RU2506949C1 - Pharmaceutical composition of sip receptor agonist for treating demyeliniating diseases - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmacology and clinical medicine, and describes a pharmaceutical composition in the form of tablets containing a S1P receptor modulator representing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol and/or a pharmaceutically acceptable salt thereof, and additive substances: microcrystalline cellulose, sodium carboxymethyl starch, calcium stearate or magnesium stearate in the following proportions.

EFFECT: composition is more stable and has less side effects.

3 cl, 4 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. 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.

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 diagnosis in children three years old and older. A feature of the disease is the simultaneous damage to 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.

- 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.

- 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 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 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 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 their solid forms that are stable during storage. The prior art attempts to create stable forms of aminodiols.

In the Russian Federation, Guilenia hard gelatin capsules from NOVARTIS PHARMA AG were 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 contain: an S1P 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.

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 S1P receptor modulator comprising 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 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.

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 -diol and / or its 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 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 present invention in the manufacturing technology of the described drug 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 excipients 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 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 invention is illustrated by the following examples.

Example 1

2-amino-2- [2- (4-octylphenyl) ethyl] propan-1,3-diol 0,00056 g Microcrystalline cellulose 0.145 g Sodium carboxymethyl starch 0.00294 g Calcium stearate 0.0015 g

Example 2

2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol hydrochloride 0,0005 g Microcrystalline cellulose 0.145 g Sodium carboxymethyl starch 0.0028 g Magnesium stearate 0.002 g

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 compounds was determined using a generally accepted technique, 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 formulations of Example 1 were prepared from solutions in DMSO and added to SPA (Amersham-Pharmacia) granules 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 HDF, 0.1% BSA and 0.2 nM GTF [ ^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 [ ^Y - ³⁵ S] using S1P1, S1P2, S1P 3, S1P4 or S1P5 receptors. Thus, these formulations can be used as effective S1P modulators.

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

Example 5

Studying dosing uniformity Dosing uniformity.

The determination is carried out in accordance with the requirements of the Global Fund XI, issue 2, p. 154.

The solvent, 1.0 ml of concentrated hydrochloric acid, is placed in a 250 ml volumetric flask, diluted, the volume of the solution is adjusted to the mark with methanol and stirred. 5 ml of the resulting solution is placed in a 500 ml volumetric flask, the solution is 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 50 ml volumetric flask, dissolved in 25 ml of solvent, adjusted to the mark with the solvent 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. 10 ml of solvent is added with a pipette, the flask is closed and stirred for 10 minutes. Adjust the volume of the solution to the mark with a solvent, mix and filter a blue ribbon through a filter.

Chromatographic conditions

Column - 50 × 4.6 mm, MS C8.3.5 μm, XTerra®. Mobile phase - 0.1 M sodium perchlorate buffer 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 needle - methanol - water (90:10)

Chromatography time - 3 min.

Chromatograph a standard solution at least 6 times. The retention time of the peak 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

$$Q(mg)=\frac{S_i\times m_0\times 25\times \mathrm{one}}{S_0\times F\times \mathrm{fifty}\times \mathrm{twenty}\times \mathrm{one\; hundred}}=\frac{S_i\times m_0\times P}{S_0\times F\times 4000\text{'}\text{'}}$$

where S _i is the peak area of the active substance in the chromatogram of the test solution;

S ₀ - peak area in the chromatogram of a standard solution;

m ₀ - a sample of a standard sample (mg);

P - active substance content in a standard sample (%);

F is the conversion factor of the hydrochloride to the base (1,119). The content in each tablet subjected to the test meets the requirements of the Global Fund XI, issue 2, p. 154. Deviations do not exceed established standards. That is, the technology and composition provide a high degree of uniformity of dosage.

Claims (3)

1. A pharmaceutical composition in the form of tablets containing an S1P receptor modulator, which is 2-amino-2- [2- (4-octylphenyl) 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 magnesium stearate as auxiliary substances, with the following content of components in g:
2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol and / or its pharmaceutically acceptable salt 0.00045 to 0.00056 Microcrystalline cellulose 0.135-0.150 Sodium carboxymethyl starch 0.0028-0.0030 Calcium Stearate or Magnesium Stearate 0.001-0.002 2. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is suitable for the treatment of autoimmune demyelinating diseases. 3. The pharmaceutical composition according to claim 2, characterized in that the autoimmune demyelinating disease is Multiple Sclerosis (MS).