PODOPHYLLOTOXIN PREPARATIONS FOR USE IN THE TREATMENT OF GENITAL WARTS

Abstract: Compositions for treating genital warts comprise from 0.05 to 10% by weight of podophyllotoxin in an excipient comprising at least one polyol.

Description: TREATMENT OF GENITAL WARTS This invention relates to pharamceutical compositions for the treatment of condylomata acuminata. Condylomata acuminata or genital warts is a sexually transmitted disease which affects both males and females. In their clinical appearance fresh condylomata appear as greyish-pink pedunculated papillomatous vegetations while older tumors may gradually turn into erythematous or pigmented papules. In noncircumcised men, the preputial cavity is most often diseased, while in the circumscised male it is normally the shaft of the penis which is affected. In females, clinically evident lesions predominantly grow in the vulvavestibular area, although the vagina is also often afflicted. Treatments hitherto have included tedious and frequently uunsuccessful surgical measures and chemotherapy. The first choice medical treatment since about 1950 has been application of an ethanolic solution of podophyllin resin. Podophyllin resin is obtained from the root extract of Podophyllum peltatum or Podophyllum emodi or hexandrum and can contain one or more of the following active ingredients: podophyllotoxin, 4' -demethylpodo phyllotoxin, CC -peltatin, and ct-peltatin. The use of ethanolic solutions of podophyllin has a number of disadvantages. Firstly, the efficacy of such solutions may be limited, secondly, the actual effect of the treatment may be difficult to reproduce, thirdly the presence of components of podophyllin resin other than podophyllotoxin in variable quantities can affect the safety of the treatment and fourthly, previous formulations had a limited shelf-life. Also neither the podophyllin resin nor the ethanolic solution can be readily standardized biologically or chemically. Purthermore the previous preparations are highly irritant to the skin and mucous membranes, which has led to a general treatment regime including washing off the drug 2 - 6 hours after application. Irritation will arise not only in the condylmata as they start becoming necrotic as a result of the antimitotic effect of the podophyllin but also in the adjacent healthy skin or mucosa. It is therefore of crucial importance that the preparations are applied precisely onto the condylomata. This is, however, only possible to some degree as e.g. on penile warts. Nhen treating female patients it is a very difficult task to carry out precise application of the drug to the condylomata only, as they are located internally. The same holds good for anal warts. For that reason, treatment of condylomata has hitherto mainly been performed in clinics or hospitals, which is a rather expensive method of treatment. Another disadvantage is that absorption of the active ingredient into the condylomata may be erratic because the preparation may be wiped off by contact with the clothes or may be rinsed off during micturition. We now have discovered that a superior therapeutic composition for treatment of condylomata may be obtained by incorporation of 0.05 10% by weight of podophyllotoxin into a pharmaceutically acceptable carrier comprising at least one polyol. Preferably the composition has a viscosity and/or water solubility characteristics such that localised application of the composition may be achieved and displacement of the composition inhibited. Examples of suitable compositions include ointments, gels, particularly hydro-gels and flexible collodion vehicles. Compositions according to the invention have been found to have an enhanced therapeutic effect, possibly due to an increase in local absorption rate of the active ingredient caused by the presence of the polyol, and to be stable. Suitable glycols include alkylene glycols such as, for example, propylene glycol and polyalkylene glycols such as, for example, polyethylene glycol. Preferably, compositions according to the invention comprise at least one polyethylene glycol having a molecular weight in the range from 100 to 1000, most preferably 200 to 600. Advantageously, the compositions according tb the invention are in the form of hydro-gels containing propyleneglycol or polyethyleneglycol 400 as solvent for the podophyllotoxin and at least one nonionic emulsifier and/or at least one surfactant. Alternatively the compositions may be in the form of lipid-based ointments which may, for example be based on white soft paraffin, beeswax, alcohol stearylicus, or mineral oil. Use of compositions according to the invention, particularly those having lipophilic characteristics and a consistency such that they can be readily and accurately applied to the condylomata by the patient himself, can considerably reduce the risk of adverse effects to the surrounding areas. Such compositions could not have been safely used as vehicles for podophyllin in the treatment of condylomata as the risk of adverse effects would have been increased. As indicated, the compositions of the invention can contain a lipid phase consisting of white soft paraffin, beeswax, alcohol stearylicus, mineral oil, or similar ingredients. The compositions (including lipid-based and non-lipid based such as hydro-gels) may also include surfactants (preferably non-ionic) such as Tagat S, Hyfatol 40 and Tween 80 and emulsifiers (also preferably non-ionic) as e.g. Eimilgator E 2155 and Arlacel 83. The composition of the invention are preferably buffered to a pH less than 7, most preferably a pH in the range 2.5 to 6.0. By selecting the p11 in this range the efficacy of the compositions of the inventions can be increased and furthermore the stability of the compositions is improved. The required buffering action may be obtained by incorporating a pharmacologically acceptable acid in the composition, for example lactic, phosphoric, malic or citric acids and/or pharmaceutically acceptable salts thereof. Thus, for example a lactic acid/lactate buffer of pH around 4.5 may be included. As indicated, the compositions of the invention are stable and they can be chemically standardized by HPLC-assay method. The compositions according to the invention are preferably produced by first dissolving podophyllotoxin in the glycol and then admixing the resulting solutions with the other ingredients of the compositions. The Following formulations of compositions according to the invention are given by way of example. 1. Formulation P.O. 2201 EMI5.1 <tb> Active <SEP> ingredient <SEP> I <SEP> Podophyllotoxin <SEP> j <SEP> <SEP> 5 <SEP> g <tb> Iactive <SEP> ingradients <SEP> Vasslinum <SEP> album <SEP> 596 <SEP> g <tb> Paraffinum <SEP> liquidum <SEP> 159 <SEP> g <tb> Tasost <SEP> 8 <SEP> 40 <SEP> | <SEP> 40 <SEP> g <tb> Polysthyleneglycol <SEP> 200 <SEP> g <tb> <SEP> 1000 <SEP> g <tb> The vaselinum album, paraffinum liquidum and Tagat S were melted and stirred together to form a first mixture and the podophyllotoxin was separately dissolved in polyethylene glycol. The two components were then mixed and the mixture stirred while cooling. 2. Formulation P.O. 2203 EMI5.2 <tb> <SEP> Active <SEP> ingredient <SEP> . <SEP> Podophyllotoxin <SEP> j <SEP> 5 <SEP> g <tb> Inaotive <SEP> ingredients <SEP> Vaselinum <SEP> album <SEP> 230 <SEP> g <tb> Paraffinum <SEP> liquidum <SEP> tanue <SEP> 150 <SEP> g <tb> Tagat <SEP> S <SEP> 100 <SEP> g <tb> Hyfatol <SEP> 40 <SEP> f <SEP> <SEP> 195 <SEP> g <tb> Polyethylenglyool <SEP> 400 <SEP> 1 <SEP> 200 <SEP> g <tb> 1000 <SEP> g <tb> The vaselinum album, paraffinum liquidum tenue, Tagat S and Hyfatol 40 were melted and stirred together to form a first mixture and the podophyllotoxin was dissolved in the polytheylene glycol 400. The two components were then mixed and the mixture stirred while cooling. 3. Formulation P.O. 3101 (A) and (B) EMI6.1 <tb> <SEP> (A) <tb> Active <SEP> ingredient <SEP> Podophyllotorin <SEP> 5 <SEP> G <tb> Inactive <SEP> ingredients <SEP> Emulgator <SEP> E <SEP> 2155 <SEP> 70 <SEP> g <tb> 1 <SEP> 1 <SEP> <tb> Aqua <SEP> purifioata <SEP> 95 <SEP> g <tb> Avicel <SEP> 60 <SEP> g <tb> I <SEP> I <SEP> <tb> <SEP> PEG <SEP> 400 <SEP> 50 <SEP> g <tb> Buffer <SEP> 20 <SEP> g <tb> 100 <SEP> g <tb> EMI6.2 <tb> <SEP> (B) <tb> Active <SEP> ingradiant <SEP> Podophyllotorin <SEP> 5 <SEP> g <tb> Inactive <SEP> ingredients <SEP> Emulgator <SEP> E <SEP> 2155 <SEP> 95 <SEP> g <tb> Aqua <SEP> purificata <SEP> 657.5 <SEP> g <tb> Avicel <SEP> 80 <SEP> g <tb> PEG <SEP> 400 <SEP> 120 <SEP> g <tb> Buffer <SEP> (lactate <SEP> pH <SEP> 4.5) <SEP> 40 <SEP> g <tb> Methyl <SEP> paraben <SEP> 2 <SEP> g <tb> Propyl <SEP> paraben <SEP> 0.5 <tb> 1000 <SEP> g <tb> The water was heated to 800C and the Emulgator E 2155 was dissolved while stirring. The solution was then cooled to 60 C. The Avicel was then added while stirring and then the buffer and the methyl and propyl parabens (formulation B). The podophyllotoxin was then separately dissolved in the polyethylene glycol 400. The two components were mixed then stirred and the total mixture homogenised. 4-7. Formulations P.0. 3102, P.O. 3103, P.O. 3104 and P.O. 3105 EMI7.1 <tb> Active <SEP> ingredient <SEP> Podophyllotoxin <SEP> 5 <SEP> g <tb> Inactive <SEP> ingredients <SEP> Vaselinum <SEP> album <SEP> 745 <SEP> g <tb> Tween <SEP> 81 <SEP> 50 <SEP> g <tb> <SEP> Propylenaglycol <SEP> 200 <SEP> g <tb> 1000 <SEP> g <tb> EMI7.2 <tb> <SEP> Active <SEP> ingredient <SEP> Podophyllotoxin <tb> Inactive <SEP> ingredients <SEP> Vaselinum <SEP> album <SEP> 550 <SEP> <SEP> g <SEP> <tb> <SEP> Cera <SEP> alba <SEP> 70 <SEP> g <tb> Mineral <SEP> oil <SEP> 135 <SEP> g <tb> <SEP> Propyleneglycol <SEP> 150 <SEP> g <tb> <SEP> Arlacel <SEP> 83 <SEP> 90 <SEP> g <tb> <SEP> 1000 <SEP> g <tb> EMI8.1 <tb> <SEP> Activo <SEP> ingrodient <SEP> Podphyllotorin <SEP> 5 <SEP> g <tb> Inactive <SEP> ingredients <SEP> Vaselinum <SEP> album <SEP> 687 <SEP> g <tb> A@@@@@@@@@@@@@@ <SEP> 30 <SEP> g <tb> <SEP> Alcohol <SEP> stearylicus <SEP> 1 <SEP> <SEP> 30 <SEP> g <tb> Cera <SEP> alba <SEP> 78 <SEP> g <tb> I <SEP> . <SEP> Polyethyleneglycol <SEP> t <SEP> 200 <tb> <SEP> 1000 <SEP> g <tb> EMI8.2 <tb> Active <SEP> ingredient <SEP> Podophyllotoxin <SEP> 5 <SEP> g <tb> Inactive <SEP> ingrodionts <SEP> Vaselinum <SEP> album <SEP> 615 <SEP> g <tb> <SEP> Cora <SEP> alba <SEP> 80 <SEP> g <tb> Mineral <SEP> oil <SEP> 200 <SEP> g <tb> Polyethyleneglycol <SEP> 100 <SEP> g <tb> <SEP> 1000 <SEP> g <tb> For each of the above formulations first the podophyllotoxin was dissolved in the propylene glycol or polyethylene glycol. Then the remaining ingredients were melted and mixed thoroughly and finally the two mixtures were eombined and the combination stirred while cooling. Stability tests carried out on the above described compositions revealed that formulations PO-2201, P0-2203, PO-3102, PO-3104 and PO-3105 were stable- for only six months. Compositions PO-3105(A) and (B) appeared to be completely stable and were consequently preferred where long shelf-life is required. It is presently believed that the enhanced stability of compositions PO-3105 (A) and (B) is due to the presence of the buffer which maintains the pH of the composition in the range of 2.5 to 6.0.

Claims: CLAIMS 1. A pharmaceutical composition suitable for treating genital warts comprising from 0.05 to 10% by weight of podophyllotoxin and a pharmaceutically acceptable excipient comprising at least one polyol. 2. A composition according to Claim 1 wherein the excipient has a viscosity and/or water solubility characteristics such that localised application of the composition may be achieved and displacement of the composition inhibited. 3. A composition according to Claim 1 or Claim 2 wherein said excipient comprises propylene glycol. 4. A composition according to any preceding claim wherein said excipient comprises at least one polyalkylene glycol. 5. A composition according to Claim 4 wherein said excipient comprises polyethylene glycol having a molecular weight in the range from 100 to 1000. 6. A composition according to any preceding claim in the form of a lipid-based ointment. 7. A composition according to any of Claims 1 to 5 in the form of an aqueous gel. 8. A composition according to any preceding claim including buffering agents maintaining the pH of the composition in the range 2.5 to 6.0. 9. A process for producing a composition as claimed in any preceding claim which comprises dissolving the podophyllotoxin in the glycol and admixing the resulting solution with other components of the composition.

Inventors: JACOBSEN, METTE KIRSTINE, MALMSTEDT, MARIANNE
Applicants: PHARMA-MEDICA A-S
Application year: 1984
Main classification: A61K31
IPC codes: A61K31