WO1997045123A1

WO1997045123A1 - Topical pharmaceutical formulations comprising aciclovir

Info

Publication number: WO1997045123A1
Application number: PCT/GB1997/001462
Authority: WO
Inventors: Dean Selleseth
Original assignee: Glaxo Group Limited
Priority date: 1996-05-29
Filing date: 1997-05-29
Publication date: 1997-12-04
Also published as: GB9611167D0; AU2969897A

Abstract

There is provided an oil-in-water topical pharmaceutical formulation comprising a dispersed oil phase and a continuous aqueous phase comprising water, solubilised aciclovir and up to 5 % by weight of a long chained polydispersed β-1,4-acetylated mannan.

Description

TOPICAL PHARMACEUTICAL FORMULATIONS COMPRISING ACICLOVIR

This invention relates to a topical pharmaceutical formulation suitable for use in treating virus infections of the skin and mucosa, and in particular it relates to topical formulations containing 9-(2-hydroxyethoxymethyl)guanine, otherwise known as aciciovir, and hereinafter referred to as such.

Aciclovir and pharmaceutically acceptable salts and esters thereof are known to have antiviral activity against various classes of DNA and RNA viruses both in vitro and in vivo, see UK patent No. 1 523 865. In particular the compound is active against herpes simplex virus which causes herpetic keratitis in rabbits, herpetic encephalitis in mice, and cutaneous herpes in guinea pigs. Aciclovir has been found to be effective in the treatment of herpes simplex virus and herpes zoster virus in humans.

Aciclovir suffers from the disadvantage that it has a low solubility in water and is almost totally insoluble in hydrophobic solvent systems. It is accordingly difficult to produce a topical formulation containing a sufficient dissolved concentration of active ingredient for it to exert its full effect and also to optimise the flux of the compound into the skin. In addition to ease of release it is also important that any formulation of a pharmaceutically active compound should be stable for long periods of time, should not lose its potency, should not discolour or form insoluble substances or complexes, and also should not be unduly irritating to the skin or mucosa.

European Patent No. 0044 543 describes an oil-in-water topical pharmaceutical formulations of aciclovir wherein the aqueous phase contains at least 30% of a water miscible polyhydric alcohol,

Within the reference Journal of Molecular Biotherapy 1991 Vol. 3, Dec. p214 the authors, Jasper B Kahlon et al, discuss the in vitro antiviral evaluation of the combination of the products aciclovir and acemannan. According to the reference a synergistic antiviral effect was found with such a combination. Despite numerous attempts we have not been able to repeat these results, no 1

synergistic antiviral effect was found in such an in vitro model system, casting serious doubt upon the claimed results of this reference.

Therefore, despite the above reference there appears to be no reason why these two ingredients, acemannan and aciclovir, should be combined in a single topical formulation.

We have now found that oil-in-water topical pharmaceutical formulations of aciclovir comprising up to 5% w/w of a long chained polydispersed β-1 ,4- acetylated mannan have particularly advantageous properties. In particular, such formulations exhibit enhanced efficacy together with low irritancy and good physical stability.

The present invention accordingly provides an oil-in-water topical pharmaceutical formulation comprising a dispersed oil phase and a continuous aqueous phase comprising water, solubilised aciclovir and up to 5% by weight of a long chained polydispersed β-1 ,4-acetylated mannan.

Preferably the long chained polydispersed β-1 ,4-acetylated mannan is a highly acetylated polydispersed linear mannan of molecular weight 1 - 2 million daltons.

Preferably the formulation of the invention contains a maximum of 50% water.

Such a topical formulation may contain 0.075% to 10% w/w aciclovir or a salt or an ester thereof, up to 5% w/w of a long chained polydispersed β-1 ,4- acetylated mannan, from 15% to 50% w/w water and an oil phase. Preferably the composition will contain up to 1% of a long chained polydispersed β-1 ,4- acetylated mannan, most desirably between 0.1% and 0.6% w/w for example 0.3-0.5% w/w. Hereafter references to aciclovir should be understood to include also its pharmaceutically acceptable salts and esters unless the context clearly indicates otherwise.

The oil phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it is desirably comprised of a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, as explained in more detail below, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred

to include both an oil and a fat. Together, the emulsifier(s) with or without stabilisers) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so called emulsifying ointment base which forms the oil dispersed phase of the emulsions.

Emulgents and emulsion stabilisers suitable for use in the formulation of the present invention include cetyl alcohol, sodium lauryl sulphate, stearyl alcohol and polyoxyethylene alkyl ethers, such as polyoxyl stearyl ethers, for example steareth 2 and steareth 21.

The formulations of the invention may also comprise additional components in the aqueous phase, for example polyhydric alcohols such as propylene glycol or diethylene glycol monoethyl ether. Preferably the formulations of the invention comprise from 0 to 40% by weight of propylene glycol.

In a preferred aspect the formulation comprises from 0.5% to 10% w/w aciclovir, up to 5% w/w of a long chained polydispersed β-1 ,4-acetylated mannan, from 20% to 40% w/w of diethylene glycol monoethyl ether, from 20% to 40% w/w water together with an oil phase, whilst the most preferred formulation comprises from 1% to 5% w/w aciclovir, up to 5% w/w of a long chained polydispersed β-1 ,4-acetylated mannan, from 30% to 40% w/w of diethylene glycol monoethyl ether, from 25% to 40% w/w water together with an oil phase.

An example of a long chained polydispersed β-1 ,4-acetylated mannan is the product sold under the name acemannan - an extract of the leaf of the aloe vera plant.

Acemannan is the non-proprietary name of the biologically active component of C CAARRRRIISSYYNN™™ aavvaaiillaabbllee ffrroomm CCaarrririnncgton Laboratories Inc., P O Box 168128, Irving, Texas, TX 75016-8128, U.S.A.

Diethylene glycol monoethyl ether is manufactured by Gattefosse S.A., 36 Chemin de Genas, b.p. 603, 69804 Saint-Priest Cedex, France, under the tradename TRANSCUTOL™. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of aciclovir in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dialkyl esters such as diisopropyl adipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixed ester of 2-ethyl hexanoic acid with a blend of cetyl or stearyl alcohols known as Crodamol CAP may be used, the last three being the preferred esters. These may be used singly or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

A preferred formulation according to the invention comprises, up to 5% w/w of a long chained polydispersed β-1 ,4-acetylated mannan, 30-40% w/w; aciclovir, approximately 5% w/w; cetyl alcohol 3-10% w/w; stearyl alcohol, 4-10% w/w; propylene glycol, 0-10% w/w; light mineral oil, 8-15% w/w; steareth 21 , 2-5% w/w; steareth 2, l-3% w/w; and purified water to 100% w/w.

The formulations of the invention may, if desired, include one or more pharmaceutically acceptable preservatives. However, we have found that the use of preservatives is not essential in the formulations of the invention, which finding represents an advantage of the said formulations.

The present invention also provides the use of aciclovir and a long chained polydispersed β-1 ,4-acetylated mannan in the preparation of a combined topical medicament for the treatment of herpes family viral infections.

Also provided is a method of treating a viral infection caused by a member of the herpes family of viruses comprising topical administration of a pharmaceutically effective amount of a formulation according to the present invention. The present invention further provides a method for the preparation of a topical pharmaceutical formulation, as hereinbefore defined, which comprises mixing the combination of aciclovir, long chained polydispersed β-1 ,4-acetylated mannan and water with the oil phase.

The manner of formulating the emulsion will of course vary according to the amount and nature of the constituents, but nevertheless follows known techniques in emulsion technology (see the Pharmaceutical Codex, London, the Pharmaceutical Press, 1979). For example the aciclovir and long chained polydispersed β-1 ,4-acetylated mannan may be initially incorporated wholly in the aqueous portion where it may form a solution alone, or a mixed solution/suspension, and then emulsified with the ointment base. Alternatively where high concentrations of aciclovir are being used, a part of the aqueous portion may be formulated as an emulsion, and the balance of the water, long chained polydispersed β-1 ,4-acetylated mannan and aciclovir added to and dispersed into the emulsion. In another technique the aciclovir may be included in the emulsifying ointment prior to emulsification with the aqueous portion. In using these procedures, it is preferable to heat the aqueous portion and the ointment base to about 40 to 80°C, preferably 50 to 70°C, prior to emulsification which may be achieved by vigorous agitation using for example a standard laboratory mixer. Finer dispersions of the oil phase may be obtained by homogenising or milling in a colloidal mill.

A topical formulation of the present invention may be used in the treatment or prevention of viral infections caused for example by Herpes zoster, Herpes varicella and Herpes simplex types I and 2, which cause diseases such as shingles, chicken pox, cold sores and genital herpes. The formulation should desirably be applied to the affected area of skin from 1 to 6 times daily, preferably from 3 to 5 times.

The following examples illustrate the invention and are not intended as a limitation thereof.

Example 1 Ingredient % w/w

TRANSCUTOL™ 35 aciclovir 5.0 acemannan 5.0 stearyl alcohol 5.0 cetyl alcohol 4.0 light mineral oil 10.2

Purified water to 100

The oil phase comprising stearyl alcohol, cetyl alcohol, light mineral oil, brij 72 and brij 721 is heated to 70-75 °C with mixing. Purified water is heated to 65- 70°C and added to the oil phase, maintaining the temperature at 70-75°C, with mixing to form an emulsion. The mixture is maintained at a temperature of 70-75 °C for approximately 5 minutes. TRANSCUTOL™ is weighed into an appropriate container and aciclovir added with mixing to form a suspension. The aciclovir suspension is added to the emulsion, rinsing in with a small amount of purified water. Acemannan is then added and the emulsion is homogenized for approximately 5 minutes, then made up to final batch weight with purified water. The resulting cream is cooled to ambient temperature (approximately 30 °C) with continuous mixing and filled into suitable tubes which are then sealed.

Example 2

Ingredient % w/w

TRANSCUTOL™ 27.5 aciclovir 5.0 acemannan 2.5 stearyl alcohol 5.0 cetyl alcohol 4.0 light mineral oil 10.2 brij 721 2.5 brij 72 2.3 propylene glycol 10.0

Purified water to 100

The oil phase comprising stearyl alcohol, cetyl alcohol, light mineral oil, brij 72 and brij 721 is heated to 70-75°C with mixing. Purified water is heated to 70- 75°C and added to the oil phase, maintaining the temperature at 70-75°C, with mixing to form an emulsion. The mixture is maintained at a temperature of 70-75 °C for approximately 5 minutes. TRANSCUTOL™ is weighed into an appropriate container and propylene glycol and aciclovir added with mixing to form a suspension which is homogenized at 65-70 °C for approximately 5 minutes. The propylene glycol aciclovir suspension is added to the emulsion at 50-70 °C, suitably 50-55 °C, rinsing in with a small amount of purified water. Acemannan is then added and the emulsion is homogenised for approximately 5 minutes, then made up to final batch weight with purified water. The resulting cream is cooled to ambient temperature (approximately 30°C) with continuous mixing and filled into suitable tubes which are then sealed.

Example 3

The formulations described in Examples 1 and 2 may alternatively be prepared by the following modified procedure.

The oil phase is weighed and heated to 70-75°C with continuous slow mixing. Purified water is heated to 65-70°C. The purified water is added to the aciclovir suspension with propeller agitation. The aqueous mixture is heated to 65-70 °C. Whilst maintaining the temperature of the oil phase at 70-75 °C, the aqueous phase is slowly added with sweep agitation for at least 5 minutes. The aqueous phase container is rinsed with purified water and the rinsings added to the main batch. The temperature of the batch is maintained at 70-75 °C and the batch is homogenized for at least 5 minutes. The batch is cooled to 30-35 °C with continuous sweep agitation and purified water added to adjust to final batch weight. The batch is mixed until uniform and cooled to 30°C.

Example 4 5% aciclovir cream (marketed under the trademark ZOVIRAX^® by Glaxo Wellcome, Glaxo Wellcome House, Berkeley Avenue Greenford, Middlesex, UB6 ONN) consists of aciclovir solubilised in the aqueous phase of the oil-in- water cream base known as "MAC-P".

MAC-P Cream Base

%w/w

Propylene Glycol 40.00

Alcohol (cetostearyl) 6.75

Sodium lauryl sulphate 0.75

Poloxamer 407 (Pluronic F127 ™) 1.00

White soft paraffin 12.50

Liquid paraffin 5.00

Purified water to 100.00

The water and propylene glycol are mixed at ambient temperature to produce an aqueous solution. If aciclovir is to be included in the formulation a part or all of it will be included in dissolved in this phase. The parrafins and emulsifiers (cetostearyl alcohol, sodium lauryl sulphate) are mixed together and heated to 60 °C to form the oil phase which is then emulsified with the aqueous phase, also at using a laboratory mixer at 8000 r.p.m. Any remaining aciclovir is then added and the mixture dispersed and allowed to cool.

The ZOVIRAX^® (5% w/w aciclovir in MAC-P cream) formulation was compared with formulations containing both aciclovir and acemannan (made by mixing acemannan powder with the ZOVIRAX^® formulation) in the mouse snout model of herpes simplex virus (HSV) infection.

Snout HSV Infection Mouse Model:

This mouse model involved infecting female HRS/J mice cutaneously with wild- type HSV-1. Groups of ten mice were inoculated on the snout with a dilution of SC-16 HSV stock (1.1 E8 PFU/ml). After the mice were anesthetized with ketamine and xylazine, the skin on the snout region was lightly abraded with a roto-tool. The abrasion area was then swabbed for ten seconds with a sterile cotton swab soaked with the viral stock. Treatment was started three days post- inoculation (P.I.) and continued until day seven P.I. Mice were treated twice daily and scored for lesion severity daily.

Scoring system for the snout model is as follows:

0 = normal skin +1 = 1 to 5 discrete lesions +2 = > 6 discrete lesions +3= confluent lesions +4 = necrotic lesions or death

Treatment groups were as follows (10 mice per group unless otherwise stated).

1. No treatment - N = 9.

2. 5% aciclovir in MAC-P (ZOVIRAX^®)

3. 0.5% w/w acemannan in ZOVIRAX^®

4. 0.4% w/w acemannan in ZOVIRAX^®

5. 0.3% w/w acemannan in ZOVIRAX^®

6. 0.2% w/w acemannan in ZOVIRAX^®

7. 0.1% w/w acemannan in ZOVIRAX^® - N = 9.

The results (average lesion score for each group) are given below in Table 1 and depicted graphically in Fig. 1.

TABLE 1

Example 5

The 0.1% w/w and 0.5% w/w acemannan plus 5% w/w aciclovir formulations of Example 4 were compared with 0.5% w/w and 1.0% w/w acemannan alone in the MAC-P cream base. The cream base was made up as described in Example 4, with no aciclovir, and acemannan powder subsequently added. The mouse model was as described in Example 4 except that treatment was continued for 8 days post infection. Again ZOVIRAX^® cream was the positive control.

Treatment groups were as follows (10 mice per group)

1. No treatment

2. ZOVIRAX^® (5% w/w aciclovir in MAC-P)

3. 0.1 % w/w acemannan in ZOVIRAX^®

4. 0.5% w/w acemannan in ZOVIRAX^®

5. 0.5% w/w acemannan in MAC-P

6. 1.0% w/w acemannan in MAC-P

The results are (average lesion score for each group) given below in Table 2 and depicted graphically in Fig. 2.

TABLE 2

In Group 4 (0.5% w/w acemannan, 5% aciclovir), 4 of the 10 mice showed no lesions on day 8. In Group 2 (aciclovir alone), 1 of the 10 mice showed no lesions on day 8 post infection.

Claims

1. An oil-in-water topical pharmaceutical formulation comprising aciclovir or a pharmaceutically acceptable salt or ester thereof and up to 5% w/w of a long chained polydispersed β-1, 4-acetylated mannan.

2. An oil-in-water topical pharmaceutical formulation comprising a dispersed oil phase and a continuous aqueous phase comprising water, solubilised aciclovir and up to 5% by weight of a long chained polydispersed β-1, 4-acetylated mannan.

3. An oil-in-water topical pharmaceutical formulation as claimed in either claim 1 or 2 wherein the long chained polydispersed β-1,4-acetylated mannan is acemannan.

4. An oil-in-water topical pharmaceutical formulation as claimed in any one of the preceding claims wherein aciclovir is present in an amount from about 0.075% to about 10% w/w.

5. An oil-in-water topical pharmaceutical formulation according to any one of claims 1 to 4, further comprising a polyhydric alcohol.

6. An oil-in-water topical pharmaceutical formulation according to claim 5 wherein the polyhydric alcohol is present in the aqueous phase in an amount up to about 40% by weight.

7. An oil-in-water topical pharmaceutical formulation according to claim 5 or claim 6 wherein the polyhydric alcohol is diethylene glycol monoethyl ether.

8. An oil-in-water topical pharmaceutical formulation according to claim 7 wherein the diethylene glycol monoethyl ether is present in an amount of from 20% to 40% w/w.

9. An oil-in-water topical pharmaceutical formulation according to claim 5 or claim 6 wherein the polyhydric alcohol is propylene glycol.

10. An oil-in-water topical pharmaceutical formulation according to claim 9 wherein the propylene glycol is present in an amount of from 1% to 3% w/w.

11. Use of aciclovir and a long chained polydispersed β-1,4-acetylated mannan in the preparation of a combined topical medicament for the treatment and/or prophylaxis of herpes family viral infections.

12. A method of combatting a viral infection caused by a member of the herpes family of viruses comprising topical administration of a pharmaceutically effective amount of a formulation according to any one of claims 1 to 10.

13. A process for the preparation of a formulation as claimed in any one of claims 1 to 10 comprising mixing aciclovir .or a pharmaceutically acceptable salt or ester thereof, a long chained polydispersed β-1, 4-acetylated mannan and water with the oil phase.