RU2482842C1 - Pharmaceutical composition of s1p receptor agonist for treatment of demyelinating diseases (versions) and method of its obtaining - Google Patents

Pharmaceutical composition of s1p receptor agonist for treatment of demyelinating diseases (versions) and method of its obtaining Download PDF

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RU2482842C1
RU2482842C1 RU2012116794/15A RU2012116794A RU2482842C1 RU 2482842 C1 RU2482842 C1 RU 2482842C1 RU 2012116794/15 A RU2012116794/15 A RU 2012116794/15A RU 2012116794 A RU2012116794 A RU 2012116794A RU 2482842 C1 RU2482842 C1 RU 2482842C1
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starch
form
pharmaceutical composition
lactose
amino
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RU2012116794/15A
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Russian (ru)
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Антон Евгеньевич Стрекалов
Владимир Викторович Нестерук
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Открытое акционерное общество "Новосибхимфарм"
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • A61K9/1623Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4858Organic compounds

Abstract

FIELD: medicine, pharmaceutics.
SUBSTANCE: claimed invention relates to field of pharmacology and clinical medicine and describes pharmaceutical compositions of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diole in free form and/or in form of pharmaceutically acceptable salt, where as auxiliary substances they contain lactose, starch and/or starch derivatives, selected from acetylated starch, sodium salt of starch carboxymethyl ether, pregelatinised starch, sodium starch glycolate, gelatin, binding agent, and lubricant with specified ratio.
EFFECT: invention makes it possible to extend possibility for cheaper in industrial manufacturing preparation for treatment of disseminated sclerosis.
7 cl, 16 ex

Description

The invention relates to the field of pharmacology and clinical medicine and relates to the pharmaceutical composition of 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol in free form and / or in the form of a pharmaceutically acceptable salt, or previously known called FTY720 for the treatment, alleviation or delay of the course and / or progression of multiple sclerosis. The present invention relates to pharmaceutical compositions that contain at least one S1P receptor agonist for the treatment of demyelinated diseases, such as multiple sclerosis and the consequences associated with this pathology.

Multiple sclerosis (PC) is a chronic autoimmune disease in which the myelin sheath of the nerve fibers of the brain and spinal cord is affected. Multiple sclerosis is accompanied by chronic inflammatory demyelination, leading to the extinction of motor and sensory functions and long-term disability. The disease occurs at the age of 15-40 years. Although at the moment there are known cases of this diagnosis in children three years of age and older. A feature of the disease is the simultaneous defeat of several different parts of the nervous system, which leads to the appearance of various neurological symptoms in patients. The morphological basis of the disease is the formation of so-called plaques of multiple sclerosis - foci of myelin destruction (demyelination) of the white matter of the brain and spinal cord. The size of the plaques, as a rule, is from several millimeters to several centimeters, but with the progression of the disease, the formation of large merged plaques is possible. One and the same patient with special research methods can detect plaques of varying degrees of activity - fresh and old.

The process can occur in four types of models of multiple sclerosis disease:

- Recurrently Weakening (RR-MS). It manifests itself in the form of separate motor, sensory, cerebellar or visual attacks of the disease. They can last more than 1-2 weeks and can weaken after about 1-2 months of treatment, and possibly even without treatment. About 85% of patients initially suffer from relapsing-relieving (RR) multiple sclerosis (MS), but within 10 years, about half of them develop a form of secondary progressive MS.

- Secondary progressive (SP-MS). It is characterized by a gradually increasing helplessness with relapses, although it is possible without them. As a rule, during the period of secondary progressive MS, disability arises, expressed in disability, up to irreversible.

- Primary Progressive (PP-MS). The disease proceeds from the very beginning without any relapse or remission; it occurs in about 15% of MS patients.

- Progressive Recurrent (PR-MS). A progressive disease, pronounced acute relapses are characteristic from the very beginning. In the periods between relapses there is a steady development of the disease.

Since the disease itself, however, as well as the consequences are accompanied by pronounced violations of the quality of life: reduced working capacity and social activity of a person, there is a pronounced need for effective medicines for the treatment of demyelination diseases - multiple sclerosis, Guillain-Barré syndrome. The use of such a medicinal product should be characterized by clinical signs, which will manifest itself in the form of reduction, mitigation, stabilization or alleviation of the symptoms of the disease.

Already known drugs, combinations containing at least one S1P receptor agonist and another therapeutically active substance, or compositions containing at least one S1P receptor agonist and pharmaceutically acceptable excipients. The proposed compositions have a therapeutically beneficial effect on demyelination diseases, such as multiple sclerosis.

An S1P receptor agonist is an agent that accelerates the migration of lymphocytes (CL), which cause lymphopenia resulting from the redistribution of mostly irreversible lymphocytes from the blood circulation to the secondary lymphatic tissue, without causing general immunosuppression.

S1P receptor agonists are typical sphingosine analogs, such as 2-amino-2-tetradecyl-1,3-propanediol or 2-aminopropanol. A particularly preferred S1P receptor agonist is the 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol compound in free form or in the form of a pharmaceutically acceptable salt, for example, in the form of a hydrochloride.

The following publications are known that characterize the described compound. International application WO 2006058316 "Dosage regimen of an S1P receptor modulator or its agonists in the treatment of patients after transplantation or patients suffering from autoimmune diseases or disorders"; WO 2005123104 “Method for the treatment of patients suffering from cancer”; WO 2004113330 “A New Class of Immunosuppressant Compounds Used in the Treatment or Prevention of Diseases or Disorders through Exposure to Lymphocytes, in particular Diseases Associated with Signal Transmission through the EDG Receptor”; RF application 2007136602 "The use of S1P receptor modulators in ophthalmology"; RF application 2009102278, describing "S1P receptor modulators for the treatment of multiple sclerosis"; RF application 2008117083 "Bicyclic aromatic compounds used as inhibitors of protein kinase-2, activated by mitogen-activated protein kinase; RF application 2009115439 "Pharmaceutical compositions comprising an S1P modulator"; RF application 2007133561 “Induction of an anti-lymphocyte antibody by a combination of an agonist / modulator of S1P RECEPTOR and immunosuppressive drugs”; RF application 2007124327 "The course of treatment using the S1P receptor agonist"; Application US 2011124605 “Use of an S1P Receptor Agonist”; application WO 2011041146 "Dosing regimen for S1P receptor modulators"; application US 2004235794 "An agent for the treatment of respiratory diseases, which includes a regulator of sphingosine-1-phosphate receptors"; application EP 2209493 "Composition comprising a S1P receptor modulator";

The following articles are known.

Antagonism of Sphingosine-1-Phosphate Receptors by FTY720 Inhibits Angiogenesis and Tumor Vascularization, / Kenneth LaMontagne et al. Cancer Res. January 2006, 66, 221-231 /; Seminars in Cell & Developmental / Biology Volume 15, Issue 5, October 2004, Pages 513-520 Timothy Hla, Biology of Lysophosphatidic Acid and Sphingosine 1-phosphate and Polarity in Mammalian Development /; Effects of a novel immunomodulating agent, FTY720, on tumor growth and angiogenesis in hepatocellular carcinoma / Ho JW, Man K, Sun CK, Lee TK, Poon RT, Fan ST. Mol Cancer Ther. 2005 Sep; 4 (9): 1430-8./; FTY720 in relapsing MS: results of a double-blind placebo-controlled trial with a novel oral immunomodulator / 23/06/2005 Kappos L, Radue EW, Antel J, et al./; Developing therapeutics for the treatment of multiple sclerosis / David J Virley NeuroRx 2 (4): 638-49 (2005) PMID 16489371 /; Angiogenesis in multiple sclerosis: is it good, bad or an epiphenomenon? / Kirk S, Frank JA, Karlik S. J Neurol Sci. 2004 Feb 15; 217 (2): 125-30.

Thus, it is known from the prior art that S1P receptor modulators are used in medical practice for various diseases. Effective representatives of this class are 2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol and its pharmaceutically acceptable salts.

However, when creating dosage forms with compounds related to aminodiols, there are significant difficulties, especially when creating solid forms that are stable during storage. Known solid dosage forms are described, for example, in the applications of the Russian Federation 2009115439 and RF 2009105403.

WO2004089341 disclosing tablets and capsules containing an S1P receptor agonist such as FTY720 and excipients including mannitol, cellulose derivatives, hydrogenated oils lubricating, for example, magnesium stearate, may be mentioned as the closest analogue.

The aim of the described invention is to provide a stable pharmaceutical composition containing an effective amount of the active substance with cheap excipients that are pharmaceutically acceptable in production, and a simpler technological implementation.

The proposed pharmaceutical composition has high therapeutic efficacy against demyelinated diseases, especially multiple sclerosis or its associated consequences and pathologies.

To implement the present invention, a composition that includes an S1P receptor modulator does not contain sugar alcohol and polyethylene glycol, which lead to the formation of unacceptable impurities during storage.

To ensure delivery of a therapeutically effective dose of an S1P receptor modulator, pharmaceutically acceptable excipients are selected to optimize the cost, ease and stability of the manufacturing process. An important condition for excipients is inertness, chemical and physical compatibility with the active ingredient.

Thus, the present invention proposes the inclusion in the composition of the first active agent either in free form and / or in the form of any pharmaceutically acceptable salt and the inclusion of concomitant adjuvants for the formation of the corresponding dosage form and variant of the disintegration of the dosage form in the gastrointestinal tract.

For the purpose of implementing this invention, the authors propose a pharmaceutical composition that comprises a therapeutically active compound, namely 2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol and / or a pharmaceutically acceptable salt thereof.

An important technological and pharmacological factor, for excipients - the inert chemical and physical properties is an absolute point, and also in terms of chemical and physical parameters - it is compatible with 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3 a diol and / or a pharmaceutically acceptable salt thereof.

Examples of pharmaceutically acceptable salts include inorganic salts such as hydrochloride, hydrobromide, phosphate and sulfate, salts with organic acids such as acetate, fumarate, maleate, benzoate, citrate, succinate, salts with metals such as sodium, potassium, calcium and aluminum salts with amines, such as triethylamine, and salts with di-amino acids, such as lysine.

Pharmaceutical excipients that are used in the claimed solid dosage forms, such as tablets, capsules, granules, troches, and the like, include milk sugar (lactose) in the form of various forms: alpha-lactose or beta-lactose, lactose monohydrate, alpha-lactose monohydrate, anhydrous alpha-lactose and beta-lactose and agglomerated lactose, starch and / or a starch derivative such as acetylated starch or sodium carboxymethyl ether of starch, gelatinized starch, modified starches, for example, sodium starch glycolate, gelatin, a binder selected from the group consisting of alginic acid, sodium salt of alginic acid, amylopectin, agar-agar or mixtures thereof, a lubricant such as talc and / or paraffin and / or tween, in particular tween -80.

The introduction of starch, which has anti-slip properties, allows to reduce the content of other similar auxiliary substances - talc - and to exclude calcium stearate.

Selected diluents, lactose (milk sugar), starch and starch derivatives have the property of both disintegrating and binding agents, and these additional factors are used according to the present invention in the manufacturing technology of the described drug composition. In order to ensure their rapid mechanical destruction in a humid and / or liquid medium, disintegrating substances are added, including to facilitate dissolution and increase the bioavailability of the active component.

Binders are used for granulation to increase the concentration of therapeutically active substance or substances and other auxiliary ingredients in the resulting granules. The binder ingredient is added to increase the fluidity of the mixture and further pressing.

Lubricants in the production of solid dosage forms are used to eliminate technological problems, for example, the sticking of the tablet mass on production surfaces, and to reduce sticking during the tablet pressing stages, and also to prevent “sintering” of the mass during storage in the case of other forms.

One of the preferred options is the use of two disintegrants, for example gelatinized starch and amylopectin.

It was unexpectedly found that the quality indicators of the dosage form are positively affected by the introduction of gelatin in the composition in certain quantities.

According to the invention, the composition can be made in the form of options.

The first option provides a pharmaceutical composition of an S1P receptor agonist for the treatment of demyelinated diseases in the form of a solid oral dosage form that contains 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol as an active principle in free form and / or in the form of its pharmaceutically acceptable salt, as excipients, lactose, starch and / or a starch derivative selected from acetylated starch, sodium salt of carboxymethyl starch ether, gelatinized starch a, sodium starch glycolate, gelatin, a binder selected from the group including alginic acid, sodium salt of alginic acid, amylopectin, agar-agar, or mixtures thereof, a lubricant selected from the group of talc and / or paraffin, in the following ratio of components, wt .%:

2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol and / or its pharmaceutically acceptable salt 0.25-1 Lactose 45-70 Starch (and / or starch derivatives) 20-38 Edible gelatin 1-2 Lubricating 1-15 Binder Rest

In a particular case, talc may be contained in an amount of 1-1.5 wt.%.

Also in a particular case, the composition may contain gelled starch as a derivative of starch, and amylopectin as a binder.

In preferred embodiments, milk sugar (lactose) is about 45-65% by weight of the composition, gelatinized starch is 5-15%, talc is about 1-10% and paraffin, but not necessarily, is about 0.2-2 , 0%.

Another option is the pharmaceutical composition of the S1P receptor agonist for the treatment of demyelinated diseases in the form of a solid dosage form for oral administration containing 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol b as an active principle free and / or in the form of its pharmaceutically acceptable salt, as excipients, lactose, starch and / or starch derivatives selected from acetylated starch, sodium salt of carboxymethyl ether of starch, gelatinized starch, sodium Akhman glycolate, gelatin, talc in mixture with a second lubricating agent selected from paraffin and / or Tween 80 under the following ratio wt.%:

2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol and / or its pharmaceutically acceptable salt 1.0-2.0 Lactose 30-45 Starch (and / or starch derivatives) 30-45 Edible gelatin 6-12 Talc 1-6 Lubricating 4-15

In some other embodiments, the implementation of 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol is 1.0% by weight of the composition, lactose (milk sugar) is 30.0-45.0 %, Tween, preferably Tween-80, is 5-15%, most preferably 10.5%, gelatinized starch 11.0%, talc and gelatin 6.0%, paraffin, optionally, about 4.0% .

The pharmaceutical composition of this invention is in the form of a solid dosage form, preferably, but not necessarily, in the form of tablets. This allows you to ensure the necessary accuracy of dosing of the active substance and the maximum manufacturability of subsequent packaging.

This ratio of auxiliary substances provides an indicator of disintegration up to 10-15 minutes, at which an optimal release profile of 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol is achieved.

A method of obtaining a pharmaceutical composition is that 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol and / or its pharmaceutically acceptable salt is mixed with a part of lactose, then the rest is gradually added with stirring the amount of lactose, the remaining excipients are administered, provided that the gelatin is used in the form of a 5% solution to obtain a solid dosage form.

A method of obtaining a solid dosage form according to this invention includes the step of preparing a trituration mixture. This allows for uniform mixing of the components. Also, for the most even distribution, gelatin is added in the form of a 5% solution. These differences are the technological advantages of the claimed method in comparison with analogues and provide optimal bioavailability of the active substance. The introduction of the remaining auxiliary components depends on the desired form and can be carried out by methods generally accepted in pharmacy. For example: granulation, dusting and pressing - in the case of tablets, granulation or mixing and filling with the obtained granules or capsule powder, etc.

The invention is illustrated by the following examples.

Example 1. An example of a composition in the form of tablets, wt.% (Composition according to the first embodiment).

2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol one Milk sugar 70 Acetylated Starch twenty Edible gelatin 2 Alginic acid 6 Paraffin one

Example 2. A method of obtaining a composition in the form of tablets for the treatment, alleviation or delay the progression of multiple sclerosis.

1) Preparation of trituration mixture. To ensure uniform mixing of a small amount of 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol with other components, its mixture is initially prepared in milk sugar, then portions of milk sugar are added successively and mixed thoroughly.

2) Obtaining wet granulate. Milk sugar, a pre-prepared mixture of 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol and milk sugar, starch (and / or starch derivatives) in an amount of about 95 are loaded into the mixing reactor % of its total mass, the mixture is stirred for several minutes, then moistened with a 5% gelatin solution in several portions until a uniformly moistened mass is obtained, mixed for a few more minutes. Next, the mixture-mass is unloaded from the mixer and granulated using a granulator with a diameter of the drum holes of 1.5 mm and transferred to the drying of the granulate.

3) Drying and dry granulation. The wet granulate is dried in a dryer at a temperature of (55 ± 5) ° C for 50-60 minutes. The residual moisture should preferably be (3.0 ± 0.5)%. Drying of the product is carried out by supplying a fan to the dryer with heated air to (60 ± 5) ° C. After drying, the dried mass is passed through a granulator with a diameter of the drum holes of 1.50 mm. Dry granulate is passed to the stage of formation of the tablet mass and further tableting.

4) Preparation of tablet mass.

Dry granulate, talc, the remaining amount of starch and, if necessary, substandard tablets crushed in the granulator are loaded into the tablet mass reactor, all are mixed for 15 minutes and unloaded into a container.

The tablet mixture is passed to the tableting step.

5) Tableting. Tableting is done on the press. The mixture is periodically fed at intervals of several minutes. During tabletting, the average weight of the tablets and their appearance are controlled at regular intervals. The resulting tablets are sent to the stage of packaging and packaging. Tablets are 0,00025; 0,0005; 0.001 g

Example 3-4 is carried out analogously to examples 1 and 2, but the sodium salt of carboxymethyl ether of starch and sodium starch glycolate are used as starch derivatives, respectively.

Example 5. An example of a composition in the form of tablets, wt.%: (Composition according to the first embodiment).

2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol 0.50 Milk sugar 68.57 Gelatinized starch 26.81 Edible gelatin 1,67 Amylopectin 1,0 Talc 1.45

Example 6 An example of a composition in the form of granules (composition according to the first embodiment).

2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol 0.25 Lactose 45.00 Starch 38.00 Gelatin 1.00 Mixture of talc and paraffin 15.00 Binder - sodium salt of alginic acid 0.75

Examples 7-8 are analogous to example 6, but agar-agar is used as a binder in one example and a mixture of alginic acid with sodium salt of alginic acid in another.

Example 9. An example of a composition in the form of granules (composition according to the second embodiment).

2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol 1.00 Lactose 39.18 Starch 36.81 Gelatin 11.60 Talc 1.30 Twin 80 10.11

Example 10. Hard gelatin capsules (composition according to the second embodiment).

2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol 2.00 Lactose 45.00 Starch + Sodium Starch Glycolate 35.71 Gelatin 6.00 Talc 1.30 Twin 80 9.99

Example 11

Hard gelatin capsules (composition according to the second option)

2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol 2.0 Lactose 35.0 Sodium Starch Glycolate 35.0 Gelatin 12.0 Talc 1,0 Twin 80 15.0

Example 12

Carried out analogously to example 11, but using gelatinized starch.

Example 13

Hard gelatin capsules (composition according to the second option)

2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol 1,0 Lactose 45.0 Sodium salt of carboxymethyl ether starch 38,0 Gelatin 6.0 Talc 6.0 Paraffin 4.0

Example 14

Analogously to example 13, but using acetylated starch

Example 15

The study of the stability of dosage forms.

The stability of the dosage forms was determined by accelerated aging during storage for a month at a temperature of 50 ° C. Characterization of the composition, including impurities, was carried out by gradient liquid chromatography. The acetylamide content in the samples according to examples 1, 3, 4 was 0%. With the exclusion of gelatin from the formulation of example 1 - 0.05% and an average of more than 2% of other impurities. In the case of replacement of example 3 of lactose with mannitol - 3%.

The claimed pharmaceutical compositions are shelf stable and have a shelf life of more than 2.5 years.

Example 16

The study of pharmacological activity.

The modulating activity of the compounds was determined using a generally accepted method, namely, using human S1P receptors: S1P 1 , S1P 3 , S1P 2 , S1P 4 and S1P 5 . Functional activation of the receptor was assessed by measuring the amount of GTP [Y- 35 S] bound to a membrane protein obtained from transfected CHO or RH7777 cells that stably express the corresponding human S1P receptor. Scintillation granules were used for analysis. Serial dilutions of the compositions of Examples 1, 3, 4 were prepared from solutions in DMSO and added to SPA granules (Amersham-Pharmacia) with an immobilized S1P receptor expressing a membrane protein (10-20 μg per well) in the presence of 50 mM Hepes, 100 mM NaCl , 10 mM MgCl 2 10 μM GDF, 0.1% BSA and 0.2 nM GTP [Y- 35 S] (1200 Ci / mmol). After incubation in a 96-well microplate at CT for 120 min, unbound GTP [Y- 35 S] was separated by centrifugation. The luminescence of SPA granules induced by a GTP membrane bound [Y- 35 S] was measured, and EC 50 values were calculated using standard curve fitting software. The affinity for binding to the S1P receptor was <50 nM according to the results of the analysis of binding to GTP [- 35 S] using the S1P 1 , S1P 2 , S1P 3 , S1P 4 or S1P 5 receptors. Thus, these formulations can be used as effective S1P modulators.

Gelatin-free forms showed the same affinity. However, when assessing the bioavailability, the absolute bioavailability when ingested of such forms was 93%, and in the case of compositions according to the invention, 94%

The composition according to the invention can be administered with additional pharmaceutical agents. The claimed compounds can be completed in a set, for example, with interferons when their content is up to 1 MIU. They can also be combined with an mTOR inhibitor, which includes, but is not limited to rapamycin (sirolimus) or its derivative in conventional therapeutic doses.

Thus, the invention provides the creation of a safe dosage form, characterized by the practical absence of decomposition products of the active substance and high bioavailability.

Claims (7)

1. The pharmaceutical composition of the S1P receptor agonist for the treatment of demyelinated diseases in the form of a solid dosage form for oral administration containing, as an active principle, 2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol in free in the form and / or in the form of its pharmaceutically acceptable salt and excipients, characterized in that as excipients it contains lactose, starch and / or starch derivatives selected from acetylated starch, sodium salt of carboxymethyl ether starch, yellow titrated starch, sodium starch glycolate, gelatin, a binder selected from the group including alginic acid, sodium salt of alginic acid, amylopectin, agar-agar, or mixtures thereof, a lubricant selected from the group of talc and / or paraffin, in the following ratio of components, wt.%:
2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol and / or its pharmaceutically acceptable salt 0.25-1 Lactose 45-70 Starch (and / or starch derivatives) 20-38 Edible gelatin 1-2 Lubricating 1-15 Binder Rest
2. The pharmaceutical composition according to claim 1, characterized in that it contains as a lubricating talc in an amount of 1-1.5 wt.%.
3. The pharmaceutical composition according to claim 1 or 2, characterized in that it contains as a derivative of starch gelatinized starch in an amount of 5-15% of the total amount of starch, and as a binder amylopectin.
4. The pharmaceutical composition according to claim 1, characterized in that the demyelinated disease is multiple sclerosis.
5. The pharmaceutical composition of the S1P receptor agonist for the treatment of demyelinated diseases in the form of a solid dosage form for oral administration containing, as an active principle, 2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol in free in the form and / or in the form of its pharmaceutically acceptable salt and excipients, characterized in that as excipients it contains lactose, starch and / or starch derivatives selected from acetylated starch, sodium salt of carboxymethyl ether starch, yellow . Tinirovannogo starch, sodium starch glycolate, gelatin, talc in mixture with a second lubricating agent selected from paraffin and / or Tween-80, with the following ratio, wt%:
2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol and / or its pharmaceutically acceptable salt 1.0-2.0 Lactose 35-45 Starch (and / or starch derivatives) 35-45 Edible gelatin 6-12 Talc 1-6 Lubricating 4-15
6. The pharmaceutical composition according to claim 5, characterized in that the demyelinated disease is multiple sclerosis.
7. A method of obtaining a pharmaceutical composition according to any one of claims 1 to 6, characterized in that 2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol and / or a pharmaceutically acceptable salt thereof are mixed with a part of lactose, then gradually the remaining amount of lactose is added with stirring, the remaining excipients are introduced, provided that the gelatin is used in the form of a 5% solution to obtain a solid dosage form.
RU2012116794/15A 2012-04-26 2012-04-26 Pharmaceutical composition of s1p receptor agonist for treatment of demyelinating diseases (versions) and method of its obtaining RU2482842C1 (en)

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