JPH0571566B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to long-term sustained release formulations.
More specifically, it relates to a long-term sustained release preparation characterized in that a) a medicinally effective component, a) collagen, and a) albumin and/or gelatin are formed into a rod or needle shape that can be administered by injection. It is something.

[Conventional technology]

Techniques have been known in which a drug encapsulated in a polymer, such as a polyethylene glycol diacrylate polymer, is implanted into the body for a sustained period of time, but this technique has had various problems.

That is, since the polymer used is not biodegradable, there are many disadvantages, such as the need for some kind of treatment after administration, and the method of implantation being very complicated and requiring surgery. On the other hand, it is strongly desired for various drugs to maintain the action of the drug in a desired amount and for a long period of time.

[Purpose of the invention]

The present inventors have focused on this point, and have finally completed the present invention as a result of intensive studies in order to obtain a superior long-lasting formulation that overcomes these difficulties.

[Structure of the invention]

That is, the present invention comprises:) a component having medicinal efficacy;
) collagen and ) albumin and/
Alternatively, it is a long-term sustained release preparation, which is prepared by drying and then molding or molding and then drying an aqueous solution of gelatin, and is molded into a rod or needle shape that can be administered by injection.

The present invention will be explained in detail below. First of all, there are no particular restrictions on the ingredients that have medicinal effects, but ingredients that are effective in small amounts and are expected to increase their medicinal efficacy by sustaining them;
For example, prostaglandin, prostacyclin and other autocoids, various biological hormones, adriamycin, bleomycin, tespamine,
Synthetic compounds such as mitomycin, cytokines such as interferons, interleukins, tumor necrosis factor, etc. are particularly useful.

Among them, various interferons, various interleukins, tumor necrosis factors, etc. have many differences in detail, but overall they are all sugars with approximately the same molecular weight as α-interferon shown in the experimental example. They are proteins or proteins, and their medicinal effects and properties as substances are extremely similar, and the present invention is expected to have similarly extremely excellent effects.

Collagen, which is a carrier, is the main protein in animal connective tissue, and is a safe protein that is already frequently used medically in surgical threads, hemostatic agents, etc. as a protein with little antigenicity. Furthermore, for the purpose of further increasing safety, atelocollagen whose antigenicity is reduced by removing the telopeptide portion by enzymatic treatment of collagen, for example, treatment with pepsin, may be used. Furthermore, gelatin is a protein derived from collagen, has little antigenicity, and has already been evaluated for medical safety as an inexpensive polyampholyte with sol-gel conversion properties.

Next, a method for preparing the long-term sustained release preparation of the present invention will be explained.

The sustained release preparation of the present invention is prepared by drying and then molding or molding and drying an aqueous solution of a) a medicinally effective component, a) collagen, and) albumin and/or gelatin. In other words, an aqueous solution containing () ingredients with medicinal properties, () collagen, and) albumin and/or gelatin is mixed and stirred as uniformly as possible without forming bubbles, and if necessary, concentrated at low temperature or optionally spray-dried or freeze-dried. . At this time, pharmaceutically acceptable stabilizers, preservatives, soothing agents, etc., and 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, the fine particles obtained are crushed under cooling with dry ice or liquid nitrogen, and if necessary, additives for molding are added and compression molded. Administerable needle-like or rod-like form (0.5 mm to 1.5 mm in diameter,
The length of the product is approximately 5 mm to 15 mm). 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. It goes without saying that each of these steps is performed aseptically due to the nature of the implant. Furthermore, the long-term sustained release preparation of the present invention can be administered by, for example, inserting a thin tube into the administration site using a catheter or the like and administering the needle-like preparation through the thin tube, or using the tip of forceps of a fiberscope. Possible methods include administering the drug directly to the lesion site deep inside the body through a needle.

Conventionally, if long-term persistence was expected, complicated techniques such as implantation had to be used, but as described above, the present invention can be administered systemically or locally to internal organs using a fiberscope. It has great significance in terms of clinical practicality because it can be administered locally on the body surface using an indwelling needle and can be administered very easily and at a moderate frequency. Moreover, it is a completely novel idea of the present invention to administer a solid state biodegradable substance in the above-described manner.

In addition, in treatment with sustained release preparations, the type of active ingredient to be applied, the target disease, the dosage,
The desired amount varies depending on the administration period, etc., but
The release rate of the formulation of the present invention can be controlled by adjusting the amount of albumin or gelatin added.

Next, the present invention will be explained in more detail with reference to examples and examples, but none of these examples is intended to limit the present invention.

Example 1 Aqueous solution containing α-interferon (potency
4.9 MU/ml), 50 g of a 2% aqueous atelocollagen solution, 150 mg of human serum albumin, and 120 mg of thimerosal are mixed and stirred uniformly to avoid foaming as much as possible, freeze-dried, and then cryogenically ground using liquid N ₂ . By compression molding this, a needle-like long-acting preparation containing 10 MU of interferon was obtained.

Example 2 Aqueous solution containing α-interferon (potency
4.9 MU/ml), 50 g of a 2% aqueous atelocollagen solution, and 400 mg of human serum albumin are mixed and stirred uniformly to avoid foaming as much as possible, freeze-dried, and then cryogenically ground using liquid N ₂ . By compression molding this, a rod-shaped long-acting preparation containing 10 MU of interferon was obtained.

Example 3 Aqueous solution containing α-interferon (potency
4.9 MU/ml), 50 g of 2% atelocollagen aqueous solution, and 150 mg of human serum albumin are mixed and stirred uniformly to avoid foaming as much as possible, freeze-dried, and then cryogenically ground using liquid N ₂ . By compression molding this, a needle-like long-acting preparation containing 10 MU of interferon was obtained.

Example 4 Aqueous solution containing α-interferon (potency
4.9 MU/ml), 50 g of 2% atelocollagen aqueous solution, and 400 mg of gelatin were mixed and stirred uniformly to avoid foaming as much as possible, and after freeze-drying, liquid N ₂ was added.
Grind at low temperature using By compression molding this, a rod-shaped long-acting preparation containing 10 MU of interferon was obtained.

Example 5 Aqueous solution containing α-interferon (potency
4.9MU/ml) 50ml and atelocollagen powder 1g,
50% aqueous solution containing 200g of albumin and 200mg of gelatin
ml is mixed and stirred uniformly without forming bubbles as much as possible, freeze-dried, and then ground at a low temperature using liquid _N2 .
By compression molding this, 10MU per piece.
A rod-shaped long-acting preparation containing interferon was obtained.

Example 6 Aqueous solution containing α-interferon (potency
15MU/ml) 100ml and atelocollagen powder 3.6g
Mix 0.4g of human serum albumin and 0.1N
After adding hydrochloric acid and dissolving it, it is put into a mold and freeze-dried. By compression molding this, a rod-shaped long-acting preparation containing 20 MU of interferon was obtained.

Comparative example Aqueous solution containing α-interferon (potency
4.9 MU/ml) and 50 g of a 2% atelocollagen aqueous solution are mixed and stirred uniformly to avoid foaming as much as possible, freeze-dried, and then ground at a low temperature using liquid N ₂ . By compression molding this, each
A rod-shaped long-acting preparation containing 10 MU of interferon was obtained (sample C).

Experimental example Effect of formulation composition on release of drug (α-interferon) from a sustained release formulation using collagen as a carrier (1) In vitro release experiment Sustained interferon rods prepared in Examples 2 and 4 Add one bottle each of the sex preparations (Samples A and B) and Sample C to a phosphate buffer solution (PH7.4,
Contains 0.5% human serum albumin, 0.01% _NaN2 )49
ml and incubated at 37°C, and the release rate of interferon was examined over time using radioimmunoassay (PIA).

(2) Results The results are shown in Figure 1.

Sample C, indicated by □ in FIG. 1, is a comparative example in which only collagen is used as a carrier, and it is observed that interferon is gradually released. On the other hand, samples A and B indicated by ○ and △
Interferon release from (Example of the present invention)
It can be seen that the release is faster than in the comparative example, and the rate is more constant. From this result, it was confirmed that drug release could be controlled by adding albumin or gelatin to the collagen carrier.

In treatments using sustained-release preparations, the desired release rate varies depending on the type of active ingredient being applied, the target disease, dosage, administration period, etc., so the release rate of the active ingredient can be controlled clinically. It is desired. Under such circumstances, the formulation of the present invention, which allows the release rate of the active ingredient to be controlled, meets these needs.

[Brief explanation of the drawing]

FIG. 1 compares drug release between the formulation of the present invention and a comparative example. The vertical axis is α-interferon release rate (%)
, and the horizontal axis represents the release time (unit: hours). ○
indicates Example 2 of the present invention, △ indicates Example 4 of the present invention, □
represents a comparative example.

Claims (1)

[Claims] 1. An aqueous solution of medicinal ingredients, collagen, albumin and/or gelatin, which is prepared by drying and molding or molding and drying, and which is molded into a rod or needle shape that can be administered by injection. A long-term sustained release formulation.