United States Patent:  6,068,851

Assignee:  Infectio Recherche, Inc. (Sainte Foy, CA)

Filed:  January 13, 1999

This invention relates to 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-forming 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. A part of the drug may also be entrapped in liposomes or other drug carriers. 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. Formulations are applicable to mucosae, skin and eye, for example.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method i) to prevent the transmission of pathogens through mucosae and/or skin, more particularly those useful to prevent the sexual transmission of human immunodeficiency virus and other sexually transmitted diseases, ii) to treat lesions of mucosae and/or skin caused by pathogens or any other disease and iii) to prevent and/or treat any other pathogen of mucosae and/or skin including any infection, cancer, inflammatory process or any other disease.

It is an object of the present invention to provide formulations to prevent the transmission of pathogens through mucosae and/or skin, more particularly those useful to prevent the sexual transmission of human immunodeficiency virus and other sexually transmitted diseases. It is another object of the present invention to provide formulations to treat lesions of the mucosae and/or skin. It is still another object of the invention to provide formulations to prevent and/or treat any other pathogen of mucosae and/or skin including any infection, cancer, inflammatory process or any other disease.

In preferred embodiments, the above method and formulations are effective to prevent the transmission of STDs, more particularly HIV, by acting as a physical, chemical and/or pharmacological barrier. The physical barrier comprises a film-forming component which is applied to the surface of mucosa or skin, preferably in the form of gel, cream or ointment. Most preferably, a thermoreversible gel is applied in a liquid form, spreads on this surface and forms a semi-solid coating after it reaches the temperature of this body surface. In a more preferred embodiment, the thermoreversible gel is composed of poloxamer 407. Similar polymers like poloxamines can also be used. The semi-solid gel alone acts as a mechanical (physical) barrier which blocks access of either free or intracellular pathogen to the mucosa or skin. The chemical and/or pharmacological barrier comprises a microbicide, a spermicide and/or any other drug. For the purpose of the invention, the term "microbicide" is intended to cover any agent effective against pathogens. A chemical barrier comprises free microbicide(s), spermicide(s) and/or any other drug entrapped in gel, which chemically destroys pathogens coming into contact with the mucosa or skin and also reduces or eliminates toxicity of the microbicides, spermicides and/or other drug to epithelial cells. Microbicides, spermicides and/or any other drug may be released from the gel or they may get in situ on pathogens or infected cells. In a more preferred embodiment, the chemical barrier is intended to be used in gel applicable on the vaginal, cervical and/or ano-rectal mucosae, and is a compound such as nonoxynol-9. A pharmacological barrier may comprise a microbicide, a spermicide and/or any other drug effective against the pathogen such as an adsorption inhibitor which prevents pathogen's entry into a target cell, an inhibitor for an enzyme necessary for the replication of the pathogen or a metabolic poison for the pathogen. In a more preferred embodiment, the pharmacological barrier is intended to be used in gel applicable on the vaginal, cervical and/or ano-rectal mucosae to prevent the sexual transmission of HIV and comprises inhibitors of HIV protease and reverse transcriptase (alone or in combination). These inhibitors are preferably encapsulated within drug carriers such as liposomes, nanoparticles or cyclodextrins, which encapsulation results in the concentration of the inhibitors within the HIV target host cells, preventing either the production of infectious viral particles or infection of uninfected cells. If infected cells in sperm can reach the mucosa, the gel formulation of anti-HIV agents could prevent HIV infection of host cells, such as macrophages, lymphocytes, Langerhans and M cells.

In a preferred embodiment, the gel formulation is composed of poloxamer 407. In a more preferred embodiment, the poloxamer 407 concentration is 19.5% (w/w). In another preferred embodiment, the gel formulation is composed of poloxamer 407 (19.5% w/w) and contains nonoxynol-9 as microbicide. In another preferred embodiment, the gel formulation is composed of poloxamer 407 (19.5% w/w) and contains liposomes composed of distearoylphosphatidylcholine (DSPC): distearoylphosphatidylglycerol (DSPG) in a molar ratio of 10:3 within which 2'-3'-dideoxyinosine (ddi) is entrapped as antiviral drug. In another preferred embodiment, the gel formulation is composed of poloxamer 407 (19.5% w/w) and contains liposomes composed of DSPC: DSPG: distearoylphosphatidylethanolamine-polyethylene-glycol (DSPE-PEG) in a molar ratio of 10:3:1.45 within which ddl is entrapped as antiviral drug. In another preferred embodiment, the gel formulation is composed of poloxamer 407 (19.5% w/w) and contains liposomes composed of dipalmitoylphosphatidylcholine (DPPC):dicetylphosphate (DP): cholesterol (CHOL) in a molar ratio of 4:1:5 within which 2'-3'-dideoxycytidine (ddC) is entrapped as antiviral drug. Yet in another preferred embodiment, the gel formulation is composed of poloxamer 407 (19.5% w/w) and contains liposomes composed of DPPC:dipalmitoylphosphatidylglycerol (DPPG) in a molar ratio of 10:3 within which foscarnet is entrapped as antiviral drug.

In another more preferred embodiment, the gel formulation is composed of poloxamer 407 (18% w/w). In another preferred embodiment, the gel formulation is composed of poloxamer 407 (18% w/w) and contains foscarnet as a microbicide. In still another preferred embodiment, the gel formulation is composed of poloxamer 407 (18% w/w) and contains acyclovir as a microbicide. In still another preferred embodiment, the gel formulation is composed of poloxamer 407 (18% w/w) and contains liposomes composed of DPPC:DPPG in a molar ratio of 10:3 within which foscarnet is entrapped as antiviral drug. In still another preferred embodiment, the gel formulation is composed of poloxamer 407 (18% w/w) and contains liposomes composed of DPPC:DPPG in a molar ratio of 10:3 within which acyclovir is entrapped as antiviral drug.

Concentrations of poloxamer may be varied upon conditions such as the liquid/gel transition temperature, the physical properties sought for the gel and the pH used in the making of the formulations.

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 the penetration of pathogens such as viruses, bacteria, fungi, parasites, ectoparasites and mycoplasmas. Furthermore, the gel formulations can be injected into the eye for ophthalmic uses. The gel formulations can be combined with microbicides and/or antimicrobials and/or chemotherapeutic agents and/or antiinflammatory agents and/or any other drug and/or spermicides and/or liposomes (or other drug carriers). Furthermore, microbicides and/or spermicides can be combined with liposomes (or other drug carriers) to prevent or treat any disease of mucosae and/or skin. In addition, our gel and/or liposome (or other drug carriers) formulations can also be used as carriers of vaccines against infections caused by pathogens or any disease.

Claim 1 of 42 Claims

1. A method for preventing the transmission of a pathogen through a person's skin or mucosa, which comprises the steps of:

contacting the skin or mucosa with a gel component in a liquid state; and

allowing the gel component to spread on the skin or mucosa;

wherein, upon contact, the gel component solidifies to form a protective semi-solid layer effective to provide a physical barrier against passage of the pathogen through the skin or mucosa.

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