WO2005009474A1 - Dry syrup agent containing hardly water soluble drug - Google Patents

Abstract

A dry syrup agent of hardly water soluble drug is produced by the use of hydroxypropylcellulose whose viscosity measured with respect to a 2(w/v)% aqueous solution at 20°C is below 3.0 mPa·s.

Description

 Specification

 Dry syrup containing poorly water-soluble drug

 Technical field

 [0001] The present invention relates to a dry syrup containing a poorly water-soluble drug, more specifically, a hydroxy syrup containing at least a poorly water-soluble drug and a 2% (w / v)% aqueous solution at 20 ° C having a viscosity of less than 3. OmPa's. The present invention relates to a dry syrup containing not less than 0.5 (w / w)% of cypropylcellulose. Background art

 [0002] Pharmaceutical dosage forms include various forms such as tablets, granules, capsules and the like. According to the Japanese Pharmacopoeia General Rules for Preparations, dry syrups, which are one of the pharmaceutical dosage forms, are equivalent to "preparations to be used by dissolving or suspending before use". Dry syrup is easy to take, especially for children who dislike the drug and elderly people who have difficulty swallowing. Further, since the dry syrup is in the form of powder or granules, it has an advantage that it can be easily packaged and weighed, and is convenient to carry.

 Patent Document 1 discloses a fast dissolving oral dosage form containing diclofenac sodium, mannitol and polybierpyrrolidone Patent Document 2 describes a dry syrup containing faropenem sodium, sucrose, hydroxypropylcellulose, etc. Power Patent Document 3 discloses a dry syrup containing ampicillin, sugar and 0.3 (wZw)% hydroxypropylcellulose. However, all of the drugs used in the above formulations have relatively high water solubility, with a water solubility at 20 ° C of 100 ppm or more.

 [0003] On the other hand, in the case of a poorly water-soluble drug, particularly a poorly water-soluble drug having a water solubility of less than 100 ppm at 20 ° C, in order to improve the suspendability of the drug and the defoaming property of the drug solution, a surfactant and It is common to add an antifoam to the dry syrup.

As a dry syrup containing no surfactant or defoamer, Patent Document 4 discloses terfenadine, sucrose, and HPC-SL (a 2% (w / v)% aqueous solution at 20 ° C) with water solubility of less than 100 ppm. Hydroxypropylcellulose having a viscosity of 3.0-5.9 mPa's] is disclosed, but the presence or absence of suspended matter and the addition of water to water after stirring are disclosed. The presence or absence of the defoaming property is disclosed.

 Patent Document 1: JP-T-2000-508649

 Patent Document 2: International Publication No. 01/26691 pamphlet

 Patent Document 3: JP-A-54-32615

 Patent Document 4: JP-A-6-15712

 Disclosure of the invention

 Problems to be solved by the invention

 [0004] Under the above circumstances, there has been a demand for a dry syrup having excellent physical properties containing a poorly water-soluble drug, particularly a poorly water-soluble drug having a water solubility at 20 ° C of less than 100 ppm. Means for solving the problem

 Therefore, the present inventors have conducted intensive studies and found that even in the case of poorly water-soluble drugs, the viscosity of a 2% (w / v)% aqueous solution in a dry syrup is less than 3.OmPa's at 20 ° C. It has been found that by including hydroxypropyl cellulose, a dry syrup having excellent physical properties can be obtained. That is, it has been found that the dry syrup preparation of the present invention exhibits excellent sedimentation when put into water. In addition, the dry syrup preparation of the present invention exhibited excellent dispersibility and redispersibility, did not produce suspended matter, and was found to have improved defoaming properties, and thus completed the present invention described below.

 (1) At least 0.5% (w / w)% of a poorly water-soluble drug and hydroxypropylcellulose whose viscosity of a 2 (w / v)% aqueous solution at 20 ° C is less than 3.0 mPa's is contained. , Dry syrup.

 (2) The dry syrup according to the above (1), wherein the water solubility of the poorly water-soluble drug is less than LOOOOOppm.

 (3) The dry syrup preparation according to the above (1) or (2), wherein the defoaming property is improved.

 (4) The dry syrup according to any of (1) to (3) above, further containing sucrose.

(5) The dry syrup preparation described in any of (1) to (4) above, which does not contain a surfactant and an antifoaming agent.

(6) A preparation in which the poorly water-soluble drug is suspended in water after the dry syrup preparation according to any one of the above (1) to (5) is put into water and stirred. (7) In a dry syrup containing a poorly water-soluble drug, hydroxypropylcellulose having a viscosity of 2 / ^% aqueous solution less than 3.OmPa's in 20% (w / w)% A method for improving the defoaming property of a drug suspension after the formulation is poured into water and stirred.

 (8) 20. A poorly water-soluble drug containing at least 0.5 (w / w)% of hydroxypropylcellulose having a viscosity of a 2 (w / v)% aqueous solution of less than 3.OmPa's in C. Method for producing lye syrup.

 The invention's effect

 [0006] The viscosity of a poorly water-soluble drug and a 2 (w / v)% aqueous solution at 20 ° C is less than 3 · OmPa's. give. BEST MODE FOR CARRYING OUT THE INVENTION

[0007] (1) Dry syrup preparation

 As a first aspect, the present invention provides, as a first embodiment, at least a poorly water-soluble drug and a hydroxypropylcellulose having a viscosity of a 2 (w / v)% aqueous solution at 20 ° C of less than 3. ) Provide dry syrup containing at least%.

 The dry syrup preparation of the present invention becomes a uniform dispersion liquid when water is used. Homogeneous dispersion means a formulation with the following physical properties:

 1. When 5g is added to lOOmL of water, it will settle within 1 minute;

 2. Pour 5g into lOOmL of water, turn it upside down and leave it standing, it will become cloudy and disperse;

3. Pour 5 g into 100 mL of water, turn it over, turn it over, leave it for one day, then turn it over again and let it stand, it will become cloudy and redisperse;

 4. Do not produce suspended matter within 1 minute after assessing dispersibility; and

 5. Foam disappears within 1 minute after evaluating dispersibility.

 The above properties are referred to as 1. sedimentation, 2. dispersibility, 3. redispersibility, 4. the presence or absence of suspended solids, and 5. defoaming, respectively. These physical properties may be collectively referred to herein as “uniform dispersibility”. Details of these physical properties will be described in Test Example 1 below.

[0008] The poorly water-soluble drug which is an active ingredient of the dry syrup preparation of the present invention is a drug, a quasi-drug The water solubility at 20 ° C. is preferably 1000 Oppm, more preferably 1000 ppm, particularly preferably 100 ppm or less. Specifically, ethenzamide, sulfamethoxazole, azathioprine, azimaline, aspirin, acetazolamide, acetylsviramycin, acetohexamide, ethamino benzoate, amphotericin B, aldoxin, aropurinol, iopanoic acid, isopropyl Antipyrine, ibuprofen, indomethacin, ursodeoxycholic acid, estazolam, estriol, ethacrynic acid, etyonamide, ethininoleestradione, ethinoresuccinate erythroxin mycin, ethin carbonate quinine, flufenadine enanthate, enoxacin, erythromycin , Ergocalcifrol, benoreverine chloride, arotinolol hydrochloride, chlorhexidine hydrochloride, cyproheptadine hydrochloride, cefetamethopivoxil hydrochloride, cefcapempi hydrochloride Boxycil, cefmenoxime hydrochloride, trihexifidinyl hydrochloride, dicardipine hydrochloride, piperidin hydrochloride, bunazosin hydrochloride, bupranolol hydrochloride, flavoxate hydrochloride, bromhexine hydrochloride, maprotiline hydrochloride, oxazolam, oxaprozin, oximetron, oxesazein, carbamazepine, Chlorphenesin rubamate, L-carbocistine, carmofo nore, clomiphene quenate, clarthromycin, griseofulvin, cloxazolam, clothiazepam, clonazepam, clofibrate, chloramphenicol, chlordazepoxide, chlorpropamide, natural kemiconic acid Magnesium phosphate, ketoprofen, tocopherol calcium succinate, cholecalciferol, guanabene acetate, chloroacetate Zinone, Tocopherol acetate, Midecamycin acetate, Methenolone acetate, Retinol acetate, Salazosulfabicillin, Magnesium oxide, Santonin, Diazepam, Digitoxin, Cyclosporin, Diclofenamide, Digoxin, Bismuth subnitrate, Disulfiram, Disopyramide, Didrogesterone, Dipyridamole , Cimetidine, Dimenhydrinate, Bismuth subgallate, Mepenzolate bromide, Ifenprodyl tartrate, Ergotamine tartrate, Isosonorebitone nitrate, Josamycin, Synfibrate, Dried aluminum hydroxide gel, Sklarfate, Erythromycin stearate , Spironolataton, Sultiam, Sulpiride, Sulfamethizole, Sulfamonomethoxine, Sulfinpyrazone, Cefixime, Cefix Train pivoxil, cefdinir, ceftibuten, cefteram pivoxil, Sefurokisaji down, cefuroxime axetil, precipitated calcium carbonate, magnesium carbonate, Dantororen'na Thorium, diphenhydramine tannate, berberine tannate, tinidazole, theophylline, dexamethasone, dehydrocholic acid, tocopherol, sultamicilin tosylate, tofisopam, tolazamide, triamcinolone, triamterene, trichlormethiazide, L-tryptophan, tonolebutone, torenolebutetone , Nystatin, nadolol, naproxen, naliditasic acid, tocopheronol nicotinate, nicomornole, niceritronore, ditirazepam, difuedipin, nostipin, norletisterone, norgesterel, norfloxacin, norfloxacin, baclofen, aminopulamide, pamoate, pamoate, pamoate Calcium salicylate, vanolebitanore, haloxazolam, noperidolone, hide Loclomouth thiazide, hydroconoretisone, pimidic acid trihydrate, pindolol, famotidine, phenacetin, phenytoin, fenirbutazone, phenobarbital, clemastine fumarate, prazepam, primimide, fludiazepam, furosemide, prothonamide, fluoridone Propion, probenecid, bromperylurea, betamethasone, perphenazine, phosphestrol, mitomycin C, prochlorperazine maleate, midecamycin, mestranol, metazepam, metoclopramide, mefenamic acid, menolecaptopurine, ubidecanone, rifampicin sulfate, penbutoline sulfate , Reserpine, roxithromycin, rokitamicin, lorazepam and the like. The amount of the poorly water-soluble drug is not particularly limited, as long as the relative mixing ratio of the drug does not decrease. Specifically, 0.01 to 50.0 (w / w)%, preferably 0.1 to 10.0 (w / w)%, more preferably 0.5 to 5.0 (w / w) / w)%, particularly preferably 0.5-3.0 (w / w)%. If the amount is larger than this, the drug may not be sufficiently suspended. If the amount is smaller, production may be difficult in terms of content uniformity.

The hydroxypropyl cellulose contained in the dry syrup of the present invention also functions as a suspending agent for stabilizing the suspendability of the drug and also as a binder for the dry syrup. The viscosity of a 2 (wZv)% aqueous solution at 20 ° C measured by a B-type viscometer is less than 3. OmPa's (hereinafter abbreviated as HPC-C). When the dry syrup is added to water at the time of use, a uniform dispersion is obtained, no suspended matter is generated, and the defoaming property is good. If the viscosity of hydroxypropinoresenololose is higher than this, the uniform dispersibility may be poor when the formulation is added to water. In addition, hydroxypropylcellulose is sold as a commercial product as long as the viscosity of an aqueous solution of 2 (w / v)% hydroxypropylcellulose is less than 3.OmPa's. It may be a mixture of one or more of various grades of hydroxypropylcellulose. The amount of the hydroxypropyl cellulose is 0.5 (w / w)% or more in the preparation, preferably 0.5 to 10.0 (w / w)%, more preferably 0.5 to 5.0 (w / w). / w) ヽ 0.5-1.0 (w / w) Q / o is particularly preferred. If the amount is less than this, physical properties such as uniform dispersibility cannot be improved.

[0010] Carbohydrates contained in the dry syrup preparation of the present invention include sugars and sugar alcohols, for example, sucrose, glucose, D-mannitol, powdered reduced maltose starch syrup, maltitol, erythritolone, D-sonorebitonere, maltose, Lactose, starch and starch derivatives, mannose, sonorebose, xylose, trehalose, hunolectose, dextran, punorellan, dextrin, cyclodextrin, soluble starch, hydroxyethyl starch, carboxymethinoresenorelose_Na, mannitolenole, sonorenothore At least one kind is selected from the group consisting of, for example, zunolesitone, xylithonore, arabitotone, raffinose, erythritonolle, manoletitonolle, lactitonolle, and palatinit. Of these, sucrose is preferred. The amount of the carbohydrate in the preparation is 20.0 (w / w)% or more, preferably 50.0 to 99.4 (w / w) o / ₀ , more preferably 80. 0 to 99.0 (w / w). %, Particularly preferably 90.0-99.0 (w / w)%. If the amount is less than this, it may not be possible to sufficiently maintain the shape of granules.

 [0011] The dry syrup preparation of the present invention contains 0.01-50.0% (w / w)% of poorly water-soluble drug and 0.5% (w / w)% or more of HPC-C, Sucrose is at least 20.0 (w / w)%, preferably 0.1-10.0 (w / w)% of poorly water-soluble drug, 0.5-10.0 (w / w)% of HPC-C, Saccharose is 50-99-4 (w / w)%, more preferably poorly water-soluble drug is 0.5-5.0 (w / w)%, UPC-C power is 0.5-5.0 (w / w) %, Sucrose power 80.0-99.0 (w / w)%, particularly preferably 0.5-3.0 (w / w)% for poorly water-soluble drugs, 0.5-1.0 (w / w)% for HPC-C, Saccharose is 90.0-99.0 (wZw)%.

 The dry syrup of the present invention may contain pharmaceutically acceptable additives other than those described above. Additives include sweeteners, lubricants, suspending agents, pH adjusters, preservatives, flavors and the like.

Lubricants include those called fillers, adsorbents or fluidizers, for example, At least one type is selected from silicon dioxide, light caffeic anhydride, sucrose fatty acid ester, magnesium stearate and the like.

 [0012] Sweeteners usually include carbohydrates or non-sugars, but here, non-sugar natural or synthetic sweeteners, such as aspartame, glycyrrhizic acid and salts thereof, and saccharin And its salts, stevia and its salts, sucralose, acesulfame potassium, and the like. pH adjusters include those called acids, bases or buffers, such as hydrochloric acid, dilute hydrochloric acid, sulfuric acid, adipic acid and its salts, citric acid and its salts, dalconic acid and its salts, succinic acid and its salts Ascorbic acid and its salts, glacial acetic acid and its salts, acetic acid and its salts, tartaric acid and its salts, fumaric acid and its salts, maleic acid and its salts, lactic acid and its salts, malic acid and its salts, phosphoric acid and The salt, glycine, sodium hydrogencarbonate, sodium carbonate, sodium hydroxide, magnesium hydroxide and the like are selected from at least one kind. Preservatives include those referred to as stabilizing (stabilizing) agents, such as benzoic acid and its salts, etedic acid and its salts, salicylic acid and its salts, dibutylhydroxytoluene, sorbic acid and its salts, sodium acetic acid sodium salt, At least one kind is selected from paraoxybenzoic acid and salts thereof. Flavors include those called fragrances, for example, orange essence, orange oil, caramenole, camphor, queich oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, spruce oil, pine oil, heart oil , Vanilla flavor, bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, menthol, lemon powder, lemon oil, rose oil, etc.

[0013] The dry syrup preparation of the present invention may contain a surfactant and an antifoaming agent. In order to obtain the excellent effects of the dry syrup of the present invention, it is preferable that the dry syrup does not contain a surfactant as described above. Examples of such surfactants include sucrose fatty acid esters, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, and sodium lauryl sulfate. In order to obtain the excellent effects of the dry syrup of the present invention, it is preferable that the dry syrup does not contain an antifoaming agent as described above. Examples of such antifoaming agents include silicone resin, silicone resin emulsion, silicone antifoaming agent, silicone oil, sucrose fatty acid ester, glycerin fatty acid ester, dimethylpolysiloxane, dimethylpolysiloxane; silicon dioxide mixture; 40, sorbitan fatty acid esters, sorbitan trioleate, polyoxyethylene sorbitan fatty acid esters.

 [0014] The particle size of the dry syrup is not particularly limited, but is generally the particle size range of powders, fine granules, and granules according to the Japanese Pharmacopoeia Fourteenth Edition.

 [0015] The dry syrup of the present invention is produced by a usual method for producing powders, granules and fine granules. For example, there are a stirring granulation method, an extrusion granulation method, a fluidized bed granulation method, a tumbling granulation method, a crushing granulator, a spray granulation method, a crushing granulator, and the like.

 The agitation granulation method will be briefly described. A predetermined amount of the poorly water-soluble drug and saccharide are weighed, sieved with a sieve having an opening of 425 μm, and the powder that has passed through the sieve is placed in a stirring granulator and mixed. Next, a predetermined amount of a binder is added, and the mixture is granulated for a certain period of time. After that, it is dried with a fluidized bed granulator and sized using a basket with an opening of 1038 μΐη. If necessary, fines can be removed with a classifier using a sieve with an aperture of 154 μΐη. An appropriate additive is blended with the obtained granules and mixed to obtain a target dry syrup. Here, some or all of the additives may be sieved simultaneously with the first poorly water-soluble drug or carbohydrate.

 [0016] The extrusion granulation method can be performed in the same manner as the stirring granulation method, except that the drug substance, the additives, and the like are mixed and granulated by the stirring granulator, and then the extrusion granulator is used. As the extrusion granulator, for example, a DGL1 type dome gran (Fuji Padal Co., Ltd., hole diameter: 0.5 mm) and a cylindrical granulator (Yamada Iron Works Co., Ltd., hole diameter: 0.53 mm) can be used.

 Fluidized bed granulation can be performed in the same manner except that a fluidized bed granulator is used instead of the stirred granulator used in the above stirred granulation method. As a fluidized-bed granulator, for example, a WSG-5 type granulation dryer (manufactured by Dai-J11 Hara Seisakusho) can be used.

 (0017) Dispersion

In another embodiment, the present invention provides a hydroxypropylcellulose having a 2 (wZv)% aqueous solution viscosity of less than 3. And a dispersion in which the poorly water-soluble drug is uniformly dispersed in water. The dispersion of the present invention can be obtained by putting the dry syrup preparation of the present invention into an appropriate amount of water and stirring.

 (3) Method for improving dispersibility of poorly water-soluble drug in water

 According to another aspect of the present invention, a dry syrup is produced by combining a poorly water-soluble drug and hydroxypropylcellulose having a viscosity of a 2 (wZv)% aqueous solution at 20 ° C of less than 3.OmPa's. The present invention provides a method for preventing the formation of suspended matter on a dispersion when a dry syrup preparation of a poorly water-soluble drug is added to water and improving the defoaming property.

 Example

 Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto. In the following Examples, the power S of using ethenzamide and sulfamethoxazole as poorly water-soluble drugs, and their water solubility are all less than 100 ppm.

 A. Presence or absence of surfactant and defoamer

 1) Production of dry syrup preparation by stirring granulation method

 A dry syrup having the following composition (w / w)% was produced together with the comparative example preparation.

[table 1]

 Unit (w / w)%

 Polysorbate 80 .: Polyoxyethylene sorbitan fatty acid ester Based on Table 1 above, the amount is appropriately converted to the amount charged and weighed. The drug used was ethenzamide listed in the Japanese Pharmacopoeia of the 14th Edition.

In the case of Example 1, 20 g of ethenzamide and 1958 g of sucrose are weighed and sieved with a sieve having openings. The powder passed through the sieve and passed through the sieve was put into a stirring granulator (10-type high-speed mixer, manufactured by Fukae Patetech Co., Ltd./Agitator: 30 (kpm, chopper: 2500i "pm)) and mixed for 1 minute. 120 g of an aqueous solution of 10 (w / v)% HPC-C was poured and kneaded and granulated for 3 minutes, and then a fluidized bed granulator (WSG-5 granulator / dryer, manufactured by Okawara Seisakusho Co., Ltd., blast temperature Drying was carried out at 55 ° C), and the process was terminated when the product temperature reached 45 ° C. If necessary, a wire mesh having an opening of 154 zm was used, and the fine powder was removed with a classifier (TMC-50-2S vibrating sieve, manufactured by Tokuju Corp.). 1791 g) was mixed with 9 g of hydrous silicon dioxide calculated from Table 1, and mixed with a mixer (8L V-type mixer) to obtain a dry syrup.

 [0020] In Comparative Example 1, a predetermined amount of ethenzamide and sucrose were weighed, sieved with a sieve having an opening of 425 µm, and the powder passed through the sieve was produced in the same manner as in Example 1. For granulation, 120 g of purified water was used. Comparative Example 24 is produced in the same manner as in Example 1, except that polysorbate 80 and the silicone resin are used by dissolving or suspending them in purified water, or by adsorbing on water-containing silicon dioxide and powdering.

 2) Production of dry syrup preparation by extrusion granulation method

 Based on Table 1 above, weigh the sample by appropriately converting the charged amount.

 In the case of Example 1, 20 g of ethenzamide and 1911 g of sucrose were weighed, sieved with a sieve having an aperture of 425 μΐη, and the powder passed through the sieve was stirred with a stirring granulator (type 10 high-speed mixer, manufactured by Fukae Patetech Co., Ltd.). / Agitator: 30 (kpm, chopper: 2500i "pm) and mixed for 1 minute. Then, 120 g of 10 (w / v) aqueous solution of HPC-C was poured, and the mixture was granulated for 3 minutes. , Granulated by an extrusion granulator (cylindrical granulator, manufactured by Yamada Iron Works, 0.53 mm in diameter), and fluidized bed drier (WSG-5 type granulation drier, manufactured by Okawara Seisakusho Co., Ltd., blowing temperature 55 ° C) and dried when the product temperature reached 45 ° C.Then, using a basket with an opening of 1038 zm, the granules were sized with a granulator (P-3 type power mill). The fine powder was removed by a classifier (TMC-50-2S vibrating sieve, manufactured by Tokuju Kogyo Co., Ltd.) using a wire mesh with a mesh size of 154 μm. Was mixed with 9 g of hydrous silicon dioxide calculated from Table 1, and mixed with a mixer (8L V-type mixer) to obtain a dry syrup.

[0022] In the case of Comparative Example 1, a predetermined amount of ethenzamide and sucrose was weighed, and a sieve having a mesh size of 425 µm was used. The powder passed through the sieve was produced in the same manner as in Example 1, but 120 g of purified water was used for pouring the liquid during granulation. Comparative Examples 2 to 4 are produced in the same manner as in Example 1, except that polysorbate 80 and a silicone resin are dissolved or suspended in purified water, adsorbed on hydrated silicon dioxide, and used in powder form.

3) Production of dry syrup preparation by fluidized bed granulation method

 Based on Table 1 above, weigh the sample by appropriately converting the charged amount.

In the case of Example 1, 50 g of ethenzamide and 4895 g of white sugar were weighed, sieved with a sieve having an opening of 425 xm, and the powder passed through the sieve was subjected to a fluidized bed granulator (WSG-5 granulator / dryer, manufactured by Okawara Was mixed for 5 minutes. Thereafter, 1500 g of an aqueous solution of 2 (wZv)% HPC_C was sprayed (spray speed: 30 g / min, spray pressure: 0.15 MPa). ₀ After that, the process was finished when the product temperature reached 45 ° C. Thereafter, a basket having a mesh size of 1038 xm was used, and sized using a sizing machine (P-3 type powder mill). Thereafter, if necessary, a wire mesh having a mesh size of 154 xm was used, and the fine powder was removed with a classifier (TMC-50-2S vibrating sieve, manufactured by Tokuju Corp.). The obtained granules (about 4776 g) were mixed with 24 g of hydrous silicon dioxide calculated from Table 1, and mixed with a mixer (22L V-type mixer) to obtain dry syrup IJ.

[0024] For Comparative Example 1, the Etenzamido and white sugar were weighed predetermined amounts, sieved mesh opening with a sieve of 425 _beta m, but to produce a powder that passed through the sieve in the same manner as in Example 1, 1500g of purified water was used for liquid injection during granulation. Comparative Examples 2 to 4 are produced in the same manner as in Example 1, except that polysorbate 80 and a silicone resin are dissolved or suspended in purified water, adsorbed on hydrated silicon dioxide, and used in powder form.

 [0025] The preparations obtained in the above Examples and Test Examples were evaluated for the following five items: 1. sedimentation, 2. dispersibility, 3. redispersibility, 4. presence or absence of suspended matter, and 5. defoaming. evaluated.

 1.Evaluation method of sedimentation

 100 mL of water was put into a stoppered measuring cylinder, 5 g of dry syrup was poured at a stretch, and the time required to settle below the water surface was measured. Judged as 〇 if settled within 1 minute, and X if not settled.

 [0026] 2. Dispersibility evaluation method

100 mL of water was put into a stoppered measuring cylinder, and 5 g of a dry syrup was poured at once. That After that, close the lid quickly, hold the upper part of the stoppered graduated cylinder with one hand, hold the lower part on the other side, and with the lower part as a fulcrum, turn over 20 rounds (180 ° rotation) at a speed of about 2 seconds for one round trip. It was left still. Visually, it was judged as 〇 if it was entirely cloudy, and X if it was not cloudy.

[0027] 3. Evaluation method of redispersibility

 The stoppered measuring cylinder used for evaluation of dispersibility was left at room temperature for one day. After that, it was judged by the same evaluation method as the dispersibility in water.

[0028] 4. Presence or absence of suspended matter

 Immediately after evaluating the dispersibility, the lid of the stoppered measuring cylinder was removed and visually observed from above. The presence / absence of suspended matter was judged as X if there was no suspended matter within 1 minute, and if there was no suspended matter within 10 minutes.

[0029] 5. Evaluation method of defoaming property

 After evaluating the dispersibility, similarly to the evaluation of the presence or absence of suspended matter, the lid of the stoppered graduated cylinder was immediately taken and visually observed from above. The bubble was reduced within one minute, and the water surface was judged to be 〇, and the water surface was judged to be X if not. Here, `` improved defoaming property '' means that bubbles can be reduced within 1 minute and the water surface can be seen, but preferably within 50 seconds, more preferably within 40 seconds, and the water surface can be reduced. I just need to see.

[0030] Test example 1

 Evaluation of formulation (1)

 The uniform dispersibility of Comparative Examples 14 and 14 and Examples 1 and 2 was evaluated by the above evaluation method. The results obtained are shown in Table 2 below.

 [Table 2]

以上の結果から、界面活性剤および/または消泡剤を配合した場合、浮遊物が生 じたり、また消泡性を改善することができなかった。一方、 HPC— Cを用いれば、均一 分散性は良好であった。 B.懸濁化剤の選択

From the above results, when a surfactant and / or an antifoaming agent was added, suspended matter was not generated, and the defoaming property could not be improved. On the other hand, when HPC-C was used, the uniform dispersibility was good. B. Selection of suspending agent

 In the same manner as in Example 1, each preparation having the compounding ratio shown in Table 3 was produced.

[Table 3]

 Unit (w / w)%

試験例 2

Test example 2

Formulation evaluation (2)

 The uniform dispersibility of the preparations of Comparative Examples 1, 57 and Example 1 was evaluated by the evaluation method in Test Example 1. The results obtained are shown in Table 4 below.

[Table 4]

比較例 1は懸濁化剤を含まず、比較例 5— 7の製剤はいずれも HPC— Cと異なる懸 濁化剤を含む。これにより、 HPC— Cのみがドライシロップ剤における水中の均一分 散性の向上に必須であることが示された。

Comparative Example 1 did not contain a suspending agent, and all of the formulations of Comparative Examples 5-7 contained a suspending agent different from HPC-C. This indicates that only HPC-C is essential for improving the uniform dispersibility in water of the dry syrup.

Examination of the addition amount of C.hydroxypropylcellulose

 In the same manner as in Example 1, each preparation having the compounding ratio shown in Table 5 was produced.

[Table 5] Unit (w / w)%

試験例 3

Test example 3

Formulation evaluation (3)

 The uniform dispersibility of the preparations of Comparative Examples 8 and 9, and Examples 1 and 3 was evaluated by the evaluation method in Test Example 1. The results obtained are shown in Table 6 below.

[Table 6]

 From the above results, when HPC-C is 0.5 (wZw)% or more, a dry syrup preparation having good uniform dispersibility, particularly good defoaming property can be produced.

D. Examination of types of hydroxypropyl cellulose

 In the same manner as in Example 1, each preparation having the compounding ratio shown in Table 7 was produced. In addition, hydroxypyrucellulose has a viscosity of less than 3.OmPa's in a 2% (w / v)% aqueous solution at 20 ° C (B-type viscometer) when HPC_B [20 ° C is used. C 2 (w / v). /. The viscosity of the aqueous solution was 3.0-5.9 mPa's (B-type viscometer)] and the HPC-A [the viscosity of a 2 (wZv)% aqueous solution at 20 ° C was 6.0-10 OmPa's (B-type viscometer)] was used. .

[Table 7]

 Unit (w / w)%

 Component Comparative Example 10 Comparative Example 1 1 Example 1

 Ethenzamide 1.0 1.0 1.0 1.0

 White sugar 97. 9 97. 9 97. 9

 HPC-A 0.6--

HPC-B 0.6-

HPC-C-― 0.6

 Hydrous silicon dioxide 0.5-0.5 0.5

Total 100.0 100.0 100.0 [0036] Test Example 4

 Formulation evaluation (4)

 The uniform dispersibility of Comparative Examples 10 and 11 and Example 1 was evaluated by the evaluation method in Test Example 1. The dispersibility refers to the number of inversions of the stoppered graduated cylinder until the preparation is dispersed, and the defoaming property refers to the time until the foam disappears. The results obtained are shown in Table 8 below.

 Faction

 From the above results, uniform dispersion, especially dispersibility and defoaming property were improved by using HPC-C with a viscosity of 3 OmPa's in a 2 (w / v)% aqueous solution at 20 ° C. .

[0037] E. Changes to Other Drugs

 In the same manner as in Example 1, each preparation having the compounding ratio shown in Table 9 was produced. As a drug, use sulfamethoxazole listed in the 14th Revised Japanese Pharmacopoeia in place of ethenzamide.

 [Table 9]

 Unit (W / W W)%

試験例 5

Test example 5

 Formulation evaluation (5)

The uniform dispersibility of Comparative Examples 12, 13 and Example 4 was evaluated by the evaluation method in Test Example 1. The results obtained are shown in Table 10 below. [Table 10]

以上の結果から、薬物としてスルファメトキサゾールを含むドライシロップ剤であって も、 HPC-Cを 0. 5 (w/w) %以上配合したならば、均一分散性は良好であった。 産業上の利用可能性

From the above results, even in the case of a dry syrup containing sulfamethoxazole as a drug, uniform dispersibility was good if 0.5 (w / w)% or more of HPC-C was added. Industrial applicability

 The dry syrup preparation of the present invention is easy to take even for children who dislike the medicine and for the elderly who have difficulty swallowing, and is easy to package and weigh. Furthermore, it is convenient to carry.

Claims

The scope of the claims  [1] At least 0.5 (w / w)% of a poorly water-soluble drug and at least 0.5 (w / w)% of hydroxypropylcellulose whose viscosity of a 2 (w / v)% aqueous solution at 20 ° C is less than 3.OmPa's , Dry syrup QI IJ.  [2] The dry syrup according to claim 1, wherein the poorly water-soluble drug has a water solubility of less than 100 ppm. [3] The dry syrup according to claim 1 or 2, wherein the defoaming property is improved. [4] The dry syrup preparation according to any one of [13] to [13], further comprising sucrose. [5] The dry syrup according to any one of [14] to [14], which does not contain a surfactant and an antifoaming agent.  [6] A preparation in which the poorly water-soluble drug is suspended in water after the dry syrup preparation according to any one of claims 11 to 5 is charged into water and stirred. [7] In a dry syrup containing a poorly water-soluble drug, 0.5% (w / w) of hydroxypropyl cellulose having a viscosity of 2 (w / v)% aqueous solution at 20 ° C of less than 3.OmPa's is used. A method for improving the defoaming property of a drug suspension after the formulation is poured into water and stirred.  [8] 20. A dry syrup preparation of a poorly water-soluble drug, characterized in that it contains 0.5 (wZw)% or more of hydroxypropyl cellulose having a viscosity of a 2 (w / v)% aqueous solution of less than 3.OmPa's in C. Production method.