JPH0952847A - Sustained release preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a sustained release preparation simpler and at a lower cost than a tablet using a microcapsule, especially containing a seamless capsule. SOLUTION: An active substance and a sustained release adjustor are packed into the interior to give a seamless capsule having 0.5-1mm diameter. The active substances may be any of oral medicines and a release adjustor is selected from oils and fats such as an olive oil, a monoglyceride, a triglyceride, a wax and a hardened oil. A sustained release preparation containing a wax/polymer matrix comprising the seamless capsule, the release adjustor (e.g. acrylic polymer) and an active component is prepared. A double nozzle consisting of a nozzle jetting a content solution composed of the active substance and the release adjustor from the center and a nozzle jetting a gelatin solution from the periphery sprays the two solutions to a cooled oil and a gelatin spherule having the content as a nucleus is formed to give the seamless capsule.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION This invention relates to the field of sustained release formulations. The invention particularly relates to sustained release formulations containing seamless capsules.

[0002]

2. Description of the Related Art In recent years, in order to prolong the action time of an orally administered drug, the drug is gradually released.

The conventional oral sustained-release preparations are roughly classified into the following:
Some are called single units and some are called multi-units. When a single unit is used as a sustained-release preparation, there is a risk that it will adhere in the digestive tract and expose sensitive tissues to high concentrations of the drug, but when administered as a multi-unit, the capsule will dissolve rapidly in the stomach, Dispersed as individual pellets, gradually spread through the pylorus into the small intestine, where individual pellets slowly release the drug,
It is said that the drug does not become a high concentration locally in the digestive tract, so that the multi-unit drug is said to be more advantageous. Various proposals have been made for the multi-unit type, but the use of tablets containing microcapsules has the advantage that the tablets themselves can be sustained-released by selecting the matrix.

Tablets containing microcapsules are disclosed in JP-A-50-36619, JP-A-53-142520, JP-A-2-72113 and JP-A-2-237914, and US Pat. No. 3,922,338. And 4,113,816.

[0005]

However, the production of microcapsules is costly and due to its structure,
There are many difficulties in making tablets, complicated process and / or
Alternatively, it is necessary to use a special additive (see the above publication).

[0006]

The inventors of the present invention have found that when seamless capsules are used instead of microcapsules, the capsules are broken and the internal components flow out into the matrix according to the usual tableting method. The present inventors have completed the present invention by finding that they can be manufactured without the need. Furthermore, we have established a simple and low-cost method for producing seamless capsules.

Therefore, the present invention is 0.5-1.0 m
Provided is a seamless capsule for sustained-release preparation, which has a diameter of m and is sustained-released by filling a release-controlling agent together with an active substance inside.

The invention also provides a sustained release tablet comprising a seamless capsule and a matrix composed of a release controlling agent and an active ingredient.

According to the present invention, further, in the cooling oil, a double nozzle composed of a nozzle for ejecting a content liquid comprising an active substance and a release controlling agent from the center and a nozzle for ejecting a gelatin liquid from the periphery thereof is used in the cooling oil. Also provided is a method for producing a seamless capsule, which comprises ejecting a liquid to form gelatin globules having the content as a nucleus by interfacial tension.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION A conceptual diagram of the tablet of the present invention is shown in FIG.

The seamless capsules of the present invention can be manufactured from gelatin and optionally glycerin, water or the like as a plasticizer.

The active substance contained in the seamless capsule may be any conventionally known drug for oral administration.

Examples of the release controlling agent to be contained in the seamless capsule of the present invention together with an active substance include oils and fats such as olive oil, monoglyceride, triglyceride, wax and hardened oil.

The seamless capsule of the present invention may contain further excipients in addition to the above-mentioned active substance and release modifier.

Examples of the release controlling agent in the wax / polymer matrix forming the tablet of the present invention include acrylic polymers such as Eudragit, celluloses such as hydroxypropyl cellulose and methyl cellulose, fats and oils such as hardened oil. .

The active substance contained in the wax / polymer matrix forming the tablets of the present invention may be any of the conventionally known orally administered drugs.

In addition to the above-mentioned active substances and modified release agents, further excipients may be included in the wax / polymer matrix forming the tablets of the invention.

The tablet of the present invention may be provided with a polymer film on the outside. The film may contain a coloring agent, a plasticizer, and a drug, if necessary.

In the method for producing the seamless capsule of the present invention, a commercially available production apparatus such as GLOBEX can be used. FIG. 2 shows a conceptual diagram of a manufacturing apparatus used in the method of the present invention.

In the method of the present invention, the content liquid is held in the content liquid tank 6 and the gelatin liquid in the gelatin liquid tank 7 while being heated, and these are gelatinized from the nozzle for ejecting the content liquid from the center and its surroundings. A double nozzle 8 composed of a nozzle for ejecting the liquid is ejected into the cooling oil 9 to form gelatin globules having the content liquid as a nucleus by interfacial tension.

[0021]

The present invention will be described in more detail with reference to the following examples.

Example 1 (Production of Seamless Capsule) A seamless capsule was produced using the apparatus shown in FIG.
While heating the mixture of the formulation shown in the table below to 70 ℃ in the content liquid tank, the gelatin is heated to 50 ℃ in the gelatin solution tank, and the nozzle that ejects the content solution from the center and the nozzle that ejects the gelatin solution from the surrounding area. The above-mentioned two liquids were jetted into the cooling oil from the double nozzle constituted by, and the gelatin small spheres having a diameter of 0.5 mm were formed by the interfacial tension with the content liquid as the nucleus. This was collected, washed and dried to obtain the desired seamless capsule.

[0023]

[Table 1]

[0024]

[Table 2]

Test Example 1 (Brovincamin Fumarate-containing Si
Dissolution test of omeless capsules) The seamless capsules obtained according to Formulations 1 to 5 of Example 1 were subjected to a dissolution test using the Japanese paddle method at 37 ° C and 100 rpm in the Japanese liquid 1 solution. The results are shown in FIG. As is clear from FIG. 3, the seamless capsule of the present invention was capable of controlling elution and imparting excellent sustained release property by selecting the base material for the content of the seamless capsule.

Test Example 2 (Seamless cap containing methyldopa
Cell Dissolution Test) The seamless capsules obtained according to Formulations 6 to 9 of Example 1 were subjected to a dissolution test at 37 ° C. and 100 rpm in the Japanese Pharmacopoeia 1 liquid using the Japanese Pharmacy Paddle method. FIG. 4 shows the results. As is clear from FIG. 4, the seamless capsule of the present invention was capable of controlling elution and providing excellent sustained release property by selecting the base material for the content of the seamless capsule.

Test Example 3 (Chlorpheniramine maleate)
Dissolution test of contained sustained-release seamless capsules) The seamless capsules obtained by the formulations 10 to 13 of Example 1 were treated with Japanese Pharmacopoeia liquid 1 and 2 at 37 ° C and 100 rpm.
A dissolution test was carried out with the solution and acetate buffer (pH 4.0) using the Japanese-Paddle method. The results are shown in FIGS. As is clear from FIGS. 5 to 7, the seamless capsule of the present invention was able to control elution without being affected by pH by the selection of the base material for the content of the seamless capsule, and it was possible to impart excellent sustained release properties.

Test Example 4 (Seamless mosquito containing phenacetin
Dissolution test of Pucelle) The seamless capsules obtained according to the formulations 14 to 16 of Example 1 were treated with 37 ° C and 100 rpm at 1st solution of JP
A dissolution test was carried out with the solution and acetate buffer (pH 4.0) using the Japanese-Paddle method. The results are shown in FIGS. 8 to 1
As is clear from 0, the seamless capsule of the present invention was able to control elution without being affected by pH by the selection of the base material for the content of the seamless capsule, and it was possible to impart excellent sustained release properties.

Example 2 (seamless capsules and sustained-release capsules)
Production of composite tablet of Trix tablet) Seamless capsule 50 of formulation 2 produced in Example 1
g, brovincamin fumarate 38.1 g, hydrogenated oil 10
g, Eudragit L-100 10 g, alginic acid 1
0 g and lactose 20 g are mixed homogeneously and ethanol 30 ml
And kneaded. This was granulated with a high-speed stirring granulator, dried, and then sized. To this, 110 g of HPC-L and 1.9 g of magnesium stearate were added and mixed, and this mixture was tabletted to give a composite tablet of a sustained release seamless capsule and a matrix tablet. At this time, no breakage of the seamless capsule was observed.

Test Example 5 (seamless capsules and sustained-release capsules)
Dissolution test of composite tablets of Trix tablets) The tablets obtained in Example 2 were tested at 37 ° C. and 100 rpm.
Dissolution tests were carried out using the Japanese Pharmacopoeia method with the Japanese Pharmacopoeia 1 liquid, the Japanese Pharmacopoeia 2 liquid, and an acetate buffer (pH 4). The results are shown in Fig. 11.
As is clear from FIG. 11, the tablet of the present invention has an excellent sustained release property which is hardly affected by pH, and by combining a seamless capsule and a sustained release matrix tablet,
The next closest elution pattern was obtained.

[Brief description of drawings]

FIG. 1 is a conceptual diagram of a tablet of the present invention.

FIG. 2 is a conceptual diagram of a seamless capsule manufacturing machine used in the method of the present invention.

FIG. 3 is a graph showing the elution of seamless capsules containing brovincamin fumarate with JP-1 solution.

FIG. 4 is a graph showing the elution of methyldopa-containing seamless capsules from JP-1 solution.

FIG. 5 is a graph showing elution of seamless capsules containing chlorpheniramine maleate with JP-1 solution.

FIG. 6 is a graph showing elution of seamless capsules containing chlorpheniramine maleate with an acetate buffer (pH 4.0).

FIG. 7 is a graph showing dissolution of seamless capsules containing chlorpheniramine maleate into JP-2 solution.

FIG. 8: Japanese Pharmacopoeia 1 of seamless capsule containing phenacetin
It is a graph which shows elution with respect to a liquid.

FIG. 9 is a graph showing the elution of phenacetin-containing seamless capsules with an acetate buffer (pH 4.0).

FIG. 10 is a graph showing the elution of phenacetin-containing seamless capsules with JP-2 solution.

FIG. 11 is a graph showing dissolution of sustained-release matrix tablets.

[Explanation of symbols]

 1 Wax / Polymer Matrix 2 Seamless Capsule 3 Gelatin Layer 4 Contents 5 Film 6 Contents Liquid Tank 7 Gelatin Liquid Tank 8 Double Nozzle 9 Cooling Oil

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 47/32 A61K 47/32 C 47/38 47/38 C 47/42 47/42 D 47 / 44 47/44 C

Claims (7)

[Claims] 1. A seamless capsule for sustained-release preparation, which has a diameter of 0.5 to 1.0 mm and is sustained-released by filling a release-controlling agent together with an active substance inside. 2. The seamless capsule according to claim 1, wherein the modified release agent comprises at least one kind of fats and oils such as olive oil, monoglyceride, triglyceride, wax and hydrogenated oil. 3. A sustained-release preparation containing the seamless capsule according to claim 1. 4. A sustained-release tablet containing the seamless capsule according to claim 1 or 2. 5. A sustained release tablet comprising the seamless capsule of claim 1 or 2 and a wax / polymer matrix composed of a release controlling agent and an active ingredient. 6. The sustained-release tablet according to claim 5, wherein the release modifier comprises at least one of an acrylic polymer such as Eudragit, celluloses such as hydroxypropyl cellulose and methyl cellulose, and fats and oils such as hardened oil. 7. The two liquids are jetted into cooling oil from a double nozzle composed of a nozzle for jetting a content liquid consisting of an active substance and a release controlling agent from the center and a nozzle for jetting a gelatin liquid from the surroundings. The method for producing seamless capsules according to claim 1 or 2, wherein gelatin globules having the content liquid as a nucleus are formed by interfacial tension.