graph in Figure 5 shows the pharmaceutically acceptable variants of the filled ampoule volumes and the mediator (y) of these variants per dose, compared to the same occurrence of pharmaceutical variants for the applied doses, demonstrating that the variations are minimum volume and volume applied. Keeping any ampoule volume versus applied volume losses below acceptable limits, it can be ensured that the proposed minimum dose delivery system to be administered to the patient therapeutically serves the purpose of the present invention.

 Already the graph of figure 6 shows the variation of the administered doses and the average of the volumes of the dispensed doses of formulation.

 The average dose dispensed was 149.34 mg and the standard deviation was 6.49 (max / min 158.5-134.4) with a delta of 24.1. These data show a high precision and accuracy of the dispensed doses in this device that was predicted to dispense 150mg of the formulation.

The main focus of the present invention therefore lies on the nasal administration of a minimal dose. of micronized testosterone, in a semi-solid gel formulation, to a patient in need of this drug by the use of an ampoule-shaped device with its constituent elements, anatomical parts and facilitating the fullest possible dispensation , of the medicament packaged in such a device.

A set of sequentially identifiable devices for controlling the administration of individual doses of testosterone constitutes the drug kit of the present invention, allowing the patient to organize and adhere to and control while minimizing the risk of loss of subsequent doses.

 [0122] The use of a disposable ampoule unit dose applicator also assists in process biosecurity because the applicator cannot be shared with others by preventing the spread of bloodborne pathogens and nasal mucosa. .

 Devices made of ampoule-shaped plastics material for administering pharmaceutical preparations are already known in the prior art.

[0124] The document BR PI0621465 published on 13/12/2011 in RPI2136, filed in Brazil through PCT application 2007/101466 published on 13/09/2007, shows opening of fluid administration contained in the container, whose opening communicates with a hollow chamber of the sealing member. Such a hollow chamber is disposed outside the container containing the substance to be administered and is separated from the sealing element by means of a rupture element, so that the administration opening is not involuntarily sealed at the time of fluid administration. This prior art, however, does not provide for a pumping device by pressure difference of the container fluid.

 EP0150751 published 07/08/1985 discloses a liquid dispenser or pharmaceutical or cosmetic preparation having opposite side flaps on the dispenser body, thin parts to be fractured at the neck height and axially elongated to form and where the outlet opening of the pharmaceutical or cosmetic content of the dispenser is arranged.

 The prior art dispenser is more specifically provided for ophthalmic preparation application whereby the thin and elongated neck where the discharge opening is arranged and the side flaps are more suitable for such application. Said side flaps are intended to assist the user to hold the device. The only break lines are provided to release the fluid discharge opening without any pumping aid from the dispenser contents. Thus, more viscous fluids, such as the present invention, are not adequately dispensed by this device, resulting in a random amount not retained in the container, which prevents the effective administration of the desired dose or prescribed for the patient's treatment.

Also, US5761885 published on 09/06/1988, deals with a method of manufacturing a plastic container, which consists of a polyethylene or polypropylene ampoule in which a separate piston is manufactured, preferably made of polyfluoroethylene. . Said piston acts as a plunger pushing the contents of the ampoule into a discharge opening, when a rectangular area constituting a chamber is pressed pushing the air contained therein, which in turn pushes the plunger to move fluid from the ampoule into the opening. discharge Said opening it is released by breaking a fragile area to be broken at the time of administration. Still the ampoule is individual and is not provided as a set of devices for programmed administration of a viscous medicament, such as the device of the present invention.

 WO2011001275, published 06/11/2011, refers to a single container made of two components of plastics material for use with pharmaceutical or cosmetic preparations, provided with a breakable element for the discharge opening release. fluid and a hollow monolithic body formed of a flexible plastics material having a concavity to be compressed to release the contents of the vial.

 Likewise, the prior art container is not intended to be provided as a set of units of a carton, constituting a monodose "KIT", and does not have an adjacent, non-integral pump element to the device body, to promote virtually complete emptying of the device by ensuring delivery of the intended dose to be administered to a patient, as proposed in the present invention.

 DESCRIPTION OF DRAWINGS

The micronized testosterone nasal delivery device of the present invention will be further described by the accompanying drawings in which:

 Figure 1 is a front view of a carton or set of devices constituting the pharmaceutical testosterone administration kit for a hormone replacement therapy to a patient;

Figure 2 is a longitudinal section (B - B ^' ) of a pharmaceutical kit card of Figure 1; Figure 3 is a cross-sectional view of a device (A - A ^' ) from the pharmaceutical kit card of Figure 1; and

 Figure 4 is a perspective view of a carton or set of devices for nasal testosterone administration as shown in Figure 1.

 CORPORATION OF THE INVENTION

In more detail, as can be seen from Figure 1, the present invention is comprised of a set of devices in the form of a carton (1) for nasal administration of testosterone to a female and / or male patient in need for hormone replacement therapy.

 Said card consists of an appropriate amount of unitary devices sequentially labeled.

(11), such as by means of numbers, in order to indicate and allow the user to control the conduct of his therapy, in view of the prescription of the frequency and amount of doses to be administered of the drug.

The sequential marking (11) of each device is embossed on the underside of the tear tab (7) of the closure head (5) of the device.

 The card (1) is formed of plastic such as low density polyethylene (LDPE). Said devices of the card (1) are provided with hollow body (2), and are obtained by extrusion molding.

 Each device consists of a hollow body (2) into which the medicament is introduced under aseptic conditions prior to sealing the closure (5-7) of the hollow cylindrical body (2) of the device. A closure head (5) is provided on the medicine discharge portion of the hollow body (2).

Said printhead (5) and tear tab (7) are anatomically arranged in the hollow body (2), in accordance with This allows the user to disconnect the device in a single simple two-finger movement from the adjacent ones, to which it was interconnected by means of a cut line (9).

Likewise, a consecutive tearing movement of said flap device (7) is made, thereby allowing the closure head (5) to detach from the hollow body (2) by breaking the cutting lines (8) , for the release of the drug fluid content, disposed in the intrasal hormone administration device testosterone.

 [0139] The device unit of the Device Kit assembly (1) is provided to be filled to a height "H" with the micronized testosterone gel formulation so as to remain a residual internal area of the hollow device filled with trapped air and not filled with the medicine. This air column, properly calculated as a function of the height "H" of the device and the thickness "e", exerts a downward pressure that will press, like a plunger, the drug upon administration.

 [0140] The height "H" of the medicinal product contained in the container is directly proportional to the volume of formulation to be contained in said hollow chamber (2). The container is provided with a total internal volume of 250mg.

Already the volume of the drug packaged in said device ranges from a total of 158.5mg to a total of 134.4 mg, which corresponds to a range of about 61 to 72% of the total volume of the device to be filled with the hormone formulation to ensure that the air column provides positive pressure on the upper area of the gel formulation to fully push it down and out of the device at administration of the drug to the patient. Given that the dosage to be administered of the hormone is on average around 148.6 mg, it can be considered that the average mass of air capable of promoting the proper emptying pressure of the device is about 72 mg / 28, 27 mm ² , or 2,546 mPa, since the hollow chamber dimension "e" of the device is about 6 mm.

 In addition, and above all, total device emptying, in addition to the viscosity index provided for in the gel formulation of micronized testosterone hormone, is ensured by providing an additional air pumping arrangement in the body of each unitary device of the present invention. , such as an isosceles, broad-based pyramidal trunk (3) extrusion chamber (3), extruded molded.

The walls of the tube (3) result from the extrusion operation at the time of molding, which are substantially thinner than the walls of the hollow container (2), so that when compressed by the user's fingers they produce an effect. pumping air contained in said chamber (3).

The expulsion or pumping chamber (3) has a height "B" substantially equal to the diameter "e" of the hollow cylindrical body (2) of the nasal delivery device, in which the hormone medicine is contained. the testosterone base.

Thus, the air volume of the air chamber (3) which is added to the air volume provided in the hollow cylindrical body (2) to promote the practically total emptying of the drug content of the device is given by the formula:

 V = 2X (Si X B / 2)

 - where Si is the area of the pyramidal base of the chamber (3) and,

- B / 2 is half of the total height "B" of the air exhaust chamber (3), or otherwise the value of the hollow body diameter (2). In this way, it is ensured that the gel medicament content of the device, coupled with its viscosity degree and the hollow body air volume that acts as an expulsion plunger of the formulation content contained in the device, is relatively high. integral form administered to the patient.

 Referring to Figure 2, it is a longitudinal section BB ', which shows the trapezoidal air-discharge chambers (3), with a larger base (4), which are part of a set of devices. molded into a carton comprising a Kit (1) having a plurality of individual, separable elements provided for application of micronized testosterone-based drug monodoses.

Said device is configured such that the larger base of the expulsion chamber "L" is substantially equal to the distance "d" between the longitudinal axes of the devices, arranged in the form of a carton or packing kit of unitary elements. for the administration of the drug.

 [0150] A median line joining identical parts of the device (13) indicates and facilitates demoulding of parts.

Referring to Figure 3, there is shown a longitudinal section AA 'of an individual device, where the tear tab (7) and the closure head (5) of the device are joined by the weakening line (1). 8).

A neck (6) is provided between the hollow chamber (2) containing the medicated gel and the air expulsion chamber (3) so as to create a device acting as a pressure valve to provide greater pressure of the air contained in the chamber (3) to provide a flow of compressed air to the air pressure of the chamber (2) so that it acts as an air piston, carrier of the total volume of the hollow chamber contents (2), ensuring the total expulsion of the drug during its administration to the patient.

 An upper flap (10), of larger surface and substantially thinner than the device and its hollow parts, is arranged externally and complementary to the device to allow it to be embossed thereon (14) , on each device, health information such as date and batch of manufacture of the drug and expiration date. Weakening or Tearing Lines

12 are disposed between each flap 10 and adjacent thereof to facilitate detachment of each device from its respective card.

 [0154] The configuration adopted for the present device is suggestive and not limiting, and it is clear that adjustments that do not interfere with the geometric relations that are part of the present invention are included in its configurative scope.

BIBLIOGRAPHY

[0155] 1. Wang C, Swerdloff RS. Androgen replacement therapy. Ann Med 1997; 29: 365-370.

 [0156] 2. Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Med Sci 2002; 57: M76-M99.

 [0157] 3. Ohdo S, Chronopharmacology focused on biological! clock Drug Metab Pharmacokinet 2007; 22: 3-14.

 [0158] 4. Nieschlag E. Testosterone treatment comes of age: new options for hypogonadal men. Endocrine Clin1 (Oxf) 2006; 65: 275-281.

 [0159] 5. Tenover JL. The androgen-deficient aging male: current treatment options. Rev Urol 2003; 5 (Suppl 1): S22-S28.

[0160] 6. Jockenhovel F. Testosterone therapy - what, when and to whom? Aging Male 2004; 7: 319-324. [0161] 7. Wang C, Swerdloff RS, Irnamanesh A, Dobs A, Snyder PJ, Cunningham G, Matsumoto AM, Weber T, Berman N,

Testosterone Gel Study Group. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab 2000; 85: 3020-3023.

[0162] 8, Swerdloff RS, Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ ^" , Weber T, Longstreth J, Berman N. Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men J Clin Endocrinol Metab 2000; 85: 4500-4510.

 9. Kunz GJ, Klein KO, Clemons RD, Gotts alk ME, Jones KL. Virilization of young children after topical androgen use by their parents. Pediatrics 2004; 114: 282-284.

[0164] 10. Brachet C, Vermeulen J, Heinrichs C. Children's virilization and the use of a testosterone gel by their fathers. Eur J Pediatr. 2005; 164: 646-647.

 [0165] 11. Spielberg TE. Abnormal testosterone levels in partners of patients using testosterone gels. J Sex Med. 2005; 2: 278.

 [0166] 12. Merhi ZQ, Santoro N. Postmenopausal virilization after spousal use of topical androgens. Fertile Steril 2007/87: 976. el3-el5.

 [0167] 13. Bhowmick SK, Ricke T, Rettig KR. Sexual precocity in a 16-month-old boy induced by indirect topical exposure to testosterone. Clin Pediatr 2007; 46: 540-543.

 [0168] 14. Morley JE. Androgens and aging. Maturitas 2001; 38: 61-71; discussion 71-73.

 [0169] 15. Gooren LJ, Bunch MC. Androgen replacement therapy: present and future. Drugs 2004; 64: 1861-1891.

[0170] 16. GheorghiuM, Badiu C, Caragheorgheopol A. Clinical efficacy of intramuscular long-acting compared to oral testosterone undecanoate in adult men with central hypogonadism. Acta Endocrinol 2008; 4: 59-73, [0171] 17. Bagchus WM, Hust R, Maris F, Schnabel PG, Houwing NS. Important effect of foocl on the bioavailability of oral testosterone undecanoate. Pharmacotherapy 2003; 23: 319-325.

 [0172] 18. Haren M, Chapman I, Coates P, Morley J, Wittert G. Effect of 12 month oral testosterone on testosterone deficiency symptoms in symptomatic elderly illnesses with low-normal gonadal status. Age Aging 2005; 34: 123-130.

 [0173] 19. Wittert GA, Chapman IM, Haren MT, MacKintosh S, Coates P, Morley JE. Oral estosterone supplementation increases muscle and decreases fat mass in healthy elderly illnesses with low-normal gonadal status. J Gerontol A Biol Sci Med Sci 2003; 58: 618-625.

 [0174] 20, Houwing NS, Maris F, Schnabel PG, Bagchus WM. Pharmacokinetic study in women of three different doses of a new formulation of oral testosterone undecanoate, Andriol Testocaps. Pharm.acothe.rapy 2003; 23: 1257-1265.

 [0175] 21. Illum L. Nasal drug delivery: new developments and strategies. Drug Discov Today 2002: 7: 1184-1189.

 [0176] 22. Hussain A. Intranasal drug administration delivery. Adv Drug Del Rev 1998; 29: 39-49.

 [0177] 23. Wattanakumtornkul S, Pinto AB, Williams DB. Intranasal hormone replacement therapy. Menopause 2003; 10: 88-98.

 [0178] 24. Danner CH, Frick J. Androgen replacement with testosterone containing nasal drops. Int J Androl 1980; 3: 429-435.

[0179] 25. Hussain AA., Kimura R, Hunag CH. Nasal absorption of testosterone in rats. J ^"Pharmaceut Sci 1984; 73: 1300-1301.

 [0180] 26. Hussain AA, Al-Bayatti AA, Dakkuri A, OkochI K, Hussain MA. Testosterone 17b-N, N-dimethylglycinate hydrochloride: a product with a potential for nasal delivery of testosterone. J Pharmaceut Sci 2002; 91: 785-789.

Claims

REINDICATIONS 1. Nasal administration pharmaceutical formulation containing testosterone characterized in that it is in the form of a single dose gel and delivered in a delivery device capable of delivering the full dose content to the patient and is composed of testosterone with a dosage of 0.05% w / pa 3.5% w / w relative to the total weight of the gel formulation; a thickener chosen from colloidal silicon dioxide, polyvinyl alcohol hydroxyethylcellulose, sodium carboxymethylcellulose, starch, and gelatin at a dosage of 2% w / w to 10% w / w relative to the total weight of the gel formulation; a surfactant chosen from benzalkonium chloride, oleoyl macrogolglycerides, nonoxynol-10, nonoxynol-9, polysorbate 80, and sodium lauryl sulfate with a dosage of 3.5% w / w 4.5% w / w relative to the total weight of gel formulation; and an oily carrier formed by one or a combination of oils chosen from cotton oil, sesame oil, castor oil or castor oil, and 85% w / w 95% w / w wheat germ oil in total weight of gel formulation; where the final gel formulation has a viscosity between 30,000 and 150,000 mPa.  Formulation according to Claim 1, characterized in that the testosterone is micronized bioidentical in semi-solid form with a mean diameter value of 5 μπι.  Formulation according to Claim 1, characterized in that the thickener is at a dosage of 2.5% w / w to 4% w / w relative to the total weight of the gel formulation. Formulation according to Claim 1, characterized in that the thickener is colloidal silicon dioxide presented as an amorphous submicroscopic powder with particles of less than 15 μπι. Formulation according to Claim 1, characterized in that the surfactant is at a dosage of 4% w / w relative to the total weight of the gel formulation.  Formulation according to Claim 1, characterized in that the surfactant is oleoyl macrogolglyceride.  Formulation according to Claim 1, characterized in that the vegetable oil is in the dosage of 88.67% w / w to 93.34% w / w based on the total weight of the gel formulation.  Formulation according to Claim 1, characterized in that the vegetable oil is castor or castor oil.  Formulation according to Claims 1 to 8, characterized in that it comprises 0.08% w / w of micronized testosterone, 4% w / w of oleoyl macrogolglyceride, 2.5% w / w of colloidal silicon dioxide and 93% w / w. , 42% w / w castor or castor oil.  Formulation according to Claims 1 to 8, characterized in that it comprises 0.16% w / w micronized testosterone, 4% w / w oleyl macrogolglyceride, 2.5% w / w colloidal silicon dioxide and , 34% w / w castor or castor oil.  Formulation according to Claims 1 to 8, characterized in that it comprises 0.32% w / w of micronized testosterone, 4% w / w of oleoyl macrogolglyceride, 2.5% w / w of colloidal silicon dioxide and , 18% w / w castor or castor oil.  Formulation according to Claims 1 to 8, characterized in that it comprises 3.33% w / w of micronized testosterone, 4% w / w of oleoyl macrogolglyceride, 4% w / w of colloidal silicon dioxide and 88.67. % w / w castor or castor oil. Device for administering the disposable ampoule formulation of claim 1 of plastics material characterized in that be made of low density polyethylene plastic (LDPE), and belonging to a card made up of other similar extruded devices, fitted with a hollow cylindrical body (2) into which the formulation is introduced, a closure head (5), a tear tab (7), formulation release cut lines (8), device separation cut lines (9),  where the hollow body (2) has a height (H) and a thickness (e) of 6mm and the total internal volume of the device is 250mg and the amount of formulation within the device is 61 to 72% of the total volume and the The remainder of the volume is filled with air at a pressure of 2 546 mPa, an extruded molded isosceles (3) pyramidal stem (4) air expulsion chamber,  where the walls of the inner tube (3) result from the extrusion operation during casting substantially thinner than the walls of the hollow container (2), so that when compressed by the user's fingers they produce a pumping effect. air contained in said chamber (3),  the air expelling or pumping chamber (3) has a height "B" substantially equal to the diameter "e" of the hollow cylindrical body (2) of the nasal delivery device, wherein the formulation of claim 1 is contained; The air volume of the air chamber (3), which is added to the air volume provided in the hollow cylindrical body (2) to promote the practically total emptying of the drug contents of the device, is given by the formula:  V = 2X (Si X B / 2) where Si is the area of the pyramidal base of the chamber (3) and is half of the total height "B" of the (3) or, on the other hand, the value of the hollow body diameter (2) ,  and said device is configured such that the larger base of the expulsion chamber "L" is substantially equal to the distance "d" between the longitudinal axes of the devices arranged in the form of a carton or packing kit of unitary elements for drug administration,  a tear tab (7) is joined to the closure head (5) of the device by the weakening line (8), and a neck (6) is provided between the hollow chamber (2) containing the medicated gel and the expulsion chamber of air (3) in order to create a pressure valve actuating device to provide greater pressure to expel the air contained in the chamber (3), to provide a flow of compressed air to the air pressure of the chamber (2) , so that it acts as an air plunger, carrying the total volume of the hollow chamber contents (2), ensuring the total expulsion of the drug during its administration to the patient,  and an upper flap (10), larger in surface and substantially thinner than the device and its hollow parts, is arranged externally and complementary to the device to allow it to be embossed (14) on it. each device, health information such as date and batch of drug manufacture and expiration date, weakening or tearing lines (12) are arranged between each flap (10) and its adjacent to facilitate detachment of each device from its respective card. 14. Kit for the administration of a single dose testosterone formulation comprising: a carton having the devices of claim 13 formed by extrusion process and detachable for single dose administration;  and the formulation of claim 1.