WO2003097102A1 - Pharmaceutical preparation improved in dissolving property of drug slightly soluble in water - Google Patents

Abstract

A pharmaceutical preparation improved in the dissolving property of a drug being slightly soluble in water, characterized in that it comprises the following components: 1) a drug being slightly soluble in water, 2) a disintegrator, and 3) a sugar alcohol, wherein the combining ratio of the disintegrator to the sugar alcohol is 0.2 to 5.

Description

 Description Formulation with improved dissolution of poorly water-soluble drug

 The present invention relates to a preparation having improved solubility of a poorly water-soluble drug, and more particularly to an oral administration preparation containing at least a poorly water-soluble drug, a disintegrant and a sugar alcohol. Background art

 It has been shown that compliance with oral dosage forms decreases when the dose is taken frequently (Monthly Pharmaceutical Affairs, Vol. 41, pp. 29, 1999). Therefore, OAD (Once aday) preparations that can be taken once a day have been developed. 0 In order to make AD preparations, it is essential to create sustained-release preparations with suppressed drug dissolution in order to maintain drug efficacy.

 Drugs taken several times a day, for example, antibiotics (+)-(6R, 7R) -7-[(Z) —2 -— (2-amino-1-4-thiazolyl) -12 —Pentenamide] 1—3-Rubamoyloxymethyl 8-octyl 5-Tia 1-azabicyclo [4.2.0] Oct-2-yl-2-pyrupyroxylate Tyl ester hydrochloride monohydrate (hereinafter referred to as cefcapene pipoxyl hydrochloride). Cefcapene pivoxil hydrochloride has a broad antibacterial spectrum from gram-positive to gram-negative bacteria. JP-A-62-89 describes compounds containing cefcapene pivoboxyl hydrochloride. Japanese Patent Application Laid-Open No. Hei 4-300821 discloses a sustained-release preparation containing cefcapene pivoxil hydrochloride.

However, in order to make a poorly water-soluble drug such as cefcapene pivoxil hydrochloride into a 0AD formulation, even if a sustained release formulation is simply prepared by ordinary means, the drug can hardly be eluted from the formulation. There is. As a result, the drug can hardly be absorbed in the body, and bioavailability may be reduced. In particular, high water content in the formulation The tendency is strong when a soluble drug is added. In order to improve this, it is necessary to enhance the dissolution of the drug from the preparation before coating with the sustained-release base (hereinafter referred to as the parent preparation). However, in the case of cefcapene pivoxil hydrochloride, none of the above-mentioned documents describes a parent drug with improved dissolution. Therefore, there has been a demand for the development of elemental preparations with improved solubility of poorly water-soluble drugs. Disclosure of the invention

 In view of the above circumstances, the present inventors improve the dissolution of poorly water-soluble drugs by blending a disintegrant and a sugar alcohol in the parent drug product and optimizing the mixing ratio of the disintegrant to the sugar alcohol. The inventors have found that the present invention described below has been completed.

 (1) At least the following components

 1) poorly water-soluble drug,

 2) disintegrants, and

 3) sugar alcohol

A dissolving agent having an improved dissolution property of a poorly water-soluble drug, wherein the mixing ratio of the disintegrant to the sugar alcohol is 0.2 to 5 times by weight.

 (2) The preparation according to the above (1), wherein the mixing ratio of the disintegrant to the sugar alcohol is 0.25 to 4.5 times by weight.

 (3) The preparation according to the above (2), wherein the mixing ratio of the disintegrant to the sugar alcohol is 0.3 to 4 times by weight.

 (4) The preparation according to any one of the above (1) to (3), wherein the disintegrant is one or more disintegrants selected from celluloses, starches and polyvinyls.

(5) The disintegrant is a low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, partially pregelatinized starch, carboxymethylsutyl sodium, pregelatinized starch and The preparation according to the above (4), which is one or more disintegrants selected from polyvinylpyrrolidone. (6) The preparation according to the above (5), wherein the disintegrant is one or more selected from the group consisting of low-substituted hydroxypropylcellulose, croscarmellose sodium and calcium carboxymethylcellulose.

 (7) The disintegrant is a low-substituted hydroxypropylcellulose, and the mixing ratio of the disintegrant to the sugar alcohol is 0.3 to 1.2 times by weight. 6) The preparation according to any one of the above.

 (8) The preparation according to any one of the above (1) to (7), wherein the sugar alcohol is a monosaccharide or a disaccharide.

 (9) The sugar alcohol is xylitol, D-mannitol, maltitol, erythritol, trehalose,! ) The preparation according to the above (8), which is one or more selected from the group consisting of sorbitol mono-lactitol.

 (10) The preparation according to the above (9), wherein the sugar alcohol is one or two or more selected from the group consisting of xylitol, D-mannitol, maltitol, erythritol, and trehalose.

 (11) The sugar alcohol described in any one of (1) to (10) above, wherein the sugar alcohol is xylitol and the dispersant is mixed in a weight ratio of 0.8 to 4 times the sugar alcohol. Formulation.

 (12) The disintegrant is low-substituted hydroxypropylcellulose, the sugar alcohol is xylitol, and the mixing ratio of the disintegrant to sugar alcohol is 0.8 to 1.2 times by weight. The preparation according to the above (1), which is characterized in that:

 (13) The disintegrant is croscarmé sodium D-sodium, the sugar alcohol is xylitol, and the mixing ratio of the disintegrant to the sugar alcohol is 2.5 to 3.5 times by weight. The preparation according to (11) above, wherein

 (14) The disintegrant is carboxymethylcellulose calcium and the sugar alcohol is xylitol, and the mixing ratio of the disintegrant to the sugar alcohol is 0.8 times or more by weight.

The preparation according to the above (1), which is 4 times as large.

(15) At least the following components 1) poorly water-soluble drug,

 2) disintegrants, and

 3) sugar alcohol

(1) from (1) above, in which the mixing ratio of the disintegrant and sugar alcohol was optimized so that the drug dissolution rate at 120 minutes after the start of the dissolution test at 37 ° C was 60% or more. )).

 (16) The poorly water-soluble drug is (+)-(6R, 7R) -17-[(Z) -12- (2-amino-4-thiazolyl) -12-pentenamide] -3 Moyloxime methyl 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-1-ene-2-carboxylic acid pivaloyloxymethyl ester hydrochloride or hydrate thereof The preparation according to any one of the above (1) to (15).

 (17) The poorly water-soluble drug is (+)-(6,7) -7-E (Z) -2- (2-Amino-1-4-thiazolyl) —2-pentenamide] -3-carbamoylo Ximetyl 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid piperyloxy methyl ester hydrochloride or hydrate thereof, disintegrant Is carboxymethylcellulose calcium, the sugar alcohol is xylitol, and the mixing ratio of the disintegrant to the sugar alcohol is 0.8 to 4 times by weight.

 (18) The preparation according to the above (17), wherein the mixing ratio of the disintegrant to the sugar alcohol is 2.5 to 3.5 times by weight.

 (1 9) (+) — (6 R, 7 R)-7-[(Z) — 2— (2-Amino-4thiazolyl) 1-2—Pentenamide] — 3—Carpamoyloxymethyl-8— Dissolution test of oxo — 5-thia-1-azabicyclo [4.2,0] oct-2-ene-2-carboxylate pivaloyloxymethyl ester hydrochloride monohydrate at 37 ° C The formulation according to (17) or (18), wherein the drug dissolution rate after 120 minutes is 60% or more.

(2 0) (+) ― (6 R, 7 R) 1 7— [(Z) — 2— (2-amino-4—thia Zolyl) 1-2-pentenamide] 1-3-Rubamoyloxymethyl-8-oxo-1-5-thia-1-1-azabicyclo [4.2.0] oct-2-ene-1- 2-pyruponic acid (17) or (18), wherein the dissolution rate of methoxymethyl ester hydrochloride 'monohydrate at 37 ° C is 120% or more after 120 minutes from the start of the drug. .

 (21) The preparation according to any one of (1) to (20) above, which is a granule.

 (22) A sustained-release preparation obtained by coating the preparation of the above-mentioned (21) with a sustained-release base or an enteric base.

 (23) The preparation according to any one of (1) to (22), which is a preparation to be taken once a day.

 (24) The poorly water-soluble drug is characterized by containing a disintegrant and a sugar alcohol in a ratio of 0.2 to 5 times the weight ratio of the disintegrant to the sugar alcohol. A method for improving the dissolution property of a sex drug. BRIEF DESCRIPTION OF THE FIGURES

 Figure 1: Relationship between the weight ratio of low-substituted hydroxypropylcellulose, a disintegrant, and xylitol, a sugar alcohol, to the dissolution rate 60 and 120 minutes after the start of the dissolution test for cefcapene pivoxil hydrochloride. Show. The vertical axis represents the dissolution rate (%) of cefcapene pipoxyl hydrochloride, and the horizontal axis represents the blending amount (mg) of disintegrant and sugar alcohol and their weight ratio. Figure 2: The relationship between the weight ratio of croscarmellose sodium, a disintegrant, and xylitol, a sugar alcohol, and the dissolution rate 60 and 120 minutes after the start of the dissolution test of cefcapene pivoxil hydrochloride. . The vertical axis shows the dissolution rate (%) of cefcapene pipoxyl hydrochloride, and the horizontal axis shows the blending amount (mg) of disintegrant and sugar alcohol and their weight ratio.

Figure 3: The weight ratio of low-substituted hydroxypropylcellulose as a disintegrant and D-mannitol as a sugar alcohol and the dissolution rate of cefcapene pivoxil hydrochloride at 60 and 120 minutes after the start of the dissolution test. Show the relationship. The vertical axis shows the dissolution rate of cefcapene pivoxil hydrochloride (%), and the horizontal axis shows the amount of disintegrant, sugar alcohol (mg) and its weight. Indicates a quantitative ratio. '

 Figure 4: Relationship between the weight ratio of low-substituted hydroxypropylcellulose, a disintegrant, and maltitol, a sugar alcohol, and the dissolution rate of cefcapene pivoxil hydrochloride 60 and 120 minutes after the start of the dissolution test. Show. The vertical axis shows the dissolution rate (%) of cefcapene pipoxyl hydrochloride, and the horizontal axis shows the blending amount (mg) of disintegrant and sugar alcohol and their weight ratio.

 Figure 5: Weight ratio of low-substituted hydroxypropyl cell mouth, a disintegrant, and erythritol, a sugar alcohol, and cefcapene pipoxyl hydrochloride at 60 and 120 minutes after the start of the dissolution test. 1 shows the relationship between the elution ratios of the compounds. The vertical axis represents the dissolution rate (%) of penifivoxil hydrochloride, and the horizontal axis represents the blending amount (mg) of disintegrant and sugar alcohol and their weight ratio.

 Figure 6: The relationship between the weight ratio of low-substituted hydroxypropylcellulose, a disintegrant, and trehalose, a sugar alcohol, and the dissolution rate of cefcapene pivoxil hydrochloride 60 and 120 minutes after the start of the dissolution test. Show. The vertical axis shows the dissolution rate (%) of cefcapene pipoxyl hydrochloride, and the horizontal axis shows the blending amount (mg) of disintegrant and sugar alcohol and their weight ratio.

 Figure 7 shows the relationship between the weight ratio of carboxymethylcellulose calcium, a disintegrant, and xylitol, a sugar alcohol, and the dissolution rate of cefpeniboxil hydrochloride at 60 and 120 minutes after the start of the dissolution test. The vertical axis shows the dissolution rate (%) of cefcapene pipoxyl hydrochloride, and the horizontal axis shows the blending ratio (%) of disintegrant and bran alcohol and their weight ratio. BEST MODE FOR CARRYING OUT THE INVENTION

The poorly water-soluble drug in the present invention is not particularly limited, such as pharmaceuticals, quasi-drugs, veterinary drugs, etc., but has a water solubility at 37 ° C., preferably 100 μg / ml or less, more preferably It is preferably at most 100 g / mL, particularly preferably at most 100 g / mL. Specifically, preferably 7? — [(Z) —2— (2—amino-4—thiazolyl) — 2—Hydroxyminoacetamide] 1—3— (1,2,3-Triazo-l—4-ylthiomethylthio) —11—Calper—3-Cefem—4-Carboxylic acid, (+) — (Z) —7 — [(1 R, 2 S, 3 S, 4 S) 1-3-benzenesulfonamidobicyclo [2.2.1] hept-2-yl] — 5-heptacalcium dihydrate, (+) -(6 R, 7 R) 1 7-[(Z) 1 2-(2 -amino 1-4 -thiazolyl) 1-1 -penteneamide] 1-3-Carpamoyloxymethyl-8-Oxo 5-1 1 —Azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid active ester, particularly preferably (+)-(6R, 7) -7-[(Z) —2 -— (2 -1-amino 4- (thiazolyl) 1- 2-pentenamide] — 3—Rubemoyloxymethyl-1 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2— Force rubon Acid piperoyloxymethyl ester or a pharmaceutically acceptable salt thereof or a hydrate thereof (eg, hydrochloride monohydrate).

The content of the poorly water-soluble drug may be such that the desired pharmacological effect can be obtained and the formulation can be formed, but it is preferably 20 to 80 (W / W) based on the total amount of the formulation. %, More preferably 30 to 60 (W / W)%, and particularly preferably 30 to 55 (W / W)%. If the content of the poorly water-soluble drug is too high, the drug is susceptible to temporal change, and the dissolution may be reduced. Conversely, if it is too low, the desired pharmacological effect cannot be obtained. The disintegrant to be used in the present invention may be any one that can disintegrate a solid preparation in water, and preferably a solid disintegrant listed in a drug rule or a food additive can be used. Starches and polyvinyls are preferred. Specifically, low-substituted hydroxypropylcellulose (L-HPC), carboxymethylcellulose, carboxymethylcellular monocalcium, carboxymethylcellulose sodium, croscarmellose sodium, partially pregelatinized starch, Carboxymethyl starch sodium, pregelatinized starch and polyvinylpyrrolidone, more preferably low-substituted hydroxypropylcellulose, croscarmellose sodium, or calcium carboxymethylcellulose (CM C-Ca). One or more of these may be used in combination. The content of the disintegrant varies depending on the content of the poorly water-soluble drug in the preparation, etc., but is preferably 5 (W / W)% or more, and more preferably 5 to 50 (W) / W)%, more preferably 7.5-45 (W / W)%, particularly preferably 10-40 or 20-30 (W / W)%. If the blending ratio of the disintegrant is too high, the formulation disintegrates immediately, and sufficient dissolution cannot be ensured. Conversely, if it is too low, the drug product does not disintegrate and almost no drug is eluted.

 The sugar alcohol used in the present invention may be any sugar alcohol that is usually soluble in water, and preferably a solid sugar alcohol described in a pharmaceutical rule or food additive can be used. More preferably, the saccharide having a solubility in water of at least 15 (W / V)% at 25 ° C., more preferably at least 30 (W / V)%, particularly preferably at least 50 (W / V)%. Alcohols, for example, sugar alcohols of monosaccharides and disaccharides. Specifically, xylitol, D-mannitol, maltitol, erythritol, trehalose, D-sorbitol, lactitol and the like can be used. Particularly preferred are xylitol, D-mannitol, maltitol, erythritol, and trehalose. One or more of these may be used in combination. The content of the sugar alcohol varies depending on the content of the active ingredient in the preparation, but is preferably 5% (W / W)% or more, more preferably 5 to 50 (WZW), based on the total amount of the preparation. %, More preferably 7.5-45 (W / W)%, particularly preferably 10-40 (W / W)%. If the mixing ratio of the sugar alcohol is too high, the composition is susceptible to temporal changes, and preparations cannot be prepared. Conversely, if it is too low, sufficient drug dissolution cannot be obtained. Further, the sugar alcohol may be added as an excipient.

The compounding ratio of the disintegrant to the sugar alcohol may be any ratio at which the dissolution property of the poorly water-soluble drug from the preparation increases, but the compounding ratio of the disintegrant to the sugar alcohol is preferably 0.2 to 0.2 by weight. It is 5 times, more preferably 0.25 to 4.5 times, particularly preferably 0.3 to 4 times. If the disintegrant is low-substituted hydroxypropylcellulose, the mixing ratio of the disintegrant to the bran alcohol is preferably 0.2 to by weight; L · 5 times, more preferably 0.25 to: 1. 25 times, particularly preferably 0. 3 to 1.2 times. If the sugar alcohol is xylitol, the mixing ratio of the disintegrant (preferably CMC-Ca) to the sugar alcohol is preferably 0.5 to 5 times by weight, more preferably 0.6 to 0.4. It is 5 times, particularly preferably 0.8 to 4 times, and further preferably 2.5 to 3.5 times. If the disintegrant is low-substituted hydroxypropylcellulose and the sugar alcohol is xylitol, the mixing ratio of the disintegrant to the sugar alcohol is preferably 0.6 to 1.4 times by weight, more preferably 0 to 1.4. The ratio is 7 to 1.3 times, particularly preferably 0.8 to 1.2 times. One of the preferred combinations of disintegrant and sugar alcohol is croscarmellose sodium and sugar alcohol is xylitol in consideration of dissolution properties and processability of the preparation. In this case, sugar is preferable. The mixing ratio of the disintegrant to alcohol is 2 to 4 times by weight, more preferably 2.25 to 3.75 times, particularly preferably 2.5 to 3.5 times, and most preferably about 3 to 3 times. It is twice. Another preferred embodiment is that the disintegrant is CM C—Ca and the sugar alcohol is xylitol. In this case, the mixing ratio of the disintegrant to the sugar alcohol is preferably 2 to 4 times by weight, more preferably 2 to 4 times. 25-3.75 times, particularly preferably 2.5-3.5 times, most preferably about 3 times. If the content of the disintegrant is too high, the granulation property is deteriorated, and the raw material becomes porous. As a result, strength that can withstand the coating cannot be obtained.

 The preparation of the present invention may further optionally contain pharmaceutically acceptable additives such as a binder, a granulation aid, an excipient, and a stabilizer.

 As the binder, those well-known in the art can be widely used, and examples thereof include methylcellulose, hydroxypropylcellulose (HPC), polyvinyl alcohol, gelatin, dextrin and the like. Cypropyl cellulose. The content of the binder is preferably usually 0.5 to 15 (W / W)%, preferably 1.0 to 10 (W / W)%, more preferably 1.5 based on the total amount of the preparation. ~ 5 (W / W)%.

As the granulation aid, those well-known in the art can be widely used. For example, hydrogenated castor oil, waxes such as stearyl alcohol, macrogol 40 Polyethylene glycols such as 000, Macrogol 600, and the like are exemplified, but hardened castor oil is preferred. The content of the granulation auxiliary is preferably usually 5 to 25 (W / W)%, preferably 3 to 20 (W / W)%, more preferably 2 to 1 based on the total amount of the preparation. 0 (W / W)%.

 As the excipient, those well known in the art can be widely used, and examples thereof include lactose, sucrose, sugar alcohol, corn starch, potato starch, hydroxypropyl starch, and synthetic aluminum silicate. But preferably lactose, sucrose, sugar alcohols, corn starch and potato starch. The content of the excipient may be appropriately set in consideration of the content of the active substance, the size of the target preparation, etc., but is usually 40 to 90 (W / W)%, preferably It is from 45 to 85 (W / W)%, more preferably from 50 to 80 (W / W)%. As the stabilizer, sodium chloride, sodium hydrogencarbonate, aminoaminoacetic acid, sodium hydrogensulfite, sodium sulfite, sodium benzoate, calcium carbonate, magnesium carbonate, calcium hydrogenphosphate, magnesium oxide, more preferably Examples include magnesium oxide and sodium sulphite. The content of the stabilizer may be appropriately determined in consideration of the content of the active ingredient, the size of the target drug product, and the like, but is usually 0.1 to 2 ◦ .0 (W / W )%, Preferably 0.5-10.0 (W / W)%. The form of the preparation of the present invention is not particularly limited, but is preferably a solid preparation such as granules, powders, fine granules and tablets, and particularly preferably granules.

When the granule of the present invention is produced, it is not particularly limited, but is preferably produced by the following method. That is, a poorly water-soluble drug, a sugar alcohol, a disintegrant and, if desired, an excipient, a stabilizer and the like are mixed, and an aqueous solution containing a binder is added to the mixed powder, followed by kneading. Then, granulate with an extrusion granulator and dry the granules. After drying, the granules may be sized and classified to produce granules. Further, in order to adjust the shape of the granules after classification, the granules may be spheroidized with a marmalizer or the like. Ma Granules can also be prepared by a tumbling granulation method, a fluidized bed granulation method, a stirring granulation method or a stirring fluidized bed granulation method.

 After preparing the preparations of the present invention into granules, they can be further tableted or filled into capsules. In this case, the tablet may contain pharmaceutically acceptable additives such as excipients, binders, and lubricants. In the case of a capsule, it can be filled into a hard capsule or a soft capsule.

When the preparation of the present invention is added to water, the drug is rapidly eluted from the preparation. Preferably, according to the paddle method of the 14th revised Japanese Pharmacopoeia (paddle stirring speed 50 rpm, test temperature 37 ° C, 14th revised Japanese Pharmacopoeia second liquid [pH 6.8]) The dissolution rate at 120 minutes after the start of the dissolution test at 37 ° C is preferably 60% or more, more preferably 70% or more, and particularly preferably 80% or more. When CMC-Ca is used as the disintegrant and xylitol is used as the sugar alcohol, the dissolution rate after 60 minutes is preferably 80% or more, more preferably 85% or more, and particularly preferably 9% or more. 0% or more. The elution rate after 120 minutes is preferably 90% or more. The drug product is basically composed of a drug, a sugar alcohol and a disintegrant, but a drug and a sugar alcohol or a drug and a disintegrant may form a complex. The granules, tablets, capsules and the like of the present invention can be formed into a sustained-release or enteric-coated preparation by coating with a sustained-release base or an enteric base after molding. Examples of the sustained-release base include ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, stearic acid, hydrogenated soybean oil, hydrogenated naptone oil, and hydrogenated oil. , Stearyl alcohol, ceanol, hydroxypyl propyl methylcellulose, paraffin, glycerin monostearate, etc. In addition, enteric film bases include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose trimellitate, hydroxypropylmethylcellulose acetate maleate, carboxymethyl ester Chilsel D-S, Metacry There are lactic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, cellulose acetate phthalate, and purified ceramic.

 The coating of the sustained-release base or the enteric base described above may be carried out, if desired, after forming an underlayer on the elementary granules. Examples of the component of the underlayer include HPMC and talc.

 The device for coating the sustained-release base and the enteric base may be any industrially used one. Examples thereof include a pan coating device, a fluidized-bed coating device, Examples include a Wurster type coating apparatus, a centrifugal fluidized bed type coating apparatus, and a stirring and tumbling fluidized bed type coating apparatus.

 The number of doses of the sustained-release or enteric-coated preparation is not particularly limited, but is preferably 1 to 3 times, more preferably 1 to 2 times, particularly preferably 1 time. The present invention preferably comprises at least a poorly water-soluble drug, a disintegrant and a sugar alcohol in the preparation, and optimizes the mixing ratio of the disintegrant and the sugar alcohol, for example, at 37 ° C. It is intended to provide a drug product whose drug dissolution rate is 120% or more 120 minutes after the start of the test. In addition, the mixing ratio of the disintegrant to the sugar alcohol is 0.2 to 5 times, preferably 0.25 to 4.5 times, more preferably 0.3 to 4 times by weight. It also provides a method for improving the dissolution of sexual drugs. Furthermore, the present invention also provides a method for producing a preparation having improved dissolution of the poorly water-soluble drug, which comprises the method for improving dissolution. '

(Examples 1-3, Comparative Examples 1-2)

 Each granule having the composition shown in Table 1 was produced according to the production method shown below.

 (Example 1 Production Method of Formulation)

The drug was used by pulverizing the above-mentioned cefcapene pipoxyl hydrochloride described in JP-A-62-89. The disintegrant is low-density hydroxypropylcellulose (hereinafter referred to as L-HPC), the sugar alcohol is xylitol, the granulation aid is hydrogenated castor oil, and the binder is hydroxypropylcellulose (hereinafter HPC-L). ) Was used. Cefcapene pivoxil hydrochloride, L-HPC, xylitol and hydrogenated castor oil were mixed in a mortar, and a 3 (W / V)% aqueous solution of HPC-L was added and kneaded. The kneaded mixture was extruded using an extrusion granulator [mesh ø0.6 mm, machine name Dome Gran (manufactured by Nonipadal)], and dried at 50 ° C for 30 minutes. Thereafter, the granules were sized using a 14-mesh sieve, and classified using a 20-42 mesh sieve to prepare granules.

 (table 1)

 (Unit: mg)

 • HPC: Low-substituted hydroxypropylcellulose

 • HPC-L: Hydroxypropylcellulose

(Dissolution test)

 A dissolution test was performed on the above drug product according to the method prescribed in the Japanese Pharmacopoeia, 14th Edition. The details of the conditions of the dissolution test are as follows. The dosage of the preparation in the test solution was about 270 mg (titer amount of cefcapene pivoxil hydrochloride 10 Omg).

 [Dissolution test conditions]

 Test method: JP method 2 (paddle method) Stirring speed 50 rpm

 Test solution: 2nd solution (pH about 6.8) 900mL, water temperature 37 ± 0.5 ° C

 Test liquid sampling time: 5, 15, 30, 45, 60, 90, 120 (min)

 Test liquid collection volume: 2 mL

Dissolution test: Dissolve the granules corresponding to the indicated amount of this product precisely, and use 90 OmL of the Disintegration Dissolution Test Solution 2 (90 OmL) maintained at 37 ° C as a test solution. No. 2 Perform the test at 50 revolutions per minute according to the method. After the start of the dissolution test, aspirate 2 mL of the eluate with a hole pipe with a cartridge-type cotton stopper over time, and add 8 mL of the test solution to this solution to make a sample solution. After collecting the eluate, replenish the same volume of the test solution into the test vial. Separately, weigh accurately about 0.015 g of cefcapene pivoxil hydrochloride standard solution, add a small amount of methanol to dissolve it, and add the test solution to make exactly 10 OmL. Pipet 1 mL of this solution, add the test solution to make exactly 50 mL, and use this solution as the standard solution. Using the difference in absorbance between the wavelengths of 245 nm and 380 nm as the absorbance, determine the absorbances and for the sample solution and the standard solution.

 (Equation 1)

Elution rate of the indicated amount of cefcapene pivoxil hydrochloride (%, i-th sampling)

= Ws

試料秤取量 ( mg)

Sample weight (mg)

W _s : Quantity of cefcapene pipoxyl hydrochloride preparation (mg)

 C: Moisture of cefcapene pivoxil hydrochloride standard (%)

 i ?: Anhydrous titer of cefcapene pivoxil hydrochloride standard (mg valency mg)

A _s : Absorbance of cefcapene pivoxil hydrochloride standard

A _T A _Ti . _X : Absorbance of the sample sampled at the i-th time and i-th time

 1/100: dilution factor

 Figure 1 shows the relationship between the dissolution rate 60 minutes and 120 minutes after the start of the dissolution test and the amounts and proportions of disintegrants and sugar alcohols. As a result, when the mixing ratio of the disintegrant to the sugar alcohol in Example 2 was 1.0 times, the dissolution property increased most, and the dissolution rate 60 minutes after the start of the dissolution test was 80% or more.

 (Examples 4-6, Comparative Examples 3-4)

Cefcapene pivoxoxy hydrochloride having different contents of croscarmellose sodium as disintegrant and xylitol as sugar alcohol by the same method as in the above example. A granule containing the same was produced. Table 2 shows the composition.

 (Table 2)

 (Unit: mg)

 HPC-L: Hydroxypropyl cellulose

 Figure 2 shows the relationship between the dissolution rate at 60 minutes and 120 minutes after the start of the dissolution test and the mixing ratio of disintegrant and sugar alcohol. As a result, when the mixing ratio of the disintegrant to the sugar alcohol in Example 6 was 3.0 times, the dissolution property increased most, and the dissolution rate 60 minutes after the start of the dissolution test was 80% or more.

 (Examples 7 to 9, Comparative Examples 5 to 6)

 In the same manner as in the above example, granules containing cefka penpivoxil hydrochloride having different contents of low-substituted hydroxypropyl cellulose as a disintegrant and D-mannitol as a sugar alcohol were produced. Table 3 shows the composition.

 (Table 3)

 (Unit: mg)

 L-HPC: Low substitution degree D xypropyl cellulose

HPC-L: Hydroxypropylcellulose Dissolution test 60 minutes and 120 minutes after the start of the dissolution test and the dissolution rate of disintegrant and sugar alcohol Figure 3 shows the relationship. As a result, when the mixing ratio of the disintegrant to the sugar alcohol in Example 7 was 0.33 times, the dissolution increased most, and the dissolution rate at 120 minutes after the start of the dissolution test was 60% or more. there were.

 (Example 10 ~; L2, Comparative example? ~ 8)

 Cefcapene pivoxil hydrochloride-containing granules having different contents of low-substituted hydroxypropylcellulose as a disintegrant and maltitol as a sugar alcohol were produced in the same manner as in the above Examples. The composition is shown in Table 4.

 (Table 4)

 (Unit: mg)

 · L-HPC: Low-substituted hydroxypropylcellulose

 • HPC-L: Hydroxypropylcellulose Figure 4 shows the relationship between the dissolution rate at 60 minutes and 120 minutes after the start of the dissolution test and the mixing ratio of disintegrant and sugar alcohol. As a result, when the blending ratio of the disintegrant to the sugar alcohol in Example 11 was 1.0, the dissolution property increased most, and the dissolution rate 60 minutes after the start of the dissolution test was 80% or more.

 (Examples 13 to 15, Comparative Examples 9 to 10)

Cefampipoxyl hydrochloride-containing granules having different contents of low-substituted hydroxypropyl cellulose as a disintegrant and erythritol as a sugar alcohol were produced in the same manner as in the above Examples. Table 5 shows the composition. (Table 5)

 (Unit: mg)

 L-HPC: Low-substituted hydroxypropylcellulose

 HPC-L: Hydroxypropylcellulose Figure 5 shows the relationship between the dissolution rate at 60 minutes and 120 minutes after the start of the dissolution test and the blending ratio of disintegrant and sugar alcohol. As a result, when the mixing ratio of the disintegrant to the sugar alcohol in Example 13 was 0.33 times, the dissolution property increased the most, and the dissolution rate after 120 minutes from the start of the dissolution test was 70% or more. Was.

(Examples 16-18, Comparative Examples 11-12)

 Cefcapene pipoxyl hydrochloride-containing granules having different contents of low-substituted hydroxypropylcellulose as a disintegrant and trehalose as a sugar alcohol were produced in the same manner as in the above Examples. Table 6 shows the composition.

 (Table 6)

 (Unit: mg)

 L-HPC: Low-substituted hydroxypropylcellulose

HPC-L: Hydroxypropyl cellulose Figure 6 shows the relationship between the dissolution rate at 60 minutes and 120 minutes after the start of the dissolution test and the mixing ratio of disintegrant and sugar alcohol. As a result, when the mixing ratio of the disintegrant to the sugar alcohol in Example 13 was 0.33 times, the dissolution property was increased most, and the dissolution rate after 120 minutes from the start of the dissolution test was 80% or more.

Example 19 A sustained release granule comprising the following components was produced. First, elementary granules were prepared according to the method of Example 1, an underlayer was formed, and then an enteric layer was coated.

 (Table 7)

Elementary granules Cefcapene pivoxil hydrochloride 390

 Xylitol 100

 CMC C a 300

 H P C 23.2

Underlayer H PMC 41.5

 Talc 207.4

Enteric layer Methacrylic acid copolymer LD 90.6

 Triethyl citrate 10.3

 Talc 70.1 Figure 7 shows the relationship between the dissolution rate at 60 minutes and 120 minutes after the start of the dissolution test (pH 6.8) and the mixing ratio of disintegrant (CMC Ca) and sugar alcohol (xylitol). . As a result, when the mixing ratio of the disintegrant to the sugar alcohol was 0.33 or more, the dissolution rate was 80% or more, and the dissolution rate was 1 to 3 times, and the dissolution rate was almost 90% or more. Under acidic conditions of pH 1.2, almost no drug dissolution was observed even after 2 days from the start of the test.

Industrial applicability

 The present invention provides a formulation having improved solubility of a poorly water-soluble drug. Sustained-release preparations containing this preparation maintain the efficacy of the drug, reduce the number of doses of the drug, and improve patient compliance. Furthermore, the stability over time of the drug incorporated in the preparation of the present invention is high, and long-term storage is possible.

Claims

The scope of the claims 1. At least the following components  1) poorly water-soluble drug,  2) disintegrants, and  3) sugar alcohol A dissolving agent having an improved dissolution property of a poorly water-soluble drug, wherein the mixing ratio of the disintegrant to the sugar alcohol is 0.2 to 5 times by weight.  2. The preparation according to claim 1, wherein the mixing ratio of the disintegrant to the sugar alcohol is 0.25 to 4.5 times by weight.  3. The preparation according to claim 2, wherein the mixing ratio of the disintegrant to the sugar alcohol is 0.3 to 4 times by weight.  4. The preparation according to any one of claims 1 to 3, wherein the disintegrant is one or more disintegrants selected from celluloses, starches, and polyvinyls. 5. Disintegrants are low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose D-sodium, croscarmellose sodium, partially pregelatinized starch, carboxymethyl starch sodium 5. The preparation according to claim 4, which is one or more disintegrants selected from pregelatinized starch and polyvinylpyrrolidone. 6. The preparation according to claim 5, wherein the disintegrant is one or more selected from the group consisting of low-substituted hydroxypropylcellulose, croscarmellose sodium and calcium carboxymethylcellulose. '  7. The claim 1 wherein the disintegrant is low-substituted hydroxypropylcellulose, and the mixing ratio of the disintegrant to the sugar alcohol is 0.3 to 1.2 times by weight. 7. The preparation according to any one of claims to 6. 8. The preparation according to any one of claims 1 to 7, wherein the sugar alcohol is a monosaccharide or a disaccharide. 9. The preparation according to claim 8, wherein the sugar alcohol is one or more selected from the group consisting of xylitol, D-mannitol, maltitol, erythritol, trehalose, D-sorbitol and lactitol.  10. The preparation according to claim 9, wherein the sugar alcohol is one or more selected from the group consisting of xylitol, D-mannitol, maltitol, erythritol, and trehalose.  11. The preparation according to any one of claims 1 to 10, wherein the sugar alcohol is xylitol, and the mixing ratio of the disintegrant to the sugar alcohol is 0.8 to 4 times by weight. 12. The disintegrant is low-substituted hydroxypropylcellulose, the sugar alcohol is xylitol, and the mixing ratio of the disintegrant to the sugar alcohol is 0.8 to 1.8 by weight. 2. The preparation according to claim 1, wherein the preparation is doubled.  13. The disintegrant is croscarmellose sodium, the sugar alcohol is xylitol, and the mixing ratio of the disintegrant to the sugar alcohol is 2.5 to 3.5 times by weight. Item 18. The preparation according to Item 11.  14. The disintegrant according to claim 1, wherein the disintegrant is calcium carboxymethylcellulose and the sugar alcohol is xylitol, and the mixing ratio of the disintegrant to the sugar alcohol is 0.8 to 4 times by weight. Formulation.  1 5. At least the following ingredients  1) poorly water-soluble drug, 2) disintegrants, and  3) sugar alcohol Claims 1 to 14 wherein the mixing ratio of the disintegrant and the sugar alcohol is optimized so that the drug dissolution rate at 120 minutes after the start of the dissolution test at 37 ° C is 60% or more. The preparation according to any one of the above. 1 6. The poorly water-soluble drug is (+)-(6R, 7R)-7-[(Z)-2-(2-amino-4- thiazolyl)-1-2-pentenamide]-3-force Lupamoyloxymethuyl 8-Oxo-5-Thia-1-Azabicyclo [4.2.0] Oct-1-2-ene The pharmaceutical preparation according to any one of claims 1 to 15, which is pivaloyloxymethyl hydrochloride or its hydrate.  1 7. The poorly water-soluble drug is (+)-(6R, 7R) -7-[(Z) —2— (2-amino-14-thiazolyl) 1-2-pentenamide] 3-carpa Moyloxymethyl 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid bivaloyloxymethyl ester hydrochloride or its hydrate The disintegrant is carboxymethylcellulose calcium, the sugar alcohol is xylitol, and the mixing ratio of the disintegrant to the sugar alcohol is 0.8 to 4 times by weight. Preparations.  1 8. The preparation according to claim 1, wherein the mixing ratio of the disintegrant to the sugar alcohol is 2.5 to 3.5 times by weight.  1 9. (+)-(6, 7 R)-7-[(Z)-2-(2-amino-4-thiazolyl) 1-2-pentenamide]-3-Carpamoyloxymethyl-8-oxo-1. 5-1-1-azabi-sik mouth [4.2.0] oct-2-ene 2--carboxylic acid piperyloxy methyl ester hydrochloride hydrochloride · Starting dissolution test at 37 ° C of monohydrate 1 19. The preparation according to claim 17, wherein the drug dissolution rate after 20 minutes is 60% or more.  2 0. (+) 1 (6 R, 7 R)-7-[(Z) 1 2— (2-Amino 4- 4-thiazolyl) 1-2-Pentenamide] 1—3-Rubamoyloxymethyl-8 —Oxo-5-thia-1-azabicyclo [4.2.0] Oct-2-ene-2-carboxylate Bivaloyloxymethyl ester hydrochloride 'monohydrate dissolution test at 37 ° C The pharmaceutical preparation according to claim 17 or 18, wherein the drug dissolution rate at 120 minutes after the start is 80% or more.  21. The preparation according to any one of claims 1 to 20, which is a granule. 22. A sustained-release preparation obtained by coating the preparation of claim 21 with a sustained-release base or an enteric base. 23. The preparation according to any one of claims 1 to 22, which is a preparation to be taken once a day. 24. Poorly water-soluble, characterized by containing a disintegrant and a sugar alcohol for the poorly water-soluble drug, and the mixing ratio of the disintegrant to the sugar alcohol is 0.2 to 5 times by weight. A method for improving the dissolution of a drug.