WO2001082915A2

WO2001082915A2 - Trans-clitoral administration of therapy

Info

Publication number: WO2001082915A2
Application number: PCT/US2001/013701
Authority: WO
Inventors: Gary W. Neal
Original assignee: Neal Gary W
Priority date: 2000-04-28
Filing date: 2001-04-27
Publication date: 2001-11-08
Also published as: AU6106801A

Abstract

The present invention relates to novel methods for administering therapeutic compounds, i.e. medications, to the clitoris of female mammals. In the addition, the present invention relates to methods for selecting therapeutic compounds and pharmaceutical compositions that may be administered via the trans-clitoral route and kits useful for administration of therapeutic compounds to the clitoris of female mammals.

Description

TRANS-CLITORAL ADMINISTRATION OF THERAPY

CROSS REFERENCE TO RELATED APPLICATION This patent application is a continuation-in-part of U.S. Application Serial No.

09/548,153, filed April 13, 2000, which is a continuation of U.S. Application Serial No. 09/391,412, filed September 8, 1999, which is a continuation-in-part of U.S. Application Serial No. 08/954,122, filed October 20, 1997, the entire disclosure of which is incorporated herein by reference. FIELD OF THE INVENTION

The present invention generally relates to novel methods for administering therapeutic compounds, i.e., medications, to the clitoris of female mammals. In the addition, the present invention relates to methods for selecting therapeutic compounds and pharmaceutical compositions that may be administered via the trans-clitoral route and kits useful for administration of therapeutic compounds to the clitoris of female mammals.

BACKGROUND OF THE INVENTION Therapeutic compounds are conventionally formulated into a variety of forms suitable for oral, parental (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal, vaginal and topical (including dermal, buccal, sublingual, intranasal, intraurethral, intrauteral and intraocular) administration to a subject in need of therapy. Each of these conventional methods of administration, however, has its limitations and complications.

For example, situations frequently arise in which it is advisable to administer a medication but it may be difficult or impossible to do so by presently available routes. The oral route is not possible in a person or other mammal without conscious cooperation and is contraindicated if unconscious, uncooperative or having difficulty swallowing (post-surgical, chewing or swallowing, disorder, persistent nausea and vomiting et cetera). Parenteral medications may be given under these circumstances with significant limitations, as well. Many medications are not available in parenteral form and all parenteral preparations are significantly more expensive than the same medication by other routes. Parenteral medications are painful to administer, generally require dosing by a medical professional and are more dangerous due to the extremely rapid rise in serum drug levels immediately after dosing. Local abscesses are often seen after an injection; and, death and other complications are common sequelae to intravenous therapy in a hospital setting.

Additionally, administration of drugs by the oral route is often characterized by poor absorption, significant losses of absorbed drugs due to local metabolism of drugs by the mucosal lining of the alimentary tract and by metabolism by the liver (the "first pass" effect), onset of action delays from 30 minutes to several hours following administration and frequent gastrointestinal side-effects.

Topical administration through the skin has proved practical for only a few medications due to difficulty in attaining sufficient drug flux through the skin, frequent allergic and irritative effects on the skin from the drug or other ingredients in the formulation, slow onset of action and the very high degree of immune surveillance seen in the dermis.

Rectal and vaginal routes are generally used only for local and not systemic drug effects. For example, medications have been administered topically to the vaginal mucosa of mammals to treat several medical disorders. These disorders include vaginal bacterial infections and treatment of vaginal mucosal atrophy secondary to deficiencies of estrogen. Treatment to induce termination of pregnancy and treatment to hasten delivery may result in spillover of medications to the vaginal mucosa

Inhalation of medications is generally used only for local drug effects on the lung. The lungs are very sensitive to irritative and allergic stimuli excluding the use of most medications. The nasal route is similarly limited generally to medications for local effect in the nasopharynx and is restricted to preparations without strong smell or irritating properties.

Heretofore, the utility of a trans-clitoral route of topically administering medications and other medical interventions has been unknown. Although prior art mentions the clitoris in connection with sexual devices and treatment of sexual dysfunction, none discloses or suggests administering medications via the clitoris to achieve a regional or systemic therapeutic effect, as in the present invention. Accordingly, there remains a need for alternative methods for effectively administering medications to female mammals without the attendant disadvantages of conventional routes of administration.

SUMMARY OF THE INVENTION It is an object of the present invention to provide methods for effectively administering therapeutic compounds, i.e., medications, to female mammals.

The above and other objects are accomplished by a method comprising contacting a therapeutic compound to the clitoris of a female mammal. The method of the present invention may be employed in any suitable manner, e.g., topically, via injection, gavage, etc., for the treatment of a limitless variety of diseases or conditions. Dosage levels and mode of application will necessarily depend on the disease or condition sought to be treated and may be selected by those of skill in the art from available methods and techniques that are disclosed herein, that are known in the art or that are readily determinable using routine experimentation. As an aid to understanding, but without wishing to be bound by theory, it is believed that the present invention achieves the above and other objects because the trans-clitoral route of drug administration affords surprisingly and unforeseen levels of bioavailability. Although our present comprehension of the anatomy and physiology of the mammalian clitoris is relatively poor, it is known that the mammalian female clitoris contains cavernous erectile tissue and that arterial blood supply to this region is achieved by the clitoral artery. An internal pudendal artery is one of the terminal branches of the internal iliac artery and provides, prior to its termination, the artery of the bulb of the vestibule to the erectile tissue of the vestibule and the dorsal artery of the clitoris to the corpora cavernosa. Venous blood from the dorsal vein of the clitoris drains into the vesicular plexus of the bladder. It is important to note that the vesicular plexus communicates freely with the venous plexi of the pelvis including the vaginal plexus, the urethral plexus, the uterine plexus and Batson's plexus (the vertebral plexus). The venous blood then drains into the interior iliac vein, the common iliac vein and, finally, into the inferior vena cava before entering the heart. See, Figures 1 and 2. See, e.g., "Atlas of Urosurgical Anatomy" by Frank Hinman, Jr.,W.B. Saunders Company, Philadelphia, PA, 1993; "Essentials of Human Anatomy" by Russell T. Woodburne, 6^TH Edition, Oxford University Press, London, 1978 and, "Bailey's Textbook of Histology", 17^th Edition, The Williams and Wilkins Company, Baltimore, MD 1978.

It is believed that administration of a drug or therapeutic compound to the clitoris leads to a route of venous drainage affording the possibility of bypassing the hepatic circulation and thereby significantly minimizing so-called detrimental "first- pass" effects on drug metabolism. Therefore, it is believed that the trans-clitoral route affords dramatically greater systemic levels of therapeutic compounds than would ordinarily be disadvantageously metabolized by the liver if taken orally. Moreover, the trans-clitoral route allows a relatively direct route for therapeutic compounds to reach the heart and lungs. The open communication of the clitoral venous blood supply with essentially all the venous plexi of the pelvis further allows the possible use of the trans-clitoral route as a method for the introduction of therapeutic compounds via the clitoris to the venous blood bathing all of the pelvic organs. As discussed above, the utility of a trans-clitoral route of administering medications and other medical interventions has been largely overlooked.

Further, the clitoris affords an easily accessible external route to this pathway. Surprisingly and against all predictions, this inventor has discovered that the clitoris also demonstrates an amazing permeability to a variety of drugs and polypeptides. This finding is unexpected for an organ covered by a stratified squamous epithelium. The combination of these two factors open a plethora of pharmaceutical possibilities for novel and useful medical treatments of mammals previously undreamed of by inventive clinicians. A further advantage of the trans-clitoral route for administration of medications versus the sublingual route or the oral route is the inherent limitation of administering bitter or unpleasant tasting medications to the oral cavity of a mammal. A variety of otherwise helpful medications will induce nausea and vomiting when placed under the tongue or given orally due to the proximity of the taste buds and the nasal cavity. The trans-clitoral route does not suffer from this significant limitation.

Furthermore, administration of medications sublingually or orally in an unconscious or semi-conscious mammal may lead to pulmonary aspiration of the medication and ensuing complications. The trans-clitoral route is clearly superior to either the oral or sublingual route in avoiding these frequently lethal pulmonary complications.

Additionally, the trans-clitoral route for administering therapeutic compounds allows for administration of polypeptides and molecules above a molecular weight of 1 ,000 daltons which are usually given parenterally due to low or absent absorption by other routes. The trans-clitoral route for administering therapeutic compounds is characterized by an unexpectedly rapid rate of absorption of medications with onset of action almost as rapid as intravenous therapy, in some cases. Quite surprisingly and totally against the teaching of prior art, topical administration to the clitoris of a variety of polypeptides with molecular weights exceeding 1 ,000 daltons demonstrate bioactivity indicating absorption through the clitoris. Accordingly, this invention offers a route for the administration of these agents that is unencumbered by the disadvantages of the parenteral route. The trans-clitoral route works equally as well in an unconscious as in a conscious subject and does not require cooperation for drug administration.

Further, the female genital tract of mammals is, by design, an area of decreased immune surveillance. The relative ease of introduction of venereal diseases and the human immunodeficiency virus (HIV) via the female genital tract is one distinct line of evidence that this anatomical region undergoes significantly less immune surveillance than other areas of an individual. Tremendous interest has arisen in the beneficial possibilities of introducing new genetic material into adult mammals, a.k.a. gene therapy. The possibility of correcting an inherited genetic defect or of correcting an acquired metabolic defect via administration of new genetic material is being investigated wherein genetic material is transfected into the nuclei of cells of an adult or pediatric mammal to supply a copy of a gene that was absent since the birth of an individual. W. French Anderson et al describe the types of vectors typically utilized in gene therapy as well as specific methods of effectively producing and using these vectors in US Patent 5,925,345 which is incorporated in whole. The trans-clitoral route may be used to provide a route of access for these vectors according to the present method. Insertion of foreign genetic material into an immunocompetent adult, however, has proven to be challenging. Introduction of genetic material via the trans-clitoral route would have the distinct advantage of bypassing many of the immunosurveillance mechanisms present in a mammal. The clitoris affords an easily accessible external route to this pathway.

Surprisingly and against all predictions, this inventor has discovered that the clitoris also demonstrates an amazing permeability to a variety of drugs and polypeptides. This finding is unexpected for an organ covered by a stratified squamous epithelium. The combination of these two factors open a plethora of pharmaceutical possibilities for novel and useful medical treatments of mammals previously undreamed of by inventive clinicians. A further advantage of the trans-clitoral route for administration of medications versus the sublingual route or the oral route is the inherent limitation of administering bitter or unpleasant tasting medications to the oral cavity of a mammal. A variety of otherwise helpful medications will induce nausea and vomiting when placed under the tongue or given orally due to the proximity of the taste buds and the nasal cavity. The trans-clitoral route does not suffer from this significant limitation. In addition, administration of medications sublingually or orally in an unconscious or semi-conscious mammal may lead to pulmonary aspiration of the medication and ensuing complications. The trans-clitoral route is clearly superior to either the oral or sublingual route in avoiding these frequently lethal pulmonary complications.

Additional aspects, features, embodiments and advantages of the present invention will be set forth, in part, in the description that follows, or may be learned from practicing or using the present invention. The objects and advantages may be realized and attained by means of the features and combinations particularly pointed out throughout this description and the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not to be viewed as being restrictive of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in, and constitute a part of, this specification, illustrate embodiments of the present invention and, together with the description, serve to exemplify the principles of the present invention. Fig. 1 depicts the human female genitalia.

Fig. 2 depicts the innervation and vasculature of the human female perineum.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS All patents, patent applications and publications cited in this description are incorporated herein by reference in their entirety.

Preferably, in accordance with the principles of the present invention, therapeutic compounds may be administered directly to the clitoris or to the lower genital tract of a female mammal. The therapeutic compound may be administered by any method allowing for contact between the therapeutic compound and clitoris or tissues surrounding the clitoris. Preferably, the therapeutic compound will be administered by topical application to the clitoris and surrounding tissues. Topical administration via application of a solution or suspension of the therapeutic compound or by placing a controlled release device such as a trans-dermal patch or osmotic pillow directly in contact with the clitoris is particularly desired. Topical application of liposomal solutions, creams, ointments, suppositories or by spraying or dusting a powder onto the clitoris are acceptable methods according to this invention. Iontophoresis or the use of ultrasound to assist in topical absorption of the therapeutic compound may also be practiced by this invention. In some situations, it may be necessary to administer the therapeutic compound by injection into the clitoris or surrounding tissues using either subcutaneous, intramuscular or intravenous injection. Injection may be achieved by any method, including, but not limited to, by an airgun.

When the clitoris is retracted and hidden underneath the clitoral hood in the normal unexcited state, however, direct administration of the drug may not be possible. Therefore, a drug may be applied to the tissues covering or surrounding the clitoris, such as the prepuce and the frenulum of the labia minora with massaging to achieve application to the clitoris. Administration topically to the clitoris may be accomplished by applying an amount of a liquid gel or solid that contains an effective amount of the drug directly onto the clitoris. In the case when the drug is contained in a liquid pharmaceutical composition, the administration may be accomplished by means of a dropper or syringe. The liquid solution mav also be sprayed or delivered in an aerosol onto the clitoris. When the drug composition is in the form of a gel, lotion, or cream, then the administration may be carried out by means of a tube, brush, swab or the finger tip. Solid pharmaceutical compositions may be administered by placing the appropriate amount directly on the clitoris or by dustinq or spraying a powder, [insert any additional modes of administration]

"Clitoral" means the clitoris (See Figures 1 and 2) and the immediately surrounding tissues when used to describe a drug application. The term is meant to include the labia, vagina, cervix and womb when used to describe administration of genetic material. The term "therapeutic compound" is used herein to refer to a chemical material or compound or pharmaceutical which, when administered to an organism (human or animal) induces a desired pharmacologic and/or physiologic effect by local and/or systemic action. Preferred examples of categories of therapeutic compounds that may be administered to a female mammal via the clitoral route to treat local or systemic diseases or conditions include, without limitation,

1. antimicrobial drugs, antiviral drugs, antifungal drugs, antiprotozoal drugs antibiotics, and antihelmintic drugs;

2. analgesics, including, but not limited to, anesthetics, opiates, non-steroidal anti-inflammatory agents, mixed agonist-antagonist analgetics and antimigraine agents;

3. chemotherapeutic and anti-cancer drugs;

4. cholinergic agents, anticholinergic agents, anticholinesterase agents, neuromuscular blocking agents and nicotinic agonists and antagonists;

5. adrenoreceptor agents, including, but not limited to, alpha receptor agonists and antagonsists, beta receptor agonists and antagonists, sympathomimetics, sympatholytics;

6. drugs affecting the cardiovascular system, including, but not limited to, antihypertensives, antianginals, ganglionic blocking agents, ergot derivatives, vasodilators, vasoconstrictors, antiarrhythmic agents, diuretics, agents to treat congestive heart failure, nitrates and nitrites, calcium channel blockers, inotropic agents, antiatherosclerotic agents, thrombolytic agents and antiplatelet agents; 7. antilipedemic agents;

8. antidiabetic agents, including, but not limited to, insulin;

9. psychoactive drugs, including, but not limited to, central nervous system stimulants such as amphetamines, sedatives, hypnotics, narcotics, major and minor tranquilizers, antidepressants, antipsychotics, agents for attention deficit disorder;

10. histaminergic agents and antihistamines, prostaglandin agonists and antagonists, proton pump inhibitors, antiemetics;

11. agents that increase or decrease smooth muscle tone in the bladder, intestines, stomach or esophagus;

12. hormonal agents, including, but not limited to, androgens, antiandrogens, testosterone, anti-testosterone agents estrogens, antiestrogens, progesterones, antiprogesterones, ovulation-inducing drugs, hormonal contraceptives, corticosteriods; 13. Peptide hormones, including but not limited to, thyroid hormone, growth hormone, glucagon, the intestinal peptides, hypothalamic and pituitary hormones; 14. Genetic material such as naked DNA or DNA incorporated into any suitable vector; 15. pulmonary medications;

16. vaccines;

17. CNS medications;

18. anti-fibrotics, anti-thrombotics;

19. cytokines; 20. vitamins and essential elements

21. antibodies, globulins and other biological agents as would routinely be under the jurisdiction of the FDA in the US or a similar agency in a foreign country.

"Therapeutic compound(s)" also include pharmaceutically acceptable salts, esters, or inclusion complexes of the foregoing. "Pharmaceutically acceptable salts, esters, or inclusion complexes" refer to those salts, esters and inclusion complexes which retain the biological effectiveness and properties of the base compounds and which are not biologically or otherwise undesirable. Salts, esters and inclusion complexes of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992).

"Therapeutic compounds" also include DNA in raw DNA form or in any available vector.

Therapeutic compounds can be in any conventional form, such as a liquid, solid gel and can be administered alone or as part of a formulation. Examples of suitable liquids include sterile solutions, suspensions, and emulsions, including creams, ointments, foams, lotions and liposomal compositions. Examples of suitable solids include polyethylene glycol (PEG), polyethylene oxide and other low melting point or water-soluble polymers including fatty acid esters made into suppositories or pellets. Examples of suitable gels include hydroxycellulose, gels composed of water, propylene glycol, hydroxypropyl methycellulose and any other gel compatible with the particular therapeutic compound. Preferred therapeutic compound formulations are controlled release, long-acting or pulsatile release solid phase systems, as well as ointments, gels and suppositories. Methods for preparing various dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed. (Easton, Pa.: Mack Publishing Company, 1990). Typically, the therapeutic compound will be present in a concentration such that an effective amount of the therapeutic compound is delivered to the clitoris with a single application of the composition. By an "effective" amount of a therapeutic compound is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect. For example, in treating anginal chest pain, an "effective" amount of drug would be an amount which is at least sufficient to provide the desired degree of treatment. Similarly, in treating early symptoms of anaphylaxis shock, , an "effective" amount of drug would be an amount which is at least sufficient to provide prompt improvement of the shock symptoms. Repeat applications may be necessary or advisable to achieve the desired therapeutic effect.

In addition to the therapeutic compound(s), the formulation administered to the clitoris will typically contain one or more pharmaceutically acceptable carriers (also termed "excipients" or "vehicles") suited to the particular type of formulation, i.e., gel, ointment, suppository, or the like. The vehicles are comprised of materials of naturally occurring or synthetic origin that do not adversely affect the therapeutic compound(s) or other components of the formulation. Suitable carriers for use herein include water, silicone, waxes, petroleum jelly, polyethylene glycol, propylene glycol, liposomes, sugars such as mannitol and lactose, and a variety of other materials, depending, again, on the specific type of formulation used.

It may in some cases be desirable or necessary to include a detergent in the formulation, in an amount effective to increase solubility of the therapeutic compound in the vehicle and bioavailability of the compound following administration. The detergent will typically be a nonionic, anionic, canonic or amphoteric surfactant. In the practice of the invention, the surfactant is selected such that local irritation at the site of administration is avoided. Examples of suitable surfactants include Tergitol.RTM. and Triton.RTM. surfactants (Union Carbide Chemicals and Plastics, Danbury, Conn.), polyoxyethylenesorbitans, e.g., TWEEN.RTM. surfactants (Atlas Chemical Industries, Wilmington, Del.), and pharmaceutically acceptable fatty acid esters such as lauryl sulfate and the like.

The formulations may also optionally include one or more components to enhance permeation of the therapeutic compound(s), i.e., "permeation enhancers." Suitable permeation enhancers include those generally useful in conjunction with topical, transdermal or transmucosal drug delivery. Examples of suitable permeation enhancers include dimethylsulfoxide ("DMSO"), dimethyl formamide ("DMF"), N,N- dimethylacetamide ("DMA"), decylmethylsulfoxide ("C.sub.lO MSO"), polyethylene glycol monolaurate ("PEGML"), glycerol monolaurate, lecithin, the 1 -substituted azacycloheptan-2-ones, particularly l-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone.RTM. from Nelson Research & Development Co., Irvine, Calif.), lower alkanols (e.g., ethanol), SEPA.RTM. (available from Macrochem Co., Lexington, Mass.), and surfactants, including, for example, Tergitol.RTM., Nonoxynol-9.RTM. and TWEEN-80.RTM. In some cases, the formulations used in the present methods will also include one or more compounds effective to inhibit enzymes present in the vaginal or vulvar areas which could degrade or metabolize the pharmacologically active agent. For example, with a prostaglandin as the vasodilating agent, it may be preferred to include an effective inhibiting amount of a compound effective to inhibit prostaglandin- degrading enzymes. Such compounds will include, for example, fatty acids, fatty acid esters, and NAD inhibitors. These formulations are believed to be novel. One may tailor the formulation to deliver a given drug via the trans-clitoral route through a wide spectrum of temporal pharmacokinetic patterns. At one end of this spectrum are formulations that simulate the rapid onset of action seen with parenteral therapy with a surprisingly rapid uptake of the topically applied drug . Formulations exhibiting a very rapid onset of action (drug delivery) may be prepared by adjustment of parameters to yield a preparation with high bioavailabilty and transdermal flux. Numerous formulation parameters are known to those skilled in the art including, among others, the use of a higher drug concentration, the use of the active drug molecule instead of a pro-drug analogue requiring metabolic activation, the addition of absorption enhancers to increase the rate of drug flux, manipulation of the pH in aqueous formulations to maximize the un-ionized fraction of the drug moiety when appropriate and the use of the free acid or free base form of a drug molecule (versus an ionic salt) when feasible in non-aqueous formulations. It may be desirable to use one or all of these formulation parameters depending upon the particular drug to be delivered via the trans-clitoral route. The other end of this spectrum is exemplified by a formulation exhibiting a slower onset of action, lower peak serum or tissue drug levels and a prolonged effect such as seen with a controlled release preparation. A variety of formulation techniques are available to one skilled in the art including the use of lower drug concentrations, the use of time-release preparations such as hydrogel preparations, the use of pro-drug analogues requiring metabolic activation, the addition of absorption retarding agents, and the use of an ionic salt of the drug when feasible. It is to be understood that it may be desirable to use a different method or to attain a different pharmacokinetic profile depending upon the drug used and the therapeutic goal desired.

In a second embodiment, the present invention provides for selection of therapeutic compounds appropriate for trans-clitoral therapy. Such selection may be performed in the following manner:

1. Apply the test drug to the clitoris and 2. Measure the serum levels thus produced and

3. Compare to serum levels produced by other routes

Alternatively, selection of a therapeutic compounds for trans-clitoral therapy may be performed in the following manner: 1. Apply the test drug to the clitoris and

2. Measure the desired physiological response thus produced (lowering of blood pressure, lowering of blood sugar, et cetera) and

3. Compare to the desired physiological response produced by other routes In a third embodiment, the present invention provides kits which are useful for trans-clitoral application of therapeutic compounds. The present kits are characterized as containing: (a) a means for containing a therapeutic compound(s) or pharmaceutical composition containing the therapeutic compound(s) ; and (b) means for administering the therapeutic compound(s) or pharmaceutical composition containing the therapeutic compound(s) to the clitoris. The means for containing the therapeutic compound(s) or pharmaceutical composition containing the therapeutic compound(s) may be a vial, a bottle, a pouch, an envelope, a can, a tube, an atomizer, an aerosol can, etc. The means for administering the therapeutic compound(s) or pharmaceutical composition containing the therapeutic compound(s) to the clitoris may be a dropper, a swab, a stick, or the nozzle or outlet of an atomizer or aerosol can. It is to be understood that the means for administering the therapeutic compound(s) or pharmaceutical composition containing the therapeutic compound(s) to the clitoris may be connected to or a part of the means for containing the therapeutic compound(s) or pharmaceutical composition containing the therapeutic compound(s). For example, the containing means may be an atomizer or an aerosol can, and the administering means may be the nozzle or outlet of the atomizer or the aerosol can.

Examples of preferred kits include:

A. A kit which includes a container which can hold 1 to 100 unit doses of the prostaglandin or the pharmaceutical composition containing the prostaglandin and a dropper which can dispense between 0.01 to 0.6 ml as a unit dose. The container is preferably glass, metal, or a plastic known not to adsorb hydrophobic compounds. B. A kit which includes a container which can hold 1 to 100 unit doses of the prostaglandin or the pharmaceutical composition containing the prostaglandin with a spray or aerosol applicator to spray the prostaglandin or pharmaceutical composition onto the clitoris. The container is preferably glass, metal, or a plastic known not to adsorb hydrophobic compounds.

C. A kit which includes a tube which holds 1 to 100 unit doses of a pharmaceutical composition containing the prostaglandin, which is in the form of a cream or gel, and an applicator which can dispense a unit dose of the composition.

D. A kit which includes 1 to 100 unit doses of pellets, film or suppositories containing a pharmaceutical composition comprising the prostaglandin and each individually wrapped in foil and sealed to protect the prostaglandin from the air. The foil is preferably opaque to eliminate the degrading effects of light on the prostaglandin.

E. A kit which includes 1 to 100 unit doses of a pharmaceutical composition which comprises the prostaglandin and which have been lypholized and sealed under inert gas in an ampoule or vial. Lyophilized compositions typically exhibit a much longer shelf life than other forms and may be reconstituted close to the time of use so that degradation of the prostaglandin is minimized. The kit may also include a suitable diluent, syringe and needle, and/or alcohol swabs. The present kits will also typically include means for packaging the container means and the administering means. Such packaging means may take the form of a cardboard or paper box, a plastic or foil pouch, etc. The present kits will also usually include written instructions which describe how to administer the prostaglandin or pharmaceutical composition containing the prostaglandin to the clitoris. It is to be understood that the written instructions may be on any of the container means, the administering means, or the packaging means, in addition to being present on a separate piece of paper.

Other features of the present invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES The present invention will be further illustrated in the following, non-limiting Examples. The Examples are illustrative only and do not limit the claimed invention regarding the materials, conditions, process parameters and the like recited herein.

EXAMPLE 1

A 53 year old female with chest pain due to angina is administered 0.5 grams of nitroglycerin paste (1% by weight) topically to the clitoris on presentation to the emergency department. The anginal chest pain is relieved in 2 minutes.

EXAMPLE 2

A 24 year old female with shellfood allergy accidentally eats shrimp in a salad and begins to experience early symptoms of anaphylaxis shock including swelling in her throat and shortness of breath. She immediately applies 0.5 milligram of epinephrine in 0.1 milliliter of saline to her clitoris followed by 50 milligrams of diphenhydramine HCL in 0.2 milliliters saline. She experiences improvement in her symptoms promptly.

EXAMPLE 3

A 44 year old female with essential hypertension notices a frontal headache as her 1 st symptom that her blood pressure is elevated. Blood pressure is found to be 200/120 with a pulse rate of 94. She administers a verapamil suppository to her clitoris composed of 2.5 milligrams of the free base in a total weight of 50 milligrams with ethyl stearate as the carrier. This dose form rapidly melts on contact with the warmth of the clitoris releasing the verapamil totally in 5 minutes. Repeat vital signs in 15 minutes demonstrate a lowering of her blood pressure to normal and resolution of her headache.

EXAMPLE 4 A 14 year old female is found to have cystic fibrosis. The cystic fibrosis transmembrane conductance regulator ((CFTR) gene is cloned and incorporated into a cationic liposome using standard techniques. This liposomal DNA is applied daily directly to the clitoris where it is absorbed and carried via venous blood return to the pulmonary microcirculation and incorporated into the pulmonary epithelium. Dosing is continued until adequate expression of the CTFR gene is accomplished and symptoms of cystic fibrosis relieved.

EXAMPLE 5

Preparation of a Rapid Onset Trans-Clitoral Preparation: PGEl (50 milligrams) is dissolved in 9.950 grams of methyl palmitate at 80 C. before pouring into a suppository mold and cooling to - 20 C. for one hour to form one hundred (100) suppositories containing 0.5 milligrams of PGEl each. A 28 year-old female with severe Raynaud's Syndrome is scheduled to fly to

Oslo, Norway for a January business trip. Raynaud's Syndrome is an idiopathic vascular disorder characterized by painful vasoconstriction of the digital arteries on exposure to cold. One method of treating Raunaud's Syndrome in many countries is by intravenous infusion of a vasodilatory prostaglandin such as Prostaglandin E-l (PGEl). She is instructed to apply one suppository to her clitoris immediately prior to deplaning in Oslo. Methyl palmitate melts at 32-34 C and the temperature of the clitoris varies from around 32-37 C. Application of these suppositories to the clitoris at a skin temperature exceeding the melting point for methyl palmitate causes complete melting and release of the PGEl in 1-2 minutes. This particular preparation is absorbed through the clitoris and delivered into the systemic circulation with sufficient rapidity to prevent an attack of Raynaud's Syndrome on exposure to the cold Oslo air. Dosing may be repeated as needed every 1-3 hours.

EXAMPLE 6

Preparation of a Controlled Release Trans-Clitoral Preparation: Addition of increments of tripalmitin (melting point 66-67 C.) to methyl palmitate from 1 - 24% by weight produces a base material for the controlled release of drugs either dissolved or suspended in it. These formulations are characterized by a thermal release mechanism that enables one to precisely tailor the delivery kinetics as desired. In practice, one would mix a series of formulas with all final ingredients including the active drug (PGEl in this example) that differ only in the final weight per cent of tripalmitin contained. For example, one may make 4, 8, 16, 20 and 20% tripalmitin suppositories each containing 10 milligrams per gram of PGEl . The melting characteristics may easily be determined by performing Differential Scanning Calorimetry on each one. In this instance, a formula containing 20 % tripalmitin will form a matrix that softens around 34 C. and begins to release the drug contained within the matrix in a slow and gradual fashion. Complete melting of the matrix will not occur until ambient temperatures of 45 - 52 C. are reached. Since the clitoral temperature will not exceed 37 - 38 C, the matrix cannot melt and rapidly release the drug as in the above example. Similar formulations have been seen to exhibit a very prolonged clinical effectiveness in the range of 10 - 12 hours. The above mentioned woman (Example 5) returns to Oslo for a one week trip the following Christmas. Prior to disembarking from the plane, she applies a 100 milligram suppository containing 1.0 milligram of PGEl in a base matrix of 20 % tripalmitin and 80 % methyl palmitate. The controlled release of PGEl is topically absorbed via the trans-clitoral route giving lower sustained levels that persist for 12 hours. Reapplication every 12 hours effectively prevents the occurrence of Raynaud's Syndrome during her trip.

PGEl is also of use in reversing atherosclerotic lesions either in the cardiac circulation or the peripheral arterial system. This valuable therapeutic modality suffers from the necessity of administering PGEl through a constant intravenous infusion with careful hemodynamic monitoring utilizing a Swan-Ganz catheter in an intensive care setting due to the possibility of inducing severe hypotension and catastrophic results. A seven day infusion is typical and can give prolonged symptomatic relief as well as documented regression of atherosclerotic lesions for at least six months. The cost of one such treatment can exceed $20,000. The following example demonstrates the advantages of using a trans-clitoral route as a substitute for the present therapy. EXAMPLE 7

Preparation Of An Anti-Atherosclerotic PGEl Formulation :

The pulmonary vasculature clears 70 - 95 % of infused PGEl per pass through the lung due to the presence of large quantities of 15 hydroxyprostaglandin deydrogenase. This enzyme deactivates PGEl by conversion of the hydroxyl in the 15 position to a ketone group. Oleic acid and palmitic acid inhibit this enzyme competitively.

PGEl (100 milligrams) is added to 1.4 grams tripalmitin, 8.6 grams methyl palmitate and 1.000 grams of palmitic acid; then heated at 85 C. until dissolved; poured into molds and cooled to - 20C. The resultant suppositories contain 1.0 milligrams of PGEl and 10 milligrams of palmitic acid per 11 1 milligrams in a controlled release form.

A 65 year-old female with Class II angina due to coronary atherosclerosis is seen in her physician's office and given one of the above suppositories clitorally while being observed for side effects for 1 - 2 hours. The release of the PGEl is more gradual than an intravenous infusion and the PGDH inhibitor partial inhibits pulmonary degradation of the administered PGEl thus permitting delivery of some fraction of the PGEl to the coronary circulation. Protection from hypotension is afforded by the gradual release of the PGEl. She experiences no difficulties with the PGEl suppository and is sent home with instructions to apply one suppository every 8 hours for one month or until cessation of exertional angina persists for 2 weeks. Repeat or continued application can be utilized at the physicians discretion.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention specifically described herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for administering a therapeutic compound to a female mammal having a clitoris, comprising the step of: applying the therapeutic compound to the clitoris or tissues surrounding the clitoris by contacting the therapeutic compound to the clitoris or tissues surrounding the clitoris.

2. The method of claim 1, wherein the therapeutic compound is applied topically.

3. The method of claim 1 wherein the therapeutic compound is injected into the clitoris or surrounding tissues using either subcutaneous, intramuscular or intravenous injection.

4. The method of claim 1 wherein therapeutic compound is administered by iontophoreseis.

5. The method of claim 3 wherein therapeutic compound is injected into the clitoris or surrounding tissues via airgun.

6. The method of claim 1 wherein therapeutic compound is applied in combination with one or more pharmaceutically acceptable carriers.

7. The method of claim 1 wherein the therapeutic compound is applied in combination with permeation enhancers

8. The method claim 7 wherein the permeation enhancer is selected from the group consisting of long chain fatty acids, SEPA.RTM, DMSO, DMF.

9. The method of claim 1 wherein therapeutic compound is in the form of a solution or suspension.

10. The method of claim 1 wherein therapeutic compound is in the form of a solid powder or suppository.

11. The method of claim 1 wherein therapeutic compound is in the form of a controlled release.

12. A method of administering genetic material to a female mammal comprising the step of applying the genetic material via any vector known in the art to the clitoris or the lower genital tract of a female by contacting the genetic material in raw DNA form or in any available vector to the clitoris or tissues surrounding the clitoris.

13. The method of claim 12 wherein the genetic material or vector is applied topically.

14. The method of claim 12 wherein the genetic material or vector is applied by injection into the clitoris or lower genital tract using either subcutaneous, intramuscular or intravenous injection.

15. The method of claim 12 wherein the genetic material or vector is applied by iontophoreseis.

16. The method of claim 14 wherein the genetic material or vector is applied via airgun.

17. The method of claim 12 wherein the genetic material or vector is applied topically with permeation enhancers.

18. The method of claim 12 wherein the genetic material or vector is applied topically in a solution or suspension.

19. The method of claim 12 wherein the genetic material or vector is applied topically as a solid powder or suppository.

20. The method of claim 12 wherein the genetic material or vector is applied via a controlled release device.

21. The method of claim 1 wherein the therapeutic compound is selected from the group consisting of an antimicrobial drug, antiviral drug, antifungal drug, antiprotozoal drug, antibiotic, antihelmintic drug, analgesic, chemotherapeutic or anti- cancer drug, cholinergic agent, anticholinergic agent, anticholinesterase agent, neuromuscular blocking agent, nicotinic agonist or antagonist, adrenoreceptor agent, drug affecting the cardiovascular system, antilipedemic agent, antidiabetic agent, psychoactive drug, histaminergic agent, antihistamine, prostaglandin agonist or antagonists, proton pump inhibitor, antiemetic, agent that increases or decrease smooth muscle tone in the bladder, intestines, stomach or esophagus, hormonal agent, peptide hormone, genetic material, pulmonary medications, vaccine, CNS medication, anti-fibrotic, anti- thrombotic, cytokines, vitamin or essential element, antibody, and globulin.