CA1295242C

CA1295242C - FORMULATIONS SUITABLE FOR THE STABILISATION OF .alpha.-INTERFERON

Info

Publication number: CA1295242C
Application number: CA000528832A
Authority: CA
Inventors: Helmut Franz
Original assignee: Dr Karl Thomae GmbH
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 1986-02-05
Filing date: 1987-02-03
Publication date: 1992-02-04
Anticipated expiration: 2009-02-04
Also published as: NO169638B; IL81472A0; ES2028796T3; ZA87793B; HUT43494A; EP0231816A2; EP0231816B1; IE870295L; FI86144B; PT84243B; FI870457A0; HU196560B; DK58387A; NZ219169A; PT84243A; KR870007698A; NO169638C; NO870441D0; NO870441L; JPS62209024A

Abstract

Abstract Pharmaceutical formulations for topical administration which stabilise the .alpha.-interferon contained therein, comprise as carrier and stabiliser a mixture of 1. a cellulose derivative, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid polymer or a mixture of any of these, and 2. gelatine, which has been subjected to acid or alkaline digestion, and, in addition, an anti-adhesion agent.

Description

5~ ~2 "Stabilized formulations of ~-interferon"

The present invention relates to stabilized formulations of ~-interferon for topical use.
Human interferons, and interferons in general, are divided into three groups, depending on their biological and chemical pro-perties and the site of their synthesis. These groups are called alpha-interferon, beta-interferon and gamma-interferon, corresponding to -IFN, ~-IFN and ~-IFN. The site of synthesis of ~-IFN, to which the present invention relates, is the leucocytes which, after sti-1~ mulation or induction by appropriate inducers (for example virusesor poly I poly C) synthesize and release ~-IFN. Bacteria trans-formed with suitable DNA sequences are able to synthesise ~-IFN
which has a biological activity analogous to that of the genuine human ~-IFN. This has the advantage that highly purified proteins which are essentially free of contamination can be obtained in com-paratively large amounts and can be used for clinical administration, for example against various viral infections and malignant tumours.
All know interferons have antiviral, antiproliferative and, but to varying extents, immunomodulating effects. Initially reco-~0 gnised as antiviral agents, their thèrapeutic uses now include theiruse as antineoplastic agents.
The application route is of particular importance with respect to the nature of the interferon effects and the rate of side effects attached thereto.
Systemic administration of interferons has particularly noticeable disadvantages since they reach and affect not onl~ the ~ . - ..

:., . :,, target tissue but also healthy, uninfected or non-transformed cells or organs and thus induce side effects which may prevent intravenous or intramuscular use. In addition, the efficacy of systemic admi-nistration has not always proved to be that desired. In some cases direct injection of interferon is possible for treatment of, for example, viral or malignant diseases or other related diseases which can be treated with interferon. If the target tissue is accessible to e~ternal and local treatment (for example skin, eyes, nose) then topical administration of interferon is the method of choice. Very ld recently there have been reports from various sources of the topical application of human leucocyte interferon (a synonym for ~-IFN) and it was surprisingly found that the success rate for various malig-nant diseases was high (for example Ikic et al, Lancet, 1022-24, 1981, Vol.l; Ikic et al., Lancet 1025-27, 1981, Vol.l). It is con-ceivable that the topical administration of ~-interferon will become o~ increasing medical importance in the future for the treatment of various viral or tumour-related diseases.
There are considerable difficulties, from various aspects, associated with the topical administration of ~-IFN, as well as with ~a interferons in general. From the aspect of the pharmaceutical for-mulation, a requirement is that sufficiently high stability is con-ferred on the biologically active ~-IFN in order for it to act over an adequately long period both at room temperature and at body tem-perature or to remain effective "in situ" over a suitable period of hours. It is known that ~-IFN is a protein which is very unstable to heat. Considerable losses of activity, of up to 80%, have been observed within 2;~2 a few weeks at 4C in a gel which contained human leucocyte interferon and, as gel component, carboxymethyl cellulose (Moller B.R. et al., Obstetrics & Gynecology 62, 625-629, 1983) used for topical administration in the treatment of cervical carcinoma in situ.

The stability-maintaining components which are therefore necessary must be of such a nature that ~hey neither cause intolerance reactions a~ the site of administration, conceivably due to the effect of biologically active foreign substances, nor impair the penetration or diffusion of ~-IFN.

Recently, various components have been used to stabilise interferons. Estis, Evans and Testa have used hydroxyethyl cellulose as an excipient for the preparation of interferon-containing gels or ointments but have only been able to prevent considerable losses of ~-IFN, ~-IFN or ~-IFN activity under realistic conditions of administration by the addition of a protease inhibitor (EP-A-0 142 345).

Those skilled in the art know that hydroxyethyl cellulose is extremely well suited for the preparation of gels or other matrices, for example because of its stability to heat, and its ready commercial availability.

The particular advantages of hydroxyethyl cellulose compared with other excipients for the preparation of a matrix containing ~-IFN is that it does not coagulate or gel at the boilinq point of water, it is very soluble in water, and the viscosity of such a solution increases with decreasing temperature.
It is not possible to stabilise interferon or ~-IFN at physiological temperatures by hydroxyethyl 2 ~2 cellulose alone. It is also well known that protein products such as interferons, which have not been highly purified and are thus contaminated, are subject to hydrolysis by proteases under suitable conditions.
Other attempts to confer suitable stability on interferons contained in pharmaceutical preparations have been made by Akagi, Miura and Hoshino (EP-A-0 150 067) using polysaccharides dif~ering chemically from hydroxy-ethyl cellulose, such as dextran and hydroxyethyl starch with the addition o~ human serum albumin, mono- or disaccharides, or amino acids, the preparations described being chiefly for the parenteral, systemic administration route via intravenous or intramuscular injection.
Various sugar alcohols such as glycerol, erythritol, arabitol, xylitol, sorbitol and mannitol, as well as various sugar acids such as iduronic acid, galacturonic acid and other uronic acids, and ascorbic acid and their salts, and various organic buffer systems such as citrate buffer, succinate bufferj tartrate buffer, fumarate buffer, glyconate buffer, oxalate buffer, lactate buffer and acetate buffer, in combination with various pharmaceutical excipients such as waxes, ~5 sodium carboxymethyl cellulose, carboxyvinyl derivatives and water have also been disclosed for the stabilisation of interferon in gels, ointments, suppositories, sprays etc. for topical administration (EP-A-0 080 879).

All the above-mentioned interferon-stabilising components, and especially the compositions of the pharmaceutical formulations and their methods of administration, are fundamentally different from the present invention and cannot be compared thereto.
There has therefore been a need for a carrier matrix for highly purified ~-interferon, specifically 5æ~% ~2 for recombinant-prepared ~-IFN, which would comply with the require-ments listed above as well as having a composition which is as fa-vourable as possible, in terms of both the preparation technique and economics, i.e. a simple composition for topical administration which does not cause loss of the requisite optimal efficacy of the biologically active substance ~-IFN contained in the excipient matrix. We have now found that by combining together a suitable ~arrier, especially hydroxyethyl cellulose, and gelatine in appro-priate proportions we obtain a carrier and stabilizer for ~-IFN
l~ which not only meets the requirements described above, at least in l~rge measure, but also, surprisingly, confers a particular stabi-lity on the biological activity of ~-IFN, and thus is extremely suitable for the topical administration of highly purified ~-IFN, especially that prepared by recombinant DNA technology.
Thus in one aspect our invention provides a pharmaceutical ~ormulation containing ~-interferon for topical administration, which formulation comprises ~-interferon and, as carrier and sta-bilizer, a mixture of (i) a cellulose derivative, polyvinyl alcohol, poly-vinylpyrrolidone, polyacrylic acid polymer or a mixture of any of t~lese, and (ii) gelatine, which has been subjected to acid or alka line di~estion, and, in addition, an anti-adhesion agent.
Another advantage of this invention is that the carrier/
stabilizing complex which has been found contains no human serum ;'' ' ' ':

. :, ' ' ' ,'. , .
' . '' :

- 5a -albumin which it is known may, especially on topical admlnistration over lengthy periods, result in local immune reactions extending up to allergies. Hence the present invention provides improved pharma-.~

ceutical formulations for the topical administration of ~-IFN.

In the formulations of the present invention the two individual components 1) and 2), which function as carrier and stabiliser, together exert an activity-maintaining effect on ~-IFN which is highly unexpected.
It is known that ~-IFN, and interferons in general, are proteins which are unstable to, for example, physical effects - both in the ~naked" form and when incorporated into other gel matrices (for example, Moller B.R. et al., see above). However the formulations according to the invention appear to have a remarkable and unexpected intrinsic or inherent synergistic effect on the stability of ~-IFN. Thus the gelatine in the present invention does not on its own act as a siqnificant stabilising agent; only in a complex together with component I) does it display the astonishing synergistic stabilising affect on ~-IFN to which this invention relates.

The pharmaceutical formulations of ~-IFN according to the invention which are for topical administration are preferably administered as viralstatics, therapeutic use being dermal, nasal, ophthalmic or intravaginal, for example, for Herpes labialis, Herpes genitalis including papilloma infections, warts and for Herpes zoster infections. The range of uses also embraces topical treatment of paracanceroses and canceroses.
The pharmaceutical formulations may additionally comprise other conventional adjuvants such as buffers and salts, humectants, preservatives, penetration-promoters, and excipients.
Components 1) of the carrier/stabiliser mixture are known substances, viz. cellulose derivatives (e.g.

2 ~ Z

carboxymethyl cellulose, methyl cellulose, hydroxypropyl-methyl cellulose) and polyvinyl alcohols, polyvinyl-pyrrolidone, polyacrylic acid polymers (CarbopolR) and mixtures of any of these, together with, as component 2), gelatine which has been subjected to acid or alkaline digestion preferably having a Bloom value of 160-200. The preferred e~cipient and stabiliser used for ~-IFN is hydroxyethyl cellulose with a degree of substitution of about 2.5, in defined mixing ratios of 0.1 to 2~ by weight with respectively from 0.1 to 10% by weight of gelatine, based on the finished product. When polyvinyl alcohols or polyvinyl pyrrolidone are used then up to 15% by weight of these are employed. This achieves special stabilisation, specifically of ~-IFN, as demonstrated for example in the stability behaviour experiments which have been carried out and as shown graphically in Figures 1 to 3, which embrace an experimental period of 14 weeks with storage temperatures of -10, +4 and +21C in each case.

It is possible to use anti-adhesion agents to improve the spreading of the gels, and as anti-adhesive filtration aids anionic, cationic as wèll as neutral surface-active substances can be used, preferably polyethoxylated sorbitan esters such as Polysorbate 20, 60 or 80 whose chemical composition is given hereinafter. Appropriate inorganic and organic buffer solutions having a pH in the range 6.5 to 7.4, which is optimal for ~-IFN preparations, are sodium phosphate buffer, potassium hydrogen phosphate-sodium dihydrogen phosphate buffer and citric acid/phos-phate buffer, potassium sodium glutamate phosphate buffer and succinate buffer.

~` ~2~2 ~:

Suitable humectants for the formulations containing ~-IFN, according to the invention are glycerol, 1,2-propylene glycol, sorbitol, butylene glycol and polyols (e.g. polyethylene glycol 400).

Examples of suitable preservatives which are tolerat~d by skin are e.g. p-hydroxybenzoic esters (Nipa-ester), preferably methyl p-hydroxybenzoate; also benzoic acid, sorbic acid, chlorhexidine digluconate, benzalkonium chloride and hexadecyltrimethylammonium bromide (cetrimonium bromide).
i A suitable penetration-promoter which is compatible with ~2-IFN is up to 50% by weight of dimethyl sulfoxide (DMSO).

The most suitable vehicle for non-alcoholic hydrogels is water.
., Suitable pharmaceutical forms for topical administration on the skin, in the eye or in the nose or other body cavities are, for example, hydrogels. ~ydrogels generally contain 0.1 to 2.0% by weight of both gelatin and cellulose derivatives and/or polyvinyl alcohols, polyvinylpyrrolidones or polyacrylic acids, it being necessary to adjust the mutual ratios depending on the desired viscosity. When polyvinyl alcohols or polyvinylpyrrolidone is used, up to 15% by weight thereof may be necessary.
In the case of the manufacture of vaginal suppositories the proportion of gelatine should be increased to as much as 10~ by weight, likewise depending on the desired viscosity.

In the following Examples there are detailed descriptions of the preparation of pharmaceutical formulations for topical administration which stabilise the ~52~;~

a-IFN contained therein, the formulations being made according to the present invention mainly of cellulose derivatives and gelatine, anti-adhesion agents and the active substance ~-IFN contained therein, and various additives. Obviously many modifications and alterations can be made, which will include the subject-matter of the invention, without departing from the scope of the invention, and the listed examples do not limit the invention.
In the Examples:

Nipagin M = methyl p-hydroxybenzoate, 5 Polysorbate 20 = Polyoxyethylene(20) sorbitan monolaurate (Tween 20), Polysorbate 60 = Polyoxyethylene(20) sorbitan monostearate (Tween~60), Polysorbate 80 = Polyoxyethylene(20) sorbitan monooleate (Tween 80), Benzalkonium = mixture of alkyldimethylbenzylammonium 25 chloride chlorides with alkyl groups having 8 to 18 carbon atoms, Cetrimonium bromide = hexadecyltrimethylammonium bromide, 3.2 x 108I.U. a2-Arg interferon i5 equivalent to 1 mg of this substance.

Example 1 (Hydrogel) 100 g of gel substance contains:

a2-IFN 1 x 108 IU
Nipagin M 0. 20 g Gelatine, Bloom 160-200 0.50 g NaCl 0.48 9 KCl 0.012 9 NaH2P04 ~ 2H2 K2HPO4 3H2O 0.0407 g Na glutamate . H2O 0.0636 g Polysorbate 20 0.1 Hydroxyethyl cellulose (e.g.
NatrosolR 250 HX) 1.75 9 Water, deionised ad 100 9 96.7944 ~

The ~2-IFN bydrogel is prepared by dissolving Nipagin M in water at 80C and then cooling the solution to room temperature (RT) and, during the cooling period, introducing the gelatine into the solution.
Once the gelatine hàs completely dissolved, at RT NaCl, KCl, NaH2PO4 . 2H20, K2HPO4 . 3H2O, Na glutamate . H2O and Polysorbate 20 are successively added to the solution. After subsequent sterilisation by filtration, microbiologically pure hydroxyethyl cellulose is sprinkled in and the solution is again heated to 80C while stirring. After having been cooled to RT, and while stirring cautiously, an acidic 1~ polysorbate 80 containing a2-IFN solution consisting of 0.01 N HCl and lyophilised a2-IFN, is added and homogeneously dispersed. This mixture is placed into sterile aluminium tubes under laminar air flow conditions.

.
:' `~ ~2~5i2 ~2 Example 2 (Hydrogel) 100 9 of gel substance contains:

S ~2-IFN 1 x 1ol0 IU
Hydroxyethyl cellulose (e.g.
NatrosolR 250 HX) 2.0 9 ; Gelatine, Bloom 160-2000.1 g NaCl 0.35 9 10 ~a2HPO4.2H2O 0.16 9 2P4 O. 09 g 1,2-propylene glycol 10.00 g Polysorbate 80 0.1 9 Benæalkonium chloride 90% 0.02 9 Water, deionised ad. 100 9 The ~2-IFN hydrogel is prepared by dissolving benzalkonium cbloride in water at 30C, adding the propylene glycol at RT, and then introducing the gelatine ~20 into the solution. Once the gela~ine has completely dissolved, at RT, NaCl, Na2HPO4.2H20, KH2PO~ and Polysorbate 80 are successively added. After sterilis-? ation by filtration, microbiologically pure hydroxyethyl cellulose is sprinkled in, and the solution is heated at 80C for 20 min with stirring. After having been cooled to RT, while stirring cautiously an acidic polysorbate ~2-IFN solution, consisting of lyophilised 2-IFN dissolved in~0.01 N HCl and 0.1~ polysorbate 80, is placed and dispersed homo-geneously. This mixture is placed into sterilealuminium tubes under laminar air flow conditions.

, ~ ~2~35~Z

Example 3 tHydrogel) 100 g of gel substance contains:

~2-IFN 1 x 106 IU
Hydroxyethyl cellulose (e.g.
NatrosolR 250 HX) 1.0 g Gelatine, Bloom 160-200 1.0 g Polysorbate 20 0.1 g Glycerol 5.0 g Succinic acid 0.24 g Cblorhexidine digluconate 0.05 g lN-NaOH (ad. pH 6.0) Water, deionised ad. 100.0 g The ~2-IFN hydrogel is prepared by dissolving chlor-hexidine gluconate, glycerol and gelatine at about 30C. Succinic acid is then added, the pH is adjusted to 6.0 with lN NaOH, and polysorbate 20 is added.
The microbiologically pure hydroxyethyl cellulose is then sprinkled in, and the solution is heated at 80C for 20 min, with stirring. After having been cooled to RT, wit~ cautious stirring the acidic polysorbate ~2-IFN solution is added and homogeneously dispersed. Filling is carried out as in Examples 1 and 2.

.

. .

z Example 4 (Hydrogel as nasal gel ) 100 9 of gel substance contains:

a2-IFN 1 x 108 IU
Hydroxypropylmethyl cellulose (e.g. MethocelR Premium) 0.1 g Polysorbate 60 0.1 9 Gelatine, Bloom 160-200 0.5 9 Sorbitol solution 70% 2.0 9 Citric acid . H2O 0.1309 Na2HPO~ . 2H2O 0.30 g NaCl 0-5 9 Benzalkonium chloride 90% 0.02 9 Water, deionised ad. 100 9 The ~2-IFN hydrogel is prepared by dissolving the hydroxypropylmethyl cellulose with water at 40C, with stirring. The solution is then cooled to RT, and during the cooling peri~d, gelatine is introduced. Once it has dissolved the following are introduced successively: benzalkonium chloride, sorbitol solution, citric acid, di-Na-hydrogen phosphate, NaCl and Polysorbate 60. The prepared gel is cautiously stirred at RT and the acidic 1 ~ polysorbate containing ~2-IFN solution is introduced and homogeneously dispersed. The product is placed into sterile aluminium tubes under laminar air flow conditions.

2 ~2 Example 5 (Hydrogel as ophthalmic gel) 100 g of gel substance contains:

2-IFN 1 x 10 IU
Polyacrylic acid (MW: ca. 3 million) 0.1 g Gelatine, Bloom 160-200 0.3 g Polysorbate 20 0.1 g Sorbitol solution 70% 2.0 g Glycerol 1.0 g NaCl 0.1 g Cetrimonium bromide 0.01 g lN NaOH (ad. pH 7.4) Water, deionised ad.l00 g The ~2-IFN hydrogel is prepared by dissolving the polyacrylic acid and gelatine in water at RT with stirring, and then the sorbitol solution, glycerol, NaCl, cetrimonium bromide and polysorbate are succesively introduced. Once dissolution is complete, the solution is sterilised by filtration and while stirring at RT, adjusted to a pH of about 7.6 with sodium hydroxide solution, during which the gel forms. Into this gel at RT, the 2-IFN solution which contains hydrochloric acid (0.001 N) and 1 ~ polysorbate is introduced, stirring cautiously, and homogeneously dispersed. The product is placed into sterile aluminium tubes under laminar air flow as in the previous Examples.

;2~2 Example 6 (Vaginal suppositories) 100 9 of vaginal suppository mass contains:

5 a2-IFN 1 x 108 IU
Hydroxyethyl cellulose0.1 g Gelatine, Bloom 160-20010.0 9 Na2HP04 . 2H20 0.16 9 2P4 .O. 0~ 9 Polysorbate 20 0.1 9 Glycerol 57.0 9 Water, deionised ad~ 100 g The ~2-IFN vaginal suppositories are prepared by 15 dissolving the hydroxyethyl cellulose together with the gelatine in a mixture of glycerol and water which already contains Na2HP04 . 2H20, KH2P04 and polysorbate, at about 40-50~C. While still viscous (at about 37-40C), the ~2-IFN solution 20 which contains 1 % polysorbate and hydrochloric u acid (O.OOlN) is cautiously stirred in and the solution is immediately poured into suitable cooled moulds for solidification.

2S Example 7 (Stability tests, hydrogel without gelatine vs. with gelatine) 100 9 of gel substance contains:
~2-IFN 1 x 108 IU1 x 108 IU
30 Nipagin M 0.2 9 0.2 9 Gelatine, Bloom 160-200 - 0.5 g NaCl 0.48 g 0.48 g KCl 0.0129 0.0129 Na2HP04 . 2H20 0.0869 0.0869 35 KH2P04 . 3H20 0.012g 0.0129 Polysorbate 20 0.1 9 0.1 9 Hydroxyethyl cellulose . 2.0 9 2.0 9 (e.g NatrosolR 250 HX) Water, deionised ad. 100 g Figures 1 to 3 show the stability of an ~2-IFN
hydrogel of the above composition withou~ the addition of gelatine (dotted lines) and with the addition of gelatine (unbroken lines), filled into aluminium tubes, Each point represents the mean of 6 deter-minations. The determinations were carried out by ELISA.

Figure 1 shows the stability on storage at -10C, Figure 2 shows stability on storage at +4C, and Figure 3 shows stability on storage at +21C, in each case comparatively.

The stability behaviour was followed over a period of 14 weeks (3~ months). It was found astonishingly and completely unexpectedly, that the differences in stability became more distinct as the storage temperature increased. On summation of the biological stability results over the entire period of 14 weeks and formation of an arithmetic mean (x) of the values (n = 11), the picture which emergès is that shown in the table which follows, in which a value of 10.0, corresponding to 108 I.U. ~2-IFN
per 100 9, was set equal to 100% activity:

Storage Hydrogel without Hydrogel with Difference temper-addition of addition of 30 aturegelatine gelatine -10Cx (11)=8.49 (=-15%) x (11)=9.72 (=-3%~ 12%
~ 4Cx (11)=7.52 (=-25~) x (11)=9.97 (=~/-0) 25%
35 +21Cx (11)=5.67 (=-43%) x ~11)=8.87 t=-11%) 32%

~L29~;~42 The stabilising effect of the combination of hydroxyethyl cellulose and gelatine is clearly evident from this table. On storage in a refrigerator (=+4C) virtually no decrease in the activity of the formulation with the addition of gelatine was found after 3 months, whereas the formulation without the addition~
of gelatine showed a decrease of about 2S%. In this connection it is practicable to store a commercial product at refrigerator temperature. On storage at 21C, the loss of activity of the formulation without the addition of gelatine was found to be almost one half the initial figure during the storage period of 3~ months, whereas the formulation according to the invention with hydroxyethyl cellulose and gelatinè showed a loss of activity of only 11%
during this period, which is equivalent to a relative increase in stability of a2-IFN of more than 30%.

Another storage test lasting 44 weeks (10 months) ~0 of a formulation as described in Example 1, filled into aluminium tubes with an inner protective lacquer and stored at temperatures of 4C and 21C, showed no loss of ELISA activity compared with the initial figure.
~5 Storage Hydrogel according to Example 1 temperature Initial Final figure figure after 10 months 4C x (6) 9.6 x (6) 11.0 21C x (6) 9.6 x (6) 9.6

Claims

1. A pharmaceutical formulation containing .alpha.-interferon for topical administration, which formulation comprises .alpha.-interferon and, as carrier and stabilizer, a mixture of (i) a cellulose derivative, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid polymer or a mixture of any of these, and (ii) gelatine, which has been subjected to acid or alkaline digestion, and, in addition, an anti-adhesion agent.

2. A pharmaceutical formulation according to claim 1 in the form of a hydrogel.

3. A pharmaceutical formulation according to claim 1 wherein the cellulose derivative comprises hydroxyethyl cellulose.

4. A pharmaceutical formulation according to claim 2 wherein the cellulose derivative comprises hydroxyethyl cellulose.

5. A pharmaceutical formulation according to claim 1 or 2 comprising hydroxyethyl cellulose and gelatine, each in an amount of 0.1 to 2.0% by weight, based on the finished product.

6. A pharmaceutical formulation according to claim 1 or 2, comprising hydroxyethyl cellulose and gelatine, the amount of gelatine being 0.1 to 10% by weight, based on the finished product.

7. A pharmaceutical formulation according to claim 1 or 2 wherein the cellulose derivative is hydroxyethyl cellulose which has a degree of substitution of about 2.5 and the gelatine has a Bloom value of 160-200.

8. A pharmaceutical formulation according to claim 1, 2 or 3 wherein the anti-adhesion agent comprises an anionic, cationic or non-ionic surfactant.

9. A pharmaceutical formulation according to claim 1, 2 or 3 wherein the anti-adhesion agent comprises a polyethoxylated sorbitan ester.

10. A pharmaceutical formulation according to claim 1, 2 or 3 wherein the anti-adhesion agent comprises the monolaurate, monostearate or monooleate of polyoxyethylene (20) sorbitan.

11. A pharmaceutical formulation according to claim 1, 2 or 3 wherein the .alpha.-interferon contained therein has been obtained from a cell culture which has been transformed with a DNA sequence coding for human .alpha.-interferon.

12. A pharmaceutical formulation according to claim 1, 2 or 3 wherein the .alpha.-interferon contained therein has been obtained from cells of E. coli which have been transformed with a DNA
sequence coding for human .alpha.-interferon.

13. A pharmaceutical formulation according to claim 1, 2 or 3 wherein the .alpha.-interferon contained therein has been obtained from cells of E. coli. which have been transformed with a DNA
sequence coding for human .alpha.-interferon and the .alpha.-interferon has a specific activity of 1 x 105 to 1 x 1010 IU/100 g finished product.

14. A pharmaceutical formulation according to claim 1, 2 or 3 which include one or more additional adjuvants selected from buffers, humectants, preservatives which are tolerated by skin, penetration promoters which are compatible with .alpha.-interferon and vehicles.

15. A pharmaceutical formulation according to claim 1, 2 or 3 which includes a buffer system which is sodium phosphate buffer, potassium hydrogen phosphate/sodium dihydrogen phosphate buffer, citric acid/phosphate buffer, potassium-sodium-glutamate-phosphate buffer, succinate buffer or a mixture of any of these.

16. A pharmaceutical formulation according to claim 1, 2 or 3 which is buffered with a buffer which has a pH in solution in the range of 6.0 to 7.4.

17. A pharmaceutical formulation according to claim 1, 2 or 3 which includes a humectant which comprises glycerol, 1,2-propylene glycol, sorbitol, butylene glycol, a polyol or a mixture of any of these.

18. A pharmaceutical formulation according to claim 1, 2 or 3 which includes a humectant which comprises glycerol, 1,2-propylene glycol, sorbitol, butylene glycol, polyethylene glycol 400 or a mixture of any of these.

19. A pharmaceutical formulation according to claim 1, 2 or 3 which includes a preservative tolerated by skin which comprises p-hydroxybenzoic esters, sorbic acid, benzoic acid, chlorhexidine digluconate, benzalkonium chloride, hexadecyltrimethylammonium bromide or a mixture of any of these.

20. A pharmaceutical formulation according to claim 1, 2 or 3 which includes dimethyl sulphoxide, in a proportion of up to 50% by weight, as a penetration promoter which is compatible with .alpha.-interferon.

21. A pharmaceutical formulation according to claim 1, 2 or in the form of a gel whose vehicle is water.

22. A process for the preparation of a pharmaceutical formulation according to claim 1, 2 or 3 for use as dermal, nasal, ophthalmic and intra-vaginal viralstatics; for Herpes labialis, Herpes genitalis including papilloma infections, warts and for Herpes zoster infections; and for the topical treatment of paracanceroses and canceroses, which process comprises admixing the respective components under conditions such that said .alpha.-interferon is stabilized.

23. A process for the preparation of a pharmaceutical formu-lation for topical use which stabilizes .alpha.-interferon contained therein, wherein:
(a) gelatine in an amount of 0.1 to 2.0% by weight, based on the finished product, is dissolved in water at up to 80°C, and an anti-adhesion agent is added to the solution, (b) optionally a preservative, humectant, salt, buffer system or penetration-promoter is introduced into this solution, (c) into this solution at up to 80°C is introduced hydroxyethyl cellulose or carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid or a mixture of any of these, in an amount of 0.1 to 2.0% by weight, based on finished product, and of up to 15% by weight in the case of polyvinyl alcohols or polyvinylpyrrolidone, and (d) .alpha.-interferon, in an amount of 1 x 105 to 1 x 1010 IU/100 g of finished product is homogeneously dispersed therein, and this mixture is filled into sterile containers.

24. Process for the preparation of pharmaceutical formula-tions for intra-vaginal administration, wherein:
(a) hydroxyethyl cellulose in an amount of 0.1 to 2.0%
by weight is dissolved together with gelatine in an amount of up to 10% by weight, in a water/glycerol mixture at temperatures up to 60°C and (b) at a temperature of 40 to 50°C, an .alpha.-IFN solution which contains polysorbate and hydrochloric acid is cautiously stirred in, and (c) this solution is immediately poured into suitable moulds.