RU2530626C1 - Pharmaceutical composition of s1p receptor agonist for treating demyeliniating diseases - Google Patents

Pharmaceutical composition of s1p receptor agonist for treating demyeliniating diseases Download PDF

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RU2530626C1
RU2530626C1 RU2013146816/15A RU2013146816A RU2530626C1 RU 2530626 C1 RU2530626 C1 RU 2530626C1 RU 2013146816/15 A RU2013146816/15 A RU 2013146816/15A RU 2013146816 A RU2013146816 A RU 2013146816A RU 2530626 C1 RU2530626 C1 RU 2530626C1
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Russia
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starch
pharmaceutical composition
treating
laquinimod
multiple sclerosis
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RU2013146816/15A
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Russian (ru)
Inventor
Марат Феликсович Фазылов
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Ооо "Валента-Интеллект"
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Abstract

FIELD: medicine.
SUBSTANCE: invention concerns the pharmaceutical composition Laquinimod (5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide) in the free form and/or in the form of a pharmaceutically acceptable salt in making a finished pharmaceutical product for treating and/or relieving, and/or delaying the clinical course and progression of multiple sclerosis. As excipients, the composition contains lactose, starch and/or starch derivatives, gelatine, talc and/or paraffin.
EFFECT: invention enables extending the range of high-bioavailability products for treating multiple sclerosis.
3 cl, 5 ex

Description

The invention relates to the field of pharmacology and clinical medicine and relates to agents for the treatment of demyelination diseases, in particular multiple sclerosis.

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 of age 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.

There are four forms of multiple sclerosis disease:

- Relapsing-Weakening (RR-MS). Identified individual motor, sensory, cerebellar or visual attacks of the disease. They last more than 1-2 weeks and weaken after about 1-2 months of treatment, as well as without treatment. Approximately 85% of patients initially suffer from relapsing-relieving (RR) multiple sclerosis (MS). Over the course of 10 years, approximately half of them develop a form of secondary progressive PC.

- Secondarily progressive (SP-MS). Helplessness with relapses is gradually increasing, however, it is possible without them. Namely, in the period of secondary progressive MS, disability occurs, expressed in disability, right up to irreversible.

- Primarily Progressive (PP-MS). The disease flows without any relapses or remissions, about 15% of MS patients are diagnosed.

- Progressive Recurrent (PR-MS). A progressive disease, initially marked by acute relapses. In the periods between relapses there is a steady development of the disease.

The disease itself, and the consequences, leads to violations of the quality of life, disability and the social role of a person. Therefore, there remains a need for effective, affordable drugs for the treatment of demyelinating diseases - multiple sclerosis, Guillain-Barré syndrome. Such a medicine, when used, has signs in the form of reduction, mitigation, stabilization or alleviation of the symptoms of the disease.

Modern drugs for PC immunotherapy include beta-interferons and glatiramer acetate, mitoxantrone, monoclonal antibodies (natalizumab, alemtuzumab, rituximab, etc.), intravenous immunoglobulins, cyclophosphamide, sphingosine-1-phosphate agonists (S1P).

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.

Medicines and / or combinations are known containing at least one S1P receptor agonist and another therapeutically active substance, or compositions having, for example, at least one S1P receptor agonist and pharmaceutically acceptable excipients. These formulations have a therapeutically beneficial effect on demyelinating diseases such as multiple sclerosis (WO 2004089341 A2, RU 2487703 C2).

Fingolimod used preferably as the active principle of such agents is an oral synthetic modulator of sphingosine-1-phosphate receptors, the registered therapeutic effects of which may be due to the prevention of the migration of effector autoaggressive lymphocytes from lymphatic tissue to sensitive target organs, such as the central nervous system. The main side effect of fingolimod is an increase in the frequency of infectious diseases associated with suppression of the immune system

Laquinimod is a new synthetic compound with high bioavailability and has been proposed as an oral medication for the treatment of multiple sclerosis. (Polman 2005; Sandberg-Wallheim, 2005). Laquinimod is described in US Pat. 6077851. Studies have shown Lakvinimod is useful for reducing the development of active foci on MRI in recurrent multiple sclerosis. However, when creating its dosage forms, the researchers encountered a problem related to the fact that 3-quinoline carboxamide derivatives are susceptible to chemical degradation in a solid pharmaceutical composition due to incompatibility with a number of excipients, as well as moisture.

Various solutions have been proposed to solve this problem.

In particular, salts were prepared where the cation is selected from Li +, Na +, K +, Mg 2+, Ca 2+, Mg 2+, Cu 2+, Zn 2+, Al 3+ and Fe 3+, providing enhanced stability of laquinimod and solid formulations in the form of a capsule or tablet containing a salt of a 3-quinoline carboxamide derivative and a uniformly distributed alkaline reaction component (WO 2005074899 A2) are provided.

Also known is US patent 8383645 B2, disclosing the use of meglumine as a filler to prevent oxidation of sodium laquimod in capsule formulations containing sodium laquimimod, mannitol, sodium carbonate, sodium stearyl fumarate, fumarate.

Known application for US patent 20130259856, publ. 10/03/2013, which relates to the combination of laquinimod and dimethyl fumarate in the form of solid dosage forms such as capsules or tablets. Tablets may contain suitable binders, lubricants, disintegrants, colorants, flavors, flow improvers. For example, for oral administration in a unit dosage form in the form of a tablet or capsule, the active drug component may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn starch, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, povidone, carboxymethyl cellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate, and the like. The application is aimed at achieving a synergistic effect with dimethyl fumarate. The source does not disclose specific formulations and does not take into account the instability of laquinimod, which is known from the prior art. Thus, there are no premises for the selection of certain auxiliary components that would provide an effective composition in the absence of dimethyl fumarate.

As the closest analogue, US Pat. No. 7,589,208 can be mentioned, which describes the preparation of pharmaceutical compositions in unit dosage form for oral administration, wherein laquinimod is mixed with a salt of a divalent metal cation or alkaline reaction component and with conventional pharmaceutical excipients. The mixture is then processed into tablets or capsule granules. In particular, an example of a tablet composition is a composition prepared from mannitol, pregelatinized starch or calcium sulfate dihydrate, sodium carbonate, water, active ingredient, sodium stearyl fumarate and coated with Opadry White. These forms do not provide high bioavailability. Excess sodium ions are harmful for a number of categories of patients.

The objective of the invention is to obtain a new stable effective composition of laquinimod.

The problem is solved by a composition that includes laquinimod and pharmaceutically acceptable excipients in a certain way: disintegrants, diluents, binders and lubricants.

In order to deliver a therapeutically effective dose of Laquinimod, 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.

The proposed pharmaceutical composition contains laquinimod in its free form or in the form of its pharmaceutically acceptable salt, for treating or alleviating or delaying the progression and / or progression of multiple sclerosis, and as excipients, milk sugar, starch and / or starch derivatives, gelatin, talc and / or paraffin in the following ratio, wt.%:

Laquinimod 0.5-2.0 Milk sugar 39.0-70.0 Starch (and / or starch derivatives) 26.0-38.0 Edible gelatin 1.6-11.6 Talc and / or paraffin 1.0-10.0

The pharmaceutical composition may further comprise Tween-80 in an amount of 10-11 wt.% Of the total weight of the composition.

The pharmaceutical composition as pharmaceutically acceptable excipients may further comprise sodium alginate, ammonium alginate, amylopectin, agar-agar. Preferably in an amount of from 0.05 to 5.0 wt.%.

Milk sugar can be selected from b / c lactose and various forms of lactose: alpha-lactose or beta-lactose.

According to this invention, it is preferable to use a starch derivative such as acetylated starch or sodium carboxymethyl ether and other modified starches, for example sodium glycolate.

The introduction of starch, which has anti-slip properties, can reduce the content of other such auxiliary substances - talc and eliminate calcium stearate.

Sugar, starch and starch derivatives according to this invention are auxiliary substances that combine the properties of a diluent and a disintegrator. Their specific content provides increased bioavailability of the active component.

Lubricants in the manufacture of solid dosage forms are used to eliminate technological problems, for example, sticking of the tablet mass to production surfaces and to reduce sticking during the stages of tablet compression. As a rule, stearic acid or its salts are used. However, they negatively affect the stability of laquinimod and are excluded in this composition.

According to this invention, talc and / or paraffin is used.

As a second diluent, an additional tween, preferably tween-80, may be included.

A disintegrant selected from gelatinized starch is preferred; in some cases, a second disintegrant is introduced, which is aminopectin and / or citric acid.

The study of various binders on the manufacturability of the process of preparing the tablet mass, as well as on the quality indicators of the dosage form, revealed the need to include gelatin in the composition.

In the most preferred embodiments, milk sugar and starch (and / or starch derivatives) comprise about 45-70% by weight of the composition, tween, preferred Tween-80 5-15%, gelatinized starch 5-15%, talc is about 1- 10% and paraffin, but not necessarily, is from about 0.2-2.0%. In some other embodiments, 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol comprises about 1.0% by weight of the composition, milk sugar and starch (and / or starch derivatives) comprise 30.0-45.0% each, Tween, preferably Tween-80, is about 10.5%, gelatinized starch is about 11.0%, talc and gelatin are about 6.0%, paraffin is not necessarily about 4, 0%

The pharmaceutical composition of this invention is in the form of a solid dosage form, preferably, but not necessarily, in the form of tablets. This allows you to ensure the necessary accuracy of dosing of the active substance and the maximum manufacturability of subsequent packaging.

This ratio of excipients provides an indicator of disintegration up to 10-15 minutes, at which an optimal release profile of Laquinimod is achieved.

The resulting pharmaceutical composition meets the requirements of the Pharmacopoeia, is stable during storage and has a shelf life of more than 2.5 years.

A method of obtaining a solid dosage form according to this invention includes the preparation of trituration mixture. This allows for uniform mixing of the components. Also, for the most uniform distribution of a binding agent such as gelatin, it is worth adding in the form of a 5% solution, but not limited to. These differences are the technological advantages of the claimed method in comparison with analogues and provide optimal bioavailability of the active substance.

The invention is illustrated by the following examples.

Example 1. An example composition, wt.%:

Laquinimod 0.60 Milk sugar 69.51 Starch Lycatab PGS 26.79 Edible gelatin 1,66 Talc 1.44

Example 2. A method of obtaining a composition for the treatment, alleviation or delay the progression of multiple sclerosis

1) Preparation of trituration mixture

To ensure uniform mixing of a small amount of Laquinimod with other components, its mixture is initially prepared in milk sugar, then portions of milk sugar are successively added and mixed thoroughly.

2) Getting wet granulate

Milk sugar, a pre-prepared mixture of Laquinimod and milk sugar, starch (and / or starch derivatives) in an amount of about 95% of its total mass are loaded into the mixer mixer, the mixture is stirred for several minutes, then moistened with a 5% gelatin solution in several portions until a uniformly moistened mass is obtained, mix for a few more minutes.

Next, the mixture-mass is unloaded from the mixer and granulated using a granulator with a diameter of the drum holes of 1.5 mm and transferred to the drying of the granulate.

3) Drying and dry granulation

The wet granulate is dried in a dryer at a temperature of (55 ± 5) ° C for 50-60 minutes. The residual moisture should preferably be (3.0 ± 0.5)%. Drying of the product is carried out by supplying a fan heated to (60 ± 5) ° C of air to the dryer with a fan.

After drying, the dried mass is passed through a granulator with a diameter of the drum holes of 1.50 mm. Dry granulate is passed to the stage of formation of the tablet mass and further tableting.

4) Preparation of tablet mass

Dry granulate, talc, the remaining amount of starch and substandard tablets crushed in the granulator are loaded into a tablet-mass reactor, all are mixed for 15 minutes and discharged into a container.

The tablet mixture is passed to the encapsulation step.

5) Encapsulation

Encapsulation is carried out on a capsulator. The mixture is periodically fed at intervals of several minutes. During encapsulation, the average weight of the capsule and appearance are monitored at regular intervals.

The resulting capsules are sent to the stage of packaging and packaging. Capsules are 0,00025; 0,0005; 0.001 g

Example 3

Laquinimod 1.00 Lactose 39.18 Corn starch 36.61 Gelatin 11.60 paraffin 1.30 Twin 80 10.31

Example 4. Capsules

Laquinimod 2.0 Lactose 51.95 Starch 38 Gelatin 6.0 talc 2.0 Ammonium alginate 0.05

Example 5. The results of the determination of bioavailability

To assess the bioavailability, a comparative study of changes in the concentrations of the drug substance in the test and standard dosage forms in blood plasma was carried out. After administration of the drug, plasma samples were taken and examined according to examples. The concentration of compounds in plasma was determined by high performance liquid chromatography / tandem mass spectrometry (LC / MS / MS). Pharmacokinetic analyzes were performed based on plasma concentration data. A time-concentration relationship was plotted and the area under the curve was calculated.

The absolute bioavailability averaged 93%.

Claims (3)

1. A pharmaceutical composition for treating, alleviating or delaying the progression and / or progression of multiple sclerosis, comprising Lacquimod in its free form or in the form of its pharmaceutically acceptable salt and excipients, characterized in that it contains milk sugar, starch and / or derivatives of starch, gelatin, talc and / or paraffin in the following ratio, wt.%:
Laquinimod 0.5-2.0 Milk sugar 39.0-70.0 Starch (and / or starch derivatives) 26.0-38.0 Edible gelatin 1.6-11.6 Talc and / or paraffin 1.0-10.0
2. The pharmaceutical composition according to claim 1, characterized in that it further comprises tween-80 in an amount of 10-11 wt.% Of the total weight of the composition.
3. The pharmaceutical composition according to claims 1 and 2, wherein the pharmaceutically acceptable excipients further comprise sodium alginate, ammonium alginate, amylopectin, agar-agar.
RU2013146816/15A 2013-10-21 2013-10-21 Pharmaceutical composition of s1p receptor agonist for treating demyeliniating diseases RU2530626C1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089341A1 (en) * 2003-04-08 2004-10-21 Novartis Ag Organic compounds
US7589208B2 (en) * 2004-02-06 2009-09-15 Active Biotech Ab Compositions containing quinoline compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089341A1 (en) * 2003-04-08 2004-10-21 Novartis Ag Organic compounds
US7589208B2 (en) * 2004-02-06 2009-09-15 Active Biotech Ab Compositions containing quinoline compounds

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