IE870295L - Stabilised formulations of alpha interferon - Google Patents
Stabilised formulations of alpha interferonInfo
- Publication number
- IE870295L IE870295L IE870295A IE29587A IE870295L IE 870295 L IE870295 L IE 870295L IE 870295 A IE870295 A IE 870295A IE 29587 A IE29587 A IE 29587A IE 870295 L IE870295 L IE 870295L
- Authority
- IE
- Ireland
- Prior art keywords
- interferon
- pharmaceutical formulations
- gelatine
- formulations according
- hydroxyethyl cellulose
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/212—IFN-alpha
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
Abstract
The pharmaceutical forms are intended for topical administration and employ as vehicle for and stabiliser of the active ingredient a composition which specifically confers special stability on the active ingredient IFN alpha. The forms are essentially composed of hydroxyethylcellulose and gelatin and preferably contain highly purified IFN alpha which has been prepared by DNA recombination as active ingredient.
Description
59697 - i - Human interferons, and interferons in general, are divided into three groups, depending on their biological and chemical properties and the site of their synthesis, which are called alpha-interferon, beta-interferon and gamma-interferon, corresponding to a-IFN, B-IFN and y-IFN. The site of synthesis of g~IFN, to which the present invention relates, is the leucocytes which, after stimulation or induction by appropriate inducers (for example viruses or poly I* polv C) synthesize and release a~IFM. Bacteria transformed with suitable DNA sequences are able to svnthesise a-IFN which has a biological activity analogous to that of the genuine human a-IFN, with the advantage that highly purified proteins which are essentially free of contamination can ^5 be obtained in comparatively large amounts and can be used for clinical administration, for example against various viral infections and malignant tumours. 10 20 25 30 35 All known interferons have antiviral, antiproliferative and, but to varying extents, immunomodulating effects. Initially recognised as antiviral agents,, their therapeutic uses now include their use 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 only 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 administration has not always proved to be that desired. In a few cases, although direct injection may be 5969 7 - 2 - possible, the agent of choice is„ for example for viral or malignant diseases or other related diseases which can be treated with interferon and which are accessable to external and local treatment (for example, skin, eyes, nose), topical administration of interferon, or of a-IFN to which this invention relates. Very recently there have been reports from various sources of the topical application of human leucocyte interferon (a synonym for a~IFM) and it was suprisingly found that the success rate for various malignant diseases was high (for example Ikic et al„ Lancet,, 1022-24, 1981,, Vol.1-; Ikic et al.. Lancet 1025-27, 1S81, Vol.1). It is conceivable that the topical administration of ce-interferon will become of increasing medical importance in the future for the treatment of various viral or tumour-related diseases.
There are considerable difficulties, from various aspects f associated with the topical administration of ce-IFM, as well as with interferons in general. From the aspect of the pharmaceutical formulation, a requirement is that sufficiently high stability is conferred on the biologically active cs-IFN in order for it to act over an adequately long period both at room temperature and at body temperature or to remain effective "in situ" over a suitable period of hours. It is known that a-IFN is a protein which is very unstable to heat. Considerable losses of activity, of to 80%, have been observed within a few weeks at 4°C in a gel which contained human leucocyte interferon andas gel component, carboxymethyl cellulose (Holier B„R» e*c s 1,e Obstetrics & Gynecology 62 - 525-629 £. 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 they neither cause intolerance reactions at the site of administration, conceivably due to the effect of biologically active foreign substances, nor impair the penetration or diffusion of a-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 a-IFN, 6=I FN or y-IFM activity under realistic conditions of administration by the addition of a protease inhibitor (EP-A-0 152 345) .
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 excipient for the preparation of a matrix containing a-IFN is that it does not coagulate or gel at the boiling point of watere 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 a-IFN at physiological temperatures by hydroxyethyl cellulose alone. It is also well known that protein products such as interferonsvhich have not been highly purified axiid 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 :%! Various sugar alcohols such as glycerol, erythritol, arabitol, xylitole 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 buffer, tartrate buffer, fumarate buffer, glyconate buffer, oxalate bufferP lactate buffer and acetate buffer, in combination ?#ith various pharmaceutical excipients such as waxes, sodium carboxymethy1 cellulose, carboxyvinyl derivatives and water have also been disclosed for the stabilisation of interferon in gels, ointmentst, 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 (for example EP-A 0 162 332), are fundamentally different from the present invention and cannot be compared thereto.
The object of the present invention was to find an excipient matrix for highly purified c-interferon, specifically for recombinant-prepared a-IFN, which would comply with the requirements listed above as well as having a composition which is as favourable 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 a™IFN contained in the excipient matrix. This complex object has been achieved in the present invention by combining together hydroxyethyl cellulose and gelatine, subjected to acid or alkaline digestion, which thus allows the production of an excipient and stabiliser for a-IFN which not only meets the requirements described above, but also, surprisingly, confers a particular stability on the biological activity of a-IFM, and thus is extremely suitable for the topical administration of highly purified a-IFN, especially that prepared by recombinant DMA technology.
Another advantage of this invention is that the excipient/stabilising complex which has been found contains no human serum albumin which it is known may, especially on topical administration over lengthy periods, result in local immune reactions extending up to allergies- Hence the present invention relates to an improved pharmaceutical formulation for the topical administration of a-IFN. According to the present invention the two individual components which function as excipient and stabiliser» namely hydroxyethyl cellulose and gelatine together exert an activity-maintaining effect on a- -XFJ-T which goes beyond the extent expected, it being necessary to take particular account of the fact that a-IFN, and interferons in general, are known to be proteins which are unstable to, for example, physical effects - both in the 91 nakedua form and when incorporated into other gel matrices (for example, Holler B.R. et al.. see above) so that the formulations according to the invention have, surprisingly and in a way which could not have been foreseen, an intrinsic or inherent synergistic effect with regard to increasing the stability of a-IFN. Thus the gelatine in the present invention does not on its own act as a stabilising agent but only in a complex together with-hydroxyethyl cellulose does it display the astonishing synergistic stabilising affect on a-IFN which has been found and to which this invention relates.
The pharmaceutical formulations of a-IFN according to the invention which are for topical administration are preferably administered as viralstatics, therapeutic use being dermal, nasalf ophthalmic or intravaginal, for example, for Heroes labialis. Herpes genitalis including papilloma infections,, warts and for Heroes zoster infections- The range of uses also embraces topical treatment of paracanceroses and canceroses, This invention relates to pharmaceutical formulations for topical administration,, with the substance human a~interferon (a-IFN) contained therein being stabilised, which consist of 1. an excipient and stabiliser in a complex with the active substance 2 an anti-adhes ion agent and 3„ where appropriate other conventional active substances such as buffers and salts, hmnect&nts P preservatives, penetration-promotersand excipients.
The excipients and stabilisers for a-IFN are hydroxyethyl cellulose,, hydroxypropylmethyl cellulose or mixtures thereof,, together with gelatine which has been subjected to acid or alkaline digestion- The preferred excipient and stabiliser used for a-IFN is hydroxyethyl cellulose with a degree of substitution of 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. This achieves special stabilisation, specifically of a-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 +21°C 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 well as neutral surface-active substances are used, preferably polyethoxylated sorbitan esters such as Polysorbate 20, 60 or 80. Appropriate inorganic and organic buffer solutions having a pH in the range 6.0 to 7.4, which is optimal for a-IFN preparations, are sodium phosphate buffer, potassium hydrogen phosphate-sodium dihydrogen phosphate buffer and citric acid/phosphate buffer, potassium sodium glutamate phosphate buffer and succinate buffer.
Suitable humectasxts for -the formulations containing a-IFN, according to the invention are glycerols 1,2-propvlene glycol, sorbitol,, butylene glycol and polyols (e.g. polyethylene glycol 400).
Examples of suitable preservatives which are tolerated by skin are e.g. p-hydroxybenzoic esters (Mipa-ester), preferably methyl p-hydroxybensoate? also sorbic acid, chlorhexidine digluconate, benzalkonium chloride and hexadecvltrimethylammoniuaia bromide (cetrimoniusa bromide). - 8 - A suitable penetration—promoter which is compatible with a2~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. Hydrogels generally contain 0.1 to 2.0% by weight of both gelatin and the cellulose derivatives, it being necessary to adjust the mutual ratios depending on the desired viscosity. In the case of the manufacture of vaginal pessaries the proportion of gelatine should be increased to as much as 10% by weight, likewise depending on the desired viscosity.
A hydrogel is generally prepared by dissolving gelatine, in an amount of 0.1 to 2.0% by weight based on the finished product, in water at temperatures up to 80°C, then adding the remaining adjuvants, e.g. humectants, salts, buffer systems and penetration promoters and then the hydroxyethyl cellulose, hydroxypropylmethyl cellulose or a mixture thereof to the solution.
Finally, the ^-interferon is added to the solution, which has been cooled to ambient temperature, in a quantity of 1 x 105 to 1 x 10i0 IU/100 g of finished product and homogeneously distributed therein. The finished product is packaged under sterile conditions.
In order to produce preparations for intravaginal administration, hydroxyethyl cellulose in an amount of 0»1 to 2.0% by weight,, together with gelatine in an amount of up to 10% by weight, is dissolved in a water/glycerol mixture at temperatures up to 60°Cf then at a temperature of 40 to 50 ° C a hydrochloric IFN-ce - 9 - solution containing polysorbate is carefully stirred in and the resulting solution is immediately poured into suitable moulds.
In the following Examples there are detailed descriptions of the preparation of pharmaceutical formulations for topical administration which stabilise the 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 a-IFN contained therein, and various' additives.
In the Examples: Nipagin® M = methyl p-hydroxybenzoate, Polysorbate 20 = Polyoxyethylene(20) sorbitan R xnonolaurate (Tween 20) , Polysorbate 60 = Polyoxyethylene(20) sorbitan R monostearate (Tween 60), Polysorbate 80 = Polyoxyethylene(20) sorbitan R Xflonooleate (Tween 80), Benz£ 1 koniurn = mixture of allcyldiitaethylbenxylajniaonium chlorides with alkvl groups having 8 to 18 carbon atoms, Cetrimonium bromide = haxadacyltrisnethylasmaoniuai bromide,, Q 3.2 x 10 I„U. c,^-interferon is equivalent to 1 xng of this substance. - 10 - Example 1 (Hydrogel) 100 g of gel substance containss 1 x 108 IU 0.20 g 0.50 g 0.48 g 0.012 g 0.0593 g 0.0407 g 0.0636 g 0.1 g 1.75 g 96»7944 g The hydrogel is prepared by dissolving Nipagin M in water at 80 °C and then cooling the solution to room temperature (RT) and, during the cooling period, introducing the gelatine into the solution. Once the gelatine has completely dissolved, at RT NaCl, KCl, NaH2P04 . 2H20f K2HPC>4 - Ma 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 80°C while stirring. After having been cooled to RT, and while stirring cautiously„ an acidic polysorbate c2~IFN solution containing 0 01 N HGl and lyophilised c^-IFN, is added and homogeneously dispersed. This aaixture is placed into sterile aluminium tubes under laminar air flow conditions. a2-IFN Nipagin M Gelatine, Bloom 160-200 NaCl KCl NaH-PO,, . 2H 0 2 4 2 K HPO . 3H_0 2 4 2 Na glutamate . H20 Polysorbate 20 Hydroxyethyl cellulose (e.g. HatrosolR 2 50 HX) Water, deionised ad 100 g ~ 11 - Example 2 (Hydrogel) 100 g of gel substance contains: a2-IFN 1 x 1010 IU Hydroxyethyl cellulose (e.g.
NatrosolR 250 HX) 2.0 g Gelatine, Bloom 160-200 0.1 g NaCl 0.35 g Na2HPC>4 . 2H20 0.16 g kh2po4 0.09 g 1,2-propylene glycol 10.00 g Polysorbate 80 0.1 g Benzalkonium chloride 90% 0.02 g Water, deionised ad. 100 g The q^-IFN hydrogel is prepared by dissolving benzalkonium chloride in water at 30°C, adding the propylene glycol at RT, and then introducing the gelatine into the solution. Once the gelatine has completely dissolved, at RT, NaCl, Na2HP04 . 2R^0, KH2P04 and Polysorbate 80 are successively added. After sterilisation by filtration, microbiologically pure hydroxyethyl cellulose is sprinkled in, and the solution is heated at 80°C for 20 min with stirring. After having been cooled to RT, while stirring cautiously an acidic polysorbate a2~IFN solution, consisting of lyophilised c^-IFN dissolved in 0.01 W HCl and 0.1% polysorbate 80, is placed and dispersed homogeneously. This mixture is placed into sterile aluminium tubes under laminar air flow conditions. - 12 - Example 3 (Hydrogel) 100 g of gel substance contains: a2-IFN 1 x 106 IU Hydroxyethyl cellulose (e.g.
NatrosolR 250 HX) 1.0 g Gelatine, Bloom 160-200 1.0 g Polysorbate 2 0 0.1 g Glycerol 5.0 g Succinic acid 0=24 g chlorohexidine digluconate 0.05 g lN-NaOH (ad- pH 6.0) Water, deionised ad. 100.0 g The a2~IFN hydrogel is prepared by dissolving chlorhexadine gluconate, glycerol and gelatine at about 30°C. Succinic acid is then added, the pH is adjusted to 6.0 with IN NaOH, and polysorbate 20 is added. The microbiologically pure hydroxyethyl cellulose is then sprinkled in? and the solution is heated at 80°C for 20 min, with stirring. After having been cooled to RT, with cautious stirring the acidic polysorbate o^-IF-N solution is added and homogeneously dispersed. Filling is carried out as in Examples 1 and 2. - 13 - Example 4 (Hydrogel as nasal gel) 100 g of gel substance contains: a2-IFN 1 x 108 IU Hydroxypropylmethyl cellulose p (e.g. Methocel Premium) 0.1 g Polysorbate 60 0.1 g Gelatine, Bloom 160-200 0,5 g Sorbitol solution 70% 2„0 g Citric acid . H20 0.130g Na2HP04 . 2H20 0.3 0 g NaCl 0.5 g Benzalkonium chloride 90% 0.02 g Water, deionised ad. 100 g The c^-IFN hydrogel is prepared by dissolving the hydroxypropylmethyl cellulose with water at 40°C, with stirring. The solution is then cooled to RTP and during the cooling period, gelatine is introduced. Once it has dissolved the following are introduced successively; benzalkonium chloride, sorbitol solution, citric acid, di-Ha-hydrogen phosphateP NaCl and Polysorbate 60. The prepared gel is cautiously stirred at RT and the acidic polysorbate a2~IFN solution is introduced and homogeneously dispersed. The product is placed into sterile aluminium tubes under laminar air flow conditions. - 14 - Example 5 (Vaginal pessaries) 100 g of vaginal pessary mass contains: a2~IFN 1 x 108 IU Hydroxyethyl cellulose Gelatine, Bloom 160-200 Na_HPO. . 2H O 2 4 2 KH PO. 2 4 Polysorbate 20 Glycerol Water, deionised ad. 100 g 0.1 g 10.0 g 0.16 g 0.09 g 0.1 g 57.0 g The a2~IFN vaginal pessaries are prepared by dissolving the hydroxyethyl cellulose together with the gelatine in a mixture of glycerol and water which already contains Ma2HPC>4 . 2n^0, KH^PO^ and polysorbate, at about 40—50°C. While still viscous (at about 37-40°C), the a2~IFN solution which contains polysorbate and hydrochloric acid (0.001N) is cautiously stirred in and the solution is immediately poured into suitable cooled moulds for solidification.
Example 6 (Stability tests, hydrogel without gelatine vs. with gelatine) 100 g of gel substance contains: o:2-IFN Mipagin M Gelatine, Bloom 160-200 NaCl KCl Ma_HP0, . 2H_0 1 x 108 IU 1 x 108 IU 0*2 g 0.2 g 0.5 g KH.P0. . 3H_0 2 4 2 Polysorbate 20 Hydroxyethyl cellulose (e.g NatrosolR 250 HX) 2* 4 " 2 0.48 g 0.48 g o.oi2g 0.0l2g 0-086g 0.086g 0,0l2g 0.012g 0.1 g 0.1 g 2.0 g 2.0 g - 15 - Water, deionised ad„ 100 g Figures 1 to 3 show the stability of an c^-IFM hydrogel of the above composition without the addition of gelatine (dotted lines) and with the addition of V. gelatine (unbroken lines), filled into aluminium tubes.
Each point represents the mean of 5 determinations. The determinations were carried out by SLISA.
Figure 1 shows the stability on storage at -10°C, Figure 2 shows stability on storage at +4"C, and Figure 3 shows stability on storage at ■f21°Cj, in each case comparatively.
The stability behaviour was followed over a period of 14 weeks (3h 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 emerges is that shown in the table which follows,, in which a value of 10.0, O corresponding to a 10 I„U. a2~IFN per 100 g,; was set equal to 100% activity? Storage temperature Hydrogel without addition of gelatine Hydrogel with addition of gelatine Difference -10*C X (11)=8.49 (=-15%) X (11)=9.72 (=~3%) 12% f 4"C X (11)=7.52 (=-25%) X (11) =9,97 (=V-0) 25% f21" C X (11)=5.67 (=-43%) 5 (11)=8 87 (=-11%) 32% The stabilising effect of the combination of hydroxyethyl cellulose and gelatine is clearly evident from this table- On storage in a refrigerator (=+4°C) - 16 - virtually no decrease in the activity of the formulation with the addition of gelatine was found after 3h months, whereas the formulation without the addition of gelatine showed a decrease of about 25%. In this connection it is practicable to store a commercial product at refrigerator temperature. On storage at 21°C, 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 gelatine showed a loss of activity of only 11% during this period, which is equivalent to a relative increase in stability of a^-IFN of more than 30%» Another storage test lasting 44 weeks (10 months) of a formulation as described in Example 1, filled into aluminium tubes with an inner protective lacquer and stored at temperatures of 4'C and 21°C, showed no loss of ELISA activity compared with the initial figure.
Storage Hydrogel according to Example 1 temperature Initial Final figure figure after 10 months i- 4 ° C x (5) 9.5 x (6) 11.0 H- 21 ° C x (6) 9. S X (6) 9.6
Claims (14)
1. hydroxyethyl cellulose, hydroxypropylmethyl cellulose or mixtures thereof, and 2. gelatine, which has been subjected to acid or alkali digestion, and, in addition, as anti-adhesion agent, anionic, cationic or neutral surface-active substances and, where appropriate, other conventional adjuvants.
2. Pharmaceutical formulations for topical administration containing c-interferon according to claim l, wherein they comprise a hydrogel.
3. Pharmaceutical formulations according to claim 2, wherein they contain as excipient and stabiliser hydroxyethyl cellulose and gelatine,, the-amount of hydroxyethyl cellulose being from 0.1 to 2.0% by weight, based on the finished product.
4. Pharmaceutical formulations according to claim 2, wherein ' they contain as excipient and stabiliser hydroxypropylmethyl cellulose and gelatine, each being in ant amount of 0.1 to 2.0% by weight, based on the finished product-
5. Pharmaceutical formulations according to claim 2, wherein they contain as excipient and stabiliser hydroxyethyl cellulose and gelatine, the amount of gelatine being 0.1 to 10% by weight, based on the finished product.
6. Pharmaceutical formulations according to one of claims 1 to 5, wherein the anti-adhesion agent is composed of polyethoxylated sorbitan esters.
7. Pharmaceutical formulations according to one of claims l to 6, wherein the ^-interferon contained therein is obtained from a cell culture which has been transformed with a DNA sequence coding for human cs-interferon.
8. Pharmaceutical formulations according to one of claims 1 to 7, wherein they contain as additional adjuvants a buffer system for a pH range from 6.0 to 7.4, humectants, preservatives which are tolerated by skin, penetration promoters which are compatible with ce-interferon and a vehicle.
9. S. Pharmaceutical formulations according to claim 8, wherein they contain, as humectants, glycerol, 1,2-propylene glycol, sorbitol, butylene glycol, a polyol such as polyethylene glycol 400 or a mixture thereof.
10. Pharmaceutical formulations according to claim 8, wherein penetration promoter which is compatible with a-interferon is up to 50% by weight of dimethyl sulphoxide.
11. Process for the preparation of pharmaceutical formulations according to claim 1 for topical use which stabilise the cs-interferon contained therein,, wherein, in order to prepare a hydrogel, gelatine in an amount of 0.1 to 2.0% by weight, based on the finished product, is dissolved in water at temperatures up to 80"Gf, and the other adjuvants such as humectants, salts, buffer systems and penetration-promoters are then introduced into this solution, then f - 19 - hydroxyethyl cellulose, hydroxypropylmethyl cellulose or a mixture thereof is introduced into the solution and, after cooling to ambient temperature, ts-interferon, in an amount of 1 x 10s to I x 1010 IU/100 g of finished 5 product is homogeneously dispersed therein, and this mixture is filled into sterile containers.
12. Process for the preparation of pharmaceutical formulations according to claim 1 for intra-vaginal 10 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, at temperatures up to SO"C in a water/glycerol mixture which also 15 contains an anti-adhesion agent and optionally salts, buffer substances and preservatives, and h. at a temperature of 40 to 50"C, an a-IFN solution which contains polysorbate and hydrochloric acid is cautiously stirred in, and 20 c- this solution is immediately poured out into suitable moulds. as defined in Claim 1
13. Pharmaceutical formulations containing a -interferon substantially as hereinbefore described by way of Example. 25 as defined in Claim 11 or
14. Process for the preparation of pharmaceutical formulation^, Claim 12, substantially as hereinbefore described by way of Example™ 30 15, A pharmaceutical formulation whenever prepared by a process as claimed in Claim 11, Claim 12 or Claim 14. Dated this 4th day of Februarys 1987. BY: T0MKINS & CO., App1i cant1s Agents, (Signed) 35 5 Dartmouth Road, Dublin 6.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863603444 DE3603444A1 (en) | 1986-02-05 | 1986-02-05 | PHARMACEUTICAL PREPARATIONS FOR STABILIZING INTERFERON ALPHA |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE870295L true IE870295L (en) | 1987-08-05 |
| IE59697B1 IE59697B1 (en) | 1994-03-23 |
Family
ID=6293372
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE29587A IE59697B1 (en) | 1986-02-05 | 1987-02-04 | Stabilised formulations of alpha-interferon |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0231816B1 (en) |
| JP (1) | JPS62209024A (en) |
| KR (1) | KR870007698A (en) |
| AT (1) | ATE63823T1 (en) |
| AU (1) | AU601712B2 (en) |
| CA (1) | CA1295242C (en) |
| DD (1) | DD284602A5 (en) |
| DE (2) | DE3603444A1 (en) |
| DK (1) | DK164202C (en) |
| ES (1) | ES2028796T3 (en) |
| FI (1) | FI86144C (en) |
| GR (1) | GR3002270T3 (en) |
| HU (1) | HU196560B (en) |
| IE (1) | IE59697B1 (en) |
| IL (1) | IL81472A0 (en) |
| NO (1) | NO169638C (en) |
| NZ (1) | NZ219169A (en) |
| PH (1) | PH24377A (en) |
| PT (1) | PT84243B (en) |
| ZA (1) | ZA87793B (en) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5275804A (en) * | 1986-02-25 | 1994-01-04 | E. B. Michaels Research Associates, Inc. | Process and composition for oral hygiene |
| DE3731255A1 (en) * | 1987-09-17 | 1989-04-06 | Boehringer Ingelheim Int | Stabilization of therapeutically active proteins in pharmaceutical preparations |
| US5266310A (en) * | 1987-09-17 | 1993-11-30 | Boehringer Ingelheim International Gmbh | Stabilization of therapeutically active proteins in pharmaceutical preparations |
| DE3803312A1 (en) * | 1988-02-04 | 1989-08-10 | Gerd Prof Dr Med Gross | Use of an interferon-containing gel |
| NZ228285A (en) * | 1988-03-11 | 1991-08-27 | Teikoku Seiyaku Kk | Pharmaceutical composition comprising a polypeptide and adapted for intravaginal administration |
| DE68917883T2 (en) * | 1988-05-06 | 1995-02-23 | Toray Industries | STABLE INTERFERON BETA COMPOSITION. |
| US5389676A (en) * | 1991-03-22 | 1995-02-14 | E. B. Michaels Research Associates, Inc. | Viscous surfactant emulsion compositions |
| US5244652A (en) * | 1991-03-22 | 1993-09-14 | E. B. Michaels Research Associates, Inc. | Viscous surface active composition |
| JPH07501320A (en) * | 1991-10-11 | 1995-02-09 | ギリーズ，マーク・セドリック | Treatment of ocular fibrosis with interferon alpha |
| US5863530A (en) * | 1991-10-11 | 1999-01-26 | Spruson & Ferguson | Treating ophthalmic fibrosis using interferon-α |
| US6630168B1 (en) * | 1997-02-20 | 2003-10-07 | Biomedicines, Inc. | Gel delivery vehicles for anticellular proliferative agents |
| FI106465B (en) * | 1998-06-10 | 2001-02-15 | Suomen Punainen Risti Veripalv | A process for preparing virus-safe pharmaceutical compositions |
| US6923966B2 (en) | 1999-04-08 | 2005-08-02 | Schering Corporation | Melanoma therapy |
| JP4536194B2 (en) * | 2000-02-17 | 2010-09-01 | 大日本住友製薬株式会社 | Stable injectable formulation |
| AU4343101A (en) * | 2000-03-07 | 2001-09-17 | Rush Presbyterian St Luke | Compositions and methods for trapping and inactivating pathogenic microbes and spermatozoa |
| US6328987B1 (en) * | 2000-11-03 | 2001-12-11 | Jan Marini Skin Research, Inc. | Cosmetic skin care compositions containing alpha interferon |
| US20050013791A1 (en) * | 2001-11-02 | 2005-01-20 | Kazuo Shinmura | Cytokine-inducing material and cytokine-inducing instrument |
| US8137677B2 (en) * | 2005-10-06 | 2012-03-20 | Allergan, Inc. | Non-protein stabilized clostridial toxin pharmaceutical compositions |
| SG176254A1 (en) * | 2009-05-29 | 2011-12-29 | Filligent Ltd | Composition for use in decreasing the transmission of human pathogens |
| CN104271142B (en) | 2012-03-01 | 2017-07-04 | 福斯特斯特林研究公司 | The topical gel of PROTEIN C end (ACT) peptide is connected containing α |
| JP6081156B2 (en) * | 2012-11-15 | 2017-02-15 | アルケア株式会社 | Hydrogel |
| DE102012222365A1 (en) | 2012-12-05 | 2014-06-05 | Aesculap Ag | Composition for use in the prophylaxis of post-surgical adhesions |
| WO2014199373A1 (en) * | 2013-06-09 | 2014-12-18 | Efranat Ltd. | Compositions comprising gc- macrophage activating factor and uses thereof |
| GB2573933B (en) | 2017-01-31 | 2022-07-13 | Kimberly Clark Co | Antibacterial composition including benzoic acid ester and methods of inhibiting bacterial growth utilizing the same |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU1234383A (en) * | 1982-03-17 | 1983-09-22 | Inter-Yeda Ltd. | Interferon stabilised with polyvinyl-pyrrolidone |
| JPS6061535A (en) * | 1983-08-24 | 1985-04-09 | エフ・ホフマン・ラ・ロシユ・ウント・コンパニ−・アクチエンゲゼルシヤフト | Pharmaceutical composition |
| JPS6069037A (en) * | 1983-09-26 | 1985-04-19 | Sunstar Inc | External preparation for erythematosus |
| DE3484951D1 (en) * | 1983-10-14 | 1991-09-26 | Sumitomo Pharma | EXTENDED PREPARATIONS WITH DELAYED DELIVERY. |
| US4680175A (en) * | 1984-02-07 | 1987-07-14 | Interferon Sciences, Inc. | Interferon administration vehicles |
| CA1248450A (en) * | 1984-04-05 | 1989-01-10 | Kazuo Kigasawa | Soft patch |
| JPS60228422A (en) * | 1984-04-26 | 1985-11-13 | Suntory Ltd | Stabilized preparation of physiologically active substance |
| JPS60260523A (en) * | 1984-06-07 | 1985-12-23 | Asahi Chem Ind Co Ltd | Lyophilized drug composition of interferon |
-
1986
- 1986-02-05 DE DE19863603444 patent/DE3603444A1/en not_active Withdrawn
-
1987
- 1987-01-21 AT AT87100792T patent/ATE63823T1/en not_active IP Right Cessation
- 1987-01-21 EP EP87100792A patent/EP0231816B1/en not_active Expired - Lifetime
- 1987-01-21 ES ES198787100792T patent/ES2028796T3/en not_active Expired - Lifetime
- 1987-01-21 DE DE8787100792T patent/DE3770280D1/en not_active Expired - Fee Related
- 1987-02-03 DD DD87299676A patent/DD284602A5/en not_active IP Right Cessation
- 1987-02-03 FI FI870457A patent/FI86144C/en not_active IP Right Cessation
- 1987-02-03 CA CA000528832A patent/CA1295242C/en not_active Expired - Lifetime
- 1987-02-04 ZA ZA87793A patent/ZA87793B/en unknown
- 1987-02-04 NO NO870441A patent/NO169638C/en unknown
- 1987-02-04 HU HU87385A patent/HU196560B/en not_active IP Right Cessation
- 1987-02-04 DK DK058387A patent/DK164202C/en not_active IP Right Cessation
- 1987-02-04 IE IE29587A patent/IE59697B1/en not_active IP Right Cessation
- 1987-02-04 PT PT84243A patent/PT84243B/en not_active IP Right Cessation
- 1987-02-04 NZ NZ219169A patent/NZ219169A/en unknown
- 1987-02-04 AU AU68292/87A patent/AU601712B2/en not_active Ceased
- 1987-02-04 IL IL81472A patent/IL81472A0/en not_active IP Right Cessation
- 1987-02-04 JP JP62024423A patent/JPS62209024A/en active Pending
- 1987-02-05 PH PH34815A patent/PH24377A/en unknown
- 1987-02-05 KR KR870000912A patent/KR870007698A/en not_active Application Discontinuation
-
1991
- 1991-07-08 GR GR91400966T patent/GR3002270T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU601712B2 (en) | 1990-09-20 |
| DK164202C (en) | 1992-10-19 |
| FI870457A0 (en) | 1987-02-03 |
| DK58387D0 (en) | 1987-02-04 |
| EP0231816B1 (en) | 1991-05-29 |
| JPS62209024A (en) | 1987-09-14 |
| KR870007698A (en) | 1987-09-21 |
| NO169638B (en) | 1992-04-13 |
| NO169638C (en) | 1992-07-22 |
| DE3603444A1 (en) | 1987-08-06 |
| NO870441L (en) | 1987-08-06 |
| FI86144B (en) | 1992-04-15 |
| NO870441D0 (en) | 1987-02-04 |
| GR3002270T3 (en) | 1992-12-30 |
| DK58387A (en) | 1987-08-06 |
| EP0231816A2 (en) | 1987-08-12 |
| ES2028796T3 (en) | 1992-07-16 |
| FI86144C (en) | 1992-07-27 |
| PH24377A (en) | 1990-06-13 |
| AU6829287A (en) | 1987-08-06 |
| DE3770280D1 (en) | 1991-07-04 |
| PT84243A (en) | 1987-03-01 |
| NZ219169A (en) | 1990-04-26 |
| DK164202B (en) | 1992-05-25 |
| PT84243B (en) | 1989-09-14 |
| CA1295242C (en) | 1992-02-04 |
| ZA87793B (en) | 1988-10-26 |
| DD284602A5 (en) | 1990-11-21 |
| EP0231816A3 (en) | 1987-09-23 |
| IL81472A0 (en) | 1987-09-16 |
| ATE63823T1 (en) | 1991-06-15 |
| HU196560B (en) | 1988-12-28 |
| FI870457A (en) | 1987-08-06 |
| IE59697B1 (en) | 1994-03-23 |
| HUT43494A (en) | 1987-11-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |