JPS5892620A - Composition containing stably compounded interferon - Google Patents

Abstract

PURPOSE:To provide the titled composition containing interferon as active component and an acidic sugar as stabilizing agent. CONSTITUTION:The objective composition containing stably compounded interferon is prepared by compounding >=1X10<4> IU of interferon (having titer of >=1X10<5> IU/mg-protein) per 100g of the composition and >=0.01wt% stabilizer comprising an acidic sugar (e.g. iduronic acid, galacturonic acid, glucuronic acid, gluronic acid, etc.) based on the whole composition. The stability of interferon can be further improved by adding an organic acid buffering agent, a sulfur-containing mild reducing agent having sulfhydryl selectivity, a human serum albumin, etc. to the composition. It can be administered in the oral cavity, to the skin, or in the rectum, vagina, urethra, eye, ear, nose, etc.

Description

[Detailed description of the invention] The present invention relates to interferon stable formulation compositions.

Interferon is a type of protein that is produced by animal cells in response to stimulation by viruses, double-stranded RNA, etc. and has the effect of suppressing the proliferation of viruses, and its effect is known to be specific to animal species.

In recent years, it has become increasingly clear that interferons derived from human cells and microorganisms incorporating human interferon genes exhibit therapeutic effects on various human diseases, and clinical applications are being attempted.

Due to the therapeutic effects of interferon, it is expected that interferon can be used as a medicinal agent to be incorporated into various compositions including pharmaceuticals, quasi-drugs, and cosmetics. However, interferon is an extremely unstable substance, and in particular, when it is purified to a clinically applicable level, its activity is significantly reduced by temperature (high temperature) or physical pressure, and it easily expires. Therefore, unless Interf□ Elon is stabilized in the composition, no effect can be expected from its inclusion.

Therefore, the present inventors continued intensive research to obtain a composition containing human-derived interferon in a stable manner, and found that, unexpectedly, the stability of interferon in the composition was significantly increased when acidic sugars were present. find improvements,
This led to the completion of the present invention.

That is, the present invention provides a stable interferon composition containing human-derived interferon as an active ingredient and containing acidic sugar as a stabilizer. According to the present invention, interferon can be formulated into compositions of various shapes, such as for intraoral application, external dermal application, rectal, vaginal or intraurethral administration, ocular, otic or intranasal administration.
Its activity is maintained stably over a long period of time.

Thus, the interferon to be incorporated into the composition of the present invention may be of any human origin, such as human leukocytes, normal diploid cells, or recombinant DNA.
Microorganism-derived products that incorporate human interferon genes using techniques are used. The amount of interferon to be added is not particularly limited and can be selected depending on the actual shape, etc. However, from the viewpoint of effectiveness, interferon having a titer of 10 international units/q protein or more is generally used in the composition. It is desirable to mix the ingredients in such a proportion that the amount per 100g will be more than 104 international countries.

Acidic sugars used as stabilizers include iduronic acid, galacturonic acid, glucuronic acid, guluronic acid, mannuronic acid, ketogluconic acid, ketogluconic acid, ketogulonic acid, ascorbic acid, and salts thereof such as sodium salts and potassium salts. may be used alone or in combination of two or more. From the viewpoint of interferon stabilization, the amount of acidic sugar is at least 0.01% based on the total amount of the composition.
(c weight 931%, the same applies hereinafter) is preferably blended.

As mentioned above, the composition of the present invention can be used in small forms for intraoral application such as pass puffs, toothpaste, and rutting agents, gels, ointments, small forms for external use on the skin, gels, mixtures, rectal, etc. Various forms can be provided, including forms for intravaginal or intraurethral administration, forms for ocular, otic or intranasal administration such as liquids, gels, lozenges, and sprays. Any of these can be manufactured according to conventional formulation techniques, and interferon may be added in the final step of enzymatic preparation. Other ingredients are not particularly limited as long as they do not affect the stability of interferon, and any of those commonly used in this type of preparation may be used. Also, along with acidic sugars, citrate buffers, cono-phosphate buffers, -tartrate buffers,
Organic acid buffers such as fumarate buffers, gluconate buffers, oxalate buffers, lactate buffers, acetate buffers, thioctic acid, N-acetylcysteine, N-acetylhomocysteine, glutathione , thiodiglycol,
One or two selected from the group consisting of sulfhydryl group-selective mild combination reducing agents such as thioethanolamine, monothioglycerol, dithiothreitol, thioalkanoic acids having 1 to 7 carbon atoms, and human serum albumin.
Since the stability of interferon is further improved by blending more than one substance, these may be blended as appropriate.

Next, the present invention will be explained in more detail with reference to Examples.

The interferon used in these Examples was obtained from human foreskin-derived fibroblasts, and its activity was measured using Sindbis virus (5indbis virus).
s virus) and human amnion-derived cell line (F
L cells) were measured by the cytopathic effect (CPE) method (Ravel I, E, A.

and Vilcek, J-(1972)+'An
timiclob, Agents Chemother,
, 2.476 HOie, H, K1. (1977
"l.

Texas#Rep, Biol, Med-+ 85+
154) In addition, the interferonka titer was compared with the activity of standard interferon measured at the same time and converted into international units (c or less, abbreviated as IU).

Example 1 A suppressant was prepared according to a conventional method using the following formulation.

Ruminant Prescription Ingredients Tisaccharin 0.02 Fragrance 0.02 Acidic Sugar (
(shown in Table 1) Purified water The remaining components were mixed, interferon was added at a ratio of 1 x 106 II/100 g of gargling agent, and the mixture was thoroughly mixed to obtain an interferon-containing metallic syrup.

After storing the obtained entrainer at 37° C. for 1 month and at 4° C. for 6 months, its interferon activity was measured, and the residual rate of interferon activity was calculated by setting the activity immediately after production as 100%. The results are shown in Table 1.

Table 1 Example 2 Pasta was prepared according to the conventional method according to the recipe shown in Table 2. After mixing each component, add 1Xl of interferon.
The mixture was added at a ratio of 0 IU/100g pasta and mixed well to obtain interferon-containing pasta.

After storing this at 37°C for 1 month and at 4°C for 6 months in the same manner as in Example 1, the residual activity of interferon was calculated. The results are shown in Table 2.

Table 2 Example 3 A gel preparation for external use on the skin was prepared according to the conventional method using the following formulation.

Gel prescription ingredients Human serum albumin 0.5 Tween 80
0.2 Sodium carboxymethyl cellulose 2.0 Acidic sugar (shown in Table 8) 1.0 Purified water Mix the remaining components, and finally add interferon to 1×107107
A 100 g gel was added and mixed to obtain an interferon-containing gel for external use on the skin.

In the same manner as in Example 1, the residual activity of the interferon was calculated after storage at 37°C for 1 month and at 4°C for 6 days. The results are shown in Table 8.

Table 3 Example 4 Macro goal 400. ．． Mix 100g of acidic sugar shown in Table 4 at a ratio of 0.05%, add interferon to this at a ratio of 1xlOlυ/100f mixture, mix well, pour into a container, cool, The mixture was molded and filled into capsules in an amount of 1 g each to obtain half of the interferon mixture. After this half-open storage at 87°C for 1 month and at 4°C for 6 months, the residual activity was calculated. The results are shown in Table 4.

Claims (1)

[Scope of Claims] (1) A composition containing interferon at a low price, characterized in that it contains interferon as an active ingredient and acid-glucose as a stabilizer. (2) the acidic sugar is iduronic acid, galacturonic acid, glucuronic acid, guluronic acid, mannuronic acid, ketocurconic acid,
The composition according to item (1) above, which contains one or more acidic sugars selected from the group consisting of ketocurconic acid, ketogulonic acid, ascorbic acid, and salts thereof. (8) The composition according to item (1) above, which contains at least 0.01 weight of acidic sugar based on the total amount of the composition. (4) Further, as a stabilizer, one or more substances selected from the group consisting of an organic acid buffer, a mild sulfur-containing reduction with sulfhydryl group selectivity, and human serum albumin are blended. ) to (8). (5) Items (1) to (4) above, which are narrow for use in the oral cavity.
) The composition of any one of the items. (6) Paragraph (1) above which is 'IIJ type of skin external preparation.
The composition of any one of paragraph (4). (7) The composition according to any one of Items (1) to (4) in Item 40, which is in a narrow form for intrarectal administration. (8) Items (1) to (4) above, which are in a narrow form for intravaginal administration.
) The composition of any one of the items. (9) Items (1) to (1) above, which are in a narrow form for intraurethral administration.
4) The composition of any one of item 4). (1) Items (1) to (4) above, which are small forms for ocular administration.
) The composition of any one of the items. (11) Items (1) to (4) above, which are small forms for re-administration.
) The composition of any one of the items. The composition of any one of items (1) to (4) above, which is in a narrow form for nasal administration.