JPS6084213A - Sustained release type anti-inflammatory and analgesic pharmaceutical - Google Patents

Abstract

PURPOSE:A sustained release type anti-inflammatory and analgesic pharmaceutical, containing ''Indomethacin'' in collagen or gelatin, and capable of remarkably enhancing the effectiveness thereof. CONSTITUTION:A sustained release type anti-inflammatory and analgesic pharmaceutical obtained by adding ''Indomethacin'' of the formula which is a nonsteroidal antirheumatic agent to a solution containing a biodegradable carrier selected from collagen and gelatin, stirring the resultant mixture, concentrating and if necessary spray-drying or freeze-drying the resultant mixture. Atherocollagen which is obtained by treating collagen with an enzyme, e.g. pepsin, removing the heteropeptide part, and reducing the antigenecity can be used to enhance further the safety thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to sustained release anti-inflammatory analgesic formulations. More specifically, it relates to a sustained release anti-inflammatory analgesic preparation characterized by containing indomethacin represented by the chemical formula in a biodegradable carrier selected from collagen and gelatin, a non-steroidal anti-rheumatic drug. While indomethacin has a strong anti-inflammatory effect on local inflamed areas, it is generally known that systemic side effects may occur on the central and digestive systems in some cases. Although there has been a strong demand for sustained-release preparations that can be administered parenterally, such as by injection, for the purpose of suppressing side effects and effectively eliciting the main effects, none have been developed yet.

As a result of repeated research on this point, the inventors found that total < 7
1. In addition, the inventors have discovered that collagen, seratin, and a biodegradable carrier containing indomethacin are excellent as sustained-release dosage forms, and have completed the present invention.

That is, the present invention was made based on the novel discovery that the purpose of sustained release can be achieved and the efficacy can be significantly enhanced in a very specific combination of indomethacin and collagen or indomethacin and seratin.

To explain the present invention in detail, we will first discuss the carrier.Collagen is the main protein in animal connective tissues, and as a protein with low antigenicity, it is a safe material that is already frequently used in medical surgical threads, etc. It is. Furthermore, for the purpose of further increasing safety, atelocollagen with lower antigenicity may be used by removing the telopeptide portion by enzymatic treatment of collagen, such as pepsin treatment.

Furthermore, gelatin is a protein derived from collagen and has already been evaluated for medical safety as an inexpensive polyampholyte with low antigenicity and sol-gel conversion properties. They can be used in proportions. The sustained-release preparation provided by the present invention is an extremely interesting preparation that uses these characteristic biological materials as carriers.

Next, the method for manufacturing the sustained release preparation of the present invention will be explained in detail.

That is, indomethacin is added to a solution containing a carrier, stirred, and concentrated, or optionally spray-dried or freeze-dried. At this time, pharmaceutically acceptable stabilizers, preservatives, soothing agents, solubilizing agents, and other additives for adjusting moldability and sustained release properties can be added as necessary.

The material thus obtained is processed as appropriate depending on the purpose.

For example, grinding to obtain a powder. At this time, the particles pulverized to an injectable particle size can be suspended in an injectable oil to form a long-acting suspension-type injection.

Alternatively, by adding oil separately, the preparation can be prepared by suspending it in oil at the time of use.

The oil used here is one that can be injected, such as sesame oil, groundnut oil, cottonseed oil, MOT, olive oil, corn oil, castor oil, silicone oil, etc. These preparations are useful for treating various joint fluid diseases. By administering it as an injection, a sustained effect at a high concentration can be expected locally.

In addition, the pulverized fine particles are collected, and if necessary, additives for molding are added and compression molded to form a needle or rod shape (diameter 0.5 tm or more) that can be administered from a fiberscope forceps needle or an indwelling needle. 1.5 meters, length 5 meters to 15 layers)
formulation.

Alternatively, it can be placed in a mold in advance, concentrated or freeze-dried at low temperature, and similarly compressed to form a needle- or rod-shaped preparation.

Furthermore, by the same method, it is possible to make an implantable preparation, that is, a preparation in the form of pellets, spheres, granules, powder, etc., which can be implanted or dispersed into the body or lesion area during surgery, etc. . These can be used depending on the situation, such as the required degree of duration, but it is natural that the larger the shape, the longer the duration.

It goes without saying that each of these steps is carried out in a sterile manner due to the nature of the injection or implant. Moreover, the present invention is such depending on its purpose.

Next, the present invention will be explained in more detail with reference to experimental examples and examples, but these examples are not intended to limit the present invention.

Note that the samples used in the experimental examples were all made according to the examples described below.

Experimental Example 1 To examine the elution of indomethacin from the sustained-release formulation of the present invention, the formulations of Example 1.2.4 (samples A, B, and D) were tested.
) and indomethacin alone as a control. The dissolution tester used was a U8F standard dissolution tester, and the rotating basket method was used.

The results are shown in Figure 1. In contrast to indomethacin alone, the elution was completed immediately, but when the carrier collagen was added to indomethacin at a weight ratio of 1=1, it took about 8 days. It was found that elution lasted for about 8 days when 31 was added at the same weight ratio, and for about 1 day when gelatin was used as a carrier.

Experimental Example 2 In order to investigate the dissolution of indomethacin from the sustained release formulation of the present invention (molded into a needle shape), a dissolution test was conducted on the formulation of Example 7.8 (Samples G and H) and the case of indomethacin alone as a control. I did it. The dissolution tester is U8
A rotating basket method was used using a P standard product.

The results are shown in FIG. 2, and while indomethacin alone completes elution immediately, elution from the acicular sustained-release preparation of the present invention lasted for 10 days or more.

Next, examples of the present invention will be shown, but these examples are not intended to limit the present invention.

Example 1 2% atelocollagen 2fM' was dissolved in 100% of distilled water followed by 0.51% indomethacin and 0.51% arginine.
292y was added and pre-lyophilized to obtain a sustained release preparation (8).

Example 2 After dissolving 2% atelocolageken 15f in 800 g of distilled water, 0.5 g of indomethacin and 0.29 g of algin were added.
Add 2F, pre-freeze and lyophilize to obtain sustained release preparation (B)
I got it.

Example 3 After dissolving 10 y of gelatin in 100 tnl of distilled water, 0.5 g of indomethacin and 0.292 y of arginine and s'
A sustained release preparation (q) was obtained by adding 1-t% formaldehyde and freeze-drying.

Example 4 The lyophilized product obtained in Example 3 was compressed into tablets under reduced pressure to obtain sustained release formulation 0.

Example 5 The freeze-dried product obtained in Example 2 was cryogenically ground and suspended in sesame oil to obtain a sustained-release oil-based suspension preparation (with odor).

Example 6 The freeze-dried product obtained in Example 3 was cryogenically ground and suspended in sesame oil to obtain a sustained-release oil-based suspension preparation (I). Example 7 Indomethacin was added to 1% atelocollagen 200f. 4 da was added and concentrated to about 20.

This was injected into a silicone tube, frozen and solidified, and then the tube was cut open and taken out. The product was crosslinked in a gas phase of geltaraldehyde for 4 days to obtain a needle-like sustained release preparation (G).

Example 8 Indomethacin 4f was added to 200g of 1% atelocollagen and concentrated to about 20g.

After injecting this into a silicone tube and freezing it,
The tube was cut open, removed and dried. 40 of this stuff
% atelocollagen was injected into the center, the tube was frozen and solidified, taken out, and crosslinked for 4 days in the gas phase of geltaraldehyde to obtain a double-structure needle-like sustained release preparation.

[Brief explanation of drawings]

FIG. 1 shows the dissolution test results of indomethacin and the sustained release formulation of the present invention. Vertical axis: Dissolution rate, unit % Horizontal axis: Dissolution time, unit time △: Present invention using collagen as a finger carrier L: Present invention sustained release preparation using gelatin as a carrier (Sample D) ○: Indomethacin alone Figure 2 1 shows the dissolution test results of indomethacin and the sustained release preparation of the present invention (shaped into a needle shape). Vertical axis: Dissolution rate (unit %) Horizontal axis: dissolution time (unit time): Sustained release preparation of the present invention formed into a needle shape (Sample G) △, Sustained release preparation of the present invention formed into a double structure needle shape (
Sample H) ○: Indomethacin alone

Claims (1)

[Claims] A sustained release anti-inflammatory analgesic preparation containing indomethacin in a biodegradable carrier selected from collagen and gelatin.