JPS63243036A - Sustained release solid agent - Google Patents

Abstract

PURPOSE:To obtain a sustained release solid agent of stomach retention type, containing calcium silicate and hydroxypropylmethyl cellulose. CONSTITUTION:Calcium silicate is blended with hydroxypropylmethyl cellulose and, if necessary, a drug and an additive and pharmaceutically manufactured by a conventional procedure to give the aimed substance. The amounts of the solid agent blended is 10-80wt.% based on sum of the solid agent of calcium silicate and 20-80wt.% hydroxypropylmethyl cellulose and in the case of the solid agent containing the drug, the amount of the drug blended is <=70wt.% related to the specific gravity of the drug. The other additive is decided so that the solid agent does not have >=1 apparent density. The solid agent of this invention is a sustained release part and can be further combined with an immediate release part to give a solid agent.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to solid depots and to solid depots comprising sustained release moieties combined with immediate release moieties. More specifically, the present invention relates to a gastroretentive solid form containing calcium silicate and hydroxypropylmethylcellulose (HPMC).

BACKGROUND OF THE INVENTION In order to maintain the effect of a drug in the stomach, it may be necessary to allow the drug to remain in the stomach for a long time and gradually release the drug. It is known that when large tablets or capsules are used, the retention time in the stomach becomes relatively long due to the selective action of the pylorus, but this varies greatly from person to person and also depends on the state of the stomach and its contents. Since the residence time changes depending on the condition, it is unreliable as a form of drug administration, and furthermore, tablets and capsules are thick and difficult to take, so they have not been put into practical use.

The present inventors have discovered that when a specific calcium silicate is used together with hydroxypropyl methylcellulose as a solid agent such as a tablet or granule, a solid agent with a lower specific gravity and superior physical properties than gastric juice can be obtained. It has been found that, as a result, the solid drug floats on the gastric fluid and its residence time in the stomach is prolonged.

Disclosure of the Invention The solid agent of the present invention is composed of calcium silicate, hydroxypropyl methylcellulose (HPMC), and f/v,
Drugs and excipients can be included, and the solid dosage form can be combined with a sustained release portion and a rapid release portion to form a solid dosage form.

The calcium silicate used in the present invention has an apparent specific gravity of 0.08 to 0.12. Particularly preferred calcium silicate is a gyrolite-type special calcium silicate having the chemical formula: % (in the formula, 1 < m < 2.2 < n (3)), and is available from Tokuyama Soda Co., Ltd. as "Florai". It is commercially available under the trade name RJ. Fluorite R has a plug body, is thick, and has good moldability. Also, regarding safety, it is compliant with Japanese Pharmacopoeia Drug Code 4600 and general purpose. It is listed in Cosmetic Ingredients 1-50, and is listed in the United States Pharmacopoeia (NF-X).
VI) also meets the standard value for calcium silicate.

Hydroxypropyl methylcellulose (HPMC) that can be used in the present invention has 20 to 3 methoxy groups.
0Fw, hydroxypropoxyl groups 4-12% and 2%
The aqueous solution has a viscosity of 3 to 30,000 cps.

Drugs that can be used in the present invention include water-soluble drugs and antacids.

The proportions of each component in the solid dosage form of the present invention are approximately 10 to 80% by weight of calcium silicate, based on the total weight of the solid dosage form;
HPMC is about 20-80% by weight, and if a drug is included, it can be incorporated up to about 70% by weight in relation to the specific gravity of the drug. The solid agent of the present invention may also contain a disintegrant, a lubricant, a binder and other additives. The amount of these additives should be determined so as to ensure that the solid agent has an apparent density of 1 or more.

The solid preparation of the present invention can be coated with sugar and/or film, and can be made into a capsule. Even in such cases, care should be taken to ensure that the specific gravity of the entire formulation does not exceed 1.

The solid dosage form of the present invention can be molded according to a conventional molding procedure. The solid dosage form of the present invention has an apparent density of 0.5 to If/
mA, 0.3-1 r/I/! in granules. and can float for a long time (more than 5 hours) in I fluid (artificial gastric fluid). Furthermore, the solid agent of the present invention has acceptable physical properties, such as hardness, friability, etc., at the above-mentioned low apparent density.

Next, a solid preparation consisting of a sustained-release portion containing calcium silicate and hydroxypropyl methylcellulose and a fast-acting portion will be described.

Since the solid agent containing calcium silicate and hydroxypropyl methyl cellulose has a specific gravity of 1 or less, it floats in the bay, and the drug that is almost incorporated into the solid agent is gradually leached out.

However, depending on the gastric symptoms, it often happens that the drug's efficacy is expected immediately after administration. Therefore, if the solid drug is a slow-release part and t is combined with a fast-acting part, the combined solid drug has a specific gravity of 1 or more.
Immediately after administration, it settles near the lower part of the stomach, but the quick-acting part dissolves first and exerts its medicinal effect. As the fast-acting portion dissolves, the total specific gravity gradually becomes less than 1, that is, only the slow-release portion remains, so it floats in the stomach.

Thus, the drug from this sustained release portion will be gradually leached out, and therefore, the immediate effect immediately after administration will be followed by a sustained drug effect.

Examples of solid preparations consisting of a sustained release part and an immediate release part include the following forms.

That is, a sustained-release portion consisting of calcium silicate, hydroxyprogyl methylcellulose, and a drug is used as a core (ie, inside), and the outside is covered with a quick-release portion containing the drug to form a dry-coated tablet.

In addition, a quick release part is laminated on the surface of a sustained release part to form a multilayer tablet, for example, a two-layer tablet.

There are no particular restrictions on the components of the quick-forming part, but examples include drugs, starch, lactose, crystalline cellulose, and Merck.

The invention will now be illustrated by examples. In the following examples, Fluorite (trademark) I (manufactured by Tokuyama Soda Co., Ltd.) was used as calcium silicate.

Example 1 Compositions A to D having the compositions shown in Table 1 were mixed respectively, and the tablet thickness was changed to 9 parts flat tablet and 180 x 7' tablet, and the apparent density of the tablet was 0.6 to 1. 0 tablets were prepared. Each tablet was tested for apparent density, hardness, friability, and floating time in liquid I, and the results are shown in Tables 2 to 4.

Table 19 Tablet composition (parts) Calcium silicate -1-70 Silicic anhydride -70- Crystalline cellulose 70 - -
- Sprayed lactose -70-- HPMC30303030 Total 101 101 101 101 Apparent density Δ B CDO, 61 Niri)
1) 1) 40.7
N 〃 〃 50
．． 8 〃 〃
〃 60, 9
1 // //
71°0 2
1/ // 8 Note: Hardness was measured using a bookstore type hardness meter.

Table 3. Friability apparent density A B CDo, 6
100% 100 100 0.1 “0.7
100 tt tt Q,QO,8
80tt tt Q, QO, 95tt
p Q , Ql, 0 2 tt
tt Q, Q Note: Appearance 1 degree as measured by rotating the tablet for 10 minutes using a tablet friability tester manufactured by Kayagaki Irika Kogyo Co., Ltd. A B CDO・6--
-5 hours or more 0.7 - - - 5 ttO
,8---5tt O09 Sedimentation Sedimentation Sedimentation 5 〃1.0
Sedimentation Sedimentation Sedimentation Sedimentation Note knee mark was not tested because the tablet hardness was low and the degree of friability was high, so it could not be formed as a sample.

As is clear from the above tables, tablets A, B, and C that do not contain calcium silicate had low hardness and high friability when the apparent density was 1 or less, and (1) did not float in the liquid. On the other hand, the tablet Dfi of the present invention containing calcium silicate has appropriate hardness even at an apparent density of 1 or less,
The friability was almost zero, and it had a floating time of 5 hours or more in liquid I.

Example 2 5 parts of riboflavin sodium phosphate (FMN), 1 part of calcium stearate, 15 or 25 or 50 or 70 parts of calcium silicate and HPMC65
Total 100 including SH4000C manufactured by Shin-Etsu Chemical Co., Ltd.
1 kg was mixed in a small Henschel mixer, and one tablet was made into flat tablets with a diameter of 9 m using a rotary tablet machine. did. This tablet was administered using the diurnal paddle method (100 rpm).
), an elution test was carried out using Solution I, and the elution amount of phosphoric acid flavin sodium was measured, and the 75% elution time is shown in FIG.

In all dissolution tests, the tablets remained suspended until 100% dissolution occurred.

Example 3 Zeflavin sodium phosphate 5 parts, calcium stearate 1 part, and calcium silicate 20, 30 or 50 parts and KHPMC (90SH1,5,000)
(Shin-Etsu Chemical Exhibition) will be added to bring the total to 100 copies. Following the same procedure as in Example 2, tablets weighing 180 mg and having an apparent density of about 0.8 f/ml were manufactured. A dissolution test was conducted in the same manner as in Example 2. The results are shown in Figure 2.

Example 4 44 parts of calcium silicate, HPMc (@Kara, Shin-Etsu Chemical (
45 parts of 90SH4000) manufactured by Co., Ltd., 10 parts of chlorpheniramine d-maleate, and 1 part of calcium stearate were mixed to prepare a powder for sustained release portion (core powder). Next, 34 parts of calcium silicate, 10 parts of d-maleic acid chloride pheniramine, 1 o of carboxymethylcellulose calcium
1 part and 1 part of calcium stearate were mixed to prepare a powder for immediate release part (rapid disintegration powder).

Next, a three-layer tablet press [C stock] Hata Iron Works] was used to reduce the core powder to 175 Tq! , "The powder part that disintegrates quickly during machining is 7511Ji.
' However, the tablets were made under the conditions of a tablet machine to form a flat tablet with a diameter of 10 mm to obtain a three-layer tablet.

The tablets obtained were 10 cm in diameter and 4.0 cm in thickness.
The weight was 250 cm, and the apparent specific gravity was about 0.8.

When this tablet was subjected to a dissolution test using diurnal XT and diurnal liquid I under stirring conditions of 100 rprn using the paddle method, the tablet portion consisting of the rapidly disintegrating powder portion disintegrated in 2 minutes, and the tablet portion consisting of the core powder portion disintegrated. , floating on the surface of the eluate. The dissolution test results of this three-layer tablet are shown in Figure 3. Example 5 90SH15.0 was used instead of 90SH4000 in Example 4.
00 (corresponding to the core powder in Example 4) was heated with a roller container lid (manufactured by Flomono Sho Sangyo Co., Ltd.) to an apparent specific gravity of approximately 0.97 y/mi. Pellets were made. This was crushed and further sieved to produce 12 mesh granules. The floating time of this product was examined using the same apparatus and method as in Example 4 based on the dissolution test method. Float time was 5 hours.

Example 6 The granules produced in Example 5 were placed in a No. 3 hard capsule with 150
■ Each capsule was filled to form a capsule.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the relationship between the amount of calcium silicate and dissolution time in the tablet of the present invention. FIG. 2 is a graph showing the influence of the amount of calcium silicate on dissolution in the tablet of the present invention. It is. FIG. 3 shows the dissolution test data of Example 4.

Claims (1)

[Claims] 1. A solid agent comprising calcium silicate and hydroxypropylmethylcellulose. 2. The solid preparation according to claim 1, which contains a drug. 3. The solid dosage form according to claim 1, wherein the solid dosage form is a tablet. 4. The solid dosage form according to claim 1, wherein the solid dosage form is granules. 5. The solid dosage form according to claim 1, wherein the solid dosage form is a capsule. 6. A solid preparation comprising a sustained release portion containing calcium silicate and hydroxypropyl methylcellulose and an immediate release portion. 7. The solid dosage form according to claim 6, wherein the solid dosage form is a dry-coated tablet. 8. The solid dosage form according to claim 6, wherein the solid dosage form is a multilayer tablet.