CN104739819A

CN104739819A - Novel Preparation

Info

Publication number: CN104739819A
Application number: CN201510050252.XA
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: 2015-07-01
Also published as: WO2009060952A1; JP2014040475A; KR20100096147A; CN101854929A; CN103393623A; JPWO2009060952A1; JP5479909B2; KR101122447B1

Abstract

It is intended to provide 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 divisional application that the application is the applying date is on November 7th, 2008, application number is 200880115418.X, denomination of invention is 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 to be selected from material in aminoalkoxy Bibenzyl compound, its pharmaceutically useful salt, its ester and their solvate and their hydrate as effective ingredient.

Background technology

At the remarkable High Level of medical treatment and complicated present, in order to the Drug therapy that implementation quality is higher, usually need development effectiveness definite and the medicine that safety is high.Develop effectively and safe drugs time, carry out formulation design according to the characteristic of each medicine and therapeutic purposes to be absolutely necessary, thus such preparation technique is necessary: it not only can obtain excellent pharmacological property, and can to heavens in Drug controlled release and body dynamically.

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

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

People are still developing energetically by the controlled release preparation reduced for the purpose of administration number of times up to now, and develop the preparation of multifunction.Disclosing the mixed proportion by regulating additive in patent documentation 1, even if also can obtain the former medicine granule of high yield with simple prilling process, thus obtaining the sustained-release granular formulation almost not having efflorescence.Such sustained-release preparation is disclosed: with water insoluble and can carry out the coated core formed by medicine and swelling agent by water-soaked coating film, after release starts, medicine is released at short notice, and can maintain concentration locally in patent documentation 2.In addition, further disclose in patent documentation 3 by the rapid disintegrate of the absorption site of enteral to improve the Enteric formulations of drug absorption.In addition, disclose such oral administration preparation in patent documentation 4, the film composition wherein by being obtained by mixing by Eudragit RS and Eudragit LD, through certain lag time, can discharge rapidly to pulsed the medicine of 100%.

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

Patent documentation 1: Japanese Unexamined Patent Publication 2007-39353 publication

Patent documentation 2: Japanese Unexamined Patent Publication 2002-212062 publication

Patent documentation 3: Japanese Unexamined Patent Publication 2001-139462 publication

Patent documentation 4: Japanese Unexamined Patent Publication 8-143476 publication

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 to be 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 present inventor has carried out conscientious research to solve the problem, found that a kind of new formulation, said preparation has lasting blood drug level compared with conventional formulation, and said preparation is to be 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 blood drug level persistence preparation, said preparation is to be selected from aminoalkoxy Bibenzyl compound, its pharmaceutically useful salt, its ester and their solvate represented by following general formula (1) and the material in their hydrate as effective ingredient.

[formula 1]

[in formula, R ¹represent hydrogen atom, halogen atom, C ₁~ C ₅alkoxyl or C ₂~ C ₆dialkyl amido, R ²represent hydrogen atom, halogen atom or C ₁~ C ₅alkoxyl, R ³represent hydrogen atom, hydroxyl ,-O-(CH ₂) _n-COOH (in formula, n represents the integer of 1 ~ 5) or-O-CO-(CH ₂) _l-COOH (in formula, l represents the integer of 1 ~ 3), R ⁴represent-N (R ⁵) (R ⁶) (in formula, R ⁵and R ⁶represent hydrogen atom or C independently of one another ₁~ C ₈alkyl) or R ⁴represent

[formula 2]

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

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

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

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

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

[6] the blood drug level persistence preparation as described in [2] ~ [5], wherein, as 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 as described in [1] ~ [6], as effective ingredient, said preparation is to be selected from aminoalkoxy Bibenzyl compound, its pharmaceutically useful salt, its ester and their solvate represented by following formula (2) and the material in their hydrate as effective ingredient.

[formula 3]

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

[formula 4]

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

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

[11] the blood drug level persistence preparation as described in [10], this blood drug level persistence preparation is Enteric formulations, slow releasing preparation, pulse release type preparation or swelling type slow releasing preparation.

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

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

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

[15] the blood drug level persistence preparation as described in [11] ~ [14], wherein, when measuring the dissolution rate in vitro of the effective ingredient of described Enteric formulations under by the condition of Rotating shaker at 100rpm, be no more than in the experimental liquid of stripping pH of the effective ingredient of setting at pH, after 2 hours, the stripping quantity of effective ingredient is less than 10 % by weight, and exceed in the experimental liquid of stripping pH of the effective ingredient of setting at pH, after 1 hour, the stripping quantity of effective ingredient is 90 ~ 100 % by weight.

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

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

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

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

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

[21] blood drug level persistence preparation as described in [20], wherein, described spheroidal particle is formed together with pharmaceutically useful additive for core with the spherical particle of mannitol.

Invention effect

According to the present invention, a kind of new formulation can be provided, this new formulation to be 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.

Accompanying drawing explanation

Fig. 1 is the figure that the dissolution results in Japanese Pharmacopoeia the 1st liquid described in test example 1 is shown.

Fig. 2 is the figure that the dissolution results in rare McIlvaine buffer (pH6.8) described in test example 1 is shown.

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

Fig. 4 is the figure of the dissolution results of the preparation that embodiment 5 described in test example 3 is shown.

Fig. 5 is the figure of the dissolution results that slow releasing preparation described in test example 4 and swelling type slow releasing preparation are shown.

Detailed description of the invention

Explain the present invention below.Preparation of the present invention contains and is selected from aminoalkoxy Bibenzyl compound, its pharmaceutically useful salt, its ester and their solvate represented by above-mentioned general formula (1) and the material (hereinafter referred to as " effective ingredient ") in their hydrate as effective ingredient.

In above-mentioned general formula (1), R ¹represent 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, methylethylamine ₂~ C ₆dialkyl amido.R ²represent hydrogen atom; The halogen atoms such as chlorine atom, fluorine atom; The C such as methoxyl group, ethyoxyl, butoxy ₁~ C ₅alkoxyl.R ³represent hydrogen atom; Hydroxyl;-O-(CH ₂) ₂-COOH ,-O-(CH ₂) ₃-the O-such as-COOH (CH ₂) _n-COOH (in formula, n represents the integer of 1 ~ 5);-O-CO-(CH ₂) ₂-COOH ,-O-CO-(CH ₂) ₃-the O-CO-such as-COOH (CH ₂) _l-COOH (in formula, l represents the integer of 1 ~ 3).R ⁴represent amino or methylamino, ethylamino, fourth is amino, oneself is amino, heptan is amino, dimethylamino, lignocaine, methylethylamine and so on there is the amino that 1 ~ 2 carbon number is the alkyl of 1 ~ 8; Or can by 4 ~ 6 ring amidos of carboxyl substituted on the ring of expression azetidine-1-base, piperidin-1-yl, 3-carboxypiperidin-1-base 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-the OCH of aminoalkoxy ₂c (R ³) H-(CH ₂) m-R ⁴the compound be 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 ⁴preferably there is at least 1 C ₁~ C ₈the amino of alkyl or 4 ~ 6 ring amidos of azetidine-1-base or piperidin-1-yl and so on; M is preferably the integer of 0 ~ 2.Particularly preferably be the compound (following, in this manual, to be sometimes called " M-1 " by this compound) of numbering 15 and the compound of numbering 14, in the compound of numbering 15, R ¹for methoxyl group, R ²for hydrogen atom, R ³for hydroxyl, R ⁴for dimethylamino, m are 1, and the compound of numbering 14 is the succinate of the compound of numbering 15.

So-called " pharmaceutically useful salt " refers to such salt: as long as the salt avirulence formed together with the aminoalkoxy Bibenzyl compound represented by above-mentioned general formula (1), whatever salt can, can enumerate: such as, 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 amine group such as lysinate, arginine salt acid-addition salts; Deng.

As the ester of the aminoalkoxy Bibenzyl compound represented by above-mentioned general formula (1), the ester by obtaining with mineral acid dehydrating condensations such as organic acid or sulphuric acid, nitric acid, phosphoric acid, carbonic 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 can be enumerated.

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

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

[formula 5]

The material be selected from the aminoalkoxy Bibenzyl compound represented by above-mentioned general formula (1), its pharmaceutically useful salt, its ester and their solvate and their hydrate is known material, easily can manufacture according to the method recorded in Japanese Laid-Open Patent Publication 58-32847 publication or based on the method for the method.

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

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

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

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

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

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

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

In the present invention, as Cmax, can 200 ~ 15000ng/mL be enumerated as, preferably be enumerated as 400 ~ 10000ng/mL, more preferably be enumerated as 1500 ~ 9000ng/mL, preferably be enumerated as 2500 ~ 6000ng/mL further, 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 the time required for the half of this value from some values.

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

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

In the present invention, so-called AUC (blood concentration-time area under a curve), refer to by blood concentration-time curve (its be the preparation containing effective ingredient is used to experimental animal after, change in time according to the blood drug level of effective ingredient and the curve described) area of part that surrounds with axis of abscissas (time shaft).

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

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

In the present invention, when adopting experimental animal to measure MRT and Tmax, the experimental animal that use application of pentagastrin or atropine sulfate in advance can be enumerated.More preferably the experimental animal using state of going on a hunger strike is enumerated.

In the present invention, so-called release-controlled film, refers to the dissolution rate in order to regulate effective ingredient, dissolution time, stripping position etc. and the film of coated former medicine preparation.Can enumerate in the present invention: containing the high molecular release-controlled film of enteric solubility (enteric film), the release-controlled film (release membranes) containing water-insoluble macromolecule and water-soluble additives, the release-controlled film containing ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride methacrylate copolymers and EUDRAGIT L100-55 (pulse release type film) or containing water-insoluble macromolecule and be the release-controlled film (thin film) of film like.

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

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

In the present invention, so-called Enteric formulations, can enumerate the preparation with obtaining containing the coated former medicine preparation of the high molecular release-controlled film of enteric solubility (enteric film).Preferably can enumerate the preparation making effective ingredient stripping in the scope of pH5.0 ~ 7.0, more preferably can enumerate the preparation making effective ingredient stripping in the scope of pH5.0 ~ 6.0, preferably can enumerate the preparation making effective ingredient in pH5.5 stripping further.

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 be made up of methacrylic acid and ethyl acrylate, its for mixed proportion be the copolymer of about 1:1.Such as can enumerate Eudragit LD (being manufactured by goldschmidt chemical corporation).Preferably can enumerate Eudragit L100-55 or L30D-55 (being manufactured by goldschmidt chemical corporation), particularly preferably enumerate Eudragit L30D-55.

In addition, so-called EUDRAGIT L100, can enumerate the copolymer be made up of methacrylic acid and methyl methacrylate, it is the copolymer Eudragit S 100 (being manufactured by goldschmidt chemical corporation) of about 1:3 ~ 1:2 for mixed proportion is the copolymer Eudragit L100 (being manufactured by goldschmidt chemical corporation) of about 1:2 ~ 1:1 and mixed proportion.

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

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

In the present invention, so-called preparation additive, can be set forth in do not damage the object of the invention scope in usual used additive.As such additive, to it, there is no particular limitation, as long as pharmaceutically allow the various additives used as additive.As such additive, such as, can enumerate excipient, binding agent, disintegrating agent, stabilizing agent, aggregation inhibitor, plasticizer, lubricant etc.

As excipient, silicic acid class or the crystalline celluloses etc. such as lactose, white sugar, starch, light anhydrous silicic acid can be enumerated.

As binding agent, 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. can be enumerated.

As disintegrating agent, 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. can be enumerated.

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

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

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

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

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.

For these preparation additives and consumption thereof, there is no particular limitation, such as, relative to the gross mass of preparation, these preparation additives can be used according to following ratio: the excipient of 0 ~ 99 % by weight, the binding agent of 0 ~ 40 % by weight, 0 ~ 20 % by weight disintegrating agent, the stabilizing agent of 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 methacrylate copolymers, 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 methacrylate copolymers etc.

Herein, so-called ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride methacrylate copolymers, be the copolymer be made up of ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride ethyl ester, the copolymer that its mixed proportion is about 1:2:0.1 or 1:2:0.2 can be enumerated.Such as can enumerate Eudragit RS (being manufactured by goldschmidt chemical corporation), preferably can enumerate Eudragit RS100, RL100, RSPO, RLPO, RS30D or RL30D (being manufactured by goldschmidt chemical corporation), 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.

For the manufacture method of Enteric formulations of the present invention, there is no particular limitation, such as, enteric solubility coating liquid can being prepared, spraying this enteric solubility coating liquid while carry out the method applied by adopting to former medicine preparation, enteric film is coated on former medicine preparation, thus manufactures Enteric formulations.

Herein, so-called enteric solubility coating liquid is the liquid obtained in a solvent by the component dissolves of the formation enteric film of enteric solubility macromolecule and preparation additive and so on.Herein, as the solvent of enteric solubility coating liquid, halogenated hydrocarbons or their mixture such as the ketone such as alcohols, acetone, dichloromethane, chloroform such as water, methanol, ethanol can be enumerated, preferably, the mixture of water, alcohols or water and alcohols.

As the painting method of enteric film, 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 can be adopted to carry out.

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

In Enteric formulations of the present invention, set pH refers to: enteric film is dissolved, effective ingredient from Enteric formulations stripping time pH.

PH during effective ingredient stripping as Enteric formulations, can be set in the scope of pH5.0 ~ 7.0, is preferably the scope of pH5.0 ~ 6.0, is more preferably pH5.5.As method stripping pH being set in pH5.0 ~ 7.0, can enumerate and use the commercially available high molecular method of enteric solubility.When preparing enteric film, according to the difference of stripping pH, the high molecular specification of commercially available enteric solubility is distinguished.Such as, if use Eudragit L30D-55, the enteric film in pH5.5 stripping can be obtained, and if use Eudragit S, the enteric film in pH7.0 stripping can be obtained.In addition, multiple enteric solubility macromolecule can also be combinationally used to regulate stripping pH.In addition, method stripping pH being set in 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 the 14 amendment, measure under in vitro conditions in experimental liquid the dissolution time of effective ingredient obtain.Herein, as experimental liquid, slaking test method the 1st liquid in Japanese Pharmacopoeia, slaking test method the 2nd liquid in Japanese Pharmacopoeia and McIlvaine buffer etc. can be enumerated, but be not limited thereto.Herein, as assay method, Rotating shaker, paddle method or slaking test installation method can be enumerated, be preferably Rotating shaker.

In the present invention, by Rotating shaker measure under the condition of 100rpm be included in the dissolution rate in vitro of the effective ingredient in Enteric formulations time, exceed in the experimental liquid of set pH at pH, 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, it is further preferred that the stripping quantity of effective ingredient is 80 ~ 100 % by weight after 20 minutes, particularly preferably is, and after 20 minutes, the stripping quantity of effective ingredient is 90 ~ 100 % by weight.Herein, the experimental liquid that so-called pH exceedes set pH refers to such experimental liquid: its pH is more partial to alkalescence than the pH effective ingredient is from Enteric formulations during stripping.

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

Herein, the experimental liquid that so-called pH is no more than set pH refers to such experimental liquid: its pH is more partial to acidity than the pH effective ingredient is from Enteric formulations during stripping.

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

If be applicable in body, the pH in digestive tract, in general, gastric is 1 ~ 2, little enteral is 4 ~ 5, large enteral is 7 ~ 8, and move along with to digestive tract bottom, pH raises.Herein, about Enteric formulations of the present invention, when its arrival has the digestive tract position making the pH of generation stripping, effective ingredient starts stripping, and move along with to gastral bottom, the stripping of effective ingredient is promoted.But, in the digestive tract position than more top, the above-mentioned digestive tract position with the pH making generation stripping, effective ingredient not stripping substantially.

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

Herein, as water-insoluble macromolecule and water-soluble additives, those materials identical with the water-insoluble macromolecule of above-mentioned record and water-soluble additives can be enumerated.

In the present invention, for water-insoluble macromolecule and water-soluble additives, there is no particular limitation for the blending ratio in release membranes, and relative 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, relative to release membranes, the ratio of water-soluble additives can be enumerated as 0.5 ~ 50 % by weight, is preferably 1 ~ 30 % by weight, is more preferably 5 ~ 15%.

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

Herein, as preparation additive, those materials identical with the preparation additive of above-mentioned record can be enumerated.

Consumption for preparation additive is not particularly limited, preferably, with the use of amount be less than 50 % by weight.

For the manufacture method of slow releasing preparation of the present invention, there is no particular limitation, slow release coating liquid can be prepared, by adopting while this slow release coating liquid of spraying on former medicine preparation is while carry out the method applied, release membranes is coated on former medicine preparation, thus manufactures slow releasing preparation.

Herein, so-called slow release coating liquid is the liquid obtained in a solvent by the component dissolves of the formation release membranes by water-insoluble macromolecule, water-soluble additives and preparation additive and so on.

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

As the cladding process of release membranes, 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 can be adopted to carry out.

For the covering amount of the release membranes on former medicine preparation, there is no particular limitation, and can enumerate relative to former medicine preparation, 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 by coated for former medicine preparation release-controlled film (pulse release type film) and obtain preparation, this release-controlled film contains ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride methacrylate copolymers and EUDRAGIT L100-55.As other features of pulse release type preparation, such preparation can be enumerated: it does not discharge medicine in the region that the pH that gastric is such is low, and gently there is gelation in overlay film in small intestinal and the such pH of large intestine are comparatively close to neutral region, 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 methacrylate copolymers and EUDRAGIT L100-55, those materials identical with the ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride methacrylate copolymers of above-mentioned record and EUDRAGIT L100-55 can be enumerated.

In the present invention, for ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride methacrylate copolymers and EUDRAGIT L100-55, there is no particular limitation for the blending ratio in pulse release type film, relative to the ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride methacrylate copolymers of 1 weight portion, 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 methacrylate copolymers and EUDRAGIT L100-55, one kind or two or more water-insoluble additive and preparation additive can also be used.

Herein, as water-insoluble additive, the silicic acid such as Pulvis Talci, light anhydrous silicic acid class, methane-siliconic acid magnalium, magnesium stearate, wax or stearic acid etc. can be enumerated, but be not limited thereto.For the use amount of water-insoluble additive, there is no particular limitation, and such as, relative to above-mentioned two kinds of copolymers of 1 weight portion, the use amount of water-insoluble additive is less than 5 % by weight, is preferably less than 3 % by weight, is particularly preferably less than 1 % by weight.

Herein, as preparation additive, those materials identical with the preparation additive of above-mentioned record can be enumerated.For the use amount of preparation additive, there is no particular limitation, and with regard to the use amount of aggregation inhibitor, preferably, relative to above-mentioned two kinds of copolymers of 1 weight portion, its consumption is 50 ~ 100 % by weight.

For the manufacture method of pulse release type preparation of the present invention, there is no particular limitation, the component dissolves of the formation pulse release type film of ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium chloride methacrylate copolymers, EUDRAGIT L100-55 and water-insoluble additive and so on can be prepared pulse release type coating liquid in a solvent, by adopting the method applying this pulse release type coating liquid on former medicine preparation, pulse release type film is coated on former medicine preparation, thus manufactures pulse release type preparation.

Herein, as the solvent of pulse release type coating liquid, halogenated hydrocarbons or their mixture such as the ketone such as alcohols, acetone, dichloromethane, chloroform such as water, methanol, ethanol can be enumerated, 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, 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 can be adopted to carry out.

For the covering amount of the pulse release type film on former medicine preparation, there is no particular limitation, and relative 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.

The dosage form of Enteric formulations of the present invention, slow releasing preparation and pulse release type preparation is not particularly limited, as long as the solid preparation of oral administration, such as, the forms such as tablet, granule, powder, pill, capsule can be made.Be preferably tablet, granule and capsule, be particularly preferably granule and capsule.In addition, also this granule can be filled in capsule and be formed as capsule.

In the present invention, so-called former medicine granule is the one in the former medicine preparation of Enteric formulations, slow releasing preparation and pulse release type preparation and so on, refers to the granule before coated by release-controlled film.

As the manufacture method of former medicine granule, such as, wet granulation etc. can be enumerated.Such as can enumerate extruding pelletization method (utilizing Screw Extrusion prilling granulator, roller extruded type prilling granulator etc.), rotary granulation (utilizing Barrate type prilling granulator, centrifugal rotary prilling granulator transition etc.), fluidized bed granulation (utilizing fluid bed granulation unit, rotary fluid bed granulation device etc.), stirring-granulating method (utilizing stirring-granulating device etc.) etc.Also can 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, for using core and former medicine granule that pelletize obtains.

Herein, so-called core, obtains for general crystallinity excipient (such as, lactose, mannitol, sucrose, cellulose etc.) is formed as form of spherical particles (spherical particle).Particularly preferably mannitol in crystallinity excipient.As the particle diameter of core, 50 ~ 1000 μm can be enumerated, be preferably 100 ~ 600 μm, be more preferably 300 ~ 500 μm.Herein, the particle diameter of core can specify according to sieve method, and sieve method adopts mesh to be set as that the sieve of object particle diameter carries out the method for sieving.

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

Extruding granule is the former medicine granule obtained 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, carry out granulate with pelletizing machines such as Spheroidgranulatemachines, then, through super-dry, sieve and obtain extruding granule.But, Spheroidgranulatemachine etc. also can not be used to process.

In the present invention, the mesh for the sieve sieving former medicine granule can be enumerated as 100 ~ 2000 μm, is preferably 300 ~ 1500 μm, is more preferably 500 ~ 1180 μm.

In the present invention, so-called swelling type slow releasing preparation, refers to the tablet obtained with carrying out coated basic sheet containing water absorption and swelling gelating agent and effective ingredient containing water-insoluble high molecular film like release-controlled film (thin film).

In the present invention, so-called basic sheet is the tablet containing water absorption and swelling gelating agent and effective ingredient, this tablet once moisture namely can be swelling.

Herein, as 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 these one kind or two or more water absorption and swelling gelating agents used in combination.

In the sheet of basis except water absorption and swelling gelating agent and effective ingredient, one kind or two or more preparation additive can also be mixed.Herein, as preparation additive, those materials identical with the preparation additive of above-mentioned record can be enumerated.

The combined amount of water absorption and swelling gelating agent is arranged according to the kind of the kind of used gelating agent or preparation additive, and such as, 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, the polymer substance of one kind or two or more water-soluble additives, preparation additive, gastric solubility coating agent and swelling water penetration can also be used.Herein, as water-insoluble macromolecule, water-soluble additives and preparation additive, those materials identical with the water-insoluble macromolecule of above-mentioned record, water-soluble additives and preparation additive can be enumerated.

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

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

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

For the use amount of the polymer substance of water-soluble additives, preparation additive, gastric solubility coating agent and swelling water penetration, there is no particular limitation, preferably with less than 50 % by weight use amount come with the use of.

For the manufacture method of swelling type slow releasing preparation of the present invention, there is no particular limitation, can by wet method or dry process basis sheet, prepare thin film coated liquid subsequently, this thin film coated liquid is coated in method on this basic sheet by film coated on basic sheet by adopting, thus manufactures swelling type slow releasing preparation.

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

As organic solvent, acetone, benzene, toluene, dichloromethane, chloroform, ethyl acetate or alcohols (ethanol, isopropyl alcohol etc.) can be enumerated, be preferably ethanol, dichloromethane, ethyl acetate.By used in combination for these organic solvents, also can add the water of about 30% and use.

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

For the covering amount of thin film, there is no particular limitation, and such as, relative 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.

To the content of the effective ingredient contained in Enteric formulations of the present invention, slow releasing preparation, pulse release type preparation or swelling type slow releasing preparation, there is no particular limitation, be 0.1 ~ 80 about % by weight relative to the gross mass of preparation, be preferably 0.5 ~ 70 about % by weight.

Oral administration preparation of the present invention can be used as medicine, specifically, the palliative of the pain that depressor of thrombus/thromboembolism forms inhibitor, the cerebral infarction of diabetics sends out preventive again, postherpetic neuralgia is adjoint in the improving agent of the ischaemic episodes such as the therapeutic agent of chronic arteria occlusion disease, ulcer, pain and creeping chill that chronic arteria occlusion disease is adjoint, the improving agent of intermittent claudication, ischemic cerebrovascular disorder can be used as.

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

Embodiment

Specifically describe the present invention further below by embodiment, but be not limited to these embodiments, only otherwise exceed main points of the present invention.In addition, the sarpogrelate hydrochloride used below manufactures according to the method recorded in Japanese Laid-Open Patent Publication 58-32847 publication.

Production Example

Selection to core during manufacture spheroidal particle

At use white sugar-starch spherical particle (ノ Application パレ Le 101, manufactured by Off ロイ Application ト company) and castor sugar spherical particle (ノ Application パレ Le 103, manufactured by Off ロイ Application ト company) core as spheroidal particle when, can coloring phenomenon be found that there is time blended with stabilizing agent.

400g セ Le Off ィア CP-305 (is manufactured by Asahi Chemical Corp, its crystalline cellulose (granular) being particle diameter 300 ~ 500 μm) join centrifugal rotation pelletize coating unit (グラニュレッ Network ス GX-20, manufactured by Off ロイ Application ト company) in, by the binding liquid spraying be made up of 12g polyvinyl alcohol, 6g tartaric acid and 282g Purified Water, add 400g sarpogrelate hydrochloride simultaneously, carry out powder coated pelletize, and make its fluidized drying.Then, mesh is used to be that the sieve of 355 ~ 850 μm carries out sieving thus obtains former medicine granule I.This former medicine granule I of 360g is joined in centrifugal rotation pelletize coating unit, by the binding liquid spraying be made up of 11.52g polyvinyl alcohol, 5.76g tartaric acid and 270.72g Purified Water, add 360g sarpogrelate hydrochloride simultaneously, carry out powder coated pelletize, and make its fluidized drying.Then, mesh is used to be that the sieve of 500 ~ 1180 μm carries out sieving thus obtains former medicine granule II.This former medicine granule II of 600g is joined rotary fluid bed granulation device (MP-01, manufactured by Co., Ltd. パウレッ Network) in, use and to be fallen apart liquid (ア Network アコート ECD by 238.2g aqueous ethylcellulose, FMC Corp. manufactures), 23.8g triethyl citrate, 14.3g Crushing of Ultrafine Pulvis Talci, the slow release coating liquid that 10.8g HPMC and 369.0g Purified Water are formed carries out rotary fluid coating, after drying, mesh is used to be that the sieve of 500 ~ 1180 μm carries out sieving thus the slow-releasing granules that to obtain with crystalline cellulose (granular) (セ Le Off ィア CP-305) be core.

Evaluate for the slow-releasing granules of core with crystalline cellulose (granular) (セ Le Off ィア CP-305), found that: think because former medicine granule II during coating is broken, efflorescence and the particle of less than 500 μm that causes is 3.2 % by weight.On the other hand, in order to reduce being mixed into of less than 500 μm particles, when applying while Suppress atomizing, the obtained particle of more than 1180 μm is made to reach more than 10 % by weight.It can thus be appreciated that, when using crystalline cellulose (granular) as the core of spheroidal particle, sufficient intensity can not be obtained as granule.

On the other hand, with mannitol spherical particle (ノ Application パレ Le 108, manufactured by Off ロイ Application ト company) core as spheroidal particle when, after carrying out coating operation same as described above, the particle of less than 500 μm is 0 % by weight, and the particle of more than 1180 μm is 0.3 % by weight.It can thus be appreciated that, when using mannitol spherical particle as the core of spheroidal particle, the granule with abundant intensity can be obtained.

Therefore, below in an example, use mannitol spherical particle as the core of spheroidal particle.

Embodiment 1

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

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

This former medicine granule B of 740g is joined rotary fluid bed granulation device (MP-01, manufactured by Co., Ltd. パウレッ Network) in, use and to be fallen apart liquid, 26.9g triethyl citrate, 12.6g Crushing of Ultrafine Pulvis Talci, 11.7g HPMC (TC-5E by 269.0g aqueous ethylcellulose, manufactured by Shin-Etsu Chemial Co., Ltd) and the slow release coating liquid that forms of 392.6g Purified Water carry out rotary fluid coating, after drying, use mesh is that the sieve of 500 ~ 1180 μm sieves thus obtains coated particle.5.2g Crushing of Ultrafine Pulvis Talci is mixed in this granule of 832g, uses throughcirculation dryer to solidify 1 hour under the condition of 60 DEG C, obtain slow-releasing granules.This slow-releasing granules of 161mg is filled in No. 2 HPMC capsules, obtains slow releasing preparation.

Embodiment 2

By 710g by adopting the former medicine granule B that obtains of the method identical with embodiment 1 to join rotary fluid bed granulation device (MP-01, manufactured by Co., Ltd. パウレッ Network) in, the enteric solubility coating liquid be made up of Eudragit L30D-55,12.5g triethyl citrate of 421.8g, 12.5g Crushing of Ultrafine Pulvis Talci and 419.6g Purified Water is used to carry out rotary fluid coating, after drying, use mesh is that the sieve of 500 ~ 1180 μm sieves thus obtains coated particle.5.1g Crushing of Ultrafine Pulvis Talci is mixed in this granule of 840.5g, obtains enteric solubility granule.By particles filled for this enteric solubility of 165.8mg in No. 2 HPMC capsules, obtain Enteric formulations.Herein, set pH is 5.5.

Embodiment 3

By 720g by adopting the former medicine granule B that obtains of the method identical with embodiment 1 to join rotary fluid bed granulation device (MP-01, manufactured by Co., Ltd. パウレッ Network) in, the enteric solubility coating liquid be made up of Eudragit S, 1227.9g dehydrated alcohol of 94.5g, 19.2g triethyl citrate, 93.8g Pulvis Talci and 70.7g Purified Water is used to carry out rotary fluid coating, after drying, use mesh is that the sieve of 500 ~ 1180 μm sieves thus obtains enteric solubility granule.By particles filled for this enteric solubility of 175mg in No. 2 HPMC capsules, obtain Enteric formulations.Herein, set pH is 7.0.

Embodiment 4

By 700g by adopting the former medicine granule B that obtains of the method identical with embodiment 1 to join rotary fluid bed granulation device (MP-01, manufactured by Co., Ltd. パウレッ Network) in, the coating liquid be made up of Eudragit RSPO, 35.0g triethyl citrate of Eudragit L100-55,122.4g of 35.0g, 157.4g Pulvis Talci, 2314.2g dehydrated alcohol and 257.0g Purified Water is used to carry out rotary fluid coating, after drying, screening obtains the coated particle that particle diameter is 500 ~ 1180 μm.Further, this granule of 700g is joined rotary fluid bed granulation device (MP-01, manufactured by Co., Ltd. パウレッ Network) in, the coating liquid be made up of Eudragit RSPO, 23.3g triethyl citrate of Eudragit L100-55,81.6g of 23.3g, 104.9g Pulvis Talci, 1542.2g dehydrated alcohol and 171.3g Purified Water is used to carry out rotary fluid coating, after drying, use mesh is that the sieve of 500 ~ 1180 μm sieves thus obtains pulse release type granule.By 271.8mg, this is particles filled in No. 1 HPMC capsule, obtains pulse release type preparation.

Embodiment 5

By 1000.0g sarpogrelate hydrochloride, 200.0g low degree of substitution hydroxypropyl cellulose (LH-11, manufactured by Shin-Etsu Chemial Co., Ltd) join stirring granulating machine (VG-10, manufactured by Co., Ltd. パウレッ Network) in, use by 36.0g hydroxypropyl cellulose, the binding liquid that 18.0g tartaric acid and 546.0g Purified Water are formed is mediated, by kneaded material at extruding granulator (DG-L1, manufactured by only パウダ Le Co., Ltd., mesh size is 0.8mm) middle extruding pelletization, and with Spheroidgranulatemachine (Q-230, manufactured by only パウダ Le Co., Ltd.) granulate, then, use fluid bed granulation unit (MP-01, manufactured by Co., Ltd. パウレッ Network) carry out fluidized drying, and use mesh to be that the sieve of 500 ~ 1180 μm sieves thus obtains former medicine granule C.This former medicine granule C of 580g is joined rotary fluid bed granulation device (MP-01, manufactured by Co., Ltd. パウレッ Network) in, the enteric solubility coating liquid be made up of Eudragit L30D-55,14.8g triethyl citrate of 496.7g, 14.8g Pulvis Talci and 494.0g Purified Water is used to carry out rotary fluid coating, after drying, use mesh is that the sieve of 500 ~ 1180 μm sieves thus obtains coated particle.4.5g Pulvis Talci is mixed in this granule of 738.0g, obtains enteric solubility granule.By particles filled for this enteric solubility of 165.0mg in No. 2 HPMC capsules, obtain Enteric formulations.Herein, set pH is 5.5.

Embodiment 6

The tartaric acid that 10.0g sarpogrelate hydrochloride, 2.1g メトローズ 90SH-100SR (being manufactured by Shin-Etsu Chemial Co., Ltd), 2.0g HPMC (TC-5RW, manufactured by Shin-Etsu Chemial Co., Ltd), 0.15g light anhydrous silicic acid, 0.15g are pulverized in advance and the mixing of 0.6g magnesium stearate, the specification being 8.0mm with every sheet 150mg, tablet radius R in gyratory press (Collect12HUK is made manufactured by chrysanthemum water) prepares basic sheet.Blank is added to 1000g in this basic sheet of 5.4g, then pan coater (HC-LABO is joined, manufactured by Off ロイ Application ト company) in, by ethyl cellulose (STD10Premium, manufactured by Dow Chemical company) be dissolved in the mixed liquor of dehydrated alcohol and Purified Water (8:2) by 1:1 with the amount that solid component concentration is 7.4 % by weight with HPMC, this coating solution is sprayed, make the ethyl cellulose and the HPMC that are coated with 3.75mg relative to every sheet basis sheet, thus obtain the swelling type slow releasing preparation of every sheet 157.5mg.

Comparative example 1

Be that the ノ Application パレ Le 108 (being manufactured by Off ロイ Application ト company) of 355 ~ 500 μm joins centrifugal rotation pelletize coating unit (グラニュレッ Network ス GX-20 by 397.2g particle diameter, manufactured by Off ロイ Application ト company) in, by the slurry spraying be made up of 7.64g polyvinyl alcohol, 3.82g tartaric acid and 179.5g Purified Water, add 397.2g sarpogrelate hydrochloride simultaneously, powder coated pelletize, after fluidized drying, use mesh is that the sieve of 355 ~ 850 μm sieves thus obtains former medicine granule D.

This former medicine granule D of 370g is joined in centrifugal rotation pelletize coating unit, by the slurry spraying be made up of 6.26g polyvinyl alcohol, 3.13g tartaric acid and 147.1g Purified Water, add 368.9g sarpogrelate hydrochloride simultaneously, powder coated pelletize, after fluidized drying, use mesh is that the sieve of 500 ~ 1180 μm sieves thus obtains former medicine granule E.

By particles filled for this former medicine of 135.8mg in No. 2 HPMC capsules, obtain immediate release preparation.

Comparative example 2

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

Test example 1

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

In addition, dissolution test carries out according to the Japanese Pharmacopoeia dissolution test method of the 14 amendment, and experimental liquid temperature is 37 DEG C, experimental liquid 900mL, N=3.

In Japanese Pharmacopoeia the 1st liquid (pH1.2), the rapid stripping of effective ingredient of comparative example 1 () and the middle preparation recorded of comparative example 2 (*), in contrast to this, embodiment 2 (zero) and embodiment 4 (△) be not even if the effective ingredient of the middle preparation recorded had stripping (Fig. 1) after 120 minutes yet.On the other hand, in McIlvaine buffer (pH6.8), the rapid stripping of effective ingredient (Fig. 2) of the preparation recorded in embodiment 2 (zero).Further, the preparation recorded in embodiment 4 (△) after some period of time its effective ingredient starts stripping (Fig. 2).

From these results, the preparation recorded in embodiment 2 is Enteric formulations, and the preparation recorded in embodiment 4 is pulse release type preparation.

Test example 2

For the preparation recorded in embodiment 3, use that the pH of rare McIlvaine buffer is 4.0 (zero), 6.0 (△), the experimental liquid of 6.8 () and 7.8 (*) carries out dissolution test (Fig. 3) respectively.

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

From this result, the preparation recorded in embodiment 3 is Enteric formulations.

Test example 3

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

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

From this result, the preparation recorded in embodiment 5 is Enteric formulations.

Test example 4

For the preparation that embodiment 1 is recorded, rare McIlvaine buffer (pH6.8) is used to carry out dissolution test according to Rotating shaker 100rpm (zero); For the preparation that embodiment 6 is recorded, rare McIlvaine buffer (pH6.8) is used to carry out dissolution test according to paddle method 50rpm (△) and use Japanese Pharmacopoeia the 1st liquid (pH1.2) to carry out dissolution test (Fig. 5) according to paddle method 50rpm ().

In either event, in 6 ~ 12 hours, the effective ingredient stripping of about 100%.From this result, the preparation recorded in embodiment 1 and embodiment 6 is slow releasing preparation.

Test example 5

The pharmacokinetics test of experimental animal

For 6 male beagle dogs, adopt atropine sulfate and pentagastrin to carry out digestive tract adjustment, and per os give preparation in fasted condition, carries out pharmacokinetics test.

Give (100mg/ body weight) experimental animal by the preparation per os recorded in embodiment 1 ~ 6 and comparative example 1 ~ 2, measure the concentration change of non-changing matter and metabolite (M-1).The results are shown in table 3 (pharmacokinetic parameter about non-changing matter) and table 4 (pharmacokinetic parameter about metabolite M-1).

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

It can thus be appreciated that compared with traditional preparation, the preparation of embodiment 1 ~ 6 can suppress the sharply rising of effective ingredient, thus can maintain blood drug level for a long time.

By above result, the preparation that the preparation of embodiment 1 ~ 6 becomes such can be expected: said preparation is long-time sustained preparation relative to traditional preparation, thus decreases administration number of times.

In addition, in embodiment 1 ~ 6, the AUC of embodiment 2,4,5 and 6 _0-24hsuitable with comparative example 2, it can thus be appreciated that although the blood drug level of effective ingredient has persistence, absorption efficiency does not reduce.

From these results, in embodiment 1 ~ 6, embodiment 2,4,5 and 6 is preferred preparation.

For the embodiment 2,3 and 5 as Enteric formulations, from the viewpoint of set pH, by above-mentioned reasons, when sarpogrelate hydrochloride is Enteric formulations, set pH is preferably 5.5.

[table 3]

[table 4]

Industrial utilizes probability

According to the present invention, such new formulation can be provided, this new formulation to be 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 based on the special Willing 2007-291570 proposed in Japan, and its full content is in this manual involved.

Claims

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

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

2. blood drug level persistence preparation as claimed in claim 1, wherein, as 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 blood drug level persistence, mean residence time (MRT) is 3.0 little of 24.0 hours.

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

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

6. the blood drug level persistence preparation as described in claim 2 ~ 5, wherein, as 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 as described in claim 1 ~ 6, as effective ingredient, to be selected from aminoalkoxy Bibenzyl compound, its pharmaceutically useful salt, its ester and their solvate represented by following formula (2) and the material in their hydrate as effective ingredient

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

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

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

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

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

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

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

15. blood drug level persistence preparations as described in claim 11 ~ 14, wherein, when measuring the dissolution rate in vitro of the effective ingredient of described Enteric formulations under by the condition of Rotating shaker at 100rpm, be no more than in the experimental liquid of stripping pH of set effective ingredient at pH, the stripping quantity of the effective ingredient after 2 hours is less than 10 % by weight, and exceeding in the experimental liquid of stripping pH of set effective ingredient at pH, the stripping quantity of the effective ingredient after 1 hour is 90 ~ 100 % by weight.

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

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

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

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

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

21. blood drug level persistence preparations as claimed in claim 20, wherein, described spheroidal particle is formed together with pharmaceutically useful additive for core with the spheroidal particle of mannitol.