JPH08325146A - Medicine composition - Google Patents

Abstract

PURPOSE: To obtain a compacted oral administration preparation containing a medicinal substance in a high content, easy in tableting, and excellent in disintegrating, eluting and absorbing properties. CONSTITUTION: 1-80wt.% of a medicinally active ingredient (e.g. thromboxane A2 -antagonizing agent) ground into fine particles having particle sizes of <=30μm by a jet grinding method is mixed with a surfactant (e.g. sodium laurylsulfate) in an amount of 1-2wt.% based on that of the medicinally active ingredient or an organic acid salt (e.g. trisodium citrate) in an amount of 0.5-4wt.% based on the medicinally active ingredient, and subsequently formed into nuclear granules. The granules are mixed with a base agent such as starch partially converted into alpha-starch, and subsequently tableted to obtain the objective medicinal composition. The starch partially converted into the alpha-starch is compounded in an amount of 1-40wt.% based on the medicinally active ingredient. The thromboxane A2 -antagonizing agent is e.g. 11-[2-(5,6-dimethyl-1- benzoimidazolyl)ethylidene]-6,1-dihydrodibenzo[b, e]oxepine-2-carboxylic acid or its salt.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preparation for oral administration which has improved disintegration property, dissolution property and absorbability.

[0002]

2. Description of the Related Art It is one of the pharmacological issues to efficiently absorb a drug active ingredient in a solid preparation, particularly a commonly used tablet, from the digestive tract to enhance its bioavailability. It is known that a preparation containing a large amount of a drug active ingredient in one tablet has a long disintegration time and a low dissolution rate, resulting in a decrease in bioavailability. The tablet diameter has been increased in order to prevent such a decrease in bioavailability, but there is a problem that it is difficult to take.

As a method for pharmaceutically preventing a decrease in bioavailability, a drug active ingredient is 1. 1. A method in which a soft capsule is prepared by dissolving in an organic solvent and filling a gelatin capsule. 2. A method in which a polymer is dissolved in a solvent and quickly dried to form a solid dispersion, or a polymer is melted to form a solid dispersion. 3. A method of increasing the surface area by dissolving it in an organic solvent and then adsorbing it in the form of fine particles on a porous substance. 4. A method of mixing and pulverizing with a polymer additive to make it amorphous. 5. A method of pulverizing a drug active ingredient alone or together with an additive to form fine particles; Examples of the method include mixing a surfactant with a formulation base, but methods 1 to 4 have problems such as difficulty in increasing the content.

In the method of microparticulation No. 5, a preparation in which only a drug active ingredient is microparticulated (JP-A-5-97670) or a method of mixing and pulverizing with a sugar or sugar alcohol to form ultrafine particles (JP-A-3-66613). No. publication) is known. Further, a method is known in which the release of the drug from the preparation is promoted by mixing the surfactant of 6 with the preparation base [Drack Development and Industrial Pharmacy, Vol. 16, No. 10, 17].
P. 17, 1990; ibid., 12, p. 6, 851, 1
986].

[0005]

The smaller the diameter of drug fine particles, the higher the bioavailability.
The drug active ingredient alone can only be pulverized to a diameter of about several μm, and it is impossible to obtain ultrafine particles larger than that. Submicron pulverization is possible with mixed pulverization with sugar or sugar alcohol, but sugar or sugar alcohol is required to be about 5 to 10 times that of the bulk drug, and a small-sized preparation with a high content of drug active ingredient is obtained. Is difficult. Further, the method of mixing a surfactant with the formulation base is not preferable as a formulation method because the release of the drug from the formulation is promoted but sticking occurs during tableting.

An object of the present invention is to provide a miniaturized tablet which is easy to tablet and has excellent dissolution properties and absorbability into the living body.

[0007]

The present invention relates to a pharmaceutical composition characterized by containing a micronized drug active ingredient and a core consisting of a surfactant or an organic acid salt and a partially pregelatinized starch. In the present invention, granules obtained by granulating finely divided drug active ingredients are sprayed with a surfactant or an organic acid salt to form core granules, which are then mixed with a base such as partially pregelatinized starch. Since it is tableted by means of a tablet, a pharmaceutical composition having excellent dissolution properties without causing a tableting problem is provided.

In the present invention, any drug active ingredient may be used as long as it can be used as a tablet, but it is preferable to apply it to a drug active ingredient having a large content in the tablet. For example, valproic acid or its salt, macrolide antibiotics such as acetylspiramycin, sulfamide oral hypoglycemic agents such as glybsol, nonsteroidal anti-inflammatory agents such as ketophenylbutazone, sulfa drugs such as sulfamethopyrazine, and lepodopa. , Medroxyprogesterone acetate, 11- [2- (5,6-dimethyl-1-benzimidazolyl) ethylidene] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid or a salt thereof (Patent Document 1) 2-91041) and other thromboxane A ₂ antagonists. Examples of salts of these compounds include metal salts such as sodium salts and potassium salts. The content of the drug active ingredient in one tablet of the present pharmaceutical composition is usually 1 to 80% by weight.
Although it may be about, it is preferably 30 to 80% by weight, more preferably 30 to 60% by weight.

Any method may be used for micronizing the drug active ingredient, but the drug active ingredient is micronized by a conventional high-speed stirring crusher or impact crusher by a jet crushing method, a hammer mill method or the like. do it. Particle diameter is 30μ
m or less, preferably 10 μm or less.

The surfactant used in the present invention is
Although any surfactant that is acceptable in an oral preparation may be used, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, sucrose fatty acid esters, sodium lauryl sulfate and the like can be mentioned, preferably sodium lauryl sulfate. The addition amount of the surfactant used in the present invention is preferably about 1 to 2% by weight with respect to the drug active ingredient. If the addition amount is less than 1% by weight, no effect is obtained, and if the addition amount exceeds 2% by weight, the hardness is lowered, causing abrasion and chipping.

The organic acid salt used in the present invention may be any organic acid salt that is acceptable for oral preparations, but is preferably trisodium citrate, disodium succinate, sodium acetate, potassium acetate, sodium glutamate and the like. And trisodium citrate is preferably used. The amount of the organic acid salt used in the present invention is 0.5 to 4% by weight, preferably 2 to 4% by weight, based on the drug active ingredient. If the amount added is less than 0.5% by weight, no effect is obtained, and if the amount added exceeds 4% by weight, tableting problems such as sticking may occur.

The partially pregelatinized starch used in the present invention may be any of those obtained by heating corn starch with water and pregelatinized without destroying the starch granules and rapidly drying it. P
Examples include CS (manufactured by Asahi Kasei Corporation), Starch 1500 (manufactured by Nippon Colorcon Co., Ltd.) and the like. The partially pregelatinized starch is usually added in an amount of about 1 to 40% by weight, preferably 20 to 30% by weight, based on the drug active ingredient.

The pharmaceutical composition of the present invention is usually a tablet.

The method for producing the pharmaceutical composition of the present invention will be described below. After the drug active ingredient is made into fine particles by a jet crushing method, a hammer mill method, etc., a binder is added to prepare a nuclear granule by a general granulation method such as a stirring granulation method or a fluidized bed granulation method, and then an interface granule. 2.5-5.0W / V activator
% Dissolved aqueous solution or 1.25 to 10.0 W / V%
An aqueous solution containing the organic acid salt of 1. is sprayed onto the granules by a fluidized bed granulator, and then mixed with partially pregelatinized starch and additives commonly used in the formulation, and compressed into tablets (Development of Pharmaceuticals, Volume 11). The pharmaceutical composition of the present invention can be obtained by unit operation and machine of the preparation, published by Hirokawa Shoten in 1989.

Examples of the binder include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, pullulan and the like. The amount of the binder added is 1 to 3% by weight, more preferably 2 to 3% by weight, based on the active drug ingredient.

[0016] Additives that are commonly used in the formulation should be those that do not impair the stability of the main drug among the commonly used excipients, disintegrants, lubricants, etc. and do not affect the tablet properties. For example, the excipients include lactose, potato starch, corn starch, crystalline cellulose, sucrose, mannitol, calcium carbonate, calcium phosphate and the like. Examples of the disintegrator include carboxymethyl cellulose, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, sodium starch glycolate, polyvinyl polyplasdone, croscarmellose sodium and the like. Examples of the lubricant include stearic acid, magnesium stearate, talc, light anhydrous silicic acid, colloidal silica and the like, and these additives may be used alone or in combination.

The amount of the excipient added is usually 0 to 70%, preferably 0 to 30% with respect to the drug active ingredient, and the amount of the disintegrant added is 1 to 50% by weight with respect to the drug active ingredient. , Preferably 25 to 30% by weight. The amount of lubricant added is
0.5 to 3% by weight, preferably 1 based on the drug active ingredient
~ 2% by weight.

The tablet of the present invention may be coated with a usual coating as required to give a film-coated tablet, a sugar-coated tablet or an enteric film-coated tablet. As a component of the film coating agent, water-soluble polymer hydroxypropylmethylcellulose, hydroxypropylcellulose, gastric-soluble polymer methyl methacrylate / butyl methacrylate / dimethyl methacrylate / aminoethyl copolymer (Eulagide ( (Hereafter referred to as Eudragit)
E100; manufactured by Rohm Pharma (hereinafter referred to as Rohm Pharma)], polyvinyl acetal diethylaminoacetate (AEA; manufactured by Sankyo Co., Ltd.), enteric polymer methacrylic acid / ethyl acrylate copolymer (Eudragit L100-55; R
ohm Pharma), methacrylic acid / methyl methacrylate copolymer (Eudragit L100, S100; Rohm Pharma), hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate,
Examples thereof include carboxymethyl ethyl cellulose, insoluble polymer such as ethyl cellulose, ethyl acrylate / methyl methacrylate / trimethyl methacrylate / ammonium ethyl copolymer (Eudragit RS; Rohm Pharma). Sugar coating ingredients include sucrose, calcium carbonate,
Gelatin etc. are mentioned.

The present invention will be described in more detail with reference to examples. It should be noted that these examples do not limit the present invention.

[0020]

【Example】

Example 1 (Composition 1) Sodium (E) -11 atomized by a jet grinding method
-[2- (5,6-Dimethyl-1-benzimidazolyl) ethylidene] -6,11-dihydrodibenzo [b,
e) 100 mg of oxepin-2-carboxylate monohydrate (hereinafter, referred to as compound A) was added to hydroxypropyl cellulose [manufactured by Nippon Soda Co., Ltd. (hereinafter, HPC-
L)]] 3 mg were granulated by a stirring granulation method to prepare nuclear granules. A solution of sodium lauryl sulfate [manufactured by Nikko Chemicals Co., Ltd. (hereinafter, referred to as SLS)] solution was added to the obtained core granules by using a fluidized bed coating apparatus so that SLS was adjusted to 1% by weight (hereinafter, simply expressed as%) relative to Compound A. It was sprayed to become. Then, in the obtained granules, partially pregelatinized starch [Asahi Kasei Kogyo Co., Ltd. (hereinafter referred to as PCS)] 28.3 mg, low-substituted hydroxypropyl cellulose [Shin-Etsu Chemical Co., Ltd. (hereinafter referred to as L-HPC )] 27.0 mg, polyvinylpolyplasdone XL-10
[GAF Chemical Co., Ltd. (hereinafter PVPP XL-10)] 1
8.0 mg, light anhydrous silicic acid [Freund Industrial (hereinafter referred to as Adsolider 101)] 0.9 mg, magnesium stearate [Sakai Chemical Co., Ltd. (hereinafter Mg-St
1.8 mg was added and the mixture was tableted by a conventional method to obtain a composition 1 (tablet). The diameter of the obtained tablets is 8m.
It was m.

Example 2 (Composition 2) 100 mg of the compound A atomized by the jet crushing method was granulated by a stirring granulation method using 3.0 mg of polyvinyl alcohol [manufactured by Nippon Synthetic Chemical Industry Co., Ltd. (hereinafter referred to as PVA)]. Granules were prepared to prepare nuclear granules. Compound A is added to the nuclear granules.
On the other hand, the SLS solution was sprayed using a fluidized bed coating apparatus so that the SLS was 2%. Then PCS 27.3m
Additives were added in the same manner as in Example 1 except that the amount was changed to g to obtain a composition 2 (tablet).

Example 3 (Composition 3) Example 3 except that the SLS solution was sprayed onto the core granules by using a fluidized bed coating apparatus so that the SLS was 1% with respect to the compound A, and PCS was 28.3 mg. Composition 3 (tablet) was obtained in the same manner as in 2.

Example 4 (Composition 4) In the same manner as in Example 1, compound A was granulated by agitation granulation method using HPC-L to prepare nuclear granules, and then the obtained nuclear granules were quenched. Tablets were prepared in the same manner as in Example 1 except that the trisodium citrate solution was sprayed using a fluidized bed coating apparatus such that trisodium acid was 4% with respect to Compound A, and PCS was 25.3 mg. A composition 4 (tablet) was produced.

Example 5 (Composition 5) Trisodium citrate was sprayed with a fluidized bed coating apparatus so that the concentration of trisodium citrate was 2% with respect to compound A, and PCS was added to 2%.
Composition 5 (tablet) was obtained in the same manner as in Example 4 except that the amount was 7.3 mg.

Example 6 (Composition 6) Trisodium citrate was sprayed with a fluidized bed coating apparatus so that the concentration of trisodium citrate was 1% with respect to Compound A, and PCS was added at 2%.
Composition 6 (tablet) was obtained in the same manner as in Example 4 except that the amount was 8.3 mg.

Example 7 (Composition 7) Trisodium citrate was sprayed with a fluidized bed coating apparatus so as to be 0.5% with respect to Compound A, and PCS was used.
Composition 7 (tablet) was obtained in the same manner as in Example 4 except that the amount was changed to 28.8 mg.

Example 8 (Composition 8) Composition 8 (tablet) was obtained in the same manner as in Example 4 except that disodium succinate was used instead of trisodium citrate.

Example 9 (Composition 9) Composition 9 (tablet) was obtained in the same manner as in Example 4 except that sodium acetate was used instead of trisodium citrate.

Example 10 (Composition 10) A tablet of composition 10 was obtained in the same manner as in Example 4 except that potassium acetate was used instead of trisodium citrate.

Example 11 (Composition 11) Composition 11 was prepared in the same manner as in Example 4 except that sodium glutamate was used instead of trisodium citrate.
(Tablets) were obtained.

Example 12 (Composition 12) The tablets obtained in Example 4 were previously prepared with hydroxypropylmethylcellulose, titanium oxide, and macrogol 60.
The coating liquid consisting of 00 was coated using Hicoater HC-48 (manufactured by Freund Sangyo) to obtain film-coated tablets.

Example 13 (Composition 13) The SLS solution was sprayed using a fluidized bed coating apparatus such that the SLS was 4% by weight with respect to the atomized compound A, and P was added.
Composition 13 (tablet) was obtained in the same manner as in Example 3 except that CS was changed to 25.3 mg.

Example 14 (Composition 14) The SLS solution was sprayed using a fluidized bed coating apparatus so that the SLS was 0.5% by weight with respect to the atomized compound A, except that the PCS was adjusted to 28.8 mg. A composition 14 (tablet) was obtained in the same manner as in Example 3.

Reference Example 1 (Composition a) 100 mg of atomized compound A was granulated by a stirring granulation method using 2 mg of HPC-L, and then lactose for direct compression [manufactured by Taiyo Kagaku; tabletose (hereinafter referred to as Tablettose)] ] 21.
3 mg, HPC-L 36 mg, PVPP XL-1018 mg, Adsolider 101 0.9 mg, Mg-St 1.8 mg were added and tableted by a conventional method, and then partially pregelatinized starch and a surfactant or a salt of an organic acid was added. Composition a prepared without
(Tablets) were obtained. The diameter of the obtained tablets was 8 mm.

Reference Example 2 (Composition b) 100 mg of atomized compound A was granulated by agitation granulation method using 3 mg of HPC-L, and then 29.3 mg of PCS and HPC-
L 27mg, PVPP XL-10 18mg, Adsolider 101
0.9 mg and Mg-St 1.8 mg were added and the mixture was tableted by a conventional method to obtain a composition b (tablet) prepared without adding a surfactant or a salt of an organic acid.

Reference Example 3 (Composition c) Composition b was applied in the same manner as in Example 12 to give composition c.
(Coating agent) was obtained.

Reference Example 4 (Composition d) Example 1 except that Compound A and trisodium citrate were mixed as powders in an amount of 4% with respect to Compound A.
The composition used in tableting after adding the additives used in
(Tablets) were obtained.

The results of comparing the disintegration properties, the elution properties of Compound A and the absorbability of the preparations obtained in the Examples and Reference Examples are described below.

Test Example 1 A composition 1 obtained in Example 1, a composition a obtained in Reference Example 1 and a composition b obtained in Reference Example 2 were subjected to a disintegration test and a comparative test for measuring hardness. It was Further, for the composition 1 and the composition b, a comparative test of the dissolution test was performed.
In the disintegration test, purified water was used as a test solution according to the Japanese Pharmacopoeia 12th revised General Test Method Disintegration Test Method. The hardness was measured using a tablet breaking strength measuring device (manufactured by Toyama Sangyo Co., Ltd.). The dissolution test is based on the Japanese Pharmacopoeia No. 12 revised general test method Dissolution test No. 2
According to the method, the paddle rotation speed was set to 100 rotations, and purified water [designated by the Japanese Pharmacopoeia] was used as a test solution.

The results of the disintegration test and hardness measurement are shown in Table 1.
The results of the dissolution test are shown in FIG.

[0042]

[Table 1]

According to Table 1, composition 1 showed a faster disintegration time than compositions a and b. Moreover, according to FIG. 1, the composition 1 showed a higher elution effect than the composition b in which the surfactant was not added.

Test Example 2 With respect to the compositions 2 and 3 obtained in Examples 2 and 3 and the compositions 13 and 14 obtained in Examples 13 and 14, the disintegration test and the measurement of hardness were performed according to Test Example 1. went.

The results of the disintegration test and the hardness measurement are shown in Table 2.

[0046]

[Table 2]

Test Example 3 Comparison of disintegration test, hardness measurement and elution test for the compositions 4 to 11 obtained in Examples 4 to 11 and the composition b containing no organic acid salt obtained in Reference Example 2 respectively. Test Example 1
It was carried out according to.

The results of the disintegration test and the hardness measurement are shown in Table 3.
The results of the dissolution test are shown in FIGS. 2 and 3.

[0049]

[Table 3]

According to Table 3, the disintegration time in water of each Example composition was shorter than that of Composition b. Moreover, according to FIG. 2 and FIG. 3, the elution rate of each Example composition was higher than that of the composition b.

Test Example 4 Composition 12 obtained in Example 12 and composition c obtained in Reference Example 3 were compared in terms of absorbency of compound A using a beagle dog. Each group consisted of 5 beagle dogs and each tablet was administered with 20 ml of water. Blood was collected over time, and the concentration of Compound A in plasma was measured by the HPLC method.

FIG. 4 shows changes in the plasma concentration of Compound A. Pharmacokinetic parameters (area under plasma concentration, maximum plasma concentration)
Is shown in Table 4.

[0053]

[Table 4]

According to FIG. 4, composition 12 containing sodium citrate has better absorption in the body than composition c,
The retention time in blood was also long. Also, according to Table 4,
Composition 12 was also high in area under plasma concentration (AUC0-8h) and maximum plasma concentration (Cmax).

Test Example 5 The composition 12 obtained in Example 12 and the composition c obtained in Reference Example 3 were subjected to a dissolution test by the method shown in Test Example 1. Results are shown in FIG. According to FIG. 5, it was shown that the composition 12 had a higher elution effect.

Test Example 6 The composition 4 obtained in Example 4 and the composition d obtained in Reference Example 4 were subjected to a disintegration test and a hardness measurement under the same conditions as in Test Example 1. The results are shown in Table 5.

[0057]

[Table 5]

According to Table 5, composition 4 and composition d
Although there was no difference in hardness, the composition 4 had a significantly increased disintegration time. Furthermore, when the tableting properties of the composition 4 and the composition d were compared, it was found that the composition d had poor tableting properties and that sticking was observed during tableting.

[0059]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to obtain a miniaturized preparation which is easy to tablet, has excellent dissolution properties and absorbability into a living body, even though it contains a high content of drug.

[Brief description of drawings]

FIG. 1 Comparison of composition 1 and composition b in dissolution test

[Explanation of symbols]

 ─ ● ─ Composition 1 ─ ○ ─ Composition b

FIG. 2 Comparison of compositions 4 to 7 and composition b in dissolution test

[Explanation of symbols]

 ─ × ─ ・ ・ ・ Composition 4 ─ ● ─ ・ ・ ・ Composition 5 ─ □ ─ ・ ・ ・ Composition 6 ─ ■ ─ ・ ・ ・ Composition 7 ─ ○ ─ ・ ・ ・..Composition b

FIG. 3 Comparison of compositions 8 to 11 and composition b in dissolution test

[Explanation of symbols]

 ─ ● ─ ・ ・ ・ ・ ・ Composition 8 ─ × ─ ・ ・ ・ ・ ・ Composition 9 ─ □ ─ ・ ・ ・ Composition 10 ─ ■ ─ ・ ・ ・ ・ ・ Composition 11 ─ ○ ─ ・ ・ ・..Composition b

FIG. 4 Comparison of changes in plasma concentration of Compound A between Composition 12 and Composition c

[Explanation of symbols]

 ─ ● ─ ・ ・ ・ ・ ・ Composition 12 ─ ○ ─ ・ ・ ・ Composition c

FIG. 5: Comparison of composition 12 and composition c in the dissolution test of compound A

[Explanation of symbols]

 ─ ● ─ ・ ・ ・ ・ ・ Composition 12 ─ ○ ─ ・ ・ ・ Composition c

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display area A61K 47/12 A61K 47/12 E 47/16 47/16 E 47/36 47/36 B

Claims (4)

[Claims] 1. A pharmaceutical composition comprising a micronized drug active ingredient, a core composed of a surfactant or an organic acid salt, and partially pregelatinized starch. 2. A composition according to claim 1 wherein the organic acid salt is selected from the group consisting of trisodium citrate, disodium succinate, sodium acetate, potassium acetate and sodium glutamate. 3. The drug active ingredient is selected from the group consisting of valproic acid or a salt thereof, a macrolide antibiotic, a sulfamide oral hypoglycemic agent, a nonsteroidal anti-inflammatory drug, a sulfa drug and a thromboxane A ₂ antagonist. The composition according to claim 1 or 2. 4. A thromboxane A ₂ antagonist is 11- [2
The composition according to claim 3, which is-(5,6-dimethyl-1-benzimidazolyl) ethylidene] -6,11-dihydrodibenzo [b, e] oxepin-2-carboxylic acid or a salt thereof.