CN101090737B - Method for stabilizing anti-dementia drugs - Google Patents

Abstract

The present invention provides a method for stabilizing an anti-dementia drug in a pharmaceutical composition containing the anti-dementia drug and a high molecular weight basic substance, comprising adding a high molecular weight acidic substance to the pharmaceutical composition. Further, the present invention is a pharmaceutical composition comprising an anti-dementia drug and a high molecular weight basic substance, wherein a high molecular weight acidic substance is contained to stabilize the anti-dementia drug. Further, the present invention provides a method for producing a pharmaceutical composition comprising the step of adding a solution or suspension containing a high molecular weight acidic substance to a mixture of an anti-dementia drug and a high molecular weight basic substance to stabilize the anti-dementia drug.

Description

Translated fromChinese

稳定抗痴呆药物的方法Ways to stabilize anti-dementia drugs

技术领域technical field

本发明涉及在包含抗痴呆药物的组合物中稳定抗痴呆药物。更具体地，本发明涉及在具有持续释放的性质并包含具有叔氨基的抗痴呆药物的药物组合物中稳定抗痴呆药物。The present invention relates to the stabilization of an anti-dementia drug in a composition comprising the anti-dementia drug. More specifically, the present invention relates to stabilizing an anti-dementia drug in a pharmaceutical composition having a sustained-release property and comprising an anti-dementia drug having a tertiary amino group.

背景技术Background technique

近年来，痴呆包括老年性痴呆、阿尔茨海默型痴呆等等的护理已经变成了一个社会问题，并发展出了很多的治疗药物。其中，多萘哌齐可以作为盐酸盐以片剂或胶囊形式使用，据观察由于其乙酰胆碱酯酶抑制活性，可以作为治疗药物在轻度和中度阿尔茨海默型痴呆中是非常有用的。近来，在口腔中崩解的片剂已经出售给舌咽困难的患者，通过软膏制剂进行的经皮给药也用于口服困难的情况(例如，参见专利文献1：日本专利申请公开H11-315016)。In recent years, care for dementia including senile dementia, Alzheimer's dementia, etc. has become a social problem, and many therapeutic drugs have been developed. Among them, donepezil, which is available as hydrochloride in the form of tablets or capsules, has been observed to be very useful as a therapeutic drug in mild and moderate Alzheimer's type dementia due to its acetylcholinesterase inhibitory activity . Recently, tablets disintegrating in the oral cavity have been sold to patients with glossopharyngeal difficulties, and transdermal administration by ointment formulations is also used in cases where oral administration is difficult (for example, see Patent Document 1: Japanese Patent Application Publication H11-315016 ).

适合患者的情况和症状的药物组合五的发展从顺应性或生活质量的观点来看是极其重要的。从这个意义上讲，持续释放制剂对于抗痴呆药物是有用的，因为药物的持续释放性质允许减少施用药物的次数，同时提供相同或更好的治疗效果，有可能改善顺应性。The development of a drug combination suitable for the patient's condition and symptoms is extremely important from a compliance or quality of life point of view. In this sense, sustained-release formulations are useful for anti-dementia drugs because the sustained-release properties of the drug allow reducing the number of times the drug is administered while providing the same or better therapeutic effect, potentially improving compliance.

一般地，包含有生理活性的药物的持续释放制剂可以分为两种类型的制剂，(1)基质型制剂，其中药物和持续释放基质均匀地分布于制剂中，和(2)包衣的持续释放制剂，其中通过用持续释放包衣包被包含生理活性药物的芯颗粒或片芯片剂的表面来控制释放。Generally, sustained-release formulations containing physiologically active drugs can be classified into two types of formulations, (1) matrix-type formulations, in which the drug and sustained-release matrix are uniformly distributed in the formulation, and (2) coated sustained-release formulations. A release preparation in which release is controlled by coating the surface of core particles or core tablets containing a physiologically active drug with a sustained release coating.

基质型持续释放制剂含有基质，药物和持续释放基质均匀地存在于其中。基质一般用作片剂或颗粒，可以给予其光屏蔽的包衣等等。包衣的持续释放制剂包括，包含持续释放基质的包衣应用于包含药物的片剂、颗粒等等的芯的那些，或包含药物的层应用于包含称作nonpareil的微晶纤维素或蔗糖的芯颗粒上，然后通过另一种持续释放包衣包被的那些。在一些情况中，也可以通过多层的包含药物的包衣或包含持续释放基质的包衣的方法来控制持续释放性质。A matrix-type sustained-release preparation contains a matrix in which a drug and a sustained-release matrix are uniformly present. The matrix is generally used as a tablet or granule, to which a light-shielding coating or the like can be given. Coated sustained release formulations include those in which a coating comprising a sustained release matrix is applied to the core of a drug-containing tablet, granule, etc., or a drug-containing layer is applied to a drug containing microcrystalline cellulose called nonpareil or sucrose. The core particles are then coated with another sustained-release coating. In some cases, the sustained-release properties may also be controlled by means of multiple layers of drug-containing coatings or coatings comprising sustained-release matrices.

但是，由于现在持续释放制剂包含持续释放基质和其他在常规、快速溶解的片剂中不包括的添加剂，因此必须注意药物的稳定性不会受到影响。特别地，许多抗痴呆药物是包含氨基的碱性药物，一般地，当与羰基碳、过氧化物、氧等反应时，高反应性的官能团，例如亲核的氨基具有容易产生降解产物的性质。However, since sustained-release formulations now contain sustained-release matrices and other additives not included in conventional, fast-dissolving tablets, care must be taken that the stability of the drug is not compromised. In particular, many anti-dementia drugs are basic drugs containing amino groups, and generally, highly reactive functional groups such as nucleophilic amino groups have the property of easily generating degradation products when reacting with carbonyl carbon, peroxides, oxygen, etc. .

由于药物或添加剂的降解产物可以影响药品的稳定性或效力，因此在制剂发展领域中正在研究预防这些降解产物产生或严重抑制所产生的量的方法。关于稳定抗痴呆药物的方法，已经公开了用包含有机酸的组合物稳定多萘哌齐免于光照损害(参见，专利文献2：日本专利申请公开H11-106353)。已经报道了，向多萘哌齐的乙醇水溶液中加入有机酸的作用可以评价光稳定性效果，加入对甲苯磺酸、甲磺酸、柠檬酸等的溶液中的多萘哌齐的残留比例高于没加入有机酸的溶液。Since degradation products of drugs or additives can affect the stability or potency of drug products, methods of preventing the production of these degradation products or severely inhibiting the amount produced are being investigated in the field of formulation development. As for a method of stabilizing antidementia drugs, it has been disclosed that donepezil is stabilized against light damage with a composition containing an organic acid (see, Patent Document 2: Japanese Patent Application Laid-Open H11-106353). It has been reported that the effect of adding an organic acid to an aqueous solution of donepezil in ethanol can be used to evaluate the photostability effect, and the residual ratio of donepezil in a solution added to p-toluenesulfonic acid, methanesulfonic acid, citric acid, etc. is high in a solution in which no organic acid was added.

发明内容Contents of the invention

因此，需要一种药物组合物，来改善抗痴呆药物的顺应性，例如具有持续释放性质的药物组合物。另一方面，当使用常规药物时，要求该持续释放制剂能确保贮存稳定性。此外，由于抗痴呆药物通常施用较长的时间(甚至在具有持续释放功能的制剂的情况中)，因此需要该药物组合物和生产该药物组合物的方法，该药物组合物可以容易和便宜地生产。因此，本发明的一个目的是在包含抗痴呆药物的组合物中稳定抗痴呆药物。更具体地，本发明的一个目的是提供包含抗痴呆药物的药物组合物，其具有持续释放的性质并且抗痴呆药物具有优秀的稳定性，和一种生产该组合物的方法，和一种在该药物组合物中稳定抗痴呆药物的方法。Therefore, there is a need for a pharmaceutical composition to improve the compliance of anti-dementia drugs, such as a pharmaceutical composition with sustained release properties. On the other hand, when conventional drugs are used, the sustained release formulation is required to ensure storage stability. In addition, since antidementia drugs are usually administered for a long period of time (even in the case of preparations with a sustained release function), there is a need for a pharmaceutical composition and a method for producing the pharmaceutical composition, which can be easily and inexpensively Production. It is therefore an object of the present invention to stabilize an anti-dementia drug in a composition comprising the anti-dementia drug. More specifically, an object of the present invention is to provide a pharmaceutical composition comprising an anti-dementia drug, which has a sustained-release property and excellent stability of the anti-dementia drug, and a method for producing the composition, and a The method for stabilizing the anti-dementia drug in the pharmaceutical composition.

在这些情况下，本发明人对包含抗痴呆药物的药物组合物进行了广泛的研究。结果，本发明人发现，来自盐酸多萘哌齐的降解产物是在基质型持续释放制剂中产生的，其中该基质型持续释放制剂包含盐酸多萘哌齐作为抗痴呆药物和高分子量碱性物质乙基纤维素作为持续释放基质，和高分子量酸性物质，当抗痴呆药物与作为持续释放基质的高分子量碱性物质接触时，高分子量酸性物质有效地防止或抑制所产生的降解产物，并且高分子量酸性物质也与低分子量酸性物质和抗氧化剂具有联合作用，由此完成了本发明。Under these circumstances, the present inventors conducted extensive research on pharmaceutical compositions containing anti-dementia drugs. As a result, the present inventors found that degradation products derived from donepezil hydrochloride were produced in a matrix-type sustained-release preparation comprising donepezil hydrochloride as an anti-dementia drug and a high-molecular-weight basic substance Ethyl cellulose is used as a sustained-release matrix, and a high-molecular-weight acidic substance. When an anti-dementia drug is in contact with a high-molecular-weight basic substance as a sustained-release matrix, the high-molecular-weight acidic substance effectively prevents or inhibits the resulting degradation products, and has a high The molecular weight acidic substance also has a joint action with the low molecular weight acidic substance and antioxidant, thereby completing the present invention.

因此，本发明涉及包含抗痴呆药物和持续释放基质的药物组合物，抗痴呆药物具有优良的贮存稳定性，其中包含高分子量酸性物质用于稳定抗痴呆药物。此外，可以使用商业可用的肠溶性聚合物等作为高分子量酸性物质，其可以容易地与抗痴呆药物和持续释放基质一起混合或制粒以容易地生产根据本发明的药物组合物。Therefore, the present invention relates to a pharmaceutical composition comprising an anti-dementia drug having excellent storage stability and a sustained release matrix, which contains a high molecular weight acidic substance for stabilizing the anti-dementia drug. In addition, commercially available enteric polymers and the like can be used as high-molecular-weight acidic substances, which can be easily mixed or granulated with anti-dementia drugs and sustained-release bases to easily produce the pharmaceutical composition according to the present invention.

在本发明的第一个方面，本发明涉及稳定抗痴呆药物的方法，包括在包含抗痴呆药物和高分子量碱性物质的药物组合物中加入高分子量酸性物质。通过加入高分子量酸性物质，可以抑制抗痴呆药物的降解产物，该降解产物是由抗痴呆药物与高分子量碱性物质接触产生的。此外，根据本发明的方法的一个优选的方面，提供一种稳定抗痴呆药物的方法，其中根据本发明在该药物组合物中加入至少一种低分子量酸性物质和抗氧化剂。In a first aspect of the present invention, the present invention relates to a method for stabilizing an anti-dementia drug, comprising adding a high-molecular-weight acidic substance to a pharmaceutical composition comprising an anti-dementia drug and a high-molecular-weight basic substance. By adding a high-molecular-weight acidic substance, it is possible to suppress the degradation products of the anti-dementia drug, which are generated by contacting the anti-dementia drug with a high-molecular-weight basic substance. Furthermore, according to a preferred aspect of the method of the present invention, there is provided a method for stabilizing an anti-dementia drug, wherein at least one low molecular weight acidic substance and an antioxidant are added to the pharmaceutical composition according to the present invention.

在本发明的第二个方面，提供一种包含抗痴呆药物和高分子量碱性物质的药物组合物，其中该组合物包含高分子量酸性物质以稳定抗痴呆药物。根据本发明的药物组合物包含至少一种低分子量酸性物质和抗氧化剂。更具体地，该药物组合物是一种组合物例如基质型持续释放制剂，其是抗痴呆药物、高分子量碱性物质和用于稳定抗痴呆药物的高分子量酸性物质的混合物，或者是一种组合物例如包衣的持续释放制剂，其包含含有抗痴呆药物的芯和含有在上述芯上包被的高分子量碱性物质的包衣层，其中高分子量酸性物质混合在至少一种上述的芯和上述的包衣层中。In a second aspect of the present invention, there is provided a pharmaceutical composition comprising an anti-dementia drug and a high-molecular-weight basic substance, wherein the composition contains a high-molecular-weight acidic substance to stabilize the anti-dementia drug. The pharmaceutical composition according to the invention comprises at least one low molecular weight acidic substance and an antioxidant. More specifically, the pharmaceutical composition is a composition such as a matrix-type sustained-release preparation, which is a mixture of an anti-dementia drug, a high-molecular-weight basic substance, and a high-molecular-weight acidic substance for stabilizing the anti-dementia drug, or a A composition such as a coated sustained-release preparation comprising a core containing an anti-dementia drug and a coating layer containing a high-molecular-weight basic substance coated on the above-mentioned core, wherein a high-molecular-weight acidic substance is mixed in at least one of the above-mentioned cores And in the coating layer mentioned above.

特别地，根据本发明的药物组合物是一种药物组合物，包含：(1)碱性药物或其盐，其在0.1N盐酸溶液和50mM磷酸盐缓冲液，pH6的溶解度为1mg/mL或更大，在50mM磷酸盐缓冲液，pH 8中的溶解度为0.2mg/mL或更小，并且该碱性药物或其盐在50mM磷酸盐缓冲液，pH 6.8中的溶解度是在50mM磷酸盐缓冲液，pH 8中的至少2倍，并且不超过在50mM磷酸盐缓冲液，pH 6中的溶解度的一半；(2)至少一种肠溶性聚合物(高分子量酸性物质)和(3)至少一种水不溶性聚合物(高分子量碱性物质)。In particular, the pharmaceutical composition according to the present invention is a pharmaceutical composition comprising: (1) a basic drug or a salt thereof, which has a solubility of 1 mg/mL or Greater, 0.2 mg/mL or less solubility in 50 mM phosphate buffer, pH 8, and the solubility of the basic drug or its salt in 50 mM phosphate buffer, pH 6.8 is 0.2 mg/mL or less in 50 mM phosphate buffer solution, pH 8 at least twice, and not more than half of the solubility in 50mM phosphate buffer, pH 6; (2) at least one enteric polymer (high molecular weight acidic substance) and (3) at least one A water-insoluble polymer (high molecular weight alkaline substance).

在本发明的第三个方面，提供一种有效实现本发明的抗痴呆药物稳定作用的方法，换句话说，即一种生产包含抗痴呆药物和高分子量碱性物质的药物组合物的方法，包括混合步骤和制粒步骤，其中，在混合步骤和制粒步骤的至少一个步骤期间将稳定抗痴呆药物的高分子量酸性物质加入到抗痴呆药物和高分子量碱性物质的混合物中。根据本发明的生产方法的一个优选的方面，除了高分子量酸性物质外，加入至少一种低分子量酸性物质和抗氧化剂以稳定抗痴呆药物。在一个更优选的方面，在混合步骤和制粒步骤的至少一个步骤期间将至少一种高分子量酸性物质、低分子量酸性物质和抗氧化剂以溶液或混悬液的形式加入。在本发明的生产方法的一个特别优选的方面，在混合步骤中加入粉末状的高分子量酸性物质后，可以在制粒步骤中向混合物中加入溶液或混悬液形式的至少一种低分子量酸性物质和抗氧化剂。In the third aspect of the present invention, there is provided a method for effectively realizing the stabilizing effect of the anti-dementia drug of the present invention, in other words, a method for producing a pharmaceutical composition comprising an anti-dementia drug and a high-molecular-weight basic substance, A mixing step and a granulation step are included, wherein during at least one of the mixing step and the granulation step, a high-molecular-weight acidic substance stabilizing the anti-dementia drug is added to the mixture of the anti-dementia drug and the high-molecular-weight basic substance. According to a preferred aspect of the production method of the present invention, in addition to the high-molecular-weight acidic substance, at least one low-molecular-weight acidic substance and an antioxidant are added to stabilize the anti-dementia drug. In a more preferred aspect, at least one of the high molecular weight acidic substance, the low molecular weight acidic substance and the antioxidant is added in the form of a solution or a suspension during at least one of the mixing step and the granulating step. In a particularly preferred aspect of the production method of the present invention, after adding the powdered high-molecular-weight acidic substance in the mixing step, at least one low-molecular-weight acidic substance in the form of a solution or suspension may be added to the mixture in the granulation step. substances and antioxidants.

此外，在本发明的第三个方面，提供一种生产药物组合物的方法，其包括下列步骤：混合(1)碱性药物或其盐，其在0.1N盐酸溶液和50mM磷酸盐缓冲液，pH 6的溶解度为1mg/mL或更大，在50mM磷酸盐缓冲液，pH 8中的溶解度为0.2mg/mL或更小，并且该碱性药物或其盐在50mM磷酸盐缓冲液，pH 6.8中的溶解度是在50mM磷酸盐缓冲液，pH 8中的至少2倍，并且不超过在50mM磷酸盐缓冲液，pH 6中的溶解度的一半，和(2)至少一种肠溶性聚合物(高分子量酸性物质)和(3)至少一种水不溶性聚合物(高分子量基质物)；和模压在混合步骤中得到的混合物。In addition, in a third aspect of the present invention, there is provided a method for producing a pharmaceutical composition, comprising the steps of: mixing (1) a basic drug or a salt thereof in 0.1N hydrochloric acid solution and 50 mM phosphate buffer, A solubility of 1 mg/mL or greater at pH 6 and 0.2 mg/mL or less in 50 mM phosphate buffer, pH 8, and the basic drug or its salt is soluble in 50 mM phosphate buffer, pH 6.8 The solubility in 50mM phosphate buffer, pH 8 is at least 2 times, and not more than half of the solubility in 50mM phosphate buffer, pH 6, and (2) at least one enteric polymer (high molecular weight acidic substance) and (3) at least one water-insoluble polymer (high molecular weight matrix substance); and molding the mixture obtained in the mixing step.

此外，在本发明的第四个模式中，提供高分子量酸性物质在控制由抗痴呆药物和高分子量碱性物质接触而产生的抗痴呆药物降解产物中的应用。这是一种所发现的高分子量酸性物质的新用途。在这种情况中，通过伴随使用低分子量酸性物质和抗氧化剂可以有效地抑制降解产物。Furthermore, in the fourth mode of the present invention, there is provided the use of a high molecular weight acidic substance for controlling degradation products of an antidementia drug produced by contacting an antidementia drug with a high molecular weight basic substance. This is a new use of the discovered high molecular weight acidic substance. In this case, degradation products can be effectively suppressed by the concomitant use of low-molecular-weight acidic substances and antioxidants.

根据本发明一个优选的方面，抗痴呆药物是具有叔氨基的化合物。根据本发明一个更优选的方面，抗痴呆药物选自利伐斯的明、加兰他敏、多萘哌齐、3-[1-(苯甲基)哌啶-4-基]-1-(2，3，4，5-四氢-1H-1-苯氮杂

-8-基)-1-丙烷和5，7-二氢-3-[2-[1-(苯甲基)-4-哌啶基]乙基]-6H-吡咯并[4，5-f]-1，2-苯异噁唑-6-酮及其药学可接受的盐。在一个特别优选的方面，该抗痴呆药物是多萘哌齐或其药学可接受的盐。According to a preferred aspect of the present invention, the anti-dementia drug is a compound with a tertiary amino group. According to a more preferred aspect of the present invention, the anti-dementia drug is selected from rivastigmine, galantamine, donepezil, 3-[1-(benzyl)piperidin-4-yl]-1- (2,3,4,5-tetrahydro-1H-1-benzazepine

-8-yl)-1-propane and 5,7-dihydro-3-[2-[1-(benzyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5- f]-1,2-benzisoxazol-6-one and pharmaceutically acceptable salts thereof. In a particularly preferred aspect, the anti-dementia drug is donepezil or a pharmaceutically acceptable salt thereof.

此外，根据本发明一个优选的方面，高分子量碱性物质是至少一种选自乙基纤维素、丙烯酸乙酯-丙烯酸甲酯共聚物和聚氧化乙烯。在一个更优选的方面，高分子量碱性物质是乙基纤维素或丙烯酸乙酯-丙烯酸甲酯共聚物，在一个特别优选的方面该高分子量碱性物质是乙基纤维素。高分子量碱性物质可以是任何的水不溶性聚合物。Furthermore, according to a preferred aspect of the present invention, the high molecular weight basic substance is at least one selected from ethyl cellulose, ethyl acrylate-methyl acrylate copolymer and polyethylene oxide. In a more preferred aspect, the high molecular weight basic material is ethyl cellulose or ethyl acrylate-methyl acrylate copolymer, and in a particularly preferred aspect the high molecular weight basic material is ethyl cellulose. The high molecular weight basic material can be any water insoluble polymer.

此外，根据本发明一个优选的方面，高分子量酸性物质是肠溶性聚合物。在一个更优选的方面，高分子量酸性物质是至少一种选自甲基丙烯酸-丙烯酸乙酯共聚物、甲基丙烯酸-丙烯酸甲酯共聚物、羟丙基甲基纤维素邻苯二甲酸酯和羟丙基甲基纤维素琥珀酸酯的物质。在一个特别优选的方面，高分子量酸性物质是甲基丙烯酸-丙烯酸乙酯共聚物。在高分子量酸性物质的量的一个优选的方面，基于100重量份的根据本发明的药物组合物，其量一般为0.1到90重量份，优选1到70重量份，更优选5到60重量份，更优选10到50重量份。Furthermore, according to a preferred aspect of the present invention, the high molecular weight acidic substance is an enteric polymer. In a more preferred aspect, the high molecular weight acidic substance is at least one selected from methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl acrylate copolymer, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose succinate substances. In a particularly preferred aspect, the high molecular weight acidic material is methacrylic acid-ethyl acrylate copolymer. In a preferred aspect of the amount of the high molecular weight acidic substance, based on 100 parts by weight of the pharmaceutical composition of the present invention, the amount is generally 0.1 to 90 parts by weight, preferably 1 to 70 parts by weight, more preferably 5 to 60 parts by weight , more preferably 10 to 50 parts by weight.

此外，根据本发明一个优选的方面，低分子量酸性物质是至少一种选自羧酸、磺酸、羟酸、酸性氨基酸和无机酸的物质。在一个优选的方面，低分子量酸性物质是至少一种选自羟酸、酸性氨基酸和无机酸的物质。在一个特别优选的方面，低分子量酸性物质是至少一种选自羟酸和酸性氨基酸的物质。Furthermore, according to a preferred aspect of the present invention, the low-molecular-weight acidic substance is at least one substance selected from the group consisting of carboxylic acids, sulfonic acids, hydroxy acids, acidic amino acids, and inorganic acids. In a preferred aspect, the low molecular weight acidic substance is at least one substance selected from the group consisting of hydroxy acids, acidic amino acids and mineral acids. In a particularly preferred aspect, the low molecular weight acidic species is at least one species selected from the group consisting of hydroxyacids and acidic amino acids.

更特别地，低分子量酸性物质是至少一种选自琥珀酸、酒石酸、柠檬酸、富马酸、马来酸、苹果酸、门冬氨酸、谷氨酸、盐酸谷氨酸、盐酸和磷酸的物质。在一个更优选的方面，低分子量酸性物质是至少一种选自柠檬酸、门冬氨酸和盐酸的物质。基于100重量份的根据本发明的药物组合物，低分子量酸性物质的量一般是0.05到4重量份，优选0.1到3重量份，更优选0.15到2重量份，更优选0.15到1.5重量份。More particularly, the 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 acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid and phosphoric acid. substance. In a more preferred aspect, the low molecular weight acidic species is at least one species selected from citric acid, aspartic acid and hydrochloric acid. The amount of the low molecular weight acidic substance is generally 0.05 to 4 parts by weight, preferably 0.1 to 3 parts by weight, more preferably 0.15 to 2 parts by weight, more preferably 0.15 to 1.5 parts by weight based on 100 parts by weight of the pharmaceutical composition according to the present invention.

根据本发明一个优选的方面，抗氧化剂是抗坏血酸和含硫的氨基酸中的至少一种。在一个优选的方面，抗氧化剂是至少一种选自甲硫氨酸、抗坏血酸和盐酸半胱氨酸的物质。基于1重量份的药物，抗氧化剂的量一般是0.01到10重量份，优选0.02到5重量份，更优选0.05到2重量份。尽管不用特别限定抗氧化剂的量，但例如基于100重量份的根据本发明的药物组合物，抗氧化剂的量是0.001到5重量份，优选0.01到3重量份，更优选0.1到2重量份，更优选0.15到1.5重量份。According to a preferred aspect of the present invention, the antioxidant is at least one of ascorbic acid and sulfur-containing amino acids. In a preferred aspect, the antioxidant is at least one substance selected from the group consisting of methionine, ascorbic acid, and cysteine hydrochloride. The amount of the antioxidant is generally 0.01 to 10 parts by weight, preferably 0.02 to 5 parts by weight, more preferably 0.05 to 2 parts by weight, based on 1 part by weight of the drug. Although the amount of the antioxidant is not particularly limited, for example, based on 100 parts by weight of the pharmaceutical composition according to the present invention, the amount of the antioxidant is 0.001 to 5 parts by weight, preferably 0.01 to 3 parts by weight, more preferably 0.1 to 2 parts by weight, More preferably 0.15 to 1.5 parts by weight.

根据本发明的第一到第三个方面的药物组合物优选是持续释放制剂，更优选是基质型持续释放制剂。此外。该药物组合物的剂型的例子优选包括片剂、胶囊、颗粒或细颗粒。因此，根据本发明一个特别优选的方面的药物组合物是包含多萘哌齐或其药学可接受的盐、高分子量碱性物质和高分子量酸性物质的基质型持续释放制剂，或者包含多萘哌齐或其药学可接受的盐、高分子量碱性物质、高分子量酸性物质和至少一种低分子量酸性物质和抗氧化剂的基质型持续释放制剂。The pharmaceutical compositions according to the first to third aspects of the present invention are preferably sustained-release preparations, more preferably matrix-type sustained-release preparations. also. Examples of dosage forms of the pharmaceutical composition preferably include tablets, capsules, granules or fine granules. Therefore, the pharmaceutical composition according to a particularly preferred aspect of the present invention is a matrix-type sustained release preparation comprising donepezil or a pharmaceutically acceptable salt thereof, a high-molecular-weight basic substance and a high-molecular-weight acidic substance, or comprising donepezil A matrix-type sustained-release formulation of a homogeneous substance or a pharmaceutically acceptable salt thereof, a high-molecular-weight basic substance, a high-molecular-weight acidic substance, at least one low-molecular-weight acidic substance, and an antioxidant.

本发明的有益效果Beneficial effects of the present invention

根据本发明，在包含抗痴呆药物和持续释放基质的药物组合物中，提供一种方法来阻止或抑制由于抗痴呆药物和持续释放基质接触而产生的降解产物，即本发明提供一种在药物组合物中稳定抗痴呆药物的方法。此外，由于根据本发明的药物组合物的高质量和高度适合顺应性，本发明提供了一种药品，特别是抗痴呆药物，其可以放心服用，并且患者和治疗人员的负担较小。本发明也提供一种简单的生产药物组合物的方法，其中在该药物组合物中持续释放性质受到控制，并且稳定了抗痴呆药物，而无需使用特别的包衣技术或生产技术或生产设备。According to the present invention, in the pharmaceutical composition comprising anti-dementia drug and sustained-release matrix, a method is provided to prevent or inhibit the degradation products produced due to the contact of anti-dementia drug and sustained-release matrix, that is, the present invention provides a Methods of stabilizing antidementia drugs in compositions. Furthermore, due to the high quality and high suitability of the pharmaceutical composition according to the present invention, the present invention provides a medicine, especially an anti-dementia medicine, which can be taken with confidence and with less burden on patients and treating personnel. The present invention also provides a simple method for producing a pharmaceutical composition in which sustained-release properties are controlled and anti-dementia drugs are stabilized without using special coating techniques or production techniques or production equipment.

附图简述Brief description of the drawings

附图1显示的是在制粒后在开放(未封闭)容器中60℃，75％RH下放置两周后的包含各种添加剂的降解产物的量与各种添加剂的2.5％水溶液或混悬液的pH的关系。Accompanying drawing 1 shows the amount of degradation products containing various additives and the 2.5% aqueous solution or suspension of various additives after granulation in an open (unclosed) container at 60° C., 75% RH for two weeks. The pH relationship of the liquid.

实施本发明的最佳方式Best Mode for Carrying Out the Invention

下面将解释本发明的实施方案。下面的实施方案是用于解释本发明的例子，而不是打算将本发明只限于这些实施方案。本发明可以以各种方式应用，而不脱离本发明的精神和范围。Embodiments of the present invention will be explained below. The following embodiments are examples for explaining the present invention, and the present invention is not intended to be limited to these embodiments. The present invention can be applied in various ways without departing from the spirit and scope of the present invention.

(抗痴呆药物)(anti-dementia drug)

对于在本发明中使用的抗痴呆药物并没有特别的限制，只要该抗痴呆药物是具有伯、仲或或叔氨基的碱性药物即可，但优选该抗痴呆药物具有叔氨基。具有伯氨基的抗痴呆药物的例子包括他克林、美金刚及其药学可接受的盐。具有叔氨基的抗痴呆药物的例子包括利伐斯的明、加兰他敏、多萘哌齐、3-[1-(苯甲基)哌啶-4-基]-1-(2，3，4，5-四氢-1H-1-苯氮杂

-8-基)-1-丙烷和5，7-二氢-3-[2-[1-(苯甲基)-4-哌啶基]乙基]-6H-吡咯并[4，5-f]-1，2-苯异噁唑-6-酮及其药学可接受的盐。具有伯氨基的抗痴呆药物的优选例子是盐酸他克林和美金刚。具有叔氨基的抗痴呆药物的优选例子是酒石酸利伐斯的明、氢溴酸加兰他敏、盐酸多萘哌齐(化学名单盐酸(±)-2-[(1-苄基哌啶-4-基)甲基]-5，6-二甲氧基茚满-1-酮)、富马酸3-[1-(苯甲基)哌啶-4-基]-1-(2，3，4，5-四氢-1-苯氮杂

-8-基)-1-丙烷(TAK-147)和马来酸5，7-二氢-3-[2-[1-(苯甲基)-4-哌啶基]乙基]-6H-吡咯并[4，5-f]-1，2-苯异噁唑-6-酮(CP118954)。更优选地，该抗痴呆药物是盐酸多萘哌齐、TAK-147或CP118954，最优选该抗痴呆药物是盐酸多萘哌齐。需要注意的是，抗痴呆药物可以以游离形式或作为有机或无机盐使用，优选有机或无机盐，特别优选无机盐。更特别地，盐的例子包括但不限于，盐酸盐、硫酸盐、乙酸盐、磷酸盐、碳酸盐、甲磺酸盐、酒石酸盐、柠檬酸盐、甲苯磺酸盐等等。There is no particular limitation on the anti-dementia drug used in the present invention as long as the anti-dementia drug is a basic drug having a primary, secondary or tertiary amino group, but preferably the anti-dementia drug has a tertiary amino group. Examples of anti-dementia drugs having primary amino groups include tacrine, memantine, and pharmaceutically acceptable salts thereof. Examples of antidementia drugs having a tertiary amino group include rivastigmine, galantamine, donepezil, 3-[1-(benzyl)piperidin-4-yl]-1-(2,3 , 4,5-tetrahydro-1H-1-benzazepine

-8-yl)-1-propane and 5,7-dihydro-3-[2-[1-(benzyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5- f]-1,2-benzisoxazol-6-one and pharmaceutically acceptable salts thereof. Preferable examples of antidementia drugs having primary amino groups are tacrine hydrochloride and memantine. Preferable examples of antidementia drugs having tertiary amino groups are rivastigmine tartrate, galantamine hydrobromide, donepezil hydrochloride (chemical list (±)-2-[(1-benzylpiperidine- 4-yl)methyl]-5,6-dimethoxyindan-1-one), 3-[1-(benzyl)piperidin-4-yl]-1-(2, 3,4,5-tetrahydro-1-benzazepine

-8-yl)-1-propane (TAK-147) and 5,7-dihydro-3-[2-[1-(benzyl)-4-piperidinyl]ethyl]-6H maleate - Pyrrolo[4,5-f]-1,2-benzisoxazol-6-one (CP118954). More preferably, the anti-dementia drug is donepezil hydrochloride, TAK-147 or CP118954, most preferably the anti-dementia drug is donepezil hydrochloride. It should be noted that the anti-dementia drugs can be used in free form or as organic or inorganic salts, preferably organic or inorganic salts, particularly preferably inorganic salts. More particularly, examples of salts include, but are not limited to, hydrochlorides, sulfates, acetates, phosphates, carbonates, methanesulfonates, tartrates, citrates, toluenesulfonates, and the like.

至于酸性水溶液、中性水溶液或碱性水溶液，对在本发明中使用的碱性药物或其盐的溶解度并没有特别的限制，但碱性药物在酸性溶液和中性溶液中的溶解度高于在碱性水溶液中的溶解度。这里，对于在制备这些水溶液中的应用，用于该应用的例子包括但不限于，磷酸盐缓冲液(例如，用50mM磷酸钠溶液和盐酸制备的缓冲液)、缓冲液例如G.L.Miller′s缓冲液、Atkins-Pantin′s缓冲液、Good′s缓冲液等等，0.1N盐酸、0.1mol/L氢氧化钠溶液等等。需要注意的是，在本发明中使用的溶解度是指在溶液温度为25℃时的溶解度。As for acidic aqueous solution, neutral aqueous solution or alkaline aqueous solution, the solubility of basic drug or its salt used in the present invention is not particularly limited, but the solubility of basic drug in acidic solution and neutral solution is higher than that in Solubility in alkaline aqueous solution. Here, for use in preparing these aqueous solutions, examples for the use include, but are not limited to, phosphate buffer (for example, a buffer prepared with 50 mM sodium phosphate solution and hydrochloric acid), buffers such as G.L. Miller's buffer solution, Atkins-Pantin's buffer, Good's buffer, etc., 0.1N hydrochloric acid, 0.1mol/L sodium hydroxide solution, etc. It should be noted that the solubility used in the present invention refers to the solubility when the solution temperature is 25°C.

在本发明中使用的术语“在酸性水溶液中的溶解度”是指当将碱性药物或其盐溶解于缓冲液等中时，碱性药物或其盐在显示酸性的溶液中的溶解度。类似地，在本发明中使用的术语“在中(碱)性水溶液中的溶解度”是指当将碱性药物或其盐溶解于缓冲液等中时，碱性药物或其盐在显示中(碱)性的溶液中的溶解度。The term "solubility in an acidic aqueous solution" used in the present invention means the solubility of a basic drug or its salt in a solution showing acidity when the basic drug or its salt is dissolved in a buffer or the like. Similarly, the term "solubility in a neutral (alkaline) aqueous solution" used in the present invention means that when a basic drug or a salt thereof is dissolved in a buffer or the like, the basic drug or a salt thereof is shown in ( Solubility in alkaline solution.

例如，在本发明中使用的碱性药物或其盐在酸性水溶液，3.0和中性水溶液，pH 6.0中的溶解度高于在碱性水溶液，pH 8.0中。在本文中使用的术语“在酸性水溶液，3.0中的溶解度”是指当将碱性药物或其盐溶解于缓冲液等中时，碱性药物或其盐在pH 3.0的酸性溶液中的溶解度。在本文中使用的术语“在酸性水溶液，6.0中的溶解度”是指当将碱性药物或其盐溶解于缓冲液等中时，碱性药物或其盐在pH 6.0的溶液中的溶解度。在本文中使用的术语“在碱性水溶液，8.0中的溶解度”是指当将碱性药物或其盐溶解于缓冲液等中时，碱性药物或其盐在pH 8.0的碱性溶液中的溶解度。For example, the basic drug or its salt used in the present invention has higher solubility in acidic aqueous solution, pH 3.0 and neutral aqueous solution, pH 6.0 than in alkaline aqueous solution, pH 8.0. The term "solubility in acidic aqueous solution, 3.0" used herein means the solubility of a basic drug or a salt thereof in an acidic solution at pH 3.0 when the basic drug or a salt thereof is dissolved in a buffer or the like. The term "solubility in acidic aqueous solution, 6.0" used herein means the solubility of a basic drug or a salt thereof in a solution at pH 6.0 when the basic drug or a salt thereof is dissolved in a buffer or the like. The term "solubility in alkaline aqueous solution, 8.0" as used herein refers to the solubility of a basic drug or a salt thereof in an alkaline solution at pH 8.0 when the basic drug or a salt thereof is dissolved in a buffer or the like. Solubility.

例如，在本发明中使用的碱性药物或其盐在0.1N盐酸溶液和中性水溶液，pH 6.0中的溶解度大于在碱性溶液，pH 8.0中的溶解度。在本文中使用的术语“在0.1N盐酸溶液中的溶解度”是指当将碱性药物或其盐溶解于0.1N盐酸溶液中时碱性药物或其盐的溶解度。例如，溶解在0.1N盐酸溶液中的盐酸多萘哌齐溶液显示的pH范围是约1到约2。For example, the solubility of the basic drug or its salt used in the present invention in 0.1N hydrochloric acid solution and neutral aqueous solution, pH 6.0 is greater than that in alkaline solution, pH 8.0. The term "solubility in 0.1N hydrochloric acid solution" as used herein refers to the solubility of a basic drug or a salt thereof when the basic drug or a salt thereof is dissolved in a 0.1N hydrochloric acid solution. For example, a solution of donepezil hydrochloride dissolved in 0.1 N hydrochloric acid solution exhibits a pH in the range of about 1 to about 2.

优选地，在本发明中使用的碱性药物或其盐在0.1N盐酸溶液和中性水溶液，pH 6.0中的溶解度大于在碱性溶液，pH 8.0中的溶解度，并且在中性水溶液，pH 6.8中的溶解度是在碱性溶液，pH 8.0中的溶解度的至少2倍，但不超过在中性水溶液，pH 6.0中的溶解度的一半。在本文中使用的“在中性水溶液，pH 6.8中的溶解度”是指将碱性药物或其盐溶解于缓冲液等中时，碱性药物或其盐在pH 6.8的溶液中的溶解度。Preferably, the solubility of the basic drug or its salt used in the present invention in 0.1N hydrochloric acid solution and neutral aqueous solution, pH 6.0 is greater than that in alkaline solution, pH 8.0, and in neutral aqueous solution, pH 6.8 The solubility in is at least twice the solubility in alkaline solution, pH 8.0, but not more than half of the solubility in neutral aqueous solution, pH 6.0. The "solubility in neutral aqueous solution, pH 6.8" used herein means the solubility of a basic drug or a salt thereof in a solution of pH 6.8 when the basic drug or a salt thereof is dissolved in a buffer or the like.

更特别地，没有特别的限制，只要碱性药物或其盐在0.1N盐酸溶液和中性水溶液，pH 6.0中的溶解度是1mg/mL或更大，碱性药物或其盐在碱性水溶液，pH 8.0中的溶解度是0.2mg/mL或更小，并且碱性药物或其盐在中性水溶液，pH 6.8中的溶解度是在碱性水溶液，pH 8.0中溶解度的2倍或更大并不超过在中性水溶液，pH 6.0中溶解度的一半即可。也就是说，在0.1N盐酸溶液和中性水溶液，pH 6.0中的碱性药物或其盐不是特别限制的，只要其上述溶解度是1mg/mL或更大即可。上述溶解度一般是1到1000mg/mL，优选5到200mg/mL，更优选5到100mg/mL，更优选10到80mg/mL。碱性药物或其盐在碱性水溶液，pH 8.0中的溶解度不是特别限制的，只要上述溶解度是0.2mg/mL或更小即可。上述溶解度一般是0.0001到0.2mg/mL，优选0.0005到0.1mg/mL，更优选0.001到0.05mg/mL，更优选0.002到0.03mg/mL。此外，碱性药物或其盐在中性水溶液，pH 6冲的溶解度不是特别限制的，只要上述溶解度是在碱性水溶液，pH 8.0中的溶解度的至少2倍并且不超过在中性水溶液，pH 6.0中溶解度的一半即可。上述溶解度优选是在碱性水溶液，pH 8.0中的溶解度的至少3倍并且不超过在中性水溶液，pH 6.0中溶解度的1/3，更优选地在碱性水溶液，pH 8.0中的溶解度的至少5倍并且不超过在中性水溶液，pH 6.0中溶解度的1/5，更优选在碱性水溶液，pH 8.0中的溶解度的至少10倍并且不超过在中性水溶液，pH 6.0中溶解度的1/10。More particularly, there is no particular limitation, as long as the solubility of the basic drug or its salt in 0.1N hydrochloric acid solution and neutral aqueous solution, pH 6.0 is 1 mg/mL or greater, the basic drug or its salt in alkaline aqueous solution, The solubility at pH 8.0 is 0.2 mg/mL or less, and the solubility of a basic drug or its salt in a neutral aqueous solution, pH 6.8, is twice or greater than that in an alkaline aqueous solution, pH 8.0 not exceeding In neutral aqueous solution, half of the solubility in pH 6.0 is sufficient. That is, the basic drug or its salt in 0.1N hydrochloric acid solution and neutral aqueous solution, pH 6.0 is not particularly limited as long as its above-mentioned solubility is 1 mg/mL or more. The above solubility is generally 1 to 1000 mg/mL, preferably 5 to 200 mg/mL, more preferably 5 to 100 mg/mL, more preferably 10 to 80 mg/mL. The solubility of a basic drug or a salt thereof in an alkaline aqueous solution, pH 8.0, is not particularly limited as long as the above solubility is 0.2 mg/mL or less. The above solubility is generally 0.0001 to 0.2 mg/mL, preferably 0.0005 to 0.1 mg/mL, more preferably 0.001 to 0.05 mg/mL, more preferably 0.002 to 0.03 mg/mL. In addition, the solubility of basic drugs or their salts in neutral aqueous solution, pH 6 is not particularly limited, as long as the above-mentioned solubility is at least twice the solubility in alkaline aqueous solution, pH 8.0 and does not exceed the solubility in neutral aqueous solution, pH Half of the solubility in 6.0 is enough. The above solubility is preferably at least 3 times the solubility in alkaline aqueous solution, pH 8.0 and no more than 1/3 of the solubility in neutral aqueous solution, pH 6.0, more preferably at least 1/3 of the solubility in alkaline aqueous solution, pH 8.0 5 times and not more than 1/5 of the solubility in neutral aqueous solution, pH 6.0, more preferably at least 10 times the solubility in alkaline aqueous solution, pH 8.0 and not more than 1/5 of the solubility in neutral aqueous solution, pH 6.0 10.

仍然是举例，在本发明中使用的碱性药物或其盐在0.1N盐酸溶液和50mM磷酸盐缓冲液，pH 6.0的溶解度大于其在50mM磷酸盐缓冲液，pH 8.0中的溶解度。在本文中使用的术语“在50mM磷酸盐缓冲液，pH 6.0的溶解度”是指当将碱性药物或其盐溶解于50mM磷酸盐缓冲液中时，该碱性药物在pH6.0的50mM磷酸盐缓冲液中的溶解度。类似地，在本文中使用的术语“在50mM磷酸盐缓冲液，pH 8.0的溶解度”是指当将碱性药物或其盐溶解于50mM磷酸盐缓冲液中时，该碱性药物在pH 8.0的50mM磷酸盐缓冲液中的溶解度。Still by way of example, the solubility of the basic drug or its salt used in the present invention in 0.1N hydrochloric acid solution and 50mM phosphate buffer, pH 6.0 is greater than its solubility in 50mM phosphate buffer, pH 8.0. The term "solubility in 50mM phosphate buffer, pH 6.0" as used herein refers to the solubility of the basic drug in 50mM phosphoric acid at pH 6.0 when the basic drug or its salt is dissolved in 50mM phosphate buffer. Solubility in salt buffer. Similarly, the term "solubility at 50 mM phosphate buffer at pH 8.0" as used herein refers to the solubility of the basic drug at pH 8.0 when the basic drug or its salt is dissolved in 50 mM phosphate buffer. Solubility in 50mM Phosphate Buffer.

优选地，碱性药物或其盐在0.1N盐酸溶液和50mM磷酸盐缓冲液，pH 6.0中的溶解度大于其在50mM磷酸盐缓冲液，pH 8.0中的溶解度，并且在50mM磷酸盐缓冲液，pH 6.8中的溶解度是其在50mM磷酸盐缓冲液，pH 8.0中的溶解度的2倍或更多倍，并且不超过其在50mM磷酸盐缓冲液，pH 6.0中的溶解度的一半。更特别地，没有特别的限制，只要碱性药物或其盐在0.1N盐酸溶液和50mM磷酸盐缓冲液，pH 6.0中的溶解度是1mg/mL或更大，碱性药物或其盐在50mM磷酸盐缓冲液，pH 8.0中的溶解度是0.2mg/mL或更小，并且碱性药物或其盐在50mM磷酸盐缓冲液，pH 6.8中的溶解度是其在50mM磷酸盐缓冲液，pH 8.0中的溶解度的2倍或更多倍，并且不超过其在50mM磷酸盐缓冲液，pH 6.0中的溶解度的一半即可。也就是说，对碱性药物或其盐在0.1N盐酸溶液和50mM磷酸盐缓冲液，pH 6.0中的溶解度没有特别的限制，只要上述溶解度是1mg/mL或更大即可。上述溶解度一般是1到1000mg/mL，优选5到200mg/mL，更优选5到100mg/mL，更优选10到80mg/mL。对碱性药物或其盐在50mM磷酸盐缓冲液，pH 8.0中的溶解度没有特别的限制，只要上述溶解度是0.2mg/mL或更小即可。上述溶解度一般是0.0001到0.2mg/mL，优选0.0005到0.1mg/mL，更优选0.001到0.05mg/mL，更优选0.002到0.03mg/mL。此外，对碱性药物或其盐在50mM磷酸盐缓冲液，pH 6.8中的溶解度没有特别的限制，只要上述溶解度是在50mM磷酸盐缓冲液，pH 8.0中的溶解度的制烧杯并且不超过在50mM磷酸盐缓冲液，pH6.0中溶解度的一半即可，优选是在碱性水溶液，pH 8.0中的溶解度的至少3倍并且不超过在中性水溶液，pH 6.0中溶解度的1/3，更优选地在碱性水溶液，pH 8.0中的溶解度的至少5倍并且不超过在中性水溶液，pH 6.0中溶解度的1/5，更优选在碱性水溶液，pH 8.0中的溶解度的至少10倍并且不超过在中性水溶液，pH 6.0中溶解度的1/10。Preferably, the solubility of the basic drug or its salt in 0.1N hydrochloric acid solution and 50mM phosphate buffer, pH 6.0 is greater than its solubility in 50mM phosphate buffer, pH 8.0, and in 50mM phosphate buffer, pH The solubility in 6.8 is 2 times or more than its solubility in 50 mM phosphate buffer, pH 8.0, and not more than half of its solubility in 50 mM phosphate buffer, pH 6.0. More specifically, there is no particular limitation as long as the solubility of the basic drug or its salt in 0.1N hydrochloric acid solution and 50 mM phosphate buffer, pH 6.0 is 1 mg/mL or greater, and the basic drug or its salt in 50 mM phosphoric acid The solubility in saline buffer, pH 8.0 is 0.2 mg/mL or less, and the solubility of the basic drug or its salt in 50 mM phosphate buffer, pH 6.8 is 0.2 mg/mL or less in 50 mM phosphate buffer, pH 8.0 2 or more times the solubility and no more than half of its solubility in 50mM phosphate buffer, pH 6.0. That is, there is no particular limitation on the solubility of basic drugs or salts thereof in 0.1N hydrochloric acid solution and 50 mM phosphate buffer, pH 6.0, as long as the above solubility is 1 mg/mL or greater. The above solubility is generally 1 to 1000 mg/mL, preferably 5 to 200 mg/mL, more preferably 5 to 100 mg/mL, more preferably 10 to 80 mg/mL. There is no particular limitation on the solubility of the basic drug or its salt in 50 mM phosphate buffer, pH 8.0, as long as the above solubility is 0.2 mg/mL or less. The above solubility is generally 0.0001 to 0.2 mg/mL, preferably 0.0005 to 0.1 mg/mL, more preferably 0.001 to 0.05 mg/mL, more preferably 0.002 to 0.03 mg/mL. In addition, there is no particular limitation on the solubility of basic drugs or their salts in 50 mM phosphate buffer, pH 6.8, as long as the above-mentioned solubility is in the beaker of the solubility in 50 mM phosphate buffer, pH 8.0 and does not exceed 50 mM Phosphate buffer, half of the solubility in pH 6.0, preferably at least 3 times the solubility in alkaline aqueous solution, pH 8.0 and not more than 1/3 of the solubility in neutral aqueous solution, pH 6.0, more preferably At least 5 times the solubility in alkaline aqueous solution, pH 8.0 and not more than 1/5 of the solubility in neutral aqueous solution, pH 6.0, more preferably at least 10 times the solubility in alkaline aqueous solution, pH 8.0 and not More than 1/10 of the solubility in neutral aqueous solution, pH 6.0.

例如，盐酸多萘哌齐的特征在于其在酸性水溶液，pH 3.0和中性水溶液，pH 6.0中的溶解度是11到16mg/mL，并且在碱性水溶液，pH 8.0中则为0.1mg/mL或更小。此外，盐酸多萘哌齐是具有叔氨基的弱碱性药物或其盐，其广泛应用于阿尔茨海默病型痴呆，特征在于其在中性水溶液，pH 6.8中的溶解度是在碱性水溶液，pH8.0中的溶解度的至少2倍，并且不超过在中性水溶液，pH 6.0中溶解度的一半。For example, donepezil hydrochloride is characterized by a solubility of 11 to 16 mg/mL in acidic aqueous solution, pH 3.0 and neutral aqueous solution, pH 6.0, and 0.1 mg/mL or 0.1 mg/mL in alkaline aqueous solution, pH 8.0. smaller. In addition, donepezil hydrochloride is a weakly basic drug with a tertiary amino group or a salt thereof, which is widely used in Alzheimer's type dementia, and is characterized in that its solubility in neutral aqueous solution, pH 6.8, is higher than that in alkaline aqueous solution , at least twice the solubility in pH 8.0, and not more than half the solubility in neutral aqueous solution, pH 6.0.

可替代地，盐酸多萘哌齐是具有叔氨基的弱碱性药物或其盐，其广泛应用于阿尔茨海默病型痴呆。盐酸多萘哌齐的特征在于其在0.1N盐酸溶液和50mM磷酸盐缓冲液，pH 6.0中的溶解度是11到16mg/mL，并且在碱性水溶液，pH 8.0中则为0.1mg/mL或更小，其在中性水溶液，pH 6.8中的溶解度是在碱性水溶液，pH 8.0中的溶解度的至少2倍，并且不超过在中性水溶液，pH 6.0中溶解度的一半。Alternatively, donepezil hydrochloride is a weakly basic drug having a tertiary amino group or a salt thereof, which is widely used in Alzheimer's type dementia. Donepezil hydrochloride is characterized by a solubility of 11 to 16 mg/mL in 0.1N hydrochloric acid solution and 50 mM phosphate buffer, pH 6.0, and 0.1 mg/mL or more in alkaline aqueous solution, pH 8.0 Small, its solubility in neutral aqueous solution, pH 6.8 is at least 2 times the solubility in alkaline aqueous solution, pH 8.0, and not more than half of the solubility in neutral aqueous solution, pH 6.0.

对于在本发明中使用的抗痴呆药物或或其盐的剂量没有特别的限制，但是在乙酰胆碱酯酶抑制剂的情况中，该剂量是0.01到50mg/日。更特别地，多萘哌齐或其药学可接受的盐的剂量是0.01到50mg/日，优选0.1到40mg/日，更优选1到30mg/日，更优选5到25mg/日。利伐斯的明或其药学可接受的盐的剂量是0.01到50mg/日，优选0.1到30mg/日，优选from 1到20mg/日，更优选1到15mg/日。加兰他敏或其药学可接受的盐的剂量是0.01到50mg/日，优选0.1到40mg/日，更优选1到30mg/日，更优选2到25mg/日。There is no particular limitation on the dose of the antidementia drug or its salt used in the present invention, but in the case of an acetylcholinesterase inhibitor, the dose is 0.01 to 50 mg/day. More specifically, the dose of donepezil or a pharmaceutically acceptable salt thereof is 0.01 to 50 mg/day, preferably 0.1 to 40 mg/day, more preferably 1 to 30 mg/day, more preferably 5 to 25 mg/day. The dose of rivastigmine or a pharmaceutically acceptable salt thereof is 0.01 to 50 mg/day, preferably 0.1 to 30 mg/day, preferably from 1 to 20 mg/day, more preferably 1 to 15 mg/day. The dose of galantamine or a pharmaceutically acceptable salt thereof is 0.01 to 50 mg/day, preferably 0.1 to 40 mg/day, more preferably 1 to 30 mg/day, more preferably 2 to 25 mg/day.

此外，在作为NMDA受体拮抗剂的美金刚或其药学可接受的盐的情况中，剂量是0.5到.100mg/日，优选1到100mg/日，更优选1到40mg/日，更优选5到25mg/日。Furthermore, in the case of memantine or a pharmaceutically acceptable salt thereof as an NMDA receptor antagonist, the dosage is 0.5 to .100 mg/day, preferably 1 to 100 mg/day, more preferably 1 to 40 mg/day, more preferably 5 to 25mg/day.

(高分子量碱性物质)(high molecular weight alkaline substance)

在本发明中使用的高分子量碱性物质是当溶解或悬浮于水中时显示碱性的高分子量物质。例如，在2.5％的水溶液或混悬液中，该高分子量碱性物质具有的pH大于7.0，优选pH为7.5到14.0，更优选8.0到14.0。此外，在本发明中使用的高分子量碱性物质可以配制成在根据本发明的药物组合物中的持续释放基质，但也可以配制用于其它目的。此外，该高分子量碱性物质也可以不溶于水，或者也可以是溶解在水中时水溶胀性的物质或形成凝胶的物质。水不溶性高分子量碱性物质的例子包括纤维素醚、纤维素酯和甲基丙烯酸-丙烯酸共聚物(商品名Eudragit，由GmbH & Co.KG，Darmstadt，Germany制造)。例子包括但不限于，纤维素烷基醚例如乙基纤维素(商品名Ethocel，由The Dow Chemical Company，U.S.制造等等)、乙基甲基纤维素、乙基丙基纤维素或异丙基纤维素、丁基纤维素等等；纤维素芳烷基醚例如苄基纤维素等等；纤维素氰基烷基醚例如氰基乙基纤维素等等；纤维素有机酸酯例如乙酸丁酸纤维素、乙酸纤维素、丙酸纤维素或丁酸纤维素、乙酸丙酸纤维素等等；丙烯酸乙酯-丙烯酸甲酯共聚物(商品名Eudragit NE，由GmbH & Co.KG，Darmstadt，Germany制造)等等。水溶性或水溶胀性高分子量碱性物质的例子包括但不限于，聚氧化乙烯(商品名Polyox，由The DowChemical Company，U.S.制造，分子量100,000-7,000,000)、地取代羟丙基纤维素(商品名L-HPC，由Shin-Etsu Chemical，Japan制造)等等。在根据本发明的药物组合物中可以包含一种或两种或更多种高分子量碱性物质。在本发明中使用的高分子量碱性物质优选是乙基纤维素，丙烯酸乙酯-甲基丙烯酸甲酯共聚物(商品名Eudragit NE)或聚氧化乙烯(商品名Polyox)。更优选地，该高分子量碱性物质是乙基纤维素和丙烯酸乙酯-甲基丙烯酸甲酯共聚物中的至少一种。在一个特别优选的方面，该高分子量碱性物质是乙基纤维素。对于在药物组合物中高分子量碱性物质的量并没有特别限制，并且可以根据目的例如药物的持续释放性质等等来适当地调节。对于在本发明中使用的高分子量碱性物质(水不溶性聚合物)的平均粒径没有特别的限制，但平均直径优选是0.1到100μm，更优选1到50μm，，更优选3到15μm，最优选5到15μm。The high-molecular-weight basic substance used in the present invention is a high-molecular-weight substance that exhibits basicity when dissolved or suspended in water. For example, in a 2.5% aqueous solution or suspension, the high molecular weight basic substance has a pH greater than 7.0, preferably a pH of 7.5 to 14.0, more preferably 8.0 to 14.0. Furthermore, the high molecular weight basic substances used in the present invention can be formulated as sustained release matrices in the pharmaceutical compositions according to the invention, but can also be formulated for other purposes. In addition, the high-molecular-weight basic substance may be insoluble in water, or may be a water-swellable substance or a gel-forming substance when dissolved in water. Examples of water-insoluble high-molecular-weight basic substances include cellulose ethers, cellulose esters, and methacrylic acid-acrylic acid copolymers (trade name Eudragit, manufactured by GmbH & Co. KG, Darmstadt, Germany). Examples include, but are not limited to, cellulose alkyl ethers such as ethyl cellulose (trade name Ethocel, manufactured by The Dow Chemical Company, US, etc.), ethyl methyl cellulose, ethyl propyl cellulose, or isopropyl Cellulose, butyl cellulose, etc.; cellulose aralkyl ethers such as benzyl cellulose, etc.; cellulose cyanoalkyl ethers such as cyanoethyl cellulose, etc.; cellulose organic acid esters such as acetate butyrate Cellulose, cellulose acetate, cellulose propionate or cellulose butyrate, cellulose acetate propionate, etc.; ethyl acrylate-methyl acrylate copolymer (trade name Eudragit NE, produced by GmbH & Co.KG, Darmstadt, Germany) etc. Examples of water-soluble or water-swellable high-molecular-weight basic substances include, but are not limited to, polyethylene oxide (trade name Polyox, manufactured by The Dow Chemical Company, US, molecular weight 100,000-7,000,000), ground-substituted hydroxypropyl cellulose (trade name L-HPC, manufactured by Shin-Etsu Chemical, Japan) and the like. One or two or more high molecular weight basic substances may be contained in the pharmaceutical composition according to the present invention. The high molecular weight basic substance used in the present invention is preferably ethyl cellulose, ethyl acrylate-methyl methacrylate copolymer (trade name Eudragit NE) or polyethylene oxide (trade name Polyox). More preferably, the high molecular weight alkaline substance is at least one of ethyl cellulose and ethyl acrylate-methyl methacrylate copolymer. In a particularly preferred aspect, the high molecular weight alkaline material is ethylcellulose. There is no particular limitation on the amount of the high-molecular-weight basic substance in the pharmaceutical composition, and can be appropriately adjusted depending on the purpose such as sustained release properties of the drug and the like. There is no particular limitation on the average particle diameter of the high-molecular-weight alkaline substance (water-insoluble polymer) used in the present invention, but the average diameter is preferably 0.1 to 100 μm, more preferably 1 to 50 μm, more preferably 3 to 15 μm, most preferably 5 to 15 μm is preferred.

对于在基质型持续释放制剂中高分子量碱性物质的量并没有特别限制，但以药物组合物为100％重量，其一般是1到90％重量，优选3到70％重量，更优选5到50％重量，更优选5到35％重量。There is no particular limitation on the amount of the high-molecular-weight basic substance in the matrix-type sustained-release preparation, but it is generally 1 to 90% by weight, preferably 3 to 70% by weight, more preferably 5 to 50% by weight, based on 100% by weight of the pharmaceutical composition. % by weight, more preferably 5 to 35% by weight.

(降解产物)(Degradation products)

在本产物中的降解产物是来自抗痴呆药物的降解产物，是由抗痴呆药物和高分子量碱性物质接触而得到的。假定降解产物来自于抗痴呆药物的氨基的反应。例如，由盐酸多萘哌齐和高分子量碱性物质得到的降解产物可以用液相色谱法通过常规方法来测定。The degradation products in this product are degradation products from anti-dementia drugs, which are obtained by contacting anti-dementia drugs and high-molecular-weight alkaline substances. It is assumed that the degradation products originate from the reaction of the amino groups of the anti-dementia drugs. For example, degradation products derived from donepezil hydrochloride and high molecular weight basic substances can be determined by conventional methods using liquid chromatography.

(高分子量酸性物质)(high molecular weight acidic substance)

在本发明中使用的高分子量酸性物质是当溶解或悬浮于水中时显示酸性的高分子量物质，例如，2.5％的高分子量酸性物质的水溶液显示的pH小于7.0，优选pH是1.0到6.5，更优选pH是1.0到6.0。在本发明中使用的高分子量酸性物质也可以不溶于水或者也可以是当溶解于水中时水溶胀性的物质或形成凝胶的物质。在本发明中使用的高分子量酸性物质，例如是肠溶性聚合物。肠溶性聚合物的例子包括但不限于，甲基丙烯酸-甲基丙烯酸甲酯共聚物(EudragitL100(甲基丙烯酸甲酯共聚物，A型)、Eudragit S100(甲基丙烯酸甲酯共聚物，B型)，由

GmbH & Co.KG，Darmstadt，Germany制造)、甲基丙烯酸-丙烯酸乙酯共聚物(Eudragit L100-55(甲基丙烯酸共聚物，C型)、Eudragit L30D-55(甲基丙烯酸共聚物，分散体)，由GmbH & Co.KG，Darmstadt，Germany制造)、羟丙基甲基纤维素邻苯二甲酸酯(HP-55、HP-50，由Shin-Etsu Chemical，Japan制造)、羟丙基甲基纤维素乙酸琥珀酸酯(AQOAT，由Shin-Etsu Chemical，Japan制造)、羧甲基乙基纤维素(CMEC，由Freund Corporation，Japan制造)、邻苯二甲酸乙酸纤维素等等。作为在本发明中使用的高分子量酸性物质，当溶解于水中时为水溶胀性的物质或形成凝胶的物质包括但不限于海藻酸、果胶、羧乙烯基聚合物、羧甲基纤维素等等。在根据本发明的药物组合物中可以包含一种或两种或更多种在本发明中使用的高分子量酸性物质。在本发明中使用的高分子量酸性物质优选是肠溶性聚合物，更优选甲基丙烯酸-丙烯酸乙酯共聚物、甲基丙烯酸-甲基丙烯酸甲酯共聚物、羟丙基甲基纤维素邻苯二甲酸酯和羟丙基甲基纤维素乙酸琥珀酸酯，更优选甲基丙烯酸-丙烯酸乙酯共聚物。The high-molecular-weight acidic substance used in the present invention is a high-molecular-weight substance that exhibits acidity when dissolved or suspended in water, for example, a 2.5% aqueous solution of a high-molecular-weight acidic substance exhibits a pH of less than 7.0, preferably a pH of 1.0 to 6.5, more preferably A preferred pH is 1.0 to 6.0. The high-molecular-weight acidic substance used in the present invention may also be insoluble in water or may also be a water-swellable substance or a gel-forming substance when dissolved in water. The high-molecular-weight acidic substance used in the present invention is, for example, an enteric polymer. Examples of enteric polymers include, but are not limited to, methacrylic acid-methyl methacrylate copolymer (Eudragit L100 (methyl methacrylate copolymer, type A), Eudragit S100 (methyl methacrylate copolymer, type B) ),Depend on

GmbH & Co.KG, Darmstadt, Germany), methacrylic acid-ethyl acrylate copolymer (Eudragit L100-55 (methacrylic acid copolymer, type C), Eudragit L30D-55 (methacrylic acid copolymer, dispersion ),Depend on GmbH & Co.KG, Darmstadt, Germany), hydroxypropylmethylcellulose phthalate (HP-55, HP-50, manufactured by Shin-Etsu Chemical, Japan), hydroxypropylmethylcellulose Acetate succinate (AQOAT, manufactured by Shin-Etsu Chemical, Japan), carboxymethylethylcellulose (CMEC, manufactured by Freund Corporation, Japan), cellulose acetate phthalate, and the like. As high-molecular-weight acidic substances used in the present invention, substances that are water-swellable when dissolved in water or substances that form gels include, but are not limited to, alginic acid, pectin, carboxyvinyl polymer, carboxymethylcellulose etc. One or two or more high molecular weight acidic substances used in the present invention may be contained in the pharmaceutical composition according to the present invention. The high-molecular-weight acidic substance used in the present invention is preferably an enteric polymer, more preferably methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, hydroxypropyl methylcellulose orthophthalene dicarboxylates and hydroxypropylmethylcellulose acetate succinate, more preferably methacrylic acid-ethyl acrylate copolymer.

当在生产药物组合物的方法中使用时，在本发明中使用的高分子量酸性物质可以是粉末或颗粒型的商业产品，或者先前已经分散在溶剂中的混悬液型，这些商业产品可以用于或分散在水或有机溶剂中。粒径较小的高分子量酸性物质是是用于本发明的，优选其是粉末型。在甲基丙烯酸-丙烯酸乙酯共聚物的情况中，粉末型的一个例子包括Eudragit L100-55。对于在本发明中使用的高分子量酸性物质的粒径并没有特别的限制，但优选是0.05到100μm，更优选0.05到70μm，最优选0.05到50μm。When used in a method for producing a pharmaceutical composition, the high-molecular-weight acidic substance used in the present invention may be a commercial product in the form of powder or granules, or a suspension type that has been previously dispersed in a solvent, and these commercial products may be used In or dispersed in water or organic solvents. High molecular weight acidic substances with smaller particle sizes are used in the present invention, preferably in powder form. In the case of methacrylic acid-ethyl acrylate copolymer, an example of the powder type includes Eudragit L100-55. The particle size of the high molecular weight acidic substance used in the present invention is not particularly limited, but is preferably 0.05 to 100 μm, more preferably 0.05 to 70 μm, most preferably 0.05 to 50 μm.

在高分子量酸性物质中，肠溶性聚合物是极其有用的，因为甚至当根据本发明的药物组合物中包含大量的该肠溶性聚合物时，它也不会丧失队抗痴呆药物的稳定作用。因此，对于高分子量酸性物质的量没有限制，但例如，基于100重量份的根据本发明的药物组合物，高分子量酸性物质的量一般是0.1到90重量份，优选1到70重量份，更优选5到60重量份，最优选10到50重量份。Among the high molecular weight acidic substances, the enteric polymer is extremely useful because it does not lose the stabilizing effect of the anti-dementia drug even when it is contained in a large amount in the pharmaceutical composition according to the present invention. Therefore, there is no limit to the amount of the high molecular weight acidic substance, but for example, based on 100 parts by weight of the pharmaceutical composition of the present invention, the amount of the high molecular weight acidic substance is generally 0.1 to 90 parts by weight, preferably 1 to 70 parts by weight, more preferably Preferably 5 to 60 parts by weight, most preferably 10 to 50 parts by weight.

在药物组合物中对肠溶性聚合物的量并没有特别的限制，但基于药物组合物为100％重量，一般是5到90％重量，优选8到70％重量，更优选10到60％重量，最优选15到50％重量。在药物组合物中对水不溶性聚合物和肠溶性聚合物的总量并没有特别的限制，但基于药物组合物为100％重量，一般是25到95％重量，优选35到95％重量，更优选40到90％重量，更优选35到90％重量，最优选35到75％重量。The amount of the enteric polymer in the pharmaceutical composition is not particularly limited, but based on 100% by weight of the pharmaceutical composition, it is generally 5 to 90% by weight, preferably 8 to 70% by weight, more preferably 10 to 60% by weight , most preferably from 15 to 50% by weight. The total amount of the water-insoluble polymer and the enteric polymer in the pharmaceutical composition is not particularly limited, but based on 100% by weight of the pharmaceutical composition, it is generally 25 to 95% by weight, preferably 35 to 95% by weight, more preferably 35 to 95% by weight. Preferably 40 to 90% by weight, more preferably 35 to 90% by weight, most preferably 35 to 75% by weight.

在药物组合物中对高分子量碱性物质(水不溶性聚合物)和高分子量酸性物质(肠溶性聚合物)的总量并没有特别的限制，但基于100重量份的根据本发明的药物组合物，其一般是25到95重量份，优选35到95重量份，更优选35到90％重量，最优选35到75％重量。There is no particular limitation on the total amount of high molecular weight basic substance (water-insoluble polymer) and high molecular weight acidic substance (enteric polymer) in the pharmaceutical composition, but based on 100 parts by weight of the pharmaceutical composition of the present invention , which is generally 25 to 95 parts by weight, preferably 35 to 95 parts by weight, more preferably 35 to 90% by weight, most preferably 35 to 75% by weight.

(低分子量酸性物质)(low molecular weight acidic substance)

对于在本发明中使用的低分子量酸性物质并没有特别的限制，只要当溶解或悬浮于水中时溶液的pH小于4.5即可，例如2.5％的水溶液或2.5％的混悬液优选pH是1.0到4.0，更优选1.0到3.5，更优选1.0到3.0。与抗痴呆药物一起服用，得到了pH 4.0到6.0的在2到5％的水溶液或混悬液中的抗痴呆药物，该水溶液的pH减去低分子量酸性物质的2.5％的水溶液或2.5％的混悬液的pH一般是0.05到5.5，优选0.5到5.5，更优选1.0到5.0，更优选1.5到5.0。There is no particular limitation on the low-molecular-weight acidic substance used in the present invention, as long as the pH of the solution is less than 4.5 when dissolved or suspended in water, for example, a 2.5% aqueous solution or a 2.5% suspension preferably has a pH of 1.0 to 4.0, more preferably 1.0 to 3.5, more preferably 1.0 to 3.0. Administered with antidementia drugs to obtain pH 4.0 to 6.0 in 2 to 5% aqueous solution or suspension, the pH of the aqueous solution minus low molecular weight acidic substances in 2.5% aqueous solution or 2.5% The pH of the suspension is generally 0.05 to 5.5, preferably 0.5 to 5.5, more preferably 1.0 to 5.0, more preferably 1.5 to 5.0.

此外，即使它除了酸性官能团还具有碱性官能团等等，在本发明中使用的低分子量酸性物质的例子包括但不限于氨基酸或乙二胺四乙酸，只要其2.5％的水溶液或2.5％的混悬液的pH小于4.5即可。在本发明中使用的术语“低分子量”是指分子量为1000或更小，这排除了在本发明中使用的高分子量酸性物质。此外，在本发明中使用的低分子量酸性物质可以是水溶性或水不溶性的，但是优选在室温下是固体，同时优选具有低挥发性。在药物组合物中可以包含一种或两种或更多种在本发明中使用的低分子量酸性物质。In addition, even if it has a basic functional group and the like in addition to the acidic functional group, examples of the low-molecular-weight acidic substance used in the present invention include, but are not limited to, amino acids or ethylenediaminetetraacetic acid as long as its 2.5% aqueous solution or 2.5% mixed The pH of the suspension is less than 4.5. The term "low molecular weight" used in the present invention means a molecular weight of 1000 or less, which excludes high molecular weight acidic substances used in the present invention. In addition, the low-molecular-weight acidic substance used in the present invention may be water-soluble or water-insoluble, but is preferably solid at room temperature while preferably having low volatility. One or two or more low molecular weight acidic substances used in the present invention may be contained in the pharmaceutical composition.

对于低分子量酸性物质并没有特别的限制，但其例子包括但不限于，有机酸、无机酸或酸性氨基酸。有机酸的例子包括但不限于，羧酸例如乙酸、苯甲酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、草酸、丙二酸、琥珀酸、己二酸、癸二酸、富马酸、马来酸、甘草酸、乌热酸、山梨酸等等；羟酸例如羟乙酸、乳酸、苹果酸、酒石酸、柠檬酸、二氢柠檬酸钠、葡糖酸、水杨酸等等；磺酸例如对甲苯磺酸、甲磺酸等等。无机酸的例子包括但不限于，盐酸、硫酸、硼酸、磷酸、磷酸二氢钠、磷酸二氢钾等等。酸性氨基酸的例子包括但不限于，门冬氨酸、谷氨酸、盐酸谷氨酸、盐酸组氨酸等等。优选羧酸、羟酸、酸性氨基酸和无机酸，更优选羟酸、酸性氨基酸和无机酸。更特别地，在本发明中使用的低分子量酸性物质的优选例子包括但不限于琥珀酸、酒石酸、柠檬酸、富马酸、马来酸、苹果酸、门冬氨酸、谷氨酸、盐酸谷氨酸、盐酸或磷酸，更优选琥珀酸、酒石酸、柠檬酸、苹果酸、门冬氨酸、谷氨酸、盐酸谷氨酸、盐酸或磷酸。仍然更优选柠檬酸、门冬氨酸和盐酸。There is no particular limitation on low molecular weight acidic substances, but examples thereof include, but are not limited to, organic acids, inorganic acids, or acidic amino acids. Examples of organic acids include, but are not limited to, carboxylic acids such as acetic acid, benzoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oxalic acid, malonic acid, succinic acid, adipic acid, sebacic acid, fumaric acid, acid, maleic acid, glycyrrhizic acid, urethane acid, sorbic acid, etc.; hydroxy acids such as glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, sodium dihydrocitrate, gluconic acid, salicylic acid, etc.; Sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid and the like. Examples of inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, boric acid, phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like. Examples of acidic amino acids include, but are not limited to, aspartic acid, glutamic acid, glutamic acid hydrochloride, histidine hydrochloride, and the like. Preferred are carboxylic acids, hydroxy acids, acidic amino acids and mineral acids, more preferred are hydroxy acids, acidic amino acids and mineral acids. More particularly, preferred examples of low molecular weight acidic substances used in the present invention include, but are not limited to, succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, aspartic acid, glutamic acid, hydrochloric acid Glutamic acid, hydrochloric acid or phosphoric acid, more preferably succinic acid, tartaric acid, citric acid, malic acid, aspartic acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid or phosphoric acid. Still more preferred are citric acid, aspartic acid and hydrochloric acid.

尤其是当联合使用低分子量酸性物质和高分子量酸性物质时可以得到本发明的效果。为达到稳定目的并不限制高分子量酸性物质的量，但可以根据持续释放性质而调节。在该情况中，如果联合使用低分子量酸性物质和高分子量酸性物质可以防止或抑制降解产物，调节量没有任何作用。例如，基于100重量份的根据本发明的药物组合物，低分子量酸性物质的量一般是0.05到4重量份，优选0.1到3重量份，更优选0.15到2重量份，更优选0.15到1.5重量份。In particular, the effects of the present invention can be obtained when a low-molecular-weight acidic substance and a high-molecular-weight acidic substance are used in combination. The amount of high molecular weight acidic substance is not limited for stabilization purposes, but can be adjusted according to sustained release properties. In this case, if the combined use of the low molecular weight acidic substance and the high molecular weight acidic substance can prevent or suppress degradation products, the adjusted amount has no effect. For example, based on 100 parts by weight of the pharmaceutical composition according to the present invention, the amount of the low molecular weight acidic substance is generally 0.05 to 4 parts by weight, preferably 0.1 to 3 parts by weight, more preferably 0.15 to 2 parts by weight, more preferably 0.15 to 1.5 parts by weight share.

(抗氧化剂)(Antioxidants)

对于在本发明中使用的抗氧化剂并没有特别的限制，只要抗氧化剂是在被氧化时产生抗氧化作用的物质即可，优选抗氧化剂本身比具有氨基的抗痴呆药物更易于被氧化。因此，在本发明中使用的抗氧化剂具有还原作用。在本发明中使用的抗氧化剂的例子包括但不限于，抗坏血酸类例如抗坏血酸、抗坏血酸钠、异抗坏血酸、异抗坏血酸钠、抗坏血酸棕榈酸酯、抗坏血酸糖苷等等；含硫的氨基酸例如半胱氨酸、盐酸半胱氨酸、甲硫氨酸等等；亚硫酸盐例如亚硫酸钠、亚硫酸氢钠等等；儿茶酚衍生物例如儿茶酚、绿原酸、咖啡酸、酪氨酸等等；氢醌衍生物例如二丁基苯甲醇、丁基对甲氧酚等等；没食子酸衍生物例如没食子酸、没食子酸酯、鞣酸等等；生育酚例如dl-α-生育酚、d-α-生育酚、d-β-生育酚、d-γ-生育酚、d-δ-生育酚、d-α-生育三烯酸、d-β-生育三烯酸、d-γ-生育三烯酸、d-δ-生育三烯酸、其混合物等等；黄酮类例如芦丁、槲皮素、橙皮苷等等；和多酚类例如儿茶素、表儿茶素、没食子儿茶酸、原花色素等等。优选抗坏血酸类、含硫的氨基酸、氢醌衍生物和生育酚。更优选抗坏血酸类或含硫的氨基酸。特别优选甲硫氨酸、抗坏血酸或盐酸半胱氨酸。在本发明中使用的抗氧化剂可以是游离或盐的形式，但优选当其溶解或悬浮于水中时该水溶液显示酸性。例如，抗坏血酸鼻抗坏血酸钠更为优选，盐酸半胱氨酸比半胱氨酸更为优选。在本发明中使用的抗氧化剂可以单独使用，或包含两种或更多种，或者其可以与低分子量酸性物质联合使用。在本发明中使用的抗氧化剂可以是水溶性或水不溶性的，但是优选在室温下是固体，同时优选具有低挥发性。The antioxidant used in the present invention is not particularly limited as long as the antioxidant is a substance that produces an antioxidant effect when oxidized, and it is preferable that the antioxidant itself is more easily oxidized than the anti-dementia drug having an amino group. Therefore, the antioxidant used in the present invention has a reducing effect. Examples of antioxidants used in the present invention include, but are not limited to, ascorbic acids such as ascorbic acid, sodium ascorbate, erythorbic acid, sodium erythorbate, ascorbyl palmitate, ascorbyl glycoside, etc.; sulfur-containing amino acids such as cysteine, Cysteine hydrochloride, methionine, etc.; sulfites such as sodium sulfite, sodium bisulfite, etc.; catechol derivatives such as catechol, chlorogenic acid, caffeic acid, tyrosine, etc.; hydrogen Quinone derivatives such as dibutyl benzyl alcohol, butyl p-methoxyphenol, etc.; gallic acid derivatives such as gallic acid, gallate, tannic acid, etc.; tocopherols such as dl-α-tocopherol, d-α- Tocopherol, d-beta-tocopherol, d-gamma-tocopherol, d-delta-tocopherol, d-alpha-tocotrienoic acid, d-beta-tocotrienoic acid, d-gamma-tocotrienoic acid , d-δ-tocotrienoic acid, mixtures thereof, etc.; flavonoids such as rutin, quercetin, hesperidin, etc.; and polyphenols such as catechin, epicatechin, gallocatechin, Proanthocyanidins and more. Preference is given to ascorbic acids, sulfur-containing amino acids, hydroquinone derivatives and tocopherols. More preferred are ascorbic acids or sulfur-containing amino acids. Particular preference is given to methionine, ascorbic acid or cysteine hydrochloride. The antioxidant used in the present invention may be in free or salt form, but preferably when dissolved or suspended in water the aqueous solution exhibits acidity. For example, ascorbic acid nasal sodium ascorbate is more preferred, and cysteine hydrochloride is more preferred than cysteine. The antioxidant used in the present invention may be used alone, or contain two or more kinds, or it may be used in combination with a low molecular weight acidic substance. Antioxidants used in the present invention may be water-soluble or water-insoluble, but are preferably solid at room temperature while preferably having low volatility.

对于在本发明中使用的抗氧化剂与药物的比例没有特别的限制，但例如基于1重量份的药物，抗氧化剂一般可以是0.01到10重量份，优选0.02到5重量份，更优选0.05到2重量份。对于抗氧化剂的量没有特别的限制，但基于100重量份的根据本发明的药物组合物，其一般是0.001到5重量份，优选0.01到3重量份，更优选0.1到2重量份，更优选0.15到1.5重量份。There is no particular limitation on the ratio of the antioxidant to the drug used in the present invention, but for example based on 1 part by weight of the drug, the antioxidant can generally be 0.01 to 10 parts by weight, preferably 0.02 to 5 parts by weight, more preferably 0.05 to 2 parts by weight. parts by weight. There is no particular limitation on the amount of antioxidant, but based on 100 parts by weight of the pharmaceutical composition according to the present invention, it is generally 0.001 to 5 parts by weight, preferably 0.01 to 3 parts by weight, more preferably 0.1 to 2 parts by weight, more preferably 0.15 to 1.5 parts by weight.

(水溶性糖和/或水溶性糖醇)(water-soluble sugars and/or water-soluble sugar alcohols)

根据本发明的药物组合物优选包含水溶性糖和/或水溶性糖醇。对于水溶性糖和/或水溶性糖醇并没有特别的限制。水溶性糖的例子包括但不限于，乳糖、蔗糖、葡萄糖、糊精、芽霉菌糖等等。水溶性糖醇的例子包括但不限于，甘露醇、赤藻糖醇、木糖醇、山梨糖醇等等，优选乳糖和甘露醇。在根据本发明的药物组合物中对于水溶性糖或水溶性糖醇的量没有特别的限制，但是基于100％重量的基质型持续释放制剂，上述量一般是3到70％重量，优选5到60％重量，更优选10到60％重量，更优选12到60％重量。The pharmaceutical composition according to the invention preferably comprises water-soluble sugars and/or water-soluble sugar alcohols. There are no particular limitations on water-soluble sugars and/or water-soluble sugar alcohols. Examples of water soluble sugars include, but are not limited to, lactose, sucrose, dextrose, dextrin, populose, and the like. Examples of water-soluble sugar alcohols include, but are not limited to, mannitol, erythritol, xylitol, sorbitol and the like, preferably lactose and mannitol. There is no particular limitation on the amount of water-soluble sugar or water-soluble sugar alcohol in the pharmaceutical composition according to the present invention, but based on 100% by weight of the matrix-type sustained release preparation, the above-mentioned amount is generally 3 to 70% by weight, preferably 5 to 70% by weight. 60% by weight, more preferably 10 to 60% by weight, more preferably 12 to 60% by weight.

(赋形剂)(excipient)

根据本发明的药物组合物包含添加剂，所述添加剂包括各种药学可接受的载体例如赋形剂、润滑剂、粘合剂和崩解剂以及防腐剂、着色剂、增甜剂、增塑剂、薄膜包衣和必需的类似物。赋形剂的例子包括但不限于，淀粉、预胶凝淀粉、结晶纤维素、轻质无水硅酸、合成硅酸铝、铝酸镁等等。润滑剂的例子包括但不限于，硬脂酸镁(Mallinckrodt Baker，Inc.USA)、硬脂酸钙(Merck KGaA，Darmstadt，Germany)、滑石、硬脂酰醇富马酸钠等等。粘合剂的例子包括但不限于，羟丙基纤维素、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、聚乙烯吡咯烷酮等等。崩解剂的例子包括但不限于，羧甲基纤维素、羧甲基纤维素钙、交联羧甲基纤维素钙、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素等等。防腐剂的例子包括但不限于，对羟基苯甲酸酯、三氯叔丁醇、苯甲醇、苯乙醇、脱氢乙酸、山梨酸等等。着色剂的优选例子包括但不限于，水不溶性莱克涂剂、天然色素(例如β-胡萝卜素、叶绿素和氧化铁)、黄色三氧化二铁、红色三氧化二铁、黑色氧化铁等等。增甜剂的例子包括但不限于，糖精钠、甘草二钾、阿司帕坦、甘油脂肪酸酯、stevia等等。增塑剂的例子包括但不限于，甘油脂肪酸酯、柠檬酸三乙酯、丙二醇、聚乙二醇等等。薄膜包衣的例子包括但不限于，羟丙基甲基纤维素、羟丙基纤维素等等。The pharmaceutical composition according to the present invention contains additives including various pharmaceutically acceptable carriers such as excipients, lubricants, binders and disintegrants as well as preservatives, colorants, sweeteners, plasticizers , film coating and the like as required. Examples of excipients include, but are not limited to, starch, pregelatinized starch, crystalline cellulose, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate, and the like. Examples of lubricants include, but are not limited to, magnesium stearate (Mallinckrodt Baker, Inc. USA), calcium stearate (Merck KGaA, Darmstadt, Germany), talc, sodium stearyl fumarate, and the like. Examples of binders include, but are not limited to, hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and the like. Examples of disintegrants include, but are not limited to, carboxymethyl cellulose, carmellose calcium, croscarmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxyl Propyl cellulose, etc. Examples of preservatives include, but are not limited to, parabens, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Preferable examples of coloring agents include, but are not limited to, water-insoluble lacquer, natural pigments such as β-carotene, chlorophyll, and iron oxide, yellow ferric oxide, red ferric oxide, black ferric oxide, and the like. Examples of sweeteners include, but are not limited to, sodium saccharin, dipotassium glycyrrhizate, aspartame, glycerin fatty acid esters, stevia, and the like. Examples of plasticizers include, but are not limited to, glycerin fatty acid esters, triethyl citrate, propylene glycol, polyethylene glycol, and the like. Examples of film coatings include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like.

(药物组合物)(pharmaceutical composition)

对于根据本发明的药物组合物并没有特别的限制，只要它是其中抗痴呆药物是稳定的组合物即可，但优选它是具有持续释放性质或是持续释放制剂，更优选它是基质型持续释放制剂。对于本发明的药物组合物的剂型也没有特别的限制，其可以以任何形式使用，包括片剂、胶囊、颗粒、微粒、粉末、软膏、注射剂、糊药、吸入剂、胶冻剂等等。优选其剂型是适合口服的制剂，例如片剂、胶囊、微粒、胶冻剂等等，更优选它是片剂、胶囊、颗粒或微粒的形式。There is no particular limitation on the pharmaceutical composition according to the present invention as long as it is a composition in which the anti-dementia drug is stable, but preferably it has sustained release properties or a sustained release preparation, more preferably it is a matrix type sustained release formulation. The dosage form of the pharmaceutical composition of the present invention is also not particularly limited, and it can be used in any form, including tablet, capsule, granule, microparticle, powder, ointment, injection, paste, inhalant, jelly and the like. Preferably, its dosage form is a preparation suitable for oral administration, such as tablet, capsule, granule, jelly, etc., more preferably it is in the form of tablet, capsule, granule or granule.

此外，根据本发明的药物组合物是包含抗痴呆药物、高分子量碱性物质和高分子量酸性物质的药物组合物。对于抗痴呆药物、高分子量碱性物质和高分子量酸性物质如何分散在该药物组合物中并没有特别的限制，这些成分可以均匀地混合在根据本发明的药物组合物的相同相中。特别地，它是包含基质的药物组合物，其中该基质包含抗痴呆药物、高分子量碱性物质和高分子量酸性物质的混合物，并且是，例如，基质型持续释放制剂。本发明的基质，其中药物和和持续释放基质在其中均匀地混合，并压模或制粒。当然，也可以在该基质种混入其他的添加剂，或者可以用包含遮蔽剂或防潮剂等等的包衣层进一步覆盖该基质。Furthermore, the pharmaceutical composition according to the present invention is a pharmaceutical composition comprising an anti-dementia drug, a high molecular weight basic substance and a high molecular weight acidic substance. There is no particular limitation on how the anti-dementia drug, high-molecular-weight basic substance and high-molecular-weight acidic substance are dispersed in the pharmaceutical composition, and these ingredients can be uniformly mixed in the same phase of the pharmaceutical composition according to the present invention. In particular, it is a pharmaceutical composition comprising a matrix comprising a mixture of an anti-dementia drug, a high-molecular-weight basic substance and a high-molecular-weight acidic substance, and is, for example, a matrix-type sustained-release preparation. The matrix of the present invention, wherein the drug and the sustained-release matrix are uniformly mixed therein, and compression molded or granulated. Of course, other additives can also be mixed into the matrix, or the matrix can be further covered with a coating layer containing a screening agent or a moisture-proof agent and the like.

药物和高分子量碱性物质也可以分别包含在根据本发明的药物组合物的相邻的相中。此外，包含药物的相和包含高分子量碱性物质的相分别都可以包含多个多层叠加的相。在该情况中，高分子量酸性物质可以包含在这些相的至少一个相中。例如，根据本发明的药物组合物可以包含含有抗痴呆药物的芯，该芯用含有高分子量碱性物质的包衣层覆盖，高分子量酸性物质混入到芯和包衣层的至少一个中例如可以是持续释放的包衣制剂。需要注意的是，对于芯并没有特别的限制，其可以是颗粒或片剂的形式，或其他形式。其例子包括，片剂，其中包含高分子量碱性物质的包衣直接包被在芯上，芯是包含药物和高分子量酸性物质的混合物的未包衣的片剂；颗粒，其中包含高分子量碱性物质和高分子量酸性物质的包衣直接包被在含有颗粒的芯上，其中该颗粒包含药物，以及包含层的聚集颗粒，其中药物和高分子量酸性物质包含在芯颗粒例如nonpareil等等以及包含高分子量碱性物质的层中。其用途是制备包含聚集的颗粒的片剂或胶囊，其中该聚集的颗粒在芯颗粒例如nonpareil等等中包含含有高分子量酸性物质和高分子量碱性物质的层，和包含药物的层。The drug and the high molecular weight basic substance may also be contained separately in adjacent phases of the pharmaceutical composition according to the invention. Furthermore, each of the drug-containing phase and the high-molecular-weight basic substance-containing phase may contain a plurality of multilayered phases. In this case, a high-molecular-weight acidic substance may be contained in at least one of these phases. For example, the pharmaceutical composition according to the present invention may comprise a core containing an anti-dementia drug, the core is covered with a coating layer containing a high-molecular-weight basic substance, and a high-molecular-weight acidic substance is mixed into at least one of the core and the coating layer, such as It is a sustained release coated formulation. It should be noted that there is no particular limitation on the core, which may be in the form of granules or tablets, or other forms. Examples include, tablets, in which a coating comprising a high molecular weight basic substance is coated directly on a core which is an uncoated tablet comprising a mixture of drug and a high molecular weight acidic substance; granules, in which a high molecular weight basic substance is contained The coating of the active substance and the high molecular weight acidic substance is directly coated on the core containing the particle, wherein the particle contains the drug, and the aggregated particle containing the layer, wherein the drug and the high molecular weight acidic substance are contained in the core particle such as nonpareil etc. and containing in the layer of high molecular weight alkaline substances. Its use is to prepare a tablet or capsule comprising aggregated particles comprising a layer containing a high-molecular-weight acidic substance and a high-molecular-weight basic substance, and a layer containing a drug in a core particle such as nonpareil or the like.

此外，根据本发明的药物组合物可以是一种药物组合物，其中包含高分子量酸性物质的相位于包含药物的相和包含高分子量碱性物质的相之间，以使得抗痴呆药物不会与高分子量碱性物质接触。也可以通过用包含高分子量酸性物质的混合物包被包含药物的芯，然后用包含高分子量碱性物质和高分子量酸性物质的包衣层覆盖该芯。In addition, the pharmaceutical composition according to the present invention may be a pharmaceutical composition in which a phase containing a high-molecular-weight acidic substance is located between a phase containing a drug and a phase containing a high-molecular-weight basic substance so that the anti-dementia drug does not mix with Contact with high molecular weight alkaline substances. It is also possible by coating a drug-containing core with a mixture containing a high-molecular-weight acidic substance, and then covering the core with a coating layer containing a high-molecular-weight basic substance and a high-molecular-weight acidic substance.

(混合高分子量酸性物质的方法)(Method of mixing high molecular weight acidic substances)

当在根据本发明的药物组合物中包含高分子量酸性物质时，在生产药物组合物的混合步骤、制粒步骤、压模步骤、包衣步骤、包装步骤或其他任何步骤期间或多个步骤期间可以使用常规的已知操作方法(例如在Japanese Pharmacopoeia，14^th Ed.，General Rules forPreparations中描述的那些)。尽管对此没有限制，但具体的例子包括(a)一种方法，其中在干法混合或湿法混合药物和高分子量碱性物质的步骤中，也加入高分子量酸性物质，(b)一种方法，其中高分子量酸性物质是悬浮于水中或将其他粘合剂用于湿法制粒药物和水不溶性聚合物的混合物，以加入高分子量酸性物质，(c)一种方法，其中当干法制粒药物和水不溶性聚合物的混合物时，加入粉末状的高分子量酸性物质，(d)一种方法，其中在混合和压模包含药物的颗粒和包含高分子量碱性物质的颗粒时，加入粉末状的高分子量酸性物质，(e)一种方法，当给予包含药物的颗粒或片剂以包含分子量碱性物质的糖包衣或薄膜包衣时，预先将高分子量酸性物质加入到包衣液等等中以形成包衣层，和(f)一种方法，用高分子量酸性物质的粉末或颗粒与包含药物的颗粒和包含高分子量碱性物质的颗粒包装成胶囊。优选在混合步骤和制粒步骤的至少一个期间，高分子量酸性物质可以作为粉末或者溶液或混悬液加入到药物和高分子量碱性物质的混合物中。这样，通过这种方法可以获得所有成分在其中均匀混合的颗粒。特别优选的方法是，将粉末状的高分子量酸性物质加入到药物和高分子量碱性物质的混合物中。需要注意的是，对于在各种生产步骤例如湿法混合和制备稳定剂的溶液或混悬液中使用的溶剂没有特别的限制，但溶剂的例子包括，醇、水，或上述物质的混合物，优选乙醇、水或它们的混合物。When a high molecular weight acidic substance is included in the pharmaceutical composition according to the present invention, during the mixing step, granulation step, compression molding step, coating step, packaging step or any other step or steps of producing the pharmaceutical composition Conventional known operating methods (such as those described in Japanese Pharmacopoeia, 14^th Ed., General Rules for Preparations) can be used. Although not limited thereto, specific examples include (a) a method in which a high molecular weight acidic substance is also added in the step of dry mixing or wet mixing a drug and a high molecular weight basic substance, (b) a A method wherein the high molecular weight acidic substance is suspended in water or other binders are used to wet granulate the mixture of drug and water insoluble polymer to add the high molecular weight acidic substance, (c) a method wherein when dry granulation When a drug and a water-insoluble polymer are mixed, a powdery high-molecular-weight acidic substance is added, (d) a method in which a powdery high-molecular-weight acidic substance, (e) a method of adding a high-molecular-weight acidic substance to a coating solution, etc. etc. to form a coating layer, and (f) a method of packing powder or granules of a high-molecular-weight acidic substance together with granules containing a drug and granules containing a high-molecular-weight basic substance into capsules. Preferably during at least one of the mixing step and the granulation step, the high molecular weight acidic substance can be added to the mixture of drug and high molecular weight basic substance as a powder or a solution or suspension. Thus, granules in which all ingredients are homogeneously mixed can be obtained by this method. A particularly preferred method is to add the powdered high molecular weight acidic substance to the mixture of drug and high molecular weight basic substance. It should be noted that there are no particular limitations on the solvents used in various production steps such as wet mixing and preparation of solutions or suspensions of stabilizers, but examples of solvents include alcohols, water, or mixtures of the above, Preference is given to ethanol, water or mixtures thereof.

(与低分子量酸性物质等等混合的组合物)(composition mixed with low molecular weight acidic substances etc.)

根据本发明的药物组合物是除了抗痴呆药物、高分子量碱性物质和高分子量酸性物质外还包含低分子量酸性物质的药物组合物。对于如何将低分子量酸性物质混入到药物组合物中并没有特别的限制，例如，它可以混入到药物、高分子量碱性物质和高分子量酸性物质均匀混合的相中。当药物和高分子量碱性物质在不同的相中时，低分子量酸性物质可以混入到根据本发明的药物组合物中的至少一个相中。它也可以独立或与高分子量酸性物质一起包被到药物组合物的基质或芯上。需要注意的是，也可以以与上述低分子量酸性物质相同的方式将抗氧化剂混入到药物组合物中。当然，抗氧化剂可以与低分子量酸性物质一起混合或可以与低分子量酸性物质分别混入到药物组合物中。The pharmaceutical composition according to the present invention is a pharmaceutical composition comprising a low molecular weight acidic substance in addition to an anti-dementia drug, a high molecular weight basic substance and a high molecular weight acidic substance. There is no particular limitation on how the low-molecular-weight acidic substance is mixed into the pharmaceutical composition, for example, it can be mixed into a phase in which the drug, the high-molecular-weight basic substance, and the high-molecular-weight acidic substance are uniformly mixed. When the drug and the high molecular weight basic substance are in different phases, the low molecular weight acidic substance can be mixed into at least one phase of the pharmaceutical composition according to the present invention. It can also be coated on the matrix or core of the pharmaceutical composition alone or together with the high molecular weight acidic substance. It should be noted that antioxidants can also be mixed into the pharmaceutical composition in the same manner as the above-mentioned low molecular weight acidic substances. Of course, the antioxidant may be mixed together with the low molecular weight acidic substance or may be separately mixed with the low molecular weight acidic substance into the pharmaceutical composition.

(加入低分子量酸性物质等等的方法)(A method of adding low-molecular-weight acidic substances, etc.)

在混合高分子量酸性物质的情况中，低分子量酸性物质或抗氧化剂可以在任意步骤或在生产药物组合物的多个步骤期间混合到组合物中。该低分子量酸性物质可以在与加入高分子量酸性物质相同的步骤或不同的步骤中混和。该低分子量酸性物质或抗氧化剂优选是在生产药物组合物的混合步骤和制粒步骤中的至少一个步骤中加入的。更优选地，高分子量酸性物质和低分子量酸性物质是在生产药物组合物的混合步骤和制粒步骤中的至少一个步骤中加入的。加入低分子量酸性物质或抗氧化剂并不限于这些方面和这些方法，低分子量酸性物质或抗氧化剂可以作为粉末加入或分散在溶液或悬浮液中或喷雾于其上。在该情况中，即使在同样的步骤中加入低分子量酸性物质、抗氧化剂和高分子量酸性物质，加入的方法也也可以根据物质而不同，或者它们都通过相同的方法加入。例如，在混合步骤中，可以加入粉末状的高分子量酸性物质，而加入的低分子量酸性物质或抗氧化剂则是溶液或混悬液，或者可以在混合步骤中加入粉末状的高分子量酸性物质，而在制粒步骤中加入的低分子量酸性物质或抗氧化剂是溶液或混悬液，但是并不限于这些例子。In the case of mixing a high-molecular-weight acidic substance, a low-molecular-weight acidic substance or an antioxidant may be mixed into the composition at any step or during multiple steps of producing the pharmaceutical composition. The low molecular weight acidic material can be mixed in the same step as the high molecular weight acidic material is added or in a different step. The low-molecular-weight acidic substance or antioxidant is preferably added in at least one of a mixing step and a granulation step in producing the pharmaceutical composition. More preferably, the high-molecular-weight acidic substance and the low-molecular-weight acidic substance are added in at least one of the mixing step and the granulating step in producing the pharmaceutical composition. The addition of the low molecular weight acidic substance or antioxidant is not limited to these aspects and these methods, and the low molecular weight acidic substance or antioxidant may be added as a powder or dispersed in a solution or suspension or sprayed thereon. In this case, even if the low-molecular-weight acidic substance, the antioxidant, and the high-molecular-weight acidic substance are added in the same step, the method of addition may differ depending on the substance, or they may all be added by the same method. For example, in the mixing step, a powdered high molecular weight acidic substance may be added while the added low molecular weight acidic substance or antioxidant is a solution or suspension, or a powdered high molecular weight acidic substance may be added in the mixing step, And the low-molecular-weight acidic substance or antioxidant added in the granulation step is a solution or a suspension, but it is not limited to these examples.

对于生产根据本发明的药物组合物的方法并没有特别的限制，只要它包含将高分子量酸性物质混入到药物组合物中的步骤即可。可以根据已知操作方法(例如在the Japanese Pharmacopoeia，14^thEd.，General Rules for Preparations中所述的那些)来生产根据本发明的药物组合物。以固体口服制剂为例，形成片剂，包括加入和混合药物和赋形剂、崩解剂等等，如果必要，加入粘合剂以形成颗粒，然后如果必要加入崩解剂、润滑剂等等。可以以相同的常规方法制备用于片剂的颗粒，包括挤出制粒或用包含药物和添加剂的粉末分散体包被nonpareil(芯，包含75％蔗糖(W/W)和25％玉米淀粉(W/W))，同时用水或包含粘合剂的溶液(浓度约0.5到70％(W/W))喷雾。在胶囊的情况中，可以用药物和赋形剂一起填充明胶、羟丙基甲基纤维素或其他胶囊。可以用包衣剂单独或遮蔽剂或本发明的低分子量酸性物质或氧化剂包被药物组合物，以掩蔽气味或给予肠溶或持续释放性质等等。可以根据下列方法来生产根据本发明的药物组合物。将130g的盐酸多萘哌齐(Eisai Co.Ltd.)、624g的乙基纤维素(商品名Ethocel 10FP，Dow Chemical Company)、780g的Eudragit100-55(

GmbH & Co.KG)和988g的乳糖在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中52g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)的水溶液。用盘架干燥器热干燥所得到的颗粒，并过筛，得到需要的粒径。在过筛后，每99g的颗粒加入1g的硬脂酸镁(Mallinckrodt Baker，Inc.)并混合，然后使用旋转压片机，形成每200mg的片剂包含10mg的盐酸多萘哌齐的直径8mm的片剂。用包衣装置，然后用包含羟丙基纤维素等等作为主要组分的水性薄膜包被这些片剂。There is no particular limitation on the method of producing the pharmaceutical composition according to the present invention as long as it includes the step of mixing a high molecular weight acidic substance into the pharmaceutical composition. The pharmaceutical composition according to the present invention can be produced according to known procedures such as those described in the Japanese Pharmacopoeia, 14^th Ed., General Rules for Preparations. Taking solid oral preparations as an example, forming tablets involves adding and mixing drugs and excipients, disintegrants, etc., adding binders to form granules if necessary, and then adding disintegrants, lubricants, etc. if necessary . Granules for tablets can be prepared in the same conventional manner, including extrusion granulation or coating of nonpareil (core, containing 75% sucrose (W/W) and 25% cornstarch ( W/W)) while spraying with water or a solution containing a binder (concentration about 0.5 to 70% (W/W)). In the case of capsules, gelatin, hydroxypropylmethylcellulose or other capsules may be filled with the drug and excipients together. The pharmaceutical composition may be coated with a coating agent alone or a masking agent or the low molecular weight acidic substance or oxidizing agent of the present invention to mask odor or impart enteric or sustained release properties and the like. The pharmaceutical composition according to the present invention can be produced according to the following methods. Donepezil hydrochloride (Eisai Co.Ltd.) of 130g, ethyl cellulose (trade name Ethocel 10FP, Dow Chemical Company) of 624g, Eudragit100-55 of 780g (

GmbH & Co. KG) and 988 g of lactose were mixed in a granulator. Wet granulation was performed comprising adding to the mixture an aqueous solution of 52 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water. The resulting granules were heat dried using a rack drier and sieved to obtain the desired particle size. After sieving, 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99 g of the granules and mixed, and then, using a rotary tablet press, tablets of 8 mm in diameter containing 10 mg of donepezil hydrochloride per 200 mg were formed tablet. Using a coating apparatus, these tablets are then coated with an aqueous film containing hydroxypropylcellulose or the like as a main component.

可替代地，可以根据下列方法来生产根据本发明的药物组合物。将130g的盐酸多萘哌齐(Eisai Co.Ltd.)、624g的乙基纤维素(商品名Ethocel 10FP，Dow Chemical Company)、780g的Eudragit100-55(GmbH & Co.KG)和975g的乳糖在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中52g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)和13g的柠檬酸的水溶液。在盘架干燥器中加热干燥所得到的颗粒，并过筛，得到需要的粒径。在过筛后，每99g的颗粒加入1g的硬脂酸镁(MallinckrodtBaker，Inc.)并混合，然后使用旋转压片机，形成每200mg的片剂包含10mg的盐酸多萘哌齐的直径8mm的片剂。用包衣装置，然后用包含羟丙基纤维素等等作为主要组分的水性薄膜包被这些片剂。Alternatively, the pharmaceutical composition according to the present invention can be produced according to the following method. Donepezil hydrochloride (Eisai Co.Ltd.) of 130g, ethyl cellulose (trade name Ethocel 10FP, Dow Chemical Company) of 624g, Eudragit100-55 of 780g ( GmbH & Co. KG) and 975 g of lactose were mixed in a granulator. Wet granulation was performed comprising adding to the mixture an aqueous solution of 52 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd) and 13 g of citric acid dissolved in an appropriate amount of purified water. The resulting granules were heat dried in a rack drier and sieved to obtain the desired particle size. After sieving, 1 g of magnesium stearate (MallinckrodtBaker, Inc.) was added per 99 g of granules and mixed, and then, using a rotary tablet press, tablets of 8 mm in diameter containing 10 mg of donepezil hydrochloride per 200 mg were formed. tablet. Using a coating apparatus, these tablets are then coated with an aqueous film containing hydroxypropylcellulose or the like as a main component.

实施例Example

下面用实施例更详细地说明本发明，但是本发明并不仅限于此。在药物组合物中使用的添加剂是商业可用的试剂，或符合法定文件，例如日本药典、the Japanese Pharmaceutical Excipients 2003(JPE2003)、和Japan Pharmaceutical Codex 1997(JPC 1997)。The present invention will be described in more detail below with examples, but the present invention is not limited thereto. The additives used in the pharmaceutical composition are commercially available agents, or comply with statutory documents such as the Japanese Pharmacopoeia, the Japanese Pharmaceutical Excipients 2003 (JPE2003), and Japan Pharmaceutical Codex 1997 (JPC 1997).

(实施例1)(Example 1)

加入适当量的纯净水中并与300mg的盐酸多萘哌齐(Eisai Co.Ltd.)、375mg的乙基纤维素(Ethocel 10FP，Dow Chemical Company)、1500mg的Eudragit L100-55(

GmbH & Co.KG)和795mg的乳糖混合，在恒温室中加热干燥该混合物。加入30mg的硬脂酸镁(Mallinckrodt Baker，Inc.)并与干燥的颗粒混合。取200mg的该混合物，用Autograph AG5000A(Shimazu Corporation)制成片剂，得到包含20mg的盐酸多萘哌齐的直径8mm的片剂。Add an appropriate amount of purified water and mix with 300 mg of donepezil hydrochloride (Eisai Co. Ltd.), 375 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), 1500 mg of Eudragit L100-55 (

GmbH & Co.KG) and 795 mg of lactose were mixed, and the mixture was heated and dried in a constant temperature room. 30 mg of magnesium stearate (Mallinckrodt Baker, Inc.) was added and mixed with the dry granules. 200 mg of this mixture was taken and tableted with Autograph AG5000A (Shimazu Corporation) to obtain tablets with a diameter of 8 mm containing 20 mg of donepezil hydrochloride.

(实施例2)(Example 2)

加入适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(

GmbH & Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel 10FP，Dow ChemicalCompany)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。Add an appropriate amount of purified water and mix with 20 mg of donepezil hydrochloride (Eisai Co.Ltd.), 500 mg of Eudragit L100-55 (

GmbH & Co.KG), the lactose of 1000mg and the ethylcellulose (Ethocel 10FP, Dow ChemicalCompany) of 500mg are mixed, and this mixture is heated and dried in constant temperature drier, obtains the polynaphthyl hydrochloride containing about 1% of the gross weight of particle Granules of pezil.

(实施例3)(Example 3)

将20mg的柠檬酸溶解于适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(GmbH &Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel 10FP，DowChemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。20 mg of citric acid was dissolved in an appropriate amount of purified water and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 ( GmbH & Co.KG), the lactose of 1000mg and the ethylcellulose (Ethocel 10FP, DowChemical Company) of 500mg are mixed, and this mixture is heated and dried in constant temperature drier, obtains the donenaphtidine hydrochloride containing about 1% of the gross weight of particle neat particles.

(实施例4)(Example 4)

将20mg的二氢柠檬酸钠溶解于适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(

GmbH & Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel10FP，Dow Chemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。20 mg of sodium dihydrocitrate was dissolved in an appropriate amount of purified water and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (

GmbH & Co.KG), the lactose of 1000mg and the ethylcellulose (Ethocel10FP, Dow Chemical Company) of 500mg are mixed, and this mixture is heated and dried in constant temperature drier, obtains the polynaphthyl hydrochloride containing about 1% of the gross weight of particle Granules of pezil.

(实施例5)(Example 5)

将20mg的门冬氨酸溶解于适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(

GmbH& Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel 10FP，Dow Chemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。20 mg of aspartic acid was dissolved in an appropriate amount of purified water and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (

GmbH & Co.KG), the lactose of 1000mg and the ethylcellulose (Ethocel 10FP, Dow Chemical Company) of 500mg are mixed, and this mixture is heated and dried in constant temperature drier, obtains the polynaphthyl hydrochloride containing about 1% of the gross weight of particle Granules of pezil.

(实施例6)(Example 6)

将20mg的抗坏血酸溶解于适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(

GmbH& Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel 10FP，Dow Chemical Company)混合。在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。20 mg of ascorbic acid was dissolved in an appropriate amount of purified water and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (

GmbH & Co. KG), 1000 mg of lactose and 500 mg of ethylcellulose (Ethocel 10FP, Dow Chemical Company) were mixed. The mixture was heated and dried in a constant temperature dryer to obtain granules containing about 1% of donepezil hydrochloride based on the total weight of the granules.

(实施例7)(Example 7)

将20mg的抗坏血酸钠溶解于适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(

GmbH & Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel10FP，Dow Chemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。20 mg of sodium ascorbate was dissolved in an appropriate amount of purified water and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (

GmbH & Co.KG), the lactose of 1000mg and the ethylcellulose (Ethocel10FP, Dow Chemical Company) of 500mg are mixed, and this mixture is heated and dried in constant temperature drier, obtains the polynaphthyl hydrochloride containing about 1% of the gross weight of particle Granules of pezil.

(实施例8)(Embodiment 8)

将20mg的半胱氨酸溶解于适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(

GmbH& Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel 10FP，Dow Chemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。20 mg of cysteine was dissolved in an appropriate amount of purified water and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (

GmbH & Co.KG), the lactose of 1000mg and the ethylcellulose (Ethocel 10FP, Dow Chemical Company) of 500mg are mixed, and this mixture is heated and dried in constant temperature drier, obtains the polynaphthyl hydrochloride containing about 1% of the gross weight of particle Granules of pezil.

(实施例9)(Example 9)

将20mg的盐酸半胱氨酸溶解于适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(

GmbH & Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel10FP，Dow Chemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。20 mg of cysteine hydrochloride was dissolved in an appropriate amount of purified water and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (

GmbH & Co.KG), the lactose of 1000mg and the ethylcellulose (Ethocel10FP, Dow Chemical Company) of 500mg are mixed, and this mixture is heated and dried in constant temperature drier, obtains the polynaphthyl hydrochloride containing about 1% of the gross weight of particle Granules of pezil.

(实施例10)(Example 10)

将20mg的甲硫氨酸溶解于适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(

GmbH& Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel 10FP，Dow Chemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。20 mg of methionine was dissolved in an appropriate amount of purified water and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (

GmbH & Co.KG), the lactose of 1000mg and the ethylcellulose (Ethocel 10FP, Dow Chemical Company) of 500mg are mixed, and this mixture is heated and dried in constant temperature drier, obtains the polynaphthyl hydrochloride containing about 1% of the gross weight of particle Granules of pezil.

(实施例11)(Example 11)

将130g的盐酸多萘哌齐(Eisai Co.Ltd.)、312g的乙基纤维素(Ethocel 10FP，Dow Chemical Company)、624g的EudragitL100-55(

GmbH & Co.KG)和1456g的乳糖在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中52g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)，在盘架干燥器中加热干燥所得到的颗粒，并过筛，得到需要的粒径。在过筛后，每99g的颗粒加入1g的硬脂酸镁(Mallinckrodt Baker，Inc.)并混合，使用旋转压片机，形成每200mg的片剂包含10mg的盐酸多萘哌齐的直径8mm的片剂。使用Opadry Yellow(Japan Colorcon)，然后给予这些片剂包含羟丙基甲基纤维素作为主要组分的水性薄膜包衣(包衣量：8mg/片)，得到薄膜包衣的片剂。Donepezil hydrochloride (Eisai Co. Ltd.) of 130 g, ethyl cellulose (Ethocel 10FP, Dow Chemical Company) of 312 g, Eudragit L100-55 of 624 g (

GmbH & Co. KG) and 1456 g of lactose were mixed in a granulator. Wet granulation was performed comprising adding 52 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water to the mixture, and heating and drying the resulting granules in a rack drier. , and sieved to obtain the required particle size. After sieving, 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99 g of the granules and mixed to form tablets of 8 mm in diameter containing 10 mg of donepezil hydrochloride per 200 mg using a rotary tablet press. tablet. Using Opadry Yellow (Japan Colorcon), these tablets were then given an aqueous film coating (coating amount: 8 mg/tablet) containing hydroxypropylmethylcellulose as a main component to obtain film-coated tablets.

(实施例12)(Example 12)

将130g的盐酸多萘哌齐(Eisai Co.Ltd.)、624g的乙基纤维素(Ethocel 10FP，Dow Chemical Company)、780g的EudragitL100-55(

GmbH & Co.KG)和988g的乳糖在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中52g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)，在盘架干燥器中加热干燥所得到的颗粒，并过筛，得到需要的粒径。在过筛后，每99g的颗粒加入1g的硬脂酸镁(Mallinckrodt Baker，Inc.)并混合，使用旋转压片机，形成每200mg的片剂包含10mg的盐酸多萘哌齐的直径8mm的片剂。使用Opadry Yellow(Japan Colorcon)，然后给予这些片剂包含羟丙基甲基纤维素作为主要组分的水性薄膜包衣(包衣量：8mg/片)，得到薄膜包衣的片剂。Donepezil hydrochloride (Eisai Co. Ltd.) of 130 g, ethyl cellulose (Ethocel 10FP, Dow Chemical Company) of 624 g, Eudragit L100-55 of 780 g (

GmbH & Co. KG) and 988 g of lactose were mixed in a granulator. Wet granulation was performed comprising adding 52 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water to the mixture, and heating and drying the resulting granules in a rack drier. , and sieved to obtain the required particle size. After sieving, 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99 g of the granules and mixed to form tablets of 8 mm in diameter containing 10 mg of donepezil hydrochloride per 200 mg using a rotary tablet press. tablet. Using Opadry Yellow (Japan Colorcon), these tablets were then given an aqueous film coating (coating amount: 8 mg/tablet) containing hydroxypropylmethylcellulose as a main component to obtain film-coated tablets.

(实施例13)(Example 13)

将130g的盐酸多萘哌齐(Eisai Co.Ltd.)、780g的乙基纤维素(Ethocel 10FP，Dow Chemical Company)、858g的EudragitL100-55(GmbH & Co.KG)和754g的乳糖在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中52g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)，在盘架干燥器中加热干燥所得到的颗粒，并过筛，得到需要的粒径。在过筛后，每99g的颗粒加入1g的硬脂酸镁(Mallinckrodt Baker，Inc.)并混合，使用旋转压片机，形成每200mg的片剂包含10mg的盐酸多萘哌齐的直径8mm的片剂。使用Opadry Yellow(Japan Colorcon)，然后给予这些片剂包含羟丙基甲基纤维素作为主要组分的水性薄膜包衣(包衣量：8mg/片)，得到薄膜包衣的片剂。Donepezil hydrochloride (Eisai Co. Ltd.) of 130 g, ethyl cellulose (Ethocel 10FP, Dow Chemical Company) of 780 g, Eudragit L100-55 of 858 g ( GmbH & Co. KG) and 754 g of lactose were mixed in a granulator. Wet granulation was performed comprising adding 52 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water to the mixture, and heating and drying the resulting granules in a rack drier. , and sieved to obtain the required particle size. After sieving, 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99 g of the granules and mixed to form tablets of 8 mm in diameter containing 10 mg of donepezil hydrochloride per 200 mg using a rotary tablet press. tablet. Using Opadry Yellow (Japan Colorcon), these tablets were then given an aqueous film coating (coating amount: 8 mg/tablet) containing hydroxypropylmethylcellulose as a main component to obtain film-coated tablets.

(实施例14)(Example 14)

将130g的盐酸多萘哌齐(Eisai Co.Ltd.)、832g的乙基纤维素(Ethocel 10FP，Dow Chemical Company)、962g的EudragitL100-55(

GmbH & Co.KG)和598g的乳糖在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中52g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)，在盘架干燥器中加热干燥所得到的颗粒，并过筛，得到需要的粒径。在过筛后，每99g的颗粒加入1g的硬脂酸镁(Mallinckrodt Baker，Inc.)并混合，使用旋转压片机，形成每200mg的片剂包含10mg的盐酸多萘哌齐的直径8mm的片剂。使用Opadry Yellow(Japan Colorcon)，然后给予这些片剂包含羟丙基甲基纤维素作为主要组分的水性薄膜包衣(包衣量：8mg/片)，得到薄膜包衣的片剂。Donepezil hydrochloride (Eisai Co. Ltd.) of 130 g, ethyl cellulose (Ethocel 10FP, Dow Chemical Company) of 832 g, Eudragit L100-55 of 962 g (

GmbH & Co. KG) and 598 g of lactose were mixed in a granulator. Wet granulation was performed comprising adding 52 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water to the mixture, and heating and drying the resulting granules in a rack drier. , and sieved to obtain the required particle size. After sieving, 1 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99 g of the granules and mixed to form tablets of 8 mm in diameter containing 10 mg of donepezil hydrochloride per 200 mg using a rotary tablet press. tablet. Using Opadry Yellow (Japan Colorcon), these tablets were then given an aqueous film coating (coating amount: 8 mg/tablet) containing hydroxypropylmethylcellulose as a main component to obtain film-coated tablets.

(实施例15)(Example 15)

将3.5g的盐酸多萘哌齐(Eisai Co.Ltd.)、37.8g的Ethocel10FP(乙基纤维素，Dow Chemical Company)、22.4g的EudragitL100-55(GmbH & Co.KG)和73.5g的乳糖(Pharmatose 200M，由DMV Corporation制造)在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中2.8g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)，在盘架干燥器中加热干燥所得到的颗粒，并过筛，得到需要的粒径。在过筛后，每5000mg的颗粒加入50mg的硬脂酸钙(Merck KGaA，Germany)并混合，使用AutographAG5000A(Shimazu Corporation)，制成每202mg的该产品中包含5mg的盐酸多萘哌齐的直径8mm的压模产品，压缩压力为1200Kgf。3.5 g of donepezil hydrochloride (Eisai Co. Ltd.), 37.8 g of Ethocel10FP (ethylcellulose, Dow Chemical Company), 22.4 g of Eudragit L100-55 ( GmbH & Co. KG) and 73.5 g of lactose (Pharmatose 200M, manufactured by DMV Corporation) were mixed in a granulator. Wet granulation was performed comprising adding 2.8 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water to the mixture, and heating and drying the obtained product in a rack drier. particles, and sieved to obtain the required particle size. After sieving, 50 mg of calcium stearate (Merck KGaA, Germany) was added per 5000 mg of granules and mixed using Autograph AG5000A (Shimazu Corporation) to make a diameter of 5 mg of donepezil hydrochloride per 202 mg of this product 8mm compression molded product, the compression pressure is 1200Kgf.

(实施例16)(Example 16)

将3.5g的盐酸多萘哌齐(Eisai Co.Ltd.)、37.8g的Ethocel1QFP(乙基纤维素，Dow Chemical Company)、22.4g的EudragitL100-55(

GmbH & Co.KG)和73.08g的乳糖(Pharmatose 200M，由DMV Corporation制造)在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中2.8g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)和0.42g的柠檬酸，在盘架干燥器中加热干燥所得到的颗粒，通过强力碾压过筛得到需要的粒径。在过筛后，每5000mg的颗粒加入50mg的硬脂酸钙(Merck KGaA，Germany)并混合，使用Autograph AG5000A(Shimazu Corporation)，制成每202mg的该产品中包含5mg的盐酸多萘哌齐的直径8mm的压模产品，压缩压力为1200Kgf。3.5 g of donepezil hydrochloride (Eisai Co. Ltd.), 37.8 g of Ethocel1QFP (ethyl cellulose, Dow Chemical Company), 22.4 g of Eudragit L100-55 (

GmbH & Co. KG) and 73.08 g of lactose (Pharmatose 200M, manufactured by DMV Corporation) were mixed in a granulator. Wet granulation was carried out, comprising adding 2.8 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd) and 0.42 g of citric acid dissolved in an appropriate amount of purified water to the mixture, and drying in a rack drier. The obtained particles are heated and dried in the middle, and the required particle size is obtained by strong rolling and sieving. After sieving, 50 mg of calcium stearate (Merck KGaA, Germany) was added per 5000 mg of granules and mixed, using Autograph AG5000A (Shimazu Corporation) to make a product containing 5 mg of donepezil hydrochloride per 202 mg of the product. The compression molded product with a diameter of 8mm has a compression pressure of 1200Kgf.

(实施例17)(Example 17)

将3.5g的盐酸多萘哌齐(Eisai Co.Ltd.)、37.8g的Ethocel10FP(乙基纤维素，Dow Chemical Company)、22.4g的EudragitL100-55(

GmbH & Co.KG)和73.5g的乳糖(Pharmatose 200M，由DMV Corporation制造)在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中2.8g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)，在盘架干燥器中加热干燥所得到的颗粒，通过强力碾压过筛得到需要的粒径。在过筛后，每5000mg的颗粒加入50mg的硬脂酸镁(Mallinckrodt Baker，Inc.)并混合，使用Autograph AG5000A(Shimazu Corporation)，制成每202mg的该产品中包含5mg的盐酸多萘哌齐的直径8mm的压模产品，压缩压力为1200Kgf。3.5 g of donepezil hydrochloride (Eisai Co. Ltd.), 37.8 g of Ethocel10FP (ethylcellulose, Dow Chemical Company), 22.4 g of Eudragit L100-55 (

GmbH & Co. KG) and 73.5 g of lactose (Pharmatose 200M, manufactured by DMV Corporation) were mixed in a granulator. Wet granulation was performed comprising adding 2.8 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water to the mixture, and heating and drying the obtained product in a rack drier. Particles are sieved by strong rolling to obtain the required particle size. After sieving, 50 mg of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 5000 mg of granules and mixed, using Autograph AG5000A (Shimazu Corporation) to make 5 mg of donepezil hydrochloride per 202 mg of the product The compression molded product with a diameter of 8mm has a compression pressure of 1200Kgf.

(实施例18)(Example 18)

将3.5g的盐酸多萘哌齐(Eisai Co.Ltd.)、37.8g的Ethocel10FP(乙基纤维素，Dow Chemical Company)、22.4g的EudragitL100-55(

GmbH & Co.KG)和73.08g的乳糖(Pharmatose 200M，由DMV Corporation制造)在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中2.8g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)和0.42g的柠檬酸，在盘架干燥器中加热干燥所得到的颗粒，通过强力碾压过筛得到需要的粒径。在过筛后，每5000mg的颗粒加入50mg的硬脂酸镁(Mallinckrodt Baker，Inc.)并混合，使用Autograph AG5000A(Shimazu Corporation)，制成每202mg的该产品中包含5mg的盐酸多萘哌齐的直径8mm的压模产品，压缩压力为1200Kgf。3.5 g of donepezil hydrochloride (Eisai Co. Ltd.), 37.8 g of Ethocel10FP (ethylcellulose, Dow Chemical Company), 22.4 g of Eudragit L100-55 (

GmbH & Co. KG) and 73.08 g of lactose (Pharmatose 200M, manufactured by DMV Corporation) were mixed in a granulator. Wet granulation was carried out, comprising adding 2.8 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd) and 0.42 g of citric acid dissolved in an appropriate amount of purified water to the mixture, and drying in a rack drier. The obtained particles are heated and dried in the middle, and the required particle size is obtained by strong rolling and sieving. After sieving, 50 mg of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 5000 mg of granules and mixed, using Autograph AG5000A (Shimazu Corporation) to make 5 mg of donepezil hydrochloride per 202 mg of the product The compression molded product with a diameter of 8mm has a compression pressure of 1200Kgf.

(实施例19)(Example 19)

将980g的盐酸多萘哌齐(Eisai Co.Ltd.)、3780g的Ethocel10FP(乙基纤维素，Dow Chemical Company)、2660g的EudragitL100-55(GmbH & Co.KG)和6188g的乳糖在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中300g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)，在盘架干燥器中加热干燥所得到的颗粒，并过筛，得到需要的粒径。在过筛后，每99.7g的颗粒加入0.3g的硬脂酸镁(Mallinckrodt Baker，Inc.)混合，使用旋转压片机，形成每200mg的片剂包含14mg的盐酸多萘哌齐的直径8mm的片剂。使用Opadry purple(Colorcon Japan Limited)，然后给予所得到的片剂包含羟丙基甲基纤维素作为主要组分的水溶性薄膜包衣(包衣量：8mg/片)，得到薄膜包衣的片剂。Donepezil hydrochloride (Eisai Co.Ltd.) of 980g, Ethocel10FP (ethylcellulose, Dow Chemical Company) of 3780g, EudragitL100-55 of 2660g ( GmbH & Co. KG) and 6188 g of lactose were mixed in a granulator. Wet granulation was performed comprising adding to the mixture 300 g of hydroxypropylcellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water, and heating and drying the resulting granules in a rack drier. , and sieved to obtain the required particle size. After sieving, 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99.7 g of the granules and mixed using a rotary tablet press to form tablets containing 14 mg of donepezil hydrochloride per 200 mg with a diameter of 8 mm. tablet. Opadry purple (Colorcon Japan Limited) was used, and then a water-soluble film coating (coating amount: 8 mg/tablet) containing hydroxypropylmethylcellulose as a main component was given to the obtained tablet to obtain a film-coated tablet. agent.

(实施例20)(Example 20)

将1050g的盐酸多萘哌齐(Eisai Co.Ltd.)、3780g的Ethocel10FP(乙基纤维素，Dow Chemical Company)、2240g的EudragitL100-55(

GmbH & Co.KG)和6538g的乳糖在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中350g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)，在流化床干燥器中加热干燥所得到的颗粒，并过筛，得到需要的粒径。在过筛后，每99.7g的颗粒加入0.3g的硬脂酸镁(Mallinckrodt Baker，Inc.)混合，使用旋转压片机，形成每200mg的片剂包含15mg的盐酸多萘哌齐的直径8mm的片剂。使用Opadry purple(Colorcon Japan Limited)，然后给予所得到的片剂包含羟丙基甲基纤维素作为主要组分的水溶性薄膜包衣(包衣量：8mg/片)，得到薄膜包衣的片剂。Donepezil hydrochloride (Eisai Co.Ltd.) of 1050g, Ethocel10FP (ethylcellulose, Dow Chemical Company) of 3780g, EudragitL100-55 of 2240g (

GmbH & Co. KG) and 6538 g of lactose were mixed in a granulator. Wet granulation was performed comprising adding 350 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water to the mixture, and heating and drying the obtained product in a fluidized bed drier. particles, and sieved to obtain the required particle size. After sieving, 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99.7 g of the granules and mixed, using a rotary tablet press, to form tablets containing 15 mg of donepezil hydrochloride per 200 mg with a diameter of 8 mm. tablet. Opadry purple (Colorcon Japan Limited) was used, and then a water-soluble film coating (coating amount: 8 mg/tablet) containing hydroxypropylmethylcellulose as a main component was given to the obtained tablet to obtain a film-coated tablet. agent.

(实施例21)(Example 21)

将1400g的盐酸多萘哌齐(Eisai Co.Ltd.)、3500g的Ethocel10FP(乙基纤维素，Dow Chemical Company)、2520g的EudragitL100-55(

GmbH & Co.KG)和6118g的乳糖在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中420g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)，在流化床干燥器中加热干燥所得到的颗粒，并过筛，得到需要的粒径。在过筛后，每99.7g的颗粒加入0.3g的硬脂酸镁(Mallinckrodt Baker，Inc.)混合，使用旋转压片机，形成每200mg的片剂包含20mg的盐酸多萘哌齐的直径8mm的片剂。使用Opadry Red(Colorcon Japan Limited)给予所得到的片剂包含羟丙基甲基纤维素作为主要组分的水溶性薄膜包衣(包衣量：8mg/片)，得到薄膜包衣的片剂。Donepezil hydrochloride (Eisai Co.Ltd.) of 1400g, Ethocel10FP (ethylcellulose, Dow Chemical Company) of 3500g, EudragitL100-55 of 2520g (

GmbH & Co. KG) and 6118 g of lactose were mixed in a granulator. Wet granulation was performed comprising adding 420 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water to the mixture, and heating and drying the obtained product in a fluidized bed drier. particles, and sieved to obtain the required particle size. After sieving, 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99.7 g of the granules and mixed using a rotary tablet press to form tablets containing 20 mg of donepezil hydrochloride per 200 mg with a diameter of 8 mm. tablet. The resulting tablet was given a water-soluble film coating (coating amount: 8 mg/tablet) containing hydroxypropylmethylcellulose as a main component using Opadry Red (Colorcon Japan Limited) to obtain a film-coated tablet.

(实施例22)(Example 22)

将1610g的盐酸多萘哌齐(Eisai Co.Ltd.)、3500g的Ethocel10FP(乙基纤维素，Dow Chemical Company)、2520g的EudragitL100-55(

GmbH & Co.KG)和5908g的乳糖在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中420g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)，在流化床干燥器中加热干燥所得到的颗粒，并过筛，得到需要的粒径。在过筛后，每99.7g的颗粒加入0.3g的硬脂酸镁(Mallinckrodt Baker，Inc.)混合，使用旋转压片机，形成每200mg的片剂包含23mg的盐酸多萘哌齐的直径8mm的片剂。使用Opadry Red(Colorcon Japan Limited)给予所得到的片剂包含羟丙基甲基纤维素作为主要组分的水溶性薄膜包衣(包衣量：8mg/片)，得到薄膜包衣的片剂。Donepezil hydrochloride (Eisai Co.Ltd.) of 1610g, Ethocel10FP (ethylcellulose, Dow Chemical Company) of 3500g, EudragitL100-55 of 2520g (

GmbH & Co. KG) and 5908 g of lactose were mixed in a granulator. Wet granulation was performed comprising adding 420 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water to the mixture, and heating and drying the obtained product in a fluidized bed drier. particles, and sieved to obtain the required particle size. After sieving, 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99.7 g of the granules and mixed using a rotary tablet press to form tablets containing 23 mg of donepezil hydrochloride per 200 mg with a diameter of 8 mm tablet. The resulting tablet was given a water-soluble film coating (coating amount: 8 mg/tablet) containing hydroxypropylmethylcellulose as a main component using Opadry Red (Colorcon Japan Limited) to obtain a film-coated tablet.

(实施例23)(Example 23)

1610g的盐酸多萘哌齐(Eisai Co.Ltd.)、3080g的Ethocel10FP(乙基纤维素，Dow Chemical Company)、2940g的EudragitL100-55(

GmbH & Co.KG)和5908g的乳糖在制粒机中混合。进行湿法制粒，包括向该混合物中加入溶解在适当量的纯净水中420g的羟丙基纤维素(HPC-L；Nippon Soda Co.，Ltd)，在流化床干燥器中加热干燥所得到的颗粒，并过筛，得到需要的粒径。在过筛后，每99.7g的颗粒加入0.3g的硬脂酸镁(Mallinckrodt Baker，Inc.)混合，使用旋转压片机，形成每200mg的片剂包含23mg的盐酸多萘哌齐的直径8mm的片剂。使用Opadry Red(Colorcon Japan Limited)给予所得到的片剂包含羟丙基甲基纤维素作为主要组分的水溶性薄膜包衣(包衣量：8mg/片)，得到薄膜包衣的片剂。Donepezil hydrochloride (Eisai Co.Ltd.) of 1610g, Ethocel10FP (ethylcellulose, Dow Chemical Company) of 3080g, Eudragit L100-55 of 2940g (

GmbH & Co. KG) and 5908 g of lactose were mixed in a granulator. Wet granulation was performed comprising adding 420 g of hydroxypropyl cellulose (HPC-L; Nippon Soda Co., Ltd) dissolved in an appropriate amount of purified water to the mixture, and heating and drying the obtained product in a fluidized bed drier. particles, and sieved to obtain the required particle size. After sieving, 0.3 g of magnesium stearate (Mallinckrodt Baker, Inc.) was added per 99.7 g of the granules and mixed using a rotary tablet press to form tablets containing 23 mg of donepezil hydrochloride per 200 mg with a diameter of 8 mm tablet. The resulting tablet was given a water-soluble film coating (coating amount: 8 mg/tablet) containing hydroxypropylmethylcellulose as a main component using Opadry Red (Colorcon Japan Limited) to obtain a film-coated tablet.

实施例24到30Examples 24 to 30

可以根据上述方法制备表1所示的薄膜包衣的片剂。The film-coated tablets shown in Table 1 can be prepared according to the method described above.

实施例31到34Examples 31 to 34

根据表2和3的组分，在研钵中混合每种组分，取200mg的该混合物，用Autograph AG5000A(Shimazu Corporation)制成包含20mg的盐酸多萘哌齐或20mg的盐酸美金刚的直径8mm的片剂(片重：200mg)。According to the components of Tables 2 and 3, each component was mixed in a mortar, and 200 mg of this mixture was taken to make a diameter containing 20 mg of donepezil hydrochloride or 20 mg of memantine hydrochloride with Autograph AG5000A (Shimazu Corporation) 8 mm tablet (tablet weight: 200 mg).

表2Table 2

表3table 3

(比较实施例1)(comparative example 1)

将300mg的盐酸多萘哌齐(Eisai Co.Ltd.)、750mg的乙基纤维素(Ethocel 10FP，Dow Chemical Company)、1920mg的乳糖和30mg的硬脂酸镁(Mallinckrodt Baker，Inc.)在研钵中混合。取200mg的该混合物，用Autograph AG5000A(Shimazu Corporation)制成片剂，得到包含20mg的盐酸多萘哌齐的直径8mm的片剂。300 mg of donepezil hydrochloride (Eisai Co. Ltd.), 750 mg of ethylcellulose (Ethocel 10FP, Dow Chemical Company), 1920 mg of lactose and 30 mg of magnesium stearate (Mallinckrodt Baker, Inc.) Mix in a bowl. 200 mg of this mixture was taken and tableted with Autograph AG5000A (Shimazu Corporation) to obtain tablets with a diameter of 8 mm containing 20 mg of donepezil hydrochloride.

(比较实施例2)(comparative example 2)

将300mg的盐酸多萘哌齐(Eisai Co.Ltd.)、750mg的乙基纤维素(Ethocel 10FP，Dow Chemical Company)、1620mg的乳糖、300mg的柠檬酸和30mg的硬脂酸镁(Mallinckrodt Baker，Inc.)在研钵中混合。取200mg的该混合物，用Autograph AG5000A(ShimazuCorporation)制成片剂，得到包含20mg的盐酸多萘哌齐的直径8mm的片剂。300 mg of donepezil hydrochloride (Eisai Co. Ltd.), 750 mg of ethylcellulose (Ethocel 10FP, Dow Chemical Company), 1620 mg of lactose, 300 mg of citric acid and 30 mg of magnesium stearate (Mallinckrodt Baker, Inc.) in a mortar and mortar. 200 mg of this mixture was taken and tableted with Autograph AG5000A (Shimazu Corporation) to obtain tablets with a diameter of 8 mm containing 20 mg of donepezil hydrochloride.

(比较实施例3)(comparative example 3)

加入适当量的纯净水并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、1500mg的乳糖和500mg的乙基纤维素(Ethocel 10FP，DowChemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。Add an appropriate amount of purified water and mix with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 1500 mg of lactose and 500 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), and heat dry the product in a constant temperature drier. mixture to obtain granules comprising about 1% of donepezil hydrochloride based on the total weight of the granules.

(比较实施例4)(comparative example 4)

将20mg的柠檬酸二钠溶解于适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(GmbH & Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel10FP，Dow Chemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。20 mg of disodium citrate was dissolved in an appropriate amount of purified water and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 ( GmbH & Co.KG), the lactose of 1000mg and the ethylcellulose (Ethocel10FP, Dow Chemical Company) of 500mg are mixed, and this mixture is heated and dried in constant temperature drier, obtains the polynaphthyl hydrochloride containing about 1% of the gross weight of particle Granules of pezil.

(比较实施例5)(comparative example 5)

将20mg的柠檬酸钠溶解于适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(

GmbH& Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel 10FP，Dow Chemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。20 mg of sodium citrate was dissolved in an appropriate amount of purified water and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (

GmbH & Co.KG), the lactose of 1000mg and the ethylcellulose (Ethocel 10FP, Dow Chemical Company) of 500mg are mixed, and this mixture is heated and dried in constant temperature drier, obtains the polynaphthyl hydrochloride containing about 1% of the gross weight of particle Granules of pezil.

(比较实施例6)(comparative example 6)

将20mg的天冬氨酸钠溶解于适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(

GmbH & Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel10FP，Dow Chemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。20 mg of sodium aspartate was dissolved in an appropriate amount of purified water and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (

GmbH & Co.KG), the lactose of 1000mg and the ethylcellulose (Ethocel10FP, Dow Chemical Company) of 500mg are mixed, and this mixture is heated and dried in constant temperature drier, obtains the polynaphthyl hydrochloride containing about 1% of the gross weight of particle Granules of pezil.

(比较实施例7)(comparative example 7)

将20mg的甘氨酸溶解于适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(

GmbH &Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel 10FP，DowChemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。20 mg of glycine was dissolved in an appropriate amount of purified water and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (

GmbH & Co.KG), the lactose of 1000mg and the ethylcellulose (Ethocel 10FP, DowChemical Company) of 500mg are mixed, and this mixture is heated and dried in constant temperature drier, obtains the donenaphtidine hydrochloride containing about 1% of the gross weight of particle neat particles.

(比较实施例8)(comparative example 8)

将20mg的依地酸二钠溶解于适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、500mg的Eudragit L100-55(

GmbH & Co.KG)、1000mg的乳糖和500mg的乙基纤维素(Ethocel10FP，Dow Chemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。20 mg of edetate disodium was dissolved in an appropriate amount of purified water and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 500 mg of Eudragit L100-55 (

GmbH & Co.KG), the lactose of 1000mg and the ethylcellulose (Ethocel10FP, Dow Chemical Company) of 500mg are mixed, and this mixture is heated and dried in constant temperature drier, obtains the polynaphthyl hydrochloride containing about 1% of the gross weight of particle Granules of pezil.

(比较实施例9)(comparative example 9)

加入适当量的纯净水并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、1000mg的乳糖和1000mg的乙基纤维素(Ethocel 10FP，DowChemical Company)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。Add an appropriate amount of purified water and mix with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 1000 mg of lactose and 1000 mg of ethyl cellulose (Ethocel 10FP, Dow Chemical Company), and heat dry the product in a constant temperature drier. mixture to obtain granules comprising about 1% of donepezil hydrochloride based on the total weight of the granules.

(比较实施例10)(comparative example 10)

加入适当量的纯净水并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)和2000mg的乳糖混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。An appropriate amount of purified water was added and mixed with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.) and 2000 mg of lactose, and the mixture was heated and dried in a constant temperature drier to obtain hydrochloric acid containing about 1% of the total weight of the granules. Granules of donepezil.

(比较实施例11)(comparative example 11)

加入适当量的纯净水中并与20mg的盐酸多萘哌齐(Eisai Co.Ltd.)、1500mg的乳糖和500mg的Eudragit L100-55(

GmbH &Co.KG)混合，在恒温干燥器中加热干燥该混合物，得到包含占颗粒的总重量约1％的盐酸多萘哌齐的颗粒。Add an appropriate amount of purified water and mix with 20 mg of donepezil hydrochloride (Eisai Co. Ltd.), 1500 mg of lactose and 500 mg of Eudragit L100-55 (

GmbH & Co. KG) were mixed, and the mixture was heated and dried in a constant temperature dryer to obtain granules containing donepezil hydrochloride in an amount of about 1% of the total weight of the granules.

(试验实施例1)(Test Example 1)

将实施例1和比较实施例1和2的包含10％盐酸多萘哌齐的片剂在开放(未密封)的恒温室中在60℃，75％RH下贮存1周，在贮存前和后测定降解产物的量。通过下面的降解产物分析法1进行降解产物的测定。The tablets containing 10% donepezil hydrochloride of Example 1 and Comparative Examples 1 and 2 were stored in an open (unsealed) thermostatic chamber at 60° C., 75% RH for 1 week, before and after storage Determination of the amount of degradation products. Determination of degradation products was carried out by the following degradation product analysis method 1.

(降解产物分析法1)(degradation product analysis method 1)

通过HPLC评价降解产物的量，使用内径4.6mm^*、长度75mm的ODS-A柱(YMC Co.LTd.)作为测量柱在35℃，流速1ml/分钟，检测波长271nm的条件下进行测定。流动相的组合物和线性梯度情况如表4所示。用在相对于主要药物峰的相对保留时间1.1到1.2附近洗脱的降解产物的峰作为基准得到的总峰面积的百分比评价降解产物的量。The amount of degradation products was evaluated by HPLC using an ODS-A column (YMC Co.LTd.) with an inner diameter of 4.6mm^* and a length of 75mm as a measuring column at 35°C, a flow rate of 1ml/min, and a detection wavelength of 271nm. The composition and linear gradient of the mobile phase are shown in Table 4. The amount of degradation product was evaluated as a percentage of the total peak area obtained with the peak of the degradation product eluting around the relative retention time 1.1 to 1.2 relative to the main drug peak as a reference.

流动相A：水/乙腈/70％高氯酸水溶液＝899/100/1混合物Mobile phase A: water/acetonitrile/70% perchloric acid aqueous solution=899/100/1 mixture

流动相B：水/乙腈/70％高氯酸水溶液＝99/900/1混合物Mobile phase B: water/acetonitrile/70% perchloric acid aqueous solution=99/900/1 mixture

表4Table 4

  分钟 minute 流动相A：Mobile phase A: 流动相Bmobile phase B  0.000.00 75％75% 25％25%  6.006.00 75％75% 25％25%  9.009.00 0％0% 100％100%  10.0010.00 0％0% 100％100%  10.0110.01 75％75% 25％25%  13.0013.00 75％75% 25％25%

在相对于多萘哌齐的相对保留时间1.1到1.2附近洗脱的降解产物的量如表5所示，作为试验实施例1的测定结果。在比较实施例1中检测到了0.12％的降解产物，而包含50％Eudragit L100-55作为高分子量酸性物质实施例1则未检测到降解产物。在实施例1或比较实施例1中未检测到其他降解产物。在分别包含10％的药物和柠檬酸的比较实施例2的情况中，不仅相对保留时间1.1到1.2附近产生0.77％的降解产物，而且产生了各种其他的降解产物，降解产物的总量达到约13％。在背景技术所述的日本专利申请公开H11-106353中在0.1％多萘哌齐溶液中加入柠檬酸有效地实现了耐光性，但显然，混入柠檬酸实际上在包含10％的盐酸多萘哌齐的片剂中增加了降解产物而影响了盐酸多萘哌齐的热稳定性。但是当以50％的高浓度加入Eudragit L100-55作为高分子量酸性物质，没有检测到降解产物，证明对于药物组合物中盐酸多萘哌齐的热稳定性具有改善作用。这表明了高分子量酸性物质在包含抗痴呆药物和高分子量碱性物质的组合物中对热稳定性的改善作用。The amounts of degradation products eluted around the relative retention time of 1.1 to 1.2 relative to donepezil are shown in Table 5 as the measurement results of Test Example 1. 0.12% of degradation products were detected in Comparative Example 1, while no degradation products were detected in Example 1 comprising 50% Eudragit L100-55 as the high molecular weight acidic substance. No other degradation products were detected in Example 1 or Comparative Example 1. In the case of Comparative Example 2 containing 10% of the drug and citric acid respectively, not only 0.77% of degradation products were produced around the relative retention time 1.1 to 1.2, but also various other degradation products were produced, and the total amount of degradation products reached About 13%. Addition of citric acid to 0.1% donepezil solution in Japanese Patent Application Publication H11-106353 mentioned in the background art is effective in achieving photostability, but it is clear that mixing citric acid actually results in 10% donepezil hydrochloride containing The thermal stability of donepezil hydrochloride is affected by the increase of degradation products in the tablet of Qi. However, when Eudragit L100-55 was added at a high concentration of 50% as a high-molecular-weight acidic substance, no degradation product was detected, proving that it has an improving effect on the thermal stability of donepezil hydrochloride in the pharmaceutical composition. This demonstrates the improved effect of high molecular weight acidic substances on thermal stability in compositions comprising anti-dementia drugs and high molecular weight basic substances.

表5table 5

(试验实施例2)(Test Example 2)

将实施例2和3和比较实施例3的包含约1％盐酸多萘哌齐的颗粒在开放(未密封)的恒温室中在60℃，75％RH下贮存1周，在贮存前和后测定降解产物的量。通过下面的降解产物分析法2进行降解产物的测定。用相同方法试验比较实施例9到11的颗粒以研究试验实施例1的作用。The granules containing about 1% donepezil hydrochloride of Examples 2 and 3 and Comparative Example 3 were stored in an open (unsealed) thermostatic chamber at 60° C., 75% RH for 1 week, before and after storage Determination of the amount of degradation products. Determination of degradation products was carried out by the following degradation product analysis method 2. The granules of Comparative Examples 9 to 11 were tested in the same manner to investigate the effect of Test Example 1.

(降解产物分析法2)(degradation product analysis method 2)

通过HPLC评价降解产物的量，使用内径4.6mm^*、长度150mm的Inertsil ODS-2柱(GL Sciences)柱作为测定柱和水/乙腈/70％高氯酸水溶液/癸烷磺酸钠的646.6/350/1/2.4混合物，条件为柱温35℃，流速1.4mL/分钟，检测波长271nm。用在相对于主要药物峰的相对保留时间1.1到1.2附近洗脱的降解产物的峰作为基准得到的总峰面积的百分比评价降解产物的量。The amount of degradation products was evaluated by HPLC, using an Inertsil ODS-2 column (GL Sciences) column with an inner diameter of 4.6mm^* and a length of 150mm as the assay column and 646.6/ 350/1/2.4 mixture, the conditions are column temperature 35°C, flow rate 1.4mL/min, detection wavelength 271nm. The amount of degradation product was evaluated as a percentage of the total peak area obtained with the peak of the degradation product eluting around the relative retention time 1.1 to 1.2 relative to the main drug peak as a reference.

在相对于多萘哌齐的相对保留时间1.1到1.2附近洗脱的降解产物的量如表6所示，作为试验实施例2的测定结果。在不包含乙基纤维素作为高分子量碱性物质的比较实施例10和11的情况中没有检测到降解产物，但在包含乙基纤维素的比较实施例3的情况中观测到了0.51％降解产物。在包含更多乙基纤维素的比较实施例9的情况中，观测到了1.26％的降解产物。这证明了降解产物是由盐酸多萘哌齐和乙基纤维素。The amounts of degradation products eluted around the relative retention time of 1.1 to 1.2 relative to donepezil are shown in Table 6 as the measurement results of Test Example 2. No degradation product was detected in the case of Comparative Examples 10 and 11 which did not contain ethyl cellulose as a high molecular weight basic substance, but 0.51% degradation product was observed in the case of Comparative Example 3 which contained ethyl cellulose . In the case of Comparative Example 9, which contained more ethylcellulose, 1.26% of degradation products were observed. This proved that the degradation products were composed of donepezil hydrochloride and ethyl cellulose.

从比较实施例3和实施例2，也证明了通过在药物组合物中包含约25％的Eudragit L100-55可以抑制降解产物。在实施例2或在实施例3中没有观测到降解产物。这又一次证明了高分子量酸性物质对于抗痴呆药物和高分子量碱性物质的联合存在而导致的降解产物的产生具有抑制作用，同时与柠檬酸具有联合作用。From comparative example 3 and example 2, it was also demonstrated that degradation products can be suppressed by including about 25% of Eudragit L100-55 in the pharmaceutical composition. No degradation products were observed in Example 2 or in Example 3. This once again proves that the high molecular weight acidic substance has an inhibitory effect on the generation of degradation products caused by the combined presence of anti-dementia drugs and high molecular weight basic substances, and has a combined effect with citric acid.

表6Table 6

(试验实施例3)(Test Example 3)

为了证明Eudragit L100-55和低分子量酸性物质的联合作用，将与柠檬酸或其盐(实施例3和4，比较实施例4和5)、氨基酸(实施例5，比较实施例6和7)或依地酸的盐(比较实施例8)混合的颗粒在开放(未密封)的恒温室中在60℃，75％RH下贮存2周，在贮存前和后测定降解产物的量。通过上面的降解产物分析法2进行降解产物的测定。此外，也测定以2.5％的浓度溶解或悬浮于纯净水中的在该试验实施例中研究的添加剂溶液的pH(即，在实施例2中的EudragitL100-55和在其他实施例和比较实施例中以20mg的量混合的添加剂)。也测定盐酸多萘哌齐的2％和5％的水溶液的pH值作为参考值。In order to prove the joint effect of Eudragit L100-55 and low molecular weight acidic substance, will combine with citric acid or its salt (embodiment 3 and 4, comparative example 4 and 5), amino acid (embodiment 5, comparative example 6 and 7) Or edetic acid salt (Comparative Example 8) mixed granules were stored in an open (unsealed) thermostatic chamber at 60° C., 75% RH for 2 weeks, and the amount of degradation products was measured before and after storage. The determination of degradation products was performed by the degradation product analysis method 2 above. In addition, the pH of the solution of the additive studied in this test example (ie, Eudragit L100-55 in Example 2 and in other examples and comparative examples) dissolved or suspended in purified water at a concentration of 2.5% was also measured. additive mixed in an amount of 20 mg). The pH values of 2% and 5% aqueous solutions of donepezil hydrochloride were also determined as reference values.

在相对于多萘哌齐的相对保留时间1.1到1.2附近洗脱的降解产物的量如表7所示，作为试验实施例3的测定结果。在比较实施例3中降解产物的量是0.51％，而在单独包含Eudragit L100-55来抑制降解产物的实施例2中仅为0.28％。此外，在混合了本发明的低分子量酸性物质的实施例3到5中降解产物不超过比较实施例3的0.51％，证明联合使用Eudragit L100-55和低分子量酸性物质抑制了降解产物。与仅混合Eudragit L100-55的实施例2相比，在包含柠檬酸的实施例3和包含门冬氨酸的实施例5的情况中进一步抑制了降解产物，证明了低分子量酸性物质和高分子量酸性物质对于包含乙基纤维素的药物组合物中盐酸多萘哌齐的热稳定性具有协同作用。然后评价在该试验中使用的添加剂(添加剂在实施例和比较实施例中以20mg的量混合)的pH(2.5％水溶液或混悬液)。附图1表明，在颗粒与那些添加剂混合后，在开放(未封闭)条件下在60℃，75％RH下贮存2周各种添加剂和降解产物的2.5％水溶液或混悬液的pH之间的关系。当pH为4.5时，降解产物的量大致等于比较实施例3，但随着pH的升高，降解产物的量增加。另一方面，在pH 4.5以下，pH月底，热稳定性越强，受到抑制的降解产物越多。由于2％的盐酸多萘哌齐的水溶液的pH是5.0并且5％盐酸多萘哌齐的水溶液的pH是4.8，比较实施例4到7的稳定性相对于比较实施例3降低，这是因为它们包含了pH值比盐酸多萘哌齐的水溶液的pH更高的添加剂。The amounts of degradation products eluted around the relative retention time of 1.1 to 1.2 relative to donepezil are shown in Table 7 as the measurement results of Test Example 3. The amount of degradation products was 0.51% in Comparative Example 3, but only 0.28% in Example 2 containing Eudragit L100-55 alone to suppress degradation products. In addition, the degradation products in Examples 3 to 5 in which the low-molecular-weight acidic substance of the present invention was mixed did not exceed 0.51% of that of Comparative Example 3, demonstrating that the combined use of Eudragit L100-55 and the low-molecular-weight acidic substance suppressed the degradation products. In the case of Example 3 containing citric acid and Example 5 containing aspartic acid, degradation products were further suppressed compared to Example 2 in which only Eudragit L100-55 was mixed, demonstrating low molecular weight acidic substances and high molecular weight The acidic substance has a synergistic effect on the thermal stability of donepezil hydrochloride in the pharmaceutical composition comprising ethylcellulose. The pH (2.5% aqueous solution or suspension) of the additives used in this test (the additives were mixed in an amount of 20 mg in Examples and Comparative Examples) was then evaluated. Figure 1 shows that after the particles were mixed with those additives, they were stored under open (unsealed) conditions at 60°C, 75% RH for 2 weeks between the pH of various additives and degradation products in 2.5% aqueous solution or suspension Relationship. When the pH was 4.5, the amount of degradation products was roughly equal to that of Comparative Example 3, but as the pH increased, the amount of degradation products increased. On the other hand, below pH 4.5, at the end of pH, the stronger the thermal stability, the more degradation products are inhibited. Since the pH of a 2% aqueous solution of donepezil hydrochloride is 5.0 and the pH of a 5% aqueous solution of donepezil hydrochloride is 4.8, the stability of Comparative Examples 4 to 7 is lowered relative to Comparative Example 3 because They contain additives having a pH higher than that of an aqueous solution of donepezil hydrochloride.

表7Table 7

(试验实施例4)(Test Example 4)

为了评价Eudragit L100-55和抗氧化剂的联合作用，将实施例6到10和比较实施例8的包含约1％盐酸多萘哌齐和各种氧化剂的颗粒在开放(未封闭)条件下在60℃，75％RH下贮存2周，在贮存前和后测定降解产物的量。根据上述的降解产物分析法2进行降解产物的测定。此外，也测定以2.5％的浓度溶解或悬浮于纯净水中的在该试验实施例中研究的添加剂(在实施例和比较实施例中以20mg的量混合的添加剂)的pH。In order to evaluate the combined effects of Eudragit L100-55 and antioxidants, the granules of Examples 6 to 10 and Comparative Example 8 containing about 1% donepezil hydrochloride and various oxidants were tested under open (unblocked) conditions at 60 °C, 75% RH for 2 weeks, and the amount of degradation products was measured before and after storage. The determination of degradation products was carried out according to the above-mentioned degradation product analysis method 2. In addition, the pH of the additive studied in this test example (the additive mixed in an amount of 20 mg in the examples and comparative examples) dissolved or suspended in purified water at a concentration of 2.5% was also measured.

在相对于多萘哌齐的相对保留时间1.1到1.2附近洗脱的降解产物的量如表8所示，作为试验实施例4的测定结果。在包含EudragitL100-55和抗氧化剂的实施例6到10中观测到了稳定作用，而且比比较实施例3更多地抑制了降解产物的产生。特别低，在包含抗坏血酸或含硫的氨基酸的实施例中没有检测到降解产物，表明了与Eudragit L100-55具有协同作用，另一方面，在包含没有发生还原反应的氧化剂(pH 4.5，2％水溶液)的比较实施例8中观测到了与比较实施例3(无添加剂)相同水平的降解产物，表明螯合抗氧化剂对于稳定性没有贡献。The amounts of degradation products eluted around the relative retention time of 1.1 to 1.2 relative to donepezil are shown in Table 8 as the measurement results of Test Example 4. Stabilization was observed in Examples 6 to 10 containing Eudragit L100-55 and an antioxidant, and the generation of degradation products was more inhibited than in Comparative Example 3. Particularly low, no degradation products were detected in the examples containing ascorbic acid or sulfur-containing amino acids, indicating a synergistic effect with Eudragit L100-55. Aqueous solution) in Comparative Example 8, the same level of degradation products as in Comparative Example 3 (no additive) was observed, indicating that the chelated antioxidant did not contribute to the stability.

当含有试验实施例3的添加剂时，附图1显示了包含具有还原作用的抗氧化剂的实施例6到10的贮存试验中降解产物的量与2.5％水溶液或混悬液的pH的关系。与试验实施例3的结果的比较表明，这些抗氧化剂的作用不同于它们作为低分子量酸性物质时的作用。Figure 1 shows the relationship between the amount of degradation products and the pH of the 2.5% aqueous solution or suspension in the storage tests of Examples 6 to 10 containing the additive of Test Example 3 when containing the additive of Test Example 3. Comparison with the results of Test Example 3 shows that the effects of these antioxidants are different from their effects as low-molecular-weight acidic substances.

表8Table 8

(试验实施例5)(Test Example 5)

在2.5％水溶液或混悬液中测定在本发明中使用的高分子量酸性物质和高分子量碱性物质的pH值。测定2％和5％盐酸多萘哌齐水溶液和2.5％乳糖水溶液的pH值作为参照值。结果如表9所示。The pH values of the high molecular weight acidic substances and high molecular weight basic substances used in the present invention are measured in 2.5% aqueous solutions or suspensions. The pH values of 2% and 5% donepezil hydrochloride aqueous solutions and 2.5% lactose aqueous solutions were measured as reference values. The results are shown in Table 9.

表9Table 9

(试验实施例6)(Test Example 6)

将实施例15，16，17和18的包含5mg的盐酸多萘哌齐的片剂在开放(未封闭)条件下在60℃，75％RH下贮存2周，在贮存前和后测定降解产物的量。根据上述的降解产物分析法2进行降解产物的测定。The tablets of examples 15, 16, 17 and 18 containing 5 mg of donepezil hydrochloride were stored under open (unsealed) conditions at 60° C., 75% RH for 2 weeks, and the degradation products were determined before and after storage amount. The determination of degradation products was carried out according to the above-mentioned degradation product analysis method 2.

在相对于多萘哌齐的相对保留时间1.1到1.2附近洗脱的在60℃，75％RH下贮存后的降解产物的量如表10所示，作为试验实施例6的测定结果。从表10中可以看出，在实施例15、16、17和18种证明了在应力条件下，可以将降解产物的量抑制到盐酸多萘哌齐含量的0.5％以下。The amounts of degradation products after storage at 60°C, 75% RH eluted around the relative retention time 1.1 to 1.2 relative to donepezil are shown in Table 10 as the measurement results of Test Example 6. As can be seen from Table 10, Examples 15, 16, 17 and 18 prove that under stress conditions, the amount of degradation products can be suppressed to less than 0.5% of the donepezil hydrochloride content.

表10Table 10

(试验实施例7)(Test Example 7)

用实施例11、12和14得到的片剂进行稳定性试验。在实施例11、12和14的每一个中，用50个片剂填充到高密度聚乙烯制成的瓶子中，用铝薄片密封该瓶。也可以用聚乙烯制成的螺旋瓶盖密封该瓶。在恒温室中在5℃和40℃，75％RH下贮存后，通过使用上述的降解产物分析法2测定贮存前和后降解产物的量。Stability tests were carried out with the tablets obtained in Examples 11, 12 and 14. In each of Examples 11, 12 and 14, 50 tablets were filled into a bottle made of high-density polyethylene, which was sealed with an aluminum foil. The bottle can also be sealed with a screw cap made of polyethylene. After storage in a constant temperature room at 5° C. and 40° C., 75% RH, the amounts of degradation products before and after storage were measured by using the above-mentioned degradation product analysis method 2.

在40℃，75％RH下贮存后在相对于多萘哌齐的相对保留时间1.1到1.2附近洗脱的降解产物的量如表11所示，作为试验实施例7的测定结果。从表11中可以看出，在实施例11、12和14中证明了，可以将降解产物的量抑制到盐酸多萘哌齐含量的0.5％以下。根据International Conference of Harmonization的方针，在每天药物的最大剂量是10mg到100mg的情况中，必须证明安全性的杂质的阈剂量是小于药物的0.5％，或每日总摄取量小于200μg。此外，如果可以在40℃，75％RH的条件下贮存6个月儿确保药物和药品的质量，就可以说能保证贮存3年(在室温下)，而3年正是药品的一般保质期。需要注意的是，在实施例11、12和14的每一个中得到的降解产物的量小于盐酸多萘哌齐的0.05％，这低于杂质的检测限。The amount of degradation products eluted around the relative retention time 1.1 to 1.2 relative to donepezil after storage at 40°C, 75% RH is shown in Table 11 as the measurement results of Test Example 7. As can be seen from Table 11, it was demonstrated in Examples 11, 12 and 14 that the amount of degradation products could be suppressed to less than 0.5% of the donepezil hydrochloride content. According to the guidelines of the International Conference of Harmonization, where the maximum daily dose of the drug is 10 mg to 100 mg, the threshold dose of impurities that must prove safety is less than 0.5% of the drug, or the total daily intake is less than 200 μg. In addition, if it can be stored at 40°C and 75% RH for 6 months to ensure the quality of drugs and drugs, it can be said that they can be stored for 3 years (at room temperature), and 3 years is the general shelf life of drugs. It should be noted that the amount of degradation products obtained in each of Examples 11, 12 and 14 was less than 0.05% of donepezil hydrochloride, which was below the detection limit of impurities.

根据试验实施例7的结果，证明了本发明提供了有用的溶液，以改善包含盐酸多萘哌齐的药物组合物的质量。From the results of Test Example 7, it was demonstrated that the present invention provides a useful solution for improving the quality of a pharmaceutical composition comprising donepezil hydrochloride.

表11Table 11

  初始initial  1个月后1 month later  3个月后3 months later 6个月后6 months later  实施例11Example 11  NSLNSL  0.06％0.06%  0.10％0.10% 0.15％0.15%  实施例12Example 12  NSLNSL  0.09％0.09%  0.18％0.18% 0.28％0.28%  实施例14Example 14  NSLNSL  0.12％0.12%  0.22％0.22% 0.37％0.37%

NSL是指不超过0.05％。NSL means not to exceed 0.05%.

工业实用性Industrial Applicability

根据本发明，在包含抗痴呆药物和持续释放基质的药物组合物中，提供一种防治或抑制由于抗痴呆药物与持续释放基质接触而导致的降解产物的方法，即本发明可以提供一种稳定药物组合物中抗痴呆药物的方法。此外，由于根据本发明的药物组合物是高质量或高度适合顺应性的，因此本发明提供了一种药品，特别是抗痴呆药物，其可以放心服用，并且患者和治疗人员的负担较小。本发明也提供一种简单的生产药物组合物的方法，其中在该药物组合物中持续释放性质受到控制，并且稳定了抗痴呆药物，而无需使用特别的包衣技术或生产技术或生产设备。According to the present invention, in the pharmaceutical composition comprising an anti-dementia drug and a sustained-release matrix, a method for preventing or inhibiting degradation products caused by the contact of the anti-dementia drug with the sustained-release matrix is provided, that is, the present invention can provide a stable Methods of anti-dementia drugs in pharmaceutical compositions. Furthermore, since the pharmaceutical composition according to the present invention is of high quality or high compliance, the present invention provides a medicine, especially an anti-dementia medicine, which can be taken with confidence and with less burden on patients and treating personnel. The present invention also provides a simple method for producing a pharmaceutical composition in which sustained-release properties are controlled and anti-dementia drugs are stabilized without using special coating techniques or production techniques or production equipment.

Claims (20)

Translated fromChinese

1.一种稳定多萘哌齐或其药学可接受的盐的方法，包括向包含多萘哌齐或其药学可接受的盐和选自乙基纤维素、丙烯酸乙酯-甲基丙烯酸甲酯共聚物和聚氧化乙烯的高分子量碱性物质的药物组合物中加入选自丙烯酸甲酯-丙烯酸乙酯共聚物、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、羟丙基甲基纤维素邻苯二甲酸酯和羟丙基甲基纤维素乙酸琥珀酸酯的高分子量酸性物质。1. A method for stabilizing donepezil or a pharmaceutically acceptable salt thereof, comprising adding donepezil or a pharmaceutically acceptable salt thereof and being selected from ethyl cellulose, ethyl acrylate-methyl methacrylate In the pharmaceutical composition of the high-molecular-weight basic substance of the copolymer and polyethylene oxide, add selected from methyl acrylate-ethyl acrylate copolymer, methyl acrylate-methyl methacrylate copolymer, hydroxypropyl methylcellulose ortho High molecular weight acidic substance of phthalates and hydroxypropylmethylcellulose acetate succinate.2.根据权利要求1的方法，其中高分子量酸性物质的加入量，可以抑制由多萘哌齐或其药学可接受的盐和高分子量碱性物质接触而产生的多萘哌齐或其药学可接受的盐的降解产物的产生。2. according to the method for claim 1, wherein the add-on of high molecular weight acidic substance, can suppress donepezil or its pharmaceutically acceptable salt produced by donepezil or its pharmaceutically acceptable salt and high molecular weight basic substance contact. Generation of degradation products of accepted salts.3.根据权利要求1或2的方法，进一步加入至少一种选自琥珀酸、酒石酸、柠檬酸、富马酸、马来酸、苹果酸、门冬氨酸、谷氨酸、盐酸谷氨酸、盐酸和磷酸的低分子量酸性物质和抗氧化剂。3. according to the method for claim 1 or 2, further add at least one selected from succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, aspartic acid, glutamic acid, glutamic acid hydrochloride , hydrochloric acid and phosphoric acid, low molecular weight acidic substances and antioxidants.4.根据权利要求3的方法，其中低分子量酸性物质是至少一种选自琥珀酸、酒石酸、柠檬酸、苹果酸、门冬氨酸、谷氨酸、盐酸谷氨酸、盐酸和磷酸的物质。4. The method according to claim 3, wherein 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 .5.根据权利要求3的方法，其中抗氧化剂是至少一种选自抗坏血酸、含硫的氨基酸、氢醌的衍生物和生育酚的物质。5. The method according to claim 3, wherein the antioxidant is at least one substance selected from the group consisting of ascorbic acid, sulfur-containing amino acids, derivatives of hydroquinone, and tocopherol.6.选自丙烯酸甲酯-丙烯酸乙酯共聚物、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、羟丙基甲基纤维素邻苯二甲酸酯和羟丙基甲基纤维素乙酸琥珀酸酯的高分子量酸性物质在抑制由于多萘哌齐或其药学可接受的盐与选自乙基纤维素、丙烯酸乙酯-甲基丙烯酸甲酯共聚物和聚氧化乙烯的高分子量碱性物质接触而产生的多萘哌齐或其药学可接受的盐的降解产物中的应用。6. Selected from methyl acrylate-ethyl acrylate copolymer, methyl acrylate-methyl methacrylate copolymer, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate The high-molecular-weight acidic substance of the ester is inhibited due to donepezil or a pharmaceutically acceptable salt thereof being in contact with a high-molecular-weight basic substance selected from ethyl cellulose, ethyl acrylate-methyl methacrylate copolymer and polyethylene oxide. And the application of the degradation product of donepezil or its pharmaceutically acceptable salt produced.7.选自丙烯酸甲酯-丙烯酸乙酯共聚物、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、羟丙基甲基纤维素邻苯二甲酸酯和羟丙基甲基纤维素乙酸琥珀酸酯的高分子量酸性物质和至少一种选自琥珀酸、酒石酸、柠檬酸、富马酸、马来酸、苹果酸、门冬氨酸、谷氨酸、盐酸谷氨酸、盐酸和磷酸的低分子量酸性物质和抗氧化剂在抑制由于多萘哌齐或其药学可接受的盐与选自乙基纤维素、丙烯酸乙酯-甲基丙烯酸甲酯共聚物和聚氧化乙烯的高分子量碱性物质接触而产生的多萘哌齐或其药学可接受的盐的降解产物中的应用。7. Selected from methyl acrylate-ethyl acrylate copolymer, methyl acrylate-methyl methacrylate copolymer, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate High molecular weight acidic substances of esters and at least one low content 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 Molecular acidic substances and antioxidants are inhibited due to donepezil or a pharmaceutically acceptable salt thereof in contact with a high molecular weight basic substance selected from the group consisting of ethyl cellulose, ethyl acrylate-methyl methacrylate copolymer and polyethylene oxide And the application of the degradation product of donepezil or its pharmaceutically acceptable salt produced.8.一种包含多萘哌齐或其药学可接受的盐和选自乙基纤维素、丙烯酸乙酯-甲基丙烯酸甲酯共聚物和聚氧化乙烯的高分子量碱性物质的药物组合物，其中该组合物进一步包含稳定多萘哌齐或其药学可接受的盐的选自丙烯酸甲酯-丙烯酸乙酯共聚物、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、羟丙基甲基纤维素邻苯二甲酸酯和羟丙基甲基纤维素乙酸琥珀酸酯的高分子量酸性物质。8. A pharmaceutical composition comprising donepezil or a pharmaceutically acceptable salt thereof and a high molecular weight basic substance selected from ethyl cellulose, ethyl acrylate-methyl methacrylate copolymer and polyethylene oxide, Wherein the composition further comprises stable donepezil or a pharmaceutically acceptable salt thereof selected from methyl acrylate-ethyl acrylate copolymer, methyl acrylate-methyl methacrylate copolymer, hydroxypropyl methylcellulose High molecular weight acidic substance of phthalates and hydroxypropylmethylcellulose acetate succinate.9.根据权利要求8的药物组合物，进一步包含至少一种稳定多萘哌齐或其药学可接受的盐的选自琥珀酸、酒石酸、柠檬酸、富马酸、马来酸、苹果酸、门冬氨酸、谷氨酸、盐酸谷氨酸、盐酸和磷酸的低分子量酸性物质和抗氧化剂。9. The pharmaceutical composition according to claim 8, further comprising at least one stabilized donepezil or a pharmaceutically acceptable salt thereof selected from the group consisting of succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, Low molecular weight acids and antioxidants of aspartic acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid and phosphoric acid.10.根据权利要求8的药物组合物，其中该组合物包含基质，其中所述基质包括一种包含多萘哌齐或其药学可接受的盐、选自乙基纤维素、丙烯酸乙酯-甲基丙烯酸甲酯共聚物和聚氧化乙烯的高分子量碱性物质和稳定多萘哌齐或其药学可接受的盐的选自丙烯酸甲酯-丙烯酸乙酯共聚物、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、羟丙基甲基纤维素邻苯二甲酸酯和羟丙基甲基纤维素乙酸琥珀酸酯的高分子量酸性物质的混合物。10. The pharmaceutical composition according to claim 8, wherein the composition comprises a matrix, wherein said matrix comprises a compound comprising donepezil or a pharmaceutically acceptable salt thereof, selected from the group consisting of ethyl cellulose, ethyl acrylate-methanol The high molecular weight basic substance of methyl acrylate copolymer and polyethylene oxide and stable donepezil or its pharmaceutically acceptable salt are selected from methyl acrylate-ethyl acrylate copolymer, methyl acrylate-methyl methacrylate Blend of high molecular weight acidic substances of ester copolymer, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate.11.根据权利要求10的药物组合物，其中稳定多萘哌齐或其药学可接受的盐的至少一种选自琥珀酸、酒石酸、柠檬酸、富马酸、马来酸、苹果酸、门冬氨酸、谷氨酸、盐酸谷氨酸、盐酸和磷酸的低分子量酸性物质和抗氧化剂被混入到基质中。11. The pharmaceutical composition according to claim 10, wherein at least one of the stable donepezil or a pharmaceutically acceptable salt thereof is selected from the group consisting of succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, phylum Low molecular weight acidic substances of aspartic acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid and phosphoric acid and antioxidants are mixed into the matrix.12.根据权利要求8的药物组合物，其中药物组合物包含含有多萘哌齐或其药学可接受的盐的芯和覆盖在芯上的含有选自乙基纤维素、丙烯酸乙酯-甲基丙烯酸甲酯共聚物和聚氧化乙烯的高分子量碱性物质的包衣层，其中选自丙烯酸甲酯-丙烯酸乙酯共聚物、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、羟丙基甲基纤维素邻苯二甲酸酯和羟丙基甲基纤维素乙酸琥珀酸酯的高分子量酸性物质混入芯和包衣层的至少一种中。12. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition comprises a core containing donepezil or a pharmaceutically acceptable salt thereof and a compound selected from the group consisting of ethyl cellulose, ethyl acrylate-methyl and covering on the core. Coating layer of high molecular weight basic substance of methyl acrylate copolymer and polyethylene oxide, wherein selected from methyl acrylate-ethyl acrylate copolymer, methyl acrylate-methyl methacrylate copolymer, hydroxypropyl methyl High molecular weight acidic substances of cellulose phthalate and hydroxypropylmethylcellulose acetate succinate are mixed into at least one of the core and the coating layer.13.根据权利要求12的药物组合物，其中稳定多萘哌齐或其药学可接受的盐的至少一种选自琥珀酸、酒石酸、柠檬酸、富马酸、马来酸、苹果酸、门冬氨酸、谷氨酸、盐酸谷氨酸、盐酸和磷酸的低分子量酸性物质和抗氧化剂进一步混入到芯和包衣层的至少一种中。13. The pharmaceutical composition according to claim 12, wherein at least one of the stabilized donepezil or a pharmaceutically acceptable salt thereof is selected from the group consisting of succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, phylum Low-molecular-weight acidic substances of aspartic acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid, and phosphoric acid, and antioxidants are further mixed into at least one of the core and the coating layer.14.根据权利要求8到13任一项的药物组合物，其中该药物组合物是持续释放制剂。14. The pharmaceutical composition according to any one of claims 8 to 13, wherein the pharmaceutical composition is a sustained release formulation.15.一种基质型持续释放制剂，包含：多萘哌齐或其药学可接受的盐；选自乙基纤维素、丙烯酸乙酯-甲基丙烯酸甲酯共聚物和聚氧化乙烯的高分子量碱性物质；和选自丙烯酸甲酯-丙烯酸乙酯共聚物、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、羟丙基甲基纤维素邻苯二甲酸酯和羟丙基甲基纤维素乙酸琥珀酸酯的高分子量酸性物质。15. A matrix type sustained release preparation comprising: donepezil or a pharmaceutically acceptable salt thereof; a high molecular weight base selected from ethyl cellulose, ethyl acrylate-methyl methacrylate copolymer and polyethylene oxide Sexual substances; and selected from the group consisting of methyl acrylate-ethyl acrylate copolymer, methyl acrylate-methyl methacrylate copolymer, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate High molecular weight acidic substance of succinate.16.根据权利要求15的基质型持续释放制剂，进一步包含至少一种选自琥珀酸、酒石酸、柠檬酸、富马酸、马来酸、苹果酸、门冬氨酸、谷氨酸、盐酸谷氨酸、盐酸和磷酸的低分子量酸性物质和抗氧化剂。16. The matrix type sustained release preparation according to claim 15, further comprising at least one 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 Low molecular weight acidic substances and antioxidants of amino acid, hydrochloric acid and phosphoric acid.17.一种生产药物组合物的方法，包括下列步骤：混合多萘哌齐或其药学可接受的盐和选自乙基纤维素、丙烯酸乙酯-甲基丙烯酸甲酯共聚物和聚氧化乙烯的高分子量碱性物质；和将该混合物制粒，其中在混合步骤和制粒步骤的至少一步中向多萘哌齐或其药学可接受的盐和所述高分子量碱性物质的混合物中加入稳定多萘哌齐或其药学可接受的盐的选自丙烯酸甲酯-丙烯酸乙酯共聚物、丙烯酸甲酯-甲基丙烯酸甲酯共聚物、羟丙基甲基纤维素邻苯二甲酸酯和羟丙基甲基纤维素乙酸琥珀酸酯的高分子量酸性物质。17. A method for producing a pharmaceutical composition comprising the steps of: mixing donepezil or a pharmaceutically acceptable salt thereof and a compound selected from the group consisting of ethyl cellulose, ethyl acrylate-methyl methacrylate copolymer and polyethylene oxide and granulating the mixture, wherein a mixture of donepezil or a pharmaceutically acceptable salt thereof and the high molecular weight basic substance is added in at least one of the mixing step and the granulating step Stabilized donepezil or a pharmaceutically acceptable salt thereof selected from methyl acrylate-ethyl acrylate copolymer, methyl acrylate-methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate and high molecular weight acidic substances of hydroxypropylmethylcellulose acetate succinate.18.根据权利要求17的方法，其中所述高分子量酸性物质是以粉末加入的。18. A method according to claim 17, wherein said high molecular weight acidic substance is added as a powder.19.根据权利要求17或18的方法，其中进一步在混合步骤和制粒步骤的至少一步中向多萘哌齐或其药学可接受的盐和所述高分子量碱性物质的混合物中加入稳定多萘哌齐或其药学可接受的盐的至少一种选自琥珀酸、酒石酸、柠檬酸、富马酸、马来酸、苹果酸、门冬氨酸、谷氨酸、盐酸谷氨酸、盐酸和磷酸的低分子量酸性物质和抗氧化剂。19. The method according to claim 17 or 18, wherein further in at least one step of the mixing step and the granulating step, a stabilizing polymer is added to the mixture of donepezil or a pharmaceutically acceptable salt thereof and the high molecular weight basic substance. At least one of napezil or a pharmaceutically acceptable salt thereof is selected from succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, aspartic acid, glutamic acid, glutamic acid hydrochloride, hydrochloric acid and phosphoric acid low molecular weight acidic substances and antioxidants.20.根据权利要求18的方法，其中至少一种所述低分子量酸性物质和抗氧化剂是以溶液或混悬液加入的。20. The method according to claim 18, wherein at least one of said low molecular weight acidic substance and antioxidant is added as a solution or suspension.