WO1996031207A1

WO1996031207A1 - Podofilox gel formulation

Info

Publication number: WO1996031207A1
Application number: PCT/NO1996/000079
Authority: WO
Inventors: Dennis W. Adair; Charles E. Lee; Joseph F. Dayton
Original assignee: Nycomed Pharma AS
Current assignee: Takeda AS
Priority date: 1995-04-05
Filing date: 1996-04-03
Publication date: 1996-10-10
Anticipated expiration: 1997-10-05
Also published as: AR001807A1; AU5349096A; IL117801A0; ZA962728B

Abstract

Pharmaceutical gel compositions that comprises the antimitotic and antiviral agent podofilox in an amount therapeutically effective to at least slow the growth of warts in a host, a solvent comprising a lower alkanol, aldehyde, ketone, or mixture thereof in an amount sufficient to form a solution with the podofilox, and a hydrophilic cellulose in an amount effective to thicken the solution to form a gel; and methods for the treatment of warts, more specifically genital warts and related conditions, with said compositions.

Description

PODOFILOX GEL FORMULATION

FIELD OF THE INVENTION

This invention relates to the manufacture and use of pharmaceutical compositions. More particularly, this invention relates to the manufacture of certain gel compositions that contain as their active

ingredient the antimitotic and antiviral agent

podofilox, and to methods for the treatment of warts, more specifically genital warts and related

conditions, with said compositions.

BACKGROUND OF THE INVENTION

Genital warts, or Condyloma acumina tum , is a sexually-transmitted cutaneous viral disease resulting from infection with a strain of Human Papilloma Virus (HPV). This disease is approaching epidemic

proportions in both industrialized and developing countries.

The drug of choice for treating genital warts, and related conditions such as perianal and mucous membrane warts, is podofilox. Podofilox, the chemical name of which is 5, 8, 8a, 9-tetrahydro-9-hydroxy-5- (3,4,5-trimethoxyphenyl) furo[3',4':6,7]naphtho [2, 3,d]- 1, 3-dioxol-6 (5aH) -one, can be purified from the plant families Coniferae and Berberidaceae (e.g. species of Juniperus and Podophyllum) or can be chemically synthesized.

Podofilox is currently formulated for use in the treatment of genital warts as an alcohol solution. For example, CONDYLOX^® 0.5% solution, a product of Oclassen Pharmaceuticals, Inc., is a formulation for topical administration in which each milliliter of solution contains 5 mg of podofilox in a vehicle containing lactic acid and sodium lactate in alcohol 95% USP.

While the alcohol solution is quite effective when properly applied, alcohol and other liquid formulations in general have certain disadvantages that are not shared by non-liquid formulations for topical application. Liquid formulations are subject to spillage, which is expensive and inconvenient.

Liquid formulations are more easily and likely to be swallowed, for instance by children. Alcohol

formulations in particular are occasionally ingested by alcoholics. Podofilox is a potent toxin

systemically.

Liquid formulations are generally applied using an applicator or absorbent medium such as tissue, a "cotton ball", or a small stick with an absorbent tip. Non-liquid topical formulations, on the other hand, can be applied with the fingertip, a procedure that is less wasteful of product. Also, fingertip self- application is easier to accomplish on areas of the body that cannot easily be seen by the patient as opposed to application by means of an applicator stick or rod medium. The more controlled the application, of course, the less potential safety concern by contamination of uninfected skin.

For a variety of reasons, therefore, it would be desirable to have a non-liquid formulation of

podofilox for topical application.

There are, of course, many different types of creams, ointments, gels, and the like that could be considered as vehicles for podofilox as for any topical antiviral agent. A water-washable ointment based upon polyethylene glycol, for instance, had been considered, but this was found to be less effective than the alcohol solution. A conventional emulsion- based cream was also found to be unsuitable do to its relative instability.

Because podofilox is soluble in alcohol and is insoluble in oil and water, an alcohol-based vehicle remains the best approach for topical application. The chemical instability of Podofilox solutions requires that the pH of the solution must be

maintained in a relatively narrow range below about 5 and above about 2 in order to stabilize the podofilox. Under basic conditions, podofilox readily undergoes a structural epimerization to form degradation products such as picropodophyllotoxin, with concomitant loss of activity. This reaction, while not totally absent, is much slower under moderately acidic conditions

characterized by a pH of less than 5. At low pH below about 2, another route of degradation becomes

predominant, resulting in rapid destruction of the active podofilox. In the alcoholic solution

formulation of podofilox referred to above, a lactic acid/sodium lactate buffer system maintains the solution at a pH of about 2.5 to 4.0,

preferably 3-3.5.

Most gelling systems are polymeric esters or ethers, which are subject to hydrolysis at low pH.

Typical gelling agents used to make pharmaceutical gels include the Carbomers, which are acidic

polysaccharides that have been neutralized with triethanolamine, and must be at a pH of around 7 in order to form a gel. Thus, formation of a gel under acidic conditions cannot be achieved with such

additives. In addition to the need with respect to podofilox of a gelling agent that can be used at a pH in the range 2-5, the gelling agent would have to be physically stable (e.g. resist hydrolysis) and would have to be able to gel in alcohol. The present invention is based upon the realization that

appropriate gelling agents would have to meet these three criteria: ability to gel in alcohol; ability to gel at pH 2-5; and physical stability (no hydrolysis).

SUMMARY OF THE INVENTION

It has been found that hydrophilic cellulose derivatives such as hydroxypropylcellulose will enable the preparation of stable topical gel formulations of podofilox. Accordingly, the present invention relates to methods for the manufacture of pharmaceutical compositions comprising solutions of podofilox in alcohol or similar solvents which are thickened by means of hydrophilic cellulose derivatives, as well as to the compositions themselves and to methods for the treatment of topical lesions resulting from infection with the Human Papilloma Virus as common, plantar, 'or genital warts and related diseases by applying these pharmaceutical compositions.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts the efficacy for the treatment of genital warts of a podofilox gel in accordance with the invention as compared to a podofilox solution providing the same dosage level.

Figure 2 depicts the same data as Figure 1, separated by male and from female patients. Figure 3 depicts the degree of local effects of a podofilox gel in accordance with the invention as compared to a podofilox solution providing the same dosage level.

Figure 4 depicts the same data as Figure 3, as derived from male and from female patients.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides a pharmaceutical composition comprising a solution of podofilox in a lower alkanol, aldehyde, and/or ketone, wherein the solution is thickened with a hydrophilic cellulose.

The amount of podofilox that may be incorporated into the gels in accordance with the present invention is any amount that is great enough to destroy or at least slow the growth of genital warts but not so great as to cause unacceptable collateral damage to uninvolved skin of the host. Therapeutically

effective relative amounts of podofilox in accordance with the present invention generally range from about 0.1 to 5 percent by weight. Currently, 0.5%

formulations of podofilox are preferred for

application to Condyloma on mucous membranes, while higher concentrations are preferred for lesions on other parts of the body.

The lower alkanol in which the podofilox may be dissolved in accordance with the present invention is any alkanol of up to 8 carbon atoms. Alkanols having from 1 to 4 carbon atoms are preferred, and ethanol is most preferred, since it is generally recognized as safe for use on humans. Alternatively to or in addition to lower alkanols, other pharmaceutically solvents such as low molecular weight aldehydes and ketones may also be used as solvents in accordance with the invention.

Evaporation of the alkanol, aldehyde, and/or ketone solvent enhances penetration of the active ingredient into the lesion. Penetration can be made to occur still faster by the inclusion in the

formulation of known penetration enhancers, such as dimethyl sulfoxide. Evaporation of the solvent also serves to increase the relative concentration of the active ingredient at the site of application.

The hydrophilic cellulose that can be used in accordance with the present invention is any cellulose derivative that is able to thicken the podofilox alcohol solution into a gel. The hydrophilic

cellulose derivative must, of course, be

pharmaceutically acceptable. It must also be stable in the moderately strongly acid conditions (pH 2-5) that are needed to stabilize the chemical the

podofilox against degradation and which will remain in solution and maintain a stable gel in the gel

structure in accordance with the present invention. Hydroxymethylcellulose, hydroxyethylcellulose,

hydroxypropylcellulose, and carboxymethylcellulose are illustrative of hydrophilic cellulose derivatives that may be used in accordance with the present invention. The hydrophilic cellulose derivative that is currently most preferred is hydroxypropylcellulose.

The gelling agents would typically be used in concentrations sufficient to prepare gels of suitable viscosity and physical characteristics. The relative amount of gelling agent used in accordance with the present invention may range from about 1% to about 10%, and is preferably from 3 to 6%, with the precise amount being selected to provide a gel viscosity in the range of about 5000 to about 100,000 centipoise. It has been found that gels made with approximately 4% hydroxypropylcellulose give excellent results.

Gels in accordance with the present invention are sufficiently viscous to provide positional stability on the skin but can still be easily dispensed from a suitable container and spread on the lesion. The hydrophilic cellulose is selected and used in an amount that provides a gel which dries readily to a non-tacky state but which is sufficiently water- soluble to permit facile clean-up from the skin of the patient.

Any pharmaceutically acceptable buffer system that can maintain the gel in accordance with the present invention at a pH in the range of

approximately 2-5 may be used. The buffer system will generally comprise a mixture of an acid and its salt. Organic mono- and polycarboxylic acids such as acetic lactic, citric, tartaric, fumaric, and so on, as well as common mineral acids such as hydrochloric,

sulfuric, or phosphoric, may be employed. The salts will be those with pharmaceutically acceptable

counterions such as those formed by sodium, potassium, ammonia, or non-toxic organic amines. It is currently preferred that the pH be maintained in the range 3-3.5 by a buffer system comprising lactic acid and sodium lactate.

Additional components may also be added to the gels of the present invention if desired. For

instance, antioxidants such as butylated

hydroxytoluene may be used to protect the podofilox from oxidation. Dispersion agents or other

formulation vehicles may be added. For instance, glycerin can be used to. promote dispersion of the hydrophilic cellulose. Pigments such as titanium dioxide may be added to provide desirable visual attributes to the gels.

EXAMPLES

Podofilox as used hereinbelow may be obtained from pHarma-medica, a-s, of Herlev, Denmark. The hydroxypropylcellulose as used hereinbelow may be obtained as "Klucel" from Aqualon Company of Hopewell, Virginia. The remaining ingredients as used

hereinbelow may be obtained from a variety of

suppliers including Spectrum Chemical and

Mallinckrodt. Stability Testing

Samples of colorless gel were packaged in 0.625- inch by 2.375-inch tubes and stored under different temperature conditions for periods of time of up to several months. The gel was then removed from the package and tested for pH, podofilox content, content of degradation products of podofilox ("related

substances"), appearance, and color. The results were as reported in Examples 1-6, in which "N/D" indicates "not detected". As can be seen from Examples 1-6, in pharmaceutical gels in accordance with the present invention, podofilox shows only minimal degradation even after nine months of storage at room temperature or three months of storage at 40°C and 75% relative humidity. Example 1 - n-PROPANOL - Clear Colorless Gel

One thousand gram lots of podofilox gel were prepared from the following components:

A clear colorless podofilox gel in accordance with the present invention was manufactured as

follows: Approximately two-thirds of the n-propanol was added to a suitable tared mixing vessel with a variable speed agitator. The podofilox and butylated hydroxytoluene as added thereto and mixed until dissolved. The lactic acid and sodium lactate were added to a reserve container and heated to about 50°C. A slurry was made with the hydroxypropylcellulose and glycerin. The heated buffers were used to aid in the formation of the slurry. The hydroxypropylcellulose/ glycerin slurry buffer mixture was added to the mixing vessel containing the podofilox and butylated

hydroxytoluene in alcohol. More of the n-propanol was added to achieve the final weight of 1000 grams. The mixing vessel was covered and mixing was continued for 30 minutes.

Example 2 - ISOBUTANOL - Clear Colorless Gel

follows: Approximately two-thirds of the isobutanol was added to a suitable tared mixing vessel with a variable speed agitator. The podofilox and butylated hydroxytoluene as added thereto and mixed until dissolved. The lactic acid and sodium lactate were added to a reserve container and heated to about 50°C. A slurry was made with the hydroxypropylcellulose and glycerin. The heated buffers were used to aid in the formation of the slurry. The hydroxypropylcellulose/ glycerin slurry buffer mixture was added to the mixing vessel containing the podofilox and butylated

hydroxytoluene in alcohol. More of the isobutanol was added to achieve the final weight of 1000 grams. The mixing vessel was covered and mixing was continued for 30 minutes.

Example 3 - n-BUTANOL - Clear Colorless Gel

follows: Approximately two-thirds of the n-butanol was added to a suitable tared mixing vessel with a variable speed agitator. The podofilox and butylated hydroxytoluene as added thereto and mixed until dissolved. The lactic acid and sodium lactate were added to a reserve container and heated to about 50°C. A slurry was made with the hydroxypropylcellulose and glycerin. The heated buffers were used to aid in the formation of the slurry. The hydroxypropylcellulose/ glycerin slurry buffer mixture was added to the mixing vessel containing the podofilox and butylated

hydroxytoluene in alcohol. More of the n-butanol was added to achieve the final weight of 1000 grams. The mixing vessel was covered and mixing was continued for 30 minutes.

Example 4 - METHANOL - Clear Colorless Gel

follows: Approximately two-thirds of the methanol was added to a suitable tared mixing vessel with a

variable speed agitator. The podofilox and butylated hydroxytoluene as added thereto and mixed until dissolved. The lactic acid and sodium lactate were added to a reserve container and heated to about 50°C. A slurry was made with the hydroxypropylcellulose and glycerin. The heated buffers were used to aid in the formation of the slurry. The hydroxypropylcellulose/ glycerin slurry buffer mixture was added to the mixing vessel containing the podofilox and butylated

hydroxytoluene in alcohol. More of the methanol was added to achieve the final weight of 1000 grams. The mixing vessel was covered and mixing was continued for 30 minutes.

Example 5 - ACETONE - Clear Colorless Gel

One thousand gram lots of podofilox gel were prepared from the following com onents:

follows: Approximately two-thirds of the acetone was added to a suitable tared mixing vessel with a

variable speed agitator. The podofilox and butylated hydroxytoluene as added thereto and mixed until dissolved. The lactic acid and sodium lactate were added to a reserve container and heated to about 50ºC. A slurry was made with the hydroxypropylcellulose and glycerin. The heated buffers were used to aid in the formation of the slurry. The hydroxypropylcellulose/ glycerin slurry buffer mixture was added to the mixing vessel containing the podofilox and butylated

hydroxytoluene in alcohol. More of the acetone was added to achieve the final weight of 1000 grams. The mixing vessel was covered and mixing was continued for 30 minutes.

Example 6 - ISOPROPANOL - Clear Colorless Gel

follows: Approximately two-thirds of the isopropanol was added to a suitable tared mixing vessel with a variable speed agitator. The podofilox and butylated hydroxytoluene as added thereto and mixed until dissolved. The lactic acid and sodium lactate were added to a reserve container and heated to about 50°C. A slurry was made with the hydroxypropylcellulose ar.d glycerin. The heated buffers were used to aid in the formation of the slurry. The hydroxypropylcellulose/ glycerin slurry buffer mixture was added to the mixing vessel containing the podofilox and butylated

hydroxytoluene in alcohol. More of the isopropanol was added to achieve the final weight of 1000 grams. The mixing vessel was covered and mixing was continued for 30 minutes.

Example 7 - ETHANOL - Clear Colorless Gel

follows: Approximately two-thirds of the alcohol was added to a suitable tared mixing vessel with a

hydroxytoluene in alcohol. More of the alcohol was added to achieve the final weight of 1000 grams. The mixing vessel was covered and mixing was continued for 30 minutes.

Stability Testing

Samples of colorless gel made as described above were packaged in 0.625-inch by 2.375-inch tubes and stored under different temperature conditions for periods of time of up to several months. The gel was then removed from the package and tested for pH, podofilox content, content of picropodophyllotoxin ("PIC", a degradation product of podofilox),

appearance, and color.

The results were as reported in Examples 7.1-7.7, (in which "N/D" indicates "not detected" and "N/T" indicates "not tested". As can be seen from Examples 7.1-7.7, in pharmaceutical compositions in accordance with the present invention, podofilox shows only minimal degradation even after nine months of storage at room temperature or three months of storage at 50°C.

Example 8 - ETHANOL - Opague White Gel

An opaque white podofilox gel in accordance with the present invention was manufactured as follows: Approximately two-thirds of the alcohol was added to a suitable tared mixing vessel with a variable speed agitator. The podofilox and butylated hydroxytoluene as added thereto and mixed until dissolved. The lactic acid and sodium lactate were added to a reserve container and heated to about 50°C. A slurry was made with the hydroxypropylcellulose and glycerin. A portion of the heated buffers were used to aid in the formation of the slurry. The titanium dioxide was added to the remainder of the heated buffers and dissolved. The titanium dioxide/buffer mixture was added to the hydroxypropylcellulose/glycerin slurry, and the resulting buffer mixture was added to the mixing vessel containing the podofilox and butylated hydroxytoluene in alcohol. More.of the alcohol was added to achieve the final weight of 1000 grams. The mixing vessel was covered and mixing was continued for 30 minutes. Comparative Examples

In order to demonstrate the criticality of the use of hydrophilic cellulose in the gels of the present invention, alternative gel formulations were prepared as follows:

Example A

A gel base was prepared using 5% ethylcellulose The ethylcellulose went into solution but the

viscosity of the solution was too low for the

preparation to be usable as a gel for the topical application of a medicinal composition.

Example B

A gel base was prepared from the following components:

The resulting gel base dried well, but was very water- insoluble. It would, therefore, result in clean-up problems in use on a patient. Example C

A gel base was prepared from the following components:

The resultant gel retained a sticky feel when dried.

COMPARATIVE USE TESTING

One thousand gram lots of podofilox gel were prepared from the following components by the

procedure described in Example 1:

One thousand gram lots of podofilox solution were prepared from the following components:

Studies were conducted with male and female patients selected on a random basis. Each patient was instructed to self-treat his or her genital warts twice daily for three consecutive days followed by a four day rest period. This cycle of. three days of therapy followed by four days or rest was continued for a minimum of two weeks, after which it was continued until all of the warts disappeared up to a maximum of eight weeks. Ten patients were treated with the solution and 14 patients were treated with the gel formulation. Inspections of the warts being treated and the surrounding areas were conducted at the inception of the testing and after 1, 2, 3, 4, 6, 8, and 12 weeks.

EFFICACY. The primary efficacy variable is the number of the treated warts at each visit. The efficacy data is graphically depicted in Figure 1. Figure 1 demonstrates that from the first week of the study through its conclusion at 12 weeks, the efficacy was better for those patients whose genital warts were treated with the gel as compared to those whose genital warts were treated with the solution. The gel produced up to an 80% reduction in the number of warts compared to up to a 60% reduction with the solution. Figure 2 subsets these data by gender, and shows that positive response to the gel formulation was

especially pronounced with the male patients.

SIDE EFFECTS. The investigators graded the patient's local tolerance to therapy on a scale of zero to seven, with zero representing no inflammation, erosion, or other signs of local adverse effects and seven representing the maximum local adverse effects across the study. Figure 3 compares the means of the sum for all local effects by week of each formulation. The data show that with the exception of week one where the gel produced more local effects, there were no significant differences in local effects between patients treated with the gel versus those treated with the solution. Figure 4 subsets these data by gender, and shows that the male patients appear to have slightly more side effects than the female patients after week one. The investigators reported that the men had slightly more irritation and pain from the gel. More serious side effects, such as erosion or bleeding, however, were not more common. There were no patient drop-outs from these studies to due side effects.

Although the present invention has been disclosed and illustrated with reference to certain specific embodiments thereof, other different specific

embodiments will readily occur to those skilled in the art based upon the teachings herein. The present invention should only be limited, therefore, by all embodiments which are covered by the spirit and scope of the appended claims.

Claims

THE CLAIMS

What is claimed is: 1. A pharmaceutical gel composition comprising: podofilox in an amount therapeutically effective to at least slow the growth of warts in a host;

a solvent comprising a lower alkanol, aldehyde, ketone, or mixture thereof, in an amount sufficient to form a solution with the podofilox; and

a hydrophilic cellulose in an amount effective to thicken the solution to form a gel.

2. The pharmaceutical gel composition of claim 1 wherein the amount of podofilox is from about 0.1 to

5 percent by weight of the composition.

3. The pharmaceutical gel composition of claim 1 wherein the amount of hydrophilic cellulose is sufficient to raise the viscosity of the composition to within the range of 5000 to 100,000 centipoise.

4. The pharmaceutical gel composition of claim 1 wherein the amount of hydrophilic cellulose is from about 0.2 to 12 percent by weight of the composition.

5. The pharmaceutical gel composition of claim 1 further comprising a buffer system to control the pH of the composition.

6. The pharmaceutical gel composition of claim 5 wherein the buffer system imparts a pH of between about 2 and 5 to the composition:

7. The pharmaceutical gel composition of claim

6 wherein the buffer system comprises an organic acid and an organic acid salt.

8. The pharmaceutical gel composition of claim

7 wherein the buffer system comprises lactic acid and sodium lactate.

9. The pharmaceutical gel composition of claim 1 wherein the solvent is a neat or an aqueous lower alkanol.

10. The pharmaceutical gel composition of claim 9 wherein the lower alkanol is a C₁-C₄ alcohol or mixture thereof.

11. The pharmaceutical gel composition of claim 1 wherein the hydrophilic cellulose is a cellulose derivative containing at least one hydroxyl group.

12. The pharmaceutical gel composition of claim 1 further comprising an antioxidant.

13. The pharmaceutical gel composition of claim 12 wherein the lower alkanol is ethanol, the

hydrophilic cellulose is hydroxypropylcellulose, and the antioxidant is butylated hydroxytoluene.

14. The pharmaceutical gel composition of claim 1 further comprising a pigment.

15. A method for treating genital warts that comprising applying to said warts a pharmaceutical composition according to one of claims 1-14.