JPH02292229A - Composition for long-acting preparation and method for producing the same - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a composition for a long-lasting preparation of a poorly soluble basic salt or a salt thereof, which has been difficult to form into a long-lasting preparation due to its low solubility in the intestine, and a simple method for producing the same. Therefore, an object of the present invention is to provide a long-acting pharmaceutical composition comprising a crystalline poorly soluble basic drug or its salt, a higher fatty acid, an enteric polymer, and a surfactant, and a simple method for producing the same. It is in. [Prior Art] Slightly soluble basic drugs or salts thereof, which have extremely low solubility in the intestine, are not suitable as they are for use in long-acting preparations. Therefore, some documents are known to solve these problems. For example, the special public service in 1983
No. 48810 describes a long-lasting composition in which nicardipine, which is one of the most difficult basic drugs, is made amorphous by ball milling or vibration ball milling to improve intestinal absorption. Furthermore, JP-A-56-493
No. 14, No. 58-116414 and No. 63-174
No. 929 discloses f& in which a certain polymeric substance is added to a solution of nicardipine in an organic solvent, spray-drying in the presence of a carrier,
Depot formulations containing amorphous dicardibine characterized by adsorption or coating have been described. All of these are characterized in that they use nicardipine in an amorphous form. As described above, for nicardipine, which is one of the poorly soluble basic drugs, it is known that amorphous dicardibine is used in a long-acting preparation. [Problems to be Solved by the Invention] However, preparations containing amorphous drugs generally have problems with long-term stability of physical properties, complexity of production, and drug administration. Specifically, the production of amorphous dicardibine is extremely complicated, and there are problems such as changes in dissolution due to drug crystallization and drug stability. for example,
When amorphization is performed by ball milling, the collision between the balls and the crystals is the rate-determining step for amorphization, so it takes a considerable amount of time, and there is a risk that the remaining crystals will become seed crystals and cause crystallization. be. In addition, when making amorphous by the solvent removal method, a drying process that takes time is required to reduce the residual solvent in the product, and it is also necessary to consider environmental pollution caused by the removed solvent, which is complicated. I am not good at it. Furthermore, in order to maintain the amorphous state over a long period of time, it is common to add several times more polymers that are compatible with the drug, which also has the disadvantage of unnecessarily increasing the size of the drug. . Furthermore, various additives are added to these amorphous nicardipine preparations in order to provide appropriate drug release control properties, but many of these additives are polymers that are frequently used in the pharmaceutical formulation field. These contain water. It is well known to those skilled in the art that this moisture has a large effect on the chemical stability of amorphous compounds and the maintenance of their amorphous state. [Several Steps to Solve the Problems] As a result of intensive studies aimed at solving the drawbacks of the prior art, the present inventors found that a crystalline poorly soluble basic drug or its salt, a crystalline poorly soluble base higher fatty acids, 0.3 to 16 times the amount of enteric polymer, and 0.002 to 2 times the weight of the sex drug or its salt, respectively.
It has been shown that a composition for long-acting preparations of poorly soluble basic drugs that is stable and has excellent sustained release properties can be obtained very easily by combining twice as much surfactant, pulverizing, and then sizing. This discovery led to the completion of the present invention. Next, the present invention will be explained in detail. In the present invention, the crystalline poorly soluble basic drug is defined as a free base or an acid addition salt thereof having a solubility of 0.0. 1 to 300 μgoal and has a basic group that forms an acid addition salt, such as crystalline nicardipine, dipyridamole, diltiazem, diazepam, ketotifen, disobiramide,
Examples include chlorpheniramine and diphenhydramine. The acid that forms the acid addition salt is not particularly limited as long as it is a pharmaceutically acceptable acid, but for example,
Inorganic acids such as saccharic acid, hydrochloric acid and phosphoric acid; Sulfonic acids such as methanesulfonic acid and p-h luenesulfonic acid;
and organic acids such as citric acid, fumaric acid and maleic acid. In addition, although it is structurally an amphoteric substance, the dissociation constant of the acidic group is small and it virtually exhibits the physical properties of a base. The solubility in the second liquid specified in the law is 0.
．． The present invention can also be applied to drugs having a dosage of about 1 to 300 μgerml, for example, pyridonecarboxylic acid drugs such as tosufloxacin. The higher fatty acids used in the present invention have 12 carbon atoms.
All 22 higher fatty acids can be used.
Examples include straight-chain saturated fatty acids, straight-chain unsaturated fatty acids, oxyfatty acids, and branched fatty acids, and these may be used in combination of TL or 2F1 or more, if necessary. Specifically, straight chain saturated fatty acids include, for example, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, and behenic acid; straight chain unsaturated fatty acids include, for example, dodecenoic acid, myristoleic acid, and the like. , valmitoleic acid, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, whale oil acid and eicosatrienoic acid; examples of oxyfatty acids include:
Ricinoleic acid and dioxystearic acid; and branched fatty acids include, for example, methylpalmitic acid. Among these higher fatty acids, higher fatty acids having 12 to 18 carbon atoms that are solid at room temperature are preferred. Enteric polymers used in the present invention include, for example, methacrylic acid-methacrylic ester copolymers, methacrylic acid-acrylic ester copolymers, cellulose succinates, cellulose phthalates, and carboxymethyl celluloses, and these are also necessary. Depending on the situation, one type or a combination of two or more types may be used. Specifically, the methacrylic acid/methacrylic ester copolymer includes methacrylic acid/methyl methacrylate copolymer (trade name: Eudragit S-100); and the methacrylic acid/acrylic ester copolymer includes, for example, methacrylate. Acid-methyl acrylate copolymer (trade name: Eudragit L-100)
and methacrylic acid-ethyl acrylate copolymer (trade name: Eudragit L-100-55) (the above,
Examples of cellulose succinates include hydroxyglobil methylcellulose acetate succinate (trade name:
AQOA? ), and the like; As cellulose phthalates, for example, hydroxybutyl methylcellulose phthalate (trade name i HP-55 and HP-50)
(Shin-Etsu Chemical i!) and the like; and carboxymethyl celluloses include, for example, carboxymethyl ethyl cellulose [trade name: CMEC (manufactured by Freund Sangyo Co., Ltd.)]. The surfactants used in the present invention include anionic,
Examples include nonionic, cationic and amphoteric surfactants, and these may be used alone or in combination of two or more, if necessary. Specifically, examples of anionic surfactants include sodium lauryl sulfate (trade name: NIKKOL SLS) and sodium polyoxyethylene (IO) lauryl ether phosphate (
Product name: NIKKOLDLP-10) (manufactured by Nikko Chemicals Co., Ltd.); Nonionic surfactants include, for example, polyoxyethylene (40) monostearate (product name: NIKκOL MYS-4).
0), polyoxyethylene (9) lauryl ether (product name: NIKKOL BL-9EX), polyoxyethylene (20) sorbitan monooleate (product name:
NIKκOL TO-10) (manufactured by Nikko Chemicals) and polyoxyethylene (105) polyoxypropylene (5) glycol [trade name: PEP
Examples of cationic surfactants include stearyltrimethylammonium chloride (trade name: NIKKOL CA-2).
465 (manufactured by Nikko Chemicals); and amphoteric surfactants such as lecithin and lauryldimethylaminobetaine [trade name: NIKKOLA
M-301 (manufactured by Nikko Chemicals)]. Among these surfactants, nonionic surfactants are preferred. Next, a method for manufacturing the long-acting pharmaceutical composition of the present invention will be explained. In an embodiment of the typical manufacturing method of the present invention, the weight ratio of the pulverized crystalline poorly soluble basic drug or its salt and the crystalline poorly soluble basic drug or its salt is 0.0.
After kneading 3 to 16 times higher fatty acids, 0.3 to 16 times more enteric polymer, and 0.002 to 2 times more surfactant,
A long-lasting pharmaceutical composition is obtained by pulverization and then granulation as known in the art. At this time, it is preferable! ¥! The carbon number is 12 to 18, which is solid at room temperature.
Using a higher fatty acid, a crystalline poorly soluble basic drug or its salt, the higher fatty acid, an enteric polymer, and a surfactant are heated to a temperature near the melting point of the higher fatty acid, and 7 g of the drug is melted. An example is an embodiment in which the kneaded mixture is cooled and solidified, and then pulverized and sized to produce the mixture. In addition, a moat in which the entire composition is granulated in advance to a desired particle size,
It is also possible to soften and melt higher fatty acids by heating under transfer conditions to obtain a sustained-release preparation. If the higher fatty acid is liquid at room temperature, it can be solidified by adding an oil-absorbing excipient such as light silicic anhydride to produce a long-lasting formulation composition. It should be noted that the purpose of pulverizing crystalline poorly soluble basic drugs or their salts is to prevent large crystal particles from being mixed in. There is no need for special pulverization, and the normal particle size achieved with a hammer-type pulverizer can be obtained. It's fine if you can. In addition, for the pulverization of the cooled f&, a pulverizer, a tornado mill, a flash mill, or the like, which is commonly used for the purpose of sizing, can be used. Next, the blending amount will be explained. The blending ratio described below represents the weight ratio of the blend to the entire composition. The amount of the crystalline poorly soluble basic drug or its salt can be arbitrarily selected depending on the drug's efficacy and solubility, and is usually 5 to 50% by weight of the entire preparation, preferably It is 10-30%. The content of higher B8 fatty acids and enteric polymers is 0.3 to 16 times, preferably 1 to 5 times, each in a 2 m ratio of the crystalline poorly soluble basic drug or its salt. , more preferably 1 to 4 times the amount of higher fatty acids and 1.3 to 5 times the amount of enteric polymers. If higher fatty acids are used in a larger amount than enteric-coated polymers, deterioration of dissolution in the second drop and adhesion of particles of the sized product may be observed as described in the Japanese Pharmacopoeia 11th Revised Disintegration Test Method. Therefore, it is better to use less higher fatty acids for -a than for enteric-coated molecules. Furthermore, if the drug is unstable in moisture, the enteric polymer may be dried before use. Note that combining an anionic surfactant with an acid addition salt drug may cause problems in formulation, such as a decrease in surfactant effect, so the combination with the drug should be selected as appropriate. The amount of the surfactant to be blended is 0.002 to 2 times, preferably 0.016 to 0.5 times, the weight ratio of the crystalline poorly soluble basic drug or its salt. The composition obtained in this way can be used as is or, if necessary, may be added with excipients such as lactose, lactose or One or more of plasticizers such as triethyl acid, antistatic agents such as magnesium stearate, and flavoring agents such as citric acid and fumaric acid may be added by conventional methods. The heating temperature is not particularly limited as long as the higher fatty acids can be softened or melted and a linear state can be achieved, but it is usually 40-40°C.
90°C is preferred. As a kneading device, a conventional machine such as a kneader or a Henschel mixer can be used. The thus obtained composition for long-acting preparations can be prepared in any known dosage form by a conventional method, but preferred dosage forms include granules, fine granules, or hard granules. Examples include capsules obtained by filling gelatin capsules. Next, tests regarding elution of poorly soluble basic drugs from the long-acting composition of the present invention, stability and blood concentration of the long-acting composition of the present invention will be described. (1) Dissolution test The Badl method (1) described in the Japanese Pharmacopoeia Dissolution Test Method
00 rpm), dissolution tests were conducted on the compositions for long-acting preparations prepared in Examples 1 to 13. 'Specifically, a long-acting formulation composition containing dicardipine hydrochloride IOB was added to 800 ml of the second liquid described in the Japanese Pharmacopoeia disintegration test method.
Add it while keeping it at 37±0.5℃, 10 minutes after addition, 3
Sampling was performed after 0 minutes of oat, 1 hour, 2 hours, and 3 hours, respectively. The sample solution was filtered through a Menpuran filter (0.3 .mu.l), and 1 liter of the filtrate was collected, and the content of dicardibine hydrochloride was determined by high performance liquid chromatography (HPLC) to determine the elution rate. The results are shown in Figures 1-3. (2) Stability test The composition for long-acting preparation of Example 1 was subjected to a stability test under the conditions shown in Table 1. Table-1 1-month test results (survival rate of nicardipine) (3) Beagle dog oral administration experiment Using 3 large beagles (a, body weight 9-10 κg) per group,
Capsules filled with the test composition for long-acting preparations were orally administered after an overnight fast. At 1, 2, 4, 6, and 8 hours after administration, blood was collected from the forelimb vein, and the content of dicardibine hydrochloride was determined by high performance liquid chromatography (H PLC) to determine the serum concentration of nicardipine. . The results are shown in Figure 4. In addition, the composition for long-acting preparation of Example 1 contained 20QJ/mouse as nicardipine hydrochloride, and Examples 2.5 and 7 contained the following:
Dicardipine hydrochloride was administered at 100 mg/mouse. From these results, the composition of the present invention has excellent dissolution properties in artificial intestinal fluid, is extremely stable, maintains a stable blood concentration of drug over a long period of time, and can be used as a long-acting composition. It is clear that it is superior.

【Example】

Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to these. In the examples, trade names are used, but their common names are as follows. Enteric polymers; HP-55: Hydroxybuvir methylcellulose fucrate (manufactured by Shin-Etsu Chemical Co., Ltd.) AQOAT: Hydroxybuvir methylcellulose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd.) CMECn Hydroxybuvir methylcellulose fucrate (manufactured by Freund Sangyo Co., Ltd.) Eudragit L-+00: Methacrylic acid-methyl acrylate cobolimer (manufactured by Rohm & Pharma) Surfactant; NIKKOL MYS-40: Polyoxyethylene (40) monostearate (manufactured by Nikko Chemicals) NIKKOL To-10: Polyoxyethylene (
2b) Sorbitan monooleate (manufactured by Nikko Chemicals Co., Ltd.) NIKKOL 8L-9EX: Polyoxyethylene (9) lauryl ether (manufactured by Nikko Chemicals Co., Ltd.) Example 1. 4 g of dicardipine hydrochloride sieved through an 83 mesh sieve
1 Stearic acid 7g, NIKKOL MYS-40
0.5 g and 8.5 g of HP-55 are mixed uniformly. This mixture is then heated to about 80° C. and kneaded while the stearic acid is melted. After cooling and solidifying, it is crushed and passed through a 30 mesh sieve.
A long-lasting pharmaceutical composition with a particle size that can be retained on a 3-mesh sieve is obtained. Example 2. As the enteric polymer, instead of 8.5 g of HP-55 in Example 1, 18.5 g of HP-55 was used as the enteric polymer.
Using 5 g, the same procedure as in Example 1 is carried out to obtain a composition for long-acting preparation. Example 3. Using 7 g of lauric acid in place of 7 g of stearin M in Example 2 as the higher fatty acid, heating to about 50°C and operating in the same manner as in Example 2, a composition for a sustained-release preparation was obtained. Example 4. Using 7 g of palmitic acid in place of 7 g of stearic acid in Example 1 as a higher fatty acid, heating to about 70°C,
The same procedure as in Example 1 is carried out to obtain a composition for sustained-release preparation. Example 5. The same procedure as in Example 1 is carried out using 8.5 g of AQOA7 instead of 8.5 g of HP-55 in Example 1 as the enteric polymer to obtain a composition for a sustained-release preparation. Example 6. The same procedure as in Example 1 is performed except that 8.5 g of CMEC is used in place of 8.5 g of HP-55 in Example 1 as the enteric polymer, and a composition for a sustained-release preparation is obtained. Example 7. NIKKOL MYS-4 of Example 5 as a surfactant
00.5g instead of NIKKOL TO-10 0.
Using 5 g, the same procedure as in Example 5 was carried out to prepare a composition for long-acting preparation. Example 8. NIKKOL 14Ys- of Example 5 as a surfactant
400.5g of water') LNIKKOL BL-9E
X G, 5g wo r. 11 Operate in the same manner as in Example 5,
A composition for long-acting preparation is obtained. Examples 9-13. As higher fatty acids, instead of 7 g of stearic acid in Example 2, high-all fatty acids shown in Table 5 were added, and the following products were prepared:
Add the enteric polymer and surfactant of 5, 'J Example 2
The compositions for long-acting preparations of Examples 9 to 13 shown in Table 5 were prepared in the same manner as above. Get each. [Effects of the Invention] Since the composition for long-acting preparations of the present invention is mostly composed of higher fatty acids that are poorly soluble in water, water and organic solvents are not required during production, so there is no problem with the stability of the drug. Also,
Since it does not require complicated operations such as coating, it is easy to obtain homogeneous results with high reproducibility. Furthermore, according to the production method of the present invention, there is no need to transform the poorly soluble basic drug into an amorphous form. 2 shows the results of a dissolution test for a composition for sexual preparation. FIG. 4 shows the change in serum concentration of nicardipine when the compositions for long-acting preparations of diludivine hydrochloride obtained in Examples 1, 2, 5, and 7 were administered to beagle dogs. (hereinafter referred to as Kinpaku) Figure 1 Results of dissolution test of the composition for depot preparation of dicardibine hydrochloride ●: Composition of Example 1 Todoroki: Composition of Example 3 0: Composition of Example 2 κ: Example 4 Dissolution rate (χ) of the composition Figure 3 Dissolution test results of long-acting preparations of dicardibine hydrochloride ヮ: Composition 1 of Example 9 Composition 12 of Example 12 Composition 10: Composition of Example 10 Dissolution: Example 13 To the composition of Example 1: Dissolution time (χ) (time) of the composition of Example 1 Composition 0: Composition of Example 6 -: Composition of Example 8 Elution vehicle (χ) 100 mg/mouse administered) Serum concentration (time)

Claims (12)

[Claims] (1) a crystalline poorly soluble basic drug or its salt, a higher fatty acid in an amount of 0.3 to 16 times the weight ratio of the crystalline poorly soluble basic drug or its salt, respectively;
A long-acting formulation composition comprising 0.3 to 16 times the enteric polymer and 0.002 to 2 times the surfactant. (2) The long-acting pharmaceutical composition according to claim (1), wherein the higher fatty acid is a fatty acid having 12 to 18 carbon atoms. (3) The enteric polymer is one or more enteric polymers selected from methacrylic acid-methacrylic ester copolymers, methacrylic acid-acrylic ester copolymers, cellulose succinates, cellulose phthalates, and carboxymethyl celluloses. The composition for long-acting preparation according to claim (1) or (2). (4) The composition for sustained-release preparation according to any one of claims (1) to (3), wherein the surfactant is a nonionic surfactant. (5) The composition for long-acting preparation according to any one of claims (1) to (4), wherein the crystalline poorly soluble basic drug or its salt is crystalline nicardipine or its salt. (6) The composition for a long-acting preparation according to any one of claims (1) to (5), wherein the dosage form of the composition for a long-acting preparation is a granule, a fine granule, or a capsule. (7) crystalline poorly soluble basic drug or its salt, higher fatty acid in a weight ratio of 0.3 to 16 times that of the crystalline poorly soluble basic drug or its salt, respectively;
1. A method for producing a long-acting pharmaceutical composition, which comprises kneading 0.3 to 16 times the amount of enteric polymer and 0.002 to 2 times the amount of surfactant, followed by pulverization and granulation. (8) The method for producing a long-acting pharmaceutical composition according to claim (7), wherein the higher fatty acid is a fatty acid having 12 to 18 carbon atoms. (9) The enteric polymer is one or more enteric polymers selected from methacrylic acid-methacrylic ester copolymers, methacrylic acid-acrylic ester copolymers, cellulose succinates, cellulose phthalates, and carboxymethyl celluloses. A method for producing a long-acting pharmaceutical composition according to claim (7) or (8). (10) The method for producing a composition for long-acting preparation according to any one of claims (7) to (9), wherein the surfactant is a nonionic surfactant. (11) The composition for long-acting preparation according to any one of claims (7) to (10), wherein the crystalline poorly soluble basic drug or its salt is crystalline nicardipine or its salt. Manufacturing method. (12) The composition for a long-acting preparation according to any one of claims (7) to (11), wherein the dosage form of the composition for a long-acting preparation is a granule, a fine granule, or a capsule. Manufacturing method.