WO2008111871A1 - Peroral memantine-based medicinal preparation and a method for the production thereof - Google Patents

Abstract

The invention relates to medicine, in particular to peroral medicinal preparations exhibiting neuroprotection action, mainly to the solid medicinal form of a memantine preparation, i.e. a glutamatergic system modulator, which is used for treating dementia, defective memory and cerebral and spinal spastic syndromes. The inventive preparation is in the form of a capsule, in which memantine is added in a therapeutically acceptable quantity to a material which is used for filling the capsule in the form a mixture of powders or granulate. The capsule matter also contains auxiliary substances: a physiological neutral filler and, optionally, desintegrating and antifriction agents. The inventive methods for producing said preparation in the form of capsules, consist in sieving and in weighting powders of memantine and auxiliary agents and in mixing them at a specified mass ratios and in filling the capsules with a material in the form of a powder mixture or with a granulate which is obtained from the powder mixture by dry or wet granulation.

Description

 Memantine-based drug and method for its preparation.

The field of technology.

The invention relates to the pharmaceutical industry and medicine, in particular to oral neuroprotective drugs, in particular, to a solid dosage form of memantine.

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

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. Nk 2343-p).

Prior level.

Known drug 3,5-dimethyl-tricyclo- [3.3.1.13,7] decane-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 tablets, coated with a polymer coating, 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%); talcum powder - 1 1, 15

SUBSTITUTE SHEET (RULE 26) 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 memantine drug in the form of tablets are the multicomponent composition of the mixture for tabletting and applying the 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 of the drug msmantine in this dosage form.

Disclosure of the invention.

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 oral preparation of memantine in solid dosage form, and, as a result, to reduce the manufacturing cost of 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 - the rest.

As auxiliary substances, the preparation contains a physiologically neutral filler, a disintegrant (baking powder), an antifriction substance, and for example, with the following component ratios (max.,%): Memantine - 0.5 - 10.0; disintegrant - 2.0 - 40.0; anti-friction substance - 0.2 - 10.0; filler - the 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 body - lactose, can be made in the form of a mixture of powders, for example, with the following ratios of components (May,%): memantine - 0.5 - 10.0; potato or rice starch - 2.0 - 40.0; magnesium stearate - 0.2 - 1.0; lactose is the rest.

In another preparation, a capsule-filling mass in the form of a powder mixture 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 (MKT) as a filler. ₁ ) and lactose, for example, with the following ratios of components (May,%): 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 is the 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 - the 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, antifriction The substance is sieved, filler, weighed and mixed in the indicated mass proportions, for example, (May,%): memantine - 0.5 - 10.0; disintegrant - 2.0 - 40.0; anti-friction substance - 0.2 - 10.0; filler - the 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 excipients and, if necessary, a disintegrant and an antifriction substance are used as excipients, with memantine and filler, or, if necessary, also a disintegrant and anti-friction substance is sieved, weighed and mixed in the following mass proportions, for example, (May,%): memantine - 0.5 -10.0; filler - the rest, or memantine - 0.5 -10.0; disintegrant - 0.2 - 40.0; anti-friction substance - 0.2 -10.0; filler - the rest, then the powder mixture is granulated by dry or wet granulation, and then the capsules are filled with granulate.

The proposed oral drug in the form of capsules memantine has a higher bioavailability compared to oral 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 medicinal product, memantine in the form of capsules 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 is introduced into the mass for encapsulation in the form of a powder mixture of the proposed oral medicinal product as a disintegrant (baking powder), for example, potato or rice starch, which contributes to the disintegration of the capsules and improves the mobility of the granular mass for encapsulation.

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

Technological processes for the manufacture of memantine capsules according to the invention are much simpler than the manufacture of tablets mantin coated with a polymer shell, due to the fact that the capsules can encapsulate the drug in an unchanged form, without exposing it to heat and pressure, as in a complex technological process of pressing in the manufacture of tablets. 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 manufacturing cost of the drug memantine in capsule form compared to the cost of the drug memantine in the form of polymer-coated tablets.

The preparation of the encapsulated memantine preparation without granulation further reduces the manufacturing cost due to its cost-effectiveness, since additional equipment for granulation is not required, 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 active substance powder - memantine - with powders of auxiliary substances - potato starch, calcium stearate, lactose - with the mandatory control of mass heterogeneity for encapsulation.

4. The prepared mass in the form of a mixture of capsule powders is poured on a Zanazi machine into Ne 1 hard gelatin capsules with compaction to a mass of 0.250 g ± 10% in each capsule, to obtain oral memantine capsules of the following composition.

The composition of one capsule.

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 medication memantine is implemented as described in Example 1, except that powders of the components indicated in the following table are used.

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

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

The composition of one capsule.

Example 3

The first three stages of the method for producing an oral medication memantine are realized, 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 ⁰ C.

7. Dry granules are dusted.

8. The prepared mass in the form of a granulate is encapsulated on a Zanazi machine in hard gelatin capsules with JVs 3, densified to a mass of 0; 200 g ± 10% in each capsule, to obtain the following memantine oral drug capsules.

The composition of one capsule.

The disintegration of the obtained capsules is less than 20 minutes, which meets the requirements of the Global Fund XI (st. 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, and receive capsules of the drug memantine of the following composition.

The composition of one capsule.

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

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

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

This is because when developing capsule mixtures, it is necessary to be based on the physical and technological properties of the active substance and excipients: 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 the composition of the capsule mass of the active substance - memantine with excipients satisfy the above requirements.

Industrial applicability.

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, a simplification of the manufacturing process of the oral preparation of memantine in solid dosage form is ensured, and, as a result, a reduction in the manufacturing cost of this drug is provided.

Claims

Claim 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 - the 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, for example, with 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 filler - the 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 filler, for example, with the following component ratios (May,%): memantine - 0.5 - 10.0; filler - the rest. 6. Oral preparation according to paragraphs. 4 or 5, characterized in that as a disintegrant use, for example, rice or potato starch, aerosil, calcium carbonate, pectin or a mixture thereof, as an antifriction substance, for example, stearic acid, aerosil, talc, calcium or magnesium stearate or their mixture, as a filler, for example, lactose, glucose, microcrystalline cellulose, sorbitol, or a mixture thereof. 7. The oral preparation according to claim 6, characterized in that the mass filling the capsules 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, for example, with the following ratios of components (May,%): memantine - 0.5 - 10.0; potato starch - 2.0 - 40.0; magnesium stearate - 0.2 - 1.0; lactose is the rest. 8. An 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, for example, in the following component ratios (May,%): 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 is the rest. 9. An oral preparation according to claim 6, characterized in that the granular mass filling gelatin capsules contains microcrystalline cellulose as a filler, for example, in the following ratio of components (May,%): memantine - 0.5 - 10.0; microcrystalline cellulose - the rest. 10. A 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 - a disintegrant, an antifriction substance and a carrier - are sieved, weighed and mixed in ratios of components, for example, (May ,%): memantine - 0.5 -10.0; disintegrant - 0.2 - 40.0; anti-friction substance - 0.2 -10.0; filler - the 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 the fact that excipients use a filler and, if necessary, a disintegrant and an antifriction substance, while powders of memantine and filler, or, if necessary, also disintegrant and antifriction substance powders are sieved, weighed and mixed in the indicated mass proportions, for example, (May,%): memantine - 0.5 -10.0; filler - the rest, or memantine - 0.5 -10.0; disintegrant - 0.2 - 40.0; anti-friction substance - 0.2 -10.0; filler - the rest, then the powder mixture is granulated by dry or wet granulation, and then the capsules are filled with granulate.