LT3987B - Stabilized interferon compositions - Google Patents

Abstract

This invention is used for the production of compositions, which include interferon and retain biological activity for at least two years. These compositions can be used as remedies for various virus inflammations etc. The proposed compositions have 1x10<6>-6.6x10<6>TV interferon, for example 1x10<6>-6.6x10<6>TV "α-interferon", 5-30 mg of polygliukine serves as a stabilizing agent for each millilitre of phosphate-salt medical form buffer system, the pH of which is 7.0-7.6.

Description

The invention relates to compositions containing interferon which retain their biological activity for a long time and which can be used as medicaments, for example against many viral infections, especially for the preparation of injection solutions, intranasal aerosols and drops, including for the eyes.

In order to avoid possible side effects and to ensure the repetition of the observed therapeutic effects, it is desirable to use interferons with high specific activity. It is well known that a high specific activity of interferon solutions ^- is biologically unstable, namely, the complicated bio-stable dosage form for clinical use in the creation.

It is known that the following biological stabilizing components may be used in formulating interferon formulations: human albumin (EP 013.3767, A61K 45/02,

1984), sugars (glucose, mannose, galactose, fructose, sucrose, etc.) (EP 0133767, A61K 45/02, 1984); dextrans and hydroxyethyl starch (EP 0150067 A6IK 45/02, 1985);

polyethylene glycol and hydroxyethylcellulose (EP 0152345, A61K 45/02

1985); polycarboxylic acids (copolymers of methyl methacrylate and maleic acid, Na salt of carboxymethylcellulose, xylitol (DE 3642223, A61K 45/02, 1988).

The use of human albumin to stabilize interferon formulations requires additional monitoring of the resulting formulations to ensure that no hepatitis B and AIDS viruses are present. In addition, human albumin use is limited by the lack of raw material, donor blood.

The closest proposed biosafety effect is a lyophilized pharmaceutical composition which is dissolved in sterile water containing the stabilizer amino acids and their derivatives (glycine, α-alanine) as well as human albumin (EP 0082481, A61K 45/02, 1982; US; 4,496,537, A61K 45/02, 1983).

However, this known formulation retained its biological activity for essentially only 6 months. In addition, human albumin is used in the composition, albeit in smaller amounts than are generally used.

The object of the present invention is to extend the time during which the composition containing the interferon retains its biological activity without the use of human albumin for stabilizing the dosage form.

This object of the invention is achieved by the use of a polyglucin in the composition of an interferon and a buffer system suitable for maintaining the pH in pharmaceutical solutions, preferably in the range 7.0-7.6.

Polyglucin (rocynapcTBeHHas cpapMaKones X, Art. 545) used in the invention to stabilize biological activity is a medium molecular fraction (60,000 ± 10,000 D), a partially hydrolyzed dextran solution in 0.9% sodium chloride isotonic solution. Polyglucin is obtained by hydrolyzing native dextran derived from sucrose using Leuconostoc mesenteroides strain C <t> -4. Polyglucin concentration in solution

5.5-6.5%.

The invention relates to compositions containing interferon which retain their biological activity for a long time and which can be used as medicaments, for example against many viral infections, especially for the preparation of injection solutions, intranasal aerosols and drops, including for the eyes and the like.

The human interferon used in the proposed compositions may be α-interferon or γ-interferon.

The biological activity of interferons was determined in culture of human skin-muscle tissue-grafted cell line against vesicular stomatitis virus.

To our knowledge, polyglucin has not previously been used to extend the time at which interferon compositions do not alter biological activity. The use of materials of similar origin, such as dextran (MM 10000-100000 D), is known but only in γ-interferon compositions and in combination with hydroxyethyl starch. However, the retention time of the biological activity achieved by these means is not more than 2 weeks at 40 ° C. Thus, it can be said that the invention is not obvious to those skilled in the art.

The invention is illustrated by the following examples:

An example. / Composition Preparation Methods /

Add 250 to 500 ml of water for injections into a 1000 ml container and add the required amount of sodium chloride. Content is shuffled. to the resulting solution, the following sodium phosphates are added, stirred until the salts are completely dissolved, and a 6% solution of polyglucin is added. The pH of the solution is further adjusted by adding phosphoric acid or caustic soda.

The solution obtained is added to interferon solution and the volume is adjusted to 1000 ml by adjusting the pH with phosphoric acid or caustic soda and diluting with water for injections.

Composition of the reconstituted solution for lyophilization (1000 ml, 1 ml in pharmaceutical form)

ot-2 interferon (BOC 42-226 BC-89) lxl0 ⁹ TV Sodium chloride (Str Art. 426 X) 8.5g Disodium hydrogen orthophosphate dodecahydrate 2.8 g Sodium dihydrogen orthophosphate dihydrate (TY 6-09-01-584-79) 0.38 g Polyglucin 6% solution (Str X Str. 545) 8 4 ml NaOH or H3PO4 to pH 7.0 Water for injections up to 1000 ml The methodology of the following examples is analogous

for example.

An example.

Composition of the reconstituted solution for lyophilization (1000 ml, 1 ml in pharmaceutical form)

γ-Interferon l, 3xlO ^y TV Sodium chloride (Str X Str. 426) 9.05am Disodium hydrogen orthophosphate dodecahydrate 2.74g Sodium dihydrogen orthophosphate dihydrate (TY 6-09-01-584-79) 0.36 g Polyglucin 6% solution (ΓΦ Art. 545 X) 500 ml NaOH or H3PO4 to pH 7.6 Water for injections up to 1000 ml

An example.

Composition of the reconstituted solution (1000 ml, 1 ml in the formulation) Interferon a-2 3.2x10 ⁹ IU

Sodium chloride - · 8.5g Disodium hydrogen orthophosphate dodecahydrate 2.74g

Sodium dihydrogen orthophosphate dihydrate 0.36 g

Polyglucin 6% solution 170 ml NaOH or H3PO4 to pH 7.0 Water for injections up to 1000 ml

Polyglucin 6% solution 170 ml NaOH or H3PO4 to pH 7.0 Water for injections up to 1000 ml Example 4.

Composition of the reconstituted solution for lyophilization (1000 ml, 1 ml in pharmaceutical form)

a-2 interferon 6.4xl0 ⁹ IU Sodium chloride 9.0g Disodium hydrogen orthophosphate dodecahydrate 2.65g

Sodium dihydrogen orthophosphate dihydrate 0.35 g

Polyglucin 6% solution 500 ml NaOH or H3PO4 to pH 7.6 Water for injections up to 1000 ml

An example.

Composition of the reconstituted solution for lyophilization (1000 ml, 1 ml in pharmaceutical form)

γ- Interferon 3, lxl0 ⁹ TV Sodium chloride 9.0g Disodium hydrogen orthophosphate dodecahydrate 2.65g Sodium dihydrogen orthophosphate dihydrate 0.35 g Polyglucin 6% solution 500 ml NaOH or H3PO4 to pH 7.6 Water for injections up to 1000 ml

6 Example. For freeze-dried preparation of this solution (1000 ml, 1 ml at the pharmacy form) γ-Interferon 6.6xl0 ⁹ IU Sodium chloride 9.0g Disodium hydrogen orthophosphate dodecahydrate 2.80g Sodium dihydrogen orthophosphate dihydrate 0.38 g Polyglucin 6% solution 500 ml NaOH or H3PO4 to pH 7.6 Water for injections up to 1000 ml

'T (0

G a

4-1 (0

G

Φ a

£ =

O

G

G (0

At • H o

ω {0 e

G r — I • i — f

Λ (0

4->

ω

G

S

G

O

M-1

G • rd

G

-H

4->

V)

G

>

G

C

O

G (U

4-4

G

Φ

4-1

C • r ~ I ω

G

G

G o

E> g • Φ r— {{U

4-J

G

O

G

biological activity * s γ-Interferon G G ε c G o o G M-1 o M-1 G G -H o G G • H c -U (Z) H Ή OJ ra l > s

>

H kO O O X® cm x ° © X o ^ · cm xO χ © © X © X O '' 1 O o C0 o rH CN CO X co o o rH cn O o cn rd χΓ r ~ < 1 r-1 r ^- 1 «—1 , —T

mo>

H ΚΏ o o o ^x X® _X o Cm © X X? X? χθ © X © X cx O i-1 o O uo sr © X C0 'T G X G O o cn θ rH O O rH »—1 i— ( T-1 i-1

G

> H cm cm χ® cm X® Cm ŽCH X? © X X® © ^ x® cm MO O O • O co C) 04 Γ OJ 00 , —1 o O cn ! -1 O t-H O o cn X co t-4 t-1 t - t t-1 r-H <—1

G>

H MO O rH X o o © ^x o o OJ i-1 cm cn 00 x® © ^x co o x® © x o cn ' \ © © X r-H O huh? co «—1 X® © ^x cn G <—1 f-H r ~ l r — I r — I 1-1

MO

> E \ ® © X huh? X® cm χ® © x x® cm x® © ^x © ^x ch MO o O > o G CO OJ f — t U0 O CN t-4 o O O cn r-1 cn t- » CN O X t-1 ι-1 r - t r — I t-i t — To i-H

G

> \ ® cm χ® cm X® © ^s £ S? H MO o O 1-1 00 (—1 rH «—I o- O • O cn o o m rH o <n rH G gH (—1 rH <—1 rH

• H

G ω • r-f w •• H K o G G -H i-1 « ε c • <H C G • G i-1 • H (Z) • H • H At ε Oh ε o Ό r-H O  H G c ra O Ή G G O o M a Oh ε G 4-1 ε Cu

C0 <0 cn CN r-1

CO

4-1

G

G

O • rH At O

G

G> 1

OT

G ε

G .G

G

G

W

G

C

O

G

Θ

M-1

G

O

4->

C • r —i I ca.

Ή> u c

• Ή i-i

4-J £

m o

Ψη

2 ′ ω

-rl

CN

As can be seen from the table, the main advantage of human interferon formulations containing polyglucin as a stabilizing agent is that they retain their biological activity for at least 2 years. The albumin-free formulation eliminates the need to control additional dosage forms to ensure that they are free of hepatitis B and AIDS viruses and the like.

Claims (2)

DEFINITION OF INVENTION Claims 1. Stabilized interferon compositions, characterized in that they contain turiθ - 6.6 x 10 6 IU of interferon and contain as a stabilizing agent 5 to 30 mg of polyglucin per ml of a pharmaceutical solution in a pH 7.0-7.6 buffer system. Compositions according to claim 1, characterized in that they contain 1x10 4 -10 4 -10 4 IU of human geno-engineered interferon α-2 and 5 to 30 mg of polyglucin for each ml of the formulation of phosphate-buffered saline, pH 7.0-7.6.