RU2326660C1 - Oral pharmaceutical composition memantin (options) and method of preparation (options) - Google Patents

Abstract

FIELD: chemical-pharmaceutical industry.

SUBSTANCE: invention covers preparation of oral formulations of medicines possessing the neuroprotective activity, particularly, Memantine, the modulator of the glutamatergic system which is used in treatment of dementia, memory impairment, cerebral and spinal spastic syndrome. The therapeutically effective amount of Memantine is prepared as a capsule dosage form containing the mixture of powders or granulated material. The encapsulated substance contains the additional auxiliary substances: the physiologically neutral filler and a disintegrator and antifriction substance. The method of preparation of pharmaceutical composition consists in sifting, weighing and mixing the powders of Memantine and auxiliary substances at specified mass proportions with following filling the capsule with the powder mixture or granulated material obtained by dry or humid pelleting, from the powder mixture.

EFFECT: invented formulation has bioavailability higher than tablets; it has prospects for using in pediatrics and gerontology while preparation cost is reduced.

14 cl, 4 ex

Description

The invention relates to the pharmaceutical industry and medicine, namely to oral neuroprotective drugs, in particular to the solid dosage form of the drug "Memantine".

Memantine is used primarily as an anti-Parkinsonian drug; it has nootropic, cerebrovasodilating, antihypoxic and psychostimulating effects.

In addition, it is indicated for use in case of spasticity of skeletal muscles (head injury, stroke, multiple sclerosis), impaired brain function of mild to moderate severity: impaired memory, decreased interest in the environment, decreased ability to concentrate.

Memantine is on the list of vital and essential medicines as a treatment for parkinsonism (Decree of the Government of the Russian Federation of December 29, 2005 No. 2343-r).

Known drug 3,5-dimethyl-tricyclo- [3.3.1.13,7] decan-1-amine with the international non-proprietary name "Memantine", manufactured by Merz Co. GmbH and Co. (Germany) in solid dosage form under the trade name "Akatinol Memantine" in the form of polymer-coated tablets with an active substance content of 10 mg (http://www.regmed.ru/).

In this case, a memantine tablet containing 10 mg of the active substance (4.0%) includes lactose - 174.75 mg (69.9%); MCC - 52.1 mg (20.84%); Aerosil (colloidal silicon dioxide) - 1.25 mg (0.5%); talc - 11.15 mg (4.46%); magnesium stearate - 0.75 mg (0.3%), and the shell contains a methacrylic acid copolymer - 1.446 mg; sodium lauryl sulfate - 0.01 mg; polysorbate 80 - 0.034 mg; SE 2 - 0.01 mg; talc - 0.35 mg (the percentage of substances in the tablet is given to the weight of the tablet without a shell of 250 mg).

The disadvantages of the oral drug “Memantine” in the form of tablets are the multicomponent composition of the mixture for tabletting and applying a polymer coating, the multi-stage process and the duration of the preparation of the tablet dosage form, that is, the complexity of the process, and, therefore, the significant cost increase in the cost of the drug “Memantine” in this drug form.

The objective of the invention is the creation of an oral drug "Memantine" in the form of capsules and a method for their preparation.

The technical result that can be obtained by using the present invention is to simplify the manufacturing process of the production of the oral drug "Memantine" in solid dosage form and, as a result, reduce the cost of manufacturing this drug.

To solve this problem, the present invention provides an oral preparation in the form of a solid dosage form containing memantine as an active substance, in which memantine is part of the mass filling capsules.

In a first embodiment, an oral preparation is provided in the form of a solid dosage form containing memantine as an active substance, which is a capsule, the mass filling the capsule containing memantine in a therapeutically effective amount is a mixture of powders.

In a second embodiment, an oral preparation is provided in the form of a solid dosage form containing memantine as an active substance, which is a capsule, the mass filling the capsule containing memantine in a therapeutically effective amount is granulate.

The capsule-filling mass containing memantine as an active substance additionally contains auxiliary substances in the following ratio of components (wt.%):

memantine 0.5-10.0 Excipients rest

As auxiliary substances, the preparation contains a physiologically neutral filler, a disintegrant (baking powder), an antifriction substance, for example, with the following component ratios (wt.%):

memantine  0.5-10.0 disintegrant  2.0-40.0 anti-friction substance  0.2-10.0 filler  rest

The disintegrant may be, for example, rice or potato starch, aerosil, calcium carbonate, pectin, or a mixture thereof. The antifriction agent may be, for example, stearic acid, aerosil, talc, calcium or magnesium stearate, or a mixture thereof. The filler may be, for example, lactose, glucose, microcrystalline cellulose (MCC), sorbitol, or a mixture thereof.

In the proposed preparation, a capsule-filling mass containing memantine as an active substance, which mainly includes potato or rice starch as a disintegrant, magnesium stearate as an antifriction substance, and lactose as a filler, can be made in the form of a mixture of powders, for example, the following ratios of components (wt.%):

memantine 0.5-10.0 potato or rice starch 2.0-40.0 magnesium stearate 0.2-1.0 lactose rest

In another preparation, a capsule-filling mass in the form of a mixture of powders containing the active substance, memantine, additionally contains mainly aerosil (colloidal silicon dioxide) as a disintegrant, talc and magnesium stearate as an antifriction substance, and microcrystalline cellulose (MCC) as a filler and lactose, for example, in the following ratios of components (wt.%):

memantine  0.5-10.0 aerosil  0.2-10.0 talc  1.0-4.5 magnesium stearate  0.2-1.0 microcrystalline cellulose  2.0-40.0 lactose  rest

In the proposed preparation, a capsule-filling mass containing memantine as an active substance can be made in the form of granules and additionally contain a filler, for example, in the following ratio of components (wt.%):

memantine  0.5-10.0 filler  rest

The filler is predominantly microcrystalline cellulose.

A method for producing an oral preparation in the form of a solid dosage form — a capsule containing memantine as an active substance, in which powders of memantine, disintegrant, anti-friction substance is sieved, excipient, weighed and mixed in the indicated mass proportions, for example, (wt.%):

memantine  0.5-10.0 disintegrant  2.0-40.0 anti-friction substance  0.2-10.0 filler  rest

after which the capsule is filled with the resulting mass (in the form of a mixture of powders). Capsules may be, for example, gelatin.

A method is also proposed for preparing an oral preparation in the form of a solid dosage form — a capsule containing memantine and excipients as an active substance, in which filler and, if necessary, a disintegrant and an antifriction substance are used as excipients, with memantine and filler powders or , if necessary, also the disintegrant and anti-friction substance are sieved, weighed and mixed in the following mass proportions, for example, (wt.%):

memantine  0.5-10.0 filler  rest or memantine  0.5-10.0 disintegrant  0.2-40.0 anti-friction substance  0.2-10.0 filler  rest

then the powder mixture is granulated by dry or wet granulation, and then the capsules are filled with granulate.

The proposed oral drug "Memantine" in the form of capsules has a higher bioavailability in comparison with the oral drug "Memantine" in the form of tablets coated with a polymer coating.

Higher bioavailability due to the fact that the capsules swell quickly and dissolve in the gastrointestinal tract. The biopolymer gelatin shell slowly, portion by portion, releases the active substance, ensuring its full absorption.

Gelatin capsules are easily and quickly absorbed even in severe disorders of the human gastrointestinal system.

The advantages of the capsules are also that they are easily swallowed, permeable to digestive juices, the therapeutic effect of the contents appears 5-10 minutes after administration, the shell of gelatin is impermeable to volatile liquids, gases, air oxygen.

Memantine capsules are the most promising for use in pediatrics and gerontology.

In the proposed oral drug “Memantine” in the form of capsules, it is mainly used as an antifriction substance, for example, magnesium stearate, and as a filler, for example, lactose or monocrystalline cellulose, which reduce hygroscopicity and increase the flowability of the mass for encapsulation,

In addition, Memantine, as a disintegrant (baking powder), for example, potato or rice starch, which promotes the disintegration of capsules and improves the mobility of the granular mass for encapsulation, is introduced into the mass for encapsulation in the form of a powder mixture of the proposed oral drug “Memantine”.

The proposed oral medicinal product uses substances and materials approved for the manufacture of medicines in Russia.

The manufacturing processes of memantine capsules according to the invention are much simpler than the manufacture of memantine tablets coated with a polymer coating, due to the fact that the capsules can encapsulate the drug unchanged without exposing it to heat and pressure, as in a complex technological process of pressing in the manufacture pills. The complicated technological process of coating with a polymer shell is also excluded, the functions of which are performed by cheap, for example, gelatin capsules. No polymer coating materials required. This reduces the cost of manufacturing the drug "Memantine" in the form of capsules in comparison with the cost of the drug "Memantine" in the form of tablets coated with a polymer coating.

The preparation of the encapsulated preparation "Memantine" without granulation further reduces the manufacturing cost due to its cost-effectiveness, since it does not require additional equipment for granulation, energy costs are reduced, and labor productivity is increased.

The possibility of carrying out the invention is illustrated by the following examples, but is not limited to.

Examples of memantine-containing drugs in the form of capsules are given for the first time, the proposed drugs differ from the formulations described previously.

Example 1

A method of obtaining an oral pharmaceutical preparation "Memantine" is implemented according to the following scheme:

1. Sift the ingredients (powders) through a sieve.

2. Weigh the ingredients (powders).

3. Prepare the mass for encapsulation by mixing the powder of the active substance - memantine - with powders of auxiliary substances - potato starch, calcium stearate, lactose - with the mandatory control of the heterogeneity of the mass for encapsulation.

4. The prepared mass in the form of a mixture of powders is encapsulated on a Zanazi machine in No. 1 hard gelatin capsules with a seal to a mass of 0.250 g ± 10% in each capsule, to obtain the following capsule capsules of the Memantine oral medicine.

Composition of one capsule

The components that make up the capsule Component weight g % Memantine 0,020 8.0 Potato starch 0,050 20,0 Calcium stearate 0.002 0.8 Lactose 0.178 71.2 The mass of the contents of the capsule 0.250 100.0

The disintegration of the obtained capsules is less than 20 minutes, which meets the requirements of the State Pharmacopoeia XI (st. Capsules).

1000 pieces of memantine capsules have been developed using this technology.

Example 2

The method of obtaining the oral drug "Memantine" is implemented as described in Example 1, except that the powders of the components indicated below are used.

The disintegration of the obtained capsules is less than 20 minutes, which meets the requirements of the Global Fund XI (Art. Capsules).

1000 pieces of memantine capsules have been developed using this technology.

The composition of one capsule.

The components that make up the capsule Component weight g % Memantine 0.010 4.0 Aerosil 0.002 0.8 Talc 0.005 2.0 Calcium stearate 0.002 0.8 Microcrystalline cellulose 0,075 30,0 Lactose 0.156 62,4 The mass of the contents of the capsule 0.250 100.0

Example 3

The first three stages of the method of obtaining the oral drug "Memantine" are implemented, as described in example 1, using other components and in a different quantity, then the following stages are performed.

4. Moisturize the resulting mixture of powders with 70% ethyl alcohol.

5. The wet mixture is sieved through a sieve with a hole diameter of 3 mm.

6. The granules are dried at a temperature not exceeding 60 ° C.

7. Dry granules are dusted.

8. The prepared mass in the form of a granulate is encapsulated on a Zanazi machine in No. 3 hard gelatin capsules with compaction to a mass of 0.200 g ± 10% in each capsule to obtain the following Memantine oral capsule.

Composition of one capsule

The ingredients that make up the capsule Ingredient mass g % Memantine 0.005 2,5 Lactose 0.195 97.5 The mass of the contents of the capsule 0,200 100.0

The disintegration of the obtained capsules is less than 20 minutes, which meets the requirements of the Global Fund XI (Art. Capsules).

1000 pieces of memantine capsules have been developed using this technology.

Example 4

The method of obtaining the oral drug "Memantine" is carried out, as described in example 3, using other components in a different amount, while receiving capsules of the drug "Memantine" of the following composition.

Composition of one capsule

The ingredients that make up the capsule Ingredient mass g % Memantine 0.0025 1.25 Lactose 0.1975 98.75 The mass of the contents of the capsule 0.2000 100.00

The disintegration of the obtained capsules is less than 20 minutes, which meets the requirements of the Global Fund XI (Art. Capsules).

According to this technology, 1000 pieces of Memantine capsules have been accumulated.

Despite the apparent simplicity of the proposed solution to the problem, a similar solution has not yet been proposed.

This is because in the development of capsule mixtures it is necessary to be based on the physical and technological properties of the active substance and auxiliary substances: the shape, size and nature of the particle surface, specific surface of the particles, adhesion and cohesion forces, surface activity, electrostatic properties, bulk density, flowability, hygroscopicity. The capsule mass should be well dosed, have insignificant moisture sorption activity, should not clump during encapsulation, should not be compacted, pressed and divided into fractions during transportation and storage.

In addition, it is necessary to take into account the chemical inertness of the active substance to the auxiliary substances that make up the mixture and the material of the capsules. In this regard, the choice of excipients for capsule mass and their percentage in it for each active substance is an individual procedure, depending on the above properties of a particular active substance. The proposed preparations containing compositions of the capsular mass of the active substance - memantine with excipients, satisfy the above requirements.

The proposed oral drug "Memantine" in the form of capsules and a method for its preparation have been successfully tested and can be used for serial production in the pharmaceutical industry.

Thus, it is shown that when using the present invention provides a simplification of the manufacturing process of the oral drug "Memantine" in solid dosage form and, as a result, reducing the cost of manufacturing this drug.

Claims (11)

1. An oral preparation in the form of a solid dosage form containing memantine as an active substance, characterized in that the dosage form is a capsule, and memantine is included in a therapeutically effective amount in the composition of the mass filling these capsules, which is a mixture of powders. 2. An oral preparation in the form of a solid dosage form containing memantine as an active substance, characterized in that the dosage form is a capsule, and memantine is included in a therapeutically effective amount in the mass of the capsule filling these granules. 3. The oral preparation according to claim 1 or 2, characterized in that the mass filling the capsules additionally contains auxiliary substances in the following ratio of components, wt.%: memantine 0.5-10.0 Excipients rest 4. The oral preparation according to claim 3, characterized in that the mass filling the capsules contains powders of a disintegrant, an antifriction substance and a physiologically neutral excipient in the following ratios of components, wt.%: memantine 0.5-10.0 disintegrant 2.0-40.0 anti-friction substance 0.2-10.0 physiologically neutral excipient rest 5. The oral preparation according to claim 3, characterized in that the mass filling the capsules in the form of granules contains as an auxiliary substance a filler in the following ratios of components, wt.%: memantine 0.5-10.0 filler rest 6. The oral preparation according to claim 4 or 5, characterized in that rice or potato starch, aerosil, calcium carbonate, pectin or a mixture thereof are used as a disintegrant, stearic acid, aerosil, talc, calcium or magnesium stearate are used as antifriction agents, or their mixture, as a filler - lactose, glucose, microcrystalline cellulose, sorbitol, or a mixture thereof. 7. The oral preparation according to claim 6, characterized in that the capsule-containing mass in the form of a mixture of powders mainly contains potato starch as a disintegrant, magnesium stearate as an antifriction substance, and lactose as a filler in the following ratios of components, wt. %: memantine 0.5-10.0 potato starch 2.0-40.0 magnesium stearate 0.2-1.0 lactose rest 8. The oral preparation according to claim 6, characterized in that the capsule-containing mass in the form of a mixture of powders mainly contains aerosil as a disintegrant, talc and magnesium stearate as an antifriction agent, and microcrystalline cellulose and lactose as a filler in the following ratios of components, wt .%: memantine 0.5-10.0 aerosil 0.2-10.0 talc 1.0-4.5 magnesium stearate 0.2-1.0 microcrystalline cellulose 2.0-40.0 lactose rest 9. The oral preparation according to claim 6, characterized in that the mass filling in gelatin capsules in the form of granules contains microcrystalline cellulose as a filler in the following ratio of components, wt.%: memantine 0.5-10.0 microcrystalline cellulose rest 10. The method of obtaining an oral preparation in the form of a solid dosage form containing memantine as an active substance, which consists in the fact that powders of memantine and excipients - disintegrant, antifriction substance and carrier - are sieved, weighed and mixed in the proportions of the components, wt.%: memantine 0.5-10.0 disintegrant 0.2-40.0 anti-friction substance 0.2-10.0 filler rest, after which the capsule is filled with a mass in the form of a mixture of powders. 11. A method of obtaining an oral preparation in the form of a solid dosage form containing memantine as an active substance, which consists in using filler and, if necessary, a disintegrant and an antifriction substance as auxiliary substances, with memantine and filler powders or, in if necessary, also disintegrant and antifriction substance powders are sieved, weighed and mixed in the indicated mass proportions, wt.%: memantine 0.5-10.0 filler rest or memantine 0.5-10.0 disintegrant 0.2-40.0 anti-friction substance 0.2-10.0 filler rest, then the powder mixture is granulated by dry or wet granulation, and then the capsules are filled with granulate.