WO2013187795A1

WO2013187795A1 - Pharmaceutical composition of an s1p receptor agonist for treating demyelinized disorders

Info

Publication number: WO2013187795A1
Application number: PCT/RU2013/000053
Authority: WO
Inventors: Марат Феликсович ФАЗЫЛОВ
Original assignee: Открытое акционерное общество "Новосибхимфарм"
Priority date: 2012-06-13
Filing date: 2013-01-25
Publication date: 2013-12-19
Also published as: RU2012124232A; RU2506949C1

Abstract

The invention relates to the field of pharmacology and clinical medicine. A pharmaceutical composition in the form of tablets, said composition comprising an S1P receptor modulator, which constitutes 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol and/or a pharmaceutically acceptable salt thereof and auxiliary substances: microcrystalline cellulose, sodium carboxymethyl starch, potassium stearate or magnesium stearate, with a defined content of the components. The composition is more stable and has fewer side effects.

Description

PHARMACEUTICAL COMPOSITION OF S1P RECEPTOR AGONIST FOR TREATMENT OF DEMIELINIZATION DISEASES

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] propan-1, 3-Diol in free form and / or in the form of a pharmaceutically acceptable salt, or previously known called FTY720. The alleged 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.

State of the art

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 between the ages of 15 - 40 years. Although, at the moment, there are known cases of 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 a variety of 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:

- Relapsing-Weakening (RR-MS). It manifests itself in the form of separate motor, sensory, cerebellar or visual attacks of the disease. May last more than 1-2 weeks and may 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.

- Secondarily progressive (SP-MS). It is characterized by a gradually increasing helplessness with relapse possible, although without them. As a rule, during the period of the second- professing MS there is a disability, expressed in disability, even irreversible.

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

Occupational Relapse (PR-MS). A professing disease, from the very beginning pronounced acute relapses are characteristic. 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 severe violations of the quality of life of the person working capacity and social activity. Therefore, there is a pronounced need for effective medicines for the treatment of demyelination diseases - multiple sclerosis, Guillain-Barré syndrome. The use of such a drug should be characterized by clinical signs, which will manifest itself in the form of a decrease, 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, for example at least one S 1P receptor agonist and pharmaceutically acceptable excipients. The proposed compositions have therapeutically useful exposure to demyelination diseases, such as multiple sclerosis.

An S 1P receptor agonist is an agent that accelerates the migration of lymphocytes (CL), which cause lymphopenia resulting from the redistribution of mainly irreversible lymphocytes from the blood circulation to the secondary lymphatic tissue, without causing general immunosuppression.

S1P receptor agonists are typical sphingosine analogues, such as 2-amino-2-tetradecyl-1, 3-propanediol or 2-aminopropanol. A particularly preferred S 1P receptor agonist is a 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"; WO2005123104 "Method for the treatment of patients suffering from cancer"; WO 20041 13330 “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 signaling via the EDG receptor "; RF application 2007136602 "The use of S1P receptor modulators in ophthalmology"; RF application 2009102278, describing "S 1P receptor modulators for the treatment of multiple sclerosis"; RF application 20081 17083 "Bicyclic aromatic compounds used as inhibitors of protein kinase-2, activated by mitogen-activated protein kinase; RF application 20091 15439 "Pharmaceutical compositions comprising a modulator S 1 P"; RF application 2007133561 “Induction of an anti-lymphocyte antibody by a combination of an agonist / modulator of RECIPTOR S 1P and immunosuppressive drugs”; RF application 2007124327 "The course of treatment using the S1P receptor agonist"; application US 201 1 124605 "Use of an agonist of the receptor S 1P"; application WO 201 1041 146 "Dosing regimen of receptor modulators S 1 P"; 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 / But JW, Man, Sun CK, Lee TK, Poon RT, Fan ST. Mol Cancer Ther. 2005 Sep; 4 (9): 1430-87; 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 S 1P 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 their solid forms that are stable during storage. The prior art attempts to create stable forms of aminodiols. In the Russian Federation, Nilartis PHARMA AG firm Guilenia gelatin capsules are registered, including the S1P receptor agonist, fingolimod and excipients

(http://health.mail.rU/drug/gilenia/#CompiledComposition).

Patent RU 2358716 C2 describes solid pharmaceutical compositions suitable for oral administration that comprise: an S 1P receptor agonist and mannitol. This source can be indicated as the closest analogue - the prototype. The resulting form is quite stable and effective. However, sugar alcohols, such as mannitol, increase plasma osmotic pressure and filtration without subsequent tubular reabsorption. That is, they are osmotic diuretics, which is not suitable for part of the group of patients with multiple sclerosis. In addition, with prolonged use of such tablets, a violation of the water-electrolyte balance is possible.

Disclosure of invention

The aim of the described invention is to provide a stable pharmaceutical composition containing an effective amount of the active substance, with cheap pharmaceutically approved excipients, in production and a simpler technological implementation. The present invention relates to a pharmaceutical composition in the form of tablets comprising an S 1P receptor modulator, which is 2-amino-2- [2- (4-octylphenyl) ethyl] propan-1, 3-diol and / or a pharmaceutically acceptable salt thereof. The proposed pharmaceutical composition has high therapeutic efficacy against demyelinated diseases, especially multiple sclerosis or its associated effects and pathologies.

To implement the present invention, a composition that includes an S 1P receptor modulator does not contain sugar alcohol and polyethylene glycol, which lead to the formation of unacceptable impurities during storage.

To ensure delivery is therapeutically effective. doses of the S 1P receptor modulator, pharmaceutically acceptable excipients are chosen 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.

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 - this is compatibility with 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3 diol and / or its a pharmaceutically acceptable salt. Microcrystalline cellulose, sodium carboxymethyl starch, calcium stearate or magnesium stearate, taken in certain amounts, are offered as auxiliary substances:

2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol

and / or its pharmaceutically

acceptable salt from 0.00045 to 0.00056 g

Microcrystalline cellulose 0.135 - 0.150 g

^~ Sodium carboxymethyl starch 0.0028 - 0.0030 g

Calcium stearate or magnesium stearate 0.001 - 0.002 g

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.

The introduction of sodium carboxymethyl starch, which has anti-slip properties, can reduce the content of other such auxiliary substances. In addition, this starch derivative has the property of both disintegrating and binding agents, and these additional factors are used according to the presented the invention in the manufacture of the described medicinal composition.

Microcrystalline cellulose is used to increase the uniformity of the distribution of the concentration of therapeutically active substance. Also, this agent increases the strength of the tablet, determines the fluidity of the mixture, necessary for direct compression.

This content 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] propan-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 excipients, tablets are compressed.

To increase bioavailability, micronization of a mixture of the active substance with microcrystalline cellulose at a ratio of 1: 10-1: 20 is previously possible.

The best example of carrying out the invention

The invention is illustrated by the following examples. Π

Example 1

2-amino-2- [2- (4-octyl phenyl) ethyl l] propane-1, 3-diol

Microcrystalline cellulose

Sodium carboxymethyl starch

Calcium stearate

Example 2

2-amino-2- [2- (4-octylphenyl) ethyl] propan-1, 3-diol

hydrochloride

Microcrystalline cellulose

Sodium carboxymethyl starch

Magnesium stearate

Example 3. 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, 2 was 0%.

The claimed pharmaceutical compositions are shelf stable and have a shelf life of more than 2.5 years. Example 4. The study of pharmacological activity

The modulating activity of the compositions was determined using a generally accepted technique, namely, using human S 1 P receptors: S IP), S IP ₃ , S IP 2, SIP ₄ and SI P5. Functional activation of the receptor was evaluated by measuring the amount of GTP- 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 formulations of Example 1 were prepared from solutions in DMSO and added to SPA (Amersham-Pharmacia) granules with an immobilized S 1P 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- ³⁵ S] was separated by centrifugation. The luminescence of the SPA granules induced by the associated GTP \ ³⁵ S] membrane was measured, and EC50 values were calculated using standard curve fitting software. The affinity for binding to the S 1P receptor was <50 nM according to the analysis of binding to GTP [- ³⁵ S] s using receptors S 1P1, S 1P2, SIP 3, S1P4 or S 1P5 person. Thus, these formulations can be used as effective S 1P modulators.

When assessing bioavailability, the absolute bioavailability when taken orally is 96%.

Example 5. The study of uniformity of dosage

Dosing uniformity. The determination is carried out in accordance with the requirements of the Global Fund XI, no. 2, p. 154.

Solvent. 1.0 ml of concentrated hydrochloric acid was placed in a 250 ml volumetric flask, diluted, the volume of the solution was adjusted to the mark with methanol and stirred. 5 ml of the resulting solution was placed in a 500 ml volumetric flask, the volume of the solution was adjusted to the mark with methanol and stirred. The solution is used freshly prepared.

Standard solution. About 23 mg (accurately weighed) of a standard sample of the active substance is placed in a volumetric flask with a capacity of 50 ml, dissolved in 25 ml of solvent, adjusted with a solvent to the mark and mixed. 1 ml of the resulting solution was placed in a 20 ml volumetric flask, the volume of the solution was adjusted with a solvent to the mark and stirred.

Test solution. The tablet of Example 1 is placed in a 25 ml volumetric flask. Add 10 with a pipette ml of solvent, close the flask and mix for

10 min. Bring the solution volume to the mark with a solvent, mix and filter through a blue ribbon filter.

Chromatographic conditions

Column - 50x4.6 mm, MS C8, 3.5 μm, XTegga®.

Mobile phase - 0.1 M buffer solution of sodium perchlorate pH 2.8 - methanol - acetonitrile (93: 7: 100)

Flow rate - 1, 5 ml / min

Column temperature - 30 ° С

Detector - 215 nm

The volume of the injected sample is 10 μl

Washing the needles - methanol - water (90: 10)

Chromatography time - 3 min.

Chromatograph a standard solution at least 6 times. The peak retention time of the active substance is about 3 minutes.

The content of fingolimod (Q,%), relative to the declared amount in each tablet, is calculated by the formula:

5, g X m _Q X P X 25 X 1 5, X t ₀ X P

S ₀ XFX 50 X 20 X 100 S _Q XFX 4000 ^J where is the peak area of the active substance in the chromatogram of the test solution;

- peak area in the chromatogram of a standard solution;

- a sample of a standard sample (mg); - the content of active substance in a standard sample (%);

is the conversion factor of the hydrochloride to the base (1, 1 19).

The content in each tablet tested is in accordance with the requirements of Global Fund XI, no. 2, p. 154. Deviations do not exceed established standards. That is, the technology and composition provide a high degree of uniformity of dosage.

Industrial applicability The invention is applicable as a pharmaceutical composition for the treatment of demyelinated diseases, such as multiple sclerosis and the consequences associated with this pathology.

Claims

CLAIM

1. The pharmaceutical composition in the form of tablets containing a modulator of the receptor S 1P, which is a 2-amino-2-

5 [2- (4-octyl phenyl) ethyl] propane-1, 3-diol and / or its pharmaceutically acceptable salt and excipients, characterized in that it contains microcrystalline cellulose, sodium carboxymethyl starch, calcium stearate or calcium stearate as auxiliary substances magnesium, with the following components in g:

2-amino-2- [2- (4-octylphenyl) ethyl] propan-1, 3-diol

and / or its pharmaceutically

acceptable salt from 0.00045 to 0.00056 g

Microcrystalline cellulose 0, 135—0, 150 g

Sodium carboxymethyl starch 0.0028 - 0.0030 g

Calcium stearate or magnesium stearate 0.001-0.002 g

2. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is suitable for the treatment of autoimmune demyelinating diseases.

fifteen

3. The pharmaceutical composition according to claim 2, characterized in that the autoimmune demyelinating disease is Multiple Sclerosis (MS).