RU2639424C2 - Solid oral pharmaceutical composition of s1p agonist or its pharmaceutically acceptable salt, method for its production and methods for treatment and reduction of frequency of clinical exacerbations of multiple sclerosis - Google Patents

Abstract

FIELD: pharmacology.SUBSTANCE: solid oral pharmaceutical composition consists of phignolimide hydrochloride in an amount of 0.4-0.65 mg, pregelatinized starch in an amount of 145-155 mg and magnesium stearate in an amount of 1.0-2.0 mg. The composition can be presented in the form of a pill or a capsule. The composition intended for treatment of relapsing-remitting multiple sclerosis, to reduce the frequency of clinical exacerbations of the disease and reduce the risk of disability progression in relapsing-remitting multiple sclerosis. The composition is administered orally in a dose of 500 μg, once a day.EFFECT: composition according to the invention is characterized by a high homogeneity of the active substance dosage, stability for prolonged storage and is capable of disintegrating and releasing the active substance rapidly during oral administration.5 cl, 10 tbl, 8 ex

Description

The invention relates to medicine and pharmaceuticals, in particular to the treatment of multiple sclerosis, and more particularly to a solid oral pharmaceutical composition (solid oral dosage unit form) of an S1P receptor agonist - fingolimod (2-amino-2- (2- [4-octylphenyl]] ethyl) -1,3-propanediol) - or a pharmaceutically acceptable salt thereof, intended for the treatment of relapsing-remitting multiple sclerosis and to reduce the frequency of clinical exacerbations of the disease and reduce the risk of progression of disability during relapse explicit remitting multiple sclerosis, to a method for producing said composition, as well as to methods for treating relapsing-remitting multiple sclerosis, reducing the frequency of clinical exacerbations of a disease with relapsing-remitting multiple sclerosis, and reducing the risk of progression of disability in relapsing-remitting multiple disseminating sclerosis, effective amounts of such a composition to patients in need thereof.

The composition according to the invention is suitable for industrial production, is stable during long-term storage and is characterized by high uniformity of dosage of fingolimod and a high dissolution rate after oral administration.

State of the art

Multiple sclerosis is a neurological autoimmune disease of unknown etiology, which is characterized by demyelination (gradual destruction of the myelin sheath) of nerve fibers and neurodegeneration in the central nervous system (CNS). Demyelination occurs through autoimmune inflammation: autoreactive lymphocytes penetrate the blood-brain barrier (BBB) and are involved in a complex of immunopathological reactions leading to the formation of multiple foci in the central nervous system. To date, the direct cause of the development of the disease is not known [1].

In this regard, the most common is the hypothesis of the multifactorial nature of multiple sclerosis, i.e. exposure to external and genetic factors leading to the development of chronic inflammatory, demyelinating and neurodegenerative processes.

Among neurological disorders, multiple sclerosis is the main reason for the disability of young people, and women get multiple sclerosis 2-3 times more often than men [2].

According to the international classification [3], several types of the course of multiple sclerosis are distinguished, among which the most common is the remitting (remitting-relapsing) type of multiple sclerosis, which affects about 85% of all patients with multiple sclerosis [2].

Within 10 years from the onset of the disease, approximately one third of these patients have a secondary progressive course of multiple sclerosis [4], in which neurodegenerative processes are not more pronounced than inflammatory processes in the central nervous system. Somewhat apart is primary progressive multiple sclerosis, in which there are no distinct exacerbations of the disease, and there is only a steady increase in symptoms, leading to disability and death.

In the past 20 years, treatment methods have appeared that help reduce the frequency of exacerbations and the rate of progression of multiple sclerosis. First-line therapy involves the use of interferon beta (betaferon or ronbetal) and glatiramer acetate (copaxone), a synthetic copolymer of natural amino acids (L-alanine, L-lysine, L-glutamic acid and L-tyrosine), developed by the Israeli company TEVA [5- 8].

The second line therapy includes the use of a recombinant humanized monoclonal antibody - natalizumab. Natalizumab specifically blocks the adhesion molecules of lymphocytes from the class of integrins (a4-integrin) [9, 10].

All these drugs act through the immune system and require parenteral administration, which can cause unwanted side effects, as well as complicate the treatment of the patient. In addition, the question of the possibility of the impact of any of these drugs on the neurodegenerative component of the pathogenesis of multiple sclerosis, and hence their effectiveness in the case of primary progressive multiple sclerosis, is also controversial [11].

The imperfection of modern therapy for multiple sclerosis is largely due to the development of numerous side effects that limit the use of drugs.

So, when using interferons, inflammatory reactions at the injection site and flu-like symptoms are common [12], as well as more rare violations of the liver and cytopenia [13].

With the use of natalizumab, the incidence of progressive multifocal leukoencephalopathy, a rare but serious infection associated with immunosuppression [14-15], resulting in a number of fatal outcomes, increased [16].

Mitoxantrone, a cytostatic drug previously used only in oncological practice (for the treatment of leukemia, lymphomas, prostate cancer, breast cancer and some other types of cancer), was shown to be active in multiple sclerosis. Mitoxantrone, however, has a cumulative, dose-dependent toxic effect on heart tissue; in addition, its use is associated with an additional risk of developing infections and secondary malignant tumors. These side effects limit the possible duration of use of this drug for the treatment of multiple sclerosis [17].

These data show the disadvantages of drugs for the treatment of multiple sclerosis, the main mechanism of action of which is immunosuppression.

Interferons - despite the fact that they have been used for 20 years - are still the most common drugs that affect the course of multiple sclerosis. This fact reflects the lack of funds that can affect the pathogenesis of this disease, and leads to constant attempts to find a new drug for the treatment of this disease.

Cladribine is an antineoplastic drug with an immunosuppressive effect. In the form of intravenous infusions, it is used to treat hairy cell leukemia. A study of phase III of the oral form (tablets) of cladribine, completed in 2008, showed a 58% decrease in the frequency of exacerbations in the cladribine group compared with placebo.

Due to the fact that the potential risk of developing cancer due to the use of this drug and the need for additional clinical trials was subsequently shown, the European Medical Agency rejected the application for registration of the drug in the EU due to the potential possibility of the drug causing cancer.

A study of the effectiveness of cladribine in patients with clinically isolated syndrome was also prematurely completed; Currently, cladribine tablets are approved for medical use for the treatment of multiple sclerosis only in the Russian Federation and Australia.

Of the monoclonal antibodies currently being developed for the treatment of multiple sclerosis, rituximab, okrelizumab and ofatumumab, the monoclonal antibodies to CD20 ⁺ receptors, should be noted, cause pre-B cells and mature B lymphocytes to be depleted without destroying plasma and progenitor cells in the bone marrow ; alemtuzumab - a preparation of lysing monoclonal antibodies to CD52 ⁺ receptors expressed on the surface of mature lymphocytes and monocytes; dimethyl fumarate (BG-12) - a regulator of the immune response and oxidative stress; laquinimod is an oral immunomodulator with an unknown cellular target; teriflunomide is a dihydroorotate dehydrogenase inhibitor that catalyzes the synthesis of pyrimidines, having an immunomodulating effect [11].

All these drugs act on lymphocytes and other immune cells [18], so it is necessary to carefully weigh the risk / benefit ratio in each individual case before introducing the drug into clinical practice.

In 2010, a new drug, fingolimod (FTY720, Gileniya ^® ) was approved for use in patients with multiple sclerosis in the United States, Europe and Russia, the first oral drug for the treatment of multiple sclerosis (registration certificate No. LSR-008272/10, state date Registration on 08/17/2010, the holder of the registration certificate - Novartis Pharma AG (CH)).

Fingolimod (2-amino-2- (2- [4-octylphenyl] ethyl) -1,3-propanediol (I), Gileniya ^® ),

the structure and synthesis of which was first described in the patent [19], is a synthetic structural analogue of myriocin (ISP-1; compound (II))

the vital product of the fungus Isaria sinclairii, which has long been used in Chinese traditional medicine [20].

иммуносупрессорную активность, чем циклоспорин, выделенный из грибка того же рода Cordiceps.Miriocin (II), exerting an effect on serine palmitoyl transferase, shows 10-100 times

immunosuppressive activity than cyclosporin isolated from a fungus of the same genus Cordiceps.

Fingolimod (I), a chemical derivative of myriocin, lost activity against serine palmitoyl transferase, but retained the modulating effect on lysophospholipid sphingosine-1-phosphate receptors (S1P receptors) [23], [24]. After phosphorylation by the sphingosine kinase enzyme, the fingolimod binds to the S1P receptors of T and B lymphocytes, which inhibits the migration of lymphocytes from lymph nodes into the bloodstream and their subsequent penetration into the organs of the central nervous system.

There are a total of 5 subtypes of S1P receptors, including S1P1, S1P2, S1P3, S1P4 and S1P5 receptors; S1P1, S1P2 and S1P3 receptors are expressed in various tissues, S1P4 receptors - mainly in the lymphoid system, S1P5 receptors - in the white matter of the central nervous system. Fingolimod has high affinity for S1P1, S1P4, and S1P5 receptors, lower affinity for S1P3 receptors, and has no effect on S1P2 receptors [25].

Unlike myriocin, fingolimod does not inhibit the activation and proliferation of T-lymphocytes, and also does not affect the production of antibodies by B-cells or cytokines by T-cells, and therefore does not inhibit the immune defense against systemic viral infection [23-24], [26 ]. This feature attracted increased attention to fingolimod and its therapeutic possibilities in the treatment of multiple sclerosis, since its mechanism of action was different from the mechanism of action of classical immunosuppressants and was not fully understood [13]. It was found that fingolimod is able to quickly penetrate into the central nervous system through the blood-brain barrier, where it binds to sphingosine-1-phosphate receptors (S1P receptors) of nerve cells (S1P1 receptors of astrocytes), which may be due to its direct effect on the central nervous system - a decrease in neurodegeneration and acceleration of remyelination, as was shown in animal models [27-30]. In addition, fingolimod, binding S1P receptors of lymphocytes, blocks the ability of lymphocytes to leave lymphoid organs [31], which leads to redistribution of lymphocytes in the body without reducing their total number. Redistribution of lymphocytes helps to reduce lymphocytic infiltration of the central nervous system, reduce the severity of inflammation and the degree of damage to the nervous tissue [24], [32].

опухолей или ингибирования роста

опухолей, отличных от опухоли груди, простаты, мочевого пузыря, почки или легкого (в виде фармацевтически приемлемой соли или фосфата, в комбинации с химиотерапевтическим средством) [40]; для лечения глазного нарушения [41]; для ингибирования репликации вируса гепатита С (HCV) [42]; и для лечения воспалительных состояний (в комбинации с макролидом) [43].It was further shown that fingolimod (as well as its pharmaceutically acceptable salts) can be used not only for multiple sclerosis, but also for progressive dementia or brain degeneration (including dementia in Alzheimer's disease and dementia with Levy bodies) [33], as well as to alleviate or delay the progression of optic neuritis [34]; to control angiogenesis (inhibition or regulation of uncontrolled angiogenesis) [35]; for modulation, prevention and treatment of nociceptive pain [36]; for the treatment and alleviation of symptoms and prolongation of the interval between relapses of autoimmune diseases of the peripheral nervous system, in particular Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), neuropathy in vasculitis [37]; for the prevention, suppression or treatment of neoangiogenesis associated with demyelinating disease, for example, multiple sclerosis, and for the prevention, suppression or treatment of relapse-remission multiple sclerosis (in particular, in combination with a VEGF receptor antagonist) [38]; for the prevention (prophylaxis) or treatment of chronic rejection of an allo- or xenograft organ or tissue in a recipient or acute xenograft rejection in a recipient [39]; for the prevention or treatment of lymphoproliferative or myeloproliferative disorder, as well as for the treatment of

tumors or growth inhibition

tumors other than a tumor of the breast, prostate, bladder, kidney or lung (in the form of a pharmaceutically acceptable salt or phosphate, in combination with a chemotherapeutic agent) [40]; for the treatment of ocular disorders [41]; for inhibiting hepatitis C virus (HCV) replication [42]; and for the treatment of inflammatory conditions (in combination with macrolide) [43].

For the treatment of multiple sclerosis, the recommended dose of fingolimod is from 0.25 to 2.5 mg per day (oral), i.e. very small doses are considered; in other words, fingolimod in the composition of the solid dosage form (capsule) is only a few percent of the weight of the capsule.

The pharmaceutical composition of fingolimod or a pharmaceutically acceptable salt thereof is known from the prior art, comprising: (a) an S1P receptor agonist, such as fingolimod or a pharmaceutically acceptable salt thereof, and (b) (non-hygroscopic) sugar alcohol, preferably mannitol or xylitol [44]. The pharmaceutical composition [44] corresponds to the actual composition of the Gileniya ^® preparation (fingolimod hydrochloride (Gingolimod GC) capsules) manufactured by Novartis AG, Switzerland (registration certificate No. LSR-008272/10).

The dissolution profile of the HILENIA ^® preparation (see Source [47]) shows that the release of the active substance is extremely slow and the peak of its concentration is reached only about 30 minutes after administration.

Although it has been reported in the prior art [45] that fingolimod is incompatible with many common auxiliary components, with the exception of mannitol ([45], see page 5, the paragraph under Table 1-1), composition [44] has its drawbacks beyond the above dissolution profile, in particular, low abrasion resistance of the granules.

The granules of the fingolimod composition [44] contain 70-90% non-hygroscopic sugar alcohol (mannitol or xylitol), and because of this, they are poorly bonded in the composition and crumble upon abrasion. As a result, a large percentage of the fine fraction is formed, which can lead to dusting, and, as a result, to losses of the active substance during encapsulation and to inhomogeneity of dosage of fingolimod in capsules (see also below).

In accordance with the application for obtaining a patent of the Russian Federation [44] filed by NOVARTIS AG (SN) and the corresponding PCT publication [45] (proposed as the closest analogue of the present invention), legal protection is claimed, in particular, for the solid pharmaceutical composition of the S1P receptor modulator (including fingolimod or its pharmaceutically acceptable salt), including: (a) an S1P receptor modulator, (b) microcrystalline cellulose in the absence of aldite (sugar alcohol), and a method for producing such a composition.

According to the corresponding application [44] of the international PCT publication [45], oral compositions of fingolimod or its pharmaceutically acceptable salt can be obtained without the use of sugar alcohol ([45], abstract (Abstract)).

The invention [44], [45] solves the problem of creating a composition (solid dosage form) of an S1P receptor modulator (such as fingolimod or a pharmaceutically acceptable salt thereof) suitable for oral administration in the form of a solid dosage form (tablet or capsule), including for patients who have difficulty swallowing tablets and capsules; in particular, the problem of creating a storage stable composition of an S1P receptor modulator having a uniform distribution of the active component and suitable for industrial production is solved.

In the application [44], [45] it is furthermore solved the problem of creating a rapidly disintegrating dosage solid oral dosage form of fingolimod (or a pharmaceutically acceptable salt of fingolimod), which dissolves within a short period of time after oral administration, and thus allows to increase bioavailability active substance.

The tasks of increasing the strength and reducing the abrasion of granules containing fingolimod (or its pharmaceutically acceptable salt), as well as reducing the dissolution time of the solid dosage form of fingolimod, were not set in the application [44] and in the corresponding PCT publication [45].

Thus, the important task is to expand the range of preparations of the S1P receptor agonist (such as fingolimod or its pharmaceutically acceptable salt) and to develop a dosage solid oral dosage form of fingolimod, devoid of the disadvantages of existing solid dosage forms, and characterized by uniform dosage of the active substance , high stability during storage and rapid disintegration when taking the drug inside.

Examples 1-40 in the PCT international publication [45] disclose specific examples of capsule and tablet formulations containing, as an active ingredient, fingolimod hydrochloride (Gingolimolod); in this case, in a significant part of the compositions disclosed in [45], sugar alcohols (mannitol, xylitol, sorbitol) and / or croscarmellose (or its pharmaceutically acceptable derivatives, such as croscarmellose sodium, etc.) are used as auxiliary components.

Croscarmellose and its derivatives, in particular, are indicated in accordance with the international publication PCT [45] as the most suitable disintegrants in the manufacture of a solid dosage form of fingolimod or its pharmaceutically acceptable salt ([45], p. 5, paragraph 5, p. 13 , para. 4, p. 18, para. 8);

according to the international publication [45], wet granulation is indicated as one of the most preferred methods for preparing a solid dosage form of fingolimod ([45], p. 10, 3rd from the bottom of the paragraph, p. 26, 3rd from the top of the paragraph.) ;

in particular, wet granulation according to [45] is the preferred method for the manufacture of solid oral dosage forms of fingolimod or its pharmaceutically acceptable salt containing sugar alcohol (mannitol, xylitol, etc.) ([45], p. 10, 3- nd below the paragraph) or microcrystalline cellulose ([45], p. 26, 3rd above the paragraph).

During the development by Biocad CJSC of the original composition of GC Fingolimod capsules capable of rapidly releasing the active substance, GC Fingolimod capsules were taken as the prototype (the closest analogue) [45].

It was unexpectedly found that in the manufacture of a fingolimod composition by wet granulation (this method produces fingolimod capsules [45]), the use of cross-linked Na-carboxymethyl cellulose (Na-CMC) prevents the formation of homogeneous wet granules, leading to an increase in the content of impurities and to a decrease in the content the active substance in capsules (up to approximately 76.5% of the original) and the heterogeneity of dosage of the active substance in solid dosage form (capsule).

This problem is of particular importance due to the fact that the doses of fingolimod used in the capsule are extremely small (0.4-0.65 mg), and therefore, it is extremely important to observe the accuracy of dosing of fingolimod in capsules and minimize its loss during the manufacture of a solid dosage form.

In this regard, the task of developing the original composition (solid oral dosage form) of fingolimod or its pharmaceutically acceptable salt (such as hydrochloride, tartrate, succinate or fingolimod malonate), which would be therapeutically equivalent to the original preparation of fingolimod ( Gileniya ^® ), stable during long-term storage, would have a high accuracy in dosing the active substance, release the active substance within a short period of time after oral administration and would be suitable for industrial production.

In the framework of the present invention, this problem was solved by creating a solid oral pharmaceutical composition (dosage form) for the treatment of relapsing-remitting multiple sclerosis and for reducing the frequency of clinical exacerbations of the disease and reducing the risk of progression of disability in relapsing-remitting multiple sclerosis, including a therapeutically effective amount of an agonist S1P receptor (sphingosine-1-phosphate), such as fingolimod or a pharmaceutically acceptable salt thereof, and a pharmaceutical a pharmaceutically acceptable carrier, characterized in that the pharmaceutically acceptable carrier does not contain microcrystalline cellulose, sugar alcohol and croscarmellose (cross-linked carboxymethyl cellulose) or pharmaceutically acceptable derivatives of croscarmellose (croscarmellose sodium, etc.).

The composition in accordance with the claimed invention is preferably in the form of capsules or tablets and can be used to treat relapsing-remitting multiple sclerosis, to reduce the incidence of clinical exacerbations of the disease in relapsing-remitting multiple sclerosis, and to reduce the risk of progression of disability in relapsing-remitting multiple sclerosis .

Most preferred, in accordance with the present invention, is the following composition of the composition according to the invention, mg:

fingolimod hydrochloride 0.4-0.65 pregelatinized starch 145.0-155.0 magnesium stearate 1.0-2.0 mg

Also included in the scope of the claims in accordance with the invention are a method for treating relapsing-remitting multiple sclerosis, a method for reducing the incidence of clinical exacerbations of a disease in relapsing-remitting multiple sclerosis, and a method for reducing the risk of progression of disability in relapsing-remitting multiple sclerosis,

where these methods include (oral) administration to a patient in need thereof according to the indicated indications of the pharmaceutical composition of the invention.

Also included in the scope of the claims in accordance with the present invention is a method for producing a solid pharmaceutical composition of an S1P receptor agonist, characterized in that:

(a) weighed portions of an S1P receptor agonist (or a pharmaceutically acceptable salt of an S1P receptor agonist);

(b) sifting through a sieve the ground sample of an S1P receptor agonist (or a pharmaceutically acceptable salt of an S1P receptor agonist), as well as a sample of a lubricant and starch, or a pharmaceutically acceptable starch derivative;

(c) mixed in a mixer, weighed portions of an S1P receptor agonist and starch;

(g) add to the mixer a portion of a lubricant for dusting;

(e) filling capsules or compressing the mixture into tablets.

The S1P receptor agonist composition can be obtained by an alternative method, which is also included in the scope of the claims in accordance with the present invention;

in accordance with the specified method,

(a) a starch sample is loaded into a fluid bed granulator mixer;

(b) granulation is carried out using an aqueous solution of an S1P receptor agonist (or a pharmaceutically acceptable salt of an S1P receptor agonist);

(c) additionally moisturize the granules with water;

(g) dried wet granules;

(e) mixing the dried granules with a weighed portion of a lubricant for dusting;

- a method of treating relapsing-remitting multiple sclerosis, comprising oral administration of a solid pharmaceutical composition of the S1P receptor agonist according to the invention in a dose of 500 μg once a day to a patient in need thereof;

- a method of reducing the frequency of clinical exacerbations of a disease in relapsing-remitting multiple sclerosis, comprising orally administering to a patient in need of a solid pharmaceutical composition (solid oral dosage form) of an S1P receptor agonist according to any one of the invention at a dose of 500 μg once a day, and

- a method of reducing the risk of progression of disability in relapsing-remitting multiple sclerosis, comprising orally administering to a patient in need of a solid pharmaceutical composition (solid oral dosage unit form) of an S1P receptor agonist according to the invention at a dose of 500 μg 1 time per day.

The following examples, which disclose the preparation of fingolimod capsules in accordance with the invention, and their characteristics (accuracy and uniformity of dosage of the drug in the capsules, storage stability of the capsules and dissolution of the capsules) are provided only to illustrate the present invention, and should not be used to limit the volume claims claimed in accordance with the formula.

Example 1. Obtaining an oral solid pharmaceutical dosage form (capsule) of fingolimod hydrochloride.

A portion of fingolimod hydrochloride (substance powder) (0.56 g) was crushed in a jet mill to particle sizes ≤0.25 mm; the crushed sample was placed in a hermetically sealed container; the crushed weighed portion of fingolimod hydrochloride and the pre-sieved weighed portion of pregelatinized starch (Starch 1500) (150 g) are loaded (through the loading hopper) into the mixer, stirred for 10-20 minutes, at a mixer rotation speed of 12-15 rpm;

upon completion of the mixing of fingolimod hydrochloride, pregelatinized starch and carmellose sodium, the apparatus is stopped, the calculated amount of magnesium stearate (1.50-1.55 g) is loaded into it and dusting is continued for 5-7 minutes at a mixer rotation speed of 12-15 rpm ;

the encapsulating mass is loaded into the hopper of the capsule filling machine to obtain 1000 capsules containing 0.56 mg of fingolimod hydrochloride (corresponding to 0.5 mg of base of fingolimod);

the obtained capsules are dusted off in a capsule dedusting plant, collected in a container and checked for compliance with quality requirements.

Example 2. The accuracy and uniformity of dosage of fingolimod hydrochloride in an oral solid pharmaceutical dosage form (capsule).

Determining the uniformity of dosage of fingolimod hydrochloride in capsules was carried out by high performance liquid chromatography (HPLC), on a liquid chromatograph with an ultraviolet detector; 10 capsules of fingolimod hydrochloride obtained in accordance with Example 1 were selected for research

5 different series (F1-F5) (10 capsules / lot, # 1- # 10).

As a criterion for homogeneity, the content of GC fingolimod in capsules was found to be in the range from 85 to 115% of the declared (State Pharmacopoeia XI, issue 2, p. 143).

The contents of 1 capsule was transferred to a 10-ml volumetric flask, capsule shells were washed with 0.5 ml of methanol, quantitatively, the wash was transferred to the flask, stirred, the volume of the solvent was adjusted to the mark, stirred until the sample was dissolved. The resulting solution was filtered through a membrane filter with a pore diameter of not more than 0.45 μm, discarding the first 0.5 ml of the filtrate.

The results of the study of the uniformity of dosage of fingolimod hydrochloride in capsules are presented in Table 1.

Capsules in accordance with the invention, thus, showed a high uniformity of dosage of fingolimod.

Example 3. The stability of the oral solid pharmaceutical dosage form (capsule) of fingolimod hydrochloride during storage.

Capsules of fingolimod hydrochloride according to the invention (5 different series, F1-F5) obtained in accordance with Example 1 were placed in bottles of high density polyethylene.

The stability of the solid dosage form of fingolimod hydrochloride (series F1-F5) in accordance with the invention was investigated (a) at a temperature of + 25 ° C and 60% relative humidity (RH), (b) at a temperature of + 40 ° C and 75% RH.

The stability of the fingolimod hydrochloride capsules in accordance with the invention was evaluated by the following indicators: appearance (color) of the samples (capsule contents), moisture content (%), in vitro dissolution and active substance content (% of the declared); these indicators were evaluated at the beginning of the study, as well as after 1 month, 2 months and 3 months from the start of the study. The results are presented in Table 2.

Example 4. Dissolution of a solid pharmaceutical dosage form (capsule) of fingolimod hydrochloride.

6 capsules (# 1- # 6) of fingolimod hydrochloride in accordance with the invention, 3 different series obtained in Example 1 (F1-F3) were selected to study the dissolution profile; the dissolution of fingolimod hydrochloride was evaluated as described above using a validated HPLC technique at a flow rate of 1.0-1.2 ml / min. The content of fingolimod transferred to the dissolution medium was evaluated after 15 min, 30 min, 45 min and 60 min from the start of the study. The results are presented in Tables 3-5.

Example 5. Obtaining an oral solid pharmaceutical dosage form (capsule) of fingolimod hydrochloride without sodium carmellose.

A portion of fingolimod hydrochloride (substance powder) (0.56 g) was ground in a jet mill to particle sizes less than 0.25 mm; the crushed sample was placed in a hermetically sealed container; the crushed weighed portion of fingolimod hydrochloride and the pre-screened weighed portion of pregelatinized starch (Starch 1500) (153.88 g) were loaded (through the loading hopper) into the mixer, mixed for 10-20 minutes, at a mixer rotation speed of 12-15 rpm;

after mixing the fingolimod hydrochloride and pregelatinized starch, the apparatus was stopped, the calculated amount of magnesium stearate (1.50-1.56 g) was loaded into it and dusted for 1-2 minutes at a mixer rotation speed of 12-15 rpm;

the encapsulating mass was loaded into the hopper of the capsule filling machine to obtain 1000 capsules containing 0.56 mg of fingolimod hydrochloride (corresponding to 0.5 mg of base of fingolimod);

the obtained capsules were dedusted in a capsule dedusting apparatus, collected in a container and checked for compliance with quality requirements.

Example 6. The accuracy and uniformity of dosage of fingolimod hydrochloride in an oral solid pharmaceutical dosage form (capsule).

Determining the uniformity of dosing of fingolimod hydrochloride in capsules was carried out by high performance liquid chromatography (HPLC) on a liquid chromatograph with an ultraviolet detector; 10 capsules of fingolimod hydrochloride obtained in accordance with Example 5, 5 different series (F6-F10) (10 capsules / lot, # 1- # 10) were selected for the study.

The dosage uniformity of fingolimod hydrochloride in capsules was determined in accordance with GF XIII, Volume 2, OFS. 1.4.2.0008.15.

The contents of 1 capsule were quantitatively transferred into a 5 ml volumetric flask. The inner shell of the capsules was washed quickly

0.5 ml of acidified ethanol, avoiding the destruction of the capsule. The rinse was quantitatively transferred to the same flask with the contents of the capsule, 3 ml of acidified ethanol was added, sonicated for 10 minutes, stirring occasionally, the solution was cooled to room temperature, the volume of the solution was acidified with ethanol to the mark, stirred. The resulting solution was placed in an Eppendorf type tube with a capacity of 5 ml and centrifuged for 10 min at 11000 rpm. The supernatant was filtered through a membrane filter (PVDF) with a pore diameter of not more than 0.45 μm, discarding the first portions of the filtrate. 3.0 ml of the resulting solution was placed in a 5 ml volumetric flask, the volume of the solution was adjusted with acidified water purified to the mark, and stirred (test solution).

The results of the study of the uniformity of dosage of fingolimod hydrochloride in capsules are presented in Table 6.

Capsules in accordance with the invention, thus, showed a high uniformity of dosage dosage of fingolimod hydrochloride.

Example 7. The stability of the oral solid pharmaceutical dosage form (capsule) of fingolimod hydrochloride during storage.

Fingolimod hydrochloride capsules of the invention (5 different batches, F6-F10) prepared in accordance with Example 5 were placed in high density polyethylene bottles.

The stability of the solid dosage form of fingolimod hydrochloride (series F6-F10) in accordance with the invention was investigated (a) at a temperature of + 25 ° C and 60% relative humidity (RH), (b) at a temperature of + 40 ° C and 75% RH.

The stability of the fingolimod hydrochloride capsules in accordance with the invention was evaluated by the following indicators: appearance (color) of the samples (capsule contents), uniformity of the mass of the capsule contents, in vitro dissolution and the active substance content (% of the declared); these indicators were evaluated at the beginning of the study, as well as after 1 month, 2 months and 3 months from the start of the study. The results are presented in Table 7.

Capsules in accordance with the invention, thus, during the 3 months of the study showed high stability (a) at a temperature of + 25 ° C and 60% relative humidity (RH), (b) at a temperature of + 40 ° C and 75% RH.

Example 8. Dissolution of a solid pharmaceutical dosage form (capsule) of fingolimod hydrochloride.

6 capsules (# 1- # 6) of fingolimod hydrochloride in accordance with the invention, obtained in Example 5 (F6-F8), were selected to study the dissolution profile; dissolution of fingolimod hydrochloride was evaluated as described above using a validated HPLC method. The content of fingolimod transferred to the dissolution medium was evaluated after 15, 20, 30, 45 minutes from the start of the study. The results are presented in Tables 8-10.

Capsules in accordance with the invention, thus, showed the release of fingolimod hydrochloride more than 95% of the claimed amount in the capsule after 15 minutes of study.

The dissolution profile of the drug HILENIA ^® (see Source [47]) shows that the release of the active substance is extremely slow and its peak concentration is reached only about 30 minutes after administration. These data correlate with the pharmacokinetics of the claimed composition and the drug HILENIA ^® , from which it follows that the active substance of the claimed composition is more rapidly absorbed into the blood and, therefore, the therapeutic effect is faster.

The presented examples confirm that in the framework of the present invention, it was possible to create a solid oral dosage form (capsule) of fingolimod or its pharmaceutically acceptable salt, suitable for the treatment of recurrent remitting multiple sclerosis and for reducing the frequency of clinical exacerbations of the disease and reducing the risk of progression of disability in relapsing remitting multiple sclerosis and characterized by high uniformity of dosage of the active substance, stability during prolonged storage SRI capable after oral rapidly disintegrate and release active agent.

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45. International publication of application WO 2008/037421 A2 “ORGANIC COMPOUNDS)), applicant NOVARTIS AG [CH], inventors AMBUEHL MICHAEL [CH]; BEYER JUTTA [CH]; CARRENO-GOMEZ BEGONA [CH]; RUEGGER COLLEEN [US]; VALAZZA STEPHEN [US], publication date 04/03/2008.

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Claims (6)

1. Solid oral pharmaceutical composition, which consists of, mg: fingolimod hydrochloride 0.4-0.65 mg pregelatinized starch 145.0-155.0 mg magnesium stearate 1.0-2.0 mg 2. The solid oral pharmaceutical composition according to claim 1, made in the form of a tablet or capsule. 3. A method for the treatment of relapsing-remitting multiple sclerosis, comprising oral administration to a patient in need of a solid pharmaceutical composition according to claim 1 at a dose of 500 μg 1 time per day. 4. A method of reducing the frequency of clinical exacerbations of the disease in case of relapsing-remitting multiple sclerosis, including oral administration of a solid pharmaceutical composition according to claim 1 at a dose of 500 μg once a day to a patient in need. 5. A method of reducing the risk of progression of disability in relapsing-remitting multiple sclerosis, including oral administration to a patient in need of this solid pharmaceutical composition according to claim 1 at a dose of 500 mcg once a day.