WO2006010589A2

WO2006010589A2 - Post foaming gel mousse

Info

Publication number: WO2006010589A2
Application number: PCT/EP2005/008108
Authority: WO
Inventors: Barry Hunt
Original assignee: Mipharm S.P.A.
Priority date: 2004-07-29
Filing date: 2005-07-26
Publication date: 2006-02-02
Also published as: WO2006010589A3

Abstract

This invention relates to formulations adapted particularly for insertion of a pharmacologically active agent into a body cavity for systemic treatment or prophylaxis of a medical condition in the patient being treated, or for localised treatment or prophylaxis of the mucosal surface of the cavity of the patient into which the formulation is inserted. More particularly this invention relates to pharmaceutical compositions suited to the treatment or prophylaxis of systemic medical conditions, or of localised medical conditions of the mucosa. The invention is also concerned with methods of treatment of bacterial or fungal mucosal infections.

Description

POST FOAMING GEL MOUSSE

This invention relates to formulations adapted particularly for insertion of a pharmacologically active agent into a body cavity for systemic treatment or prophylaxis of a medical condition in the patient being treated, or for localised treatment or prophylaxis of the mucosal surface of the cavity of the patient into which the formulation is inserted. More particularly this invention relates to pharmaceutical compositions suited to the treatment or prophylaxis of systemic medical conditions, or of localised medical conditions of the mucosa. The invention is also concerned with methods of treatment of bacterial or fungal mucosal infections. The mucosal surfaces of the human body represent a relatively unexplored mechanism by which pharmacologically active agents may be delivered to patients requiring either local or systemic prophylactic or medical treatment. This is because the kinetics of uptake across epithelial membranes, by reason of their lesser protective purpose than skin, may be more rapid than traditional methods of active agent delivery. Moreover, the immediate physiological vicinity of certain mucosal surfaces to organs and physiological regions to be treated may also lead to improved treatment outcomes for patients having regard to those regions.

In the case of local infections of mucosal surfaces, such as fungal and bacterial infections of the vagina, for example, Thrush, a Candida infection, difficulty and unpleasantness of the mode of treatment often mitigates against positive outcomes. Treatment is especially difficult in immune suppressed patients and in patients where multiple treatments must occur. At least part of the reason for the difficulty is associated with poor patient compliance with treatment regimes. This in turn is related to relative unacceptability of treatment products. Bacterial and fungal infections of mucosal surfaces, and particularly of the mucosal surfaces of the vagina are commonly treated by formulations that are in the form of creams or pessaries. Gel treatments are also known. The limitation on these treatments is that, in the case of widespread infection, the area that can be covered by these products is restricted to the area over which the product can be manually applied. Little contact with, for example, the vaginal epithelium occurs, and hence that area, and others, remain untreated, or not as effectively treated, and can be the source of resurgent infection and delayed recovery. One alternative mode of delivery of pharmacologically effective ingredients to the mucosal surface of the vagina has been via the use of non pre expanded foams. These foams develop on expulsion from a container and can cause severe discomfort or pain from the means of inserting the foam into the vagina, or from the rapid rate of expansion of the foam within the vagina of the patient. These foam products are also conventionally thin in texture and will easily flow from the vagina, thereby limiting their medical effect because most of the product is, in fact, lost. One further disadvantage is their restricted coverage of the epithelium due to limited expansion. One known means of inserting contraceptive foam into the vagina is by the use of an applicator syringe. The foam is expanded in the syringe, the syringe inserted in to the vagina, and the foam then syringed into the cavity.

Post-foaming gel mousses have been used for some time in the toiletry industry, especially for shaving gels such as for example in US 5,186,857 (RAMIREZ et al), US 5,500,211 (GEORGE et al), and US 6,165,456 (BARNET et al). The main foaming agents (propellants) used in these products are n-pentane and/or iso-pentane. These allow the product to be dispensed as a non-expanded gel, which then expands slowly to a foam, mainly from the warming effect of skin temperature. Neither of these materials is approved for use in pharmaceutical products.

The pharmaceutically-acceptable propellants all have too high a pressure to be used in a post- foaming gel, as they cause rapid expansion of the gel, causing the pain or discomfort referred to previously. Several years ago it would have been possible to use the CFC propellants, eg combinations of CFCs 11, 12 and 114, but these are now prohibited because of their effect on the ozone layer.

It is thus one object of this invention to provide an improved formulation for systemic treatment or prophylaxis of a medical condition in a patient, or for localised treatment or prophylaxis of the mucosal surface of the cavity of the patient into which the formulation is inserted. It would be desirable to develop a product that was not inclined to leak out of a cavity due to thinning, and/or the lack of mucoadhesive properties, and the consequent effects of gravity. It would also be desirable to produce a product which does not have pain as a side-effect upon delivery to a cavity due to the unacceptably rapid rate of foam expansion, but which at the same time achieves good epithelial coverage for maximum medical effect.

To this end in one embodiment of the invention there is provided a formulation suited to the delivery of pharmacologically active agent into the body cavity of a patient to be treated, said formulation comprising foaming agents, surfactants, thickeners and optionally when required, vapour pressure reducers. Preferably the foaming agent is a pharmaceutically acceptable propellant and more preferably, the foaming agent is n-butane. Preferably the formulation is a gel at room temperature, until upon application, it expands into a mousse or foam at a rate so as to not cause discomfort, and to a degree sufficient to adequately coat the mucosal surface of the body cavity.

Throughout this specification, the term "comprising" shall be taken to mean that the subject matter to which it relates may contain additional components, features, characteristics, ingredients or combinations thereof which are not specifically mentioned, and shall not be taken so as to exclude additional components, features, characteristics, ingredients or combinations thereof which are not specifically mentioned. Throughout this specification, the term "pharmacologically active agent" shall be taken to mean any chemical substance listed in any pharmacopoeia for prophylactic or therapeutic treatment of a medical condition or a potential medical condition in a patient.

It has been found that by use of the formulations of the invention, treatment of medical conditions, particularly of the vagina, may be achieved quicker and more easily than with conventional known treatments. It is also well known that products that improve compliance tend to be more effective. Patient compliance is expected to improve using the compositions of the invention in the treatment of thrush. Improved treatment occurs by virtue of the slow formation of foam upon delivery of the gel composition into the body cavity. Expansion of the foam occurs very slowly at ambient temperature and slightly quicker at body temperature.

The formulations of the invention may be used to deliver contraceptives, lubricants, anti fungal and anti bacterial substances, and other known pharmacologically active agents for localised use, but may also be used for delivery of immunogenic substances such as vaccines or for other known medical substances for local or systemic treatment of, for example, wounds, ulcers and psoriasis. Any medical application in which mucosal treatment or mucosal delivery of an active agent is advantageous will be suitably treated by formulations of the invention incorporating pharmacologically active agents. Suitable pharmacologically active agents may include anabolic steroids such as methyltestosterone, ethyloestrenol; NSAID drugs (non-steroidal anti¬ inflammatory drugs), such as asprin, ibuprofen, indomethacin, ketoprofen; sedatives and hypnotics such as diazepam, lorazepam, oxazepam; the barbiturates, including pentobarbitone, phenobarbitone, chloral hydrate; thyroid hormones such as thyroxine and liothyronine; vaccines such as cholera, diphtheria, hepatitis A, hepatitis B, H. influenzae type B, influenza, measles, mumps, polio, rubella, pertussis, tenanus, typhoid, yellow fever; anti¬ migraines such as ergotamine, methysergide, propranolol, anti-oestrogens such as tamoxifen and clomiphene; beta-blockers such as alprenolol, propranolol; corticosteroids such as betmethasone, budesonide, cortisone, hydrocortisone, prednisolone, clobetasol; female sex hormones such as oestradiol, medroxyprogesterone; fertility drugs such as clomiphene; immune suppressants such as cyclosporin, methotrexate; inhibitors of bone reabsorption such as etridronate; anti-emetics (nausea and vomiting) such as metroclopramide, promethazine; anti-endometriosis drugs such as nafarelin; analgesics such as aspirin, paracetamol, codeine, methadone, morphine and oxycodone; anti-anginals such as amyl nitrite, glyceryl trinitrate; antibiotics such as acyclovir (herpes), zidovudine (HIV), doxycycline, ketoconazole, miconazole, nystatin, silver sulphadiazine, metronidazole, doxycycline, erythromycin; anti-cancer drugs such as methotrexate, interferon; anti¬ depressants such as amitryptiline, doxepin; anti-dementia drugs such as tacrine. Also suited to delivery via the formulation of the invention are peptide based drugs which are not orally ingestible nor active via the gut mucosa, or which exert action locally, such as relaxin.

Thus there is also provided in another embodiment of the invention, a pharmaceutical composition suited to insertion into the body cavity of a patient to be treated, said composition comprising one or more pharmacologically active agents, foaming agents, surfactants, thickeners and optionally, when required, vapour pressure reducers. Preferably the foaming agent is a pharmaceutically acceptable propellant and more preferably, the foaming agent is n-butane. Preferably the composition is a gel at room temperature, until upon application, it expands into a mousse or foam at a rate so as to not cause discomfort, and to a degree sufficient to adequately coat the mucosal surface of the body cavity. The pharmaceutical compositions of the invention may be suited to treatment of medical conditions in the vaginal, anal, ear, oral and nasal cavities, wound cavities/fissures, or may be suited to treatment of systemic medical conditions via these cavities. They may also be suited to the delivery of immunogenic substances which may pass into the patients circulation for the purposes of generating antibodies via the mucosal lining of the site of application. Suitable pharmacologically active agents for delivery in this embodiment of the invention are those previously listed.

Thickeners used according to the invention may be selected from the group comprising povidone, cellulose gums such as sodium carmellose, xanthan gum and other pharmaceutically acceptable thickeners, or combinations thereof. These thickeners may also act as stabilisers for the composition and help it slowly develop from a gel to a foam after application to the body cavity of interest, as well as improving the mucoadhesive qualities of the formulation. Surfactants desirably included in the formulations and compositions of the invention so as to assist in formation of the foam, the emulsification of the vapour pressure reducers, and the solubilisation of the active agents, may include but are not limited to nonoxinol, polysorbate, glyceryl stearate, glycol stearate, sorbitan esters, polyoxylated stearates, polyoxylated castor oil, macrogol alkyl ethers such as macrogol lauryl ether, and other pharmaceutically acceptable surfactants or combinations of the foregoing.

Suitable foaming agents may be selected from but are not limited to hydrocarbons such as n-butane, chlorofluorocarbons, hydrofluorocarbons, dimethyl ether, nitrogen, nitrous oxide and carbon dioxide. These foaming agents must not cause excessively rapid expansion of the foam in the body cavity of a patient since discomfort and/or pain will result.

The foaming agents may be combined with oily substances such as for example caprylic/capric triglycerides which act as vapour pressure reducers or solvents. Other pharmaceutically suitable vapour pressure reducers or solvents may be used alone or in combination.

The compositions may also include other excipients such as for example pH buffers, solvents, carriers, diluents and preservatives. Suitable pH buffers may include citrates, phosphates or acetates, or other pharmaceutically acceptable buffers. Suitable preservatives may include benzyl alcohol or parabens, and other pharmaceutically acceptable preservatives. Suitable carriers and diluents may include purified water.

The compositions and formulations of the invention are desirably packaged as a metered aerosol, a single-shot vial, or as a two-compartmental system such as a "bag-in-can" type aerosol product. Packaging in a pressurized container is desirable to mitigate against premature expansion of the mousse.

In pharmaceutical compositions according to the invention, preferred ranges of the components of the compositions are as follows. Thickeners may be present in an amount of 0.1 - 30% m/m, more preferably 1.0 - 15% m/m. Surfactants may be present in an amount of 1.0 - 60% m/m, more preferably 4.0 - 40% m/m. pH buffers may be present in an amount of 0 - 10% m/m, more preferably 0.1 - 2.0% m/m. Oily substances may be present in an amount of 1.0 - 30% m/m, more preferably 5.0 - 20% m/m. Preservatives may be present in an amount of 0.01 - 5.0% m/m, more preferably 0.2 - 2.0% m/m. The pharmacologically active agent may be present in varying amounts depending on the profile of the drug, the condition to be treated and whether or not localised or systemic treatment is required. In the case of anti-fungal agents, amounts may vary from 0.05 - 20% m/m. The bulk of the compositions according to the invention is made up by a suitable solvent such as water lower alcohols and glycols and combinations thereof which may be present in amounts of 10 - 95% m/m, more preferably 40 - 80% m/m.

According to the invention there is also provided a method of treatment of a fungal or bacterial infection of the vagina comprising administering to a patient requiring such treatment an effective amount of a pharmaceutical composition according to the invention wherein the pharmacologically active agent is an anti fungal or anti bacterial agent.

Preferably the pharmacologically active agent is selected from the group consisting of clotrimazole, ketoconazole, miconazole and terconazole.

The following formulations and composition examples are not indicative of the full scope of the invention, but are examples merely of compositions falling within the scope of the invention.

One formulation according to the invention is as follows:

Example 1

This formulation is simply prepared by blending all ingredients into the water using an overhead stirrer. Sodium CMC is premixed with part of the nonoxinol 9. Mixing is continued for approximately 30 minutes. The pH and viscosity are adjusted to suit application to a body cavity as a gel.

Compositions including a pharmacologically active agent according to the invention are as follows:

Example 2

Example 3

Example 4

Example 5

The compositions and formulations exemplified in accordance with the invention may be rendered suitable for use by the addition of approximately 10% n-butane in one preferred embodiment.

Comparative Example 1 - COMPARISON OF EVENNESS OF DISTRIBUTION OF GEL MOUSSE VERSUS CREAM

This example compares the retention and distribution of the post foaming gel mousse according the invention with the widely used anti-fungal Canesten® Cream.

In figure 1, the regions of the vaginal mucosa are designated as follows:

A and B = upper right and left quadrants

C and D - lower right and left quadrants

Region E is a sanitary pad collection means external of the vagina of a patient being treated. Healthy, non-pregnant pre-menopausal women gave informed consent. Following an induction health screen, the subjects were studied twice, with the test or control formulation administered in random order 28 days apart. Canesten cream (Bayer Australia) was radio-labelled (by continuous mixing) with ^99mmTcDTPA, so that the administered dose was 4MBq in the standard 6g applicator. ^99mmTcDTPA was added to 0.5ml of a formulation according to the invention prior to pressurisation and production of a foaming gel, so that 4MBq was incorporated in the test dose. Preparations were weighed and counted before, and after administration to determine accurately the amount administered. A standard was produced, so that gamma-camera, and gamma counter results could be cross-calibrated. All counts were decay corrected.

Simultaneous anterior and posterior images (Picker Prism 2000) were obtained 15 minutes after dosing and at 15 minute intervals for the first hour. Hourly images were then obtained for 7 hours, with a final image at 24 hours. Geometric mean counts were recorded for the whole vagina, and four arbitrary quadrants, and for an extra- vaginal region. Tomography was obtained at 1, 4 and 7 hours. A sanitary pad was changed after each imaging event, and counted to determine the activity lost. The difference between the sum of the activity seen on the gamma camera, and counted on the sanitary pad, and that administered was the activity not accounted for.

The figures 2 and 3 show the distribution in a typical subject of the Gel Mousse according to the invention and the Canesten Cream within the vagina over 24 hours. Figure 2 indicates virtually all the dose is equally distributed between the two upper quadrants, and slowly and evenly diffuses into the lower quadrants. The Canesten Cream according to figure 3 is unevenly located in upper quadrant A, with minimal amounts in the other upper quadrant. It also diffuses into the lower quadrants, but remains unevenly distributed in the right hand side of the vagina. This is confirmed by the scintigrams, figures 4 and 5.

The series of scintigrams (figures 4 and 5) show the position of the

Cream and the Gel Mousse within the vagina of a typical subject over 24 hours. The scintigrams are in pairs, anterior and posterior. The uneven distribution of the cream mentioned above is clearly seen in these images. Some areas of the vaginal epithelium are not in contact with the cream.

The Gel Mousse has expanded fairly rapidly to fill the vaginal cavity, and has given extensive coverage of the epithelium and good retention within the vaginal cavity.

The formulations and compositions developed in accordance with the invention result in a product which has a delayed expansion upon application so as to minimise discomfort to a patient. The product may be prepared and stored under pressure as a gel but upon delivery assumes the form of a foam or mousse. Good coverage of the epithelium of the cavity being treated is demonstrably achieved.

Claims

1. Formulations suited to the delivery of pharmacologically active agent into the body cavity of a patient to be treated, said formulation comprising foaming agents, surfactants, thickeners and optionally when required, vapour pressure reducers.

2. Formulations according to claim 1 wherein the foaming agent is a pharmaceutically acceptable propellant.

3. Formulations according to claim 2 wherein the foaming agent is n- butane.

4. Formulations according to any one of claims 1-3 which is in form of a gel at room temperature, until upon application, it expands into a mousse or foam at a rate so as to not cause discomfort, and to a degree sufficient to adequately coat the mucosal surface of the body cavity.

5. Formulations according to any one of claims 1-4, wherein the active ingredient is selected from contraceptives, lubricants, anti fungal, anti bacterial substances, vaccines anabolic steroids, NSAID drugs (non-steroidal anti-inflammatory drugs), sedatives, hypnotics, barbiturates, thyroid hormones, anti-migraines, anti-oestrogens, beta-blockers, corticosteroids, female sex hormones, fertility drugs, immune suppressants, inhibitors of bone reabsorption, anti-emetics, anti-endometriosis drugs, analgesics, anti-anginals, antibiotics, anti-cancer drugs, anti-depressants, anti-dementia drugs, peptide based drugs which are not orally ingestible nor active via the gut mucosa, or which exert action locally.

6. Formulations according to any one of claims 1-5 wherein the thickeners are selected from the group comprising povidone, cellulose gums, sodium carmellose, xanthan gum or combinations thereof.

7. Formulations according to any one of claims 1-6 wherein the surfactants are selected from nonoxinol, polysorbate, glyceryl stearate, glycol stearate, sorbitan esters, polyoxylated stearates, polyoxylated castor oil, macrogol alkyl ethers or combinations thereof.

8. Formulations according to any one of claims 1-7 wherein the foaming agents are combined with caprylic/capric triglycerides.

9. Formulations according to any one of claims 1-8 comprising thickeners in an amount of 0.1 - 30% m/m, surfactants in an amount of 1.0 - 60% m/m, pH buffers in an amount of 0 - 10% m/m, oily substances in an amount of 1.0 - 30% m/m, preservatives in an amount of 0.01 - 5.0% m/m.

10. A method of treatment of a fungal or bacterial infection of the vagina comprising administering to a patient requiring such treatment an effective amount of a formulation of claims 1-9 wherein the pharmacologically active agent is an anti fungal or anti bacterial agent.

11. A method according to claim 10, wherein the pharmacologically active agent is selected from the group consisting of clotrimazole, ketoconazole, miconazole and terconazole.