Title:  Composition and method for prevention of sexually transmitted diseases, including aids

United States Patent:  6,328,991

Appl. No.:  451362

A chemical composition, method and product for administration into the vaginal canal. The composition, method and product are effective in preventing the spread of sexually transmitted diseases, including the spread of AIDS.

SUMMARY OF THE INVENTION

These objects of the present invention are achieved by providing various chemical compositions for introduction into the vaginal canal, and a chemical delivery system for delivery of the chemical agents into the canal, as described herein.

A variety of chemical compositions are disclosed which act as a highly effective microbiocide. The preferred chemical composition for microbiocidal action comprises a mixture of Nonoxynol-9, Benzalkonium Chloride, and Povidone Iodine. This composition is valuable both as a broad spectrum microbiocide, useful in killing a broad spectrum of harmful microorganisms, and as a preparation useful in killing the HIV virus.

As an alternative to the above, a combination of Nonoxynol-9 and Povidone Iodine in which Benzethonium Chloride is substituted for Benzalkonium Chloride may also be used.

Numerous other chemical compositions are disclosed in this application as well. They include microbiocide preparations, chemical compositions for contraceptive use, and compositions effective for a variety of differing disorders.

For example, a novel spermicide, Benzethonium Chloride, is disclosed as well. Benzethonium Chloride may also be used on its own as a spermicide, or microbiocide. Alternatively, it can be used in conjunction with Benzalkonium Chloride, which is already well known in the art. The present chemical composition can be directly applied to the vaginal canal, or incorporated in a device for insertion into the vaginal canal, such as a vaginal sponge, or in another appropriate vaginal device.

In the preferred embodiment for a delivery system for the chemical composition, these objects of the invention are also achieved in a product designed for delivery of chemical agents into the vaginal canal. The product comprises a sponge impregnated with the liquid containing an effective amount of the active pharmaceutical agents, the liquid being present in an amount greater than that which is blocked within said sponge, but less than the saturation value of the sponge so that when the sponge is implanted in the vaginal canal it will release liquid therefrom. The sponge is preferably provided in a sealed, air-tight package. Thus, the present invention now provides a removable, premoistened vaginal sponge impregnated with a solution containing a carrier and an active pharmaceutical agent. The sponge contains both an amount of solution that is tightly held by the sponge, i.e. blocked therein, and a freely releasable amount of solution that is released upon mechanical deflection, i.e. squeezing of the sponge.

In addition, a method is disclosed in the application for voluntarily releasing chemical agents into the vaginal canal, from the sponge, at will, while the sponge is seated within the vaginal canal. The method involves the use of Kegel's exercises to compress a vaginal sponge to release chemical agent from the sponge at will.

As used in the specification and claims of this application, the term "microbiocide" refers to chemical compounds and agents effective in destroying microorganisms. The terms "releasable" or "freely releasable" or "mechanically releasable" are used interchangeably and mean an amount of liquid that can be expelled from the sponge by simple compression or squeezing of the sponge. The term "tightly bound" or "blocked" means an amount of liquid retained by the sponge even when compressed and which is only removable from the sponge by some type of non-mechanical means, such as evaporation. The term "saturation value" means the maximum amount of liquid that can be held by the sponge. A saturated sponge will release liquid immediately upon being squeezed.

According to one embodiment of the invention there is provided a vaginal device comprising a hermetically sealed air tight package enclosing therein a sponge impregnated with a liquid containing an active pharmaceutical agent, the amount of liquid being sufficient to provide a reservoir of the liquid while the sponge is in place in the vagina. The sponge contains a mechanically releasable amount of liquid containing an active pharmaceutical agent and that releasable amount of liquid may contain or itself may comprise a prescribed unit dosage for a specific window of therapy or half-life drug metabolism.

According to another embodiment of the present invention, there is provided a vaginal device comprising a hermetically sealed, air tight package enclosing therein a sponge impregnated with an amount of liquid containing an active agent, such that when the sponge is implanted in the vaginal canal, prescribed body movements of the wearer will cause the sponge to be squeezed to thereby provide release of liquid from the sponge.

The invention is also in a sponge that is easy to insert and remove. It is a vaginal for administration of both systemic and topical drugs. It can provide for topical protection from sexually transmitted microorganisms, provide a method for removing vaginal debris and can also be used to provide non-systemic contraceptive birth control.

How the Vaginal Sponge Invention Works

The freely releasable or excess amount of the solution acts as a reservoir of the active agent. Liquid is released from the sponge as it is inserted into the vagina and the released solution coats the vaginal tissue. Similarly, the sponge releases additional liquid from the reservoir as it is removed from the vaginal cavity. When the sponge is in place, additional amounts of liquid are released over time from the reservoirs as the sponge is compressed or squeezed by prescribed body movements, at prescribed time intervals.

The "freely releasable" portion of the solution is released upon the simple squeezing of the sponge. When the sponge is inserted into the vagina it provides its own lubricating action. It gently expands the entire vaginal tissue and applies a film of solution which fully coats the vaginal tissue for both topical or systemic active pharmaceutical compound absorption.

Upon reaching its seating position in the vagina, the sponge containing the predetermined liquid reservoir of carrier and active agent may then release liquid by the gentle mechanical pressure created by intercourse or by certain muscle groups and tissue generated by what is known as "Kegels exercises" or by similar naturally occurring bodily movement. The released quantities of solution are distributed throughout the entire vaginal cavity by simple diffusion. Such release provides a "well" of formulated solution at the point of the external os of the cervix wherein capillary action then draws the solution into the cervical cavity.

During this process of releasing active agents, the sponge device is in position to block the entire vaginal fornix. The released solution provides a liquid gasket surrounding the entire device. The device accommodates the protruding cervix providing for additional blocking action of the external os.

The sponge of the invention may be used for sustained release of a liquid containing a carrier and an active agent for a prolonged period of time to a targeted site within the vagina. The active agent may be a medicament. Alternatively, the sponge may contain a carrier containing a spermicide that is released from the reservoir to the vagina, thereby acting as a contraceptive. Upon bodily movements of the wearer that squeeze the sponge the "freely releasable" amount of the liquid containing the spermicide or other active agent etc. is released from the reservoir. Some liquid will travel into the cervix. Some liquid will travel down the vaginal canal. Some liquid will form a film covering the sponge. The sponge may be maintained within the vagina for prolonged periods of time while continuing to provide release of the active agent from the reservoir.

Use of the Vaginal Sponge Invention as a Contraceptive

Attempts to find safer, and more effective contraceptive methods have long been sought. The sponge of the invention provides a 24-hour period of vaginal conception protection by releasing not only an active spermicide, but also by blocking the entire vaginal fornix cavity, thereby encompassing the external os and providing a wall to prevent the transmission of sexually transmitted diseases, as well as by blocking the cervical cavity to prevent intrusion thereinto. The configuration of the sponge accommodates the female anatomy by embedding the external os into its soft foam construction. Such configuration ensures that a fountain or well of medicated solution is absorbed by capillary action well into the cervical canal.

The sponge of the invention provides for the subsequent absorption and removal of debris after a sexual occurrence. It coats the entire vaginal tissue with a microbiological killing formula during removal, providing for additional protection from sexually transmitted organisms. By its ability to release active formula over a 24-hour period, the sponge of the invention accommodates anticipated as well as multiple sexual episodes. Thus, each time the wearer anticipates coitus, she will cause the implanted sponge to be squeezed by Kegels exercises or other similar naturally occurring bodily movements, to release an effective amount of spermicide.

The sponge is completely disposable. It offers the substantial advantage of having no side effects common to oral contraceptives. Its predetermined and controlled level of active ingredients have no side effects common to other barrier or medicament contraceptives, including allergic reactions, lesions, and pain. No additional water or activators are necessary for use. The invention is available for immediate use from its sterile air tight package.

When used as a contraceptive the sponge containing a solution of a spermicide immobilizes sperm five ways:

(a) By completely swabbing the entire vaginal wall upon insertion;

(b) By providing a liquid gasket to prevent sperm from bypassing the fornix cavity;

(c) By release of freely releasable liquid which bathes vaginal tissue during the period of use;

(d) By providing a blocking action by maintaining a "tightly bound" residue within the device; and

(e) Upon removal of the device, by releasing a more active agent.

Use of the Vaginal Sponge Invention for Delivery of other Active Pharmaceutical Agents

Systemic drug products have historically been formulated for administration to the body by oral, buccal, sublingual, rectal, parental, topical, and inhalation routes. The invention provides for vaginal absorption of systemic drugs.

The prerequisite for absorption of any drug through the human skin, and vaginal tissue is of the same characteristic as the human skin, is that the drug be dissolved in an appropriate solvent. Drugs taken orally or by other methods other than direct introduction into the blood stream, undergo enzymatic destruction in the body. A substantial portion of the drug may be rendered inactive by various metabolic processes. Substantial excesses of the drug thus must be added to the "window of therapy" to compensate for this destruction. The result can be to cause side effects characteristic of the drug.

In the process of absorption through the skin, all drugs must penetrate several semi-permeable cell membranes before reaching the blood stream. In the case of skin absorption, the stratum corneum of the skin tissue represents the controlling phase between the entry of the drug at the skin surface and its passage into the lower layers of the skin which distribute the drug into the blood stream.

The lower the molecular weight of the compound being administered, the higher the rate of diffusion. With the use of penetration enhancers delivery of the molecules is enhanced, diffusion is accelerated and penetration through the vaginal membrane is accomplished. The invention contemplates the use of drugs in an appropriate carrier at high concentrations. The drug will be released on a sustained basis over a relatively long period of time without the need of extensive and expensive clinical visitations. The device is one that can be self-administered with relative ease.

Because all applications for this form of drug delivery require water as the preferred solvent, a properly designed polyurethane foam structure is preferred to achieve the administration of systemic drugs. Such structures are also preferred for administration of topical medicaments for specific local vaginal conditions.

For the correction of soft tissue pelvic infections, the antibiotics of choice are quickly destroyed, and poorly absorbed. Oral penicillin requires higher dose levels to cover gram/negative anaerobes. Cephalosporines (because oral agents are not equivalent) must be delivered by other than oral administration. The invention achieves the delivery of the required antibiotics and other medicaments through the vaginal cavity, provides the advantage of self-administration, and, more importantly, assures effective dose levels in the blood stream.

For example, the sponge of the invention may be used for:

(a) estrogen replacement therapy, by sustained release from the sponge of estrogen;

(b) vaginal pH control, by sustained release of acidic agents;

(c) vaginal cleansing, by coating the vaginal wall during insertion of the sponge with suitable agents and removal of debris from the vagina during removal of the sponge from the vagina;

(d) treatment of viral infections, such as genital herpes, by sustained release of an antiviral agent, such as acyclovir;

(e) treatment of N. gonorrhea, by sustained release of a suitable agent, such as tetracycline;

(i) treatment of vaginal yeast infections, by sustained release of a suitable agent, such as Metronidazole;

(g) treatment of vaginal infections, such as cervicitis and endometritis, by sustained release of tetracycline or other broad spectrum antibiotics;

h) cure of neisseria gonorrhea by administering a tetracycline at materially lower dose rates per systemic application;

i) cure of chlamydia and candida albicans vaginitis using an appropriate sustained release violet dye solution;

j) cure of trichomonas vaginalis vaginitis using a sustained release metronidazole solution; and

k) relief of vaginal itch caused by non-specific yeast infections by administering an appropriate medication designed for overnight application.

In topically medicating the vaginal cavity, the primal concern is that the prescribed dosage reach the targeted area for treatment and that the medicament remains in place for the prescribed period of time at effective dose strength. Other methods of administering active pharmaceuticals, including the use of suppositories, foams, gels, or even mechanical swabbing do not achieve these desired objectives. None of these other methods provides for the cleansing of blood, mucus, cells, and other destructive debris. The ability to provide for sustained release from a sponge which remains in the desired therapeutic position assures target penetration and complete cleansing of the tissue.

Suitable active agents can be delivered by the sponges of the invention, including without limitation:

(a) Anti-infectives, such as antibiotics, including penicillin, tetracycline, chlortetracycline, bacterin nystatin, streptomycin, neomycin, polymyxin (sulfate salt form), gramicidin, oxytetracycline, chloramphenicol and erythromycin; sulfonamides, including sulfamethizole, and sulfisoxazole; antivirals, including idouridine; and other topical antibacterials, including nitrofurazone, providoneidine, and sodium propionate; magnesium gluconate; benzalkonium chloride; benzethonium chloride;

(b) Anti-inflammatories such as hydrocortisone, cortisone, dexamethasone, fluocinolone acetonife, triamcinolone, and various prednisolone acetonide; triamcinolone, and various prednisolone compounds;

(c) Estrogenic steroids such as estrone, 17 N-estradiol ethanol estradiol and diethylstilbestrol;

(d) Progestational agents such as progesterone, 19-norprogesterone, norethynodrel, and 17-hydroxy-progesterone; and

(e) Prostaglandius such as PGE 1, PGE 2, PGF1, PGF2a, and the like.

The active agents can be in a variety of forms, such as uncharged molecules, components of molecular complexes, or nonirritating, pharmacologically acceptable salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate, tartrate, salicylate and the like. For acidic drugs (e.g. quaternary ammonium) can be used. Additionally, simple derivatives of the active agent such as ethers, ester, amides and the like which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, etc. can be used.

The amount of active agent incorporated in the vaginal device of the present invention varies, depending on the particular active agent, and the desired therapeutic or prophylactic therapy. The upper limit and the lower limit will depend on the activity of the active agent and the time span of its release from the device. Thus, it is not practical to define a range for the therapeutically effective amount of active agent to be incorporated in or released by the specific vaginal device administrating the medicament.

In connection with the present invention, "active agent" or "chemical composition" includes without limitation, "drug", "medication", "medicament", "spermicide" and other physiologically or pharmacologically active substances for producing a localized or systemic effect upon human tissue or effects in animals, especially mammals.

The above agents and other active ingredients can be present alone or in combination with pharmaceutical carriers to make the active agents more easily absorbed through the surface of the vaginal tissue. The device may also contain adjuvants for preserving, stabilizing, wetting, emulsifying and the like. Such compounds have also been used in combination as antibiotics, anti-yeast, or anti-fungal agents, as well as agents to destroy sexually transmitted diseases.

The Physical Nature of the Sponge

The sponge is a specifically configured polyurethane foam structure having characteristics specific for the administration of selected medicinal agents. Generally it is known that (a) the larger the cells of the sponge, the more liquid the sponge will contain (per cubic measure) and conversely, the smaller the cells, the less liquid it will contain (per cubic measure), (b) the amount of liquid absorbed within a sponge varies in relation to the viscosity of the liquid being absorbed and is also affected by the design of the sponge skeleton, (c) the construction of the component cells forming the foam skeleton, although equal in their number per lineal inch of sponge, determines its absorbent capacity, and (d) the density of the sponge, the compression deflection (pressure required to move the sponge in various directions), the water wicking and the tensile strength of the material used are all important factors in determining the characteristics of a given sponge for its assigned use and all bear upon the retention and release of the liquid contained therein.

Polyurethane polymers are a family of foamable hydrophilic polyurethane prepolymers derived from toluene diisocyanate. They react with protic compounds to form elastomeric foams. The shape of the resulting foam skeleton structure, the size and shape of the individual cells forming the structure, the size and shape of the resulting foam skeleton structure, the size and shape of the individual cells forming the structure, and the number of cells in a given structure are all determined by choice of and amount of surfactant additives suspended in the aqueous solutions from which the foams are added and by the conditions of the foam-forming methods.

These variables determine the specific characteristics of absorption and release of a solution retained in the structure. Each of these variables must be custom considered to provide for the flow characteristics of the solvent to be used and the nature of the molecular structure of the compounds being administered.

Polyurethane copolymers are used because they offer medical softness. "Polyether" compounds as opposed to a "polyester" compounds are used because the primary solvent, water, will destroy polyester compounds. Most polyurethane foams have a long shelf life if protected from moisture. It is important to this invention that a "polyether" copolymer structure be used, because it allows the foam to be fully subjected to and immersed in aqueous solutions which are the carriers of the medicaments of choice.

The commercial grades of polyurethane polymers are based on toluene diisocyanate. This compound is water activated and no catalysts are required. A high level of additives can be introduced into the aqueous phase to determine the properties required for cell structure design. This provides for high foam purity by eliminating the need for catalysts and allows for a broad range of cell structure design by varying the choice and amount of surfactants.

Although the foams of the invention will be subjected to a wide variety of medicinal chemical compounds it has been found that these do not materially affect the performance of the sponge. The prepolymers used for producing the foam of the invention must be thoroughly safety tested to assure that there is no toxicity of any kind including oral, inhalation, dermal and mutagenicity.

The design of the individual cell structure and resulting skeletal structure of the foam is important to the proper operation of the tampon of the invention. The chemical reaction and the release of heat and gases in the foam-forming process is actuated by water. The process is designed to create a foam specific to the molecular characteristics of the medicament to be delivered.

A given surfactant, which creates the cell shape, is really a form to which the plastic polymers adhere. It develops the size and shape characteristics of the foam components. The resulting gases released from the chemical reaction also help form and determine the physical characteristics and shape of the individual cells that link themselves to form the spherical skeleton of the foam structure. The surfactants determine how many cells are formed in the spherical skeleton of the foam structure, the size of the individual cells, the number of them being linked and whether the individual cells are open or closed. Each of these parameters materially affects the construction and therefore the fluid dynamics of a specific foam device. The solution flow dynamics, or how fast or how slow a solvent will be absorbed and/or released from the sponge, is a major factor in the design of the sponge.

Foam flexibility and texture are controlled by varying the amount of water and additives. In some instances catalysts are used to generate heat to produce certain configurations; however, the residues of both catalysts and additives have a significant effect upon the toxicity and the biocompatibility of the resulting foam structure with skin tissue and in particular with vaginal tissue.

Claim 1 of 27 Claims

What is claimed is:

1. A chemical composition for administration into the vaginal canal to prevent the transmission of sexually transmitted diseases, said composition comprising:

(a) Nonylphenoxpoly-(Ethyleneoxy)-Ethanol (Nonoxynol-9);

(b) Benzalkonium Chloride; and,

(c) Povidone Iodine.

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