CN101090737A - Matrix type sustained-release preparation - 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 by adding a high molecular weight acidic substance to said pharmaceutical composition. Further, the present invention provides a pharmaceutical composition containing an anti-dementia drug and a high molecular basic substance in which a high molecular weight acidic substance is contained for stabilizing the anti-dementia drug. Furthermore, the present invention provides a method for manufacturing a pharmaceutical composition which comprises steps wherein a solution or suspension containing a high molecular weight acidic substance is added to a mixture of an anti-dementia drug and a high molecular weight basic substance for the sake of stabilizing the anti-dementia drug.

Description

Stablize the method for antidementia agent

Technical field

The present invention relates in comprising the compositions of antidementia agent, stablize antidementia agent.More specifically, the present invention relates in having the pharmaceutical composition that continues the character that discharges and comprise antidementia agent, stablize antidementia agent with uncle's amino.

Background technology

In recent years, dementia comprises that the nursing of alzheimer disease, dementia of the Alzheimer type or the like has become a social problem, has concurrently put on display a lot of medicines.Wherein, many naphthalenes piperazine can be used as hydrochlorate together and uses with tablet or capsule form, and according to observations owing to its inhibiting activity of acetylcholinesterase,, can be used as medicine is very useful in slight and moderate dementia of the Alzheimer type.Recently, the tablet of disintegrate has been sold to the patient of glossopharyngeum difficulty in the oral cavity, and the percutaneous dosing that is undertaken by ointment formulation also is used for oral situation of difficult (for example, referring to patent documentation 1: Japanese Patent Application Publication H11-315016).

The development of suitable patient's the situation and the drug regimen five of symptom is extremely important from compliance or view of life quality.In this sense, extended release preparation is useful for antidementia agent, because the sustained releasing property of medicine allows to reduce the number of times of drug administration, provides identical or better therapeutic effect simultaneously, might improve compliance.

Usually; the extended release preparation that includes the medicine of physiologically active can be divided into two types preparation; (1) matrix type preparation; its Chinese medicine and lasting release matrix are distributed in the preparation equably; (2) extended release preparation of coating is wherein by coming sustained release with the slug particle that continues the involved physiologically active medicine of release coating bag or the surface of core tablet.

The matrix type extended release preparation contains substrate, and medicine and lasting release matrix are present in wherein equably.Substrate generally as tablet or granule, can give coating of its light shield or the like.The extended release preparation of coating comprises, those of core that comprise tablet that the coating that continues release matrix is applied to comprise medicine, granule or the like, or the layer that comprises medicine is applied to comprise on the slug particle of the microcrystalline Cellulose that is called nonpareil or sucrose, continues to discharge those of coating bag quilt by another kind of then.In some cases, also can control sustained releasing property by the multiwalled method that comprises the coating of medicine or comprise the coating that continues release matrix.

But,, therefore must be noted that stability of drug can not be affected because extended release preparation comprises lasting release matrix and other additives not to be covered in routine, rapidly-soluble tablet now.Especially, many antidementia agents are to comprise amino alkalescent medicine, usually, when reacting with carbonyl carbon, peroxide, oxygen etc., the functional group of high response, for example nucleophilic amino has the character that is easy to generate catabolite.

Owing to the catabolite of medicine or additive can influence the stability or the effectiveness of medicine, so in the preparation development field, studying the method for preventing these catabolites generations or the amount that severe inhibition produced.About stablizing the method for antidementia agent, disclose with comprising many naphthalenes of organic acid composition stable piperazine and avoided illumination infringement together (referring to, patent documentation 2: Japanese Patent Application Publication H11-106353).Reported, in the neat ethanol water of many naphthalenes piperazine, added the organic acid effect and can estimate the light stability effect, added the neat residual ratio of many naphthalenes piperazine in the solution of p-methyl benzenesulfonic acid, methanesulfonic acid, citric acid etc. and be higher than and do not add organic acid solution.

Summary of the invention

Therefore, need a kind of pharmaceutical composition, improve the compliance of antidementia agent, the pharmaceutical composition that for example has sustained releasing property.On the other hand, when using conventional medicine, require this extended release preparation can guarantee bin stability.In addition, because antidementia agent is used the long time (even in situation of the preparation with lasting release function) usually, therefore need this pharmaceutical composition and the method for producing this pharmaceutical composition, this pharmaceutical composition can be produced easily and cheaply.Therefore, an object of the present invention is in comprising the compositions of antidementia agent, to stablize antidementia agent.More specifically, an object of the present invention is to provide the pharmaceutical composition that comprises antidementia agent, it has the character of lasting release and method and a kind of method of stablizing antidementia agent in this pharmaceutical composition that antidementia agent has outstanding stability and a kind of production said composition.

In these cases, the inventor has carried out extensive studies to the pharmaceutical composition that comprises antidementia agent.The result, the inventor finds, the catabolite neat from many naphthalenes of hydrochloric acid piperazine produces in the matrix type extended release preparation, wherein this matrix type extended release preparation comprises many naphthalenes of hydrochloric acid piperazine together as antidementia agent and the lasting release matrix of high molecular alkaline matter ethyl cellulose conduct, with the acid material of high molecular, when the high molecular alkaline matter of antidementia agent and the lasting release matrix of conduct contacts, the catabolite that the acid material of high molecular prevents effectively or suppresses to be produced, and the acid material of high molecular also has synergy with acid material of low-molecular-weight and antioxidant, has finished the present invention thus.

Therefore, the present invention relates to comprise the pharmaceutical composition of antidementia agent and lasting release matrix, antidementia agent has good storing stability, wherein comprises the acid material of high molecular and is used for stablizing antidementia agent.In addition, can use commercial available enteric polymer etc. as the acid material of high molecular, it can easily be mixed together with antidementia agent and lasting release matrix or granulate easily to produce according to pharmaceutical composition of the present invention.

Aspect first, the present invention relates to stablize the method for antidementia agent of the present invention, be included in and add the acid material of high molecular in the pharmaceutical composition that comprises antidementia agent and high molecular alkaline matter.By adding the acid material of high molecular, can suppress the catabolite of antidementia agent, this catabolite contacts generation by antidementia agent with the high molecular alkaline matter.In addition, a preferred aspect of the method according to this invention provides a kind of method of stable antidementia agent, wherein adds acid material of at least a low-molecular-weight and antioxidant in this pharmaceutical composition according to the present invention.

Aspect second of the present invention, a kind of pharmaceutical composition that comprises antidementia agent and high molecular alkaline matter is provided, wherein said composition comprises the acid material of high molecular to stablize antidementia agent.Pharmaceutical composition according to the present invention comprises acid material of at least a low-molecular-weight and antioxidant.More specifically, this pharmaceutical composition is a for example matrix type extended release preparation of a kind of compositions, it is the mixture that antidementia agent, high molecular alkaline matter and being used for stablized the acid material of high molecular of antidementia agent, or a kind of compositions extended release preparation of coating for example, it comprises the core that contains antidementia agent and contains the coatings of the high molecular alkaline matter of bag quilt on above-mentioned core, and wherein the acid material of high molecular is blended at least a above-mentioned core and the above-mentioned coatings.

Especially, pharmaceutical composition according to the present invention is a kind of pharmaceutical composition, comprise: (1) alkalescent medicine or its salt, it is at 0.1N hydrochloric acid solution and 50mM phosphate buffer, the dissolubility of pH6 is 1mg/mL or bigger, at the 50mM phosphate buffer, dissolubility among the pH 8 is 0.2mg/mL or littler, and this alkalescent medicine or its salt are at the 50mM phosphate buffer, dissolubility among the pH 6.8 is at the 50mM phosphate buffer, among the pH 8 at least 2 times, and be no more than the phosphate buffer at 50mM, half of the dissolubility among the pH 6; (2) at least a enteric polymer (the acid material of high molecular) and (3) at least a insoluble polymer (high molecular alkaline matter).

Aspect the 3rd of the present invention, the method of a kind of effective realization antidementia agent Stabilization of the present invention is provided, in other words, it is the method that a kind of production comprises the pharmaceutical composition of antidementia agent and high molecular alkaline matter, comprise blend step and granulation step, wherein, the acid material of high molecular that will stablize antidementia agent during at least one step of blend step and granulation step joins in the mixture of antidementia agent and high molecular alkaline matter.A preferred aspect in accordance with the present production process except the acid material of high molecular, adds acid material of at least a low-molecular-weight and antioxidant to stablize antidementia agent.One preferred aspect, during at least one step of blend step and granulation step, the acid material of at least a high molecular, the acid material of low-molecular-weight and the antioxidant form with solution or suspension is added.Of production method of the present invention particularly preferred aspect, after in blend step, adding the acid material of pulverous high molecular, can in granulation step, in mixture, add the acid material of at least a low-molecular-weight and the antioxidant of solution or suspension form.

In addition, aspect the 3rd of the present invention, a kind of method of producing pharmaceutical composition is provided, it comprises the following steps: to mix (1) alkalescent medicine or its salt, it is at 0.1N hydrochloric acid solution and 50mM phosphate buffer, the dissolubility of pH 6 is 1mg/mL or bigger, at the 50mM phosphate buffer, dissolubility among the pH 8 is 0.2mg/mL or littler, and this alkalescent medicine or its salt are at the 50mM phosphate buffer, dissolubility among the pH 6.8 is at the 50mM phosphate buffer, among the pH 8 at least 2 times, and be no more than phosphate buffer, half of the dissolubility among the pH 6 and (2) at least a enteric polymer (the acid material of high molecular) and (3) at least a insoluble polymer (high molecular weight substrate thing) at 50mM; Be embossed in the mixture that obtains in the blend step.

In addition, in the 4th pattern of the present invention, provide the acid material of high molecular to contact with the high molecular alkaline matter by antidementia agent and application in the antidementia agent catabolite that produces in control.This is the new purposes of the acid material of a kind of high molecular of finding.In this case, use acid material of low-molecular-weight and antioxidant can suppress catabolite effectively by following.

Preferred aspect according to the present invention, antidementia agent is the chemical compound with uncle's amino.Preferred aspect according to the present invention, antidementia agent is selected from profit and cuts down this bright, galantamine, neat, 3-[1-(benzyl) piperidin-4-yl of many naphthalenes piperazine]-1-(2,3,4,5-tetrahydrochysene-1H-1-benzene azepine -8-yl)-1-propane and 5,7-dihydro-3-[2-[1-(benzyl)-4-piperidyl] ethyl]-6H-pyrrolo-[4,5-f]-1,2-Ben isoxazole-6-ketone and the acceptable salt of pharmacy thereof.One particularly preferred aspect, this antidementia agent is the neat or acceptable salt of its pharmacy of many naphthalenes piperazine.

In addition, preferred aspect according to the present invention, the high molecular alkaline matter is at least a ethyl cellulose, ethyl acrylate-methyl acrylate copolymer and the polyethylene glycol oxide of being selected from.One preferred aspect, the high molecular alkaline matter is ethyl cellulose or ethyl acrylate-methyl acrylate copolymer, one particularly preferred aspect this high molecular alkaline matter be ethyl cellulose.The high molecular alkaline matter can be any insoluble polymer.

In addition, preferred aspect according to the present invention, the acid material of high molecular is an enteric polymer.One preferred aspect, the acid material of high molecular is at least a material that is selected from EUDRAGIT L100-55, methacrylic acid-methyl acrylate copolymer, hydroxypropylmethyl cellulose phthalate and hydroxypropyl methyl cellulose succinate.One particularly preferred aspect, the acid material of high molecular is an EUDRAGIT L100-55.Of the acid amount of substance of high molecular preferred aspect, based on 100 weight portions according to pharmaceutical composition of the present invention, its amount is generally 0.1 to 90 weight portion, preferred 1 to 70 weight portion, more preferably 5 to 60 weight portions, more preferably 10 to 50 weight portions.

In addition, preferred aspect according to the present invention, the acid material of low-molecular-weight is at least a material that is selected from carboxylic acid, sulfonic acid, hydroxy acid, acidic amino acid and mineral acid.One preferred aspect, the acid material of low-molecular-weight is at least a material that is selected from hydroxy acid, acidic amino acid and mineral acid.One particularly preferred aspect, the acid material of low-molecular-weight is at least a material that is selected from hydroxy acid and acidic amino acid.

More particularly, the acid material of low-molecular-weight is at least a material that is selected from succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, Aspartic Acid, glutamic acid, acidogen, hydrochloric acid and phosphoric acid.One preferred aspect, the acid material of low-molecular-weight is at least a material that is selected from citric acid, Aspartic Acid and hydrochloric acid.Based on 100 weight portions according to pharmaceutical composition of the present invention, the acid amount of substance of low-molecular-weight generally is 0.05 to 4 weight portion, preferred 0.1 to 3 weight portion, more preferably 0.15 to 2 weight portion, more preferably 0.15 to 1.5 weight portion.

Preferred aspect according to the present invention, antioxidant are at least a in the aminoacid of ascorbic acid and sulfur-bearing.One preferred aspect, antioxidant is at least a material that is selected from methionine, ascorbic acid and cysteine hydrochloride.Based on 1 medicaments in part by weight, the amount of antioxidant generally is 0.01 to 10 weight portion, preferred 0.02 to 5 weight portion, more preferably 0.05 to 2 weight portion.Although need not limit the amount of antioxidant especially, but for example based on 100 weight portions according to pharmaceutical composition of the present invention, the amount of antioxidant is 0.001 to 5 weight portion, preferred 0.01 to 3 weight portion, more preferably 0.1 to 2 weight portion, more preferably 0.15 to 1.5 weight portion.

According to the pharmaceutical composition of of the present invention first to the 3rd aspect extended release preparation preferably, be more preferably the matrix type extended release preparation.In addition.The example of the dosage form of this pharmaceutical composition preferably includes tablet, capsule, granule or fine grained.Therefore, the pharmaceutical composition of a particularly preferred aspect is the matrix type extended release preparation that comprises the neat or acid material of the acceptable salt of its pharmacy, high molecular alkaline matter and high molecular of many naphthalenes piperazine according to the present invention, perhaps comprises the matrix type extended release preparation of many naphthalenes piperazine neat or the acceptable salt of its pharmacy, high molecular alkaline matter, the acid material of high molecular and acid material of at least a low-molecular-weight and antioxidant.

Beneficial effect of the present invention

According to the present invention, in the pharmaceutical composition that comprises antidementia agent and lasting release matrix, provide a kind of method to stop or suppress and promptly the invention provides a kind of method of in pharmaceutical composition, stablizing antidementia agent owing to antidementia agent contacts the catabolite that produces with lasting release matrix.In addition, owing to according to the high-quality of pharmaceutical composition of the present invention and highly suitable compliance, the invention provides a kind of medicine, particularly antidementia agent, it can relievedly be taken, and patient and treatment personnel's burden is less.The present invention also provides a kind of method of simple production pharmaceutical composition, and wherein sustained releasing property is controlled in this pharmaceutical composition, and has stablized antidementia agent, and need not to use special packaging technique or production technology or production equipment.

The accompanying drawing summary

Accompanying drawing 1 shows is to open in (sealing) container 60 ℃ after the granulation, and 75%RH places the relation of the pH of 2.5% aqueous solution of the amount of the catabolite that comprises various additives after two weeks and various additives or suspension down.

Implement best mode of the present invention

To explain embodiment of the present invention below.Following embodiment is to be used to explain example of the present invention, rather than plans the present invention is only limited to these embodiments.The present invention can use in every way, and does not break away from the spirit and scope of the present invention.

(antidementia agent)

For the not special restriction of the antidementia agent that uses in the present invention, if this antidementia agent be have primary, secondary or or the alkalescent medicine of uncle's amino, but preferably this antidementia agent has uncle's amino.Example with antidementia agent of primary amino radical comprises the acceptable salt of tacrine, memantine and pharmacy thereof.Example with antidementia agent of uncle's amino comprises that profit cuts down this bright, galantamine, neat, 3-[1-(benzyl) piperidin-4-yl of many naphthalenes piperazine]-1-(2,3,4,5-tetrahydrochysene-1H-1-benzene azepine -8-yl)-1-propane and 5,7-dihydro-3-[2-[1-(benzyl)-4-piperidyl] ethyl]-6H-pyrrolo-[4,5-f]-1,2-Ben isoxazole-6-ketone and the acceptable salt of pharmacy thereof.Preferred example with antidementia agent of primary amino radical is romotal and memantine.Preferred example with antidementia agent of uncle's amino is neat (chemical list hydrochloric acid (±)-2-[(1-benzyl piepridine-4-yl) methyl of bright, galanthamine hydrobromide, many naphthalenes of hydrochloric acid piperazine that the tartaric acid profit is cut down this]-5,6-dimethoxy indan-1-one), fumaric acid 3-[1-(benzyl) piperidin-4-yl]-1-(2,3,4,5-tetrahydrochysene-1-benzene azepine -8-yl)-1-propane (TAK-147) and maleic acid 5,7-dihydro-3-[2-[1-(benzyl)-4-piperidyl] ethyl]-6H-pyrrolo-[4,5-f]-1,2-Ben isoxazole-6-ketone (CP118954).More preferably, this antidementia agent is that many naphthalenes of hydrochloric acid piperazine is neat, TAK-147 or CP118954, and most preferably this antidementia agent is that many naphthalenes of hydrochloric acid piperazine is neat.It should be noted that antidementia agent can use with free form or as organic or inorganic salt, preferred organic or inorganic salt, preferred especially inorganic salt.More particularly, the example of salt includes but not limited to, hydrochlorate, sulfate, acetate, phosphate, carbonate, mesylate, tartrate, citrate, toluene fulfonate or the like.

As for acidic aqueous solution, neutral aqueous solution or alkaline aqueous solution, the alkalescent medicine of use in the present invention or the dissolubility of its salt are not limited especially, but the dissolubility of alkalescent medicine in acid solution and neutral solution is higher than the dissolubility in alkaline aqueous solution.Here, for the application in these aqueous solutions of preparation, being used for this examples of applications includes but not limited to, phosphate buffer (for example, buffer with the preparation of 50mM sodium radio-phosphate,P-32 solution and hydrochloric acid), buffer for example G.L.Miller ' s buffer, Atkins-Pantin ' s buffer, Good ' s buffer or the like, 0.1N hydrochloric acid, 0.1mol/L sodium hydroxide solution or the like.It should be noted that the dissolubility that uses in the present invention is meant the dissolubility when solution temperature is 25 ℃.

When the term of Shi Yonging " dissolubility in acidic aqueous solution " is meant in alkalescent medicine or its salt being dissolved in buffer etc. in the present invention, alkalescent medicine or its salt dissolubility in showing tart solution.Similarly, in the present invention the term of Shi Yonging " in dissolubility in (alkali) property aqueous solution " when being meant in alkalescent medicine or its salt being dissolved in buffer etc., the dissolubility in the solution of alkalescent medicine or its salt (alkali) property in demonstration.

For example, the alkalescent medicine of Shi Yonging or its salt is at acidic aqueous solution in the present invention, and 3.0 and neutral aqueous solution, the dissolubility among the pH 6.0 is higher than at alkaline aqueous solution, among the pH 8.0.When the term of Shi Yonging " at acidic aqueous solution, the dissolubility in 3.0 " is meant in alkalescent medicine or its salt being dissolved in buffer etc. in this article, alkalescent medicine or the dissolubility of its salt in the acid solution of pH 3.0.When the term of Shi Yonging " at acidic aqueous solution, the dissolubility in 6.0 " is meant in alkalescent medicine or its salt being dissolved in buffer etc. in this article, alkalescent medicine or the dissolubility of its salt in the solution of pH 6.0.When the term of Shi Yonging " at alkaline aqueous solution, the dissolubility in 8.0 " is meant in alkalescent medicine or its salt being dissolved in buffer etc. in this article, alkalescent medicine or the dissolubility of its salt in the alkaline solution of pH 8.0.

For example, the alkalescent medicine of Shi Yonging or its salt is at 0.1N hydrochloric acid solution and neutral aqueous solution in the present invention, and the dissolubility among the pH 6.0 is greater than at alkaline solution, the dissolubility among the pH 8.0.The term of Shi Yonging " dissolubility in the 0.1N hydrochloric acid solution " is meant the dissolubility of when being dissolved in alkalescent medicine or its salt in 0.1N hydrochloric acid solution alkalescent medicine or its salt in this article.For example, being dissolved in the pH scope that the neat solution of many naphthalenes of hydrochloric acid piperazine in the 0.1N hydrochloric acid solution shows is about 1 to about 2.

Preferably, the alkalescent medicine of Shi Yonging or its salt are at 0.1N hydrochloric acid solution and neutral aqueous solution in the present invention, dissolubility among the pH 6.0 is greater than at alkaline solution, dissolubility among the pH 8.0, and at neutral aqueous solution, the dissolubility among the pH 6.8 is at alkaline solution, at least 2 times of the dissolubility among the pH 8.0, but be no more than at neutral aqueous solution half of the dissolubility among the pH 6.0." at the neutral aqueous solution, the dissolubility among the pH 6.8 " of Shi Yonging is meant when being dissolved in alkalescent medicine or its salt in the buffer etc. in this article, alkalescent medicine or the dissolubility of its salt in the solution of pH 6.8.

More particularly, have no particular limits, as long as alkalescent medicine or its salt are at 0.1N hydrochloric acid solution and neutral aqueous solution, dissolubility among the pH 6.0 is 1mg/mL or bigger, and alkalescent medicine or its salt are at alkaline aqueous solution, and the dissolubility among the pH 8.0 is 0.2mg/mL or littler, and alkalescent medicine or its salt are at neutral aqueous solution, dissolubility among the pH 6.8 is at alkaline aqueous solution, and among the pH 8.0 2 of dissolubility times or bigger and be no more than at neutral aqueous solution, half of dissolubility gets final product among the pH 6.0.That is to say that at 0.1N hydrochloric acid solution and neutral aqueous solution, the alkalescent medicine among the pH 6.0 or its salt are not special the restrictions, as long as its above-mentioned dissolubility is 1mg/mL or bigger.Above-mentioned dissolubility generally is 1 to 1000mg/mL, preferred 5 to 200mg/mL, more preferably 5 arrive 100mg/mL, and more preferably 10 arrive 80mg/mL.Alkalescent medicine or its salt are at alkaline aqueous solution, and the dissolubility among the pH 8.0 is not special the restriction, as long as above-mentioned dissolubility is 0.2mg/mL or littler.Above-mentioned dissolubility generally is 0.0001 to 0.2mg/mL, preferred 0.0005 to 0.1mg/mL, more preferably 0.001 arrive 0.05mg/mL, and more preferably 0.002 arrive 0.03mg/mL.In addition, alkalescent medicine or its salt are at neutral aqueous solution, and the dissolubility among the pH 6. is not special the restriction, as long as above-mentioned dissolubility is at alkaline aqueous solution, at least 2 times of dissolubility among the pH 8.0 and be no more than at neutral aqueous solution, half of dissolubility gets final product among the pH 6.0.Above-mentioned dissolubility is preferably at alkaline aqueous solution, at least 3 times of dissolubility among the pH 8.0 and be no more than at neutral aqueous solution, among the pH 6.0 1/3 of dissolubility, more preferably at alkaline aqueous solution, at least 5 times of dissolubility among the pH 8.0 and be no more than at neutral aqueous solution, among the pH 6.0 1/5 of dissolubility, more preferably at alkaline aqueous solution, at least 10 times of dissolubility among the pH 8.0 and be no more than at neutral aqueous solution, among the pH 6.0 1/10 of dissolubility.

Remain for example, the alkalescent medicine of Shi Yonging or its salt is at 0.1N hydrochloric acid solution and 50mM phosphate buffer in the present invention, the dissolubility of pH 6.0 greater than it at the 50mM phosphate buffer, the dissolubility among the pH 8.0.The term of Shi Yonging " at the 50mM phosphate buffer, the dissolubility of pH 6.0 " is meant when being dissolved in alkalescent medicine or its salt in the 50mM phosphate buffer in this article, the dissolubility of this alkalescent medicine in the 50mM of pH6.0 phosphate buffer.Similarly, the term of Shi Yonging " at the 50mM phosphate buffer, the dissolubility of pH 8.0 " is meant when being dissolved in alkalescent medicine or its salt in the 50mM phosphate buffer in this article, the dissolubility of this alkalescent medicine in the 50mM of pH 8.0 phosphate buffer.

Preferably, alkalescent medicine or its salt are at 0.1N hydrochloric acid solution and 50mM phosphate buffer, dissolubility among the pH 6.0 greater than it at the 50mM phosphate buffer, dissolubility among the pH 8.0, and at the 50mM phosphate buffer, the dissolubility among the pH 6.8 be its at the 50mM phosphate buffer, 2 times or more times of the dissolubility among the pH 8.0, and be no more than it at the 50mM phosphate buffer, half of the dissolubility among the pH 6.0.More particularly, have no particular limits, as long as alkalescent medicine or its salt are at 0.1N hydrochloric acid solution and 50mM phosphate buffer, dissolubility among the pH 6.0 is 1mg/mL or bigger, alkalescent medicine or its salt are at the 50mM phosphate buffer, dissolubility among the pH 8.0 is 0.2mg/mL or littler, and alkalescent medicine or its salt are at the 50mM phosphate buffer, dissolubility among the pH 6.8 is that it is at the 50mM phosphate buffer, 2 times or more times of dissolubility among the pH 8.0, and be no more than it at the 50mM phosphate buffer, half of the dissolubility among the pH 6.0 gets final product.That is to say that at 0.1N hydrochloric acid solution and 50mM phosphate buffer, the dissolubility among the pH 6.0 has no particular limits to alkalescent medicine or its salt, as long as above-mentioned dissolubility is 1mg/mL or bigger.Above-mentioned dissolubility generally is 1 to 1000mg/mL, preferred 5 to 200mg/mL, more preferably 5 arrive 100mg/mL, and more preferably 10 arrive 80mg/mL.At the 50mM phosphate buffer, the dissolubility among the pH 8.0 has no particular limits to alkalescent medicine or its salt, as long as above-mentioned dissolubility is 0.2mg/mL or littler.Above-mentioned dissolubility generally is 0.0001 to 0.2mg/mL, preferred 0.0005 to 0.1mg/mL, more preferably 0.001 arrive 0.05mg/mL, and more preferably 0.002 arrive 0.03mg/mL.In addition, to alkalescent medicine or its salt at the 50mM phosphate buffer, dissolubility among the pH 6.8 has no particular limits, as long as above-mentioned dissolubility is at the 50mM phosphate buffer, the system beaker of the dissolubility among the pH 8.0 and be no more than phosphate buffer at 50mM, half of dissolubility gets final product among the pH6.0, preferably at alkaline aqueous solution, at least 3 times of dissolubility among the pH 8.0 and be no more than at neutral aqueous solution, among the pH 6.0 1/3 of dissolubility, more preferably at alkaline aqueous solution, at least 5 times of dissolubility among the pH 8.0 and be no more than at neutral aqueous solution, among the pH 6.0 1/5 of dissolubility, more preferably at alkaline aqueous solution, at least 10 times of dissolubility among the pH 8.0 and be no more than at neutral aqueous solution, among the pH 6.0 1/10 of dissolubility.

For example, many naphthalenes of hydrochloric acid piperazine is neat to be characterised in that it at acidic aqueous solution, and pH 3.0 and neutral aqueous solution, the dissolubility among the pH 6.0 are 11 to 16mg/mL, and at alkaline aqueous solution, then are 0.1mg/mL or littler among the pH 8.0.In addition, many naphthalenes of hydrochloric acid piperazine is weakly basic drugs or its salt with uncle's amino together, it is widely used in Alzheimer type dementia, be characterised in that it is at neutral aqueous solution, dissolubility among the pH 6.8 is at alkaline aqueous solution, at least 2 times of dissolubility among the pH8.0, and being no more than at neutral aqueous solution, half of dissolubility among the pH 6.0.

Alternately, many naphthalenes of hydrochloric acid piperazine is weakly basic drugs or its salt with uncle's amino together, and it is widely used in Alzheimer type dementia.Many naphthalenes of hydrochloric acid piperazine is neat to be characterised in that it is at 0.1N hydrochloric acid solution and 50mM phosphate buffer, dissolubility among the pH 6.0 is 11 to 16mg/mL, and at alkaline aqueous solution, then 0.1mg/mL or littler among the pH 8.0, it is at neutral aqueous solution, and the dissolubility among the pH 6.8 is at alkaline aqueous solution, at least 2 times of the dissolubility among the pH 8.0, and be no more than at neutral aqueous solution half of dissolubility among the pH 6.0.

For the antidementia agent that uses in the present invention or or the dosage of its salt have no particular limits, but in the situation of acetylcholinesteraseinhibitors inhibitors, this dosage is 0.01 to 50mg/ day.More particularly, many naphthalenes piperazine dosage neat or the acceptable salt of its pharmacy is 0.01 to 50mg/ day, preferred 0.1 to 40mg/ day, more preferably 1 to 30mg/ day, more preferably 5 to 25mg/ day.The dosage that profit is cut down the bright of this or the acceptable salt of its pharmacy is 0.01 to 50mg/ day, and preferred 0.1 to 30mg/ day, preferred from 1 more preferably 1 arrives 15mg/ day to 20mg/ day.The dosage of galantamine or the acceptable salt of its pharmacy is 0.01 to 50mg/ day, preferred 0.1 to 40mg/ day, more preferably 1 to 30mg/ day, more preferably 2 to 25mg/ day.

In addition, in the situation as the memantine of nmda receptor antagonist or the acceptable salt of its pharmacy, dosage is 0.5 to .100mg/ day, preferred 1 to 100mg/ day, more preferably 1 to 40mg/ day, more preferably 5 to 25mg/ day.

(high molecular alkaline matter)

The high molecular alkaline matter of Shi Yonging is the high molecular weight material that shows alkalescence when dissolving or suspending in water in the present invention.For example, in 2.5% aqueous solution or suspension, the pH that this high molecular alkaline matter has is greater than 7.0, and preferred pH is 7.5 to 14.0, and more preferably 8.0 to 14.0.In addition, the high molecular alkaline matter of Shi Yonging can be mixed with the lasting release matrix in pharmaceutical composition according to the present invention in the present invention, is used for other purpose but also can prepare.In addition, this high molecular alkaline matter also can be water insoluble, perhaps also can be the material of water-swellable when being dissolved in the water or the material that forms gel.The example of water-insoluble high molecular weight alkaline matter comprises cellulose ether, cellulose esters and methacrylic acid-acrylic copolymer, and (trade name Eudragit is by R  hm GmbH﹠amp; Co.KG, Darmstadt, Germany makes).Example includes but not limited to, the cellulose alkyl ether is ethyl cellulose (trade name Ethocel for example, by The Dow Chemical Company, U.S. makes or the like), ethylmethylcellulose, ethyl propyl cellulose or isopropyl cellulose, butyl cellulose or the like; The cellulose aralkyl ethers is benzylcellulose or the like for example; Cellulose cyano group alkyl ether is cyano ethyl cellulose or the like for example; Cellulose organic ester is cellulose acetate-butyrate, cellulose acetate, cellulose propionate or cellulose butyrate, cellulose-acetate propionate or the like for example; (trade name Eudragit NE is by R  hm GmbH﹠amp for ethyl acrylate-methyl acrylate copolymer; Co.KG, Darmstadt, Germany makes) or the like.The example of water solublity or water-swellable high molecular alkaline matter includes but not limited to, polyethylene glycol oxide (trade name Polyox, by The DowChemical Company, U.S. make molecular weight 100,000-7,000,000), replaces hydroxypropyl cellulose (trade name L-HPC, by Shin-Etsu Chemical, Japan makes) or the like.In pharmaceutical composition according to the present invention, can comprise one or both or more kinds of high molecular alkaline matter.The high molecular alkaline matter of Shi Yonging ethyl cellulose preferably in the present invention, EUDRAGIT NE 30 D EUDRAGIT NE 30D (trade name Eudragit NE) or polyethylene glycol oxide (trade name Polyox).More preferably, this high molecular alkaline matter is at least a in ethyl cellulose and the EUDRAGIT NE 30 D EUDRAGIT NE 30D.One particularly preferred aspect, this high molecular alkaline matter is an ethyl cellulose.Amount for high molecular alkaline matter in pharmaceutical composition is not particularly limited, and can according to purpose for example the sustained releasing property or the like of medicine suitably regulate.Mean diameter for the high molecular alkaline matter (insoluble polymer) that uses in the present invention has no particular limits, but average diameter 0.1 to 100 μ m preferably, more preferably 1 to 50 μ m, and, more preferably 3 to 15 μ m, most preferably 5 to 15 μ m.

Amount for high molecular alkaline matter in the matrix type extended release preparation is not particularly limited, but with pharmaceutical composition is 100% weight, and it generally is 1 to 90% weight, preferred 3 to 70% weight, more preferably 5 to 50% weight, more preferably 5 to 35% weight.

(catabolite)

Catabolite in this product is the catabolite from antidementia agent, is contacted with the high molecular alkaline matter and is obtained by antidementia agent.Suppose that catabolite comes from the reaction of the amino of antidementia agent.For example, catabolite neat by many naphthalenes of hydrochloric acid piperazine and that the high molecular alkaline matter obtains can be measured by conventional method with liquid chromatography.

(the acid material of high molecular)

The acid material of the high molecular of using is to show tart high molecular weight material when dissolving or suspending in water in the present invention, for example, the pH that the aqueous solution of the acid material of 2.5% high molecular shows is less than 7.0, and preferred pH is 1.0 to 6.5, and more preferably pH is 1.0 to 6.0.The high molecular acidity material that uses in the present invention also can water insoluble or also can be the material of water-swellable when being dissolved in the water or the material that forms gel.The acid material of the high molecular of using for example is an enteric polymer in the present invention.The example of enteric polymer includes but not limited to, methacrylic acid-methylmethacrylate copolymer (EudragitL100 (methylmethacrylate copolymer, the A type), Eudragit S100 (methylmethacrylate copolymer, Type B), by R  hm GmbH﹠amp; Co.KG, Darmstadt, Germany makes), (Eudragit L100-55 (methacrylic acid copolymer, C type), Eudragit L30D-55 (methacrylic acid copolymer, dispersion) are by R  hmGmbH﹠amp for EUDRAGIT L100-55; Co.KG, Darmstadt, the Germany manufacturing), hydroxypropylmethyl cellulose phthalate (HP-55, HP-50, by Shin-Etsu Chemical, the Japan manufacturing), hydroxypropyl emthylcellulose acetate succinate (AQOAT, by Shin-Etsu Chemical, Japan makes), carboxymethylethylcellulose (CMEC, by Freund Corporation, Japan makes), cellulose acetate phthalate or the like.As the acid material of the high molecular of using in the present invention, be that the material of water-swellable or the material that forms gel include but not limited to alginic acid, pectin, carboxy vinyl polymer, carboxymethyl cellulose or the like when being dissolved in the water.In pharmaceutical composition according to the present invention, can comprise one or both or the acid material of more kinds of high molecular of using in the present invention.The high molecular acidity material that uses in the present invention is enteric polymer preferably, more preferably EUDRAGIT L100-55, methacrylic acid-methylmethacrylate copolymer, hydroxypropylmethyl cellulose phthalate and hydroxypropyl emthylcellulose acetate succinate, more preferably EUDRAGIT L100-55.

When using in the method for producing pharmaceutical composition, the acid material of the high molecular of using can be powder or corpuscular commercial product in the present invention, perhaps before be dispersed in the suspension type in the solvent, these commercial products can be used for or be dispersed in water or organic solvent.The acid material of the less high molecular of particle diameter is to be used for of the present inventionly, and preferably it is a powder-type.In the situation of EUDRAGIT L100-55, an example of powder-type comprises Eudragit L100-55.For the not special restriction of the particle diameter of the acid material of the high molecular of using in the present invention, but preferably 0.05 to 100 μ m, more preferably 0.05 to 70 μ m, most preferably 0.05 to 50 μ m.

In the acid material of high molecular, enteric polymer is exceedingly useful because even when comprising this a large amount of enteric polymer in the pharmaceutical composition according to the present invention, it also can not lose the Stabilization of group antidementia agent.Therefore, for the acid amount of substance of high molecular without limits, but for example, based on 100 weight portions according to pharmaceutical composition of the present invention, the acid amount of substance of high molecular generally is 0.1 to 90 weight portion, preferred 1 to 70 weight portion, more preferably 5 to 60 weight portions, most preferably 10 to 50 weight portions.

To the not special restriction of the amount of enteric polymer, but being 100% weight based on pharmaceutical composition in pharmaceutical composition, generally is 5 to 90% weight, preferred 8 to 70% weight, more preferably 10 to 60% weight, most preferably 15 to 50% weight.In pharmaceutical composition, do not limit the total amount of insoluble polymer and enteric polymer is special, but based on pharmaceutical composition is 100% weight, generally be 25 to 95% weight, preferred 35 to 95% weight, more preferably 40 to 90% weight, more preferably 35 to 90% weight, most preferably 35 to 75% weight.

In pharmaceutical composition, do not limit the total amount of high molecular alkaline matter (insoluble polymer) and the acid material of high molecular (enteric polymer) is special, but based on 100 weight portions according to pharmaceutical composition of the present invention, it generally is 25 to 95 weight portions, preferred 35 to 95 weight portions, more preferably 35 to 90% weight, most preferably 35 to 75% weight.

(the acid material of low-molecular-weight)

For the not special restriction of the acid material of the low-molecular-weight of using in the present invention, as long as the pH of solution is less than 4.5 when dissolving or suspending in water, for example 2.5% aqueous solution or 2.5% the preferred pH of suspension are 1.0 to 4.0, more preferably 1.0 to 3.5, more preferably 1.0 to 3.0.Take with antidementia agent, obtained pH 4.0 to 6.0 at 2 to 5% aqueous solution or the antidementia agent in the suspension, the pH of this aqueous solution deducts 2.5% aqueous solution of the acid material of low-molecular-weight or the pH of 2.5% suspension generally is 0.05 to 5.5, preferred 0.5 to 5.5, more preferably 1.0 to 5.0, more preferably 1.5 to 5.0.

In addition, even it also has basic functionality or the like except acidic functionality, the acid examples of substances of the low-molecular-weight of using includes but not limited to aminoacid or ethylenediaminetetraacetic acid in the present invention, as long as the pH of the suspension of its aqueous solution of 2.5% or 2.5% is less than 4.5.The term of Shi Yonging " low-molecular-weight " is meant that molecular weight is 1000 or littler in the present invention, and this has got rid of the acid material of the high molecular of using in the present invention.In addition, the acid material of the low-molecular-weight of using can be a water solublity or water-insoluble in the present invention, but preferably at room temperature is solid, preferably has low volatility simultaneously.In pharmaceutical composition, can comprise one or both or the acid material of more kinds of low-molecular-weight of using in the present invention.

For the not special restriction of the acid material of low-molecular-weight, but its example includes but not limited to organic acid, mineral acid or acidic amino acid.The organic acid example includes but not limited to that carboxylic acid is acetic acid, benzoic acid, lauric acid, myristic acid, Palmic acid, stearic acid, oxalic acid, malonic acid, succinic acid, adipic acid, decanedioic acid, fumaric acid, maleic acid, glycyrrhizic acid, biosone, sorbic acid or the like for example; Hydroxy acid is glycolic, lactic acid, malic acid, tartaric acid, citric acid, dihydro sodium citrate, gluconic acid, salicylic acid or the like for example; Sulfonic acid is p-methyl benzenesulfonic acid, methanesulfonic acid or the like for example.The example of mineral acid includes but not limited to, hydrochloric acid, sulphuric acid, boric acid, phosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate or the like.The example of acidic amino acid includes but not limited to, Aspartic Acid, glutamic acid, acidogen, histidine monohydrochloride or the like.Optimization acid, hydroxy acid, acidic amino acid and mineral acid, more preferably hydroxy acid, acidic amino acid and mineral acid.More particularly, the preferred example of the acid material of the low-molecular-weight of using includes but not limited to succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, Aspartic Acid, glutamic acid, acidogen, hydrochloric acid or phosphoric acid in the present invention, more preferably succinic acid, tartaric acid, citric acid, malic acid, Aspartic Acid, glutamic acid, acidogen, hydrochloric acid or phosphoric acid.Still more preferably citric acid, Aspartic Acid and hydrochloric acid.

Especially when uniting acid material of use low-molecular-weight and high molecular acidity material, can obtain effect of the present invention.Stablize purpose and do not limit the acid amount of substance of high molecular for reaching, but can regulate according to sustained releasing property.In this case, use acid material of low-molecular-weight and the acid material of high molecular to prevent or to suppress catabolite if unite, regulated quantity is without any effect.For example, based on 100 weight portions according to pharmaceutical composition of the present invention, the acid amount of substance of low-molecular-weight generally is 0.05 to 4 weight portion, preferred 0.1 to 3 weight portion, more preferably 0.15 to 2 weight portion, more preferably 0.15 to 1.5 weight portion.

(antioxidant)

For the not special restriction of the antioxidant that uses in the present invention, as long as antioxidant is the material that produces antioxidation when oxidized, preferred anti-oxidant itself is easier to oxidized than having amino antidementia agent.Therefore, the antioxidant that uses in the present invention has reduction.The examples of antioxidants of Shi Yonging includes but not limited in the present invention, and the ascorbic acid class is ascorbic acid, sodium ascorbate, arabo-ascorbic acid, sodium erythorbate, ascorbyl palmitate, ascorbic acid glucosides or the like for example; The aminoacid of sulfur-bearing is cysteine, cysteine hydrochloride, methionine or the like for example; Sulphite is sodium sulfite, sodium sulfite or the like for example; Catechol derivatives is catechol, chlorogenic acid, caffeic acid, tyrosine or the like for example; Hydroquinone derivatives is dibutyl benzyl alcohol, butyl mequinol or the like for example; Gallic acid-derivate is gallic acid, epicatechol gallate, tannic acid or the like for example; Tocopherol is d1-alpha-tocopherol, d-alpha-tocopherol, d-betatocopherol, d-Gamma-Tocopherol, d-Delta-Tocopherol, d-α-tocotrienol, d-β-tocotrienol, d-γ-tocotrienol, d-δ-tocotrienol, its mixture or the like for example; Flavonoid is rutin, Quercetin, Hesperidin or the like for example; With Polyphenols for example catechin, epicatechin, gallo catechin, proanthocyanidin or the like.Aminoacid, hydroquinone derivatives and the tocopherol of preferred ascorbic acid class, sulfur-bearing.The more preferably aminoacid of ascorbic acid class or sulfur-bearing.Preferred especially methionine, ascorbic acid or cysteine hydrochloride.The antioxidant of Shi Yonging can be free or the form of salt in the present invention, but preferably when its dissolving or when suspending in water this aqueous solution show acidity.For example, ascorbic acid nose sodium ascorbate is more preferred, and CYSTEAMINE HCL acid ratio cysteine is more preferred.The antioxidant of Shi Yonging can use separately in the present invention, or comprises two or more, and perhaps it can unite use with the acid material of low-molecular-weight.The antioxidant of Shi Yonging can be a water solublity or water-insoluble in the present invention, but preferably at room temperature is solid, preferably has low volatility simultaneously.

Have no particular limits for the antioxidant that uses in the present invention and the ratio of medicine, but for example based on 1 medicaments in part by weight, antioxidant generally can be 0.01 to 10 weight portion, preferred 0.02 to 5 weight portion, more preferably 0.05 to 2 weight portion.Amount for antioxidant has no particular limits, but based on 100 weight portions according to pharmaceutical composition of the present invention, it generally is 0.001 to 5 weight portion, preferred 0.01 to 3 weight portion, more preferably 0.1 to 2 weight portion, more preferably 0.15 to 1.5 weight portion.

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

Preferably comprise water-soluble sugar and/or water solublity sugar alcohol according to pharmaceutical composition of the present invention.For water-soluble sugar and/or the not special restriction of water solublity sugar alcohol.The example of water-soluble sugar includes but not limited to, lactose, sucrose, glucose, dextrin, pullulan or the like.The example of water solublity sugar alcohol includes but not limited to, mannitol, erythritol, xylitol, Sorbitol or the like, preferred lactose and mannitol.Amount for water-soluble sugar or water solublity sugar alcohol in pharmaceutical composition according to the present invention has no particular limits, but be based on the matrix type extended release preparation of 100% weight, above-mentioned amount generally is 3 to 70% weight, preferred 5 to 60% weight, more preferably 10 to 60% weight, more preferably 12 to 60% weight.

(excipient)

Pharmaceutical composition according to the present invention comprises additive, and described additive comprises various pharmaceutically acceptable carriers for example excipient, lubricant, binding agent and disintegrating agent and antiseptic, coloring agent, sweetener, plasticizer, film coating and essential analog.The example of excipient includes but not limited to, starch, pregelatinized starch, crystalline cellulose, light anhydrous silicic acid, synthetic aluminium silicate, magnesium aluminate or the like.The example of lubricant includes but not limited to, magnesium stearate (Mallinckrodt Baker, Inc.USA), calcium stearate (Merck KGaA, Darmstadt, Germany), Talcum, sodium stearyl fumarate or the like.The example of binding agent includes but not limited to, hydroxypropyl cellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone or the like.Examples of disintegrants includes but not limited to, carboxymethyl cellulose, carboxymethylcellulose calcium, cross-linked carboxymethyl cellulose calcium, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose or the like.Examples of preservatives includes but not limited to, p-Hydroxybenzoate, chlorobutanol, benzyl alcohol, phenethanol, dehydroactic acid, sorbic acid or the like.The preferred example of coloring agent includes but not limited to, water-insoluble lake pigment, natural pigment (for example beta-carotene, chlorophyll and ferrum oxide), yellow iron sesquioxide, red iron sesquioxide, black iron oxide or the like.The example of sweetener includes but not limited to, saccharin sodium, Radix Glycyrrhizae dipotassium, aspartame, fatty acid glyceride, stevia or the like.The example of plasticizer includes but not limited to, fatty acid glyceride, triethyl citrate, propylene glycol, Polyethylene Glycol or the like.Film-coated example includes but not limited to, hydroxypropyl emthylcellulose, hydroxypropyl cellulose or the like.

(pharmaceutical composition)

For the not special restriction of pharmaceutical composition according to the present invention, as long as it is that wherein antidementia agent is a stable compositions, but preferably it is to have sustained releasing property or extended release preparation, and more preferably it is the matrix type extended release preparation.Dosage form for pharmaceutical composition of the present invention also has no particular limits, and it can use in any form, comprises tablet, capsule, granule, microgranule, powder, ointment, injection, poultice, inhalant, jelly or the like.Preferred its dosage form is to be fit to oral preparation, for example tablet, capsule, microgranule, jelly or the like, and more preferably it is the form of tablet, capsule, granule or microgranule.

In addition, pharmaceutical composition according to the present invention is the pharmaceutical composition that comprises the acid material of antidementia agent, high molecular alkaline matter and high molecular.How to be dispersed in not special restriction in this pharmaceutical composition for antidementia agent, high molecular alkaline matter and the acid material of high molecular, these compositions can be blended in the phase homophase according to pharmaceutical composition of the present invention equably.Especially, it is the pharmaceutical composition that comprises substrate, and wherein this substrate comprises the mixture of the acid material of antidementia agent, high molecular alkaline matter and high molecular, and is, for example, and the matrix type extended release preparation.Substrate of the present invention, its Chinese medicine and and lasting release matrix mix and pressing mold or granulation therein equably.Certainly, also can sneak into other additive, perhaps can further cover this substrate with the coatings that comprises screening agent or anti-blushing agent or the like in this substrate kind.

Medicine and high molecular alkaline matter also can be included in respectively according to pharmaceutical composition of the present invention adjacent mutually in.In addition, the phase that comprises medicine with comprise the high molecular alkaline matter can comprise the synergetic phase of a plurality of multilamellars mutually respectively.In this case, the acid material of high molecular can be included in these phases at least one mutually in.For example, can comprise the core that contains antidementia agent according to pharmaceutical composition of the present invention, this core covers with the coatings that contains the high molecular alkaline matter, and it for example can be to continue the coated preparation that discharges that the acid material of high molecular is blended at least one of core and coatings.It should be noted that it can be the form of granule or tablet, or other forms for the not special restriction of core.Its example comprises, tablet, and the coating direct coated that wherein comprises the high molecular alkaline matter is on core, and core is the tablet of not coating that comprises the mixture of the acid material of medicine and high molecular; Granule, the coating direct coated that wherein comprises the acid material of high molecular alkaline matter and high molecular is containing on the particulate core, wherein this granule comprises medicine, and the aggregated particle that comprises layer, the acid material of its Chinese medicine and high molecular is included in for example nonpareil or the like and comprising in the layer of high molecular alkaline matter of slug particle.Its purposes is that preparation comprises accumulative particulate tablet or capsule, and wherein this accumulative granule for example comprises layer that contains acid material of high molecular and high molecular alkaline matter and the layer that comprises medicine among nonpareil or the like at slug particle.

In addition, according to pharmaceutical composition of the present invention can be a kind of pharmaceutical composition, wherein comprise the acid material of high molecular in the phase that comprises medicine and comprise between the phase of high molecular alkaline matter so that antidementia agent can not contact with the high molecular alkaline matter.Also can cover this core with the coatings that comprises the acid material of high molecular alkaline matter and high molecular then by core with the involved medicine of mixture bag that comprises the acid material of high molecular.

(method of mixing the acid material of high molecular)

When in pharmaceutical composition according to the present invention, comprising high molecular acidity material, during producing blend step, granulation step, pressing mold step, coating steps, packaging step or other any steps of pharmaceutical composition or can use conventional known operation method during a plurality of step (for example in Japanese Pharmacopoeia, 14 ^ThEd., those that describe among the General Rules forPreparations).Although be not limited in this respect; but concrete example comprises (a) a kind of method; wherein in the step of dry mixed or wet-mixed medicine and high molecular alkaline matter; also add the acid material of high molecular; (b) a kind of method; wherein the acid material of high molecular is to suspend in water or other binding agents are used for the mixture of wet granulation medicine and insoluble polymer; to add the acid material of high molecular; (c) a kind of method; wherein when the mixture of dry granulation medicine and insoluble polymer; add the acid material of pulverous high molecular; (d) a kind of method; wherein mix and granule that pressing mold comprises medicine when comprising the granule of high molecular alkaline matter; add the acid material of pulverous high molecular; (e) a kind of method; when the granule that comprises medicine or tablet during with the sweet tablet that comprises the molecular weight alkaline matter or film coating; in advance the acid material of high molecular is joined in coating solution or the like to form coatings; (f) a kind of method becomes capsule with the granule that comprises medicine with the granule packaging that comprises the high molecular alkaline matter with the powder or the granule of the acid material of high molecular.Preferably during at least one of blend step and granulation step, the acid material of high molecular can be used as powder or solution or suspension and joins in the mixture of medicine and high molecular alkaline matter.Can obtain the mixed uniformly therein granule of all the components like this, by this method.Particularly preferred method is that the acid material of pulverous high molecular is joined in the mixture of medicine and high molecular alkaline matter.It should be noted that, have no particular limits for the solvent that for example uses in wet-mixed and preparation solution of stabilizing agent or the suspension at various production stages, but the example of solvent comprises alcohol, water, or the mixture of above-mentioned substance, preferred alcohol, water or their mixture.

(with the acid material of low-molecular-weight or the like blended compositions)

Pharmaceutical composition according to the present invention is the pharmaceutical composition that also comprises the acid material of low-molecular-weight except the acid material of antidementia agent, high molecular alkaline matter and high molecular.For how the acid material of low-molecular-weight is blended into not special restriction in the pharmaceutical composition, for example, it can be blended into the acid material of medicine, high molecular alkaline matter and high molecular mixed uniformly mutually in.When medicine and high molecular alkaline matter different mutually in the time, the acid material of low-molecular-weight can be blended into according in the pharmaceutical composition of the present invention at least one mutually in.It also can independently or with the acid material of high molecular wrap by on the substrate or core of pharmaceutical composition.It should be noted that also and can antioxidant be blended in the pharmaceutical composition in the mode identical with the acid material of above-mentioned low-molecular-weight.Certainly, antioxidant can be mixed together with the acid material of low-molecular-weight or can be blended in the pharmaceutical composition respectively with the acid material of low-molecular-weight.

(method that adds acid material of low-molecular-weight or the like)

In the situation of mixing the acid material of high molecular, acid material of low-molecular-weight or antioxidant can be mixed in the compositions at arbitrary steps or during a plurality of steps of production pharmaceutical composition.The acid material of this low-molecular-weight can be mixed in step identical with adding the acid material of high molecular or different step.Acid material of this low-molecular-weight or antioxidant preferably add in the blend step of producing pharmaceutical composition and at least one step in the granulation step.More preferably, acid material of high molecular and the acid material of low-molecular-weight are to add in the blend step of producing pharmaceutical composition and at least one step in the granulation step.Add acid material of low-molecular-weight or antioxidant and be not limited to these aspects and these methods, acid material of low-molecular-weight or antioxidant can be used as powder add be dispersed in solution or the suspension or spraying thereon.In this case, even add the acid material of low-molecular-weight, antioxidant and the acid material of high molecular in same step, the method for adding also can be according to material and difference, and perhaps they are all by identical method adding.For example, in blend step, can add the acid material of pulverous high molecular, acid material of the low-molecular-weight that adds or antioxidant then are solution or suspension, perhaps can in blend step, add the acid material of pulverous high molecular, and acid material of the low-molecular-weight that adds in granulation step or antioxidant are solution or suspension, but are not limited to these examples.

For producing, the acid material of high molecular is blended into step in the pharmaceutical composition as long as it comprises according to the not special restriction of the method for pharmaceutical composition of the present invention.Can be according to the known operation method (for example in the Japanese Pharmacopoeia, 14 ^ThEd., those described in the General Rules for Preparations) produce according to pharmaceutical composition of the present invention.With the solid orally ingestible is example, forms tablet, comprises adding and hybrid medicine and excipient, disintegrating agent or the like, if necessary, adds binding agent to form granule, if necessary adds disintegrating agent, lubricant or the like then.The granule that can be used for tablet with identical conventional method preparation; comprise extrusion granulator or with the powder dispersion bag that comprises medicine and additive by nonpareil (core; comprise 75% sucrose (W/W) and 25% corn starch (W/W)), water or comprise solution (about 0.5 to 70% (W/W) of the concentration) spraying of binding agent simultaneously.In capsular situation, can fill gelatin, hydroxypropyl emthylcellulose or other capsules together with medicine and excipient.Can with coating materials separately or screening agent or the acid material of low-molecular-weight of the present invention or oxidant package by pharmaceutical composition, with odour masking or give enteric or sustained releasing property or the like.Can produce according to pharmaceutical composition of the present invention according to following method.With many naphthalenes of hydrochloric acid piperazine of 130g neat (Eisai Co.Ltd.), the ethyl cellulose (trade name Ethocel 10FP, Dow Chemical Company) of 624g, Eudragit100-55 (the R  hm GmbH﹠amp of 780g; Co.KG) and the lactose of 988g in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 52g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., aqueous solution Ltd).With tray dryer heated drying resulting granules, and sieve, obtain the particle diameter that needs.After sieving, the granule of every 99g adds the magnesium stearate of 1g, and (Mallinckrodt Baker Inc.) and mix, uses rotary tablet machine then, and the tablet that forms every 200mg comprises the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 10mg.Use coating device, then with comprise hydroxypropyl cellulose or the like as the aqueous thin film bag of key component by these tablets.

Alternately, can produce according to pharmaceutical composition of the present invention according to following method.With many naphthalenes of hydrochloric acid piperazine of 130g neat (Eisai Co.Ltd.), the ethyl cellulose (trade name Ethocel 10FP, Dow Chemical Company) of 624g, Eudragit100-55 (the R  hm GmbH﹠amp of 780g; Co.KG) and the lactose of 975g in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 52g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd) and the Fructus Citri Limoniae aqueous acid of 13g.Heat drying resulting granules in tray dryer, and sieve, the particle diameter that needs obtained.After sieving, the granule of every 99g adds the magnesium stearate of 1g, and (MallinckrodtBaker Inc.) and mix, uses rotary tablet machine then, and the tablet that forms every 200mg comprises the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 10mg.Use coating device, then with comprise hydroxypropyl cellulose or the like as the aqueous thin film bag of key component by these tablets.

Embodiment

Illustrate in greater detail the present invention with embodiment below, but the present invention is not limited to this.The additive that uses in pharmaceutical composition is commercial available reagent, or meet statutory document, for example Japanese Pharmacopoeia, the Japanese Pharmaceutical Excipients 2003 (JPE2003) and Japan Pharmaceutical Codex 1997 (JPC 1997).

(embodiment 1)

Add in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine of 300mg neat (Eisai Co.Ltd.), the ethyl cellulose (Ethocel 10FP, Dow Chemical Company) of 375mg, Eudragit L100-55 (the R  hm GmbH﹠amp of 1500mg; Co.KG) and the lactose of 795mg mix this mixture of heat drying in thermostatic chamber.(Mallinckrodt Baker Inc.) and with dried granules mixes the magnesium stearate of adding 30mg.Get this mixture of 200mg, make tablet, obtain comprising the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 20mg with Autograph AG5000A (Shimazu Corporation).

(embodiment 2)

Add in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L100-55 (the R  hm GmbH﹠amp of 500mg; Co.KG), the ethyl cellulose (Ethocel 10FP, Dow ChemicalCompany) of the lactose of 1000mg and 500mg mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(embodiment 3)

The citric acid of 20mg is dissolved in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L100-55 (the R  hm GmbH﹠amp of 500mg; Co.KG), the ethyl cellulose (Ethocel 10FP, DowChemical Company) of the lactose of 1000mg and 500mg mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(embodiment 4)

The dihydro sodium citrate of 20mg is dissolved in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L100-55 (the R  hmGmbH﹠amp of 500mg; Co.KG), the ethyl cellulose (Ethocel10FP, Dow Chemical Company) of the lactose of 1000mg and 500mg mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(embodiment 5)

The Aspartic Acid of 20mg is dissolved in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L100-55 (the R  hm GmbH﹠amp of 500mg; Co.KG), the ethyl cellulose of the lactose of 1000mg and 500mg (Ethocel 10FP, Dow Chemical Company) mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(embodiment 6)

With the dissolution of ascorbic acid of 20mg in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L 100-55 (the R  hm GmbH﹠amp of 500mg; Co.KG), the ethyl cellulose of the lactose of 1000mg and 500mg (Ethocel 10FP, Dow Chemical Company) mixes.This mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(embodiment 7)

The sodium ascorbate of 20mg is dissolved in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L100-55 (the R  hmGmbH﹠amp of 500mg; Co.KG), the ethyl cellulose (Ethocel10FP, Dow Chemical Company) of the lactose of 1000mg and 500mg mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(embodiment 8)

The cysteine of 20mg is dissolved in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L100-55 (the R  hm GmbH﹠amp of 500mg; Co.KG), the ethyl cellulose of the lactose of 1000mg and 500mg (Ethocel 10FP, Dow Chemical Company) mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(embodiment 9)

The cysteine hydrochloride of 20mg is dissolved in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L100-55 (the R  hmGmbH﹠amp of 500mg; Co.KG), the ethyl cellulose (Ethocel10FP, Dow Chemical Company) of the lactose of 1000mg and 500mg mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(embodiment 10)

The methionine of 20mg is dissolved in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L100-55 (the R  hm GmbH﹠amp of 500mg; Co.KG), the ethyl cellulose of the lactose of 1000mg and 500mg (Ethocel 10FP, Dow Chemical Company) mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(embodiment 11)

With many naphthalenes of hydrochloric acid piperazine of 130g neat (Eisai Co.Ltd.), the ethyl cellulose (Ethocel 10FP, Dow Chemical Company) of 312g, EudragitL100-5 5 (the R  hm GmbH﹠amp of 624g; Co.KG) and the lactose of 1456g in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 52g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd), heat drying resulting granules in tray dryer, and sieve, obtain the particle diameter that needs.After sieving, the granule of every 99g adds the magnesium stearate of 1g, and (Mallinckrodt Baker Inc.) and mix, uses rotary tablet machine, and the tablet that forms every 200mg comprises the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 10mg.Use Opadry Yellow (Japan Colorcon), give these tablets then and comprise aqueous film coating (the coating amount: 8mg/ sheet), obtain film-coated tablet of hydroxypropyl emthylcellulose as key component.

(embodiment 12)

With many naphthalenes of hydrochloric acid piperazine of 130g neat (Eisai Co.Ltd.), the ethyl cellulose (Ethocel 10FP, Dow Chemical Company) of 624g, EudragitL100-55 (the R  hm GmbH﹠amp of 780g; Co.KG) and the lactose of 988g in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 52g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd), heat drying resulting granules in tray dryer, and sieve, obtain the particle diameter that needs.After sieving, the granule of every 99g adds the magnesium stearate of 1g, and (Mallinckrodt Baker Inc.) and mix, uses rotary tablet machine, and the tablet that forms every 200mg comprises the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 10mg.Use Opadry Yellow (Japan Colorcon), give these tablets then and comprise aqueous film coating (the coating amount: 8mg/ sheet), obtain film-coated tablet of hydroxypropyl emthylcellulose as key component.

(embodiment 13)

With many naphthalenes of hydrochloric acid piperazine of 130g neat (Eisai Co.Ltd.), the ethyl cellulose (Ethocel 10FP, Dow Chemical Company) of 780g, EudragitL100-55 (the R  hm GmbH﹠amp of 858g; Co.KG) and the lactose of 754g in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 52g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd), heat drying resulting granules in tray dryer, and sieve, obtain the particle diameter that needs.After sieving, the granule of every 99g adds the magnesium stearate of 1g, and (Mallinckrodt Baker Inc.) and mix, uses rotary tablet machine, and the tablet that forms every 200mg comprises the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 10mg.Use Opadry Yellow (Japan Colorcon), give these tablets then and comprise aqueous film coating (the coating amount: 8mg/ sheet), obtain film-coated tablet of hydroxypropyl emthylcellulose as key component.

(embodiment 14)

With many naphthalenes of hydrochloric acid piperazine of 130g neat (Eisai Co.Ltd.), the ethyl cellulose (Ethocel 10FP, Dow Chemical Company) of 832g, EudragitL100-55 (the R  hm GmbH﹠amp of 962g; Co.KG) and the lactose of 598g in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 52g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd), heat drying resulting granules in tray dryer, and sieve, obtain the particle diameter that needs.After sieving, the granule of every 99g adds the magnesium stearate of 1g, and (Mallinckrodt Baker Inc.) and mix, uses rotary tablet machine, and the tablet that forms every 200mg comprises the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 10mg.Use Opadry Yellow (Japan Colorcon), give these tablets then and comprise aqueous film coating (the coating amount: 8mg/ sheet), obtain film-coated tablet of hydroxypropyl emthylcellulose as key component.

(embodiment 15)

With many naphthalenes of hydrochloric acid piperazine of 3.5g neat (Eisai Co.Ltd.), the Ethocel10FP (ethyl cellulose, Dow Chemical Company) of 37.8g, EudragitL100-55 (the R  hm GmbH﹠amp of 22.4g; Co.KG) and the lactose of 73.5g (Pharmatose 200M, by DMV Corporation make) in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 2.8g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd), heat drying resulting granules in tray dryer, and sieve, obtain the particle diameter that needs.After sieving, the granule of every 5000mg adds calcium stearate (the Merck KGaA of 50mg, Germany) also mix, use AutographAG5000A (Shimazu Corporation), make the compression-moulded product of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of comprising 5mg in this product of every 202mg, compression pressure is 1200Kgf.

(embodiment 16)

With many naphthalenes of hydrochloric acid piperazine of 3.5g neat (Eisai Co.Ltd.), the Ethocel1QFP (ethyl cellulose, Dow Chemical Company) of 37.8g, EudragitL100-55 (the R  hm GmbH﹠amp of 22.4g; Co.KG) and the lactose of 73.08g (Pharmatose 200M, by DMV Corporation make) in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 2.8g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd) and the citric acid of 0.42g, heat drying resulting granules in tray dryer rolls to sieve by brute force and obtains the particle diameter that needs.After sieving, the granule of every 5000mg adds calcium stearate (the Merck KGaA of 50mg, Germany) also mix, use Autograph AG5000A (Shimazu Corporation), make the compression-moulded product of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of comprising 5mg in this product of every 202mg, compression pressure is 1200Kgf.

(embodiment 17)

With many naphthalenes of hydrochloric acid piperazine of 3.5g neat (Eisai Co.Ltd.), the Ethocel10FP (ethyl cellulose, Dow Chemical Company) of 37.8g, EudragitL100-55 (the R  hm GmbH﹠amp of 22.4g; Co.KG) and the lactose of 73.5g (Pharmatose 200M, by DMV Corporation make) in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 2.8g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd), heat drying resulting granules in tray dryer rolls to sieve by brute force and obtains the particle diameter that needs.After sieving, the granule of every 5000mg adds magnesium stearate (the Mallinckrodt Baker of 50mg, Inc.) also mix, use Autograph AG5000A (Shimazu Corporation), make the compression-moulded product of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of comprising 5mg in this product of every 202mg, compression pressure is 1200Kgf.

(embodiment 18)

With many naphthalenes of hydrochloric acid piperazine of 3.5g neat (Eisai Co.Ltd.), the Ethocel10FP (ethyl cellulose, Dow Chemical Company) of 37.8g, EudragitL100-55 (the R  hm GmbH﹠amp of 22.4g; Co.KG) and the lactose of 73.08g (Pharmatose 200M, by DMV Corporation make) in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 2.8g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd) and the citric acid of 0.42g, heat drying resulting granules in tray dryer rolls to sieve by brute force and obtains the particle diameter that needs.After sieving, the granule of every 5000mg adds magnesium stearate (the Mallinckrodt Baker of 50mg, Inc.) also mix, use Autograph AG5000A (Shimazu Corporation), make the compression-moulded product of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of comprising 5mg in this product of every 202mg, compression pressure is 1200Kgf.

(embodiment 19)

With many naphthalenes of hydrochloric acid piperazine of 980g neat (Eisai Co.Ltd.), the Ethocel10FP (ethyl cellulose, Dow Chemical Company) of 3780g, EudragitL100-55 (the R  hm GmbH﹠amp of 2660g; Co.KG) and the lactose of 6188g in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 300g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd), heat drying resulting granules in tray dryer, and sieve, obtain the particle diameter that needs.After sieving, the granule of every 99.7g adds the magnesium stearate of 0.3g, and (Mallinckrodt Baker Inc.) mixes, and uses rotary tablet machine, and the tablet that forms every 200mg comprises the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 14mg.Use Opadry purple (Colorcon Japan Limited), give resulting tablet then and comprise water-soluble film coating (the coating amount: 8mg/ sheet), obtain film-coated tablet of hydroxypropyl emthylcellulose as key component.

(embodiment 20)

With many naphthalenes of hydrochloric acid piperazine of 1050g neat (Eisai Co.Ltd.), the Ethocel10FP (ethyl cellulose, Dow Chemical Company) of 3780g, EudragitL100-55 (the R  hm GmbH﹠amp of 2240g; Co.KG) and the lactose of 6538g in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 350g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd), heat drying resulting granules in fluidized bed dryer, and sieve, obtain the particle diameter that needs.After sieving, the granule of every 99.7g adds the magnesium stearate of 0.3g, and (Mallinckrodt Baker Inc.) mixes, and uses rotary tablet machine, and the tablet that forms every 200mg comprises the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 15mg.Use Opadry purple (Colorcon Japan Limited), give resulting tablet then and comprise water-soluble film coating (the coating amount: 8mg/ sheet), obtain film-coated tablet of hydroxypropyl emthylcellulose as key component.

(embodiment 21)

With many naphthalenes of hydrochloric acid piperazine of 1400g neat (Eisai Co.Ltd.), the Ethocel10FP (ethyl cellulose, Dow Chemical Company) of 3500g, EudragitL100-55 (the R  hm GmbH﹠amp of 2520g; Co.KG) and the lactose of 6118g in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 420g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd), heat drying resulting granules in fluidized bed dryer, and sieve, obtain the particle diameter that needs.After sieving, the granule of every 99.7g adds the magnesium stearate of 0.3g, and (Mallinckrodt Baker Inc.) mixes, and uses rotary tablet machine, and the tablet that forms every 200mg comprises the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 20mg.Use Opadry Red (Colorcon Japan Limited) to give resulting tablet and comprise water-soluble film coating (the coating amount: 8mg/ sheet), obtain film-coated tablet of hydroxypropyl emthylcellulose as key component.

(embodiment 22)

With many naphthalenes of hydrochloric acid piperazine of 1610g neat (Eisai Co.Ltd.), the Ethocel10FP (ethyl cellulose, Dow Chemical Company) of 3500g, EudragitL100-55 (the R  hm GmbH﹠amp of 2520g; Co.KG) and the lactose of 5908g in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 420g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd), heat drying resulting granules in fluidized bed dryer, and sieve, obtain the particle diameter that needs.After sieving, the granule of every 99.7g adds the magnesium stearate of 0.3g, and (Mallinckrodt Baker Inc.) mixes, and uses rotary tablet machine, and the tablet that forms every 200mg comprises the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 23mg.Use Opadry Red (Colorcon Japan Limited) to give resulting tablet and comprise water-soluble film coating (the coating amount: 8mg/ sheet), obtain film-coated tablet of hydroxypropyl emthylcellulose as key component.

(embodiment 23)

Many naphthalenes of hydrochloric acid piperazine of 1610g neat (Eisai Co.Ltd.), the Ethocel10FP (ethyl cellulose, Dow Chemical Company) of 3080g, EudragitL100-55 (the R  hm GmbH﹠amp of 2940g; Co.KG) and the lactose of 5908g in granulator, mix.Carry out wet granulation, comprise the hydroxypropyl cellulose (HPC-L that in this mixture, adds 420g in the pure water that is dissolved in appropriate amount; Nippon Soda Co., Ltd), heat drying resulting granules in fluidized bed dryer, and sieve, obtain the particle diameter that needs.After sieving, the granule of every 99.7g adds the magnesium stearate of 0.3g, and (Mallinckrodt Baker Inc.) mixes, and uses rotary tablet machine, and the tablet that forms every 200mg comprises the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 23mg.Use Opadry Red (Colorcon Japan Limited) to give resulting tablet and comprise water-soluble film coating (the coating amount: 8mg/ sheet), obtain film-coated tablet of hydroxypropyl emthylcellulose as key component.

Embodiment 24 to 30

Can be according to the film-coated tablet shown in the method for preparing table 1.

The component title	The seller	Embodiment 24	Embodiment 25	Embodiment 26	Embodiment 27	Embodiment 28	Embodiment 29	Embodiment 30
									Many naphthalenes of hydrochloric acid piperazine is neat	Eisai	12	12	14	18	18	30	30
Ethocel?10FP	Dow Chemical	54	54	48	54	44	50	44
									Eudragit L100-55	Rhm	32	38	44	38	42	36	42
Lactose (Pharmatose 200M)	DMV Corporation	97. 4	91.4	88. 4	84. 4	90. 4	77. 4	77. 4
									HPC-L	Nippon?Soda	4	4	5	5	5	6	6
Magnesium stearate	Mailinckrodt	0.6	0.6	0.6	0.6	0.6	0.6	0.6
									Gross weight (mg)		200	200	200	200	200	200	200
Opadry purple (mg/ sheet)	Colorcon Japan	8	8	8	8	8	8	8
									Film-coated tablet (mg)		208	208	208	208	208	208	208

Embodiment 31 to 34

Component according to table 2 and 3, in mortar, mix every kind of component, get this mixture of 200mg, make the tablet of diameter 8mm of memantine of the neat or 20mg of many naphthalenes of the hydrochloric acid piperazine that comprises 20mg (sheet is heavy: 200mg) with Autograph AG5000A (Shimazu Corporation).

Table 2

The component title	The seller	Embodiment 31
			Many naphthalenes of hydrochloric acid piperazine is neat	Eisai	?300
Ethocel?10FP	Dow?Chemical	?750
			Eudragit?L100	Rhm	?1500
Lactose (FlowLac 100)	Meggle	?420
			Magnesium stearate	Mallinckrodt	?30
Always (mg)		?3000

Table 3

The component title	The seller	Embodiment 32	Embodiment 33	Embodiment 34
					Memantine	Lachema s.r.o	300	?300	?300
Ethocel 10FP	Dow Chemical	750	?750	?750
					Eudragit L100-55	Rhm	1500	?-	?-
Eudragit L100	Rhm	-	?1500	?-
					AQOAT?LF	SHIN-ETSU CHEMICAL	-	?-	?1500
Lactose (FlowLac 100)	Meggle	420	?420	?420
					Magnesium stearate	Mallinckrodt	30	?30	?30
Always (mg)		3000	?3000	?3000

(comparing embodiment 1)

With many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 300mg, ethyl cellulose (the Ethocel 10FP of 750mg, Dow Chemical Company), (Mallinckrodt Baker Inc.) mixes in mortar the magnesium stearate of the lactose of 1920mg and 30mg.Get this mixture of 200mg, make tablet, obtain comprising the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 20mg with Autograph AG5000A (Shimazu Corporation).

(comparing embodiment 2)

With many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 300mg, ethyl cellulose (the Ethocel 10FP of 750mg, Dow Chemical Company), (Mallinckrodt Baker Inc.) mixes in mortar the magnesium stearate of the citric acid of the lactose of 1620mg, 300mg and 30mg.Get this mixture of 200mg, make tablet, obtain comprising the tablet of the neat diameter 8mm of many naphthalenes of hydrochloric acid piperazine of 20mg with Autograph AG5000A (ShimazuCorporation).

(comparing embodiment 3)

Add appropriate amount pure water and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, the lactose of 1500mg and ethyl cellulose (the Ethocel 10FP of 500mg, DowChemical Company) mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(comparing embodiment 4)

The disodium citrate of 20mg is dissolved in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L100-55 (the R  hmGmbH﹠amp of 500mg; Co.KG), the ethyl cellulose (Ethocel10FP, Dow Chemical Company) of the lactose of 1000mg and 500mg mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(comparing embodiment 5)

The sodium citrate of 20mg is dissolved in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L100-55 (the R  hm GmbH﹠amp of 500mg; Co.KG), the ethyl cellulose of the lactose of 1000mg and 500mg (Ethocel 10FP, Dow Chemical Company) mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(comparing embodiment 6)

The NaAsp of 20mg is dissolved in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L100-55 (the R  hmGmbH﹠amp of 500mg; Co.KG), the ethyl cellulose (Ethocel10FP, Dow Chemical Company) of the lactose of 1000mg and 500mg mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(comparing embodiment 7)

The glycine of 20mg is dissolved in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L100-55 (the R  hm GmbH﹠amp of 500mg; Co.KG), the ethyl cellulose (Ethocel 10FP, DowChemical Company) of the lactose of 1000mg and 500mg mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(comparing embodiment 8)

The disodium edetate of 20mg is dissolved in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, Eudragit L100-55 (the R  hmGmbH﹠amp of 500mg; Co.KG), the ethyl cellulose (Ethocel10FP, Dow Chemical Company) of the lactose of 1000mg and 500mg mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(comparing embodiment 9)

Add appropriate amount pure water and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, the lactose of 1000mg and ethyl cellulose (the Ethocel 10FP of 1000mg, DowChemical Company) mixes, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(comparing embodiment 10)

Add the pure water of appropriate amount and mix with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) and the lactose of 2000mg of 20mg, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(comparing embodiment 11)

Add in the pure water of appropriate amount and with many naphthalenes of hydrochloric acid piperazine neat (Eisai Co.Ltd.) of 20mg, the lactose of 1500mg and Eudragit L100-55 (the R  hm GmbH﹠amp of 500mg; Co.KG) mix, this mixture of heat drying in thermostatic drier obtains comprising the neat granule of many naphthalenes of hydrochloric acid piperazine that accounts for particulate gross weight about 1%.

(experimental example 1)

With embodiment 1 and comparing embodiment 1 and 2 comprise the neat tablet of 10% many naphthalenes of hydrochloric acid piperazine in the thermostatic chamber of opening (unsealing) at 60 ℃, 75%RH stored for 1 week down, before storage and the back measure the amount of catabolite.Carry out the mensuration of catabolite by following catabolite analytic process 1.

(catabolite analytic process 1)

By the amount of HPLC evaluation catabolite, use internal diameter 4.6mm ^*, length 75mm ODS-A post (YMC Co.LTd.) as measurement column at 35 ℃, flow velocity 1ml/ minute, detect under the condition of wavelength 271nm and measure.The compositions of mobile phase and linear gradient situation are as shown in table 4.The percentage ratio that is used in the total peak area that obtains as benchmark with respect near the peak of the catabolite of the eluting relative retention time 1.1 to 1.2 at main medicine peak is estimated the amount of catabolite.

Mobile phase A: water/acetonitrile/70% high chloro acid solution=899/100/1 mixture

Mobile phase B: water/acetonitrile/70% high chloro acid solution=99/900/1 mixture

Table 4

Minute	Mobile phase A:	Mobile phase B
			0.00	?75％	25％
6.00	?75％	25％
			9.00	?0％	100％
10.00	?0％	100％
			10.01	?75％	25％
13.00	?75％	25％

The amount of the catabolite of eluting is as shown in table 5 near the relative retention time 1.1 to 1.2 neat with respect to many naphthalenes piperazine, as the measurement result of experimental example 1.In comparing embodiment 1, detected 0.12% catabolite, comprised 50%Eudragit L100-55 and then do not detect catabolite as the acid material embodiment 1 of high molecular.In embodiment 1 or comparing embodiment 1, do not detect other catabolites.In the situation of the comparing embodiment 2 that comprises 10% medicine and citric acid respectively, not only produce 0.77% catabolite near the relative retention time 1.1 to 1.2, and produced various other catabolites, the total amount of catabolite reaches about 13%.In the described Japanese Patent Application Publication H11-106353 of background technology, in the neat solution of the piperazine of naphthalene more than 0.1%, add citric acid and realized light resistance effectively, but obviously, sneaking into citric acid has in fact increased catabolite and has influenced the neat heat stability of many naphthalenes of hydrochloric acid piperazine in the neat tablet of many naphthalenes of the hydrochloric acid piperazine that comprises 10%.But when the high concentration with 50% adds Eudragit L100-55 as the acid material of high molecular, do not detect catabolite, prove for the neat heat stability of many naphthalenes of hydrochloric acid piperazine in the pharmaceutical composition to have the improvement effect.This has shown the improvement effect to heat stability in the compositions that comprises antidementia agent and high molecular alkaline matter of the acid material of high molecular.

Table 5

	The component title	Embodiment 1	Comparing embodiment 1	Comparing embodiment 2
					Amount (mg)	Many naphthalenes of hydrochloric acid piperazine is neat	300	?300	?300
Ethyl cellulose	375	?750	?750
				Eudragit L100-55		1500	?-	?-
Lactose	795	?1920	?1620
				Citric acid		-	?-	?300
Magnesium stearate	30	?30	?30
				Always		3000	?3000	?3000
Catabolite (%)		＜0.05	?0.12						?0.77

(experimental example 2)

With embodiment 2 and 3 and comparing embodiment 3 comprise the neat granule of about 1% many naphthalenes of hydrochloric acid piperazine in the thermostatic chamber of opening (unsealing) at 60 ℃, 75%RH stored for 1 week down, before storage and the back measure the amount of catabolite.Carry out the mensuration of catabolite by following catabolite analytic process 2.Test of the effect of the granule of comparing embodiment 9 to 11 with same procedure with development test embodiment 1.

(catabolite analytic process 2)

By the amount of HPLC evaluation catabolite, use internal diameter 4.6mm ^*, length 150mm Inertsil ODS-2 post (GL Sciences) post as the 646.6/350/1/2.4 mixture of measuring column and water/acetonitrile/70% high chloro acid solution/decane sodium sulfonate, condition is 35 ℃ of column temperatures, flow velocity 1.4mL/ minute, detect wavelength 271nm.The percentage ratio that is used in the total peak area that obtains as benchmark with respect near the peak of the catabolite of the eluting relative retention time 1.1 to 1.2 at main medicine peak is estimated the amount of catabolite.

The amount of the catabolite of eluting is as shown in table 6 near the relative retention time 1.1 to 1.2 neat with respect to many naphthalenes piperazine, as the measurement result of experimental example 2.In not comprising the situation of ethyl cellulose, do not detect catabolite, but in the situation of the comparing embodiment 3 that comprises ethyl cellulose, observed 0.51% catabolite as the comparing embodiment 10 of high molecular alkaline matter and 11.In the situation of the comparing embodiment 9 that comprises more ethyl celluloses, observed 1.26% catabolite.This has proved that catabolite is neat and ethyl cellulose by many naphthalenes of hydrochloric acid piperazine.

From comparing embodiment 3 and embodiment 2, also proved by in pharmaceutical composition, comprising about 25% Eudragit L100-55 and can suppress catabolite.Do not observe catabolite at embodiment 2 or in embodiment 3.This has proved that again the acid material of high molecular is inhibited for the generation of uniting the catabolite that exists and cause of antidementia agent and high molecular alkaline matter, has synergy with citric acid simultaneously.

Table 6

	The component title	Embodiment 2	Embodiment 3	Comparing embodiment 10	Comparing embodiment 11	Comparing embodiment 3	Comparing embodiment 9
								Amount (mg)	Many naphthalenes of hydrochloric acid piperazine is neat	20	20	20	20	?20	?20
Ethyl cellulose	500	500	-	-	?500	?1000
							Eudragit L100-55		500	500	-	500	?-	?-
Lactose	1000	1000	2000	1500	?1500	?1000
							Citric acid		-	20	-	-	?-	?-
Always	2020	2040	2020	2020	?2020	?2020
							Catabolite (%)		0.28	＜0.1	＜0.1	＜0.1	?0.51	?1.26

(experimental example 3)

In order to prove the synergy of the acid material of Eudragit L100-55 and low-molecular-weight, will with citric acid or its salt (embodiment 3 and 4, comparing embodiment 4 and 5), (embodiment 5 for aminoacid, comparing embodiment 6 and 7) or the blended granule of the salt of edetic acid (comparing embodiment 8) in the thermostatic chamber of opening (unsealing) at 60 ℃, 75%RH stored for 2 weeks down, measured the amount of catabolite before storage with the back.Carry out the mensuration of catabolite by top catabolite analytic process 2.In addition, also measure with the dissolving of 2.5% concentration or be suspended in the pH (that is, the EudragitL100-55 in embodiment 2 and in other embodiment and comparing embodiment with the blended additive of the amount of 20mg) of the additive solution of in this experimental example, studying in the pure water.Also measure 2% and 5% neat pH value of aqueous solution of many naphthalenes of hydrochloric acid piperazine as with reference to value.

The amount of the catabolite of eluting is as shown in table 7 near the relative retention time 1.1 to 1.2 neat with respect to many naphthalenes piperazine, as the measurement result of experimental example 3.The amount of catabolite is 0.51% in comparing embodiment 3, and only is 0.28% in comprising the embodiment 2 that Eudragit L100-55 suppresses catabolite separately.In addition, catabolite is no more than 0.51% of comparing embodiment 3 in the embodiment 3 to 5 that has mixed the acid material of low-molecular-weight of the present invention, proves to unite to use Eudragit L100-55 and the acid material of low-molecular-weight to suppress catabolite.Compare with the embodiment 2 that only mixes Eudragit L100-55, in the situation of embodiment 3 that comprises citric acid and the embodiment 5 that comprises Aspartic Acid, further suppressed catabolite, proved that acid material of low-molecular-weight and the acid material of high molecular have synergism for the neat heat stability of many naphthalenes of hydrochloric acid piperazine in the pharmaceutical composition that comprises ethyl cellulose.Estimate the pH (2.5% aqueous solution or suspension) of the additive (additive amount with 20mg in embodiment and comparing embodiment is mixed) that in this test, uses then.Accompanying drawing 1 shows,, opening under (sealing) condition at 60 ℃ with after those additives mix at granule, and 75%RH stores the relation between the pH of 2.5% aqueous solution of 2 all various additives and catabolite or suspension down.When pH was 4.5, the amount of catabolite was substantially equal to comparing embodiment 3, but along with the rising of pH, the amount of catabolite increases.On the other hand, below 4.5, at the bottom of the pH month, heat stability is strong more at pH, and the catabolite that is suppressed is many more.Because the pH of the aqueous solution that many naphthalenes of hydrochloric acid piperazine of 2% is neat is that the pH of the neat aqueous solution of 5.0 and 5% many naphthalenes of hydrochloric acid piperazine is 4.8, the stability of comparing embodiment 4 to 7 reduces with respect to comparing embodiment 3, and this is because they have comprised the higher additive of pH of the pH value aqueous solution neater than the hydrochloric acid naphthalene of manying piperazine.

Table 7

	The component title	Embodiment 2	Embodiment 3	Embodiment 4	Comparing embodiment 4	Comparing embodiment 5	Embodiment 5	Comparing embodiment 6	Comparing embodiment 7	Comparing embodiment 8	Comparing embodiment 3
												Amount (mg)	Many naphthalenes of hydrochloric acid piperazine is neat	20	20	20	20	20	20	20	20	20	20
Ethyl cellulose	500	500	500	500	500	500	500	500	500	500
											Eudragit L100-5 5		500	500	500	500	500	500	500	500	500	-
Lactose	100 0	100 0	100 0	100 0	100 0	100 0	100 0	100 0	100 0	150 0
											Citric acid		-	20	-	-	-	-	-	-	-	-
Monobasic sodium citrate	-	-	20	-	-	-	-	-	-	-
											Disodium citrate		-	-	-	20	-	-	-	-	-	-
Sodium citrate	-	-	-	-	20	-	-	-	-	-
											Aspartic Acid		-	-	-	-	-	20	-	-	-	-
Monosodium L-aspartate	-	?-	-	-	-	-	20	-	-	-
											Glycine		-	-	-	-	-	-	-	20	-	-
Disodium edetate	-	-	-	-	-	-	-	-	20	-
											Always		202 0	204 0	204 0	204 0	204 0	204 0	204 0	204 0	204 0	202 0
Catabolite (%)		0.28	＜0.1	0.27	0.76	0.86	0.18	1.09	0.70	0.53													0.51
											The pH of additive (2.5% aqueous solution or suspension)		3.4	2.0	3.7	5.2	8.3	3.0	6.8	6.2	4.5	-

(experimental example 4)

In order to estimate the synergy of Eudragit L100-55 and antioxidant, comprising of embodiment 6 to 10 and comparing embodiment 8 of about 1% many naphthalenes of hydrochloric acid piperazine granule neat and various oxidants is being opened under (not sealing) condition at 60 ℃, 75%RH stored for 2 weeks down, measured the amount of catabolite before storage with the back.Carry out the mensuration of catabolite according to above-mentioned catabolite analytic process 2.In addition, also measure with the dissolving of 2.5% concentration or be suspended in the pH of the additive of in this experimental example, studying in the pure water (in embodiment and comparing embodiment with the blended additive of the amount of 20mg).

The amount of the catabolite of eluting is as shown in table 8 near the relative retention time 1.1 to 1.2 neat with respect to many naphthalenes piperazine, as the measurement result of experimental example 4.In the embodiment 6 to 10 that comprises EudragitL100-55 and antioxidant, observe Stabilization, and suppressed the generation of catabolite frequently than embodiment 3 more.Low especially, in comprising the amino acid whose embodiment of ascorbic acid or sulfur-bearing, do not detect catabolite, shown with Eudragit L100-55 and had synergism, on the other hand, (pH 4.5 comprising the oxidant that reduction reaction does not take place, 2% aqueous solution) observed the catabolite with comparing embodiment 3 (additive-free) par in the comparing embodiment 8, shown that the chelating antioxidant is for not contribution of stability.

When containing the additive of experimental example 3, accompanying drawing 1 has shown the relation of the pH of the amount of catabolite in the storage test of the embodiment 6 to 10 that comprises the antioxidant with reduction and 2.5% aqueous solution or suspension.With comparison shows that of the result of experimental example 3, the effect the when effect of these antioxidants is different from them as the acid material of low-molecular-weight.

Table 8

	The component title	Embodiment 2	Embodiment 6	Embodiment 7	Embodiment 8	Embodiment 9	Embodiment 10	Comparing embodiment 8	Comparing embodiment 3
										Amount (mg)	Many naphthalenes of hydrochloric acid piperazine is neat	20	20	20	20	20	20	20	20
Ethyl cellulose	500	500	500	500	500	500	500	500

	Eudragit L100-5 5	500	500	500	500	500	500	500	-
										Lactose	1000	1000	1000	1000	1000	1000	1000	1500
	Citric acid	-	-	-	-	-	-	-	-
										Ascorbic acid	-	20	-	-	-	-	-	-
	Sodium ascorbate	-	-	20	-	-	-	-	-
										Cysteine	-	-	-	20	-	-	-	-
	Cysteine hydrochloride	-	-	-	-	20	-	-	-
										Methionine	-	-	-	-	-	20	-	-
	Disodium edetate	-	-	-	-	-	-	20	-
										Always	2020	2040	2040	?2040	2040	2040	2040	2020
	Catabolite (%)		0.28	＜0.1	0.30	＜0.1	＜0.1	＜0.1	0.53										0.51
The pH of additive (2.5% aqueous solution or suspension)										3.4	2.6	7.5	?5.1	1.5	5.9	4.5	-

(experimental example 5)

In 2.5% aqueous solution or suspension, measure the pH value of acid material of the high molecular of using in the present invention and high molecular alkaline matter.The pH value of measuring 2% and 5% neat aqueous solution of many naphthalenes of hydrochloric acid piperazine and 2.5% lactose aqueous solution is as reference value.The result is as shown in table 9.

Table 9

The component title	Trade name	The seller	?pH
				The hydroxypropyl emthylcellulose acetate succinate	AQOAT?LF	?SHIN-ETSU ?CHEMICAL	?3.9
The hydroxypropyl emthylcellulose acetate succinate	HPMCP?HP-55S	?SHIN-ETSU ?CHEMICAL	?3.3

Carboxy vinyl polymer	Carbopol?71G	?Noveon	?3.1
				Methacrylic acid-methylmethacrylate copolymer	Eudragit?L100	?Rhm	?3.3
Methacrylic acid-methylmethacrylate copolymer	Eudragit?S100	?Rhm	?3.2
				Methacrylic acid-methylmethacrylate copolymer	Eudragit?NE30D	?Rhm	?8.6
Polyethylene glycol oxide	POLYOX WSR301	?Dow?Chemical ?Company	?9.3
				Ethyl cellulose	Ethocel?7FP	?Dow?Chemical ?Company	?9.4
Ethyl cellulose	Ethocel?10FP	?Dow?Chemical ?Company	?9.2
				Ethyl cellulose	Ethocel?10	?Dow?Chemical ?Company	?8.6
Ethyl cellulose	Ethocel?100FP	?Dow?Chemical ?Company	?8.1
				Lactose	FloWLac?100	?Meggle	?5.5
Many naphthalenes of hydrochloric acid piperazine neat (2% aqueous solution)	-	?EISAI	?5.0
				Many naphthalenes of hydrochloric acid piperazine neat (5% aqueous solution)	-	?EISAI	?4.8

(experimental example 6)

With embodiment 15,16, the neat tablet of 17 and 18 many naphthalenes of the hydrochloric acid piperazine that comprises 5mg is being opened under (sealing) condition at 60 ℃, and 75%RH stored for 2 weeks down, before storage and the back measure the amount of catabolite.Carry out the mensuration of catabolite according to above-mentioned catabolite analytic process 2.

Near the relative retention time 1.1 to 1.2 neat with respect to many naphthalenes piperazine eluting at 60 ℃, the amount of the catabolite after 75%RH stores down is as shown in table 10, as the measurement result of experimental example 6.As can be seen from Table 10, proved under stress condition, the amount of catabolite can be suppressed to below 0.5% of the neat content of hydrochloric acid many naphthalenes piperazine embodiment 15,16,17 and 18 kind.

Table 10

	The component title	Embodiment 15	Embodiment 16	Embodiment 17	Embodiment 18
						Amount (mg)	Many naphthalenes of hydrochloric acid piperazine is neat	5	?5	?5	?5
Ethyl cellulose	54	?54	?54	?54
					?Eudragit ?L100-55		32	?32	?32	?32
Lactose	105	?104.4	?105	?104.5
					HPC-L		4	?4	?4	?4
Citric acid	-	?0.6	?-	?0.6
					Calcium stearate		2	?2	?-	?-
Magnesium stearate	-	?-	?2	?2
					Always		202	?202	?202	?202
Catabolite (%)		0.20	?0.15	?0.33							?0.26

(experimental example 7)

The tablet that obtains with embodiment 11,12 and 14 carries out stability test.In each of embodiment 11,12 and 14, be filled in the bottle that high density polyethylene (HDPE) makes with 50 tablets, seal this bottle with aluminum slice.Also can seal this bottle with the screw top closure that polyethylene is made.In thermostatic chamber,, after 75%RH stores down, store amount preceding and the back catabolite by using above-mentioned catabolite analytic process 2 to measure at 5 ℃ and 40 ℃.

At 40 ℃, it is as shown in table 11 that 75%RH stores near back amount of the catabolite of the eluting relative retention time 1.1 to 1.2 neat with respect to many naphthalenes piperazine down, as the measurement result of experimental example 7.As can be seen from Table 11, in embodiment 11,12 and 14, proved, the amount of catabolite can be suppressed to below 0.5% of the neat content of hydrochloric acid many naphthalenes piperazine.Policy according to International Conference of Harmonization, the maximal dose of medicine is that 10mg is in the situation of 100mg in every day, the threshold dose that must prove the impurity of safety is less than 0.5% of medicine, or every day total intake less than 200 μ g.In addition,, store the quality that 6 months youngsters guarantee medicine and medicine under the condition of 75%RH, just we can say can guarantee 3 years (at room temperature) of storage if can be at 40 ℃, and 3 years general shelf-lifves of medicine just.The amount that it should be noted that the catabolite that in each of embodiment 11,12 and 14, obtains less than many naphthalenes of hydrochloric acid piperazine neat 0.05%, this is lower than the detectability of impurity.

According to the result of experimental example 7, proved to the invention provides useful solution, comprise the quality of the neat pharmaceutical composition of many naphthalenes of hydrochloric acid piperazine with improvement.

Table 11

	Initially	After 1 month	After 3 months	After 6 months
					Embodiment 11	?NSL	?0.06％	0.10％	0.15％
Embodiment 12	?NSL	?0.09％	0.18％	0.28％
					Embodiment 14	?NSL	?0.12％	0.22％	0.37％

NSL is meant and is no more than 0.05%.

Industrial applicibility

According to the present invention, in the pharmaceutical composition that comprises antidementia agent and sustained release matrix, a kind of method of preventing and treating or suppressing to contact with sustained release matrix owing to antidementia agent the catabolite that causes is provided, i.e. the present invention can provide the method for antidementia agent in a kind of stabilizing pharmaceutical composition. In addition, because pharmaceutical composition according to the present invention is high-quality or highly is fit to compliance that therefore the invention provides a kind of medicine, particularly antidementia agent, it can relievedly be taken, and patient and treatment personnel's burden is less. The present invention also provides a kind of method of simple production pharmaceutical composition, and wherein sustained releasing property is controlled in this pharmaceutical composition, and has stablized antidementia agent, and need not to use special packaging technique or production technology or production equipment.

Claims (31)

1. the method for a stable antidementia agent comprises adding the acid material of high molecular in the pharmaceutical composition that comprises antidementia agent and high molecular alkaline matter.

2. according to the process of claim 1 wherein the addition of the acid material of high molecular, can suppress to contact with the high molecular alkaline matter and the generation of the product of the degraded of the antidementia agent that produces by antidementia agent.

3. according to the method for claim 1 or 2, wherein antidementia agent is the chemical compound with uncle's amino.

4. according to each method of claim 1 to 3, wherein antidementia agent is to be selected from profit to cut down this bright, galantamine, neat, 3-[1-(benzyl) piperidin-4-yl of many naphthalenes piperazine]-1-(2,3,4,5-tetrahydrochysene-1H-1-benzene azepine -8-yl)-1-propane and 5,7-dihydro-3-[2-[1-(benzyl)-4-piperidyl] ethyl]-6H-pyrrolo-[4,5-f]-1,2-benzene is different

Azoles-6-ketone and the acceptable salt of pharmacy thereof.

5. according to each method of claim 1 to 4, wherein antidementia agent is the neat or acceptable salt of its pharmacy of many naphthalenes piperazine.

6. according to each method of claim 1 to 5, wherein the high molecular alkaline matter is an insoluble polymer.

7. according to each method of claim 1 to 6, wherein the high molecular alkaline matter is at least a material that is selected from ethyl cellulose, EUDRAGIT NE 30 D EUDRAGIT NE 30D and polyethylene glycol oxide.

8. according to each method of claim 1 to 7, wherein the acid material of high molecular is an enteric polymer.

9. according to each method of claim 1 to 8, wherein the acid material of high molecular is at least a material that is selected from acrylic acid methyl ester .-ethyl acrylate copolymer, acrylic acid methyl ester .-methylmethacrylate copolymer, hydroxypropylmethyl cellulose phthalate and hydroxypropyl emthylcellulose acetate succinate.

10. according to each method of claim 1 to 9, further add acid material of at least a low-molecular-weight and antioxidant.

11. according to the method for claim 10, wherein the acid material of low-molecular-weight is at least a material that is selected from carboxylic acid, sulfonic acid, hydroxy acid, acidic amino acid and mineral acid.

12. according to the method for claim 10 or 11, wherein the acid material of low-molecular-weight is at least a material that is selected from hydroxy acid, acidic amino acid and mineral acid.

13. according to each method of claim 10 to 12, wherein the acid material of low-molecular-weight is at least a material that is selected from succinic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, Aspartic Acid, glutamic acid, acidogen, hydrochloric acid and phosphoric acid.

14. according to each method of claim 10 to 13, wherein the acid material of low-molecular-weight is at least a material that is selected from succinic acid, tartaric acid, citric acid, malic acid, Aspartic Acid, glutamic acid, acidogen, hydrochloric acid and phosphoric acid.

15. according to each method of claim 10 to 14, wherein antioxidant is at least a aminoacid of ascorbic acid, sulfur-bearing, the derivant of hydroquinone and the material of tocopherol of being selected from.

16. the application of the acid material of high molecular in suppressing to contact with the high molecular alkaline matter catabolite of the antidementia agent that produces owing to antidementia agent.

17. the acid material of high molecular and the acid material of at least a low-molecular-weight and the antioxidant application in suppressing to contact with the high molecular alkaline matter catabolite of the antidementia agent that produces owing to antidementia agent.

18. a pharmaceutical composition that comprises antidementia agent and high molecular alkaline matter, wherein said composition further comprises the acid material of the high molecular of stablizing antidementia agent.

19., further comprise the acid material of low-molecular-weight and the antioxidant of at least a stable antidementia agent according to the pharmaceutical composition of claim 18.

20. according to the pharmaceutical composition of claim 18, wherein said composition comprises substrate, wherein said substrate comprises a kind of mixture that comprises the acid material of high molecular of antidementia agent, high molecular alkaline matter and stable antidementia agent.

21. according to the pharmaceutical composition of claim 20, acid material of at least a low-molecular-weight and the antioxidant of wherein stablizing antidementia agent are blended in the substrate.

22. according to the pharmaceutical composition of claim 18, wherein pharmaceutical composition comprises the core that contains antidementia agent and covers the coatings that contains the high molecular alkaline matter on the core, wherein the acid material of high molecular is sneaked in core and coatings at least a.

23., wherein stablize the acid material of at least a low-molecular-weight of antidementia agent and antioxidant and further be blended in core and coatings at least a according to the pharmaceutical composition of claim 22.

24. according to each pharmaceutical composition of claim 18 to 23, wherein this pharmaceutical composition is an extended release preparation.

25. according to each pharmaceutical composition of claim 18 to 24, wherein the acid material of high molecular is an enteric polymer.

26. a matrix type extended release preparation comprises: the neat or acceptable salt of its pharmacy of many naphthalenes piperazine; The high molecular alkaline matter; With the acid material of high molecular.

27., further comprise acid material of at least a low-molecular-weight and antioxidant according to the matrix type extended release preparation of claim 26.

28. a method of producing pharmaceutical composition comprises the following steps: to mix antidementia agent and high molecular alkaline matter; With with this granulating mixture, wherein at least one step of blend step and granulation step, in the mixture of antidementia agent and high molecular alkaline matter, add the high molecular acidity material stablize antidementia agent.

29. according to the method for claim 28, wherein the acid material of high molecular adds with powder.

30., wherein further at least one step of blend step and granulation step, in the mixture of antidementia agent and high molecular alkaline matter, add acid material of at least a low-molecular-weight of stablizing antidementia agent and antioxidant according to the method for claim 28 or 29.

31. according to the method for claim 29, acid material of wherein at least a low-molecular-weight and antioxidant add with solution or suspension.

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