This invention relates to formulations for the prevention of infection and/or abnormal conditions of mucosae and/or skin caused by any pathogen and/or any disease, and more particularly for the prevention of sexually transmitted infections specially HIV and HSV. This invention also relates to formulations for the treatment of infection and/or abnormal conditions of skin and/or mucosac and more particularly for the treatment of herpetic lesions. The formulations could be used as a prophylactic agent to prevent accidental infection of health care workers. The formulations could be used for the healing and/or treatment of bum wounds and prevention of further infection. This invention also relates to the development of a unique vaginal/ano-rectal applicator for the uniform delivery of any topical formulations to treat and/or prevent any infection and/or abnormal conditions of mucosa cavity caused by any pathogen and/or disease.

FIELD OF THE INVENTION

This invention relates to formulations comprising film-forming components and any active ingredient, particularly to topical formulations. More particularly, this invention relates to topical formulations to prevent or to treat diseases associated with or transmitted through mucosae or skin, caused by any causative agent, particularly a pathogen. This invention also relates to an applicator for the uniform delivery of topical formulations to prevent or to treat any disease associated with or transmitted through mucosal cavity, or to prevent invasion by an external agent such as sperm or microbe.

BACKGROUND OF THE INVENTION

The spread of sexually transmitted diseases (STDs) caused by human immunodeficiency virus (HIV), herpes and other pathogens is going at a bewildering rhythm. The global incidence, morbidity, and mortality of STDs are very significant. Worldwide, it is estimated that over 900 million individuals are infected with sexually transmitted pathogens. Each year more than 12 million people in the United States are newly infected with a pathogen responsible for STDs. Herpes simplex virus type-1 (HSV-1) and type-2 (HSV-2), are the most common causes of genital ulceration in developed countries. Genital herpes infection is life-long and may result in painful and recurrent genital lesions, systemic complications, psychosocial morbidity and also serious neonatal disease following intrapartum transmission of HSV. The genital transmission of this pathogen is usually due to asymptomatic viral shedding by people who are unaware that they are infected. HSV-2 is now detectable in 1 out of 5 americans 12 years of age or older. In addition, it is estimated that over one-third of the world's population has recurrent HSV infections and has therefore the capability to transmit the virus during episodes of productive infection. Neisseria gonorrheae and Chlamydia trachomatis are recognized as two of the most prevalent sexually transmitted bacterial infections. Worldwide, there is an estimated annual incidence of 25 million cases of gonorrhea and 50 million cases of chlamydia. On the other hand, recent epidemiologic data indicate that the number of individuals infected with HIV is growing dramatically throughout the world. According to United Nations officials, epidemiologic data estimates suggest that as many as 16,000 individuals become infected with HIV every day during 1997. Recent statistics (as of end 1997) from the World Health Organization (WHO) indicated that there are about 31 million people infected with HIV worldwide and this number is projected to reach 40 millions by year 2000.

Globally, heterosexual transmissions may account for 85 90% of HIV infection. As there is no vaccine against HIV, preventive measures are the only tools that can presently reduce the transmission of this retrovirus. The consistent and careful use of condoms represents an effective barrier against the sexual transmission of HIV and other sexually transmitted pathogens, but they should be used in all risky sexual intercourses to significantly reduce the probability of acquiring infection. In Africa, the most intensive prevention programs were only able to increase condom use to approximately 70% of all sexual intercourses in female prostitutes. Consequently, doubts arise about the possibilities of condom promotion in controlling the AIDS epidemic in high risk groups. In situations where heterosexual transmission of HIV is important, preventive measures where women could prevent their risk of contracting STDs could be an additional tool to restrain the epidemic. Such a protective tool may also be used in male homosexual relations as it could provide additional protection under the control of the receptive partner. Therefore, it is important to develop barrier method that could be used as an alternative to condoms where the person could protect themselves against infection without having to ask their sexual partners. Preventive measures aimed at blocking the initial transmission of pathogens that are the causative agents of AIDS, herpes and other STDs will lead, of course, to enormous benefits.

The development of safe topical microbicides is actually a very high priority for the World Health Organization (WHO) and the National Institutes of Health (NIH) in the field of HIV prevention. A topical microbicide is often composed of an active ingredient and a vehicle. Active ingredients may act via a variety of mechanisms including: i) disrupting the organism cell membrane, envelope or capside lipid or protein constituents (e.g. detergent-type spermicides/microbicides such as nonoxynol-9), ii) blocking the receptor-ligand interactions essential for infectivity (e.g. microbial adhesion inhibitors such as sulfated compounds), iii) inhibiting the intracellular or extracellular replication of the pathogen (e.g. antimicrobial drugs), iv) altering the vaginal environment and reducing susceptibility to infection (e.g. buffering agents and products that maintain normal vaginal flora and environment) or v) enhancing local immune responses (e.g. immune response modifiers). The overall efficacy of a topical microbicide against the sexual transmission of pathogens causing STDs depends on the efficacy of the active ingredient to be delivered and its ability to cover the entire vaginal/cervix area for maximal efficacy against pathogens. The capacity of these active agents to cover the entire vaginal cavity greatly depends of the type of vehicle used. Typical formulations of vehicles include gels, creams, foams, suppositories, sponges and films.

Most currently available vaginal formulations use the spermicide nonoxynol-9, a nonionic surfactant, as a microbicide. In vitro, nonoxynol-9 inactivates enveloped viruses, such as HSV, HIV and other microorganisms including Chlamydia trachonatis, Neisseria gonorrhoeae. However, the potential efficacy of nonoxynol-9 against HIV is not yet clearly established and results of clinical trials are controversial. A recent controlled trial conducted among 1292 HIV-negative female sex-workers in Cameroon showed that the use of a vaginal film containing 70 mg nonoxynol-9 did not reduce the rate of new HIV, gonorrhea or chlamydia infection (Roddy et al., 1998, N. Engl. J. Med., 339:504 510). The failure of nonoxynol-9 film in reducing the transmission of infectious agents could be attributed to the incomplete coverage of the entire vagina/cervix area with the drug delivery system for nonoxynol-9 or to the occurrence of mucosal toxicity favoring infection of microorganisms. Because of the dramatic increase in the number of individuals throughout the world who are infected with HIV, herpes, or other sexually transmitted pathogens, there is an urgent need to develop active products and/or appropriate delivery systems that can reduce the sexual transmission of these pathogens with minimal mucosal irritation and minimal effects on the vaginal flora and pH.

Sodium lauryl sulfate (SLS) is a sulfated surfactant that denatures membrane proteins of pathogens. It thus has a dual action as a detergent and as a chaotropic agent. With this notion, we have performed experiments to evaluate the potential microbicidal effect of SLS on HSV and HIV. Our preliminary studies clearly demonstrated that SLS modifies in vitro the infectivities of both viruses. More recently, Howett et al have confirmed our findings that SLS is also a potent inactivator of HSV-2, HIV-1 (Antimicrob. Agents Chemother. 43(2): 314 321, 1999). In addition, they have shown that SLS is effective against rabbit, bovine and human papillomaviruses (non-enveloped viruses) after brief treatment with low concentrations of this product. However, this reference does not teach the use of a vehicle to deliver this potential microbicide. The choice of vehicle is very important because it affects the concentration of available drugs, the duration of drug availability and the degree of mucosal coverage by the formulation which are key factors for offering protection against invading pathogens. Another interesting category of candidate microbicides is microbial adhesion inhibitors, such as sulfated compounds, which block the interaction between host cell receptor and microbe. A known example of microbial adhesion inhibitors is dextran sulfate (DS), a polysulfated carbohydrate, which has been shown to inhibit in vitro the infectivities of HIV and herpesviruses.

We have recently developed a gel formulation that could be applied to the vaginal, cervical or ano-rectal mucosae and which could be effective to prevent sexually transmitted pathogens. One paramount characteristic of this gel formulation is its thermoreversible property. The transition from the liquid state at room temperature to the gel state at body temperature is of prime importance because when applied on rough biological surfaces such as the vaginal or ano-rectal epithelia, the gel should penetrate into the smallest irregularities forming a good physical barrier against infectious agents. The gel formulation has the following key characteristics that both FDA and NIH consider important: i) it is colorless, odorless and non-staining, ii) it should cover the whole vagina/cervix because it is applied in liquid state, iii) it is compatible with male latex condom, iv) it resists to elution by aqueous flow, v) it has a pH similar to that of a healthy vagina (pH 4.0 4.5), vi) it maintains the desired rheological properties under extreme heat and cold conditions and vii) it does not affect, in vitro, the normal vaginal flora, especially Lactobacillus spp.

Our international publication (WO 97/42962) discloses the use of formulations comprising film-forming components capable of forming per se a physical barrier to pathogens. Thermoreversible gels such as poloxamers are particularly preferred for that use. The film-forning formulations may further comprise microbicides, spermicides or any other drug, which choice is guided by the pathogen, organism or the disease to be inactivated or treated. The formulations are therefore efficient as a physical, and optionally, as a chemical or pharmacological barrier as well as usable as a sustained drug-release system at the locus of administration. These formulations are intended for use in the prevention of sexually transmitted diseases, as well as in the treatment of infections, cancer, inflammation or any disease or state which requires a pharmacological treatment. In addition, this publication teaches that the formulation decreases the toxicity of potent spermicides/microbicides such as nonoxynol-9. However, this publication does not specifically teach the use of SLS as a chemical candidate of choice incorporated into the topical formulations.

HSV-1 and HSV-2 are neurotropic viruses which infect principally the neuroectodermal tissues including the skin, the peripheral nerves and the central nervous system. Mucosal or skin surfaces are the usual sites of primary infection. Recurrent labialis herpes and genital herpes represent the most common clinical manifestations associated with HSV-1 and HSV-2 infections, respectively. Recurrences are spontaneous but are associated with physical or emotional stress, fever, exposure to ultraviolet light, tissue damage and immune suppression. Although it is a mild disease in immunocompetent individuals, HSV infections are troublesome, especially for patients with frequent episodes. Patients compromised by either immune therapy or underlying disease have increased risk to develop HSV infections. Renal and cardiac transplant recipients demonstrated an increased severity of infection. In addition, the outbreak of AIDS has reinforced the severity of HSV clinical disease in immunocompromised hosts.

The current available topical antiviral treatments have only a limited efficacy particularly against symptomatic recurrent herpes. The limited efficacy of these topical formulations on the development of herpetic mucocutaneous lesions may be due to the poor ability of the drugs to penetrate into the skin. The stratum corneum or horny layer constitutes the barrier for the penetration of most substances into the skin. This layer consists of corneocytes embedded in a double-layered lipid matrix composed of cholesterol, free fatty acids and ceramides. Consequently, the use of skin penetration enhancers could represent a convenient strategy to increase the penetration of topical drug formulations into the skin.

SLS is a surfactant which possesses skin penetration enhancer property by increasing the fluidity of epidermal lipids. The skin penetration enhancer property of SLS combined with its ability to modify viral infectivity via its detergent and chaotropic properties could further increase the efficacy of topical drug formulations. Furthermore, because of its chaotropic properties, SLS may have a broader spectrum of activity against sperm, bacteria, fungi and viruses than another simple detergent.

Poloxamers are widely used in numerous pharmaceutical applications and their non-toxic properties make them suitable for sustained drug delivery systems. Poloxamers represent suitable matrices for dermatological applications. Indeed, when applied in liquid form, poloxamers allow a better surface coverage by penetrating into the smallest irregularities of the mucosa and/or skin. In addition, the reticular array formed by these poloxamers may act as a sustained drug release system prolonging drug action.

SUMMARY OF THE INVENTION

In accordance with the present invention, it is a first object to provide formulations which comprise a film-forming component which is applied to the surface of mucosae or skin, preferably in the form of gel, cream or ointment. The gel formulations are to be used for coating different types of mucosae such as vaginal, cervical, ano-rectal, eye, mouth, nose, or skin to prevent infection and/or abnormal conditions of mucosae and/or skin. Furthermore, the gel formulations can be applied topically to the eye for the treatment and/or prevention of infection of ophthalmic conditions. Preferably, a thermoreversible gel is used, which is applied in a liquid form, spreads on the surface and forms a semi-solid coating after it reaches the temperature of this body surface. More preferably, the thermoreversible gel is composed of poloxamer 407. Similar polymers such as poloxamines can also be used. The above formulations also comprise an agent capable of interfering with the organism cell membrane, envelope or capside lipid or protein constituents in a target cell, tissue or microbe. The above combination of the film-forming component and the above agent may provide for formulations with improved efficacy and reduced toxicity.

In a specific embodiment, the agent is capable of interfering with the binding of a microbial outer protein to a host receptor. In a more specific embodiment, the agent is a microbial adhesion inhibitor, or is a detergent or a chaotropic agent capable of disrupting the integrity of said microbial outer protein. In an even a more specific embodiment, the microbial adhesion inhibitor is dextran sulfate; the detergent is selected from the group consisting of sodium lauryl sulfate, benzalkonium chloride, lauroyl sarcosine, polyoxyethylene fatty acyl derivatives and polyoxyethylene sorbitan fatty acyl ester derivatives; and the chaotropic agent is sodium lauryl sulfate or guanidine. In the most specific embodiment, the agent is SLS, the latter being a chemical candidate of choice because of its numerous properties as a detergent and a chaotropic agent and a putative microbial adhesion inhibitor. SLS alone is efficient against microbes. SLS efficacy is further improved when incorporated into the present formulations. Therefore, it is contemplated that SLS or any equivalent product can be used alone or in combination with the above film-forming component to prevent microbial infection. SLS may be used alone or in combination with the above formulations at any suitable concentration, preferably at a concentration of about 0.1 25% (w/v), and more preferably at a concentration of about 1 15% (w/v). Poloxamer 407 concentration may be used at any suitable concentration, preferably at a concentration of about 5 50% (w/v) and more preferably at a concentration of about 15 35% (w/v) The physical properties of the final formulations largely depends on the drug to be incorporated in them, on the pH and solutes used in the making of the formulations and on the viscosity sought for a given purpose. The above formulations could further comprise a drug which is effective to prevent infection and/or abnormal conditions of the mucosae or skin. Vaginal formulations constitute a physical and a chemical barrier due to its film-forming and microbial disrupting components. It goes along that, with an activity against infective agents, these formulations may also be effective for preventing pregnancy. SLS will advantageously replace nonoxynol-9 in the formulations. SLS having a broader spectrum of activity against, inter alia, sperm, enveloped and non-enveloped viruses, it is a candidate of choice in the present formulation. The gel could contain a drug which is effective to prevent infection and/or abnormal conditions of mucosae and/or skin. For the purpose of the invention, the term "drug" is intended to cover any antimicrobial, bactericidal, virucidal, chemotherapeutic, antiinflammatory, antineoplastic, immunomodulator or any other agent or combination of them which is effective for the prevention of infection of mucosae and/or skin. The term "drug" also refers to cytokines or antigens that could stimulate an immune response that would protect against infection. The drugs could be incorporated within drug carriers such as gels, liposomes, nanoparticles or cyclodextrins, whose encapsulation result in an improved prevention of infection.

It is further an object of the present invention to provide a unique applicator that can be used vaginally and/or ano-rectally to deliver topical formulations for treatment and/or prevention of infection and/or abnormal conditions of mucosae. The applicator can be designed in different ways to give the same required characteristics specified under detailed description of the invention. Examples of some different concepts are also discussed under the detailed description which are intended to describe some of the general design possibilities of the applicator, but are in no way intended to limit the scope thereof. It is important to mention that the final shape and appearance of the applicator can differ from the examples given herein.

In other preferred embodiments, the present formulations are used to treat viral diseases and they further comprise as a drug an antiviral agent such as acyclovir or foscarnet, or any other antimicrobial agents, used alone or in combination, at any suitable concentration. In a most preferred embodiment, the formulation is composed of poloxamer 407 and contains foscamet at a concentration ranging from 0.5 to 5% (w/v). In another most preferred embodiment, the formulation is composed of poloxamer 407 and contains acyclovir at a concentration ranging from 0.5 to 5% (w/v). In still another most preferred embodiment, the formulation is composed of poloxamer 407 and contains SLS at a concentration ranging from 1 to 10% and foscamet or acyclovir at the above concentrations.

It is an object of the present invention to develop new topical formulations to prevent infection of mucosae and/or skin, more particularly those sexually transmitted infections and even more particularly those caused by HIV and herpes. The microbicides or any other drug can be entrapped into the gel formulations either as free or encapsulated into drug carriers such as liposomes, nanoparticles or cyclodextrins. Such microbicidal gels could prolong the local microbicidal activity, eliminate local irritation and reduce systemic side effects of incorporated active agents.

It is also an objective of the invention to develop, for vaginal applications, a unique applicator which allows uniform distribution of the content to the entire vagina (delivery to sides) and cervix (delivery to front) for maximal protection against the sexual transmission of pathogens. Therefore, we have designed a unique applicator which allows about 360.degree. distribution of its content into the vagina and far to the cervix which is a great improvement over existing conventional vaginal applicators which deliver contents only to front (cervix area only).

It is another object of the present invention to develop topical formulations of drugs which could improve the efficacy of chemically or pharmacologically active agents against mucocutaneous infections and more particularly those caused by HSV infections. The improved efficacy of drugs upon incorporation within suitable matrices and/or drug carriers could reduce the dosing interval and consequently improve the quality of life of patients. It is also an objective of the present invention to develop topical formulations for the treatment and/or healing of burn wounds as well as to prevent their potential infection.

Claim 1 of 7 Claims

1. A method of treating or reducing infection by infectious agent capable of causing a sexually transmitted disease or reducing the risk of pregnancy by providing a patient's skin or mucosa with a physical barrier and a chemical barrier against said infectious agent or against a sperm, the method comprising applying to said patient's skin or mucosa, a topical formulation consisting essentially of (a) a poloxamer at a concentration of about 15% to 35% (w/w), (b) a buffer solution and (c) an effective amount of an agent capable of disrupting membrane or protein conformation of said infectious agent or sperm said agent being selected from the group consisting of polyoxyethylene fatty acid-comprising detergent, guanidine, lauroyl sarcosine and sodium lauryl sulfate, whereby, when applied to the surface of a person's skin or mucosa, the composition forms a protective semi-solid layer on the skin or mucosa, said semi-solid layer being resistant to elution by aqueous flow.

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