JPS6097918A - Long action pharmaceutical preparation of interferon - Google Patents

Abstract

PURPOSE:The titled pharmaceutical preparation obtained by adding interferon to a carrier consisting of a substance having decomposition properties in organism, capable of being embedded in organism, having low toxicity. CONSTITUTION:Interferon is added to a carrier (e.g., protein such as collagen, gelatin, albumin, etc., glucide such as chitin, etc, synthetic high polymer such as polyglycollic acid, polylactic acid, polyglutamic acid, etc.), to give pharmaceutical preparation of interferon. Preferably collagen or gelatin or a mixture of them is used with respect to safety and simplicity in use. In order to raise safety further, collagen is treated with an enzyme, telopeptide part is removed, to give atherocollagen having reduced antigen properties, which may be used. The dosage form of the pharmaceutical preparation is suspension injection, pellet, sphere, granule, powder, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to long-acting interferon formulations. More specifically, the present invention relates to a long-acting preparation that contains interferon as a medicinal ingredient and is designed to maintain blood concentration or intralesional concentration to a clinically useful extent.

Interferon is a type of glycoprotein that is originally produced by animal cells, including humans, when stimulated by viruses or other substances, and is a very useful substance that has viral growth-inhibiting and antitumor effects. In recent years, interferon has begun to be used in various clinical applications as a therapeutic agent for viral diseases and malignant tumors, and it is expected that its effects will be enhanced by sustaining its blood concentration or intralesional concentration. However, such a long-acting formulation has not yet been developed.

The present inventors focused on this point and attempted to develop a clinically useful long-lasting interferon preparation, and as a result of intensive study, the present invention was completed.

That is, it has been extremely difficult to sustain the action of interferon using various conventionally known techniques. This is because interferon is an extremely unstable protein, not only in vivo but also as a pharmaceutical product. Therefore, its activity cannot be reduced by treatment with heat or radiation, or by chemical methods using organic solvents or aldehydes. This is because interferon preparations have many problems, including the fact that interferon preparations contain only trace amounts of interferon and are water-soluble substances, so they are released extremely quickly after administration into the body. Furthermore, since this preparation is administered parenterally, such as by injection, the accumulation of carriers is a problem, and carriers that are difficult to decompose in the body, such as silicone, which have recently been used in some medical applications, are used. There were even more restrictions. Under these circumstances, as a result of extensive research over many years, the present inventors have overcome many of the difficulties and problems described above by using the method of the present invention, and have achieved a long-lasting product that is expected to be extremely useful clinically. A preparation was obtained and the present invention was completed.

That is, the present invention provides interferon with biodegradable and low toxicity carriers that can be implanted in the body - proteins such as collagen, gelatin, albumin, high molecular weight carbohydrates such as chitin, or polyglycolic acid,
polylactic acid.

The blood concentration or local white concentration is sustained to the extent that it is contained in synthetic polymers such as polyglutamic acid.

Now, regarding interferon, which is a medicinal ingredient, interferon may be used alone, it may be used together with an interferon activity activator, or it may be used in combination with interferon and other medicinal ingredients that can be expected to have additive or additive effects. There may be. Note that the interferon referred to herein may be any of α, β, γ, and other interferons, and of course, may also be a combination thereof.

As for the carrier, any of the carriers mentioned above can be selected, but from the viewpoint of safety and ease of use, it is preferable to use collagen, gelatin, or a mixture of both. Collagen is a major protein in animal connective tissue, and is a safe protein that is already frequently used in medical surgical threads as a protein with little antigenicity.

Furthermore, for the purpose of further increasing safety, atelocollagen with lower antigenicity may be used by removing the telopeptide portion by treating the collagen with an enzyme, for example, with pepsin. Furthermore, gelatin is a protein derived from collagen, and has already been evaluated for safety in medicine (5) as an inexpensive polyampholyte with low antigenicity and sol-gel conversion properties.

Next, an example of a method for incorporating interferon into the carrier of the present invention will be explained. That is, the interferon-containing solution and the carrier-containing solution are mixed and stirred as uniformly as possible without forming bubbles, and if necessary, they are concentrated at a low temperature or, if necessary, 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, it is crushed under cooling with dry ice, liquid nitrogen, etc. to obtain a powder. At this time, the particles crushed and micronized to an injectable particle size can be suspended in a viscous injection solvent to form a long-lasting suspension injection. Alternatively, by separately adding a viscous solvent for injection, a preparation can be prepared that is suspended before use. The interferon and the carrier may be made into fine particles by other general methods as appropriate.

The viscous injection solvent is compression molded with an additive for sesame (6), for example, into a needle-like or rod-like form (diameter 0.5n) that can be administered with a fiberscope forceps needle or an indwelling needle. ~1.5 mm, length 5□n~15f
Make a preparation of about 1 liter). 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. In addition, the same method is used to prepare implantable preparations, i.e., preparations in the form of pellets, spheres, granules, or powder that can be implanted or dispersed into the body or lesion during surgery, etc. be able to. These can be used depending on the situation, such as the degree of duration required at that time, but it is natural that the larger the shape, the longer the duration.

It goes without saying that each of these steps is performed aseptically because of the nature of the injection or implant.

Next, the present invention will be explained more clearly by experimental examples and examples, but these examples are not intended to limit the present invention.

Experimental Example 1 An oil-based suspension preparation of collagen prepared in Example 1 (sample a), a acicular preparation of collagen prepared in example 2 (sample b), and an aqueous α-interferon (derived from Namalva cells) as a control. Each of the injections (sample C) was administered intramuscularly to rabbits, and the time course of the blood concentration was examined using quantification using the RI method.

Two rabbits were used each, and the dose was 106 for each.
It was administered at a dose of V/1g. The average value of two birds was used for the numerical value.

The results are shown in Figure 1. As can be seen in Figure 1, sample a
and b shows a persistent tendency, even after 48 hours, several tens of U/m
The blood concentration of 1 is maintained, and is particularly sustained in the needle-shaped preparation.

In this way, in vitro experiments using domestic rabbits also suggested the clinical usefulness of the formulation of the present invention.

Example 1 A solution containing α-type interferon (potency 4°9 MU/go) 100 s/g and 2% atelocollagen 50 f were mixed and stirred uniformly without forming bubbles as much as possible, and after freeze-drying, liquid N2 was used. Grind at low temperature. This was suspended in sesame oil to obtain an oil-based suspension type long-acting preparation containing 4 MU of interferon per Ivial.

C Samprom) Example 2 By compression molding the pulverized product obtained in Example 1,
A needle-shaped long-acting preparation containing IQMU of interferon per bottle was obtained. (Sample b) Example 8 (9) The pulverized product obtained in Example 1 was suspended in castor oil to obtain an oil-based suspension type long-acting preparation containing 4 MU of interferon per vial.

Example 4 The pulverized product obtained in Example 1 was compression-molded into pellets to obtain a sustained-release preparation containing IQMU of interferon per pellet.

Example 5 Solution containing α-type interferon (potency 4°9 MU/g
/) l 00+w (and 50g of 2% 4-teterocollagen)
, human serum albumin 150 mg and Himetyrosal 12
Mix and stir 0 μf uniformly without forming bubbles as much as possible, freeze-dry, and then cryogenically grind using liquid N2. By suspending this in sesame oil, per 1 vial,
An oily suspension type long-acting preparation containing 4MU of interferon was obtained.

Example 6 (10) Solution containing α-type interferon (potency 4°9 MU/
me) 100 ml of 2% collagen and 50 g of 2% collagen are mixed uniformly and stirred to avoid foaming as much as possible, freeze-dried, and then cryogenically ground using liquid N2. This was suspended in sesame oil to obtain an oil-based suspension type long-acting preparation containing 4 MU of interferon per 1 Iyia.

Example 7 Solution containing α-type interferon (potency 4°9 MU/g
l) Mix loOt/ and atelocollagen powder lf.
．． After adding IN-hydrochloric acid and dissolving it, it is put into a mold and freeze-dried. By compression molding this, each piece has an I
A needle-like long-acting preparation containing OMU interferon was obtained.

Example 8 Solution containing α-type interferon (potency 4°9MU/*
l) Mix and stir 100 ml of gelatin ly uniformly at 60°C without forming bubbles as much as possible, freeze-dry, and then grind at a low temperature using liquid Nz. By suspending this in sesame oil, an oil-based suspension type long-acting preparation containing 4 MU of interferon per vial was obtained.

Example 9 The pulverized product obtained in Example 1 was suspended in PEG to obtain a suspended long-acting preparation containing 4 MU of interferon per Ivial.

Example 1O To the pulverized product obtained in Example 1, 25% by weight of methylcellulose was added, and distilled water for injection was added to make the solid content 20%, followed by freezing. This was placed in a mold, lyophilized, and then compression molded to obtain a needle-shaped long-acting preparation containing 1QMU of interferon per bottle.

Example 11 Solution containing α-type interferon (potency 4°9 FLU
/ml) 100ml and 2% atelocollagen 5ON
and Tespamine 98 Da are mixed and stirred uniformly to avoid foaming as much as possible, freeze-dried, and then cryogenically ground using liquid N2.

By compression molding this, a needle-shaped long-acting preparation containing IQMU of Inferon and about 2 mg of tespamine was obtained.

Example 2 By suspending the pulverized product obtained in Example 1 in iodinated poppy oil fatty acid ethyl ester (Libiodol Ultrafluid, handled by Kodama Shoji), 4. MU's oil-based suspension containing interferon -←→-fur]ton deficiency -o-

[Brief explanation of the drawing]

FIG. 1 shows the change in blood concentration after intramuscular administration to rabbits, and compares two preparations of the present invention with an aqueous injection of α-interferon as a control. Vertical axis: α-interferon blood concentration unit: unit/lsl Horizontal axis: 2 hours Unit: 2 hours 0; Collagen oil suspension of the present invention △; Collagen acicular preparation of the present invention; α-interferon aqueous injection ( 11 complete)

Claims (1)

[Scope of Claims] (1) Interferon is contained in a carrier consisting of one type or a mixture of two or more types selected from biodegradable and low-toxic substances that can be implanted in the body. A long-acting interferon preparation. (2) The long-acting preparation according to claim 1, wherein the interferon and the carrier are atomized and suspended in a viscous injection solvent. (8) The long-acting preparation according to claim 1, wherein the interferon carrier is a rod-shaped or needle-shaped preparation. (4) The long-acting preparation according to claim 1, which is a preparation in which interferon and ←← are combined and the +→4 carrier is formed into granules, powders, spheres, pellets, or the like. (5) Claims 1 and 2, wherein the carrier is collagen, gelatin, or a mixture of collagen and gelatin. The long-acting preparation according to item 8 or 4.