CN103393623A

CN103393623A - Novel preparation

Info

Publication number: CN103393623A
Application number: CN2013102428866A
Authority: CN
Inventors: 今田康嗣; 新海康成; 井墉松男
Original assignee: Mitsubishi Tanabe Pharma Corp
Current assignee: Mitsubishi Tanabe Pharma Corp
Priority date: 2007-11-09
Filing date: 2008-11-07
Publication date: 2013-11-20
Also published as: CN104739819A; JP2014040475A; WO2009060952A1; CN101854929A; KR101122447B1; JP5479909B2; JPWO2009060952A1; KR20100096147A

Abstract

The invention provides a novel preparation containing a substance selected from the group consisting of aminoalkoxybibenzyls, pharmaceutically acceptable salts thereof, esters thereof, solvates thereof, and hydrates thereof as an active ingredient. According to the invention, the novel preparation which contains a substance selected from the group consisting of aminoalkoxybibenzyls, pharmaceutically acceptable salts thereof, esters thereof, solvates thereof, and hydrates thereof as an active ingredient and achieves a sustained blood concentration can be provided.

Description

New formulation

The application is that international application no is that PCT/JP2008/070338, international filing date are that after the PCT international application on November 7th, 2008 entered China's stage, national applications number was 200880115418.X, denomination of invention dividing an application for the application of " new formulation ".

Technical field

The present invention relates to a kind of new formulation with blood drug level persistence, said preparation is usingd and is selected from material in aminoalkoxy Bibenzyl compound, its pharmaceutically useful salt, its ester and their solvate and their hydrate as effective ingredient.

Background technology

The remarkable High Level of medical treatment and complicated now, for the higher Drug therapy of implementation quality, usually need the definite and safe medicine of development effectiveness.When developing effective and safe drugs, according to the characteristic of each medicine and therapeutic purposes, carrying out the preparation design is absolutely necessary, thereby such preparation technique is necessary: it not only can obtain excellent pharmacological property, and can control to heavens in drug release and body dynamic.

Be known that the aminoalkoxy Bibenzyl compound with ad hoc structure take sarpogrelate hydrochloride as representative is to 5HT ₂Receptor demonstrates high selectivity, can effectively improve up to now the various microcirculation disturbance by thrombosis generation and vasoconstriction initiation in the diseases such as disturbance of cerebral circulation, ischemic heart desease, peripheral circulation disorders.

Sarpogrelate hydrochloride is tablet at the beginning of listing in 1994, afterwards, consider the patient of dysphagia and increased granule, but these preparations are all to need every day to take the preparation of 3 times.But, in the situation that the such needs of peripheral circulation disorders continue the disease of Long-term taking medicine, take every day 3 times to patient be bear larger.Therefore, from the viewpoint of the compliance medical scene (compliance), consider people's few sarpogrelate hydrochloride preparation of administration number of times that waits in expectation.Yet sarpogrelate hydrochloride is the compound with following character: be easy to be hydrolyzed, with the match ratio of additive, be easy to change, water solublity is high, it is fast etc. to dissolve.In addition, be known that in order to make sarpogrelate hydrochloride demonstrate the effectiveness as the peripheral circulation disorders curative, must adopt higher dosage.Therefore, with respect to the preparation of taking 3 every day, prepare the content of sarpogrelate hydrochloride higher, take the preparation of 2 times every day and be considered to difficulty.

People are still developing to reduce the controlled release preparation that administration number of times is purpose energetically up to now, and have developed the preparation of multifunction.In patent documentation 1, disclosed by regulating the mixed proportion of additive, even with simple prilling process, can obtain the former medicine granule of high yield, thereby acquisition does not almost have the sustained-release granular formulation of efflorescence yet.In patent documentation 2, disclosed such sustained-release preparation: with water insoluble and can coat the core that is formed by medicine and swelling agent by water-soaked coating film, discharge start after at short notice medicine be released, and can remain local concentration.In addition, in patent documentation 3, also disclosed by the rapid disintegrate of the absorption site at enteral to improve the enteric solubility preparation of drug absorption.In addition, in patent documentation 4, disclose such oral administration preparation, wherein, by Eudragit RS and Eudragit LD are mixed to the film composition that obtains, the lag time through certain, can discharge rapidly to pulsed 100% medicine.

But, in any document, all less than the record about controlled release preparation (it discloses and has been intended to be applicable to contain the concrete means of sarpogrelate hydrochloride as the medicament of effective ingredient), even do not disclose this technical problem yet.

Patent documentation 1: TOHKEMY 2007-39353 communique

Patent documentation 2: TOHKEMY 2002-212062 communique

Patent documentation 3: TOHKEMY 2001-139462 communique

Patent documentation 4: Japanese kokai publication hei 8-143476 communique

Summary of the invention

Technical problem to be solved by this invention

Technical problem of the present invention is to provide a kind of new formulation with blood drug level persistence, and said preparation is usingd and is selected from material in aminoalkoxy Bibenzyl compound, its pharmaceutically useful salt, its ester and their solvate and their hydrate as effective ingredient.

The technological means of dealing with problems

The inventor has carried out conscientious research in order to address the above problem, found that a kind of new formulation, said preparation is compared and is had lasting blood drug level with conventional formulation, and said preparation is usingd and is selected from material in aminoalkoxy Bibenzyl compound, its pharmaceutically useful salt, its ester and their solvate and their hydrate as effective ingredient.

That is, the present invention is as described below.

[1] a kind of blood drug level persistence preparation, said preparation are usingd and are selected from material in the represented aminoalkoxy Bibenzyl compound of following general formula (1), its pharmaceutically useful salt, its ester and their solvate and their hydrate as effective ingredient.

[formula 1]

[in formula, R ¹Expression hydrogen atom, halogen atom, C ₁～C ₅Alkoxyl or C ₂～C ₆Dialkyl amido, R ²Expression hydrogen atom, halogen atom or C ₁～C ₅Alkoxyl, R ³Expression hydrogen atom, hydroxyl ,-O-(CH ₂) _nIn-COOH(formula, n represents 1～5 integer) or-O-CO-(CH ₂) _lIn-COOH(formula, l represents 1～3 integer), R ⁴Expression-N (R ⁵) (R ⁶) (in formula, R ⁵And R ⁶Represent independently of one another hydrogen atom or C ₁～C ₈Alkyl) or R ⁴Expression

[formula 2]

(in formula, A represents can be by the C of carboxyl substituted ₃～C ₅Alkylidene), m represents 0～5 integer.]

[2] blood drug level persistence preparation as described as [1], wherein, as the blood drug level persistence, mean residence time (MRT) is more than 3.0 hours.

[3] blood drug level persistence preparation as described as [1], wherein, as the blood drug level persistence, mean residence time (MRT) is 3.0 hours to 24.0 hours.

[4] blood drug level persistence preparation as described as [1], wherein, as the blood drug level persistence, mean residence time (MRT) is 3.0 hours to 12.0 hours.

[5] blood drug level persistence preparation as described as [1], wherein, as the blood drug level persistence, mean residence time (MRT) is 3.0 hours to 10.0 hours.

[6] the blood drug level persistence preparation described in [2]～[5], wherein, as the blood drug level persistence, mean residence time (MRT) is the mean residence time (MRT) after using to experimental animal.

[7] the blood drug level persistence preparation described in [1]～[6], as effective ingredient, said preparation is usingd and is selected from material in the represented aminoalkoxy Bibenzyl compound of following formula (2), its pharmaceutically useful salt, its ester and their solvate and their hydrate as effective ingredient.

[formula 3]

[8] the blood drug level persistence preparation described in [1]～[6], as effective ingredient, said preparation is usingd and is selected from material in the represented aminoalkoxy Bibenzyl compound of following formula (3), its pharmaceutically useful salt, its ester and their solvate and their hydrate as effective ingredient.

[formula 4]

[9], as [7] or [8] described blood drug level persistence preparation, wherein, as the aminoalkoxy Bibenzyl compound of effective ingredient, be the form of hydrochlorate.

[10] the blood drug level persistence preparation described in [1]～[9], this blood drug level persistence preparation is coated by release-controlled film.

[11] blood drug level persistence preparation as described as [10], this blood drug level persistence preparation is enteric solubility preparation, slow releasing preparation, pulse release type preparation or swelling type slow releasing preparation.

[12] blood drug level persistence preparation as described as [11], wherein, described enteric solubility preparation is to be coated with the preparation that contains the high molecular release-controlled film of enteric solubility on former medicine preparation.

[13] as [11] or [12] described blood drug level persistence preparation, wherein, the stripping pH of the effective ingredient of described enteric solubility preparation is arranged in the scope of pH5.0～7.0.

[14] blood drug level persistence preparation as described as [13], wherein, the stripping pH of the effective ingredient of described enteric solubility preparation is set to pH5.5.

[15] the blood drug level persistence preparation described in [11]～[14], wherein, when when turning under the condition of basket method at 100rpm the dissolution rate in vitro of the effective ingredient of measuring described enteric solubility preparation, at pH, be no more than in the experimental liquid of stripping pH of effective ingredient of setting, after 2 hours, the stripping quantity of effective ingredient is below 10 % by weight, and in the experimental liquid of pH over the stripping pH of the effective ingredient of setting, after 1 hour, the stripping quantity of effective ingredient is 90～100 % by weight.

[16] blood drug level persistence preparation as described as [11], wherein, described slow releasing preparation is on former medicine preparation, to be coated with the preparation of the release-controlled film that contains water-insoluble macromolecule and water-soluble additives.

[17] blood drug level persistence preparation as described as [11], wherein, described pulse release type preparation is on former medicine preparation, to be coated with the preparation of release-controlled film, and this release-controlled film contains ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride ethyl ester copolymer and EUDRAGIT L100-55.

[18] blood drug level persistence preparation as described as [11], it is characterized in that, described swelling type slow releasing preparation is the preparation that is coated with release-controlled film on the basic sheet of water absorption and swelling gellant and effective ingredient containing, and this release-controlled film contains water-insoluble macromolecule and is film like.

[19] as [12], [16], [17] described blood drug level persistence preparation, wherein, the former medicine preparation of described enteric solubility preparation, slow releasing preparation or pulse release type preparation is former medicine granule.

[20] blood drug level persistence preparation as described as [19], wherein, described former medicine granule is spheroidal particle or extrudes granule.

[21] blood drug level persistence preparation as described as [20], wherein, described spheroidal particle is that the spherical particle take mannitol forms as core and together with pharmaceutically useful additive.

The invention effect

According to the present invention, a kind of new formulation can be provided, this new formulation is usingd and is selected from material in aminoalkoxy Bibenzyl compound, its pharmaceutically useful salt, its ester and their solvate and their hydrate as effective ingredient, and has lasting effective ingredient blood drug level.

The accompanying drawing explanation

Fig. 1 is the figure that the dissolution test result in Japanese Pharmacopoeia the 1st liquid of putting down in writing in test example 1 is shown.

Fig. 2 is the figure that the dissolution test result in rare McIlvaine buffer (pH6.8) of putting down in writing in test example 1 is shown.

Fig. 3 is the figure that the dissolution test result of preparation in rare McIlvaine buffer (various experimental liquid pH) of the embodiment 3 that puts down in writing in test example 2 is shown.

Fig. 4 is the figure of dissolution test result that the preparation of the embodiment 5 that puts down in writing in test example 3 is shown.

Fig. 5 is the figure that the dissolution test result of the slow releasing preparation put down in writing in test example 4 and swelling type slow releasing preparation is shown.

The specific embodiment

Below explain the present invention.Preparation of the present invention contains the material (being designated hereinafter simply as " effective ingredient ") that is selected from the represented aminoalkoxy Bibenzyl compound of above-mentioned general formula (1), its pharmaceutically useful salt, its ester and their solvate and their hydrate as effective ingredient.

In above-mentioned general formula (1), R ¹The expression hydrogen atom; The halogen atoms such as chlorine atom, fluorine atom; The C such as methoxyl group, ethyoxyl, butoxy ₁～C ₅Alkoxyl; The C such as dimethylamino, lignocaine, Methylethyl amino ₂～C ₆Dialkyl amido.R ²The expression hydrogen atom; The halogen atoms such as chlorine atom, fluorine atom; The C such as methoxyl group, ethyoxyl, butoxy ₁～C ₅Alkoxyl.R ³The expression hydrogen atom; Hydroxyl;-O-(CH ₂) ₂-COOH ,-O-(CH ₂) ₃-COOH etc.-O-(CH ₂) _nIn-COOH(formula, n represents 1～5 integer);-O-CO-(CH ₂) ₂-COOH ,-O-CO-(CH ₂) ₃-COOH etc.-O-CO-(CH ₂) _lIn-COOH(formula, l represents 1～3 integer).R ⁴Expression amino or methylamino, ethylamino, fourth is amino, oneself is amino, heptan is amino, dimethylamino, lignocaine, Methylethyl amino and so on have the amino that 1～2 carbon number is 1～8 alkyl; Perhaps representing can be by 4～6 ring amido of carboxyl substituted on the ring of azetidine-1-base, piperidin-1-yl, 3-carboxyl piperidin-1-yl and so on.

In the compound that above-mentioned general formula (1) comprises, be preferred for compounds more of the present invention and be shown in table 1 and table 2.

[table 1]

[table 2]

Wherein, as aminoalkoxy-OCH ₂C(R ³) H-(CH ₂) m-R ⁴The compound that is combined on the 2-position of phenyl is preferred.In addition, R ¹Be preferably hydrogen atom, C ₁～C ₅Alkoxyl or C ₂～C ₆Dialkyl amido; R ²Be preferably hydrogen atom; R ⁴Be preferably and have at least 1 C ₁～C ₈4～6 ring amidos of the amino of alkyl or azetidine-1-base or piperidin-1-yl and so on; M is preferably 0～2 integer.Particularly preferably be the compound of numbering 15 compound (below, in this manual, sometimes this compound is called to " M-1 ") and numbering 14, in numbering 15 compound, R ¹For methoxyl group, R ²For hydrogen atom, R ³For hydroxyl, R ⁴For dimethylamino, m are 1, and number 14 the compound succinate for the compound of numbering 15.

So-called " pharmaceutically useful salt " refers to such salt: so long as together with the represented aminoalkoxy Bibenzyl compound of above-mentioned general formula (1) formed salt avirulence, whatever salt can, can enumerate: for example, the inorganic acid addition salts such as hydrofluoride, hydrochlorate, hydrobromate, hydriodate, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; The organic acid addition salts such as formates, acetate, trifluoroacetate, propionate, oxalates, glycollate, succinate, lactate, maleate, hydroxymaleic acid salt, citraconic acid salt, fumarate, adipate, tartrate, malate, citrate, benzoate, cinnamate, Ascorbate, Salicylate, 2-acetoxyl group benzoate, nicotinate .gamma.-pyridinecarboxylic acid salt; The organic sulfonic acid addition salts such as mesylate, esilate, isethionate, benzene sulfonate, tosilate, naphthalene sulfonate, phenolsulfonate, dihydroxy benzenes sulfonic acid salt; The acidic amino acid such as aspartate, glutamate, Glu addition salts; The alkali metal salt such as sodium salt, potassium salt; The alkali earth metal salt such as magnesium salt, calcium salt; Ammonium salt; Front three amine salt, triethylamine salt, pyridiniujm, picoline salt, dicyclohexyl amine salt, N, N '-organic base addition salts such as dibenzyl ethylenediamine salt; The basic amino acid such as lysinate, arginine salt addition salts; Deng.

As the ester of the represented aminoalkoxy Bibenzyl compound of above-mentioned general formula (1), can enumerate by the ester that obtains with mineral acid dehydrating condensations such as the organic acid such as formic acid, acetic acid, trifluoroacetic acid, propanoic acid, oxalic acid, glycolic, succinic acid, lactic acid, maleic acid, hydroxymaleic acid, citraconic acid, fumaric acid, adipic acid, tartaric acid, malic acid, citric acid, benzoic acid, cinnamic acid, ascorbic acid, salicylic acid, 2-acetoxyl group benzoic acid, nicotinic acid .gamma.-pyridinecarboxylic acid or sulphuric acid, nitric acid, phosphoric acid, carbonic acid.

In addition, these compounds, except above-mentioned salt, ester, can be also solvate or the hydrate that forms with water or alcohol etc. in some cases.

In these compounds, particularly preferably be the ethyl by represented (±)-1-[O-[2-of following formula (4) (m-methoxyphenyl)] phenoxy group]-hydrochlorate of 3-(dimethylamino)-2-propyl group hydrogen succinate ester (below, in this manual, also this material is called to " sarpogrelate hydrochloride ").

[formula 5]

The material that is selected from the represented aminoalkoxy Bibenzyl compound of above-mentioned general formula (1), its pharmaceutically useful salt, its ester and their solvate and their hydrate is known material, can or easily manufacture based on the method for the method according to the method for putting down in writing in Japanese kokai publication sho 58-32847 communique.

So-called mean residence time (MRT) in the present invention, refer to by after containing the preparation administration of effective ingredient the average time that effective ingredient is detained in vivo.

In the present invention, as mean residence time MRT, can be enumerated as more than 3.0 hours, preferably be enumerated as 3.0 hours to 24.0 hours, more preferably be enumerated as 3.0 hours to 12.0 hours, further preferably be enumerated as 3.0 hours to 10.0 hours, most preferably be enumerated as 3.0 hours to 6.0 hours.

In the present invention, so-called Tmax(maximum plasma concentration peak time), refer to by after containing the preparation administration of effective ingredient the time the when concentration of effective ingredient in blood plasma reaches the highest.

In the present invention, as Tmax, can be enumerated as 1.0 hours to 12.0 hours, preferably be enumerated as 1.0 hours to 10.0 hours, more preferably be enumerated as 1.0 hours to 7.0 hours, further preferably be enumerated as 1.0 hours to 6.7 hours, most preferably be enumerated as 1.5 hours to 4.5 hours.

In the present invention, combination as MRT and Tmax, except above-mentioned each combination, can enumerate MRT and be 2.5 hours to 3.5 hours and Tmax is that preparation, the MRT of 1.5 hours to 3.0 hours is that 5.0 hours to 6.0 hours and Tmax are that preparation, the MRT of 3.5 hours to 4.5 hours is that 3.5 hours to 4.5 hours and Tmax are the preparation of 2.5 hours to 3.5 hours.

More particularly, can enumerate: the enteric solubility preparation of spheroidal particle and its MRT are that 2.5 hours to 3.5 hours and Tmax are 2.0 hours to 3.0 hours; Extrude the enteric solubility preparation of granule and its MRT and be 2.5 hours to 3.5 hours and Tmax is 1.5 hours to 2.5 hours; Pulse release type preparation and its MRT are that 5.0 hours to 6.0 hours and Tmax are 3.5 hours to 4.5 hours; Swelling type slow releasing preparation and its MRT are that 3.5 hours to 4.5 hours and Tmax are 2.5 hours to 3.5 hours.

In the present invention, so-called Cmax(maximum plasma concentration), after referring to the preparation that contains effective ingredient being used to animal, effective ingredient is at the maximum of Plasma.

In the present invention, as Cmax, can be enumerated as 200～15000ng/mL, preferably be enumerated as 400～10000ng/mL, more preferably be enumerated as 1500～9000ng/mL, further preferably be enumerated as 2500～6000ng/mL, most preferably be enumerated as 4000～6000ng/mL.

In the present invention, so-called t _1/2(half-life), refer to that the blood drug level of effective ingredient reduces to half needed time of this value from some values.

In the present invention, as t _1/2, can be enumerated as 1.0 hours to 12.0 hours, preferably be enumerated as 1.5 hours to 10.0 hours, more preferably be enumerated as 1.5 hours to 5.0 hours, further preferably be enumerated as 1.5 hours to 3.5 hours, most preferably be enumerated as 2.0 hours to 3.5 hours.

In the present invention, as Cmax, Tmax and t _1/2Combination, except above-mentioned each the combination, can enumerate: Cmax is that 4500～5500ng/mL, Tmax are 3.5 hours to 4.5 hours, t _1/2It is the preparation of 2.5 hours to 3.5 hours; Cmax is that 2500～3500ng/mL, Tmax are 3.5 hours to 4.5 hours, t _1/2It is the preparation of 2.5 hours to 3.5 hours; Cmax is that 4500～5500ng/mL, Tmax are 1.5 hours to 2.5 hours, t _1/2It is the preparation of 1.5 hours to 2.5 hours.Demonstrate in such blood that dynamic preparation is preferably slow releasing preparation, enteric solubility preparation, pulse release type preparation, swelling type slow releasing preparation, immediate release preparation or by their preparation that is combined to form.

In the present invention, area under so-called AUC(blood drug level-time graph), refer to the area of the part that is surrounded by blood drug level-time graph (it is for after the preparation that will contain effective ingredient uses to experimental animal, the curve of describing according to the blood drug level temporal evolution of effective ingredient) and axis of abscissas (time shaft).

In the present invention, as AUC, can enumerate 2000～15000h/ng/mL, preferably enumerate 3000～12000h/ng/mL, more preferably enumerate 5000～12000h/ng/mL, further preferably enumerate 7000～12000h/ng/mL, most preferably enumerate 9000～11000h/ng/mL.

In the present invention, experimental animal can be enumerated as dog, preferably is enumerated as beasle dog.

In the present invention, while adopting experimental animal to measure MRT and Tmax, can enumerate the experimental animal that pentagastrin or atropine sulfate have been used in use in advance.More preferably enumerate the experimental animal that uses the state of going on a hunger strike.

In the present invention, so-called release-controlled film, refer to for the dissolution rate of regulating effective ingredient, dissolution time, stripping position etc. and coat the film of former medicine preparation.In the present invention, can enumerate: contain the high molecular release-controlled film of enteric solubility (enteric film), contain water-insoluble macromolecule and water-soluble additives release-controlled film (release membranes), contain the release-controlled film (pulse release type film) of ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride ethyl ester copolymer and EUDRAGIT L100-55 or contain water-insoluble macromolecule and be the release-controlled film of film like (thin film).

In the present invention, so-called former medicine preparation refers to the state before being coated by release-controlled film in enteric solubility preparation, slow releasing preparation or pulse release type preparation, and it is by effective ingredient and the one kind or two or more preparation formulated preparation of additive.Former medicine preparation comprises granule, tablet etc.

In the present invention, so-called blood drug level persistence preparation, can enumerate enteric solubility preparation, slow releasing preparation, pulse release type preparation or swelling type slow releasing preparation.

In the present invention, so-called enteric solubility preparation, can enumerate the preparation that obtains with containing the high molecular release-controlled film of enteric solubility (enteric film) the former medicine preparation of coating.Preferably can enumerate the preparation that makes effective ingredient stripping in the scope of pH5.0～7.0, more preferably can enumerate the preparation that makes effective ingredient stripping in the scope of pH5.0～6.0, further preferably can enumerate and make the preparation of effective ingredient in the pH5.5 stripping.

In the present invention, so-called enteric solubility macromolecule, can enumerate EUDRAGIT L100-55, EUDRAGIT L100, hydroxypropylmethyl cellulose phthalate 220824(HP50), hydroxypropylmethyl cellulose phthalate 220731(HP55), hydroxypropyl methyl cellulose acetate succinate, carboxymethylethylcellulose or cellulose acetate phthalate etc.Preferably can enumerate EUDRAGIT L100-55, EUDRAGIT L100, hydroxypropylmethyl cellulose phthalate 220824(HP50) or hydroxypropylmethyl cellulose phthalate 220731(HP55).

Herein, so-called EUDRAGIT L100-55, can enumerate the copolymer that consists of methacrylic acid and ethyl acrylate, and it is the copolymer of about 1:1 for mixed proportion.For example can enumerate Eudragit LD(by the goldschmidt chemical corporation manufacture).Preferably can enumerate Eudragit L100-55 or L30D-55(by the goldschmidt chemical corporation manufacture), particularly preferably enumerate Eudragit L30D-55.

In addition, so-called EUDRAGIT L100, can enumerate the copolymer that consists of methacrylic acid and methyl methacrylate, it is that the copolymer Eudragit L100(of about 1:2～1:1 is by the goldschmidt chemical corporation manufacture for mixed proportion) and mixed proportion be that the copolymer Eudragit S100(of about 1:3～1:2 is by the goldschmidt chemical corporation manufacture).

These enteric solubility macromolecules can use separately wherein any one, in addition, also can mix as required two or more uses.

In enteric film of the present invention, except above-mentioned enteric solubility macromolecule, can also use one kind or two or more preparation additive, water-insoluble macromolecule and water-soluble additives etc.

In the present invention, so-called preparation additive, can be set forth in the common additive that uses in the scope of not damaging the object of the invention.As such additive, there is no particular limitation to it, so long as pharmaceutically allow to get final product as the various additives that additive uses.As such additive, such as enumerating excipient, binding agent, disintegrating agent, stabilizing agent, aggregation inhibitor, plasticizer, lubricant etc.

As excipient, can enumerate the silicic acid classes such as lactose, white sugar, starch, light anhydrous silicic acid or crystalline cellulose etc.

As binding agent, can enumerate water, ethanol, propanol, simple syrup, Glucose Liquid, starch fluid, Lac, arabic gum powder, hydroxypropyl cellulose, methylcellulose, sodium carboxymethyl cellulose, hypromellose, polyvinylpyrrolidone or polyvinyl alcohol etc.

As disintegrating agent, can enumerate agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulphate, starch, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, carboxymethyl cellulose, carboxymethyl starch sodium, polyvidon, cross-linked pvp, cross-linked carboxymethyl cellulose sodium or low degree of substitution hydroxypropyl cellulose etc.

As stabilizing agent, can enumerate ascorbic acid, citric acid, maleic acid, tartaric acid or fumaric acid etc.

As aggregation inhibitor, can enumerate the silicic acid classes such as Pulvis Talci, light anhydrous silicic acid or methane-siliconic acid magnalium etc.

As plasticizer, can enumerate triethyl citrate, glycerol, propylene glycol, polysorbate, medical polyethylene glycol Macrogol or glyceryl monostearate etc.

As lubricant, can enumerate Pulvis Talci, sucrose fatty acid ester, stearate or Polyethylene Glycol etc.

In addition, the interpolation reason of these additives is not limited to as excipient, binding agent, disintegrating agent, stabilizing agent, aggregation inhibitor, plasticizer, lubricant etc.

There is no particular limitation for these preparations, to use additive and consumption thereof, for example, with respect to the gross mass of preparation, can use according to following ratio these preparation additives: the stabilizing agent of the binding agent of the excipient of 0～99 % by weight, 0～40 % by weight, the disintegrating agent of 0～20 % by weight, 0～10 % by weight, the lubricant of 0～5 % by weight.

in the present invention, as water-insoluble macromolecule, can enumerate: ethyl cellulose, ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride ethyl ester copolymer, EUDRAGIT L100-55, EUDRAGIT L100, carmethose (glycolic cellulose sodium), low degree of substitution hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked pvp, arabic gum, Tragacanth, propylene glycol alginate, agar powder, gelatin, starch based, producing starch, oils and fats, phospholipid (lecithin), or glucomannan etc.Preferably can enumerate: EUDRAGIT L100-55, ethyl cellulose or ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride ethyl ester copolymer etc.

Herein, so-called ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride ethyl ester copolymer, be the copolymer that is formed by ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride ethyl ester, can enumerate the copolymer that its mixed proportion is about 1:2:0.1 or 1:2:0.2.For example can enumerate Eudragit RS(by the goldschmidt chemical corporation manufacture), preferably can enumerate Eudragit RS100, RL100, RSPO, RLPO, RS30D or RL30D(by the goldschmidt chemical corporation manufacture), particularly preferably can enumerate Eudragit RS100, RL100, RSPO or RLPO.

In the present invention, as water-soluble additives, can enumerate: polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxypropyl cellulose, hypromellose, carboxymethylethylcellulose, pulullan polysaccharide (Pullulan), dextrin, sodium alginate, methacrylic acid aminoalkyl ester copolymer E or polyvinyl acetal lignocaine acetas etc.Preferably can enumerate: polyvinylpyrrolidone, hypromellose, carboxymethylethylcellulose, methylcellulose or hydroxypropyl cellulose etc.

There is no particular limitation for the manufacture method of enteric solubility preparation of the present invention, for example, can prepare the enteric solubility coating liquid, on one side by adopting on one side to the former medicine preparation method that this enteric solubility coating liquid applies of spraying, enteric film is coated on former medicine preparation, thereby manufactures the enteric solubility preparation.

Herein, so-called enteric solubility coating liquid, be that enteric solubility macromolecule and preparation are dissolved in solvent and the liquid that obtains with the composition of the formation enteric film of additive and so on., as the solvent of enteric solubility coating liquid, can enumerate halogenated hydrocarbons or their mixture such as the ketones such as the alcohols such as water, methanol, ethanol, acetone, dichloromethane, chloroform herein, preferably, the mixture of water, alcohols or water and alcohols.

As the painting method of enteric film, can adopt those skilled in the art's customary ways such as common fluidized bed coating, pan coating method (pan coating) or rotating fluidized bed cladding process to carry out.

There is no particular limitation for the covering amount of the enteric film on former medicine preparation, can enumerate with respect to former medicine preparation, and covering amount is 5～100 % by weight, and preferably 5～70 % by weight, particularly preferably be 10～30 % by weight.

In enteric solubility preparation of the present invention, the pH that sets refers to: enteric film is dissolved, the pH of effective ingredient when starting stripping the enteric solubility preparation.

PH during as the effective ingredient stripping of enteric solubility preparation, can be set in the scope of pH5.0～7.0, is preferably the scope of pH5.0～6.0, more preferably pH5.5.As stripping pH being set in to the method for pH5.0～7.0, can enumerate the commercially available high molecular method of enteric solubility of using.In preparation during enteric film, according to the difference of stripping pH, the high molecular specification of commercially available enteric solubility is distinguished.Use Eudragit S for example, if use Eudragit L30D-55, can obtain the enteric film in the pH5.5 stripping, and if can obtain the enteric film in the pH7.0 stripping.In addition, also can be used in combination multiple enteric solubility macromolecule to regulate stripping pH.In addition, the method that stripping pH is set in to pH5.0～7.0 is not limited to these methods.

In the present invention, external (in vitro) dissolution rate of effective ingredient is according to the dissolution test method in the Japanese Pharmacopoeia of revising for the 14 time, is determined under vitro conditions the dissolution time of effective ingredient in experimental liquid and obtains.Herein, as experimental liquid, can enumerate slaking test method the 1st liquid, slaking test method the 2nd liquid in Japanese Pharmacopoeia and McIlvaine buffer etc. in Japanese Pharmacopoeia, but be not limited to this., as assay method, can enumerate the basket method that turns, oar method or slaking test installation method herein, be preferably the basket method that turns.

In the present invention, by turning the basket method, under the condition of 100rpm, measure while being included in the dissolution rate in vitro of the effective ingredient in the enteric solubility preparation, at pH, surpass in the experimental liquid of the pH that sets, after 1 hour, the stripping quantity of effective ingredient is 90～100 % by weight.Preferably, after 20 minutes, the stripping quantity of effective ingredient is 70～100 % by weight, and more preferably, after 20 minutes, the stripping quantity of effective ingredient is 80～100 % by weight, particularly preferably is, and after 20 minutes, the stripping quantity of effective ingredient is 90～100 % by weight.Herein, the so-called pH experimental liquid that surpasses the pH set refers to such experimental liquid: the pH when starting stripping the enteric solubility preparation more is partial to alkalescence to its pH than effective ingredient.

In contrast, at pH, be no more than in the experimental liquid of the pH that sets, after 2 hours, the stripping quantity of effective ingredient is below 10 % by weight.

Herein, the so-called pH experimental liquid that is no more than the pH that sets refers to such experimental liquid: the pH when starting stripping the enteric solubility preparation more is partial to acidity to its pH than effective ingredient.

Herein, the condition of the dissolution rate under the pH that sets and pH surpass in the condition of the condition of experimental liquid of the pH set and the experimental liquid that pH is no more than the pH that sets any one is all inconsistent.

If it is applicable in body, the pH in digestive tract, in general, gastric is 1～2, in small intestinal be 4～5, large enteral is 7～8, along with to the digestive tract bottom, moving, pH raises.Herein, about enteric solubility preparation of the present invention, effective ingredient starts stripping when its arrival has the digestive tract position of the pH that makes to occur stripping, and along with to gastral bottom, moving, the stripping of effective ingredient is promoted.But, than above-mentioned digestive tract position with the pH that makes to occur stripping more in the digestive tract position on top, effective ingredient not stripping basically.

In the present invention, so-called slow releasing preparation, can enumerate the preparation that former medicine preparation is coated with release-controlled film (release membranes) and obtain, and this release-controlled film contains water-insoluble macromolecule and water-soluble additives.As other features of slow releasing preparation, have and effective ingredient is disperseed and be included in substrate and the preparation that obtains, this substrate consists of water-insoluble macromolecule and water-soluble additives.

As water-insoluble macromolecule and water-soluble additives, can enumerate those materials identical with the water-insoluble macromolecule of above-mentioned record and water-soluble additives herein.

In the present invention, there is no particular limitation for blending ratio in release membranes for water-insoluble macromolecule and water-soluble additives, and with respect to release membranes, water-insoluble high molecular ratio can be enumerated as 10～90 % by weight, be preferably 30～80 % by weight, be particularly preferably 45～65 % by weight.In addition, with respect to release membranes, the ratio of water-soluble additives can be enumerated as 0.5～50 % by weight, is preferably 1～30 % by weight, and more preferably 5～15%.

In release membranes of the present invention, except water-insoluble macromolecule and water-soluble additives, can also use one kind or two or more preparation additive.

As the preparation additive, can enumerate preparation those materials that additive is identical with above-mentioned record herein.

For preparation, with the consumption of additive, be not particularly limited, preferably, the amount that is used in conjunction with is below 50 % by weight.

There is no particular limitation for the manufacture method of slow releasing preparation of the present invention, can prepare the slow release coating liquid, by adopting on one side the method that applies to this slow release coating liquid of spraying on former medicine preparation on one side, release membranes is coated on former medicine preparation, thereby manufactures slow releasing preparation.

Herein, so-called slow release coating liquid is by water-insoluble macromolecule, water-soluble additives and preparation are dissolved in to the liquid that obtains in solvent with the composition of the formation release membranes of additive and so on.

, as the solvent of slow release coating liquid, can enumerate halogenated hydrocarbons or their mixture such as the ketones such as the alcohols such as water, methanol, ethanol, acetone, dichloromethane, chloroform herein, be preferably the mixture of water, alcohols or water and alcohols.

As the cladding process of release membranes, can adopt those skilled in the art institute customary ways such as common fluidized bed coating, pan coating method (pan coating) or rotating fluidized bed cladding process to carry out.

There is no particular limitation for the covering amount of the release membranes on former medicine preparation, can enumerate with respect to former medicine preparation, and covering amount is 5～100 % by weight, is preferably 5～70 % by weight, is particularly preferably 10～30 % by weight.

In the present invention, so-called pulse release type preparation, can enumerate the preparation that former medicine preparation is coated with release-controlled film (pulse release type film) and obtain, this release-controlled film contains ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride ethyl ester copolymer and EUDRAGIT L100-55.Other features as pulse release type preparation, can enumerate such preparation: it does not discharge medicine in the low zone of the such pH of gastric, and gelation gently occurs in overlay film in small intestinal and the such pH of large intestine comparatively approach neutral zone, after certain hour, overlay film is all by gelation, and medicine 100% discharges at short notice simultaneously.

Herein, as ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride ethyl ester copolymer and EUDRAGIT L100-55, can enumerate those materials identical with the ethyl acrylate-methyl methacrylate of above-mentioned record-methacrylic acid trimethyl ammonium chloride ethyl ester copolymer and EUDRAGIT L100-55.

In the present invention, there is no particular limitation for blending ratio in pulse release type film for ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride ethyl ester copolymer and EUDRAGIT L100-55, with respect to the ethyl acrylate-methyl methacrylate of 1 weight portion-methacrylic acid trimethyl ammonium chloride ethyl ester copolymer, EUDRAGIT L100-55 is 0.2～10 weight portion, be preferably 0.3～8 weight portion, be particularly preferably 0.3～5 weight portion.

In pulse release type film of the present invention, except aforesaid propylene acetoacetic ester-methyl methacrylate-methacrylic acid trimethyl ammonium chloride ethyl ester copolymer and EUDRAGIT L100-55, can also use one kind or two or more water-insoluble additive and preparation additive.

Herein, as water-insoluble additive, can enumerate the silicic acid classes such as Pulvis Talci, light anhydrous silicic acid, methane-siliconic acid magnalium, magnesium stearate, wax or stearic acid etc., but be not limited to this.There is no particular limitation for the use amount of water-insoluble additive, and for example, with respect to above-mentioned two kinds of copolymers of 1 weight portion, the use amount of water-insoluble additive is below 5 % by weight, is preferably below 3 % by weight, is particularly preferably below 1 % by weight.

As the preparation additive, can enumerate preparation those materials that additive is identical with above-mentioned record herein.There is no particular limitation with the use amount of additive for preparation, and with regard to the use amount of aggregation inhibitor, preferably, with respect to above-mentioned two kinds of copolymers of 1 weight portion, its consumption is 50～100 % by weight.

There is no particular limitation for the manufacture method of pulse release type preparation of the present invention, the composition of the formation pulse release type film of ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride ethyl ester copolymer, EUDRAGIT L100-55 and water-insoluble additive and so on can be dissolved in solvent and preparation pulse release type coating liquid, by adopting to the method that applies this pulse release type coating liquid on former medicine preparation, pulse release type film is coated on former medicine preparation, thereby manufactures pulse release type preparation.

Herein, solvent as pulse release type coating liquid, can enumerate halogenated hydrocarbons or their mixture such as the ketones such as the alcohols such as water, methanol, ethanol, acetone, dichloromethane, chloroform, be preferably the mixture of alcohols or water and alcohols, be particularly preferably the mixture of dehydrated alcohol or dehydrated alcohol and water.

As the cladding process of pulse release type preparation, can adopt those skilled in the art institute customary ways such as common fluidized bed coating, pan coating method (pan coating) or rotating fluidized bed cladding process to carry out.

There is no particular limitation for the covering amount of the pulse release type film on former medicine preparation, and with respect to former medicine preparation, this covering amount is 20～300 % by weight, is preferably 50～200 % by weight, is particularly preferably 80～150 % by weight.

Dosage form to enteric solubility preparation of the present invention, slow releasing preparation and pulse release type preparation is not particularly limited, so long as the solid preparation of oral administration gets final product, for example, can make the forms such as tablet, granule, powder, pill, capsule.Be preferably tablet, granule and capsule, be particularly preferably granule and capsule.In addition, also this granule can be filled in capsule and form capsule.

In the present invention, so-called former medicine granule is a kind of in the former medicine preparation of enteric solubility preparation, slow releasing preparation and pulse release type preparation and so on, refers to the granule before being coated by release-controlled film.

As the manufacture method of former medicine granule, such as enumerating wet granulation etc.Such as enumerating extruding pelletization method (utilizing Screw Extrusion prilling granulator, roller extruded type prilling granulator etc.), rotating granulation method (utilizing Barrate type prilling granulator, centrifugal rotary prilling granulator transition etc.), fluidized bed granulation (utilizing fluid bed granulation unit, rotating fluidized bed prilling granulator etc.), stirring-granulating method (utilizing stirring-granulating device etc.) etc.Also can be by the one kind or two or more combination in these methods.

As former medicine granule of the present invention, preferably use spheroidal particle or extrude granule.

In the present invention, so-called spheroidal particle, be the former medicine granule that uses the core pelletize to obtain.

Herein, so-called core, obtain for the crystallinity excipient by general (for example, lactose, mannitol, sucrose, cellulose etc.) forms form of spherical particles (spherical particle).Mannitol particularly preferably in the crystallinity excipient.As the particle diameter of core, can enumerate 50～1000 μ m, be preferably 100～600 μ m, more preferably 300～500 μ m.Herein, the particle diameter of core can stipulate according to sieve method, and sieve method is the method that the sieve that adopts mesh to be set as the purpose particle diameter sieves.

Endorse to use general those commercially available materials, such as using ノ Application パレ Le 108(to be manufactured by Off ロイ Application ト company) etc.The binder solution that is formed by excipient, binding agent, water etc. can be sprayed on this core, simultaneously effective ingredient and one kind or two or more preparation be vibrated repeatedly with the mixture that additive forms, then, through super-dry, sieve and obtain spheroidal particle.Resulting spheroidal particle can directly use, and also can further implement granulating working procedure to it.

Extruding granule is the former medicine granule that obtains by the pelletize of extruding pelletization method.When granule is extruded in manufacture, in excipient, binding agent, this effective ingredient, add water, solvent etc. and mediate.By this kneaded material extruding pelletization, with pelletizing machines such as Spheroidgranulatemachines, carry out granulate, then, through super-dry, sieve and obtain extruding granule.But, also can not use Spheroidgranulatemachine etc. to process.

In the present invention, be used to the mesh of the sieve that sieves former medicine granule, can be enumerated as 100～2000 μ m, be preferably 300～1500 μ m, more preferably 500～1180 μ m.

In the present invention, so-called swelling type slow releasing preparation, refer to containing water-insoluble high molecular film like release-controlled film (thin film) and coat the basic sheet that contains water absorption and swelling gelating agent and effective ingredient and the tablet that obtains.

In the present invention, so-called basic sheet is the tablet that contains water absorption and swelling gelating agent and effective ingredient, and this tablet is in a single day moisture namely can swelling.

Herein, as the water absorption and swelling gelating agent, can enumerate: hydroxypropyl cellulose, hypromellose, EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO, EUDRAGIT NE 30 D EUDRAGIT NE 30D emulsion, pulullan polysaccharide (Pullulan), collagen protein, casein, agar, arabic gum, carmethose or methylcellulose etc.In addition, can mix and use these one kind or two or more water absorption and swelling gelating agents.

In the sheet of basis, except water absorption and swelling gelating agent and effective ingredient, can also mix one kind or two or more preparation additive.As the preparation additive, can enumerate preparation those materials that additive is identical with above-mentioned record herein.

The combined amount of water absorption and swelling gelating agent arranges with the kind of additive according to kind or the preparation of the gelating agent of using, and for example, every basic sheet is more than 10 % by weight, and preferred every basic sheet is more than 20 % by weight.

In thin film of the present invention, except water-insoluble macromolecule, can also use one kind or two or more water-soluble additives, the preparation polymer substance of additive, gastric solubility coating agent and swelling water penetration.As water-insoluble macromolecule, water-soluble additives and preparation additive, can enumerate water-insoluble macromolecule, water-soluble additives and preparation those materials that additive is identical with above-mentioned record herein.

In addition, water-insoluble macromolecule and water-soluble additives as in thin film, using, be preferably the combination of single ethyl cellulose and ethyl cellulose and hypromellose, more preferably the combination of ethyl cellulose and hypromellose.

As the gastric solubility coating agent, can enumerate polyvinyl acetal lignocaine acetas or amino alkyl methacrylate copolymer E etc.

As the polymer substance of swelling water penetration, can enumerate EudragitRS PO EUDRAGIT RSPO eudragit RS-100 eudragit RS-PO etc.

There is no particular limitation with the use amount of the polymer substance of additive, gastric solubility coating agent and swelling water penetration for water-soluble additives, preparation, preferably with the use amount below 50 % by weight, is used in conjunction with.

There is no particular limitation for the manufacture method of swelling type slow releasing preparation of the present invention, can be by wet method or dry process basis sheet, prepare subsequently thin film coated liquid, by adopt by this thin film coated liquid be coated in method on this basis sheet by film coated on basic sheet, thereby manufacture the swelling type slow releasing preparation.

Herein, so-called thin film coated liquid is that water-insoluble macromolecule, water-soluble additives, preparation are dissolved in organic solvent and the liquid that obtains with thin film compositions such as additive, gastric solubility coating agent and swelling water penetration polymer substances.

As organic solvent, can enumerate acetone, benzene, toluene, dichloromethane, chloroform, ethyl acetate or alcohols (ethanol, isopropyl alcohol etc.), be preferably ethanol, dichloromethane, ethyl acetate.These organic solvents can be mixed and use, also can add the water of 30% left and right and use.

As the cladding process of thin film, can enumerate the pan coating method that those skilled in the art habitually practise, coating method is preferably nebulization, can adopt automatically or manual any one mode.

There is no particular limitation for the covering amount of thin film, and for example with respect to base, this covering amount is 0.1～30 % by weight, is preferably 0.5～20 % by weight, is particularly preferably 1～10 % by weight.

There is no particular limitation to the content of the effective ingredient that contains in enteric solubility preparation of the present invention, slow releasing preparation, pulse release type preparation or swelling type slow releasing preparation, gross mass with respect to preparation is 0.1～80 % by weight left and right, is preferably 0.5～70 % by weight left and right.

Oral administration preparation useful as drug of the present invention, specifically, can be as the improving agent of the therapeutic agent of chronic arteria occlusion disease, ischemic symptoms such as ulcer, pain and creeping chill that chronic arteria occlusion disease is followed, the improving agent of intermittent claudication, the thrombosis in the ischemic cerebral vascular obstacle

The cerebral infarction that inhibitor/thromboembolism forms inhibitor, diabetics is sent out the palliative of the pain that preventive, postherpetic neuralgia follow again.

The dosage of oral administration preparation of the present invention can suitably determine according to following condition: the conditions such as patient's age, health status, body weight; Use at the same time in the situation of other drug the conditions such as the kind of these other drugs and administration frequency; Perhaps character of desired effect etc.In general, dosage every day of effective ingredient is 0.5～50mg/kg body weight, is generally 1～30mg/kg body weight, can be once a day or multiple dosing.

Embodiment

Below by embodiment, further specifically describe the present invention, but be not limited to these embodiment, only otherwise exceeding main points of the present invention gets final product.In addition, the sarpogrelate hydrochloride that uses below is to manufacture according to the method for putting down in writing in Japanese kokai publication sho 58-32847 communique.

Production Example

While manufacturing spheroidal particle to the selection of core

Using white sugar-starch spherical particle (ノ Application パレ Le 101, by Off ロイ Application ト company, manufactured) and castor sugar spherical particle (ノ Application パレ Le 103, by Off ロイ Application ト company, manufactured) in situation as the core of spheroidal particle, during with the stabilizing agent blend, can find that there is coloring phenomenon.

400g セ Le Off ィア CP-305(is manufactured by Asahi Chemical Corp, it is the crystalline cellulose (granular) of particle diameter 300～500 μ m) join centrifugal rotation pelletize coating unit (グラニュレッ Network ス GX-20, by Off ロイ Application ト company, manufactured) in, to be sprayed by the binding liquid that 12g polyvinyl alcohol, 6g tartaric acid and 282g Purified Water form, add simultaneously the 400g sarpogrelate hydrochloride, carry out the powder coated pelletize, and make its fluidized drying.Then, thus using mesh is that the sieve of 355～850 μ m sieves and obtains former medicine granule I.This former medicine granule I of 360g is joined in centrifugal rotation pelletize coating unit, to be sprayed by the binding liquid that 11.52g polyvinyl alcohol, 5.76g tartaric acid and 270.72g Purified Water form, add simultaneously the 360g sarpogrelate hydrochloride, carry out the powder coated pelletize, and make its fluidized drying.Then, thus using mesh is that the sieve of 500～1180 μ m sieves and obtains former medicine granule II.this former medicine granule II of 600g is joined to rotating fluidized bed prilling granulator (MP-01, by the パウレッ of Co., Ltd. Network, manufactured) in, use is by 238.2g ethyl cellulose aqueous dispersions (ア Network アコート ECD, FMC Corp. manufactures), 23.8g triethyl citrate, 14.3g Crushing of Ultrafine Pulvis Talci, 10.8g the slow release coating liquid that HPMC and 369.0g Purified Water form is rotated fluidisation and applies, after drying, using mesh is thereby that the sieve of 500～1180 μ m sieves and obtains with the slow-releasing granules of crystalline cellulose (granular) (セ Le Off ィア CP-305) as core.

To take crystalline cellulose (granular) (セ Le Off ィア CP-305), as the slow-releasing granules of core, estimating, found that: the particle below the 500 μ m that while thinking due to coating, former medicine granule II is broken, efflorescence causes is 3.2 % by weight.On the other hand, in order to reduce sneaking into of the following particle of 500 μ m, in the situation that apply in Suppress atomizing, make more than the above particle of resulting 1180 μ m reaches 10 % by weight.Hence one can see that, in the situation that using crystalline cellulose (granular) as the core of spheroidal particle, as granule, can not obtain sufficient intensity.

On the other hand, in with the situation of mannitol spherical particle (ノ Application パレ Le 108 is manufactured by Off ロイ Application ト company) as the core of spheroidal particle, after carrying out coating operation same as described above, the following particle of 500 μ m is 0 % by weight, and the above particle of 1180 μ m is 0.3 % by weight.Hence one can see that, in the situation that using the mannitol spherical particle as the core of spheroidal particle, the granule that can obtain having abundant intensity.

Therefore, in following embodiment, use the core of mannitol spherical particle as spheroidal particle.

Embodiment 1

The ノ Application パレ Le 108(that by the 397.2g particle diameter is 355～500 μ m is manufactured by Off ロイ Application ト company) join centrifugal rotation pelletize coating unit (グラニュレッ Network ス GX-20, by Off ロイ Application ト company, manufactured) in, to be sprayed by the binding liquid that 7.67g polyvinyl alcohol, 3.83g tartaric acid and 180.2g Purified Water form, add simultaneously the 397.2g sarpogrelate hydrochloride, carry out the powder coated pelletize, and make its fluidized drying, thereby then with the sieve that mesh is 355～850 μ m, sieve and obtain former medicine granule A.

This former medicine granule A of 380g is joined in centrifugal rotation pelletize coating unit, to be sprayed by the binding liquid that 6.14g polyvinyl alcohol, 3.07g tartaric acid and 144.2g Purified Water form, add simultaneously the 378.9g sarpogrelate hydrochloride, carry out the powder coated pelletize, and fluidized drying.Then, thus with the sieve that mesh is 500～1180 μ m, sieve and obtain former medicine granule B.

This former medicine granule B of 740g is joined to rotating fluidized bed prilling granulator (MP-01, by the パウレッ of Co., Ltd. Network, manufactured) in, use is by 269.0g ethyl cellulose aqueous dispersions, 26.9g triethyl citrate, 12.6g Crushing of Ultrafine Pulvis Talci, 11.7g HPMC (TC-5E, by Shin-Etsu Chemial Co., Ltd, manufactured) and the slow release coating liquid that forms of 392.6g Purified Water be rotated fluidisation and apply, after drying, thereby sieve and obtain coated particle with the sieve that mesh is 500～1180 μ m.5.2g Crushing of Ultrafine Pulvis Talci is blended in this granule of 832g, uses throughcirculation dryer to solidify 1 hour under the condition of 60 ℃, obtain slow-releasing granules.This slow-releasing granules of 161mg is filled in No. 2 HPMC capsules, obtains slow releasing preparation.

Embodiment 2

The former medicine granule B that passes through to adopt the method identical with embodiment 1 to obtain of 710g is joined to rotating fluidized bed prilling granulator (MP-01, by the パウレッ of Co., Ltd. Network, manufactured) in, the enteric solubility coating liquid that use consists of Eudragit L30D-55,12.5g triethyl citrate, 12.5g Crushing of Ultrafine Pulvis Talci and the 419.6g Purified Water of 421.8g is rotated fluidisation and applies, after drying, thereby sieve and obtain coated particle with the sieve that mesh is 500～1180 μ m.5.1g Crushing of Ultrafine Pulvis Talci is blended in this granule of 840.5g, obtains the enteric solubility granule.This enteric solubility of 165.8mg is particles filled in No. 2 HPMC capsules, obtain the enteric solubility preparation.Herein, the pH that sets is 5.5.

Embodiment 3

The former medicine granule B that passes through to adopt the method identical with embodiment 1 to obtain of 720g is joined to rotating fluidized bed prilling granulator (MP-01, by the パウレッ of Co., Ltd. Network, manufactured) in, the enteric solubility coating liquid that use consists of EudragitS, 1227.9g dehydrated alcohol, 19.2g triethyl citrate, 93.8g Pulvis Talci and the 70.7g Purified Water of 94.5g is rotated fluidisation and applies, after drying, thereby sieve and obtain the enteric solubility granule with the sieve that mesh is 500～1180 μ m.This enteric solubility of 175mg is particles filled in No. 2 HPMC capsules, obtain the enteric solubility preparation.Herein, the pH that sets is 7.0.

Embodiment 4

The former medicine granule B that passes through to adopt the method identical with embodiment 1 to obtain of 700g is joined to rotating fluidized bed prilling granulator (MP-01, by the パウレッ of Co., Ltd. Network, manufactured) in, the coating liquid that use consists of Eudragit RSPO, 35.0g triethyl citrate, 157.4g Pulvis Talci, 2314.2g dehydrated alcohol and the 257.0g Purified Water of Eudragit L100-55, the 122.4g of 35.0g is rotated fluidisation and applies, after drying, screening obtains the coated particle that particle diameter is 500～1180 μ m.Further, this granule of 700g is joined to rotating fluidized bed prilling granulator (MP-01, by the パウレッ of Co., Ltd. Network, manufactured) in, the coating liquid that use consists of Eudragit RSPO, 23.3g triethyl citrate, 104.9g Pulvis Talci, 1542.2g dehydrated alcohol and the 171.3g Purified Water of Eudragit L100-55, the 81.6g of 23.3g is rotated fluidisation and applies, after drying, thereby sieve and obtain pulse release type granule with the sieve that mesh is 500～1180 μ m.This is particles filled in No. 1 HPMC capsule by 271.8mg, obtains pulse release type preparation.

Embodiment 5

by the 1000.0g sarpogrelate hydrochloride, 200.0g low degree of substitution hydroxypropyl cellulose (LH-11, by Shin-Etsu Chemial Co., Ltd, manufactured) join stirring granulating machine (VG-10, by the パウレッ of Co., Ltd. Network, manufactured) in, use is by the 36.0g hydroxypropyl cellulose, 18.0g the binding liquid that tartaric acid and 546.0g Purified Water form is mediated, by kneaded material at extruding granulator (DG-L1, by only パウダ Le Co., Ltd., manufactured, mesh size is 0.8mm) middle extruding pelletization, and with Spheroidgranulatemachine (Q-230, by only パウダ Le Co., Ltd., manufactured) granulate, then, use fluid bed granulation unit (MP-01, by the パウレッ of Co., Ltd. Network, manufactured) carry out fluidized drying, thereby and sieve and obtain former medicine granule C with the sieve that mesh is 500～1180 μ m.This former medicine granule C of 580g is joined to rotating fluidized bed prilling granulator (MP-01, by the パウレッ of Co., Ltd. Network, manufactured) in, the enteric solubility coating liquid that use consists of EudragitL30D-55,14.8g triethyl citrate, 14.8g Pulvis Talci and the 494.0g Purified Water of 496.7g is rotated fluidisation and applies, after drying, thereby sieve and obtain coated particle with the sieve that mesh is 500～1180 μ m.The 4.5g Pulvis Talci is blended in this granule of 738.0g, obtains the enteric solubility granule.This enteric solubility of 165.0mg is particles filled in No. 2 HPMC capsules, obtain the enteric solubility preparation.Herein, the pH that sets is 5.5.

Embodiment 6

10.0g sarpogrelate hydrochloride, 2.1g メトローズ 90SH-100SR(are manufactured by Shin-Etsu Chemial Co., Ltd), 2.0g HPMC (TC-5RW, by Shin-Etsu Chemial Co., Ltd manufacture), 0.15g light anhydrous silicic acid, 0.15g tartaric acid and the 0.6g magnesium stearate pulverized in advance mix, in gyratory press (Collect12HUK makes manufacturing by chrysanthemum water), take every 150mg, tablet radius R as the specification of 8.0mm, prepare basic sheet.to 5.4g, should in the sheet of basis, add the base sheet to 1000g, then join disc type seed-coating machine (HC-LABO, by Off ロイ Application ト company, manufactured) in, by ethyl cellulose (STD10 Premium, by Dow Chemical company, manufactured) with HPMC, by the amount of 1:1 take solid component concentration as 7.4 % by weight, be dissolved in the mixed liquor of dehydrated alcohol and Purified Water (8:2), by this coating solution spraying, make the ethyl cellulose and the HPMC that with respect to every basic sheet, are coated with 3.75mg, thereby obtain the swelling type slow releasing preparation of every 157.5mg.

Comparative example 1

The ノ Application パレ Le 108(that by the 397.2g particle diameter is 355～500 μ m is manufactured by Off ロイ Application ト company) join centrifugal rotation pelletize coating unit (グラニュレッ Network ス GX-20, by Off ロイ Application ト company, manufactured) in, to be sprayed by the slurry that 7.64g polyvinyl alcohol, 3.82g tartaric acid and 179.5g Purified Water form, add simultaneously the 397.2g sarpogrelate hydrochloride, the powder coated pelletize, after fluidized drying, thereby sieve and obtain former medicine granule D with the sieve that mesh is 355～850 μ m.

This former medicine granule D of 370g is joined in centrifugal rotation pelletize coating unit, to be sprayed by the slurry that 6.26g polyvinyl alcohol, 3.13g tartaric acid and 147.1g Purified Water form, add simultaneously the 368.9g sarpogrelate hydrochloride, the powder coated pelletize, after fluidized drying, thereby sieve and obtain former medicine granule E with the sieve that mesh is 500～1180 μ m.

This former medicine of 135.8mg is particles filled in No. 2 HPMC capsules, obtain the immediate release preparation.

Comparative example 2

The Anplag sheet that derives from Tanabe Mitsubishi Pharmaceutical Co of 100mg is used as to ordinary tablet.

Test example 1

Use Japanese Pharmacopoeia the 1st liquid (pH1.2), each preparation of putting down in writing in embodiment 2, embodiment 4, comparative example 1 and comparative example 2 is carried out to dissolution test (Fig. 1).In addition, use rare McIlvaine buffer (pH6.8) to carry out dissolution test (Fig. 2) to each preparation of record in embodiment 2 and embodiment 4.

In addition, dissolution test is to carry out according to the Japanese Pharmacopoeia dissolution test method of the 14 modification, and the experimental liquid temperature is 37 ℃, experimental liquid 900mL, N=3.

In Japanese Pharmacopoeia the 1st liquid (pH1.2), comparative example 1() and comparative example 2(*) in the rapid stripping of effective ingredient of preparation of record, in contrast to this, embodiment 2(zero) and embodiment 4(△) even the effective ingredient of the preparation of middle record did not have stripping (Fig. 1) yet after 120 minutes.On the other hand, the rapid stripping of effective ingredient (Fig. 2) of the preparation of record in McIlvaine buffer (pH6.8), embodiment 2(zero).And, embodiment 4(△) in the record preparation at its effective ingredient after certain hour, start stripping (Fig. 2).

As can be known by these results, in embodiment 2, the preparation of record is the enteric solubility preparation, and in embodiment 4, the preparation of record is pulse release type preparation.

Test example 2

For in embodiment 3 record preparation, use respectively the pH of rare McIlvaine buffer to be 4.0(zero), 6.0(△), 6.8() and experimental liquid 7.8(*) carry out dissolution test (Fig. 3).

At pH, be no more than in the experimental liquid (pH4.0,6.0 and 6.8) of the pH that sets, the dissolution rate less than 10% of its effective ingredient after 120 minutes, on the other hand, at pH, surpass in the experimental liquid (pH7.8) of the pH that sets the rapid stripping of its effective ingredient after time delay.

As can be known by this result, in embodiment 3, the preparation of record is the enteric solubility preparation.

Test example 3

For the preparation of record in embodiment 5, use respectively 0.1mol/L hydrochloric acid (zero) and rare phosphate buffer (pH6.8) (△) to carry out dissolution test (Fig. 4).

Identical with the embodiment 2 of test example 1 record, at pH, be no more than in the experimental liquid (0.1mol/L hydrochloric acid) of the pH of setting, even effective ingredient did not have stripping yet after 120 minutes, and at pH, surpass in the experimental liquid (rare phosphate buffer (pH6.8)) of the pH that sets the rapid stripping of effective ingredient.

As can be known by this result, in embodiment 5, the preparation of record is the enteric solubility preparation.

Test example 4

Preparation for embodiment 1 record, use rare McIlvaine buffer (pH6.8) according to turning basket method 100rpm(zero) carry out dissolution test; Preparation for embodiment 6 record, uses rare McIlvaine buffer (pH6.8) according to oar method 50rpm(△) carry out dissolution test and use Japanese Pharmacopoeia the 1st liquid (pH1.2) according to oar method 50rpm() carry out dissolution test (Fig. 5).

In either event, in 6～12 hours, about 100% effective ingredient stripping.As can be known by this result, in embodiment 1 and embodiment 6, the preparation of record is slow releasing preparation.

Test example 5

The pharmacokinetics test of experimental animal

For 6 male beasle dogs, adopt atropine sulfate and pentagastrin to carry out the digestive tract adjustment, and per os give preparation under fasted conditions, carries out pharmacokinetics test.

By the preparation per os of record in embodiment 1～6 and comparative example 1～2, give (100mg/ body weight) experimental animal, measure the not concentration change of changing matter and metabolite (M-1).The results are shown in table 3(about the pharmacokinetic parameter of changing matter not) and table 4(about the pharmacokinetic parameter of metabolite M-1) in.

When giving the preparation of comparative example 1 or 2, the blood drug level of effective ingredient all increases sharp, then promptly disappears.With the comparative example 2 as conventional formulation, compare, find that the Cmax of the preparation of record in embodiment 1～6 all reduces and Tmax and MRT prolongation.

Hence one can see that, with traditional preparation, compares, and the preparation of embodiment 1～6 can suppress the sharply rising of effective ingredient, thereby can remain for a long time blood drug level.

By above result, can expect that the preparation of embodiment 1～6 becomes such preparation: said preparation continues the type preparation with respect to traditional preparation for long-time, thereby has reduced administration number of times.

In addition, in embodiment 1～6,

embodiment

2,4,5 and 6 AUC _0-24hSuitable with comparative example 2, hence one can see that, although the blood drug level of effective ingredient has persistence, absorption efficiency does not reduce.

As can be known by these results, in embodiment 1～6,

embodiment

2,4,5 and 6 is preferred preparation.

For the embodiment 2,3 and 5 as the enteric solubility preparation, from the aspect of the pH that sets, consider, as can be known by above-mentioned reason, in the situation that sarpogrelate hydrochloride is the enteric solubility preparation, the pH that sets is preferably 5.5.

[table 3]

[table 4]

The industrial probability of utilizing

According to the present invention, such new formulation can be provided, this new formulation is usingd and is selected from material in aminoalkoxy Bibenzyl compound, its pharmaceutically useful salt, its ester and their solvate and their hydrate as effective ingredient, and has lasting blood drug level.

The application is take the special Willing 2007-291570 in Japan's proposition as basis, and its full content is in this manual involved.

Claims

1. blood drug level persistence preparation, said preparation are usingd and are selected from material in the represented aminoalkoxy Bibenzyl compound of following general formula (1), its pharmaceutically useful salt, its ester and their solvate and their hydrate as effective ingredient,

(in formula, A represents can be by the C of carboxyl substituted ₃～C ₅Alkylidene), m represents 0～5 integer].

2. blood drug level persistence preparation as claimed in claim 1, wherein, as the blood drug level persistence, mean residence time (MRT) is more than 3.0 hours.

3. blood drug level persistence preparation as claimed in claim 1, wherein, as the blood drug level persistence, mean residence time (MRT) is 3.0 hours to 24.0 hours.

4. blood drug level persistence preparation as claimed in claim 1, wherein, as the blood drug level persistence, mean residence time (MRT) is 3.0 hours to 12.0 hours.

5. blood drug level persistence preparation as claimed in claim 1, wherein, as the blood drug level persistence, mean residence time (MRT) is 3.0 hours to 10.0 hours.

6. blood drug level persistence preparation as described as claim 2～5, wherein, as the blood drug level persistence, mean residence time (MRT) is the mean residence time (MRT) after using to experimental animal.

7. blood drug level persistence preparation as described as claim 1～6, as effective ingredient, using and be selected from material in the represented aminoalkoxy Bibenzyl compound of following formula (2), its pharmaceutically useful salt, its ester and their solvate and their hydrate as effective ingredient.

8. blood drug level persistence preparation as described as claim 1～6, as effective ingredient, using and be selected from material in the represented aminoalkoxy Bibenzyl compound of following formula (3), its pharmaceutically useful salt, its ester and their solvate and their hydrate as effective ingredient.

9. blood drug level persistence preparation as claimed in claim 7 or 8 wherein, is the form of hydrochlorate as the aminoalkoxy Bibenzyl compound of effective ingredient.

10. blood drug level persistence preparation as described as claim 1～9, this blood drug level persistence preparation is coated by release-controlled film.

11. blood drug level persistence preparation as claimed in claim 10, this blood drug level persistence preparation is enteric solubility preparation, slow releasing preparation, pulse release type preparation or swelling type slow releasing preparation.

12. blood drug level persistence preparation as claimed in claim 11, wherein, described enteric solubility preparation is to be coated with the preparation that contains the high molecular release-controlled film of enteric solubility on former medicine preparation.

13. blood drug level persistence preparation as described as claim 11 or 12, wherein, the stripping pH of the effective ingredient of described enteric solubility preparation is arranged in the scope of pH5.0～7.0.

14. blood drug level persistence preparation as claimed in claim 13, wherein, the stripping pH of the effective ingredient of described enteric solubility preparation is set to pH5.5.

15. blood drug level persistence preparation as described as claim 11～14, wherein, when when turning under the condition of basket method at 100rpm the dissolution rate in vitro of the effective ingredient of measuring described enteric solubility preparation, at pH, be no more than in the experimental liquid of stripping pH of the effective ingredient that sets, the stripping quantity of the effective ingredient after 2 hours is below 10 % by weight, and in the experimental liquid of pH over the stripping pH of the effective ingredient that sets, the stripping quantity of the effective ingredient after 1 hour is 90～100 % by weight.

16. blood drug level persistence preparation as claimed in claim 11, wherein, described slow releasing preparation is on former medicine preparation, to be coated with the preparation of the release-controlled film that contains water-insoluble macromolecule and water-soluble additives.

17. blood drug level persistence preparation as claimed in claim 11, wherein, described pulse release type preparation is on former medicine preparation, to be coated with the preparation of release-controlled film, and this release-controlled film contains ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride ethyl ester copolymer and EUDRAGIT L100-55.

18. blood drug level persistence preparation as claimed in claim 11, it is characterized in that, described swelling type slow releasing preparation is the preparation that is coated with release-controlled film on the basic sheet of water absorption and swelling gellant and effective ingredient containing, and this release-controlled film contains water-insoluble macromolecule and is film like.

19. as claim 12,16,17 described blood drug level persistence preparations, wherein, the former medicine preparation of described enteric solubility preparation, slow releasing preparation or pulse release type preparation is former medicine granule.

20. blood drug level persistence preparation as claimed in claim 19, wherein, described former medicine granule is spheroidal particle or extrudes granule.

21. blood drug level persistence preparation as claimed in claim 20, wherein, described spheroidal particle is that the spheroidal particle take mannitol forms as core and together with pharmaceutically useful additive.