JPS61249914A - Production of slightly soluble drug preparation - Google Patents

Abstract

PURPOSE:To obtain the titled preparation having increased dissolution rate, keeping a supersaturated state, by dissolving a slightly soluble drug in an organic solvent capable of dissolving both the slightly soluble drug and a high polymer compound, adding powder or granule insoluble in the solvent, kneading them and removing the solvent. CONSTITUTION:A slightly soluble drug (e.g., chlormadinone acetate) and a high polymer compound (e.g., hydroxypropyl cellulose) are used in a ratio of 1:1, dissolved in an organic solvent (e.g., dichloromethane) capable of dissolving both the substances, at 0-30 deg.C, the solution is kneaded with 10-70W/V% powder or granule (e.g., magnesium aluminate metasilicate) insoluble in the solvent, the solvent is removed by drying under reduced pressure, heat drying, etc., to give the titled preparation. In the preparation, the slightly soluble drug is easily dissolved in digestive organs when the preparation is orally administered and the preparation sustains increase in elution ratio and/or durability of supersaturated state of elution.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a poorly soluble drug formulation that increases the dissolution rate of the poorly soluble drug and/or maintains a sustained state of supersaturation.

After oral administration, pharmaceuticals that are poorly soluble in water have a slow dissolution rate in the gastrointestinal tract and poor absorption, resulting in extremely low bioavailability and failure to achieve prompt drug efficacy.

In order to improve these drawbacks, for example, a poorly soluble substance is dissolved in an aqueous solution of cyclodextrin to produce a clathrate compound in which the drug is inserted into the hollow part of the cyclodextrin (Japanese Patent Application Laid-Open No. 57-4914). A method of improving solubility by dissolving one of polyvinylpyrrolid/, hydroxypropyl cellulose, hydroxypropyl methylcellulose and cinnarizine, which is a kind of poorly soluble drug, in Iku Ia solvent and co-precipitating it 58-16458
2 Publication), and furthermore, dissolve stearyl glycoside monopalmitic acid ester in *Il solvent and add 0.5% as necessary.
Various studies have been conducted, including a method of adding more than twice as much organic or inorganic granular material (Japanese Patent Publication No. 55-23246).

However, these methods involve complicated processes for producing poorly soluble drug preparations, the resulting preparations have insufficient dissolution rate and amount in water, and the drug does not dissolve easily during oral administration. Although it is absorbed and its blood concentration quickly reaches a high level, it is also rapidly metabolized and excreted, and its blood concentration rapidly decreases and there is no sustained effect.

In the present invention, an intractable disease drug and a polymer compound are dissolved in an organic solvent in which both substances are soluble, and then powder and granules insoluble in the organic solvent are added to the solution and kneaded, and then the solvent is removed. The object of the present invention is to provide a method for producing a preparation in which a poorly soluble drug is easily dissolved in the gastrointestinal tract when administered orally, and has an increased dissolution rate and/or a supersaturated tooth profile of dissolution.

The poorly water-soluble drugs used in the present invention include steroids such as chlormadinone acetate, estrone, progesterone, methyltestosterone, and hydrocortiscin, mefenamic acid, flufenamic acid, indomethane/,
Examples include anti-inflammatory agents such as anotranilic acid and methyl salicylate, and fat-soluble vitamins such as vitamin A and vitamin E.

In addition, examples of polymer compounds include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, polyethylene glycol, polyvinylpyrrolidone, glycerides, span, etc. It is also possible to use one type or a combination of two or more types.

In the present invention, first, a poorly soluble drug and a polymer compound are dissolved in an organic solvent in which both are soluble. As the ikuvA solvent used here, any \i'a solvent may be used as long as it dissolves the m-soluble drug and the polymer compound and does not dissolve the powder or granules added to the solution. Examples of organic solvents that can be used include dichloromethane, chloroform, methylene chloride, methanol, ethanol, impropatol, acetone, methyl ethyl ketone, ethylene glycol monoethyl ether, etc., and it is possible to use one type or a mixture of two or more of these. can.

Although the ratio of the poorly soluble drug to the polymer compound depends on the type of m-soluble drug, it can be used in a ratio of about 1:0.1 to 1:10, and preferably in a ratio of about 1:1. The concentration of the poorly soluble drug and polymer compound in the organic solvent is not particularly limited, but the amount of the organic solvent used must be at least sufficient for the solution to warm the entire powder or granule when the powder or granule is added and kneaded. Good to have. As the organic #i used at this time, it is particularly preferable to use a solvent in which there is not much difference in the solubility of both the poorly soluble drug and the polymer compound. Further, the temperature for dissolving can be about 0 to 30°C, and it is particularly preferable to melt at room temperature.

Next, the powder and granules are added to the organic solvent in which the poorly soluble drug and polymer compound obtained as described above are dissolved and kneaded.

The powder used in the present invention includes magnesium aluminate metasilicate, aluminum silicate, silicic anhydride,
Examples include aluminum hydroxide and tricalcium phosphate.

The proportion of the powder in the organic solvent is not particularly limited, but it is used at about lθ to 70 W/V%. Further, the particle size of the powder or granules used can be appropriately selected depending on the type of poorly soluble drug used, and particles having a size of about 0.0 I to 200 microns can be used.

A commonly used method is used to disperse and knead the powder or granules in an organic solvent, such as adding the powder or granules to an organic solvent in which poorly soluble drugs and polymeric compounds have been dissolved, and then kneading using an ordinary kneader. Although the rubbing is sufficient, methods such as centrifugal granulation and spray granulation may be used if necessary.

Next, by removing the organic solvent in which the obtained poorly soluble drug, polymer compound, and powder/granular material are dissolved and dispersed, the desired product can be obtained in a solid state, which can be further subjected to a drying operation. .

To remove and dry the organic solvent, methods commonly used in pharmaceutical preparations can be used, such as vacuum drying, heat drying, spray drying, and the like.

The organic solvent is distilled off, and the resulting solid is crushed with a hammer mill or the like to form a powder, or after removing a certain amount of the organic solvent, it is passed through a sieve of a certain size and made into granules.
It may also be subjected to a drying process. The manufactured powders or granules can be taken as they are, or they can be filled into capsules to form capsules, and if necessary, appropriate excipients may be added to form granules or tablets.

Examples will be described below.

In addition, the elution test was conducted according to the following method.

After using JPI solution as the eluent and following the elution test method (paddle rotation speed 100 rpm) according to the Revised Pharmacopoeia,
4ml of test liquid! Pour 4ml of pork in advance! Collected in a test tube containing
After centrifuging for 5 minutes, the absorbance of the butanol layer was measured using a wavelength of 320 m5 in Example 1 and 284 nt* in Example 2, and the elution rate was calculated from the amount corresponding to the standard curve of each test sample prepared in advance. Calculated.

Example 1 0.3 g of indomethacin and 0.3 g of hydroxypropyl cellulose were dissolved in 4.5 volumes of dichloromethane. Magnesium metasilicate aluminate 1 is added to the solution under stirring.
．． After adding 2 g and kneading, the mixture was dried under reduced pressure using a rotary evaporator in a 60°C hot bath. After drying, crush in a mortar and sieve through a 6o mesh sieve to obtain a target material of 0.5
7g was obtained.

Comparative Example 1-a The same operation as in Example 1 was performed except that 0.3 g of i/domethacin was dissolved in dichloromethano No. 7 and No. 5 saliva.

Comparative Example 1-b 0.3 g of domethacin and 0.3 g of hydroxypropyl cellulose were dissolved in 4.5 g of dichloromethane, and the mixture was heated to 80°C.
It was dried under reduced pressure in a hot bath using a rotary evaporator.

After drying, the mixture was crushed in a mortar to obtain granules that were passed through a 60-mesh sieve.

The elution test results of Example 1, Comparative Example 1-a, and Comparative Example 1-b are shown in FIG.

Example 2 80 g of chlormadinone acetate and GOg of hydroxypropyl cellulose were dissolved in dichloromethane 900 No. 1i.

Add 240 g of magnesium aluminate metasilicate to the solution.
was added and kneaded, followed by drying with warm air at 40°C. After drying, the mixture was forcibly sieved using a 60 mesh sieve to obtain granules.

Comparative Example 2-a 60 g of chlormadinone acetate was added to dichloromethane 900 No. 1
The same operation as in Example 2 was performed except that the solution was dissolved in .

Comparative Examples 2-b Comparative Example 1 except that 3 g of chlormadinone acetate and 3 g of hydroxypropyl cellulose were dissolved in 45 g of dichloromethane.
-The same operation as in b was performed.

The elution test results of Example 2, Comparative Example 2-a, and Comparative Example 2-b are shown in FIG.

Example 3 50 g of ethinyl estradiol and 50 g of hydroxypropylcellulose were mixed with dichloromethane:ethanol (4:
1) Dissolve the mixed liquid 850 first. After adding 200 g of tricalcium phosphate to the solution and kneading, drying was performed at 40°C. After drying, it was sieved using a 60 mesh sieve to obtain granules.

[Brief explanation of drawings]

Figure 1 shows the dissolution test results of the formulations obtained in Example 1 and Comparative Examples 1-a and 1-b, and Figure 2 shows the dissolution test results of the formulations obtained in Example 2 and Comparative Examples 2-a and 2-b. Shows the dissolution test results of the formulation. In the figure, the vertical line represents the elution rate (%), and the horizontal axis represents time (minutes). Applicant Teikoku Zoki Seiyaku Co., Ltd. Figure 2 Time (minutes) Procedure Amendment April 8, 1986 Michibe Uga, Commissioner of the Patent Office 1, Indication of Case Patent Application No. 88800 1985 2, Title of the invention: Process for producing poorly soluble drug preparations 3; Relationship with the case of the person making the amendment; Patent applicant address: 2-5-1 Akasaka, Minato-ku, Tokyo; 6. Contents of amendment (1) Lines m5 to 17 of page 1 of the specification (Claims) are corrected as shown in the attached sheet. (2) Add "and solubility" next to "dissolution rate" in the $2 line from the bottom. (3) In the third line of page 2, the phrase "dissolution rate is slow" is corrected to "poor solubility." (4) In lines 12 and 13 of page 3 of the same, the phrase "has a sustained state of supersaturation" is corrected to "J that maintains a state of supersaturation and is stable over time." (5) No. 4 of the same. On the 8th line of the page, add the words "Glycerides" and the next phrase. r Dimethylaminoethyl methacrylate/methyl methacrylate copolymer, methacrylic acid/methyl methacrylate copolymer” (6) Same page m5, lines 4-5: [Can be used,
In particular, it is preferable to use the ratio of about 1=1. ” should be corrected to “can be used.” (7) On page 6, line 9 of the same page, the text ``kneading it'' should be corrected to ``r kneading it''. (8) On page 8, line 5, it says rO, 57gJ.
l, corrected as 57gJ.
Above (Attachment) Claims rl II A soluble drug and a polymer compound are dissolved in an organic solvent in which both substances are soluble, and then powder and granules insoluble in the organic solvent are added to the solution and kneaded, and then, A method for producing a poorly soluble drug formulation, which comprises removing a solvent. 2. The method for producing a poorly soluble drug preparation according to claim 1, wherein the It-soluble drug is a steroid.

Claims (1)

[Claims] 1. A poorly soluble drug and a polymer compound are dissolved in an organic solvent in which both substances are soluble, and then powder and granules insoluble in the organic solvent are added to the solution and kneaded, and then the solvent is removed. A method for producing a poorly soluble drug preparation, which is characterized by removing the drug. 2. Claim 1 in which the poorly soluble drug is a steroid
2. Method for producing poorly soluble drug formulations as described in Section 1. 3. The method for producing a poorly soluble drug preparation according to claim 2, wherein the steroid is chlormadinone acetate. 4. The method for producing a poorly soluble drug preparation according to claim 1, wherein the poorly soluble drug and the polymer compound are used in a ratio of 1:1.