Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• 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.
• PC Multiple sclerosis
• Multiple sclerosis 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 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:
• RR-MS Relapsing-Weakening
• SP-MS Secondarily progressive
• PP-MS Primary occupational
• Occupational Relapse 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.
• 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.
• CL lymphocytes
• 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.
• 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.
• 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.
• 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.
• 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.
• compositions of the S 1P receptor modulator 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.
• 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.
• 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
• salts with di-amino acids such as lysine.
• sodium carboxymethyl starch which has anti-slip properties, can reduce the content of other such auxiliary substances.
• 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.
• micronization of a mixture of the active substance with microcrystalline cellulose at a ratio of 1: 10-1: 20 is previously possible.
• 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 ⁇ g per well) in the presence of 50 mM Hepes, 100 mM NaCl, 10 mM MgCl 2 10 ⁇ M 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.
• these formulations can be used as effective S 1P modulators.
• the absolute bioavailability when taken orally is 96%.
• 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
• the volume of the injected sample is 10 ⁇ l
• 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:
• 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.

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• 2012
  • 2012-06-13 RU RU2012124232/15A patent/RU2506949C1/ru active
• 2013
  • 2013-01-25 WO PCT/RU2013/000053 patent/WO2013187795A1/fr not_active Ceased

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