RU2493845C1 - Composition for treating multiple sclerosis (versions) - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and psychoneurology, particularly to agents for treating multiple sclerosis.

EFFECT: composition (the solid oral dosage form) is applicable for sublingual, buccal delivery or gingival mucosal delivery of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluoromethylphenyl)-amide (Teriflunomide) as an active agent.

3 cl, 7 ex

Description

The invention relates to the field of the chemical-pharmaceutical industry and to the field of neuropsychiatry, in particular to new drugs for the treatment of multiple sclerosis.

The present invention relates to a pharmaceutical composition containing, as an active ingredient, (Z) -2-cyano-3-hydroxy-but-2-enoic acid- (4′-trifluoromethylphenyl) -amide (Aubagio ^TM - Teriflunomide) according to the formula (I ):

Teriflunomide is an active metabolite with an immunomodulating, antirheumatic property of 5-methyl-N- [4- (trifluoromethyl) phenyl] isoxazole-4-carboxamide (leflunomide), according to formula II:

Leflunomide was disclosed in US patent No. 4087535. In US patent No. 4284786, it was disclosed that this compound can be used to treat multiple sclerosis. Teriflunomide according to US patent No. 4965276 is used in the treatment of transplant versus host reactions. US patent No. 5459163 and US patent No. 5679709 disclose compositions based on teriflunomide used for the treatment of autoimmune diseases, in particular lupus erythematosus. Teriflunomide has an antiproliferative effect on a wide range of immune cells and cell lines [Cherwinski N.M., et al., J Pharmacol. Exp. Ther. 1995; 272: 460-8; Prkash A., et al., Drugs 1999; 58 (6): 1137-66; Bartlett R.R. et al., Agent Action 1991; 32 (1-2): 10-21). It also inhibits the enzyme dihydrate dehydrogenase, an enzyme necessary for the synthesis of pyrimidines (Bruneau JM, et al., Biochem.J. 1998; 36: 299-303]. Teriflunomide is mentioned in US Pat. No. 679,410 as a method for treating patients with disseminated diseases sclerosis.

MULTIPLE SCLEROSIS - a chronic disease of the central nervous system, often with a progressive course. In multiple sclerosis, the brain, optic nerves, and spinal cord are affected, which leads to a violation of the corresponding functions of the body. The disease is characterized by the formation of randomly dispersed foci of demyelination - the loss of myelin, a substance that covers the axons of nerve fibers, which leads to disruption of innervation.

Multiple sclerosis usually begins in youth, but can occur in any period from 15 to 60 years. Women are more prone to disease than men. The highest incidence is among white people living in a temperate climate. The disease is not inherited. In the list of causes of complete disability in the productive period of life, multiple sclerosis is in third place after injuries and rheumatological diseases.

Multiple sclerosis has an unpredictable course. Sometimes it proceeds benignly, with exacerbations and remissions, but spasmodic or steady progression of the disease is also possible. In the early years of the disease, exacerbations are often replaced by spontaneous, i.e. without any treatment, remissions, which makes it difficult to assess the effectiveness of a drug. The average life expectancy from the onset of the disease is approximately 35 years.

Four types of clinical disease models are classified [SLHauserand D.E. Goodkin, multiple Sclerosis and Other Demyelinating Diseases in Harrison’s Principles of Internal Medicine 14 ^th Edition, vol.2, McGraw-Hill, 1998, pp.2409-2419]:

1) remitting

2) secondary progressive,

3) primary progressive,

4) progressively relapsing.

The exact etiology of multiple sclerosis is unknown, but there is reason to believe that multiple sclerosis may occur as a result of the interaction of a number of adverse external and internal factors. Adverse external factors include viral and / or bacterial infections; the effects of toxic substances and radiation (including solar); nutrition features; geoecological place of residence; injuries frequent stressful situations. The genetic predisposition to multiple sclerosis is probably associated with a combination of several genes in a given individual that cause disorders, especially in the immunoregulation system.

Because the cause is not identified, therefore, etiotropic treatment is absent. The main effect remains the pathogenetic treatment, which is aimed primarily at stopping the active autoimmune inflammatory process, the result of which is demyelination. In the treatment of exacerbations and the progressive course of multiple sclerosis, corticosteroid (CS) drugs, adrenocorticotropic hormone (ACTH) and its analogues are used. These are prednisone, methylprednisolone, methipredmedrol, methylprednisolone Na succinate, dexamethasone, cortisol. These drugs reduce the duration and severity of the inflammatory process, have an immunosuppressive effect.

Therapeutic approaches to treating multiple sclerosis are not successful. Although they allow patients to receive limited benefits, they are usually associated with potentially serious serious side effects. It is worth noting that more effective and safer drugs are currently officially not available. The introduction of interferon preparations provided efficacy in the treatment of multiple sclerosis, the beneficial effects noted in this case are associated with the effects of interferons on the immune system. But, because the beneficial effect is realized only for a part of the subgroup of patients specially selected for treatment, the problem associated with insufficient control of the disease with the help of the above drugs remains unresolved. The limited effectiveness of modern therapy using immunomodulators for the treatment of multiple sclerosis is probably due to the inability of these agents to influence the degeneration of oligodendroglial cells, neurons and axons associated with this disease.

As the closest analogue, a composition regarding solid dosage forms containing teriflunomide 1-30% or its salt, 9-40% disintegrant, 0.1-2% binder, 1-20% lubricant, 0.1-0 , 5% acid component and diluent - the rest, and in a preferred embodiment, the diluent does not include colloidal silicon dioxide (international application WO 2011/032929). It is noted that solid dosage forms can be in any form: oral, sublingual, buccal, transdermal, intranasal, rectal, etc. However, there are no examples of rapidly dispersible solid forms suitable for sublingual, buccal or mucosal delivery of the gum of the active substance.

The objective of the invention is to expand the arsenal of effective drugs that are convenient for use by people diagnosed with multiple sclerosis, especially those with swallowing disorders, having pronounced pharmacological activity for the treatment of multiple sclerosis, having high therapeutic efficacy, reducing unwanted side effects, and reducing the cost of treatment.

The problem is solved by variants of compositions containing teriflunomide or its pharmaceutically acceptable salts and target auxiliary additives in the form of an active principle, in the form of solid orodispersible forms suitable for sublingual, buccal or gum mucosal delivery. The term meets the following definition: “A tablet that is dispersed when placed in the mouth before swallowing” (Pharmeuropa, Volume 10, No. 4, December 1998, p. 547).

The effect of the orodispersible form - there is no need to drink it with water, dissolve or chew. This form disintegrates in the presence of a small amount of saliva, usually within a minute, possibly longer, if the features of the therapeutically active substance require it.

It is known that people with a diagnosis of Multiple Sclerosis may have swallowing problems. Thus, the use of such forms of delivery can contribute to adherence to therapy and, as a result, to achieve therapeutic effects. Since this disease has a protracted nature, the convenience and ease of use are a significant factor.

A pharmaceutical composition in the form of a tablet, suitable for sublingual, buccal or mucosal delivery of the gum of the active substance, characterized in that it contains teriflunomide or a pharmaceutically acceptable salt thereof as active ingredient, lactose as its target additives or its mixture with LCE ludipress, cellulose microcrystalline and / or hypromellose, VA-64 collidone, starch, Benecel MP-824, at least one antifriction agent in the following ratio, wt.%:

Teriflunomide 3.0-13.5 Lactose or its mixture with ludipress LCE 48.5-60.0 Starch 7.0-16.0 Microcrystalline cellulose and / or hypromellose 20.0-30.0 Kollidon VA-64 3.5-4.5 Antifriction agent 0.8-2.4 Benecel MP-824 rest

A method of producing tablets. Teriflunomide, lactose granules (or its mixture with ludipress) / starch are charged into the reactor. The resulting mixture is fed into the mixer, microcrystalline cellulose and / or hypromellose are added, moistened with VA-64 collidone solution, granulated. The granulate is dried at 400 ° C to a residual moisture content of 3-4%. Dry granulation is carried out. Granulation is carried out by feeding through a sieve with holes of 1.2-2 mm and loaded into the mixer, dusting the mixture with an antifriction agent and Benecel MP-824. The mixture was analyzed by HPLC. In the case of positive data, it is passed to the tableting step.

Tableting is carried out on the press using biconvex punches with a diameter of 16 mm (semi-deep sphere), but not necessarily, and the possibility of printing with the logo on one side.

Another embodiment of the invention is a pharmaceutical composition in the form of a tablet, suitable for sublingual, buccal or mucosal delivery of the active ingredient in the gums, characterized in that it contains teriflunomide or a pharmaceutically acceptable salt thereof as an active ingredient, lactose, starch as target additives, polyhydric alcohol selected from the group: mannitol, sorbitol, maltitol, xylitol, erythritol, lactitol, flavoring, at least one antifriction agent, sweetener further short component ratio, wt.%:

Teriflunomide 1.5-2.5 Mannitol 16.50-33.5 Flavoring 1.5-4.0 Sweetener 0.50-1.0 Antifriction agent 0.50-1.0 Lactose 49.0-61.0 Starch 12.0-15.5

A method of producing tablets. Teriflunomide, lactose / starch granules are charged to the reactor. The resulting mixture is fed into the mixer, polyhydric alcohol, flavoring, sweetener, antifriction agent are added. The mixture was analyzed by HPLC. In case of positive data, they are passed to the tableting step. Tableting is carried out by direct pressing on a press, using biconvex punches with a diameter of 16 mm (semi-deep sphere), but not necessarily, and the possibility of printing with a logo on one side.

Teriflunomide can be included in the form of both a base and pharmaceutically acceptable salts, for example, salts of potassium, sodium, calcium.

As starch, tablets may include corn starch, potato, modified.

In a preferred embodiment of the invention, one or more sweeteners are included in the mixture to improve the organoleptic properties and to stabilize the mechanical properties of the resulting mixture. The sweetener should have properties that do not violate the dispersibility characteristics of the tablets. Sweeteners are selected from the group of sugars, dextrose, maltose, fructose, maltodextrins. In one embodiment, the sweetener is aspartame.

As a flavoring agent, any pharmaceutically acceptable flavoring agent suitable for oral use may be used, for example, based on essential oils, fruit juices, menthol, citral, vanillin and the like.

As antifriction agents, stearic acid or its salts, such as magnesium, calcium, aerosil, polyethylene oxide, can be used.

In order to implement a rapidly dispersible dosage form, it is possible, but not exclusively, to change the degree of its hydrophilicity by coating with a colloidal film. Film coating is carried out using various substances. These are cellulose derivatives, in particular hydroxypropyl cellulose, ethyl cellulose, hydroxyethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose, cellulose acetate, including various mixtures, polymethacrylates, mixtures of cellulose polymers and other polymers such as “polyvinylpyridine, for example, sold, for example. All of the polymers described, including mixtures thereof, can be used together with polyethylene glycol. Coating with a colloidal film is carried out by methods, but not exclusively, in a layer of liquefied air, by a turbine method, microencapsulation, coacervation, extrusion, giving a spherical or other necessary shape.

It is also used, as a technology for coating the active substance, the manufacture of dragees. This technology is implemented using sugars or polyols, which, if necessary, are mixed with film-forming polymeric substances.

Coating tablets has several positive aspects, firstly aesthetic: giving the tablets a beautiful appearance, and secondly, practical: the coating makes it possible to increase the mechanical strength of the tablets, eliminate unpleasant taste and smell, and also protects against environmental influences, like then: light, moisture, oxygen, allows you to slow down or prolong the action of the drug substance, reduce or even avoid the aggressive effects on the mucous membranes of the esophagus and stomach of the drug substances.

According to this invention, the active substance is mixed with auxiliary substances, such as a mixture of starch and lactose in the form of granules. The options by which the granules are obtained are different. It could be drying. In this embodiment, the granules are obtained by mixing lactose and starch and spraying them further.

The composition of the granules in solid form may vary depending on the dosage of the incoming active substance. Granules preferably comprise from 20 to 96%, preferably from 40 to 90%, of said solid form.

Dyes and flavoring agents can be added to the composition of the solid form.

Preferably, but not necessarily, the inclusion of organic acids, to obtain sublingual tablets with the effect of hissing in the oral cavity. Because the tablet hissed slightly in the mouth when it exerted in a humid environment.

For implementation, about 5% by weight of such an acid – base pair is used, for example citric acid — sodium bicarbonate.

The resulting solid forms have dispersion in the oral cavity.

The proposed composition of the active and auxiliary substances is optimal and provides high-quality tablets with a fast dispersing effect in the oral cavity and the therapeutic effect of the active substances. Forms can be dispersed in the oral cavity within 2-3 minutes.

Examples of compositions.

Example 1

Teriflunomide 3.0 Lactose 49.0 Starch 9,4 Microcrystalline cellulose 20,0 Kollidon VA-64 3,5 Aerosil 0.8 Calcium stearate 0.8 Benecel MP-824 13.5

Example 2

Teriflunomide 13.5 Lactose with ludipress 48.5 Starch 9.5 Microcrystalline cellulose and hypromellose 20,0 Kollidon VA-64 3.0 Magnesium stearate 1,6 Benecel MP-824 3.9 Shell Opadry II 1% of the total weight of the composition

Example 3

Teriflunomide 3 Lactose 60.0 Starch 7.0 Microcrystalline cellulose 20,0 Kollidon VA-64 4,5 Magnesium stearate 1,0 Benecel MP-824 4,5

Example 4

Teriflunomide 2,5 Mannitol 33.5 Menthol 1,5 Aspartame 0.50 Magnesium stearate 0.50 Lactose 49.5 Starch 12.0

Example 5

Teriflunomide 2.0 Mannitol 16.50 Orange concentrate 3,5 Dextrose 0.50 Stearic acid 0.5 Magnesium stearate 0.5 Lactose 61.0 Starch 15,5

Example 6

Teriflunomide 1,5 Mannitol 20,0 Peppermint oil 1,5 Maltose 1,0 PEO 1,0 Lactose 59.5 Starch 15,5

The result is a dosage form having good technological properties in the process of granulation and tabletting, and the resulting tablets have properties that meet the requirements of the pharmacopeia. In particular, disintegration in water is not more than 10 minutes, preferably 3.8-5.7 minutes; dissolution, "rotating basket" - 94.5% (if necessary - at least 75%). Tablets with the active ingredient have a high bioavailability (89.8%) at p> 0.95, which indicates the effectiveness of the proposed pharmaceutical composition, with a fixed shelf life of at least 2 years.

Glucose can be added to the lactose / starch mixture.

Example 7

The study of the pharmacokinetics of Teriflunomide was carried out in healthy white rats.

Animals were quarantined.

After this, the animals were divided into 2 groups of 7 animals. Group 1 was given Teriflunomide (in powder form) at a dose of 1 mg / kg using an intragastric tube. The 2nd group of Teriflunomide was administered to a fixed animal by placing a gauze bag with Teriflunomide moistened in sweet water (imitation of sublingual / oral dispersable / buccal administration) in the same dosages in the oral cavity as the 1st group.

Heparinized blood samples were collected every hour, namely every 0, 1, 2, 4, 8, 12 hours on the 1st day and once a day for 2, 4, 6, 8, 10 days after ingestion at a dose of 1 mg / kg teriflunomide. Plasma by centrifugation for 30 minutes after blood sampling was frozen until analysis. Teriflunomide concentrations were measured using HPLC analysis. The average time the drug was present in plasma was 27.6 hours with intragastric administration and 25.9 with administration through the oral mucosa. The half-life of T1 / 2 for intragastric administration was 22.1 (hours) and for administration through the mucosa of the oral cavity 21.5. With _max with intragastric administration of 4.7, in the 2nd group of 5.6. Moreover, AUC (area under the curve) did not statistically differ in both groups.

These data allow us to draw a preliminary conclusion that the route of administration through the mucous membrane, although different, is not statistically significant. In addition to the maximum concentration when introduced through the mucous membrane of the oral cavity. This allows you to achieve a maximum concentration, significantly higher than with absorption through the mucous membrane of the stomach and intestines, which leads to an earlier onset of therapeutic effect. Therefore, the introduction of Teriflunomide through the mucous membrane of the oral cavity allows you to provide a therapeutic effect on the pathological process earlier than when the substance enters through the mucous membrane of the stomach and intestines. Thus, such an appointment will allow patients, including those suffering from swallowing disorders, to more effectively influence the degree and severity of the disease and control the treatment of a clinical specialist.

Claims (3)

1. A pharmaceutical composition in the form of a tablet, suitable for sublingual, buccal or mucosal delivery of the gum of an active substance, characterized in that it contains teriflunomide or a pharmaceutically acceptable salt thereof as an active ingredient, lactose, or a mixture thereof with LCE ludipress, as target additives , microcrystalline cellulose and / or hypromellose, collidone VA-64, starch, Benecel MP-824, at least one antifriction agent in the following ratio of components, wt.%:
Teriflunomide 3.0-13.5 Lactose or a mixture thereof with ludipress LCE 48.5-60.0 Starch 7.0-16.0 Microcrystalline cellulose and / or hypromellose 20.0-30.0 Kollidon VA-64 3.5-4.5 Antifriction agent 0.8-2.4 Benecel MP-824 rest 2. A pharmaceutical composition in the form of a tablet, suitable for sublingual, buccal or mucosal delivery of the gum of an active substance, characterized in that it contains teriflunomide or a pharmaceutically acceptable salt thereof as an active substance, lactose, starch, polyhydric alcohol as target additives, selected from the group: mannitol, sorbitol, maltitol, xylitol, erythritol, lactitol, flavoring, at least one anti-friction agent, sweetener in the following ratio, wt.%:
Teriflunomide 1.5-2.5 Mannitol 16.50-33.5 Flavoring 1.5-4.0 Sweetener 0.50-1.0 Antifriction agent 0.50-1.0 Lactose 49.0-61.0 Starch 12.0-15.5 3. The pharmaceutical composition according to claim 2, characterized in that it is coated with a colloidal film membrane.