Method of antidementia drug stabilisation

FIELD: medicine.

SUBSTANCE: method of antidementia drug stabilisation, particularly donepezil or its pharmaceutically acceptable salt, includes the addition of high-molecular acidic substance. Besides the present invention offers a pharmaceutical composition containing an antidementia drug and high-molecular base substance, as well as a high-molecular acidic substance to ensure antidementia drug stabilisation. The invention presents a method of manufacturing of the pharmaceutical composition which involves the stages whereat a solution or a suspension containing the high-molecular acidic substance is added to the pre-mixed antidementia drug and high-molecular base substance for the purpose of antidementia drug stabilisation.

EFFECT: preparation of the stabilised antidementia drug.

20 cl, 11 tbl, 1 dwg, 7 ex

 

The technical field

The present invention relates to the stabilization of drugs against dementia in a composition containing the drug against dementia. More specifically, the present invention relates to the stabilization of drugs against dementia in a pharmaceutical composition, which has the parameters of a slow-release, and includes a drug against dementia, containing a tertiary amino group.

Background of invention

In recent years, the treatment of dementia, including senile dementia, dementia in medical literature type and others, has become a social problem and therefore are developed of numerous medicines. Most often as a drug for the treatment of mild and moderate dementia of Alzheimer's use of donepezil, which inhibits the action of acetylcholinesterase, which is sold in the form of a hydrochloride in the form of tablets or granules. Recently, for patients who have problems with swallowing, designed tablet, disintegrating in the mouth, and in cases when it is difficult to oral administration, offer transcutaneous introduction to the use of the drug ointment (for example, see patent document 1: laid patent application of Japan No. H11-315016).

The development of such pharmacist is a political song, suitable for patients with certain conditions and symptoms is extremely important from the viewpoint of compatibility or quality of life. In this context, as drugs against dementia, you can use the drug with a slow release, since the parameters of the slow release allow to reduce the number of injections and to preserve or improve therapeutic effects with the potential to increase compatibility.

As a rule, drugs with a slow release containing a physiologically active substance, can be divided into two types, namely (1) preparations of matrix type, in which evenly distributed the drug and the base, providing a slow release, and (2) preparations of coating, in which the release is regulated by coating the surface of the Central core particles or tablets containing a physiologically active agent.

Matrix preparations contain a slow release matrix in which is distributed homogeneously remedy and the basis for slow release. The matrix is usually used in the form of tablets or granules, it may have a light shielding coating, etc. Covered drugs with a slow release include drugs that floor, soderzhaschiymnogo, provides slow release, applied to the Central core of granules, tablets or the like, containing a drug, or drugs, in which the Central core consisting of crystalline cellulose or sucrose, the so-called "nonpareil"cover first layer containing the drug, and then coating for delayed release. In some cases, a slow-release also provided with several layers of coatings containing drug, or coatings containing base, providing slow release.

However, because these drugs with a slow release contain the basis for the slow release, and other additives that are not part of the traditional bystrorastvorimaya tablets, etc. should be careful and make sure that the data of the additive does not affect the stability of the medicinal product. In particular, many drugs against dementia are basic and contain an amino group, often highly reactive functional group such as amino group, which is nucleophilic and can easily produce decomposition products when interacting with the carbonyl carbon, peroxide, oxygen, etc.

Because roducti decay medicines or supplements may affect the stability or efficacy of pharmaceutical products, in the field of drug development is the study of ways to prevent or substantially suppress the formation of these degradation products. With regard to stabilizing drugs against dementia, disclosed a composition comprising an organic acid, to stabilize donepezil when exposed to light (for example, see patent document 2: patent application laid Japan No. H11 - 106353). Described that the light shielding effect due to the addition of organic acids to donepezil in water-ethanol solution, and that the share of the remaining donepezil above in the solution to which is added paratoluenesulfonyl acid, methylsulfonate acid, citric or other acid than in solution, not containing organic acids.

Description of the invention

Thus, there is a need for pharmaceutical compositions, which improves the compatibility of drugs against dementia, such as a pharmaceutical composition with parameters a slow-release. On the other hand, as with conventional medicines, the drug delayed release must meet the requirements of stability during storage. In addition, because the medicine against dementia often administered for a long period, even in the case of the drug with its the STV slow release, there is a need for the development of pharmaceutical compositions, as well as a simple and cheap method for industrial preparation of such compositions. Accordingly, the aim of the present invention is the provision of stabilizing drugs against dementia in pharmaceutical compositions containing a drug against dementia. More specifically, the present invention is to provide pharmaceutical compositions containing a drug against dementia, which has the parameters of a slow-release and provides excellent stability of drugs against dementia, as well as the method for industrial preparation of pharmaceutical compositions and method of stabilizing drugs against dementia in pharmaceutical compositions.

To achieve these goals, the authors of the present invention have conducted extensive studies to pharmaceutical compositions containing drugs against dementia. In the result it was found that in the matrix the drug delayed release containing donepezil hydrochloride as a drug against dementia and ethylcellulose, which is a high molecular weight basic substance as the basis, providing slow wysw the leave, formed decomposition products of donepezil hydrochloride, and high molecular weight acidic substance effectively prevents or inhibits the formation of degradation products formed during the contacting drugs against dementia with high molecular weight basic substance, which is the basis of providing a slow release, and high molecular weight acidic substance has a joint action with low molecular weight acidic substance and an antioxidant, which is the subject of the present invention.

Accordingly, the present invention relates to pharmaceutical compositions containing a drug against dementia and Foundation that provides slow release, and the drug against dementia has excellent storage stability, where the composition comprises a high molecular weight acidic substance, providing stability of drugs against dementia. As the high molecular weight acidic substance can be used commercially available intersolubility polymeric substance and the like, which is easily mixed or granulated together with the cure of dementia and the basis for slow release, and thus to develop a simple method for industrial floor the treatment the pharmaceutical composition of the present invention.

In the first aspect of the present invention relates to a method of stabilizing drugs against dementia, which involves the addition of a high molecular weight acidic substance in a pharmaceutical composition comprising a drug against dementia and high molecular weight basic substance. Adding high molecular weight acidic substance can suppress the formation of degradation products drugs against dementia, which are formed in the contact drugs against dementia with high molecular weight basic substance. In addition, in a preferred aspect of the present invention proposes a method of stabilizing drugs against dementia, including adding in the pharmaceutical composition of the present invention, at least one substance selected from low molecular weight acidic substance and antioxidant.

In a second aspect the present invention provides a pharmaceutical composition comprising a drug against dementia and high molecular weight basic substance, and for stabilizing drugs against dementia in the composition is injected high molecular weight acidic substance. The pharmaceutical composition of the present invention also contains at least one shall emesto, selected from low molecular weight acidic substance and antioxidant. More specifically, the pharmaceutical composition is a composition as matrix drug delayed release, which contains a matrix representing a mixture of drugs against dementia, high molecular weight basic substance and a high molecular weight acidic substance for stabilizing drugs against dementia, or such a composition as a covered drug delayed release, which contains the Central core with the cure of dementia and the covering layer includes a high molecular weight basic substance deposited on the above-mentioned Central core, where high molecular weight acidic substance is mixed at least with the Central core or the above-mentioned covering layer.

In particular, the pharmaceutical composition of the present invention is a pharmaceutical composition comprising: (1) a basic drug or the salt, the solubility of which in 0.1 N hydrochloric acid solution and the 50 mm phosphate buffer, pH 6, is 1 mg/ml or more and a solubility in the 50 mm phosphate buffer, pH 8, 0.2 mg/ml or less, and the solubility of the basic drug or its salts in 50 mm phosphate BU the ore, pH of 6.8 at least twice its solubility in the 50 mm phosphate buffer, pH 8, and is no more than half of their solubility in the 50 mm phosphate buffer, pH 6; (2)at least one intersolubility polymeric substance (high molecular weight acidic substance) and (3)at least one water-insoluble polymeric substance (high molecular weight basic substance).

In a third aspect the present invention provides a method for industrial preparation, providing effective stabilization drugs against dementia of the present invention, in other words, the method for industrial preparation of pharmaceutical compositions containing a drug against dementia and high molecular weight basic substance, comprising a stage of mixing and granulation, where the mixture of drugs against dementia and high molecular weight basic substance added high molecular weight acidic substance for stabilizing drugs against dementia in the process, at least one of the stages of mixing and granulation. In accordance with a preferred aspect of the method for industrial preparation of the present invention, for stabilizing drugs against dementia in addition to the high molecular weight acidic substance can be added, on ENISA least low molecular weight acidic substance or an antioxidant. In a more preferred aspect, at least, of high molecular weight acidic substance, a low molecular weight acidic substance and an antioxidant is added in the form of a solution or suspension in the process, at least one of the stages of mixing and granulation. In a particularly preferred aspect of the method for industrial preparation of the present invention, after adding the high molecular weight acidic substance in powder form at the stage of mixing at least a low molecular weight acidic substance or an antioxidant can be added to the mixture in the form of a solution or suspension at the stage of granulation.

In addition, in the third aspect of the present invention provides a method for industrial preparation of pharmaceutical compositions, comprising the stage of: mixing (1) a basic drug or its salts, the solubility of which in 0.1 N hydrochloric acid solution and the 50 mm phosphate buffer, pH 6, is 1 mg/ml or more and a solubility in the 50 mm phosphate buffer, pH 8, 0.2 mg/ml or less, and the solubility in the 50 mm phosphate buffer, pH 6,8, at least twice its solubility in the 50 mm phosphate buffer, pH 8, and is no more than half its solubility in the 50 mm phosphate buffer, pH 6; (2)at least one intersolubility the m polymeric substance (high molecular weight acidic substance) and (3), at least one water-insoluble polymeric substance (high molecular weight basic substance); and formed by compressing the mixture obtained at the stage of mixing.

Further, in the fourth aspect of the present invention provides the use of high molecular weight acidic substance to suppress the formation of degradation products drugs against dementia in the interacting drugs against dementia with high molecular weight basic substance. This is a new way of application, which discloses high molecular weight acidic substance. In this case, the formation of decomposition products can be effectively suppressed by the additional use of low molecular weight acidic substance and antioxidant.

In accordance with a preferred aspect of the present invention remedy against dementia is a compound containing a tertiary amino group. In accordance with the preferred aspect of the present invention remedy against dementia selected from the group consisting of rivastigmine, galantamine, donepezil, 3-[1-(phenylmethyl)piperidine-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propane, 5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-she their pharmaceutically acceptable salts. The OS is especially preferred aspect of drug against dementia represents donepezil or its pharmaceutically acceptable salt.

In addition, in accordance with a preferred aspect of the present invention high molecular weight basic substance is at least one substance selected from the group consisting of ethyl cellulose, copolymer of acrylate and methacrylate and polyethylene oxide. In a more preferred aspect, the high molecular weight basic substance is either ethylcellulose, or a copolymer of acrylate and methacrylate, and in a particularly preferred aspect, the high molecular weight basic substance is ethylcellulose. As the high molecular weight basic substance can also be used any water-insoluble polymeric substance.

Further, in accordance with a preferred aspect of the present invention, high molecular weight acidic substance is intersolubility polymeric substance. In a more preferred aspect, the high molecular weight acidic substance is at least one substance selected from the group consisting of a copolymer of methacrylic acid and ethyl acrylate, a copolymer of methacrylic acid and methyl methacrylate, phthalate of hydroxypropylmethylcellulose and acetate succinate of hydroxypropylmethylcellulose. In a particularly preferred aspect, the high molecular weight acidic substance is a FOSS the emer methacrylic acid and ethyl acrylate. In a preferred aspect, the amount of high molecular weight acidic substance is usually from 0.1 to 90 parts by weight, preferably from 1 to 70 parts by weight, more preferably from 5 to 60 parts by weight, even more preferably from 10 to 50 parts by weight, relative to 100 mass parts of the pharmaceutical compositions of the present invention.

Further, in accordance with a preferred aspect of the present invention low molecular weight acidic substance is at least one selected from the group consisting of carboxylic acids, sulfonic acids, hydroxyl acids, acidic amino acids and inorganic acids. In a more preferred aspect, the low molecular weight acidic substance is at least one selected from the group consisting of hydroxyl acids, acidic amino acids and inorganic acids. In a particularly preferred aspect, the low molecular weight acidic substance is at least one selected from the group consisting of hydroxyl acids and acidic amino acids.

More specifically, low molecular weight acidic substance is at least one selected from the group consisting of succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, aspartic to the slots, glutamic acid, glutamic acid hydrochloride, hydrochloric acid and phosphoric acid. In a more preferred aspect, the low molecular weight acidic substance is at least one selected from the group consisting of succinic acid, tartaric acid, citric acid, malic acid, aspartic acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid and phosphoric acid. In a particularly preferred aspect, the low molecular weight acidic substance is at least one selected from the group consisting of citric acid, aspartic acid and hydrochloric acid. The amount of low molecular weight acidic substance is usually from 0.05 to 4 parts by weight, preferably from 0.1 to 3 parts by weight, more preferably from 0.15 to 2 parts by weight, even more preferably from 0.15 to 1.5 parts by weight, relative to 100 mass parts of the pharmaceutical compositions of the present invention. In accordance with a preferred aspect of the present invention, the antioxidant is at least one of ascorbic acid and sulfur-containing amino acids. In a more preferred aspect, the antioxidant is at least one substance selected from the group consisting of m is of thionine, ascorbic acid and cysteine hydrochloride. The amount of antioxidant is usually from 0.01 to 10 parts by weight, preferably from 0.02 to 5 parts by weight, more preferably from 0.05 to 2 parts by mass, relative to 1 mass part of the drugs. Although the amount of the antioxidant is not particularly limited, and it is, for example, from 0.001 to 5 parts by weight, preferably from 0.01 to 3 parts by weight, more preferably from 0.1 to 2 parts by weight, even more preferably from 0.15 to 1.5 parts by weight, relative to 100 mass parts of the pharmaceutical compositions of the present invention.

The pharmaceutical composition according to the first-third aspects of the present invention preferably is a drug with a slow release, more preferably the matrix, the drug delayed release. Examples of dosage forms of the pharmaceutical compositions preferably include tablets, capsules, granules or fine granules. Thus, the pharmaceutical composition in accordance with a particularly preferred aspect of the present invention is a matrix, the drug delayed release containing donepezil or pharmaceutically acceptable salt, a high molecular weight basic substance and the polymer sciense ser is popular acidic substance, or matrix, the drug delayed release containing donepezil or pharmaceutically acceptable salt, a high molecular weight basic substance of high molecular weight acidic substance and at least one low molecular weight acidic substance and antioxidant.

The advantages of this invention

In accordance with the present invention, to pharmaceutical compositions containing a drug against dementia and Foundation that provides slow release, proposes a method of preventing or suppressing the formation of degradation products in the interacting drugs against dementia with basis, providing slow release, namely, the present invention provides a method of stabilizing drugs against dementia in the pharmaceutical composition. In addition, since the pharmaceutical composition of the present invention has a high quality and meets the requirements of compatibility, the present invention provides pharmaceutical products, in particular drugs against dementia, the use of which does not cause concern and is not burdensome for patients and caregivers for them. The present invention also provides a simple way of industrial gaining the pharmaceutical compositions with controlled parameters of slow release and stabilization of drugs against dementia without the use of special methods of coating or special equipment.

Brief description of drawings

In Fig. 1 shows the dependence of the amount of degradation products formed after storage granules containing different additives, in the open (unsealed) container for 2 weeks at 60°C and 75% RH pH of a 2.5% aqueous solutions or suspensions containing different additives.

The best way of carrying out the invention

Further explanation of embodiments of the present invention. The following embodiments are examples for explaining the present invention and should not be construed as limiting the present invention. The present invention can be made in various ways, without departing from the essence and scope of the invention.

(Medicine against dementia)

Special restrictions on medicinal remedy for dementia, used in the present invention, there is provided that the drugs against dementia is a major drug containing primary, secondary or tertiary amino group, but preferably, if the drug against dementia contains a tertiary amino group. Examples of drugs against dementia, containing a primary amino group, include taken, memantine and pharmaceutically acceptable salts. Examples of the drug is the main tool against dementia, containing a tertiary amino group include rivastigmine, galantamine, donepezil, 3-[1-(phenylmethyl)piperidine-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propane and 5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-she and their pharmaceutically acceptable salts. Preferred examples of drugs against dementia, containing a primary amino group, are taken and of memantine hydrochloride. Preferred examples of drugs against dementia, containing a tertiary amino group, are rivastigmine tartrate, galantamine hydrobromide, hydrochloride donepezil (chemical name monohydrochloride (+-)-2-[(1-benzylpiperidine-4-yl)methyl]-5,6-dimethoxyindole-1-it), fumarate 3-[1-(phenylmethyl)piperidine-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propane (TAK-147) and maleate 5,7-dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-she (CP118954). More preferably, the drug against dementia is a hydrochloride donepezil, TAK-147 or CP118954, and most preferably a drug against dementia is donepezil hydrochloride. It should be noted that the drugs against dementia can be used either in free form or in the form of organic or inorganic salts, and prefer is Ino to use it in the form of organic or inorganic salts, especially preferably in the form of inorganic salts. Specific examples of salts include, without limitation, hydrochloride, sulphates, acetates, phosphates, carbonates, mesylates, tartratami, citrates, tozilaty etc.

There is no special limitation on the solubility of the basic drug or its salt used in the present invention, in the case of acidic aqueous solutions, neutral aqueous solutions or basic aqueous solutions, however, the solubility of the basic drug or its salts in an acidic aqueous solution and a neutral aqueous solution must be higher than the solubility of mostly water solution. Examples of these aqueous solutions used in the present invention include, without limitation, phosphate buffer (such as buffer obtained using a 50 mm solution of sodium phosphate and hydrochloric acid), such buffers as a buffer Miller (G. L. Miller's buffer), buffer Atkins-Pantin (Atkins-Pantin''s buffer), buffer hood (Hit s buffer) and the like, of 0.1 N hydrochloric acid, 0.1 mol/l sodium hydroxide solution and the like, it Should be noted that referred to in the present invention, the solubility is determined in solution at 25°C.

The term "solubility in an acidic aqueous solution" in the present invention relates to the solubility of the basic drug or the salt dissolve in the e, having acidic properties, by dissolving the basic drug or the salt in the buffer, etc. in a Similar way, the term "solubility in the neutral (ground) water solution" in the present invention relates to the solubility of the basic drug or its salts in solution with a neutral (basic) properties, by dissolving the basic drug or the salt in the buffer, etc.

For example, the solubility used in the present invention of the basic drug or its salts in an acidic aqueous solution, pH 3.0, and neutral aqueous solution, pH of 6.0, is higher than in the basic aqueous solution, pH 8.0. The term "solubility in an acidic aqueous solution, pH 3.0" in this description refers to the solubility of the basic drug or its salts in acidic solution having a pH of 3.0, by dissolving the basic drug or the salt in the buffer, etc. the Term "solubility in the neutral aqueous solution, pH of 6.0" in this description refers to the solubility of the basic drug or its salts in solution, having a pH of 6.0, by dissolving the basic drug or the salt in the buffer, etc. in a Similar way, the term "solubility in predominantly aqueous solution, pH 8.0" the description refers to the solubility of the basic drug or its Sol is in solution, having pH 8.0, by dissolving the basic drug or the salt in the buffer, etc.

In another example, the solubility used in the present invention of the basic drug or its salts in 0.1 N hydrochloric acid solution and a neutral aqueous solution, pH of 6.0, is higher than in the basic aqueous solution, pH 8.0. The term "solubility in the 0.1 N hydrochloric acid solution" in this description refers to the solubility of the basic drug or its salt by dissolving the basic drug or its salts in 0.1 N hydrochloric acid. For example, a solution of donepezil hydrochloride in 0.1 N hydrochloric acid solution has a pH in the range from about 1 to 2.

Preferably the solubility used in the present invention of the basic drug or its salts in 0.1 N hydrochloric acid solution and a neutral aqueous solution, pH of 6.0, is higher than in the basic aqueous solution, pH 8.0, and solubility in a neutral aqueous solution, pH of 6.8 at least twice its solubility in the main aqueous solution, pH 8.0 and is not more than half its solubility in the neutral aqueous solution, pH of 6.0. The term "solubility in the neutral aqueous solution, pH of 6.8" in this description refers to the solubility basically what about the drug or its salts in solution, having a pH of 6.8, by dissolving the basic drug or the salt in the buffer, etc.

More specifically, there are no particular restrictions, provided that the solubility of the basic drug or its salts in 0.1 N hydrochloric acid solution and a neutral aqueous solution, pH of 6.0 is 1 mg/ml or more, the solubility of the basic drug or its salts mainly aqueous solution, pH 8.0, 0.2 mg/ml or less, and the solubility of the basic drug or its salts in neutral aqueous solution, pH of 6.8, two or more times greater than its solubility in predominantly aqueous solution, pH 8.0 and is not more than half its solubility in the neutral aqueous solution, pH of 6.0. That is, the solubility of the basic drug or its salts in 0.1 N hydrochloric acid solution and a neutral aqueous solution, pH of 6.0, not particularly limited, provided that the above solubility is 1 mg/ml or more. The above solubility is usually from 1 to 1000 mg/ml, preferably from 5 to 200 mg/ml, more preferably from 5 to 100 mg/ml, even more preferably from 10 to 80 mg/ml solubility of the basic drug or its salts mainly aqueous solution, pH 8.0, not particularly limited, provided that the above rastvorimo the ü is 0.2 mg/ml or less. The above solubility is usually from 0.0001 to 0.2 mg/ml, preferably from 0.0005 to 0.1 mg/ml, more preferably from 0.001 to 0.05 mg/ml, even more preferably from 0.002 to 0.03 mg/ml in Addition, the solubility of the basic drug or its salts in neutral aqueous solution, pH of 6.8, not particularly limited, provided that the above solubility of at least twice its solubility in the main aqueous solution, pH 8.0 and is not more than 1/2 of its solubility in the neutral aqueous solution pH of 6.0. The above solubility is preferably at least 3 times greater than the solubility mainly aqueous solution, pH 8.0 and is not more than 1/3 of the solubility in a neutral aqueous solution, pH to 6.0, more preferably at least 5 times greater than the solubility mainly aqueous solution, pH 8.0 and is not more than 1/5 of the solubility in a neutral aqueous solution, pH of 6.0, even more preferably at least 10 times greater than the solubility mainly aqueous solution, pH 8.0 and is not more than 1/10 of solubility in a neutral aqueous solution, pH of 6.0.

In the following example, the solubility used in the present invention of the basic drug or its salts in 0.1 N hydrochloric acid solution and the 50 mm phosphate buffer, pH 6.0 and above, h is m its solubility in the 50 mm phosphate buffer, pH 8.0. The term "solubility in the 50 mm phosphate buffer, pH to 6.0" in this description refers to the solubility of the basic drug or its salts in 50 mm phosphate buffer having a pH of 6.0, by dissolving the basic drug or its salts in 50 mm phosphate buffer. Similarly, the term "solubility in the 50 mm phosphate buffer, pH 8.0" in this description refers to the solubility of the basic drug or its salts in 50 mm phosphate buffer with pH 8.0, by dissolving the basic drug or its salts in 50 mm phosphate buffer.

Preferably the solubility of the basic drug or its salts in 0.1 N hydrochloric acid solution and the 50 mm phosphate buffer, pH 6,0, higher than its solubility in the 50 mm phosphate buffer, pH 8.0, and solubility in the 50 mm phosphate buffer, pH 6,8, two or more times greater than the solubility in the 50 mm phosphate buffer, pH 8.0 and is not more than half its solubility in the 50 mm phosphate buffer, pH of 6.0. More specifically, there are no particular restrictions, provided that the solubility of the basic drug or its salts in 0.1 N hydrochloric acid solution and the 50 mm phosphate buffer, pH 6,0, is 1 mg/ml or more, the solubility of the basic drug or its salts in 50 mm phosphate buffer, pH 8.0, 0.2 mg/ml and less, and the solubility of the basic drug or its salts in 50 mm phosphate buffer, pH 6,8, two or more times greater than its solubility in the 50 mm phosphate buffer, pH 8.0 and is not more than half its solubility in the 50 mm phosphate buffer, pH of 6.0. That is, the solubility of the basic drug or its salts in 0.1 N hydrochloric acid solution and the 50 mm phosphate buffer, pH 6,0 not particularly limited, provided that the above solubility is 1 mg/ml or more. The above solubility is usually from 1 to 1000 mg/ml, preferably from 5 to 200 mg/ml, more preferably from 5 to 100 mg/ml, even more preferably from 10 to 80 mg/ml solubility of the basic drug or its salts in 50 mm phosphate buffer, pH 8.0, not particularly limited, provided that the above solubility is 0.2 mg/ml or less. The above solubility is usually from 0.0001 to 0.2 mg/ml, preferably from 0.0005 to 0.1 mg/ml, more preferably from 0.001 to 0.05 mg/ml, even more preferably from 0.002 to 0.03 mg/ml. moreover, the solubility of the basic drug or its salts in 50 mm phosphate buffer, pH 6,8, not particularly limited, provided that the above solubility of at least twice its solubility in the 50 mm phosphate buffer, pH 8.0, and faced the t is not more than 1/2 its solubility in 50 mm phosphate buffer, pH of 6.0. The above solubility is preferably at least 3 times greater than the solubility in the 50 mm phosphate buffer, pH 8.0 and is not more than 1/3 of the solubility in the 50 mm phosphate buffer, pH to 6.0, more preferably at least 5 times greater than the solubility in the 50 mm phosphate buffer, pH 8.0 and is not more than 1/5 of the solubility in the 50 mm phosphate buffer, pH to 6.0, still more preferably at least 10 times greater than the solubility in the 50 mm phosphate buffer, pH 8.0 and is not more than 1/10 of solubility in the 50 mm phosphate buffer, pH 6,0.

For example, the solubility of donepezil hydrochloride in an acidic aqueous solution, pH 3.0, and in neutral aqueous solution, pH of 6.0, is from 11 to 16 mg/ml, and in the basic aqueous solution, pH 8.0, she is 0.1 mg/ml or less. Moreover, donepezil hydrochloride is a weakly basic drug, or its salt containing one tertiary amino group, which is widely used for the treatment of dementia in Alzheimer's disease, and is characterized by solubility in the neutral aqueous solution, pH of 6.8, which is at least twice the solubility in predominantly aqueous solution, pH 8.0 and is not more than 1/2 of solubility in the neutral aqueous solution, pH of 6.0.

Alternatively, the donepezil hydrochloride is a weakly basic, Lekarstvo the e tool or its salt containing one tertiary amino group, which is widely used for the treatment of dementia in Alzheimer's disease. The solubility of donepezil hydrochloride is from 11 to 16 mg/ml in 0.1 N hydrochloric acid solution and the 50 mm phosphate buffer, pH of 6.0, and 0.1 mg/ml or less in 50 mm phosphate buffer, pH 8.0, and solubility in the 50 mm phosphate buffer, pH 6,8, at least twice the solubility in the 50 mm phosphate buffer, pH 8.0 and is not more than 1/2 of solubility in the 50 mm phosphate buffer, pH 6,0.

There is no specific restriction on the amount of dose of the drug against dementia, or its salt used in the present invention, however, in the case of acetylcholinesterase inhibitor dose is from 0.01 to 50 mg/day. More specifically, the dose of donepezil or its pharmacologically acceptable salt is from 0.01 to 50 mg/day, preferably from 0.1 to 40 mg/day, more preferably from 1 to 30 mg/day, more preferably from 5 to 25 mg/day. The dose of rivastigmine or its pharmaceutically acceptable salt is from 0.01 to 50 mg/day, preferably from 0.1 to 30 mg/day, more preferably from 1 to 20 mg/day, more preferably from 1 to 15 mg/day. The dose of galantamine or its pharmacologically acceptable salt is from 0.01 to 50 mg/day, preferably from 0.1 to 40 mg/day, more preference is sustained fashion from 1 to 30 mg/day, even more preferably from 2 to 25 mg/day.

In addition, in the case of memantine or its pharmacologically acceptable salts, which act as antagonists of the NMDA receptor, the dose is from 0.5 to 100 mg/day, preferably from 1 to 100 mg/day, more preferably from 1 to 40 mg/day, more preferably from 5 to 25 mg/day.

(High molecular weight basic substance)

High molecular weight basic substance used in the present invention is a macromolecular substance which possesses the basic properties when dissolved or suspendirovanie in the water. For example, a 2.5% aqueous solution or 2.5% aqueous suspension of high molecular weight basic substance has a pH above to 7.0, preferably from 7.5 to 14.0, more preferably from 8.0 to 14.0. High molecular weight basic substance in the present invention can be used as a framework to provide slow release of the pharmaceutical compositions of the present invention, and for other purposes. In addition, high molecular weight basic substance may be soluble in water, or it can be a substance, swellable in water or a substance that dissolves in water to form a gel. Examples of the water-insoluble high molecular weight basic substance include ethers, cellulose esters of all the vines and copolymers of methacrylic acid and acrylic acid (trade name Eudragit, is Röhm GmbH & Co. KG, Darmstadt, Germany). Examples include, without limitation, alkyl ethers of cellulose, such as ethylcellulose (trade name Ethocel, manufactured by The Dow Chemical Company, the U.S. and others), athletically, ethylpropylamine or isopropylethylene, butyltoluene etc.; kalkilya cellulose ethers, such as benzyltoluene etc.; cyanoaniline cellulose ethers, such as cyanoacrylate and the like; esters of cellulose and organic acids, such as butyrate cellulose acetate, cellulose acetate, cellulose propionate or cellulose butyrate, propionate, cellulose acetate and the like; a copolymer of acrylate and methacrylate (trade name Eudragit NE is Röhm GmbH & Co. KG, Darmstadt, Germany), etc. are Examples of water-soluble or swelling in water of high molecular weight basic substance include, without limitation, polyethylene oxide (trade name Polyox, manufactured by The Dow Chemical Company, U.S., molecular weight 100000-7000000), hydroxypropylcellulose with a low degree of substitution (trade name L-HPC, manufactured by Shin-Etsu Chemical, Japan), etc. Pharmaceutical composition of the present invention may contain one, two or more high molecular weight basic substance. High molecular weight basic substance used in the present invention, preferably is ethylcellulose,a copolymer of acrylate and methacrylate (trade name Eudragit NE) or polyethylene oxide (trade name Polyox). More preferably high molecular weight basic substance is at least one of ethyl cellulose and a copolymer of acrylate and methacrylate. In a particularly preferred aspect, the high molecular weight basic substance is ethylcellulose. The amount of high molecular weight basic substance in the pharmaceutical composition is not particularly limited and may vary depending on the purpose of its application, such as the regulation of the parameters of the slow release of drugs, etc. there is No special limitation on the average particle size of the high molecular weight basic substance (water-soluble polymeric substance)used in the present invention, however, the average particle size is preferably from 0.1 to 100 μm, more preferably from 1 to 50 μm, even more preferably from 3 to 15 μm, most preferably from 5 to 15 microns.

The amount of high molecular weight basic substance in the matrix, the drug delayed release not particularly limited, however it usually takes from 1 to 90% by weight, preferably from 3 to 70% by weight, more preferably from 5 to 50% by weight, even more preferably from 5 to 35% by mass, if the mass of the pharmaceutical composition is taken as 100%.

(Breakdown products)

The products of the disintegration of the present invention represent breakdown products of drugs against dementia, the resulting contact drugs against dementia with high molecular weight basic substance. Suppose that the decay products are formed as a result of the reactions taking place involving the amino groups of drugs against dementia. For example, the decomposition products formed upon contact hydrochloride donepezil with high molecular weight basic substance can be detected by ordinary methods using liquid chromatography.

(High molecular weight acidic substance)

High molecular weight acidic substance used in the present invention is a macromolecular substance which shows acidic properties after dissolution or suspension in water, for example, a 2.5% aqueous solution of high molecular weight acidic substance has a pH less than 7.0, preferably from 1.0 to 6.5, more preferably from 1.0 to 6.0. High molecular weight acidic substance used in the present invention may be insoluble in water, or it can be a substance, swellable in water or a substance that dissolves in water to form a gel. High molecular weight acidic substance used in the present invention is, for example, intersolubility polymeric substance. Examples Intercollege polymeric substances include, be the restrictions copolymer of methacrylic acid and methyl methacrylate (Eudragit L100 (methacrylic acid copolymer, type a), Eudragit S100 (methacrylic acid copolymer, type B)that are produced by Röhm GmbH & Co. KG, Darmstadt, Germany), a copolymer of methacrylic acid and ethyl acrylate (Eudragit L100-55 (methacrylic acid copolymer, type C), Eudragit L30D-55 dispersion of a copolymer of methacrylic acid), is made by Röhm GmbH & Co. KG, Darmstadt, Germany), the phthalate of hydroxypropylmethylcellulose (HP-55, HP-50, manufactured by Shin-Etsu Chemical, Japan), succinate acetate hydroxypropylmethylcellulose (AQOAT, manufactured by Shin-Etsu Chemical, Japan), carboximetilzellulozu (CMEC, manufactured by Freund Corporation, Japan), phthalate cellulose acetate and other Examples used in the present invention high molecular weight acidic substance that is able to swell in water to form gels when dissolved in water, include, without limitation, alginic acid, pectin, carboxyvinyl polymer, carboxymethyl cellulose, etc. Pharmaceutical composition of the present the invention can contain one, two or more high molecular weight acidic substances of the present invention. High molecular weight acidic substance used in the present invention, preferably is intersolubility polymeric substance, more preferably a copolymer of methacrylic acid and ethyl acrylate, a copolymer of methacrylic acid and of methyl methacrylate, phthalate of hydroxypropylmethylcellulose and succinate acetate hydroxypropylmethylcellulose, even more preferably a copolymer of methacrylic acid and ethyl acrylate.

In an industrial production method of the pharmaceutical composition of the present invention, the high molecular weight acidic substance can be used a commercial product in the form of powder, granules or suspension, previously distributed in the solvent, and such commercial products can be used as is, or dispergirovannykh in water or an organic solvent. For use in the present invention are suitable high molecular weight acidic substance with particles of small size, preferably powdery substance. In the case of a copolymer of methacrylic acid and ethyl acrylate example of a powdery product is Eudragit L100-55. The diameter of the particles of high molecular weight acidic substance used in the present invention, not particularly limited, but preferably it ranges from 0.05 to 100 μm, more preferably from 0.05 to 70 μm, most preferably from 0.05 to 50 μm.

Among the high molecular weight acidic substance is more preferable intersolubility polymeric substance, because of its stabilizing effect on drug against dementia is not lost, even the if in the pharmaceutical compositions of the present invention intersolubility polymeric substance is found in large quantities. Accordingly, there is no limit on the number of high molecular weight acidic substance, however, for example, the amount of high molecular weight acidic substance is usually from 0.1 to 90 parts by weight, preferably from 1 to 70 parts by weight, more preferably from 5 to 60 parts by weight, most preferably from 10 to 50 parts by weight, relative to 100 mass parts of the pharmaceutical compositions of the present invention.

The number Intercollege polymer in the pharmaceutical composition is not particularly limited, however it usually takes from 5 to 90% by weight, preferably from 8 to 70% by weight, more preferably from 10 to 60% by weight, most preferably from 15 to 50% by weight, if the weight of the pharmaceutical composition is taken for 100%. The total amount of the water-insoluble polymer and Intercollege polymer in the pharmaceutical composition is not particularly limited, but usually it ranges from 25 to 95% by weight, preferably from 35 to 95% by weight, more preferably from 40 to 90% by mass, even more preferably from 35 to 90% by weight, most preferably from 35 to 75% by weight, if the weight of the pharmaceutical composition is taken for 100%.

The total amount of high molecular weight basic substance (not water-soluble polymeric substances) and high molecular weight is about acidic substances (Intercollege polymeric substances) in the pharmaceutical composition is not particularly limited, however, it usually ranges from 25 to 95 parts by weight, preferably from 35 to 95 parts by weight, even more preferably from 35 to 90% by weight, most preferably from 35 to 75% by weight, relative to 100 mass parts of the pharmaceutical composition.

(Low molecular weight acidic substance)

There is no special limitation on low molecular weight acidic substance used in the present invention, provided that the pH is less than 4.5 by dissolving or suspendirovanie in water, for example, upon receipt of a 2.5% aqueous solution of 2.5% suspension, preferably the pH is from 1.0 to 4.0, more preferably from 1.0 to 3.5, even more preferably of 1.0 to 3.0V. In the application, along with the cure dementia specified drug against dementia used in the form of 2-5% aqueous solution or suspension with a pH of from 4.0 to 6.0, and pH of this aqueous solution minus the pH of a 2.5% aqueous solution of 2.5% suspension of low molecular weight acidic substance is usually from 0.05 to 5.5, preferably from 0.5 to 5.5, more preferably from 1.0 to 5.0, more preferably from 1.5 to 5.0.

Examples of low molecular weight acidic substance used in the present invention, even if it contains a basic functional group, etc. in addition to the acidic functional groups include, but are not limited the Iceni, amino acid or ethylenediaminetetraacetic acid, provided that the pH of a 2.5% aqueous solution of 2.5% suspension is less than 4.5. The term "low molecular weight" in the present invention refers to a molecular weight of 1000 or less and does not cover the high molecular weight acidic substance used in the present invention. Low molecular weight acidic substance used in the present invention may be soluble or insoluble in water, but preferably it is a solid at room temperature and low-volatile. The pharmaceutical composition may contain one, two or more low molecular weight substances used in the present invention.

There is no special limitation on low molecular weight acidic substance, however, examples include, without limitation, organic acids, inorganic acids or acidic amino acids. Examples of organic acids include, without limitation, carboxylic acids such as acetic acid, benzoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oxalic acid, malonic acid, succinic acid, adipic acid, sabotinova acid, fumaric acid, maleic acid, glycyrrhizin acid, glycyrrhetic acid, sorbic acid and the like; hydroxy acid (Aha), the same is as glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, digitaltruth sodium, gluconic acid, salicylic acid and the like; sulfonic acids such as paratoluenesulfonyl, methylsulfonate etc. are Examples of inorganic acids include, without limitation, hydrochloric acid, sulfuric acid, boric acid, phosphoric acid, sodium dihydrophosphate, potassium dihydrophosphate, etc. are Examples of acidic amino acids include, without limitation, aspartic acid, glutamic acid, glutamic acid hydrochloride, histidine hydrochloride, and the like, it is Preferable to use a carboxylic acid, a hydroxy acid, an acidic amino acid and inorganic acid, and preferred hydroxy acids, acidic amino acids and inorganic acids. More specifically, preferred examples of low molecular weight acidic substance used in the present invention include, without limitation, succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, aspartic acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid or phosphoric acid, and more preferred are succinic acid, tartaric acid, citric acid, malic acid, Aspara the new acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid or phosphoric acid. Even more preferred are citric acid, aspartic acid and hydrochloric acid.

Best effects of the present invention can be achieved using low molecular weight acidic substance in combination with a high molecular weight acidic substance. The amount of high molecular weight acidic substance is not limited to the desired stability, but it can vary depending on the parameters of the slow release. In this case, if the low molecular weight acidic substance is used in combination with the high molecular weight acidic substance, the change in the number does not affect the prevention or suppression of the formation of degradation products. For example, the amount of low molecular weight acidic substance is usually from 0.05 to 4 parts by weight, preferably from 0.1 to 3 parts by weight, more preferably from 0.15 to 2 parts by weight, even more preferably from 0.15 to 1.5 parts by weight, relative to 100 mass parts of the pharmaceutical compositions of the present invention.

(Antioxidant)

There is no special limitation on the antioxidant used in the present invention, provided that the antioxidant is oxidized and thereby prevents ocil is of the medicinal product, therefore, it is preferable that the oxidation of the antioxidant flowed easier than the oxidation of drugs against dementia, containing amino groups. Therefore, the antioxidant used in the present invention, has regenerative properties. Examples of the antioxidant used in the present invention include, without limitation, ascorbic acid, such as ascorbic acid, sodium ascorbate, erythropenia acid, erythorbate sodium palmitate ascorbic acid, ascorbic acid glucoside, and the like; sulfur-containing amino acids such as cysteine, hydrochloride, cysteine, methionine and the like; sulfites such as sodium sulfite, hydrosulfite sodium and the like; derivatives of catechol, such as catechol, chlorogenic acid, caffeic acid, tyrosine and the like; derivatives of hydroquinone, such as dibutylaminoethanol, butylhydroxyanisole and the like; derivatives of gallium acid, such as gallium acid, esters of gallium acid, tannic acid and the like; Tocopherols, such as dl-α-tocopherol, d-α-tocopherol, d-β-tocopherol, d-γ-tocopherol, d-δ-tocopherol, d-α - tocotrienol, d-β-tocotrienol, d-γ-tocotrienol, d-δ-tocotrienol, mixtures thereof and the like; flavones, such as rutin, quercetin, hesperidin, and the like; and polyphenols such as catechin, epicatechin, gallocatechin, the proanthocyanidin etc. Preferred ASC is benavie acid, sulfur-containing amino acids, derivatives of hydroquinone and Tocopherols. More preferred ascorbic acid or sulfur-containing amino acids. Especially preferred are methionine, ascorbic acid or cysteine hydrochloride. The antioxidant used in the present invention may be in free form or in salt form, however, it is preferable that it be dissolved or suspended in water to obtain an acidic aqueous solution. For example, ascorbic acid is preferred over sodium ascorbate and cysteine hydrochloride preferable to cysteine. In accordance with the present invention can be used alone, two or more antioxidants, or a combination of antioxidant with low molecular weight acidic substance. The antioxidant used in the present invention, can be both water-soluble and not soluble in water, but preferably at room temperature it was in solid form, and more preferably, it was a low-volatile substance.

There is no special limitation on the ratio of antioxidant to the amount of drug used in the present invention, however, such as the amount of antioxidant may range from 0.01 to 10 parts by weight, preferably from 0.02 to 5 parts by mass, b is more preferably from 0.05 to 2 parts by weight, in relation to 1 part by weight of the drug. There is no specific limit on the number of antioxidant, which is usually from 0.001 to 5 parts by weight, preferably from 0.01 to 3 parts by weight, more preferably from 0.1 to 2 parts by weight, even more preferably from 0.15 to 1.5 parts by weight, relative to 100 mass parts of the pharmaceutical compositions of the present invention.

(Water-soluble sugar and/or water-soluble sugar alcohol)

The pharmaceutical composition of the present invention preferably also contains a water-soluble sugar and/or water-soluble sugar alcohol. There is no specific limit on soluble sugar and/or water-soluble sugar alcohol. Examples of water-soluble sugars include, without limitation, lactose, sucrose, glucose, dextrin, pullulan etc. are Examples of water-soluble sugar alcohols include, without limitation, mannitol, erythritol, xylitol, sorbitol and the like, and lactose and mannitol are preferred. There is no specific limit on the number of water-soluble sugar or water-soluble sugar alcohol in the pharmaceutical compositions of the present invention, however, the above number is usually from 3 to 70% by weight, preferably from 5 to 60% by weight, more preferably from 10 to 60% by mA is CE, even more preferably from 12 to 60% by mass, if the mass matrix of the drug delayed release is taken as 100%.

(Filler)

The pharmaceutical composition of the present invention contains additives, including various pharmaceutically acceptable carriers such as excipients, lubricants, binders and dezintegriruetsja funds, as well as preservatives, colorants, sweeteners, plasticizers, film coating, etc. as needed. Examples of fillers include, without limitation, starch, gelatinising starch, crystalline cellulose, light anhydrous silicic acid, synthetic aluminum silicate, metasilicate aluminate magnesium, etc. are Examples of lubrication include, without limitation, magnesium stearate (Mallinckrodt Baker, Inc. USA), calcium stearate (Merck KGaA, Darmstadt, Germany), talc, stearyl fumarate, sodium, etc. are Examples of binders include, without limitation, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose sodium, hypromellose, polyvinylpyrrolidone, etc. Examples dezintegriruetsja means include, without limitation, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium salt of carboxymethyl amylum, nitrosamino hydroxypropylcellulose etc. Examples to the sideboards include, without limitation, esters of peroxybenzoyl acid, chlorbutanol, benzyl alcohol, finitely alcohol, along with dehydroacetic acid, sorbic acid and the like, Preferred examples of the dyes include, without limitation, water soluble colorful lacquers, natural pigments (such as β-carotene, chlorophyll and iron oxide), Queen-size iron oxide yellow, half red iron oxide, black iron oxide, etc. are Examples of sweeteners include, without limitation, saccharin sodium, glycyrrhizin of dicale, aspartame, stevia and the like, examples of the plasticizers include, without limitation, esters of glycerol and fatty acids, triethylcitrate, propylene glycol, polyethylene glycol, etc. are examples of the basics of film coatings include, without limitation, hypromellose, hydroxypropylcellulose etc.

(Pharmaceutical composition)

The pharmaceutical composition of the present invention is not particularly limited, provided that it is a composition containing stabilized medicinal remedy for dementia, but preferably it is a composition having the properties of a slow-release, or a drug with a slow release, and more preferably it is a matrix, the drug delayed release. Non-existent is there special restrictions on the dosage form of the pharmaceutical composition of the present invention, which may include tablets, capsules, granules, fine granules, powders, ointments, drugs for injection, observation, preparations for inhalation, jelly, etc. Preferably the composition is in the form of a dosage form suitable for oral administration such as tablets, capsules, granules, fine granules, jelly and the like, more preferably it is in the form of tablets, capsules, granules or fine granules.

In addition, the pharmaceutical composition of the present invention contains a drug against dementia, high molecular weight basic substance and a high molecular weight acidic substance. There is no special restriction on the distribution of drugs against dementia, high molecular weight basic substance and a high molecular weight acidic substance in the pharmaceutical composition, the ingredients can be uniformly mixed in the same phase of the pharmaceutical compositions of the present invention. In particular, the pharmaceutical composition may contain a matrix in which is distributed a drug against dementia, high molecular weight basic substance and a high molecular weight acidic substance, and may represent, for example, matrix drug delayed release. The matrix of the present invention is a matrix in which uniformly raspredelenie drug and base, provides slow release, with subsequent molding or granulating. Of course, in such matrices can contain other additives, or the matrix may optionally be covered with a covering layer containing the tool, protect from light, or a tool that protects from moisture, etc.

The drug and the high molecular weight basic substance may be contained separately in the adjacent phases of the pharmaceutical compositions of the present invention. Moreover, each phase containing the drug, and phase containing a high molecular weight basic substance may contain several phases, layered. In this case, the high molecular weight acidic substance may be contained at least in one of the phases. For example, the pharmaceutical composition of the present invention may contain a Central core containing a medicinal remedy for dementia, which is covered with the outer layer containing the high molecular weight basic substance and a high molecular weight acidic substance may be added, at least one Central core and covering layer and, for example, can be a drug with a slow release. It should be noted that there are no particular restrictions on the Central core, which may be in the form of g is zero or tablets, or in other form. Examples include tablets, in which the coating containing high molecular weight basic substance applied directly to the Central core, which is an uncoated tablet containing a mixture of drug and the high molecular weight acidic substance, the granules of which the coating containing high molecular weight basic substance and a high molecular weight acidic substance applied directly to the Central core, which consists of granules containing the drug, and laid a stack of pellets containing layer in which the drug and the high molecular weight acidic substance contained in the granules of the Central core, such as nonpareil and the like, and the layer containing the high molecular weight basic a substance. Use of tablets or capsules containing stacked in the stack of pellets containing layer with a high molecular weight acidic substance and a high molecular weight basic substance in the granules of the Central core, such as nonpareil and the like, and the layer with the drug.

In addition, the pharmaceutical composition of the present invention may be a pharmaceutical composition, in which the phase containing a high molecular weight acidic substance is located between the phase containing the drug, and the phase containing you homomolecular base material, to remedy against dementia had no contact with the high molecular weight basic substance. Granules can be obtained by covering the Central core containing the drug, a mixture containing high molecular weight acidic substance, and then cover the Central core, the coating layer containing the high molecular weight basic substance and a high molecular weight acidic substance.

(Method of making a mixture of high-molecular

acidic substances)

Upon receipt of the pharmaceutical compositions of the present invention containing high molecular weight acidic substance, it is possible to use traditional methods (such as described in Japanese Pharmacopoeia, 14thEd., General Rules for Preparations) as at the stage of mixing, and at the stage of granulation, molding, pressing, covering, packaging, or at any other stage of the industrial production of pharmaceutical compositions, or in multiple stages. Specific examples include without limitation (a) the way in which at the stage of dry or wet mixing drugs and high molecular weight basic substance also add high molecular weight acidic substance, (b) the way in which high molecular weight acidic substance is suspended in water or other connecting means used for wet granulation of a mixture of lcars the governmental funds and are not water-soluble polymeric substances, with the addition of high molecular weight acidic substance, (c) the way in which high molecular weight acidic substance is added in the form of a powder when dry granulating a mixture of a drug and the water-insoluble polymer substance, (d) the way in which at the stage of mixing and extrusion molding granules containing the drug, and granules containing high molecular weight basic substance of high molecular weight acidic substance is added in powder form, (e) a method of adding a high molecular weight acidic substance before applying the covering liquid, etc. to obtain a coating layer, if the granules or tablets provided with a sugar coating or film coating containing high molecular weight basic substance, and (f) the method of filling capsules, powders or granules of high molecular weight acidic substance together with granules containing the drug, and granules containing high molecular weight basic substance. High molecular weight acidic substance is preferably added at least at one stage of mixing and the stage of granulation. More preferred is a method in which high molecular weight acidic substance is added in powder form or in the form of a solution or suspension of a mixture of drugs and high molecular weight basic substance, what about the least at one stage mixing stage and granulation. Using this method, you can get pellets, in which all the ingredients are uniformly mixed. In a particularly preferred method, the high molecular weight acidic substance in powder form is added to a mixture of medicines and high molecular weight basic substance. It should be noted that there are no particular restrictions on the solvent used at different stages of production, including at the stages of wet mixing and obtain a solution or suspension stabilizers, examples of the solvent include alcohol, water or a mixture thereof, preferably ethanol, water or a mixture.

(Composition, mixed with low-molecular

the acidic substance and the like)

The pharmaceutical composition of the present invention contains a low molecular weight acidic substance in addition to drugs against dementia, high molecular weight basic substance and a high molecular weight acidic substance. There are no restrictions on the method of making a low molecular weight acidic substance in the pharmaceutical composition, for example, you can add in phase, which are uniformly distributed drug, high molecular weight basic substance and a high molecular weight acidic substance. If the drug and the high molecular weight basic prophetic the TWT are in different phases, low molecular weight acidic substance can be added, at least one of the phases of the pharmaceutical compositions of the present invention. On the matrix or the Central core of the pharmaceutical composition can be coated, either separately or together with the high molecular weight acidic substance. It should be noted that the antioxidant can be entered into the composition of the pharmaceutical composition according to the method described above for the low molecular weight acidic substance. Of course, the antioxidant can be mixed with the low molecular weight acidic substance, or it may be administered in the form of pharmaceutical compositions separately from the low molecular weight acidic substance.

(Method of adding low-molecular

acidic substances, etc.)

In the case of adding a high molecular weight acidic substance is a low molecular weight acidic substance or an antioxidant can be added to the composition at any stage or at multiple stages of the industrial production of pharmaceutical compositions. Low molecular weight acidic substance can be added at the same stage as high molecular weight acidic substance, or at another stage. Low molecular weight acidic substance or an antioxidant is preferably added at least at one stage of mixing and granulating production of pharmaceutical compositions. More preferably high molecular weight acidic substances the creation and low molecular weight acidic substance is added, at least one of the stages of mixing and granulating production of pharmaceutical compositions. Adding a low molecular weight acidic substance or antioxidant is not limited to these aspects and how to add, low molecular weight acidic substance or an antioxidant can be added in powder form, or dispersing the solution or suspension, or they can be applied by spraying. In this case, even if a few low molecular weight acidic substances, antioxidants and high molecular weight acidic substance added at one stage, how to add may be the same or different depending on the substances. For example, at the stage of mixing the high molecular weight acidic substance can be added in powder form, whereas the low molecular weight acidic substance or an antioxidant is added in the form of a solution or suspension, or high molecular weight acidic substance can be added in powder form at the stage of mixing, and the low molecular weight acidic substance or an antioxidant is added in the form of a solution or suspension at the stage of granulation, however, these examples are not restrictive.

There is no special limitation on the method for industrial preparation of pharmaceutical compositions of the present invention, provided that it includes a stage of introduction of the high-molecular KIS the CSOs substances in the form of pharmaceutical compositions. The pharmaceutical composition of the present invention can be obtained in the industry through a combination of known production methods (such as described in Japanese Pharmacopoeia, 14thEd., General Rules for Preparations). As an example of the solid preparation for oral administration, tablets can be obtained by adding and mixing the filler, dezintegriruetsja tools, etc. with medication, if necessary, by adding binders to obtain granules, and then dezintegriruetsja tools, lubricants, etc. Granules can be obtained in a similar way as the pill, by extrusion granulation, or by covering nonpareil (kernel containing 75% sucrose (wt./wt.) and 25% corn starch (wt./wt.)) powder dispersion containing the drug and additives, by spraying with water or solution (with a concentration of approximately from 0.5 to 70% (wt./wt.)), containing the binder. In the case of capsules, gelatin, hydroxypropylmethylcellulose or other capsules can be filled with the medication together with filler. These pharmaceutical compositions can also cover covering the tool, one or together with the light shielding means or a low molecular weight acidic substance or an antioxidant present izaberete the Oia, to mask the taste or to give intersolubility properties or parameters of a slow-release, etc.

The pharmaceutical composition of the present invention can be obtained in industry the following ways. 130 g of donepezil hydrochloride (Eisai Co. Ltd.), 624 g of ethyl cellulose (trade name Ethocel 10FP, Dow Chemical Company), 780 g of Eudragit 100-55 (Röhm GmbH & Co. KG) and 988 g of lactose are mixed in a granulator. Wet granulation is carried out by adding to the mixture an aqueous solution of 52 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd.), dissolved in a suitable amount of purified water. The obtained granules are dried at elevated temperature using a tray dryer and sieved, receiving granules of the desired size. After sifting add 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) 99 g of granules, mix and then use a rotary machine for tabletting get tablets with a diameter of 8 mm and a weight of 200 mg, containing 10 mg of donepezil hydrochloride. Then with the help of the apparatus for coating tablets cover water film containing hydroxypropylcellulose or the like as a main component.

Alternative pharmaceutical composition of the present invention can be obtained in industry using the following methods. 130 g of donepezil hydrochloride (Eisai Co. Ltd.), 624 g of ethyl cellulose (trade name the Finance Ethocel 10FP, The Dow Chemical Company), 780 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 975 g of lactose are mixed in a granulator. Wet granulation is carried out by adding to the mixture an aqueous solution of 52 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd) and 13 g of citric acid, which is dissolved in a suitable amount of purified water. The obtained granules are dried at elevated temperature using a tray dryer and sieved, receiving granules of the desired size. After sifting add 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) 99 g of granules, mix and then use a rotary machine for tabletting get tablets with a diameter of 8 mm and a weight of 200 mg, containing 10 mg of donepezil hydrochloride. Then with the help of the apparatus for coating tablets cover water film containing hydroxypropylcellulose or the like as a main component.

EXAMPLES

Below the present invention is explained in greater detail using examples, but these examples do not limit the present invention. The additives used in the pharmaceutical compositions are commercially available reagents, or they can be obtained in accordance with official documents such as Japanese Pharmacopoeia, the Japanese Pharmaceutical Excipients 2003 (JPE 2003) and the Japan Pharmaceutical Codex 1997 (JPC 1997).

(Example 1)

A suitable amount of purified water mixed with 300 mg of the hydrochloride to upazila (Eisai Co. Ltd.), 375 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), 1500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG) and 795 mg of lactose, after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control. Add 30 mg of magnesium stearate (Mallinckrodt Baker, Inc.) and mixed with the dried granules. From this mixture by using Autograph AG5000A (Shimazu Corporation) get a tablet with a diameter of 8 mm and a weight of 200 mg, containing 20 mg of donepezil hydrochloride.

(Example 2)

A suitable amount of purified water mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Example 3)

20 mg of citric acid dissolved in a suitable amount of purified water, mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Example 4)

20 mg digit is sodium citrate, dissolved in a suitable amount of purified water, mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP1 Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Example 5)

20 mg aspartic acid, dissolved in a suitable amount of purified water, mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Example 6)

20 mg of ascorbic acid, dissolved in a suitable amount of purified water, mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total m the SSE granules.

(Example 7)

20 mg of sodium ascorbate dissolved in a suitable amount of purified water, mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Example 8)

20 mg of cysteine dissolved in a suitable amount of purified water, mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Example 9)

20 mg of cysteine hydrochloride, dissolved in a suitable amount of purified water, mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of the hydrochloride of done the ZIL in relation to the total weight of the granules.

(Example 10)

20 mg of methionine dissolved in a suitable amount of purified water, mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Example 11)

130 g of donepezil hydrochloride (Eisai Co. Ltd.), 312 g of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), 624 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 1456 g of lactose were mixed in a granulator. Wet granulation is carried out by adding to the mixture an aqueous solution of 52 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd.), dissolved in a suitable amount of purified water, the obtained granules are dried at elevated temperature using a tray dryer and sieved, receiving granules of the desired size. After sifting add 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) 99 g of granules, mix and using a rotary machine for tabletting get tablets with a diameter of 8 mm and a weight of 200 mg, containing 10 mg of donepezil hydrochloride. Using Opadry Yellow (Japan use), the obtained tablet cover water-soluble film (amount of coating: 8 mg/tablet), which contains hydroxypropylmethyl the vine as a main component, and get a tablet with a film coating.

(Example 12)

130 g of donepezil hydrochloride (Eisai Co. Ltd.), 624 g of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), 780 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 988 g of lactose are mixed in a granulator. Wet granulation is carried out by adding to the mixture an aqueous solution of 52 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd.), dissolved in a suitable amount of purified water, the obtained granules are dried at elevated temperature using a tray dryer and sieved, receiving granules of the desired size. After sifting add 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) 99 g of the granules and mix, then using a rotary machine for tabletting get tablets with a diameter of 8 mm and a weight of 200 mg, containing 10 mg of donepezil hydrochloride. Using Opadry Yellow (Japan use), the obtained tablet cover water-soluble film (amount of coating: 8 mg/tablet), which contains hypromellose as a main component, and get a tablet with a film coating.

(Example 13)

130 g of donepezil hydrochloride (Eisai Co. Ltd.), 780 g of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), 858 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 754 g of lactose are mixed in a granulator. Wet granulation is carried out by adding to the mixture an aqueous solution of 52 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd.), dissolved in a suitable Koli is este purified water, the obtained granules are dried at elevated temperature using a tray dryer and sieved, receiving granules of the desired size. After sifting add 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) 99 g of the granules and mix, then using a rotary machine for tabletting get tablets with a diameter of 8 mm and a weight of 200 mg, containing 10 mg of donepezil hydrochloride. Using Opadry Yellow (Japan use), the obtained tablet cover water-soluble film (amount of coating: 8 mg/tablet), which contains hypromellose as a main component, and get a tablet with a film coating.

(Example 14)

130 g of donepezil hydrochloride (Eisai Co. Ltd.), 832 g of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), 962 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 598 g of lactose were mixed in a granulator. Wet granulation is carried out by adding to the mixture an aqueous solution of 52 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd.), dissolved in a suitable amount of purified water, the obtained granules are dried at elevated temperature using a tray dryer and sieved, receiving granules of the desired size. After sifting add 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) 99 g of the granules and mix, then using a rotary machine for tabletting get tablets with a diameter of 8 mm and a weight of 200 mg, containing 10 mg of the hydrochloride is donepezil. Using Opadry Yellow (Japan use), the obtained tablet cover water-soluble film (amount of coating: 8 mg/tablet), which contains hypromellose as a main component, and get a tablet with a film coating.

Example 15

3.5 g of donepezil hydrochloride (Eisai Co. Ltd.), of 37.8 g of Ethocel 10FP (ethylcellulose, Dow Chemical Company, of 22.4 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 73.5 g of lactose (Pharmatose 200M, DMV made Corporation) are mixed in a granulator. Wet granulation is carried out by adding to the mixture an aqueous solution of 2.8 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd.), dissolved in a suitable amount of purified water, the obtained granules are dried at elevated temperature using a tray dryer and sieved, receiving granules of the desired size using an electric mill. After sorting by size, add 50 mg of calcium stearate (Merck KGaA, Germany) at 5000 mg pellets, mixed, molded by pressing with Autograph AG5000A (Shimazu Corporation) at a pressure of 1200 kgf and get the product with a diameter of 8 mm and a weight of 202 mg, which contains 5 mg of donepezil hydrochloride.

Example 16

3.5 g of donepezil hydrochloride (Eisai Co. Ltd.), of 37.8 g of Ethocel 1QFP (ethylcellulose, Dow Chemical Company, of 22.4 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 73,08 g of lactose (Pharmatose 200M, DMV made Corporation) are mixed in a granulator. Wet granulation is carried out by added the mixture to an aqueous solution of 2.8 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd) and 0.42 g of citric acid dissolved in a suitable amount of purified water, the obtained granules are dried at elevated temperature using a tray dryer and sieved, receiving granules of the desired size using an electric mill. After sorting by size, add 50 mg of calcium stearate (Merck KGaA, Germany) at 5000 mg pellets, mixed, molded by pressing with Autograph AG5000A (Shimazu Corporation) at a pressure of 1200 kgf and get the product with a diameter of 8 mm and a weight of 202 mg, which contains 5 mg of donepezil hydrochloride.

Example 17

3.5 g of donepezil hydrochloride (Eisai Co. Ltd.), of 37.8 g of Ethocel 10FP (ethylcellulose, Dow Chemical Company, of 22.4 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 73.5 g of lactose (Pharmatose 200M, DMV made Corporation) are mixed in a granulator. Wet granulation is carried out by adding to the mixture an aqueous solution of 2.8 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd.), dissolved in a suitable amount of purified water, the obtained granules are dried at elevated temperature using a tray dryer and sieved, receiving granules of the desired size using an electric mill. After sorting by size, add 50 mg of calcium stearate (Merck KGaA, Germany) at 5000 mg pellets, mixed, molded by pressing with Autograph AG5000A (Shimazu Corporation) at a pressure of 1200 kgf and get the product with a diameter of 8 mm and a weight of 202 mg, which is contains 5 mg of donepezil hydrochloride.

Example 18

3.5 g of donepezil hydrochloride (Eisai Co. Ltd.), of 37.8 g of Ethocel 10FP (ethylcellulose, Dow Chemical Company, of 22.4 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 73,08 g of lactose (Pharmatose 200M, DMV made Corporation) are mixed in a granulator. Wet granulation is carried out by adding to the mixture an aqueous solution of 2.8 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd) and 0.42 g of citric acid dissolved in a suitable amount of purified water, the obtained granules are dried at elevated temperature using a tray dryer and sieved, receiving granules of the desired size using an electric mill. After sorting by size, add 50 mg of calcium stearate (Merck KGaA, Germany) at 5000 mg pellets, mixed, molded by pressing with Autograph AG5000A (Shimazu Corporation) at a pressure of 1200 kgf and get the product with a diameter of 8 mm and a weight of 202 mg, which contains 5 mg of donepezil hydrochloride.

Example 19

980 g of donepezil hydrochloride (Eisai Co. Ltd.), 3780 g of Ethocel 10FP (ethylcellulose, Dow Chemical Company), 2660 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 6188 g of lactose are mixed in a granulator. Wet granulation is carried out by adding to the mixture an aqueous solution of 300 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd.), dissolved in a suitable amount of purified water, the obtained granules are dried at elevated temperature using the dryer fluidized bed and sift, receiving granules wish what about the size. After sorting by size add 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) 99.7 g of granules, mix and then use a rotary machine for tabletting get tablets with a diameter of 8 mm and a weight of 200 mg, which contain 14 mg of donepezil hydrochloride. Using Opadry purple (use Japan Limited), the obtained tablet cover water-soluble film that contains hypromellose as a main component (amount of coating: 8 mg/tablet), and get a tablet with a film coating.

Example 20

1050 g of donepezil hydrochloride (Eisai Co. Ltd.), 3780 g of Ethocel 10FP (ethylcellulose, Dow Chemical Company), 2240 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 6538 g of lactose are mixed in a granulator. Wet granulation is carried out by adding to the mixture an aqueous solution of 350 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd.), dissolved in a suitable amount of purified water, the obtained granules are dried at elevated temperature using the dryer fluidized bed and sift, receiving granules of the desired size. After sorting by size add 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) 99.7 g of granules, mix and then use a rotary machine for tabletting get tablets with a diameter of 8 mm and a weight of 200 mg, which contain 15 mg of donepezil hydrochloride. Using Opadry purple (use Japan Limited), the obtained tablet cover moderator is my film, which contains hypromellose as a main component (amount of coating: 8 mg/tablet), and get a tablet with a film coating.

Example 21

1400 g of donepezil hydrochloride (Eisai Co. Ltd.), 3500 g of Ethocel 10FP (ethylcellulose, Dow Chemical Company), 2520 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 6118 g of lactose are mixed in a granulator. Wet granulation is carried out by adding to the mixture an aqueous solution of 420 g hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd.), dissolved in a suitable amount of purified water, the obtained granules are dried at elevated temperature using the dryer fluidized bed and sift, receiving granules of the desired size. After sorting by size add 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) 99.7 g of granules, mix and then use a rotary machine for tabletting get tablets with a diameter of 8 mm and a weight of 200 mg, containing 20 mg of donepezil hydrochloride. Using Opadry red (use Japan Limited), the obtained tablet cover water-soluble film that contains hypromellose as a main component (amount of coating: 8 mg/tablet), and get a tablet with a film coating.

Example 22

1610 g of donepezil hydrochloride (Eisai Co. Ltd.), 3500 g of Ethocel 10FP (ethylcellulose, Dow Chemical Company), 2520 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 5908 g of lactose are mixed in a granulator. VL is the author granulation is carried out by adding to the mixture an aqueous solution of 420 g hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd.), dissolved in a suitable amount of purified water, the obtained granules are dried at elevated temperature using the dryer fluidized bed and sift, receiving granules of the desired size. After sorting by size add 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) 99.7 g of granules, mix and then use a rotary machine for tabletting get tablets with a diameter of 8 mm and a weight of 200 mg, which contain 23 mg of donepezil hydrochloride. Using Opadry red (use Japan Limited), the obtained tablet cover water-soluble film that contains hypromellose as a main component (amount of coating: 8 mg/tablet), and get a tablet with a film coating.

Example 23

1610 g of donepezil hydrochloride (Eisai Co. Ltd.), 3080 g of Ethocel 10FP (ethylcellulose, Dow Chemical Company), 2940 g of Eudragit L100-55 (Röhm GmbH & Co. KG) and 5908 g of lactose are mixed in a granulator. Wet granulation is carried out by adding to the mixture an aqueous solution of 420 g hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd.), dissolved in a suitable amount of purified water, the obtained granules are dried at elevated temperature using the dryer fluidized bed and sift, receiving granules of the desired size. After sorting by size add 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) 99.7 g of granules, mix and then SIP is using a rotary machine for tabletting get tablets with a diameter of 8 mm and a weight of 200 mg, containing 23 mg of donepezil hydrochloride. Using Opadry red (use Japan Limited), the obtained tablet cover water-soluble film that contains hypromellose as a main component (amount of coating: 8 mg/tablet), and get a tablet with a film coating.

Examples 24-30

Tablet film-coating are shown in table 1, can be obtained using the methods described above.

Table 1
The name of the componentProviderExample 24Example 25Example 26Example 27Example 28Example 29Example 30
Donepezil HClEisai12121418183030
Ethocel 10 FPDow Chemical5454 4854445044
Eudragit L100-55Röhm32384438423642
Lactose (Pharmatose 200M)DMV International97,491,488,484,490,477,477,4
HPC-LNippon Soda4455566
Magnesium stearateMallinckrodt0,60,60,60,60,60,60,6
200200200200200200200
Opadry purple (mg/tablet)Use Japan8888888
The total mass of the tablet with a film coating (mg)208208208208208208208

Examples 31-34

In accordance with the amounts of components shown in tables 2 and 3, all the components are mixed in a mortar. Using Autograph AG5000A (Shimazu Corporation) get a tablet with a diameter of 8 mm and a weight of 200 mg, which contains 20 mg of donepezil hydrochloride and 20 mg of memantine hydrochloride.

Table 2
The name of the componentProvider Example 31
Donepezil HClEisai300
Ethocel 10 FPDow Chemical750
Eudragit L100Röhm1500
Lactose (FlowLac 100)Meggle420
Magnesium stearateMallinckrodt30
Total (mg)3000

Table 3
The name of the componentProviderExample 32Example 33Example 34
Memantine HClLachema s.r.o.300300300
Ethocel 10 FPDow Chemical750750750
Eudragit L100-551500--
Eudragit L100Röhm-1500-
AQOAT LFSHIN-ETSU CHEMICAL--1500
Lactose (FlowLac 100)Meggle420420420
Magnesium stearateMallinckrodt303030
Total (mg)300030003000

(Comparative example 1)

300 mg of donepezil hydrochloride (Eisai Co. Ltd.), 750 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company, 1920 mg of lactose and 30 mg of magnesium stearate (Mallinckrodt Baker, Inc.) mix in a mortar. Using Autograph AG5000A (Shimazu Corporation) get a tablet with a diameter of 8 mm and a weight of 200 mg, containing 20 mg of donepezil hydrochloride.

(Comparative example 2)

300 mg of donepezil hydrochloride (Eisai Co. Ltd.), 750 mg of ethyl cellulose (Ethocel 10FP, Dow Chemica Company), 1620 mg of lactose, 300 mg of citric acid and 30 mg of magnesium stearate (Mallinckrodt Baker, Inc.) mix in a mortar. Using Autograph AG5000A (Shimazu Corporation) get a tablet with a diameter of 8 mm and a weight of 200 mg, containing 20 mg of donepezil hydrochloride.

(Comparative example 3)

A suitable amount of purified water mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 1500 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Comparative example 4)

20 mg of disodium citrate dissolved in a suitable amount of purified water, mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Comparative example 5)

20 mg of sodium citrate dissolved in a suitable amount of purified water, mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethcel 10FP, The Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Comparative example 6)

20 mg aspartate sodium, dissolved in a suitable amount of purified water, mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Comparative example 7)

20 mg of glycine dissolved in a suitable amount of purified water, mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Comparative example 8)

20 mg of disodium salt of ethylenediaminetetraacetic acid, dissolved in a suitable amount of purified water) is t with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Comparative example 9)

A suitable amount of purified water mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 1000 mg of lactose and 1000 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Comparative example 10)

A suitable amount of purified water mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.) and 2000 mg of lactose, after which the mixture is dried at an elevated temperature in the chamber with automatic temperature control and receive granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Comparative example 11)

A suitable amount of purified water mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 1500 mg of lactose and 500 mg of Eudragit L100-55 (Röhm GmbH & Co. KG), after which the mixture is dried at an elevated temperature in the chamber with Avtomaticheskaya temperature and obtain granules, which contain approximately 1% of donepezil hydrochloride in relation to the total weight of the granules.

(Test example 1)

Tablets, which contain 10% of donepezil hydrochloride, obtained by the methods of example 1 and comparative examples 1 and 2, is kept for one week in the open (unsealed) camera with automatic control of temperature at 60°C and 75% RH, the number of decay products measured before and after storage. The number of decay products measured using the method described below, the decay products 1.

(Method of analysis of the decay products 1)

The amount of degradation products determined by HPLC using to measure column ODS-A (YMC Co. LTd.) with an inner diameter of 4.6 mm and a length of 75 mm under the following conditions: column temperature 35°C, flow rate 1 ml/min, wavelength detection 271 nm. The composition of the mobile phase and conditions of the linear gradient shown in table 4. The number of decay products is calculated as the percentage of the total area under the peak, using as reference the maximum peak of the decay products, eluruumist with a relative retention time of from about 1.1 to 1.2, with respect to the area under the peak of the main drugs.

The mobile phase A: water/acetonitrile/70% water solution perchloro acid = mixture 899/100/1

Mobile phase: water/acetonitrile/70% water the initial solution perchloro acid = mixture 99/900/1

Table 4
minMobile phase AndMobile phase b
0,0075%25%
6,0075%25%
9,000%100%
10,000%100%
10,0175%25%
13,0075%25%

The number of decay products, eluruumiks with a relative retention time of from about 1.1 to 1.2 relative to donepezil in table 5, the results of the measurements performed in test example 1. At that time, both the tablets obtained according to the method of comparative example 1, the number of decay products is 0.12%, the tablets obtained according to the method of example 1, which contain 50% Eudragit L100-55 as a high molecular weight acidic substance, the decomposition products are not observed. Other products RESPA is not in example 1, neither in comparative example 1 are not observed. Tablets obtained by the method of comparative example 2, which contain 10% of the medicinal product and citric acid, is formed not only 0.77% of the products with a relative retention time of from 1.1 to 1.2, but a number of other decay products, the total number of which is approximately 13%. It was found that the addition of citric acid, which effectively provides the photostability of donepezil in 0.1% solution of donepezil, as described in patent application laid Japan No. H11-106353 specified in the section "Background of invention", in fact, leads to an increase in the number of decay products under the condition of thermal stability of donepezil hydrochloride in the tablet, which contains 10% of donepezil hydrochloride. Even though the composition as a high molecular weight acidic substance added Eudragit L100-55 at high concentrations of 50%, the decay products are not detected, which confirms the improvement of thermostability of donepezil hydrochloride in pharmaceutical compositions. This result demonstrates that high molecular weight acidic substance increases thermal stability of the composition, which contains as a medicinal remedy for dementia, and high molecular weight basic substance.

0,12
Table 5
The name of the componentExample 1Comparative example 1Comparative example 2
Amount (mg)Hydrochloride donepezil300300300
Ethylcellulose375750750
EUDRAGIT L100-551500--
Lactose79519201620
Citric acid--300
Magnesium stearate303030
Only300030003000
The decay products (%)<0,050,77

(Test example 2)

Granules, which contain approximately 1% of donepezil hydrochloride, obtained by the methods of examples 2 and 3 and comparative example 3, stored for 2 weeks in an open (unsealed) camera with automatic control of temperature at 60°C and 75% RH, the number of decay products measured before and after storage. The number of decay products measured using the method described below, the decay products 2. Granules obtained in comparative examples 9-11, analyzed according to the method described in test example 1.

(Method of analysis of the decay products 2)

The amount of degradation products determined by HPLC using to measure column Inertsil ODS-2 (GL Sciences) with an inner diameter of 4.6 mm and a length of 150 mm, a mixture 646,6/350/1/2,4 water/acetonitrile/70% water solution perchloro acid/decanesulfonate sodium in the following conditions: column temperature 35°C, flow rate of 1.4 ml/min, wavelength detection 271 nm. The number of decay products is calculated as the percentage of the total area under the peak, using as reference the maximum peak of the decay products, eluruumist with a relative retention time of from about 1.1 to 1.2, with respect to the area under the peak of the main drugs.

The number of decay products, eluruumi is consistent with the relative retention time of from about 1.1 to 1.2 relative to donepezil, in table 6, the results of the measurements performed in test example 2. The decay products are not detected in the granules obtained according to the methods of comparative examples 10 and 11, which do not contain ethylcellulose as high molecular weight basic substance, however, 0.51% of degradation products observed in the granules of comparative example 3, which contain ethylcellulose. In the granules of comparative example 9, which contain more of ethyl cellulose, there 1,26% decay products. This confirms the formation of degradation products in the joint presence of donepezil hydrochloride and ethyl cellulose.

Comparative example 3 and example 2 also confirm that the formation of degradation products is suppressed when incorporated in a pharmaceutical composition approximately 25% of Eudragit L100-55. The granules of example 2 or example 3, which contains approximately 1% of citric acid, the decomposition products are not observed. This again proves that the high molecular weight acidic substance inhibits the formation of degradation products observed in the joint presence of drugs against dementia and high molecular weight basic substance, and has the effect of joint actions with citric acid.

The table is 6
The name of the componentExample 2Example 3EUR. example 10EUR. example 11EUR. example 3EUR. example 9
The number (mg)Hydrochloride donepezil202020202020
Ethylcellulose500500--5001000
EUDRAGIT L100-55500500-500--
Lactose100010002000150015001000
Citric acid -20----
Only202020402020202020202020
The decay products (%)0,28<0,1<0,1<0,10,511,26

(Test example 3)

To confirm the effect of the joint action of Eudragit L100-55 and a low molecular weight acidic substance, granules, mixed with citric acid or its salt (examples 3 and 4, comparative examples 4 and 5), amino acid (example 5, comparative examples 6 and 7) or salt ethylenediaminetetraacetic acid (comparative example 8), stored for 2 weeks in an open (unsealed) camera with automatic control of temperature at 60°C and 75% RH, the number of decay products measured before and after storage. The number of decay products measured using the method described below, the decay products 2. Also measure the pH of solutions of additives analyzed in this test example is f (i.e. Eudragit L100-55 in example 2 and additives, add in the amount of 20 mg in the other examples and comparative examples), dissolved or suspended in purified water at a concentration of 2.5%. As reference values also measure the pH values of 2% and 5% aqueous solutions of donepezil hydrochloride.

The number of decay products, eluruumiks with a relative retention time of from about 1.1 to 1.2 relative to donepezil in table 7, the results of the measurements performed in test example 3. The number of decay products in the comparative example 3 is of 0.51%, and in example 2, in which obtain granules containing only Eudragit L100-55 to suppress degradation products, only 0.28 per cent. Moreover, the number of decay products in examples 3-5, which add low molecular weight acidic substance present invention is not more than 0.51% of the number observed in comparative example 3, it is confirmed that the formation of degradation products is suppressed as a result of joint application of Eudragit L100-55 and a low molecular weight acidic substance. The formation of degradation products also suppressed in example 3, in which obtain granules containing citric acid and in example 5, which receive granules containing aspartic acid, in comparison with example 2, in which only add Eudragit L100-55, which confirms sinergi the definition effect of low molecular weight acidic substance and a high molecular weight acidic substance on thermal stability of donepezil hydrochloride in pharmaceutical compositions contains ethylcellulose. Then determine the pH (2.5% aqueous solution or suspension) additives used in this test (in the examples and comparative examples, the additives are added in amounts of 20 mg). Figure 1 shows the relationship between the pH of a 2.5% aqueous solutions or suspensions of different additives and formation of degradation products after storage granules containing data supplements for 2 weeks in an open (unsealed) the chamber at 60°C and 75% RH. At pH 4.5 the number of decay products is approximately the same as in comparative example 3, however, with increasing pH, the number of decay products increases. On the other hand, if pH is below 4.5, the lower the pH, the stronger the effect of thermal stabilization and suppression of formation of degradation products. Because the pH of 2% aqueous solution of donepezil hydrochloride is 5.0, and pH of 5% aqueous solution of the hydrochloride donepezil equal to 4.8, stability in comparative examples 4-7 less than in comparative example 3, since the products of these examples contain additives with higher pH values than that of an aqueous solution of donepezil hydrochloride.

Table 7
The name of the componentExample 2Example 3 Example 4EUR. Example 4EUR. Example 5Example 5EUR. Example 6EUR. Example 7EUR. Example 8EUR. Example 3
The number (mg)Hydrochloride donepezil20202020202020202020
Ethylcellulose500500500500500500500500500500
EUDRAGIT L100-55500500500500500500500500 500-
Lactose1000100010001000100010001000100010001500
Citric acid-20---------
Digitaltruth sodium--20-------
The disodium citrate---20---- --
Sodium citrate----20-----
Aspartic acid-----20----
Aspartate sodium------20---
Glycine-------20-/td> -
the disodium salt of ethylenediaminetetraacetic acid--------20-
Only2020204020402040204020402040204020402020
The decay products (%)0,28<0,10,270,760,860,181,090,700,530,51
pH additives (2.5% aqueous solutions or suspensions)3,42,03,75,2 8,33,06,86,24,5-

(Test example 4)

To assess the cumulative effect of Eudragit L100-55 and antioxidant granules of examples 6-10 and comparative example 8, which contains approximately 1% of donepezil hydrochloride and different antioxidants, stored for 2 weeks in an open (unsealed) camera with automatic control of temperature at 60°C and 75% RH, the number of decay products measured before and after storage. The number of decay products measured using the previously described method of analysis of the decay products 2. In addition, determine the pH of the additives are dissolved or suspended in purified water at a concentration of 2.5%used in this test (in the examples and comparative examples, the additives are added in amounts of 20 mg).

The number of decay products, eluruumiks with a relative retention time of from about 1.1 to 1.2 relative to donepezil in table 8, the results of the measurements performed in test example 4. The stabilization effect is observed in examples 6-10, in which the receiving pellets containing Eudragit L100-55 and antioxidant, and the formation of degradation products is suppressed more than in comparative example 3. In particular, the products RESPA is not detected in the samples, in which obtain granules containing ascorbic acid or sulfur-containing amino acid, indicating a synergistic effect with Eudragit L100-55. On the other hand, the same level of degradation products, as in comparative example 3 (with no additives), is observed in comparative example 8, which receive granules containing antioxidant, not reacts recovery (pH 4.5, 2% aqueous solution), this suggests that hepatoblastoma antioxidants not contribute to stability.

As in the case of additives test example 3, Fig. 1 shows the dependence of the number of decay products after storage for examples 6-10, which are granules containing antioxidants with restorative effects from pH values of 2.5% aqueous solutions or suspensions. Compared with the results of test example 3 shows that the effects of these antioxidants differ from the effects that they have as low molecular weight acidic substance.

(Test example 5)

Measure the pH of a 2.5% aqueous solutions or suspensions of high molecular weight acidic substance and a high molecular weight basic substance used in the present invention. As reference values also measure the pH values of 2% and 5% aqueous solutions of donepezil hydrochloride and 2.5% water is aStore lactose. The results are shown in table 9.

Table 9
The name of the componentTrade nameProviderpH
Succinate acetate hydroxypropylmethylcelluloseAQOAT LFSHIN-ETSU CHEMICALa 3.9
Phthalate of hydroxypropylmethylcelluloseHPMCP HP-55SSHIN-ETSU CHEMICAL3,3
Carboxyvinyl polymerCarbopol 71GA Noveon3,1
Copolymer of methacrylic acid and methylmethacrylateEudragitL100Röhm3,3
Copolymer of methacrylic acid and methylmethacrylateEudragitS100Röhm3,2
A copolymer of acrylate and methacrylateEudragitNE30DRöhm 8,6
The polyethylene oxidePOLYOX WSR301Dow Chemical Company9,3
EthylcelluloseEthocel 7FPDow Chemical Company9,4
EthylcelluloseEthocel 10FPDow Chemical Company9,2
EthylcelluloseEthocel 10Dow Chemical Company8,6
EthylcelluloseEthocel 100FPDow Chemical Company8,1
LactoseFlowLac100Meggle5,5
Of donepezil hydrochloride (2% aqueous solution)-EISAI5,0
Hydrochloride donepezil (5% aqueous solution)-EISAI4,8

(Test example 6)

Tablets that contain 5 mg of donepezil hydrochloride, obtained in PR which measures 15, 16, 17 and 18, stored for 2 weeks in an open (unsealed) camera with automatic control of temperature at 60°C and 75% RH, the number of decay products measured before and after storage. The number of decay products measured using the above method of analysis of the decay products 2.

The number of decay products after storage at 60°C and 75% RH, eluruumiks with a relative retention time of from about 1.1 to 1.2, compared to donepezil in table 10, the results of the measurements performed in test example 6. As can be seen from table 10, examples 15, 16, 17 and 18 confirm that the number of decay products can be reduced less than 0.5% with respect to the content of donepezil hydrochloride in a stressful environment.

Table 10
The name of the componentExample 15Example 16Example 17Example 18
Amount (mg)Hydrochloride donepezil5555
Ethyl is ellulose 54545454
EUDRAGIT L100-5532323232
Lactose105104,4105104,4
HPC-L4444
Citric acid-0,6-0,6
Calcium stearate22--
Magnesium stearate--22
Only202202202202
The decay products (%)0,2 0,150,330,26

(Test example 7)

The stability tests carried out with the use of the tablets obtained in examples 11, 12 and 14. In each of examples 11, 12 and 14 50 tablets placed in a bottle made of high density polyethylene, after which the vial is closed with sheet aluminum. The bottle is also closed with screw cap made of polypropylene. After storage in a camera with automatic temperature control at 5°C and 40°C, 75% RH, the number of decay products measured before and after storage using the above method of analysis of the decay products 2.

The number of decay products after storage at 40°C and 75% RH, eluruumiks with a relative retention time of from about 1.1 to 1.2, compared to donepezil in table 11, the results of the measurements performed in test example 7. As can be seen from table 11, examples 11, 12 and 14 confirm that the number of decay products can be reduced less than 0.5% with respect to the content of donepezil hydrochloride. In accordance with the guidelines of the International conference on harmonization, if the maximum dose of the drug is 10 to 100 mg / day, maximum dose of impurities, security must be less than 0.5%in relation to the medicinal product, or less than 200 µg total number per day. Moreover, we can say that if the quality of medicines and healthcare products is retained after storage at 40°C and 75% RH for six months, the usual guarantee period for the medical products is three years (at room temperature). It should be noted that the amount of degradation products in tablets obtained in each of examples 11, 12 and 14 is less than 0.05% relative to donepezil hydrochloride, which is below the detection limit for impurities.

The results of test example 7 confirm that the present invention offers solutions that can improve the quality of the pharmaceutical composition containing donepezil hydrochloride.

Table 11
The original numberOne monthThree monthsAfter six months
Example 11NSL0,06%0,10%0,15%
Example 12NSL0,09%0,18% 0,28%
Example 14NSL0,12%0,22%0,37%
NSL means: not more than 0.05%

Application in industry.

In accordance with the present invention, to pharmaceutical compositions containing a drug against dementia and Foundation that provides slow release, proposes a method of preventing or suppressing the formation of degradation products in the interacting drugs against dementia with basis, providing slow release, namely, the present invention provides a method of stabilizing drugs against dementia in the pharmaceutical composition. Moreover, since the pharmaceutical composition of the present invention has a high quality and meets the requirements of compatibility, the present invention provides pharmaceutical products, in particular drugs against dementia, the use of which does not cause concern and is not burdensome for patients and caregivers for them. The present invention also provides a simple method for industrial preparation of pharmaceutical compositions to control the alignment parameters slow release and stabilization of drugs against dementia without the use of special methods of coating or special equipment.

1. The method of stabilization of donepezil or pharmaceutically acceptable salts, including the addition of high molecular weight acidic substance selected from the group consisting of a copolymer of methacrylic acid and ethyl acrylate, a copolymer of methacrylic acid and methyl methacrylate, phthalate of hydroxypropylmethylcellulose and succinate acetate hydroxypropylmethylcellulose, the pharmaceutical composition comprising donepezil or its pharmaceutically acceptable salt and a high molecular weight basic substance selected from the group consisting of ethyl cellulose, copolymer of acrylate and methacrylate and polyethylene oxide.

2. The method according to claim 1, where the high molecular weight acidic substance is added in a quantity which is able to suppress the formation of the degradation product of donepezil or pharmaceutically acceptable salts, resulting from the contact of the medicinal product with high molecular weight basic substance.

3. The method according to claim 1 or 2, further comprising adding at least one low molecular weight acidic substance selected from the group consisting of succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, aspartic acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid and the phosphorus is Oh acid, and antioxidant.

4. The method according to claim 3, where the low molecular weight acidic substance is at least one substance selected from the group consisting of succinic acid, tartaric acid, citric acid, malic acid, aspartic acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid and phosphoric acid.

5. The method according to claim 4 or 3, where the antioxidant is at least one substance selected from the group consisting of ascorbic acid, sulfur-containing amino acids, derivatives of hydroquinone and Tocopherols.

6. The use of high molecular weight acidic substance selected from the group consisting of a copolymer of methacrylic acid and ethyl acrylate, a copolymer of methacrylic acid and methyl methacrylate, phthalate of hydroxypropylmethylcellulose and succinate acetate hydroxypropylmethylcellulose, to suppress the formation of degradation product of donepezil or pharmaceutically acceptable salt, which is formed in the contact drugs with high molecular weight basic substance selected from the group consisting of ethyl cellulose, copolymer of acrylate and methacrylate and polyethylene oxide.

7. The use of high molecular weight acidic substance selected from the group consisting of a copolymer of methacrylic what Islami and acrylate, copolymer of methacrylic acid and methyl methacrylate, phthalate of hydroxypropylmethylcellulose and succinate acetate hydroxypropylmethylcellulose, and at least one low molecular weight acidic substance selected from the group consisting of succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, aspartic acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid and phosphoric acid, and antioxidant to suppress the formation of degradation product of donepezil or pharmaceutically acceptable salt, which is formed in the contact drugs with high molecular weight basic substance selected from the group consisting of ethyl cellulose, copolymer of acrylate and of methyl methacrylate and polyethylene oxide.

8. Pharmaceutical composition comprising donepezil or its pharmaceutically acceptable salt and a high molecular weight basic substance selected from the group consisting of ethyl cellulose, copolymer of acrylate and methacrylate and polyethylene oxide, where the composition further comprises a high molecular weight acidic substance selected from the group consisting of a copolymer of methacrylic acid and ethyl acrylate, a copolymer of methacrylic acid and methyl methacrylate, phthalate Hydra is nsiproperties and succinate acetate hydroxypropylmethylcellulose, for stabilization of donepezil or its pharmaceutically acceptable salt.

9. The pharmaceutical composition of claim 8, further containing at least one low molecular weight acidic substance selected from the group consisting of succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, aspartic acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid and phosphoric acid, and an antioxidant for the stabilization of donepezil or its pharmaceutically acceptable salt.

10. The pharmaceutical composition of claim 8, where the composition includes a matrix containing a mixture of donepezil or pharmaceutically acceptable salts, high molecular weight basic substance selected from the group consisting of ethyl cellulose, copolymer of acrylate and methacrylate and polyethylene oxide, and high molecular weight acidic substance selected from the group consisting of a copolymer of methacrylic acid and ethyl acrylate, a copolymer of methacrylic acid and methyl methacrylate, phthalate of hydroxypropylmethylcellulose and succinate acetate hydroxypropylmethylcellulose, for stabilization of donepezil or its pharmaceutically acceptable salt.

11. The pharmaceutical composition of claim 10, where at least one low molecular weight acidic substance is a curse from the group consisting of succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, aspartic acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid and phosphoric acid, and an antioxidant for the stabilization of donepezil or pharmaceutically acceptable salt mixed in the matrix.

12. The pharmaceutical composition of claim 8, where the pharmaceutical composition comprises a Central core containing donepezil or pharmaceutically acceptable salt, and an outer layer containing the high molecular weight basic substance selected from the group consisting of ethyl cellulose, copolymer of acrylate and methacrylate and polyethylene oxide, which covers the core, and where the high molecular weight acidic substance selected from the group consisting of a copolymer of methacrylic acid and ethyl acrylate, a copolymer of methacrylic acid and methyl methacrylate, phthalate of hydroxypropylmethylcellulose and succinate acetate hydroxypropylmethylcellulose add, at least in the core or cover layer.

13. The pharmaceutical composition according to item 12, where at least one low molecular weight acidic substance selected from the group consisting of succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, Aspar is genoway acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid and phosphoric acid, and an antioxidant for the stabilization of donepezil or pharmaceutically acceptable salts also add, at least in the core or cover layer.

14. The pharmaceutical composition according to any one of PP-13, where the pharmaceutical composition is a drug with a slow release.

15. Matrix drug delayed release, containing donepezil or its pharmaceutically acceptable salt; high molecular weight basic substance selected from the group consisting of ethyl cellulose, copolymer of acrylate and methacrylate and polyethylene oxide; and high molecular weight acidic substance selected from the group consisting of a copolymer of methacrylic acid and ethyl acrylate, a copolymer of methacrylic acid and methyl methacrylate, phthalate of hydroxypropylmethylcellulose and succinate acetate hydroxypropylmethylcellulose.

16. Matrix drug delayed release indicated in paragraph 15, further containing at least one low molecular weight acidic substance selected from the group consisting of succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, aspartic acid, glutamic acid, glutamic hydrochloride Ki is lots hydrochloric acid and phosphoric acid, and an antioxidant.

17. A method for industrial preparation of pharmaceutical compositions, comprising the stage of:
mixing donepezil or pharmaceutically acceptable salts and high molecular weight basic substance selected from the group consisting of ethyl cellulose, copolymer of acrylate and methacrylate and polyethylene oxide; and
granulating the mixture,
where high molecular weight acidic substance selected from the group consisting of a copolymer of methacrylic acid and ethyl acrylate, a copolymer of methacrylic acid and methyl methacrylate, phthalate of hydroxypropylmethylcellulose and succinate acetate hydroxypropylmethylcellulose designed for stabilization of donepezil or pharmaceutically acceptable salt, add to mixture medicines and high molecular weight basic substance during at least one stage of mixing and granulation.

18. The method according to 17, where the high molecular weight acidic substance is added in powder form.

19. The method according to 17 or 18, where at least one low molecular weight acidic substance selected from the group consisting of succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, aspartic acid, glutamic acid, glutamic hydrochloride is th acid, hydrochloric acid and phosphoric acid, and an antioxidant for the stabilization of donepezil or pharmaceutically acceptable salt is also added to the mixture of drugs and high molecular weight basic substance during at least one stage of mixing and granulation.

20. The method according to p, where at least one low molecular weight acidic substance and an antioxidant is added in the form of a solution or suspension.



 

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