Devices, methods, and compositions for cancer therapy by administration of chemotherapeutic agents and/or inhibitors of membrane efflux systems to the vagina for topical and systemic tumor targets.

DETAILED DESCRIPTION OF THE INVENTION

This invention concerns a method, composition and a device for topical mucosal and transmucosal vaginal delivery of chemotherapeutic agents and inhibitors of membrane efflux systems for cancer therapy. The cancer therapy according to the invention is achieved by contacting vaginal mucosa with a mucosal composition or with a device incorporated with a mucosal composition comprising a chemotherapeutic agent or inhibitor of membrane efflux system or a combination thereof.

A device, composition and a method for administration of chemotherapeutic agents and/or inhibitors of membrane efflux systems are suitable for both the transmucosal delivery to the systemic circulation and a topical delivery to the vaginal mucosa.

The method of the invention provides a novel route of delivery of chemotherapeutic agents for treatment, control or maintenance of cancer which eliminates the need for parenteral administration, permits extended continuous or pulsed delivery of the drug to the vaginal mucosa locally and topically and transmucosal delivery of the drug to the general circulation. Additionally, the vaginal delivery of inhibitors of membrane efflux systems reduces the risk of toxic side effects following administration to cancer patients diagnosed with drug-resistant tumors.

I. Mucosal and Transmucosal Vaginal Delivery

A method for transmucosal and topical mucosal vaginal delivery comprises intravaginal administration of the mucoadhesive vaginal composition or the intravaginal device of the invention incorporated with such composition. The composition or the device delivers a chemotherapeutic agent and/or inhibitor of membrane efflux systems to and through the vaginal mucosa into the general circulation. Such delivery occurs without intravenous administration and thus eliminates serious adverse reactions typically connected with intravenously administered chemotherapeutic agents or inhibitors of membrane efflux systems.

A. Advantages of Vaginal Delivery

Existing systemic cancer therapy is almost exclusively limited to parenteral administration due to the barrier properties of the intestinal mucosa. Oral administration of chemotherapeutic agents prevents these agents to reach the systemic circulation in therapeutically relevant concentrations. Furthermore, oral administration of chemotherapeutic agents and inhibitors of membrane efflux systems, when attempted, often leads to significant gastrointestinal side effects such as acute nausea and vomiting, stomatitis, esophagitis, ulceration of stomach and colon, or increases risk of infections and/or toxic reactions as a result of reduced activity of membrane efflux systems in the alimentary and gastrointestinal mucosa. Extended or repeated parenteral administration of chemotherapeutic agents, as discussed above, has a potential to cause vascular collapse, vascular damage, phlebosclerosis, vascular hypersensitivities and other complications.

The vaginal route of delivery permits extended, continuous or pulsed delivery and administration of the drugs without need to visit the doctor's office or hospital. Using the mucosal composition and intravaginal device of the invention, the length of the drug delivery can be extended and the delivered dose may be lowered as the vaginal delivery by-passes the gastrointestinal tract and eliminates the intravenous administration with all its adverse effects and requirements.

The invention thus concerns discovery of an improved delivery of chemotherapeutic agents and inhibitors of the membrane efflux systems that overcomes the side effects and limitations observed during the parenteral and oral administration of chemotherapeutic agents and inhibitors of membrane efflux systems in the female by focusing the delivery of drug therapy directly to the vaginal mucosa and using a specifically formulated mucosal composition or an intravaginal device incorporated with such specifically formulated composition containing an appropriate amount of a therapeutical agent. Such composition promotes adhesion of the composition, including the drug released from the device, to the vaginal mucosa and further promotes a transmucosal delivery of the drug through vaginal mucosa to the general circulation.

The therapy according to the invention is suitable for treatment of all cancers via transmucosal delivery and also for treatment of ovarian, cervical or uterine cancers using a topical vaginal or transmucosal delivery, or both. Contacting the vaginal mucosa with chemotherapeutic drugs and/or inhibitors of membrane efflux systems incorporated into the composition according to this invention greatly increases concentrations of the drugs in the localized area of tumor and circumvents the gastrointestinal tract and intravenous delivery.

The newly developed vaginal delivery of the chemotherapeutic agents or inhibitors of membrane efflux system according to the invention thus represents an important improvement in the delivery of the chemotherapeutic agents and important advancement in cancer therapy.

B. Confirmation of Transmucosal Delivery

Mucosal or preferably transmucosal delivery according to the invention is suitable for delivery of chemotherapeutic agents as well as inhibitors of membrane efflux systems that belong to the ABC transporter superfamily. Examples of such inhibitors are P-glycoprotein (P-gp) and multidrug-resistance associated protein (MRP).

Biochemically, efflux systems in the gastrointestinal tract are related to the proteins that cause failure of chemotherapy in cancer patients as a result of multidrug resistance (MDR). Overexpression of membrane efflux systems such as P-gp and MRP in tumor cells result in multidrug resistance (MDR) by actively decreasing intracellular accumulation of cytotoxic drugs. Inhibitors of membrane efflux systems are therefore valuable anti-cancer agents that permit a significant increase in accumulation of chemotherapeutic agents in drug-resistant tumor cells. These inhibitors provide a more effective tumor therapy at lower doses of the chemotherapeutic agents.

To confirm that transmucosal delivery of the inhibitors, studies using verapamil, a membrane efflux system inhibitor for p-glycoprotein were performed. As discussed above, the p-glycoprotein is overexpressed in the gastrointestinal mucosa, however, its expression in the vaginal mucosa is significantly reduced. Consequently, transvaginal delivery systems of the invention, if experimentally confirmed, would prove to be an effective means of delivering therapeutic quantities of chemotherapeutic drugs for the treatment of neoplasms in the female.

The objective of this study was to determine whether vaginal delivery of verapamil leads to significantly improved bioavailability of verapamil. Studies were designed to compare bioavailability of verapamil administered orally, i.v., or transmucosally through vagina into systemic circulation.

Plasma pharmacokinetic of verapamil was determined in anesthetized female white New Zealand rabbits after intravenous and vaginal administration of verapamil at dose between 0.15-0.19 mg/kg. For analytical purpose, each dose was supplemented with a trace amount of [³H] verapamil. Pharmacokinetic parameters were obtained by non-compartmental analysis using WinNonlin. Results are shown in FIGS. 1 and 2 (see Original Patent) and in Table 1.

FIG. 1 (see Original Patent) is a graph showing concentration-time profiles of the P-glycoprotein substrate verapamil in plasma of female white New Zealand rabbits following intravenous and vaginal administration of a single dose (0.15-0.19 mg/kg). Results are represented as mean±S.E.M (n=2-3).

Results seen in FIG. 1 show that following i.v. administration of a verapamil solution, verapamil rapidly disappeared from the vascular system, followed by a slower elimination phase with a mean terminal half-life of 9.5 hours. When delivered vaginally in form of a suppository formulated with 15% (w/w) of the sorption promoter transcutol, verapamil concentrations in plasma slowly increased to a maximum of 21.3±2.3 ng/ml measure after 5.5 hours.

Comparison of the dose-normalized areas under the curve (AUCs) for verapamil following vaginal and intravenous administration revealed an absolute bioavailability of 62.3±25.1%. Results are seen in FIG. 2 (see Original Patent).

FIG. 2 is a graph showing an absolute bioavailability of P-glycoprotein substrate verapamil following intravenous and vaginal administration to female white New Zealand rabbits (0.15-0.19 mg/kg, n=2-3). In comparison to the oral bioavailability of this drug in humans (J. Clin.Pharmacol., 40: 219-230 (2000)), vaginal bioavailability in the rabbit model is significantly greater (p<0.001).

Table 1 lists individual pharmacokinetic parameters of verapamil following intravenous and vaginal administration in female white New Zealand rabbits.
 

Pharmacokinetic parameters were calculated from plasma verapamil drug concentration using the model-independent analysis module of WinNonlin.

The calculated terminal half-lives of verapamil, seen in Table 1, show that absorption across the vaginal mucosa after release of verapamil from the suppository is not rate-limiting.

The findings seen in FIGS. 1 and 2 and Table 1 confirm that verapamil, as a P-glycoprotein substrate, readily permeates the vaginal mucosal barrier. In contrast, oral absorption of verapamil is significantly reduced as demonstrated by a low oral bioavailability of 20-25%. These results show that vaginal delivery of substrates for membrane efflux systems, such as P-glycoprotein, increases the systemically available fraction of these therapeutic agents when compared to oral administration. Consequently, vaginal delivery of substrates for membrane efflux systems improves the therapeutic benefit of drugs used in the treatment of cancer.

C. Method for Delivery of the Cancer Therapy

A method of the invention is developed and particularly suitable for non-parenteral delivery of effective doses of a chemotherapeutic agent and/or inhibitor of membrane efflux systems topically to the vaginal mucosa or transmucosally to the general blood circulation.

The method, useful for treatment, management and control of cancer, comprises steps of contacting vaginal mucosa with a mucoadhesive composition or with an intravaginal device incorporated with such composition. Said composition comprises at least one chemotherapeutic agent or one inhibitor of membrane efflux systems selected from the group consisting of antiestrogens, androgen inhibitors, antibiotic derivatives, antimetabolites, cytotoxic agents, hormones, nitrogen mustard derivatives and steroids, alone, in combination with another chemotherapeutic agent or said inhibitor of membrane efflux systems, or in combination with another pharmaceutical agent or a pharmaceutically acceptable excipient, and maintaining said composition or device in contact with said vaginal mucosa for a period of time permitting a continuous or pulsed delivery of the agent to or through vaginal mucosa and necessary to deliver a therapeutic amount of the chemotherapeutic agent. Such time is typically one to several hours.

The delivery route utilizes the transmucosal composition directly or incorporated into an intravaginal device for transmucosal delivery and comprises delivery of a combination of the chemotherapeutic drug and/or inhibitors of membrane efflux systems with mucoadhesive agents, solubilizing agents, carriers and, optionally, penetration enhancing agents and solubilizers for transvaginal delivery.

Additionally, more than one drug may be present in the composition and the combination of a chemotherapeutic or any other pharmacologically active drug in tumor therapy, including inhibitors of membrane efflux systems, is intended to be within the scope of the invention.

The method thus includes a delivery of anti-cancer drugs in a combination with drugs which may enhance immune system, fight bacterial or viral infections, have analgesic effect and such other therapeutically and/or pharmaceutically active agents.

Specifically, the anti-cancer compounds suitable for delivery according to the method are selected from but are not limited to the group consisting of daunorubicin, doxorubicin, idarubicin, amrubicin, pirarubicin, epirubicin, mitoxantrone, etoposide, teniposide, vinblastine, vincristine, mitomycin C, paclitaxel, docetaxel, actinomycin D, colchicine, topotecan, irinotecan, gemcitabine cyclosporin, verapamil, valspodor, probenecid, MK571, GF120918, LY335979, biricodar, terfenadine, quinidine, pervilleine A, and XR9576. Compounds may be administered alone or in combination with another pharmaceutical agent or a pharmaceutically acceptable excipient.

The method may be practiced either by administering the mucoadhesive composition directly to the vagina as a cream, lotion, foam, ointment, suppository, liposomal suspension, microemulsion, capsule, capsule containing microparticles, bioadhesive microparticle, bioadhesive nanoparticle, fluid or gel or by inserting the intravaginal device medicated with the above described mucosadhesive composition comprising a chemotherapeutic agent and/or inhibitor of membrane efflux systems incorporated therein. The device suitable for these purposes is selected from the group consisting of an intravaginal tampon, intravaginal ring, intravaginal pessary, intravaginal sponge, intravaginal tablet, intravaginal capsule, intravaginal cup and intravaginal strip.

Cancer therapy according to the invention comprises contacting the vaginal mucosa directly with a composition of the invention comprising the chemotherapeutic agent and/or inhibitor of membrane efflux systems. Such direct contact permits an immediate, extended continuous or pulsed delivery and efficacious treatment. Such direct treatment also permits use of only such a dosage of the chemotherapeutic agent and/or inhibitor of membrane efflux system as is therapeutically required for topical and/or systemic treatment of the affected tissue.

The method of the invention, suitable for cancer therapy, comprises providing a specifically formulated mucosal composition comprising the chemotherapeutic agent and/or inhibitor of membrane efflux systems or an intravaginal device incorporated with said composition, inserting said composition or device into the vagina and maintaining said composition or device in the vagina for a period of time required for a therapeutic effect of said mucosal composition. The composition is formulated to deliver the chemotherapeutic agent and/or inhibitor of membrane efflux systems to the target organ for treatment of cancer. For each of the treatments, the drug is formulated differently.

The method for cancer therapy using transmucosal delivery of the drug to systemic circulation involves adding to the composition of the invention components promoting absorption and/or transport and penetration of the drug through the vaginal mucosa. Such components are added in amounts sufficient to facilitate transmucosal delivery to the general circulation.

Transmucosal treatment is based on the concept that the upper vagina and the uterus have specific blood flow characteristics, either by a portal type circulation or by venous and lymphatic channels, permitting preferential transport and delivery of the pharmacological agents from the vagina directly to the blood circulation thereby by-passing the gastrointestinal tract absorption and liver detoxification.

The most specific demonstration of the transvaginal concept has been achieved by inventors with several types of drugs, as described in U.S. Pat. Nos. 6,086,909, and 6,197,327 and 6,416,779 B1, incorporated by reference. Chemotherapeutic agents or inhibitors of membrane efflux systems, when properly formulated, are transported through the vaginal wall in the same manner as described in the above patents.

The composition is a stand alone treatment or it is incorporated into a suitable intravaginal delivery device which assures the contact with the vaginal mucosa.

The composition or the medicated device according to the method is applied, that is, inserted intravaginally for from about ten minutes, preferably half an hour, to several hours once, twice or several times a day or week, as needed, or according to a treatment regimen. The device is typically provided in dry or wet form or may be wetted prior to insertion.

The method of the invention, as described herein and confirmed experimentally, provides several advantages over oral or intravenous administration of chemotherapeutic drugs and/or inhibitors of membrane efflux systems.

First, there is a continuous concentration of drug delivered to the vaginal mucosa and to the blood. This provides for higher bioavailability of the drug. Second, there is prevention of first-pass elimination of the drug in the intestinal mucosa and the liver by avoiding the gastrointestinal system. Third, the device of the invention provides a continuous drug depot which allows continuous and uninterrupted delivery of drug to the vaginal mucosa over a long period of time. Fourth, and very important, is the reduction of side effects due to avoidance of repeated intravenous administration of the drug or inhibition of gastrointestinal efflux systems that act as crucial physiological barriers to protect the interior milieu of the body from environmental toxins.

II. Mucoadhesive Compositions

A mucoadhesive composition of the invention for transmucosal delivery consists typically of four essential components. These components are a therapeutically active agent, a mucoadhesive agent, a lipophhilic or hydrophillic carrier and a sorption promoter. For topical delivery to the vaginal mucosa, the composition consists at least of two components, a therapeutically active agent and a mucoadhesive agent. The therapeutically active agents is either a chemotherapeutic agent and/or inhibitor of membrane efflux systems. These agents are formulated either alone or in admixture with another pharmaceutical agent or a pharmaceutically acceptable excipient. All the above mentioned components of the composition must be suitable for administration to the vagina or for incorporation into an intravaginal device for the vaginal or transmucosal vaginal delivery of the drug through the vaginal mucosa into the general circulation. The therapeutically active compound is present in an amount sufficient to assert its therapeutic effect, typically from about 0.001 to about 3000 mg, preferably from 1 to 1000 mg, most preferably from 100 to about 500 mg.

The mucoadhesive composition is typically formulated in dosage unit form, and contains a chemotherapeutic agent or an inhibitor of membrane efflux systems selected generally from antiestrogens, androgen inhibitors, antibiotic derivatives, antimetabolites, cytotoxic agents, hormones, nitrogen mustard derivatives and steroids, alone, in combination, or in combination with other pharmaceutical agents or pharmaceutically acceptable component and excipients for intravaginal or transvaginal delivery to a human female.

The composition typically contains from 0.001 to about 3000 mg, preferably from 1 to 1000 mg, of a chemotherapeutic agent and/or inhibitor of membrane efflux systems with at least a 5-25% of mucoadhesive agent promoting adhesion of the composition to the vaginal mucosa, from about 5 to about 25% of sorption promoter assuring the penetration of the drug through the mucosa and from about 40 to about 95% of a lipophilic or hydrophilic carrier serving as a vehicle for the drug, and optionally, from about 0 to about 30%, preferably about 1 to 5% of a permeation enhancer or solubilizer for transmucosal delivery of the agent through the vaginal mucosa to the systemic circulation.

Specific therapeutical anti-cancer drug suitable for delivery according to this invention using the above composition are daunorubicin, doxorubicin, idarubicin, amrubicin, pirarubicin, epirubicin, mitoxantrone, etoposide, teniposide, vinblastine, vincristine, mitomycin C, paclitaxel, docetaxel, actinomycin D, colchicine, topotecan, irinotecan, gemcitabine, cyclosporin, verapamil, valspodor, probenecid, MK571, GF120918, LY335979, biricodar, terfenadine, quinidine, pervilleine A, and XR9576, alone, or in combination.

The composition is formulated as a cream, lotion, foam, ointment, suppository, liposomal suspension, microemulsion, bioadhesive microparticle, bioadhesive nanoparticle, capsule, capsule containing microparticles, solution or gel, and can be delivered as stand alone or incorporated within an intravaginal device.

Alternatively, the composition can be incorporated into an intravaginal device or a coating of such device, for example, a tampon or tampon-like device coating, or incorporated into a sponge, foam, strip, pessary, or other material. Absorbent material or matrix of such devices may be impregnated with a drug containing liquid solution, suspension lotion, cream, microemulsions or suspension of liposomes, bioadhesive nanoparticles, or bioadhesive microparticles. The devices of the invention are described in greater detail below in section III.

Any form of drug delivery system which will effectively deliver the anti-cancer agent to the vaginal mucosa or transmucosally through the vaginal mucosa into the systemic circulation is intended to be included within the scope of this invention.

A. Anti-cancer Therapeutical Agents

The anti-cancer therapeutical agents are chemotherapeutic agents or inhibitors of membrane efflux system generally selected from the following groups and types of compounds: antiestrogens, androgen inhibitors, antibiotic derivatives, antimetabolites, cytotoxic agents, hormones, nitrogen mustard derivatives or steroids.

Specific chemotherapeutic compounds are selected from but not limited to the group of compounds including daunorubicin, doxorubicin, idarubicin, amrubicin, pirarubicin, epirubicin, mitoxantrone, etoposide, teniposide, vinblastine, vincristine, mitomycin C, paclitaxel, docetaxel, actinomycin D, colchicine, topotecan, irinotecan, gemcitabine and any other compound know now or which will become known in future to have similar chemotherapeutic properties. All these compounds are intended to be covered by this invention.

Specific inhibitors of membrane efflux system are generally compounds which are substrates and/or inhibitors for the membrane efflux systems, such as P-glycoprotein or MDR. The inhibitors a P-glycoprotein are selected from but not limited to the group of compounds represented by cyclosporin, verapamil, valspodor, biricodar, quinidine, terfenadine, pervilleine A, and investigational drugs currently known under their coded names GF120918, LY335979, OC144-093 (Ontogen) and XR9576. The MRP2 inhibitors are probenecid and the Merck investigational compound known under its coded name MK571. Any other compound know now or which will become known in future to have similar inhibitory properties is intended to be covered by this invention.

The compounds of the invention are administered in from about 0.001 to about 3000 mg/day, preferably in about 1 to about 1000 mg/day dosages. The individual chemotherapeutic agents and inhibitors are administered in different dosages and ranges depending on their activity. Exemplary dosage for colchicin are, for example in a range from about 4 to about 8 mg/day, paclitaxel from about 60 to about 100 mg/m², topotecan from about 0.5 to about 1.5 mg/m², doxorubicin from about 100 to about 1000 mg/day, vincristine about 1-2 mg/dose, verapamil from about 10 to about 125 mg/dose and cyclosporin in about 60 mg/dose.

The chemotherapeutic agents or inhibitors of membrane efflux systems are formulated in said composition alone, in admixture of two or more or in admixture of the chemotherapeutic agent and inhibitor and/or in combination with another pharmaceutical agent or a pharmaceutically acceptable component or excipient.

B. Pharmaceutical Compositions and Formulations

In order to achieve desirable drug release at a site where it can act either directly on the vaginal mucosa or to be transported transmucosally through the vaginal wall to the systemic circulation, the chemotherapeutic drug and/or inhibitor of membrane efflux systems is formulated in conjunction with other components which permit its adhesion to the vaginal mucosa and absorption through the vaginal mucosa to the systemic circulation. A resulting composition typically contains at least a mucoadhesive agent, a sorption promoter and a non-toxic lipophilic or hydrophilic carrier, and optionally, a permeation enhancer and/or a solubilizing agent and/or another pharmaceutically acceptable excipient suitable for vaginal delivery, such as a buffer, filler, stabilizer, emulsifier, and any such other excipient as is known in the art to be useful for these purposes.

Any component and/or excipient used in formulations of this invention needs to be approved for human use and acceptable for use in the vagina with understanding that not all excipients approved for oral use may be approved and/or suitable for vaginal use.

• 5. Bioadhesive Systems and Microemulsions

Bioadhesive systems and microemulsions are formulations particularly suitable for vaginal transmucosal delivery.

The microemulsion may contain pharmaceutically acceptable surfactants, for example, LABRASOL®, PLUROL® isostearate (Gattefossé), co-solvents such as isopropanol or ethanol, and water. Microemulsions containing one or more of the above components have been shown to improve bioavailability of chemotherapeutic drugs.

Bioadhesive microparticles or bioadhesive nanoparticles constitute still another intravaginal drug delivery system suitable for use in the present invention.

The bioadhesive systems use derivatives of cellulose such as hydroxypropyl cellulose and polyacrylic acid. They release the cytotoxic or chemotherapeutic drugs for up to five days once they are placed in the appropriate formulation. This system represents a multi-phase liquid or semi-solid preparation which does not seep from the vagina as do most current suppository formulations. The microparticles or nanoparticles cling to the wall of the vagina and release the drug over a several hour period of time. Many of these systems were designed for nasal use, as described in U.S. Pat. Nos. 4,756,907, and 6,200,590 incorporated herein by reference, but can be easily modified for use in the vagina. The bioadhesive system may comprise microparticles or nanoparticles filled with the chemotherapeutic agent and/or inhibitor of membrane efflux systems and may contain a surfactant for enhancing solubility and/or uptake of the drug. The microparticles have a diameter of 1-100 μm, whereas nanoparticles have a diameter of 10-1000 nm. Microparticles and nanoparticles can be prepared from starch, gelatin, albumin, collagen, or dextran according to methods known in the art.

Bioadhesive tablets are another drug delivery system suitable for transmucosal delivery. These bioadhesive systems use hydroxypropyl cellulose and polyacrylic acid. They release drugs for up to five days once they are placed in the appropriate formulation. The tablet of the invention has the shape of a suppository or a tampon so that the maximum contact is achieved between the vaginal wall and the tablet surface or such a shape as is suitable for incorporation into the device.

Bioadhesive microparticles- or nanoparticles, described above, constitute still another drug delivery system suitable for use in the present invention. This system is a multi-phase liquid or semi-solid preparation which does not seep from the vagina as do most current suppository formulations. The substances cling to the wall of the vagina and release the drug over a several hour period of time or are released from the device.

The drug can also be incorporated into creams, lotions, foams, paste, ointments, microemulsions, liposomal suspensions, and gels which can be applied to the vagina using an applicator. Processes for preparing pharmaceuticals in these vehicles can be found throughout the literature.

Suitable nontoxic pharmaceutically acceptable excipients for use in the compositions of the present invention will be apparent to those skilled in the art of pharmaceutical formulations and examples are described in REMINGTON: The Science and Practice of Pharmacy, 20^th Edition, A. R. Gennaro, ed., (2000). The choice of suitable carriers will depend on the exact nature of the particular vaginal dosage form desired, e.g., whether the chemotherapeutic agent and/or inhibitor of membrane efflux systems is/are to be formulated into a cream, lotion, foam, ointment, paste, solution, microemulsions, liposomal suspension, microparticles, nanoparticles or gel, as well as on the physicochemical properties of the active ingredient(s).

Although the compositions described above typically contain only one pharmaceutically active ingredient from the group of chemotherapeutic agents or inhibitors of membrane efflux systems for treatment of cancer and neoplastic growth, such compositions may additionally contain other pharmaceutical agents or a combination thereof, such as, for example, pain killers, antivirals, antipruritics, corticosteroids and other agents which may enhance the therapeutic effect of the primary drug.

All bioadhesive systems described above may be administered directly or via an intravaginal device.

III. Device and/or System for Transvaginal Drug Delivery

The composition of the invention for transmucosal delivery is administered either directly to the vagina or is incorporated into the intravaginal device.

The intravaginal device of the invention is typically a tampon, tampon-like device, ring, pessary, strip, cup or foam which has a solid structure into which the formulation is incorporated and from which it is released in a timely fashion over a period of time. The time period is typically limited to from several minutes to 24 hours, preferably 4-8 hours, which is a hygienically acceptable time to leave the device in place.

Advantages of the medicated intravaginal device include continuous delivery of a predictable amount of the drug. The device may also have a washable and reusable design, such as, vaginal ring or pessary.

The intravaginal device for vaginal or transmucosal vaginal delivery of a chemotherapeutic agent and/or inhibitor of membrane efflux systems is an intravaginal tampon, intravaginal ring, intravaginal pessary, intravaginal sponge, intravaginal tablet or intravaginal strip incorporated with a composition comprising a chemotherapeutic agent and/or inhibitor of membrane efflux systems formulated as a cream, lotion, foam, ointment, suppository, liposomal suspension, microemulsion, bioadhesive microparticle, bioadhesive nanoparticle, solution or gel.

The device may be configured for controlled release of the chemotherapeutic drugs or inhibitors of membrane efflux system where the drug incorporated into the device is formulated as a sustained release system, as described above.

In one embodiment, the invention provides a tampon device for delivering a chemotherapeutic agent and/or inhibitor of membrane efflux systems across the vaginal mucosa comprising an absorbent vaginal tampon having a proximal end and a distal end. A cup-shaped porous foam portion at the distal end fits around the cervix of the systemic circulation and contains a pharmaceutical agent for delivery to the cervix. The device may also include a nonabsorbing axial tube having a distal opening and extending through the porous foam cup into the tampon for conducting blood flow to the absorbent material. Optionally, a retrieval string or tape connected to the tampon device is also included. The absorbent vaginal tampon contains any of the above-mentioned drugs or be coated with the drug and be used as a medicated tampon for individual drug or drug combination delivery.

In another embodiment of a tampon device, the distal porous foam cup has a rim which encircles the cervix. The rim has high concentrations of medication and is positioned away from the direct flow of blood which exudes from the cervix during menstruation.

In another embodiment of a tampon device, the distal porous foam cup has a rim which encircles the cervix. The rim has fingers extending into the fornix areas around the cervix and the tips of the fingers have high concentrations of medication and are positioned away from the direct flow of menstrual blood.

In another embodiment of a tampon device, a distal porous foam section is in the shape of a scoop, which only partially encircles the cervix. The porous foam scoop has a nib-like shape which is designed to wedge itself into the posterior fornix. The porous foam scoop is designed to deliver medication to the vaginal wall along the entire length of the porous foam scoop.

In another embodiment, a tampon device is sheathed in a thin, supple, non-porous material such as a plastic film or a coated gauze that surrounds the absorbent tampon material like a skirt and opens like an umbrella when it comes in contact with the vaginal environment. A drug incorporated into a strip, ideally suspended in a wax-like carrier that melts at body temperature, encircles the sheathed tampon. Contact with vaginal fluids or menstrual flow causes the tampon to swell, forcing the skirt to open like an umbrella and to press tightly against the vaginal wall, putting the drug in contact with the vaginal mucosa while effectively preventing the drug from being absorbed into the tampon.

In another embodiment of a tampon device, distal fibers of the tampon which contact the cervix have high concentrations of pharmaceutical agent for delivery of the agent to the cervical tissue.

In another embodiment of a tampon device, the tampon device has an outer tubing having perforations, the outer tubing is concentric around an axial tube. The device has a distal porous foam section which in its dehydrated state is tight around the outer tubing. A bladder is located proximally to the porous foam and filled with liquid pharmaceutical agent. The bladder is connected to the outer tubing. An outer sheath covers the tampon. The sheath has an annular constriction distal to the bladder such that deployment of the tampon through the distal end of the sheath causes the liquid in the bladder to be forced out distally through the perforated outer tubing and into the porous foam.

In another embodiment of a tampon device, the tampon device has an annular delivery composition around the distal end. The composition contacts the vaginal mucosa for delivery of the chemotherapeutic agent and/or inhibitor of membrane efflux systems. A non-absorbing axial tube opens distally and extends into the tampon for conducting blood flow to the absorbent material proximal to the porous foam. The annular composition can be a suppository, cream, ointment, foam, microparticles, paste, or gel.

Embodiments of the invention may include tampon devices of a standard length, or may be longer or shorter than standard tampons to facilitate positioning the tampon device closer to or in contact with the vaginal wall or with the cervix, depending on the location of tumor.

For purposes of simplifying the description of the invention and not by way of limitation, tampon or tampon-like devices, such as a suppository, for drug delivery will be described hereinafter, it being understood that all effective delivery systems are intended to be included within the scope of this invention.

 

Claim 1 of 33 Claims

1. A method for a transmucosal delivery of chemotherapeutic agents and inhibitors of membrane efflux systems to a systemic circulation for treatment, control and maintenance of cancer in a human female patient, wherein said agents and inhibitors are delivered into the systemic circulation transmucosally through a vaginal mucosa from a mucoadhesive composition or from an intravaginal device incorporated with said composition, said method comprising steps of:

a) providing the transmucosal vaginal composition consisting essentially of from about 0.001 to about 3000 mg of a chemotherapeutic agent selected from the group consisting of daunorubicin, doxorubicin, idarubicin, amrubicin, pirarubicin, epirubicin, mitoxantrone, etoposide, teniposide, vinblastine, vincristine, mitomycin C, paclitaxel, docetaxel, actinomycin D, colchicine, topotecan, irinotecan and gemcitabine or an inhibitor of a membrane efflux system selected from the group consisting of cyclosporin, verapamil, valspodor, biricodar, quinidine, terfenadine, pervilleine A, GF120918, LY335979, OC144-093, XR9576, probenecid, MK571 and a mixture thereof;

from about 30 to about 95% of a lipophilic or hydrophilic carrier selected from the group consisting of saturated mono-, di- or triglyceride of fatty acids from 8 to 18 carbons, a mixture thereof, polyethylene glycol of molecular weight between about 200 and 8000, a derivative thereof and a mixture thereof; from about 5 to about 25% of a mucoadhesive agent selected from the group consisting of a cellulose derivative, natural gum, alginate and pectin; and from about 5 to about 25% of a sorption promoter selected form the group consisting of a non-ionizable glycol ester derivative, a non-ionizable glycol ether derivative and an interesterified stone oil;

wherein said composition is formulated as, or incorporated into the device as, a suppository, cream, gel, foam, ointment, microparticles, microcapsules, nanoparticles or a capsule containing microparticles, microcapsules or nanoparticles, or a liposome suspension; and

b) delivering said composition to the vaginal mucosa by administering said composition into the vagina or inserting said device incorporated with said composition into the vagina

wherein said vaginal device is a vaginal tampon, vaginal ring, vaginal strip, vaginal capsule, vaginal tablet, vaginal pessary, vaginal cup or vaginal sponge.

 

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