RU2497504C1 - Pharmaceutical composition for treating urinary disturbances - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to pharmaceutical compositions for treating urination disturbance that is a syndrome manifested by frequent urination, urinary incontinence, urine retention, etc. The pharmaceutical composition contains an anticholinergic preparation that is diphenyl-acetic acid tropine ester, and preparations of the other mode of action, including Tamsulosin hydrochloride or calcium channels or baclofen in the form of prolonged release tablets or capsules or transdermal dosage forms (gels, ointments or plasters).

EFFECT: using the invention enables extending the range of therapeutic agents and improving the clinical effectiveness in urination disturbances accompanying a variety of common urological, neurological and gynaecological conditions alongside with improving the quality of life in patients with the urination disturbance.

4 cl, 24 tbl, 3 ex

Description

The invention relates to medicine, namely to pharmaceutical compositions that can be used to treat a violation of the act of urination, which is a syndrome manifested by frequent urination, urinary incontinence, urinary retention, etc.

Currently, treatment of disorders of urination (NAM), which is a syndrome manifested by frequent urination, urgent urinary incontinence, urinary retention, etc., associated mainly with neurogenic disorders of the function of accumulation and retention of urine in the bladder, defined in the literature as “neurogenic” , “Unstable” or “overactive / overactive bladder” (“Overactive Bladder”, hereinafter referred to as OV), “unstable detrusor”, “detrusor-sphincter dysinergy”, etc., which is an actual measure a medical and social problem that attracts the attention of specialists due to the significant prevalence and sharp negative (and in some cases disabling) effects on the quality of life of patients.

NAMs are among the very serious and common disabling complications of a number of diseases - urological: acute and chronic cystitis, benign prostatic hyperplasia (BPH), prostate and bladder cancer (up to 30% of patients), neurological: cerebral stroke and other cerebrovascular disorders (24-78% of patients), multiple sclerosis (10-97% of patients), Parkinson's disease and Parkinson's disease (more than 40% of patients), brain and spinal cord injuries (up to 100% of patients), neuroinfection, amyotrophic lateral sclerosis, etc., manifestations of menopausal syndrome in postmenopausal women (26-30% of women) and others. NAMs are among the very serious disabling complications of these diseases, the essential aspects of which are not only purely medical, but also medical and social aspects associated with a sharp violation of the life and condition of patients, their labor and social activity, i.e. those aspects of life that determine the main indicators of its quality. In this regard, treatment of NAM is an urgent task of medicine.

NAM links with OS are diagnosed in from 2-7% to 20% of the population, and the total number of patients in the world with these disorders is from 50 to 100 million people (Mazo E.B., Krivoborodov G.G., 2003, etc. ) Gender-specific features of NAM were noted: the ratio of men: women is 1: 2-3, as well as a significant increase in the number of cases with age (especially at the age of 45-50 years and older) (Pushkar D.Yu., 2003). In people aged 70-85 years, up to 30-50% of the populations of both sexes have manifestations of NAM and OM expressed in varying degrees. In the United States, OM is on the list of 10 most common diseases, with diabetes and peptic ulcer in the first and second place.

Given the prevalence of these types of pathology, as well as based on the proportion of elderly people in the Russian population (more than 20%), it can be assumed that 5-10 million patients suffer from various forms of OM in our country.

The main causes of NAM with OS and leading mechanisms of pathogenesis include:

- disturbances of the micturitional reflex (reflex urination),

- impaired transmission from the central nervous system of nerve impulses that regulate the processes of urine accumulation in the bladder (MP) and emptying of the latter,

- violations of the contractile function of the detrusor muscle MP,

- Synergy disorders between contractions of the detrusor muscle and sphincters of the MP

- behavioral and psychological disorders.

According to modern concepts, cholinergic innervation plays a particularly important role in the functioning of MP in both physiological and pathological conditions (Andersen, Blok et al, 1997, Chapple Jonas, 2000). Contraction of the detrusor muscle, which actually forms the wall of this organ, is carried out due to the stimulation of muscarinic cholinergic receptors by the neurotransmitter acetylcholine released from the presynaptic structures. The bladder contains M ₁ , M ₂ and M ₃ subtypes of muscarinic receptors. Violations of urination in acute obesity in most cases are caused by a violation of the transmission of regulatory nerve impulses from the central nervous system to the periphery, including the lower urinary tract. In this case, the functions of the sensitive pathways responsible for controlling the filling of the MP, as well as the control of motor functions that determine the activity of the detrusor muscle, sphincter and pelvic floor muscles in the processes of accumulation and excretion of urine, usually suffer.

The adrenergic (sympathetic) innervation of the detrusor muscle of the MP in comparison with the cholinergic is presented in a smaller volume. However, the neurotransmitter in adrenergic synapses, norepinephrine (NA), can play an inhibitory role in the functioning of MPs, both due to inhibition of the transmission of nerve impulses in the parasympathetic ganglia by feedback and possibly due to stimulation of beta-adrenergic receptors, which leads to relaxation of the detrusor in the filling phase MP. In contrast to the situation with MP detrusor, both beta and alpha adrenoreceptors are widely represented in the muscles of the sphincter of the bladder and the bottom of the MP, the prostate and urethra, which play an important role in urine retention.

It is these features of the parasympathetic and sympathetic innervation of the organs of UCID that are the basis for the selection of drugs with a different mechanism of action for the treatment of NAM

Treatment of NAM with OS is carried out using the following 4 methods (Andersen, Maso E.B., Krivoborodov G.G., 2003, Pushkar D.Yu., 2003, Schwartz G.Ya. et al., 2000, Schwartz P .G. 2006 and others):

- Pharmacotherapy

- Surgical treatment

- Non-operational non-pharmacological methods

- Patient education

In terms of frequency of use and effectiveness, pharmacotherapy occupies a leading position among the indicated methods of treating NAM for OV (more than 95% of cases) (Al-Shukri et al., 1999, Pushkar D.Yu., 2003, Schwartz G.Ya. et al., 2000 , Schwartz P.G. 2006, Andersen, et al.).

For the treatment of NAM with OS, several groups of drugs differing in the mechanism of action are used (Table 1).

Table 1 Medicines used in the treatment of NAM Types of drugs Medicines Mechanism of action Anticholinergics Atropine, propantheline bromide, trospium, tolterodine, darifenacin Muscarinic receptors inhibit Mixed-action drugs Oxybutynin, Dicyclomine, Propivirin, Flavoxate Muscarinic receptors inhibit, antispasmodic Calcium antagonists Nifedipine, verapramil Block the intake of calcium in myofibrils, which leads to a decrease in their contractile activity Potassium channel opening drugs Cromacaline, pinacidil They open membrane potassium channels, which reduces the flow of calcium into the cell and leads to muscle relaxation. Α ₁ -adrenoreceptor blockers Prazosin, alfuzosin, terazosin, doxazosin, tamsulosin Decreased intraurethral resistance and hyperactivity of the detrusor Β-adrenoreceptor stimulants Terbutaline, salbutomol Stimulation of detrusor β-adrenergic receptors leads to its relaxation Tricyclic antidepressants Imipramine, amitriptyline They inhibit the reuptake of norepinephrine, serotonin and dopamine. Central and peripheral anticholinergic action, sedative properties Prostaglandin Synthesis Inhibitors Indomethacin, diclofenac sodium Relaxation of the bladder when it is full and a decrease in the spontaneous contractile activity of the detrusor Vasopressin analogues Desmopressin Antidiuretic effect Vanilloid receptor blocking drugs Capsaicin, resinferotoxin Reversible blockade of vanilloid receptors of afferent C-fibers

Among the above-mentioned groups, in recent years, due to the rather high effectiveness, the most attention has been attracted to the group of anticholinergics (also called atropine-like or muscarinic antagonists), combining the ability of blockade of muscarinic cholinergic receptors, with myotropic antispasmodic activity expressed to a different extent.

Among the anticholinergics used for OS, in recent years, oxybutynin, trospium and tolterodine have been used especially widely in the world.

These drugs have a similar mechanism of action and are close in therapeutic efficacy (Du Beau S.T., 2009). At the same time, none of these drugs fully meets the criteria for good tolerance and safety (Al-Shukri S.Kh. et al., 1999, Pushkar D.Yu. 2003, Schwartz P.G. 2006 DuBeau S. T., 2009). Their use is accompanied by a number of adverse side effects, significantly limiting the use.

An important disadvantage of this group of drugs is the lack of a therapeutic effect in one of the common forms of NAM - detrusor-sphincter dysinergy (DSD), in which there is a lack of reticulo-spinal innervation, which often causes a violation of synergy between the external urethral sphincter formed by the longitudinal muscles , and detrusor muscle MP, as well as incomplete relaxation and paralysis of the sphincter. In addition, these disorders can lead to a simultaneous reduction of the detrusor and the external sphincter - DSD, which manifests itself clinically as a feeling of incomplete emptying of the MP, incomplete urination or its complete delay, which can become chronic. Common complications of DSD include the appearance of residual urine, its infection, the development of bacterial cystitis, etc.

Lack of effectiveness and side effects limit the use of drugs of this mechanism of action and are the basis for the search for new well-tolerated drugs suitable for long-term (almost lifetime) use.

Diphenylacetic acid tropic ester hydrochloride is approved for medical use by order of the USSR Minister of Health dated December 31, 1971 No. 945 under the name tropacin. In terms of chemical structure and pharmacological properties, tropacin is close to atropine; it reduces the excitability of peripheral M-cholinergic receptors (M2, M3) and in this regard causes relaxation of smooth muscles, decreased secretion, and dilated pupil. In this regard, it is less active than atropine, but more active than atropine in terms of its effect on central M- and H-cholinergic receptors. Tropacin has moderate ganglion-blocking properties, as well as anti-serotonin and antihistamine activity, and, moreover, has a direct relaxing effect on the smooth muscles of internal organs and blood vessels (Mashkovsky M.D., 1953, 1954, 1998, 2005, Mashkovsky M.D., Schwartz G.I., 1973).

The main indication for the medical use of this drug in the 50-70 years of the XX century. was the treatment of parkinsonism and Parkinson's disease (Mashkovsky M.D., 1953, 1954, 2005). Tropacin has been used to a limited extent as a corrector for a neuroleptic syndrome that develops with the use of chlorpromazine and other antipsychotics, as well as for spastic paresis, paralysis, and other diseases accompanied by an increase in muscle tone. Subsequently, with the advent of new anti-Parkinsonian drugs of a different mechanism of action, tropacin lost its significance and its use in medicine is limited.

The closest mechanisms of action to tropacin are oxybutynin and tolterodine, the effectiveness and safety of which are described in the publications: Laurent O.B. et al. et al. The use of oxybutynin in patients with imperative forms of urinary disorders. Urology, 1998, No. 4, pp. 24-26, Maso E.B., Krivoborodov G.G. Overactive Bladder, M .: 2003, 159 p., Schwartz G.Ya. et al. 2000, Schwartz P.G., 2004.

The clinical efficacy of the most widely used drug of this group - oxybutynin reaches an average of 67% according to controlled clinical trials. Moreover, 50-70% of patients have characteristic side effects, the most common of which is dry mouth and an increase in the volume of residual urine in the bladder (MP). Other systemic side effects of anticholinergics that block muscarinic cholinergic receptors of various organs (exocrine glands, eyes, heart, gastrointestinal tract, etc.) include visual clarity disorders, decreased tonus of smooth muscle organs and the associated inhibition of intestinal motility and constipation, tachycardia, in some cases, central effects (drowsiness), etc., which are particularly unfavorable in elderly patients with concomitant cardiovascular pathologies, the disease iyami CNS etc.

Side effects of anticholinergics used in the treatment of neurogenic disorders of urination are given in Farmateka, 2005, Abrams P. et al. "Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutinin in patients with overactive bladder" (Br.J. Urol., 1998, Vol.81, P.801-810).

Clinical and pharmacological studies of tropacin in the form of tablets in doses of 3-10 mg 2 times a day in patients with different forms of OS (Clinic of Urology of Russian State Medical University, Research Institute of Neurology RAMS, Clinic of Nervous Diseases and Neurosurgery MMA named after IM Sechenov) showed that it has a therapeutic effect in patients with NAM and is well tolerated by patients. It was also shown that in terms of effectiveness it is close to modern medicines used to treat OB - oxybutynin and tolterodine. It surpasses oxybutynin in tolerability and practically does not differ from one of the most effective modern drugs of this group - tolterodine.

Thus, the widespread dissemination of urination disorders and their negative (often disabling) effect on the quality of life of patients, the lack of domestic medicines for the treatment of this type of pathology, previous experience with the use of diphenylacetic acid tropic ester hydrochloride, and the results of its limited clinical study on new indications indicate the prospect of using this substance in a new direction is for the treatment of NAM in patients with OB and BPH. At the same time, given the need for pharmacotherapy of NAM for a long time (years), in constant mode and with minimal side effects, it is necessary to use the formulations in the appropriate dosage forms, allowing to fully realize the properties of the drug and increase the consistency of treatment.

Tropacin (hydrochloride of tropinic diphenylacetic acid ester, diphenyltropine hydrochloride) is approved for release in the form of tablets [FS VNIHFI] of the following composition:

Ingredient 0.001 g tablets 0.003 g tablets 0.005 g tablets 0.01 g tablets Tropacin (tropic ester of diphenylacetic acid hydrochloride) 0.001 g 0.003 g 0.005 g 0.01 g Milk sugar (lactose) 0.044 g 0.087 g 0.135 g 0.25 g Potato starch 0.0045 g 0.009 g 0.009 g 0.012 g Calcium stearate 0,0005 g 0.001 g 0.001 g 0.002 Tablet weight 0.05 0.1 0.15 0.25

The aim of the invention is the creation of a new affordable highly effective domestic composition / pharmaceutical composition with minimal side effects in the treatment of the main forms of urination disorders.

This goal is achieved by creating a pharmaceutical composition of tropacin with drugs of a different mechanism of action - blockers of α ₁ -adrenoreceptors, or calcium channels, or GABA- _B receptor agonists in the form of tablets or capsules with prolonged release, or transdermal dosage forms (gels, ointments or plasters) with weight ratio of tropacin: blocker of α ₁ -adrenoreceptors (1 ÷ 20) to (1 ÷ 10), mainly 5 to (1 ÷ 4); tropacin: calcium channel blocker (1 ÷ 20) to (10 ÷ 40), mainly 5 to (2 ÷ 4); tropacin: agonist of GABAA receptors (1 ÷ 20) to (2 ÷ 10), mainly 5 to (1 ÷ 5). Moreover, as blockers of α ₁ -adrenoreceptors, it is preferable to use doxazosin; as calcium channel blockers, it is preferable to use a compound from the group of phenylalkylamine derivatives - verapamil, 1,4-dihydropyridines - nifedipine, benzothiosepine - diltiazem, diphenylpiperazine - cinnarizine, diarylaminopropylamine - bepridil; as agonists of GABA _B receptors, baclofen or tizanidine.

The technical result of the invention, both when using a pharmaceutical composition containing tropacin, and when using a pharmaceutical composition containing tropacin and blockers of α ₁ -adrenoreceptors, or calcium channels, or agonists of GABA _B receptors, is to increase the effectiveness of treatment of NAM with a number of common urological, neurological and gynecological diseases and improving the quality of life of patients with OS due to the elimination of characteristic side effects, along with the expansion of the arsenal of drugs ny funds.

Increasing the effectiveness of pharmacotherapy and improving its tolerability of combined dosage forms, including drugs with different mechanisms of action, is associated with the ability to simultaneously affect several links in the pathogenesis of diseases. The field of application of such combined dosage forms is NAM, the pathogenesis of which includes impaired urination due to not only the work of the detrusor muscle, but also the muscles of the neck of the MP and ureter, in which, as already noted, alpha1-adrenergic receptors and other prescription structures are localized.

According to modern concepts, NAM in BPH is associated with dysregulation of the functioning of these receptors, when there is not only instability of the detrusor and detrusor-sphincter dysinergy, but infravesical obstruction due to the pressure of the hyperplastic tissue of the prostate gland on the urethral canal. The use of alpha1-andrenoreceptor blockers is currently considered to be an effective and well-tolerated pharmacotherapy of BPH and, in particular, the NAM accompanying this disease due to elimination of detrusor-sphincter dysinergy, reduction of irritative symptoms, and reduction of prostate tonus, thereby improving the dynamic component of infravesical obstruction.

Formulations / pharmaceutical compositions of the present invention include the following dosage forms:

1. Ordinary / simple tablets containing diphenylacetic acid tropinic ester hydrochloride in an amount of 1 to 20 mg / tablet (preferably 5 mg).

2. Sustained-release tablets containing diphenylacetic acid tropic ester hydrochloride in an amount of 1 to 50 mg with a duration of 6-8 hours

3. Sustained-release capsules containing diphenylacetic acid tropic ester hydrochloride in an amount of 1 to 50 mg with a duration of 6-8 hours

4. Sustained-release tablets containing 1 to 50 mg diphenylacetic acid tropic ester hydrochloride and an alpha1-adrenergic blocker, for example, doxazazine, in an amount of 1 to 10 mg (preferably 5 mg) with a duration of 6-24 hours

5. Sustained-release capsules containing 1 to 50 mg diphenylacetic acid tropic ester hydrochloride and an alpha1-adrenergic blocker, for example, doxazazine in an amount of 1 to 10 mg (preferably 5 mg) with a duration of 6-24 hours

6. Sustained-release tablets containing 1 to 50 mg diphenylacetic acid tropic ester hydrochloride and a nifedipine calcium channel blocker with a duration of 6-24 hours (or another calcium channel blocker from phenylalkylamine derivative groups (eg, verapamil, etc.). ), 1,4-dihydropyridines (nifedipine, etc.), benzothiosepine (diltiazem, etc.), diphenylpiperazine (cinnarizine, etc.), diarylaminopropylamine (bepridil, etc.)

7. Sustained-release capsules containing 1 to 50 mg diphenylacetic acid tropic ester hydrochloride and 10-80 mg calcium channel blocker nifedipine with a duration of 6-24 hours (or another calcium channel blocker from phenylalkylamine derivative groups (eg ., verapamil, etc.), 1,4-dihydropyridines (nifedipine, etc.), benzothiosepine (diltiazem, etc.), diphenylpiperazine (cinnarizine, etc.), diarylaminopropylamine (bepridil, etc.).

8. Sustained-release tablets containing diphenylacetic acid tropic ester hydrochloride in an amount of 1 to 50 mg and baclofen or tizanidine in a dose of 15-25 mg.

9. Transdermal therapeutic system for skin application.

Transdermal dosage forms of the proposed pharmaceutical compositions are extremely convenient to use, since when undesirable side effects appear, the effect of the drugs can be easily terminated and resumed if treatment is needed for NAM.

The release duration is preferably 6-8 hours. The following examples illustrate, but are not limited to, the application of the alleged invention.

EXAMPLES

The pharmaceutical compositions of the present invention are in the form of tablets, coated tablets, time-controlled (prolonged) release tablets of the active substance, sublingual tablets, hard gelatine capsules, suspension granules, as well as combined dosage forms, and a transdermal therapeutic system.

Each dosage form contains the recommended doses of the active substance: from 5 to 10 mg of diphenyltropine hydrochloride or its other pharmaceutically acceptable salts. The following examples illustrate the implementation of the invention in various dosage forms.

TABLETS ORDINARY

Composition 1.

Components amount g % of the mass. g % of the mass. Diphenyltropine hydrochloride 0.005 9.62 0.01 9.62 Lactose 0.01 19.23 0.02 19.23 Microcrystalline cellulose 101 0.0265 50.96 0,053 50.96 Polyvinylpyrrolidone 12600 ± 2700 MM 0.005 9.62 0.01 9.62 Magnesium stearate 0,0005 0.96 0.001 0.96 Modified starch (VIVASTAR® P 5000) 0.005 9.62 0.01 9.62 Tablet weight: 0,052000 one hundred 0.104 one hundred

The tablets are prepared by wet granulation. A granulate of the composition is prepared: diphenyltropine hydrochloride, lactose, microcrystalline cellulose, a solution of low molecular weight polyvinylpyrrolidone is used as a binding solution. The resulting wet mass is calibrated and dried. The dried granulate is calibrated and dusted with a mixture of dried starch and magnesium stearate in a mixer for dry mixtures. The resulting mass is tabletted on a tablet press (option 1).

The tablets are prepared by wet granulation. A granulate of the composition is prepared: lactose, microcrystalline cellulose, a solution of low molecular weight polyvinylpyrrolidone is used as a binding solution. The resulting wet mass is calibrated and dried. The dried granulate is calibrated and dusted with a mixture of diphenyltropine hydrochloride, dried starch and magnesium stearate in a mixer for dry mixtures. The resulting mass is tabletted on a tablet press (option 2).

Composition 2.

Components amount g % of the mass. g % of the mass. Diphenyl tropin hydrochloride 0.005 9.62 0.01 9.62 Lactose 0,04040 77.69 0,0808 77.69 Starch 0.00380 7.31 0.0076 7.31 Collidon 30 0.00150 2.88 0.003 2.88 Collidon CL 0,00080 1,54 0.0016 1,54 Magnesium stearate 0,00050 0.96 0.001 0.96 Tablet weight: 0,05200 one hundred 0.104 one hundred

Tablets are prepared by direct compression. Ready-mixed mixtures of lactose with polyvinylpyrrolide (Ludipress, tabletose, etc.) are used as filler. All ingredients are mixed dry and tabletted.

Composition 3.

Components amount g % of the mass. g % of the mass. Diphenyltropine hydrochloride 0.005 9.62 0.01 9.67 Lactose 0,0278 53.46 0,0556 53.77 Starch 0.0169 32,50 0,0338 32.69 Kollidon VA 64 0.002 3.85 0.004 3.87 Magnesium stearate 0,0003 0.58 0,000 0.00 Tablet weight: 0,05200 one hundred 0.1034 one hundred

The tablets are prepared by wet granulation. A granulate of the composition is prepared: diphenyltropine hydrochloride, starch, lactose, an aqueous solution of VA 64 collidone is used as the binding solution. The resulting wet mass is calibrated and dried. The dried granulate is calibrated and dusted with magnesium stearate. The resulting mass is tabletted on a tablet press.

Composition 4.

Components amount g % of the mass. g % of the mass. Diphenyltropine hydrochloride 0.005 9.62 0.01 9.62 Microcrystalline cellulose 200 0.0415 79.81 0,083 79.81 Magnesium stearate 0,0005 0.96 0.001 0.96 Modified starch (VIVASTAR® P 5000) 0.005 9.62 0.01 9.62 Tablet weight: 0,052 one hundred 0.104 one hundred

Tablets are prepared by direct compression. All ingredients are mixed in a mixer for dry mixtures, the resulting mixture is tabletted.

Composition 5.

Components amount g % of the mass. g % of the mass. Diphenyltropine base 0.005 9.62 0.01 9.58 Lactose 0,0248 47.69 0.05 47.89 Microcrystalline cellulose 200 0.015 28.85 0,03 28.74 Collidon 90 F 0.005 9.62 0.01 9.58 Collidon CL 0.0012 2,31 0.002 1.92 Powdered Polyethylene Glycol 0,0008 1,54 0.002 1.92 Aerosil A 200 0,0002 0.38 0,0004 0.38 Tablet weight: 0,052 one hundred 0.1044 one hundred

Tablets are prepared by direct compression. All ingredients are mixed in a mixer for dry mixtures, the resulting mixture is tabletted.

Composition 6.

Components amount g % of the mass. g % of the mass. Diphenyltropine hydrochloride 0.01 9.62 0.01 9.62 Collidon 30 0.04 78.85 0,082 78.85 Lactose 0.00 3.85 0.004 3.85 Starch 0.00 7.69 0.008 7.69 Tablet weight: 0.05 one hundred 0.104 one hundred

Tablets are prepared by direct compression. Prepare two dry mixes. A mixture of 1 (diphenyltropine hydrochloride, collidone 30) and mixture 2 (dried starch lactose) are loaded into the mixer and mixed. The resulting mixture was tabletted.

COATED TABLETS

Shell composition 1.

Components The amount,% of the mass. Titanium dioxide 7,500% Hydroxypropyl cellulose 50,000% Medium molecular weight polyvinylpyrrolidone 25,000% Polyethylene glycol 10,000% Talc 7,500% Water q.s.

Shell composition 2.

Components Amount,% wt. Sucrose 56.30% Collidon 30 5.93% Titanium dioxide 6.67% Calcium carbonate 6.67% Talc 21.48% Glycerol 2.96% Dye (Sicovit) q.s., until the desired color is obtained Water q.s., until suspension

The core tablets obtained by one of the previously listed methods and compositions dedust. An aqueous suspension of the above composition is prepared and applied in a coating apparatus by spraying onto a tablet core.

Shell composition 3.

Components The amount,% of the mass. Kollidon VA 64 21.03% Macrogol 6000 4.76% Hydroxypropyl methylcellulose 31.35% Titanium dioxide 14.29% Sykovit 7.14% Talc 21.43% Water q.s., until suspension

The core tablets obtained by one of the previously listed methods and compositions dedust. A solution of the composition is prepared (in parts): VA64 collidone (4.42), macrogol 6000 (1.00), hydroxypropyl methylcellulose (6.58), purified water (61.00). A suspension of the composition of titanium dioxide (2.00), sykovite (1.00), talc (3.00), water (12.11) is prepared. The resulting aqueous solution and suspension are mixed. Dusty tablets - cores are coated with the resulting suspension in a spray coating apparatus.

TABLETS WITH CONTROLLED TIME OF EXEMPTION OF AN ACTING SUBSTANCE

Components Amount mg Diphenyltropine hydrochloride 2,5 10 twenty Hypromellose 75.0 75,5 75,5 (USP NF, or BP, or Eur. Ph.) Lactose Monohydrate 30,0 30,0 30,0 (USP NF, or BP, or Eur. Ph.) Microcrystalline Cellulose 138.75 136.25 131.25 (Eur. Ph. Or BP or USP) Colloidal silicon dioxide 2,5 2,5 2,5 (USP NF or BP, or Eur. Ph.) Magnesium stearate 1.25 1.25 1.25 (USP NF, or Eur.Ph., or BP) Weight of tablet without shell: 250.0 255.0 260,0 Opadry II 7.0 7.0 7.0 The mass of the tablet with the shell: 257.0 262.0 267.0

The tablets are prepared by wet granulation. A granulate of the composition is prepared: diphenyltropine hydrochloride, hypromellose, lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide and a sufficient amount of water are mixed in a granulator mixer until a homogeneous granular mass is obtained. The resulting wet mass is calibrated and dried. The dried granulate is calibrated and dusted with magnesium stearate. The resulting mass is tabletted on a tablet press.

Dust pills. An aqueous suspension is prepared. Opadry II is applied in a coating apparatus by spraying onto a tablet core. The resulting coated tablets are dried in the same apparatus to constant weight.

Hard Gelatine Capsules

Composition 1.

Components amount g % of the mass. g % of the mass. Diphenyltropine hydrochloride 0.005 9.09 0.01 9.09 Lactose 0,044 80.00 0,088 80.00 Aerosil 0,0005 0.91 0.001 0.91 Starch 0.0025 4,55 0.005 4,55 Magnesium stearate 0,0005 0.91 0.001 0.91 Polyvinylpyrrolidone low molecular weight. 0.0025 4,55 0.005 4,55 The mass of the contents of the capsule: 0,055 one hundred 0.11 one hundred

The encapsulation mixture is prepared by wet granulation. A granulate of the composition is prepared: diphenyltropine hydrochloride, lactose, a solution of low molecular weight polyvinylpyrrolidone is used as a binding solution. The resulting wet mass is calibrated and dried. The dried granulate is calibrated and dusted with a mixture of dried starch, magnesium stearate and aerosil. The resulting mixture is dosed in hard gelatin capsules on a capsule filling machine.

Composition 2.

Components amount g % of the mass. g % of the mass. Diphenyltropine hydrochloride 0.005 9.69 0.01 9.62 Lactose 0.02 38.76 0.04 38.46 Starch 0,0204 39.53 0,0408 39.23 Kollidon VA 64 0.003 5.81 0.006 5.77 Collidon CL 0.002 3.88 0.004 3.85 Magnesium stearate 0,0006 1.16 0.002 1.92 Aerosil A 200 0,0006 1.16 0.0012 1.15 The mass of the contents of the capsule: 0,0516 one hundred 0.104 one hundred

Option 1.

The encapsulation mixture is prepared by wet granulation. A granulate of the composition is prepared: diphenyltropine hydrochloride, lactose, starch; an aqueous solution of VA 64 collidone is used as the binding solution. The resulting wet mass is calibrated and dried. The dried granulate is calibrated and dusted with a mixture of CL collidone, magnesium stearate and aerosil. The resulting mixture is dosed in hard gelatin capsules on a capsule filling machine.

Option 2

Get a tablet of the following composition:

Components amount g % of the mass. g % of the mass. Diphenyltropine base 0.005 16.64 0.01 16.64 Lactose 0.011 36.61 0,022 36.61 Corn starch 0.0114 37.94 0.0228 37.94 Kollidon VA 64 0.0012 3.99 0.0024 3.99 Collidon CL 0,0008 2.66 0.0016 2.66 Magnesium stearate 0,0004 1.33 0,0008 1.33 Aerosil A 200 0,00025 0.83 0,0005 0.83 Tablet Weight 1: 0,03005 one hundred 0.0601 one hundred The mass of the contents of the capsule: 0,03005 one hundred 0.0601 one hundred

A diphenyltropine hydrochloride tablet is prepared by wet granulation. A granulate of the composition is prepared: diphenyltropine hydrochloride, lactose, starch; an aqueous solution of VA 64 collidone is used as the binding solution. The resulting wet mass is calibrated and dried. The dried granulate is calibrated and dusted with a mixture of CL collidone, magnesium stearate and aerosil.

The resulting tablet is dedusted and placed one tablet in hard gelatin capsules on a capsule filling machine.

SUBLINGUAL TABLETS

Components amount g % of the mass. g % of the mass. Diphenyltropine hydrochloride 0.005 15.63 0.01 15.63 Direct sorbitol (Parteck SI) 0,02695 84.22 0,0539 84.22 Sodium Stearyl Fumarate 0.00005 0.16 0.0001 0.16 Tablet weight 0,032 one hundred 0,064 one hundred

Tablets are prepared by direct compression. Ready filler mixtures of sorbitol (Parteck) are used as filler. All ingredients are mixed dry and tabletted.

GRANULES FOR PREPARING ORAL SUSPENSION

Composition 1.

Components amount g % of the mass. g % of the mass. Diphenyltropine hydrochloride 0.005 1.016 0.01 1,02 Sorbitol (Parteck SI) 0.4 81,301 0.8 81.30 Sucrose 0,08695 17,673 0.1739 17.67 Sodium Stearyl Fumarate 0.00005 0.010 0.0001 0.01 Mass of one dose 0.492 one hundred 0.984 one hundred

Composition 2.

Components amount g % of the mass. g % of the mass. Diphenyltropin Base 0.005 1,02 0.01 1,02 Kollidon CL-M 0,054 10.98 0.108 10.98 Fructose 0.37288 75.79 0.7458 75.79 Crystalline sorbitol 0,045 9.15 0.09 9.15 Flavoring Additive (Banana) 0.0065 1.32 0.013 1.32 Collidon 90 F 0.0065 1.32 0.013 1.32 Flavoring Additive (Banana) 0.002 0.41 0.004 0.41 Saccharin sodium 0.00012 0.02 0,0002 0.02 Mass of one dose 0.492 one hundred 0.984 one hundred

Composition 3.

Components amount g % of the mass. g % of the mass. Diphenyltropine hydrochloride 0.005 1,02 0.01 1,02 Fructose 0.15 30.49 0,30000 30.49 Kollidon CL-M 0.16 32.52 0.32000 32.52 Crystalline sorbitol 0.14 28.46 0.28000 28.46 Flavoring Additive (Orange) 0.0166 3.37 0,03320 3.37 Collidon 90 F 0.02 4.07 0.04000 4.07 Saccharin sodium 0,0004 0.08 0,00080 0.08 Mass of one dose 0.4920 100.00 0.9840 100.00

The components are mixed in a mixer, the resulting product is dispensed into jars (bottles) or single-dose packets (contour bezel-less packaging).

The dosage forms obtained according to the present invention satisfy all the requirements for pharmaceutical preparations. Carefully selected qualitative composition and quantitative ratios of components determine the high technological effectiveness of their production using available excipients.

The present method provides complete mechanization of the manufacturing process, its high performance, purity and hygiene of the tablets, good stability of the solid dosage form during storage.

COMBINED MEDICINAL FORMS

Sustained-Release Tablets

Components amount g % of the mass. Diphenyltropine base 0.01 6.58 Tamsulosin hydrochloride 0.004 0.26 Metolose sr 0.0645 42,43 Magnesium stearate 0.015 9.87 Titanium Dioxide (E 171) 0.0011 0.72 Macrogol 6000 0.014 9.21 Kollidon VA 64 0,021 13.82 Hydroxypropyl methylcellulose 0,026 17.11 Amount: 0.152 100.00

The core tablets are prepared by wet granulation. A granulate of the composition is prepared: diphenyltropine base, tamsulosin hydrochloride, Metolose SR, magnesium stearate and a sufficient amount of water are mixed in a granulator mixer until a homogeneous granular mass is obtained. The resulting wet mass is calibrated and dried. The dried granulate is calibrated and additionally dusted with magnesium stearate. The resulting mass is tabletted on a tablet press.

Dust pills. An aqueous suspension of macrogol 6000, colidone VA 64, hydroxypropyl methylcellulose and titanium dioxide is prepared. The shell is applied in a coating apparatus by spraying onto a tablet core. The resulting coated tablets are dried in the same apparatus to constant weight. Sustained Release Capsules

Components amount g % of the mass. Diphenyltropine base 0.01 4.73 Tamsulosin hydrochloride 0.004 0.19 Polysorbate 80 0,084 39.72 Calcium stearate 0,062 29.31 A copolymer of polymethacrylic acid and acrylic acid esters 0,054 25.53 Triacetin 0.0011 0.52 Amount: 0.2115 one hundred

The encapsulation mixture is prepared by wet granulation. A granulate of the composition is prepared: diphenyltropine base, tamsulosin hydrochloride, polysorbate 80, a copolymer of polymethacrylic esters and acrylic acid esters, a solution of triacetin is used as a binding solution. The resulting wet mass is calibrated and dried. The dried granulate is calibrated and dusted with dried calcium stearate. The resulting mixture is dosed in hard gelatin capsules on a capsule-filling machine.

Sustained-Release Tablets

Components amount g % of the mass. g % of the mass. Diphenyltropine base 0.01 6.19 0.01 4.40 Baclofen 0.015 9.29 0,025 10.99 Metolose sr 0.0645 39.94 0,071 31.21 Magnesium stearate 0.015 9.29 0,021 9.23 Titanium Dioxide (E 171) 0.002 1.24 0.0035 1,54 Macrogol 6000 0.014 8.67 0,021 9.23 Kollidon VA 64 0,021 13.00 0,042 18.46 Hydroxypropyl methylcellulose 0.02 12.38 0,034 14.95 Amount: 0.1615 one hundred 0.2275 one hundred

The core tablets are prepared by wet granulation. A granulate of the composition is prepared: diphenyltropine base, tamsulosin hydrochloride, Metolose SR, magnesium stearate and a sufficient amount of water are mixed in a granulator mixer until a homogeneous granular mass is obtained. The resulting wet mass is calibrated and dried. The dried granulate is calibrated and additionally dusted with magnesium stearate. The resulting mass is tabletted on a tablet press.

Dust pills. An aqueous suspension of macrogol 6000, colidone VA 64, hydroxypropyl methylcellulose and titanium dioxide is prepared. The shell is applied in a coating apparatus by spraying onto a tablet core. The resulting coated tablets are dried in the same apparatus to constant weight.

TRANSDERMAL DRUG FORM

Option 1.

Components amount g % of the mass. g % of the mass. Diphenyltropine base 0.005 0,03 0.01 0.04 Lactose 0.05 0.26 0.1 0.35 Water 2.00 10.23 0.4 1.41 Glycerol 4.00 20.46 0.8 2.83 Polyethylene glycol (PEG-400) 7.00 35.80 fourteen 49.45 Polyvinylpyrrolidone (PVP) 6.50 33.24 13 45.92 Material balance (mass of one dose) 19.56 one hundred 28.31 one hundred

The diphenyltropine base is preliminarily ground in a dispersant until a homogeneous mass with a particle size of 2-3 microns is obtained. The components are mixed in a mixer at a temperature of 55-70 ° C until a homogeneous hydrogel is formed containing diphenyltropine base adsorbed on lactose. In a coating installation, the resulting product is distributed in a layer onto a foil film and dried at a temperature of from 45 to 120 ° C. The result is a layer with a density of 95-98 g / m ² . A coating film of PVP or other suitable material is applied to the freshly dried layer and rolled between two rollers to remove air and adhere. Strips of the transdermal patch are obtained with a split stamp, which are packaged in a sealed package.

Option 2

Components amount g % of the mass. g % of the mass.

Diphenyltropine base 0.005 0.004 0.010 0.01 Staybelite Ester 3E® 76.00 56.50 73.00 54.07 Staybelite Ester 10E® 10.30 7.66 14.40 10.67 Ethyl Cellulose (NF50 NF) ® 13.70 10.19 12.59 9.33 Petroleum ether (60-80 ° C) 34.50 25.65 35.00 25.93 Material balance: 134.51 100,000 135.00 100.00

Staybelite Ester 3E® and Staybelite Ester 10E® are homogenized at a temperature of 85-90 ° C in a homogenizer at a stirrer speed of 80-90 rpm for 10-15 minutes until a translucent homogeneous mass is formed. Cool the mass to a temperature of 50 ° C and add petroleum ether. A pre-micronized (up to 4-9 micron) Tropacin base is added and stirring is continued for another 35-40 minutes until a finely dispersed suspension forms. The mass is heated to a temperature of 120-123 ° C and ethyl cellulose (NF50 NF) ® is added. Stirring is continued until the petroleum ether is completely removed and a crumpled elastic mass is obtained, which is applied to the protective surface of the nonwoven base material. A single-layer patch with an active layer content of 75-85 g / m ^{2 is} rolled on a rolling machine with simultaneous cooling. The active layer is covered with a polymer film and the plates necessary for area and shape are cut into a punching machine, which are then packed in sealed laminated packages.

CLINICAL EXAMPLES

Example 1

Patient A., 39 years old, elementary school teacher, married, has 1 child. Suffers from a cerebral form of multiple sclerosis with a remitting course and incomplete remissions for 5 years. The first symptoms of the disease appeared after childbirth. In the debut of the disease, among clinical manifestations, frequent urination up to 15 times per day and nocturia up to 3 times were noted. Violation of sleep, as well as work (forced interruption of lessons due to the need to visit the toilet) served as the basis for highlighting complaints from urination in the circle of leading complaints. Among the neurological manifestations noted the shakiness of the gait, double vision, decreased tone of the lower extremities. In connection with urgent urinary incontinence, with strong urination and motor impairments, I used pads daily. The diagnosis of multiple sclerosis was made on the 3rd year from the onset of the disease after performing an MRI of the brain.

As a pathogenetic therapy received the drug Copaxone. Against the background of treatment, there was a positive dynamics on the part of neurological symptoms and a decrease in the frequency and duration of exacerbations of the underlying disease, however, there were no changes in impaired urination. During the examination, the total symptom score of I-PSS was 14 due to the presence of imperative urges, frequent urination, nocturia. The level of quality of life according to QOL is 6 points (the lowest point).

In a general analysis and urine culture, there were no signs of inflammation or infection of the urinary tract. Ultrasound of the kidneys and bladder showed no deviations, there is no residual urine, the average effective volume of the bladder (SOMP) is 70 ml. When conducting a comprehensive urodynamic study, an involuntary detrusor contraction was detected, with an amplitude of up to 90 cm of water. Art.

Thus, our data indicate that the clinical picture of irritative urination clearly correlates with neurogenic detrusor hyperactivity detected during urodynamic examination (cystometry). This form of urination is a violation of the accumulative function of the bladder.

Against the background of symptomatic treatment according to the specified method at a dose of 6 mg / day, a decrease in the symptom score was noted to 3 due to the disappearance of peremptory urination, nocturia and perennial urinary incontinence. Symptoms disappeared within 3 weeks of taking the drug and the therapeutic effect persisted throughout the treatment period: more than six months.

Example 2

Patient B., 65 years old, Russian language teacher, not working, married, 2 children. He suffers from Parkinson's disease, a rigid-trembling form for about 10 years. Urination disorders were manifested in the 3rd year of the disease along with tremor of the extremities, gait disorders, salivation and spastic constipation, and a change in psycho-emotional status. Complaints from the NMA were of a constant and unchanging nature and were manifested by poliakuria up to 9 times a day, nocturia up to 4-5 times, episodes of urgent urinary incontinence. Urologist was not observed. She received pathogenetic therapy for PD with L-dopa drugs.

At the initial urological examination, the total symptom score of I-PSS was 15 due to all the symptoms described in the scale. The quality of life according to QOL is 6 points.

With ultrasound, the kidneys and bladder were not changed, residual urine was not determined. With an urodynamic study, there is a strong urge to urinate, accompanied by involuntary contractions of the detrusor with the introduction of already 120 ml of fluid. Cystometric capacity of 170 ml. When urinating, there were no signs of obstruction. Spontaneous detrusor contractions were observed, accompanied by an increase in intravesical pressure up to 47 cm of water. Art., which corresponds to neurogenic detrusor hyperactivity.

As a symptomatic correction of urinary symptoms, I received treatment according to the specified method at a dose of 20 mg / day. There was a decrease in the symptom score to 2 due to the disappearance of peremptory urination, nocturia and peremptory urinary incontinence. Symptoms disappeared within 2 weeks of taking the drug and the therapeutic effect persisted throughout the treatment period: more than six months.

Example 3

Patient V., 69 years old, senior citizen, widow, has 2 sons of a child. Suffers from dyscirculatory encephalopathy and arterial hypertension for 6 years.

The first symptoms of the disease appeared about 6 years and were manifested by a decrease in memory, later walking disorders and imperative urinary incontinence joined. Notes frequent urination up to 12 times a day and nocturia up to 5 times. Sleep disturbance and the need to use sanitary pads served as the basis for highlighting complaints from urination in the circle of leading complaints. Among neurological manifestations noted frontal apraxia of walking, cognitive deficit, mild extrapyramidal symptoms. The diagnosis of discirculatory encephalopathy was made on the 2nd year from the onset of the disease after performing an MRI of the brain in which lateral leukoaraiosis and single lacunar infarcts in the region of the warolium bridge and paraventricular nucleus of the hypothalamus were detected.

She received enalapril maleate and piracetam as a pathogenetic therapy. Against the background of treatment, positive dynamics were noted on the part of neurological symptoms and blood pressure figures, however, there were no changes on the part of impaired urination. During the examination, the total symptom score of I-PSS was 15 due to the presence of imperative urges, frequent urination, nocturia up to 5 times. The quality of life according to QOL is 6 points.

In a general analysis and urine culture, there were no signs of inflammation or infection of the urinary tract. Ultrasound of the kidneys and bladder showed no deviations, there is no residual urine, the average effective volume of the bladder (SOMP) is 70 ml. When conducting a comprehensive urodynamic study, an involuntary detrusor contraction was detected, with an amplitude of up to 45 cm of water. Art.

Thus, our data indicate that the clinical picture of irritative urination clearly correlates with neurogenic detrusor hyperactivity detected during urodynamic examination (cystometry). This form of urination is a violation of the accumulative function of the bladder.

Against the background of symptomatic treatment according to the specified method at a dose of 6 mg / day, a decrease in the symptom score was noted to 4 due to the disappearance of peremptory urination, nocturia and perennial urinary incontinence. Symptoms disappeared within 2 weeks of taking the drug and the therapeutic effect persisted throughout the treatment period: more than six months.

Example 4

Patient B., 35 years old, carpenter, married, 3 children. Suffers from chronic pelvic pain syndrome and overactive bladder for about 2 years. Urination disorders were manifested in the 1st year of the disease along with pain in the perineum. Complaints from the NMA were of a constant and unchanging nature and were manifested by poliakuria up to 18 times per day. Anti-inflammatory therapy (preliminary diagnosis of exacerbation of prostatitis), including non-steroidal anti-inflammatory drugs and antibiotics, did not lead to a cure.

At the initial urological examination, the total symptom score of I-PSS was 10 due to all the symptoms described in the scale. The quality of life according to QOL is 6 points.

Ultrasound of the kidney and bladder were not changed, residual urine was not determined, the prostate was not changed. With an urodynamic study, moderate urge to urinate is observed, accompanied by involuntary contractions of the detrusor with the introduction of 220 ml of liquid. Cystometric capacity of 270 ml. When urinating, there were no signs of obstruction. Spontaneous detrusor contractions were observed, accompanied by an increase in intravesical pressure up to 23 cm aq. Art., which corresponds to idiopathic detrusor hyperactivity.

As a symptomatic correction of urinary symptoms, I received treatment according to the specified method at a dose of 20 mg / day. There was a decrease in the symptom score to 5 due to a reduction in urination. Pain in the perineum persisted. Rapid urination disappeared within 10 days of taking the drug and the therapeutic effect persisted throughout the treatment period: more than six months.

Claims (4)

1. A pharmaceutical composition for the treatment of disorders of urination, containing as an active ingredient tropinium diphenylacetic acid or its pharmaceutically acceptable salts in an effective amount with pharmaceutically acceptable carriers in the form of tablets or capsules with prolonged release, or transdermal dosage forms. 2. A pharmaceutical composition for the treatment of disorders of urination, containing as active active substances tropinium diphenylacetic acid or its pharmaceutically acceptable salts and tamsulosin hydrochloride or baclofen, in an effective amount with pharmaceutically acceptable carriers in the form of tablets or capsules with prolonged release, or transdermal drugs forms. 3. The pharmaceutical composition according to claim 1, characterized in that the weight ratio of tropinium diphenylacetic acid: tamsulosin hydrochloride is (1 ÷ 20) :( 1 ÷ 10). 4. The pharmaceutical composition according to claim 1 or 2, characterized in that the weight ratio of tropic ether of diphenylacetic kiltsota: tamsulosin hydrochloride is 5: (1 ÷ 4).