A vaginal device for delivery of an anti-migraine or anti-nausea drug to the uterus and/or to the general circulation through vaginal mucosa. The device is at least partially coated with one or several layers of fluid impermeable material forming a cap, film, foam, foil or strip incorporated with mucoadhesive composition comprising the anti-migraine or anti-nausea drug.

Description of the Invention

SUMMARY OF THE INVENTION

One aspect of the current invention is a vaginal device completely or partially coated with a layer or layers of the fluid impermeable material such as an impermeable film, foam, foil or xerogel forming a strip or an attached or removable cap or cup, said layer(s) being completely or partially incorporated with a mucoadhesive composition comprising a therapeutic and/or palliative amount of an anti-migraine or anti-nausea drug.

Another aspect of the current invention is a vaginal tampon, tampon-like foam or another vaginal device coated with a layer or layers of the fluid impermeable material such as an impermeable film, foam, foil or xerogel forming an attached or removable cap, cup or strip, said layer(s) incorporated with a composition comprising a therapeutic and/or palliative amount of the anti-migraine or anti-nausea drug for delivery to the uterus and/or to the general circulation through vaginal wall.

Still another aspect of the current invention is a method for targeted delivery of drugs to the uterus or to the general circulation using a vaginal device which is coated, or of which a proximal portion closest to uterus is coated, with a fluid impermeable layer or layers of material such as a impermeable film, foam, foil or xerogel forming an attached or removable cap, cup or strip, said layer(s) incorporated with a mucoadhesive composition comprising an anti-migraine or anti-nausea drug or a combination thereof.

Still another aspect of the current invention is a method for targeted delivery of drugs to the uterus or to the general circulation using a vaginal tampon, tampon-like foam or another vaginal device of which a proximal portion is covered with a fluid impermeable layer or layers of a coating material such as an impermeable film, foam, foil or xerogel forming an attached or removable cap, cup or strip, said layer(s) incorporated with a mucoadhesive composition comprising an anti-migraine or anti-nausea drug, a combination thereof, or a combination of either an anti-migraine or anti-nausea drug with another therapeutically effective agent or pharmaceutically acceptable excipient.

Still yet another aspect of the current invention is a mucoadhesive composition comprising an anti-migraine or anti-nausea drug, or a combination thereof, incorporated into an impermeable layer(s) covering a proximal portion of a vaginal device wherein said impermeable layer(s) of the fluid impermeable coating material is an impermeable film, foam, xerogel or foil forming an attached or removable cap, cup or strip wherein said composition is quantitatively released from said layer(s) thereby delivering an effective amount of an anti-migraine or anti-nausea drug into the uterus or directly to the general circulation thereby bypassing the gastrointestinal tract.

Still another aspect of the current invention is a mucoadhesive composition for incorporation into an impermeable layer of a coating of a vaginal device wherein said composition comprises an anti-migraine or anti-nausea drug selected from the group consisting of ergot alkaloid, ergot alkaloid derivative, antihistamine, barbiturate, non-steroidal anti-inflammatory agent, analgesic, serotonin antagonist, neurokinin-1 antagonist, cannabinoid, calcitonin gene-related peptide (CGRP) antagonist, steroid, sympathomimetic, tranquilizer and anti-epileptic agent, each alone or in combination with an anti-nausea drug selected from the group consisting of metoclopramide, prochlorperazine, domperidone, ondansetron, tropisetron, dolasetron, nabilone, dronabinol, levonantradol, CP55940, SR 144528, aprepitant, cyclizine, and promethazine, BIBN-4096BS, SB-(+)-273779, each alone and/or further in combination with another therapeutically effective agent or a pharmaceutically acceptable excipient.

Still another aspect of the current invention a mucoadhesive composition comprising an anti-migraine drug selected from the group consisting of ergotamine, dihydroergotamine, ergostine, butalbital, phenobarbital, acetaminophen, diclofenac sodium, ketoprofen, ketorolac, ibuprofen, piroxicam, naproxen, acetylsalicylic acid, flurbiprofen, tolfenamic acid, butorphanol, meperidine, methadone, sumatriptan, naratriptan, razatriptan, zolmitriptan, almotriptan, eletriptan, dexamethasone, hydrocortisone, isometheptene, chlorpromazine, diazepam, droperidol, valproic acid, gabapentin, topiramate, divalproex sodium, or an anti-nausea drug selected from the group consisting of metoclopramide, prochlorperazine, domperidone, ondansetron, tropisetron, dolasetron, nabilone, dronabinol, levonantradol, CP55940, SR 144528, aprepitant, cyclizine, and promethazine, BIBN-4096BS and SB-(+)-273779, each alone or in combination, or further in combination with another therapeutically effective agent.

Another aspect of the current invention is a method for treatment, management and control of migraine and headache pain, nausea, and vomiting associated with migraine or other conditions, such as, for example, infection, pregnancy, poisoning, surgery, radiotherapy or administration of chemotherapeutic drugs, said method comprising steps of contacting vaginal mucosa with a vaginal device coated or partially coated with one or several layers of an impermeable coating material incorporated with a mucoadhesive composition, said composition comprising an anti-migraine drug selected from the group consisting of ergot alkaloid, ergot alkaloid derivative, antihistamine, barbiturate, non-steroidal anti-inflammatory agent, analgesic, serotonin antagonist, neurokinin-1 antagonist, cannabinoid, calcitonin gene-related peptide (CGRP) antagonist, steroid, sympathomimetic, tranquilizer and anti-epileptic agent, each alone or in combination with an anti-nausea drug and/or further in combination with another therapeutically effective agent or a pharmaceutically acceptable excipient and maintaining said device in contact with vaginal mucosa for a period of time permitting a quantitative, controlled, rapid or slow, continuous or pulsed delivery of the agent to and through the vaginal mucosa, said composition further comprising at least one mucoadhesive agent and/or one lipophilic or hydrophilic carrier and/or one permeation enhancer and/or, optionally, another pharmaceutically acceptable excipient.

Still another aspect of this invention is a method for treating a human female subject suffering from migraine or headache and/or nausea and vomiting associated with migraine or other diseases or conditions, said method comprising steps of contacting vaginal mucosa with a mucoadhesive composition or with an intravaginal device incorporated with said composition, said mucoadhesive composition comprising at least one anti-migraine and/or one anti-nausea drug.

Still yet another aspect of this invention is a mucoadhesive composition for delivery of anti-migraine and/or anti-nausea drugs said composition comprising, in dosage unit form, from 0.00001 to 45 mg/kg body weight, preferably from 0.001 to 15 mg/kg body weight and most preferably from 0.1 to 8 mg/kg/body weight of an anti-migraine drug selected from the group consisting of but not limited to ergotamine, dihydroergotamine, ergostine, butalbital, phenobarbital, acetaminophen, diclofenac sodium, ketoprofen, ketorolac, ibuprofen, piroxicam, naproxen, acetylsalicylic acid, flurbiprofen, tolfenamic acid, butorphanol, meperidine, methadone, sumatriptan, naratriptan, razatriptan, zolmitriptan, almotriptan, eletriptan, dexamethasone, hydrocortisone, isometheptene, chlorpromazine, diazepam, droperidol, valproic acid, gabapentin, topiramate, divalproex sodium, or an anti-nausea drug selected from the group consisting of metoclopramide, prochlorperazine, domperidone, ondansetron, tropisetron, dolasetron, nabilone, dronabinol, levonantradol, CP55940, SR 144528, aprepitant, cyclizine, and promethazine, BIBN-4096BS, SB-(+)-273779, each alone, in combination, or in combination with another therapeutically effective pharmaceutical agent and/or with a pharmaceutically acceptable excipient suitable for delivery of said drug to a human female subject through vaginal mucosa, said composition consisting essentially of a combination of an effective amount of said antimigraine and/or anti-nausea drug with at least a mucoadhesive agent promoting adhesion of the composition to the vaginal mucosa for delivery of the drug to and through the vaginal mucosa or with a combination comprising at least a mucoadhesive agent and/or a permeation enhancer and/or a lipophilic or hydrophilic carrier.

Yet another aspect of this invention is a vaginal device for vaginal delivery of an antimigraine and/or anti-nausea drug, wherein said device is a vaginal tampon, vaginal tampon-like foam, vaginal ring, vaginal pessary, vaginal sponge or vaginal tablet coated or partially coated with a layer(s) of an impermeable film, foam, foil or xerogel, or with an attached or removable cap, cup or strip, said layer incorporated with a composition comprising at least one anti-migraine and/or anti-nausea drug wherein said composition is formulated as a powder, cream, lotion, tablet, capsule, ointment, suppository, liposomal suspension, microemulsion, bioadhesive microparticles or microcapsules, bioadhesive nanoparticles or nanocapsules, solution, emulsion or gel.

Yet another aspect of the current invention is a mucoadhesive composition comprising an anti-migraine and/or anti-nausea drug in combination with an excipient selected from a lipophilic carrier such as semi-synthetic glyceride of saturated fatty acids, a hydrophilic carrier such as polyethylene glycol having an average molecular weight of 6000, polyethylene glycol having an average molecular weight of 1500, polyethylene glycol having an average molecular weight of 400, block polymers consisting of several repeating units in various sizes, co-polymers thereof or mixtures thereof, a muco-adhesive agent such as alginate, pectin, or a cellulose derivative, such as hydroxypropyl methylcellulose and a penetration enhancer such as a bile salt, organic solvent, ethoxydiglycol, interesterified stone oil, polyoxyethylene lauryl ether, polyoxyethylene monooleyl ether, polyoxyethylene nonylphenol, polyoxyethylene octylphenol ether, polyoxyethylene cholesterol ether, polyoxyethylene soya sterol ether, polyoxyethylene monooleate, polyoxyethylene dilaurate, polyoxyethylene dioleate, polyoxyethylene glyceryl laurate, polyoxyethylene glyceryl oleate, propylene glycol oleate, propylene glycol stearate, polyoxyethylene sorbitan monooleate, polyoxyethylene tristearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene almond oil, polyoxyethylene apricot kernel oil, polyoxyethylene caprylic or capric glyceride, lauroyl macrogol glyceride, polyoxyethylene oleate or polyoxyethylene glyceryl stearate.

Still another aspect of the current invention is a mucoadhesive composition comprising a pharmaceutically acceptable excipient, wherein said excipient is a lipophilic or hydrophilic carrier, penetration enhancer and a mucoadhesive agent, wherein said lipophilic or hydrophilic carrier is present in amounts between about 60 to 90%, by weight, wherein said mucoadhesive agent is present in amounts between about 5 to 25%, by weight and wherein said penetration enhancer is present in amounts between about 5 to 20%, by weight.

Still another aspect of the current invention is a composition comprising about 75% lipophilic carrier (SUPPOCIRE.RTM.), about 10% hydroxypropyl methylcellulose (HPMC) and about 15% ethoxydiglycol (TRANSCUTOL.RTM.).

Still yet another aspect of the current invention is a tampon, a tampon-like foam or another vaginal device for delivering an anti-migraine or anti-nausea agent to the uterus or to the general circulation, said tampon, foam or device comprising a proximally placed cap or cup-shaped portion covered with a permanent or detachable cap or cup made of a fluid impermeable material incorporated with a mucoadhesive composition comprising an anti-migraine or anti-nausea drug.

Yet another aspect of the current invention is a tampon, tampon-like foam or another vaginal device comprising a proximally placed removable or permanently attached cup or cap coated with a fluid impermeable coating material further comprising a rim or strip containing a mucoadhesive composition containing a high concentration of an anti-migraine or anti-nausea drug.

Still yet another aspect of the current invention is a tampon, tampon-like foam or another vaginal device comprising a proximally placed fluid impermeable cap or cup encircled with a permanent or removable rim wherein said rim has fingers extending into the fornix areas around the cervix and wherein either the cap, cup or the tips of the fingers contain a mucoadhesive composition containing at least one anti-migraine or one anti-nausea drug.

Another aspect of the current invention is a tampon, tampon-like foam or another vaginal device completely or partially coated at its proximal end with a temperature-sensitive material, such as wax, that melts at the body temperature, said material comprising at least one anti-migraine or one anti-nausea drug suspended therein, wherein said tampon or device is further sheathed by one or several layers of fluid impermeable degradable or non-degradable thin, supple, non-porous material such as a plastic film, coated gauze, polyethylene, high density polyethylene, synthetic polymers or their combination with polysaccharides such as alginate, dextran, cellulose, collagen or proteins, such as albumin or gelatin, or polyhydroxy acids, such as polylactides, polyglycolides, polyethylene terephthalate, polybutyric acid, polyvaleric acid, polylactide-co-caprolactone, polyanhydrides, polyorthoesters, and blends and co-polymers thereof, or non-degradable polymers such as polyamides, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polymethacrylic acid, and derivatives thereof, or any other suitable impermeable material that coats the device or surrounds the device like a skirt and opens like an umbrella when it comes in contact with the vaginal environment.

In yet another aspect of the current invention, a mucoadhesive composition comprising an anti-migraine or anti-nausea drug is formulated as a bioadhesive microparticle, cream, tablet, soft gel capsule, lotion, ointment, solution, gel or thermo-reversible sol-gel, all in a regular, controlled or sustained controlled release form and placed on, attached to or incorporated into an impermeable material coating of a vaginal device, tampon or tampon-like foam.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the discovery that a vaginal device, such as a tampon, tampon-like foam or another type of vaginal device comprising impermeably sealed proximal end with a fluid impermeable coating material such as film, foam, foil, xerogel or another impermeable material attached permanently or removably to the vaginal device as a layer, layers, cap, cup, strip or strips incorporated with a mucoadhesive composition comprising a therapeutic and/or palliative amount of an anti-migraine and/or anti-nausea drug represents a suitable means for delivery of said drug to the uterus and/or to the general circulation for control and treatment of migraine and nausea.

The invention thus concerns a targeted delivery of anti-migraine and/or anti-nausea drugs to the uterus and/or to the general circulation using a vaginal device completely or at least partially coated with a layer or layers of the fluid impermeable coating material incorporated with or having attached to a mucoadhesive composition comprising an anti-migraine and/or anti-nausea drug, or a combination thereof. The vaginal device allows delivery of the an anti-migraine or anti-nausea drug directly to the uterus or to the general systemic circulation and permits a treatment of migraine or nausea with lower concentrations of anti-migraine or anti-nausea drugs than those needed for oral administration and thus provides for lower systemic concentration and fewer side effects.

Additionally, the invention concerns the discovery that when drugs are administered intra or transvaginally, preferably using an intravaginal tampon or tampon-like foam or another vaginal device for delivery of the anti-migraine or anti-nausea drug, uterus allows for preferential uptake of the drug into the uterus and into the general circulation thereby bypassing the first pass hepatic degradation and detoxification.

The current invention provides several previously unrecognized advantages. When a vaginal device coated with a fluid impermeable material at its proximal end additionally contains a layer containing the mucoadhesive composition comprising the drug, the released drug from the mucoadhesive composition is prevented from being absorbed into the distal porous non-coated portion of the device thereby making the whole dose of the drug available for transmucosal absorption. Additionally, when the mucoadhesive composition is incorporated into a layer of a temperature-sensitive carrier, such as, for example, wax, this carrier melts upon insertion into the vagina and releases the composition and the drug therefrom. Under these conditions, the mucoadhesive composition containing the entire dose of the drug is released and delivered to the upper vaginal wall closest to the uterus where, through its mucoadhesive properties, the composition adheres to said vaginal wall and the drug is transported through the vaginal wall to the uterus and/or to the general circulation. The invention thus permits a quantitatively more efficacious delivery of the drug wherein the substantially whole drug dose formulated as the mucoadhesive composition attached to or incorporated into the fluid impermeable coating or a layer is released and delivered.

Transmucosal vaginal delivery systems according to the invention offers a viable alternative to deliver anti-migraine and/or antiemetic (anti-nausea) drugs to a female subject suffering from migraine or other disease or conditions that result in headache, nausea or vomiting. In contrast to the oral route, administration of anti-migraine and/or anti-nausea drugs using vaginal drug delivery systems as described herein does not stimulate vomiting reflexes and, therefore, reduces migraine-associated vomiting. In addition, drugs delivered transmucosally through vaginal mucosa enter the systemic circulations system bypassing the first pass liver detoxification and degradation. Consequently, this route of administration is particularly advantageous for drugs, including anti-migraine and anti-nausea drugs, that undergo substantial first-pass hepatic metabolism which deactivates a large portion of the drug.

This type of drug delivery is particularly suitable for treatment of migraine because, typically, migraine is accompanied by severe headaches, nausea and vomiting. Nausea and vomiting prevent effective treatment of migraine by oral route because the recipient is usually not able to hold the drug in the stomach for long enough time to be absorbed and to achieve needed relief from the pain and nausea. Thus, the oral drug delivery for treatment of migraine and other conditions accompanied by nausea and vomiting is unpredictable and ineffective insofar as the actual delivered drug dose. Furthermore, women are generally accustomed, on a routine basis, to the insertion of a vaginal device such as a tampon for menstrual control and are expected to embrace this alternative route of delivery for therapeutic control of migraine condition without dramatic emotional distress.

The method of the invention provides a novel and more efficacious route of delivery of anti-migraine and/or anti-nausea drugs for treatment and control of the migraine condition as well as for control of nausea accompanying other conditions, such as drug-induced nausea, chemotherapy, radiotherapy, post-surgery nausea, pre-operative medication, PMS, menstruation, pregnancy, breast feeding and menopause, where administration of these drugs provides relief of similar symptoms in the female subject. The method avoids drug administration to the gastrointestinal tract of nauseated patients, protects the therapeutic agent from extensive hepatic first-pass metabolism, permits rapid or slow, continuous or pulsed delivery of the anti-migraine and/or anti-nausea drugs, and achieves therapeutically effective concentrations of such agents in the blood circulation with much smaller amounts of the drug.

The method for treatment and control of headache pain, nausea and vomiting comprises administration of a mucoadhesive composition containing a therapeutically effective amount of the appropriate anti-migraine or anti-nausea drug incorporated into a vaginal device of the invention before or after onset of migraine, before surgery, during menstrual period or pregnancy, or before or after headache, nausea and vomiting appear. The mucoadhesive composition attached to or incorporated into an impermeable layer covering at least a portion of the vaginal device is introduced into vagina attached to the vaginal device and brought into a close contact with a vaginal mucosa for direct absorption and transport through the mucosa into uterus and/or to the systemic circulation.

Administration of anti-migraine and/or anti-nausea drug via the vaginal route as described herein reduces the portion of the drug dose which would be eliminated by the liver during its first pass circulation in the blood system, which further enhances the drug's therapeutic effect.

I. A Method for Vaginal Delivery of Anti-Migraine or Anti-Nausea Drugs

A method for vaginal delivery of anti-migraine or anti-nausea drugs comprises preparation of a vaginal device at least partially coated with a layer or layers of fluid impermeable material that is incorporated with or having attached thereto a mucoadhesive composition comprising at least one anti-migraine or one anti-nausea drug. The mucoadhesive composition may contain a mixture of anti-migraine and anti-nausea drugs and may additionally and optionally also contain other therapeutic agents and/or other pharmaceutically acceptable excipients.

The mucoadhesive composition typically contains at least one mucoadhesive agent permitting the adhesion of the composition to the vaginal wall for a time needed for the active anti-migraine and/or anti-nausea drug to be absorbed through the vaginal mucosa into the uterus and/or general systemic circulation. Such delivery of the anti-migraine and/or anti-nausea drugs occurs without oral administration and thus eliminates therapy-induced vomiting typically occurring with oral administration of anti-migraine and/or anti-nausea drugs for treatment and control of headache, pain, nausea and vomiting. Headache, light sensitivity, pain, nausea and vomiting are primary symptoms associated with migraine but are also associated with other conditions or diseases and occur, for example, as a result of administration of chemotherapeutic drugs, following radiotherapy, before or after surgery, during menstrual period, pregnancy, breast-feeding, and menopause, among others.

A. Advantages of Vaginal Delivery

Existing therapeutic approaches used to control migraine symptoms and/or headache pain, nausea and vomiting mostly depend on oral, intravenous, nasal or rectal drug delivery systems. Unfortunately, drug administration via the gastrointestinal tract in migraine patients stimulates rather than eliminates vomiting and, consequently, results in inadequate treatment of these conditions. Alternatively, parenteral intramuscular or subcutaneous injections, nasal sprays, or insertion of rectal suppositories are employed to bypass problems and difficulties encountered with oral administration of these drugs to migraine patients. In this regard, injection methods usually require visit to a medical facility and assistance of a trained health care professional, whereas many patients find insertion of a rectal dosage form uncomfortable and/or emotionally unpleasant. Nasal delivery systems for migraine therapy have been only partially successful as the drug dose needed to achieve a relief from pain and nausea needs to be adjusted to consider first pass liver deactivation of the substantial amount of the drug and thus is efficacious only for drugs that are highly resistant to hepatic metabolism.

The vaginal route of delivery allows rapid or slow, continuous or pulsed delivery of drugs in a patient-controlled environment without the need to have access to a skilled health care professional in a doctor's office or hospital. Using the mucoadhesive composition and a vaginal device of the invention, an effective dose of a desired therapeutic agent can be delivered reproducibly to the systemic circulation while vomiting, which frequently occurs after oral drug administration in migraine patients, is prevented and eliminates parenteral injection with all its adverse effects and requirements. Furthermore, since the blood circulation into which the drugs are delivered through vaginal mucosa circumvents the liver first-pass circulation, the dose of the vaginally delivered drug is substantially smaller compared to the portion of the drug administered orally. In this regard, the vaginal delivery is many times more efficacious.

The invention, thus, concerns discovery of an improved delivery route of anti-migraine and anti-nausea drugs that overcomes the side effects and limitations observed during oral, parenteral, and nasal administration of these agents in subjects suffering from headaches or nausea. The invention utilized anatomic advantage of female subjects by focusing the delivery of drug therapy directly to the vaginal mucosa using a specifically formulated mucoadhesive composition attached to or incorporated into a fluid impermeable layer of a vaginal device.

The newly developed vaginal delivery strategy of anti-migraine and/or anti-nausea drugs according to the invention, therefore, represents an important improvement in the systemic delivery of these drugs and an important advancement of migraine therapy as well as the therapy of conditions leading to headache pain, nausea and vomiting associated with other diseases and conditions as described above.

B. Anti-Migraine and Anti-Nausea Drugs

Vaginal delivery of anti-migraine and/or anti-nausea drugs comprises formulating said anti-migraine or anti-nausea drugs into a mucoadhesive composition, incorporating said composition or attaching it to a layer, layers, strip, cup or cap of a fluid impermeable material coating at least a portion of a vaginal device and introducing said vaginal device into the vagina.

Examples of anti-migraine drugs suitable to be used in the current invention are therapeutic agents of type of ergot alkaloids and ergot alkaloids derivatives, antihistamines, barbiturates, non-steroidal anti-inflammatory agents, analgesics, serotonin antagonists, neurokinin-1 antagonists, cannabinoids, calcitonin gene-related peptide (CGRP) antagonists, steroids, sympathomimetics, tranquilizers and antiepileptics.

The anti-migraine drug useful for treatment of migraine according to this invention is selected from the group consisting of ergotamine, dihydroergotamine, ergostine, butalbital, phenobarbital, acetaminophen, diclofenac sodium, ketoprofen, ketorolac, ibuprofen, piroxicam, naproxen, acetylsalicylic acid, flurbiprofen, tolfenamic acid, butorphanol, meperidine, methadone, sumatriptan, naratriptan, razatriptan, zolmitriptan, almotriptan, eletriptan, dexamethasone, hydrocortisone, isometheptene, chlorpromazine, diazepam, droperidol, valproic acid, gabapentin, topiramate and divalproex sodium, among others.

A specific anti-nausea drug useful for treatment of nausea according to his invention is selected from the group consisting of metoclopramide, prochlorperazine, domperidone, ondansetron, tropisetron, dolasetron, nabilone, dronabinol, levonantradol, aprepitant, cyclizine and promethazine.

Each anti-migraine or anti-nausea drug may be formulated and delivered alone or in combination with each other or with another therapeutically effective agent or with a pharmaceutically acceptable excipient. Typically, the drug will be formulated in combination with at least one mucoadhesive agent, one carrier and one penetration agent.

The anti-migraine or anti-nausea drug is present in a dose sufficient to assert its therapeutic effect, typically from about 0.00001 to about 45 mg/kg body weight, preferably from 0.001 to 15 mg/kg body weight, most preferably from 0.1 to 8 mg/kg body weight.

C. Confirmation of Vaginal Delivery of Anti-Migraine and Anti-Nausea Drugs

Transmucosal delivery of anti-migraine and anti-nausea agents across the vaginal mucosa results in therapeutically useful systemic plasma concentrations. Consequently, vaginal administration represents a viable alternative to oral dosing for pharmacological agents with beneficial effects in the treatment of migraine and nausea, respectively.

To confirm feasibility of the method according to the invention, a series of in vivo pharmacokinetic studies was performed using female white New Zealand rabbits. Following administration of the anti-migraine drug sumatriptan and the anti-nausea drug metoclopramide as a solution intravenously by injection into the marginal ear vein or via the oral route using a rubber tubing inserted into the stomach as well as vaginally whereby the drug was incorporated into a suppository, plasma samples were withdrawn from the animal at predetermined time points and the drug concentration was quantitatively analyzed applying sensitive analytical methodologies.

Model-dependent pharmacokinetic analysis was further utilized to calculate relevant pharmacokinetic parameters such as maximum plasma concentration (c.sub.max) time required to reach maximum plasma concentration (t.sub.max), total exposure of the body to the drug extrapolated to infinity (AUC.sub..infin.), and elimination half-life (t.sub.1/2). All studies were repeated at least three times in different animals, and pharmacokinetic calculations were performed using WinNonlin 4.1.

The results for the anti-migraine drug sumatriptan are shown in FIGS. 1A and 1B (see Original Patent).

FIG. 1A (see Original Patent) is a graph illustrating pharmacokinetics of an anti-migraine drug sumatriptan in female white New Zealand rabbits following vaginal administration. Each animal received 0.7 mg of sumatriptan per kg body weight administered as a solution. Open circles (.largecircle.) denote plasma concentration following intravenous injection, whereas closed squares (.box-solid.) represent corresponding drug concentration measured in the plasma after oral dosing of the drug solution. Experiments were performed in three different animals and results are presented as means.+-.S.D. FIG. 1B shows systemic plasma concentrations of anti-migraine drug sumatriptan in female white New Zealand rabbits after vaginal insertion of a lipophilic delivery device. Each animal received 0.7 mg of sumatriptan per kg body weight and plasma concentrations were normalized to c.sub.max measured in similar experiments after oral administration of a dose-equivalent sumatriptan solution. Experiments were performed in three different animals and results were presented as means.+-.S.D.

In these studies, a dose of 0.7 mg sumatriptan per kg body weight of the animal was used. For analytical purpose, the dose was supplemented with a trace amount of [.sup.3H]sumatriptan, which was used to quantify plasma drug concentrations by liquid scintillation counting. Results are presented as means.+-.SD.

FIG. 1A (see Original Patent) demonstrates that parenteral injection of the drug solution results almost immediately in high plasma concentrations that rapidly decrease with an apparent t.sub.1/2 of 191.+-.6 min. Therapeutically, the initial high concentrations with a c.sub.max of 15.4.+-.4.5 .mu.g/mL suggest fast onset of an effective relief of migraine headache and associated symptoms. However, since the drug is administered as a bolus into the blood stream, there is no constant supply that would support a longer duration of the action. Elimination of sumatriptan from the systemic circulation through metabolism and renal excretion are the predominant mechanisms by which the time of the anti-migraine effect is determined after injection.

In contrast, oral administration results in a very slow increase of systemic plasma concentrations of sumatriptan in the rabbit. This underlines kinetically the absorption phase required for the drug to physically move from the gastrointestinal tract across the epithelial barrier into the blood vessels of the submucosa. Physicochemical properties of the drug molecule, including ionization, lipophilicity, and hydrodynamic radius determine the rate of absorption.

Comparison of the two systemic profiles clearly suggests that oral administration of sumatriptan will result in a delayed anti-migraine effect as compared to parenteral injection. The t.sub.max values estimated for both i.v. and oral routes of administered drug indicate that the maximum effect of sumatriptan after oral administration is delayed by at least a factor of 100, which is therapeutically a dramatic disadvantage.

The overall exposure of the body to the same dose administered via the intravenous and the oral routes are significantly different as shown by the respective total area under the time/plasma concentration curve. The AUC.sub..infin. calculated for oral administration is 958.+-.163 .mu.g.times.min/mL and 10868.+-.90 .mu.g.times.min/mL (approximately 11 times higher) for parenteral administration, respectively. The apparent t.sub.1/2 of 1210.+-.163 minutes for oral administration is significantly longer than calculated from the intravenous data, which suggests that absorption rather than elimination becomes pharmacokinetically the rate-limiting process for this drug after oral administration.

To contrast the therapeutic potential of vaginal administration of anti-migraine drugs to the more frequently used oral route of administration, systemic plasma levels of sumatriptan measured after insertion of lipophilic vaginal device comprising sumatriptan composition were normalized to the maximum concentration attained after oral administration. Results are seen in FIG. 1B (see Original Patent). In this representation, a straight line indicates similar kinetic processes involved in the absorption of this drug across the vaginal and oral mucosa, respectively. However, the early peak in this profile strongly suggests that vaginal administration of sumatriptan using said vaginal device as described in this application provide more rapid delivery of the drug into the systemic circulation that traditional oral administration. The calculated t.sub.max for vaginal administration is .about.15 min, which implies that this delivery method may provide almost 6 times faster onset of anti-migraine efficacy when compared to the oral route. This therapeutic benefit could be compared with the previously described bolus effect after intravenous injection. The total body exposure to sumatriptan after an equivalent dose is <5% of that measured after oral administration. This requires incorporation of greater amounts of anti-migraine drugs into vaginal delivery device than for oral delivery methods due to incomplete absorption. The AUC.sub..infin. calculated for 0.7 mg/kg after vaginal delivery was 23.0.+-.0.1 .mu.g.times.min/mL.

Similar studies as performed with the anti-migraine drug sumatriptan were performed to demonstrate the value of vaginal delivery of anti-nausea drugs. Metoclopramide was selected as a model drug for this therapeutic class. Results are seen in FIGS. 2A and 2B (see Original Patent).

FIG. 2A (see Original Patent) shows an anti-nausea agent metoclopramide plasma concentrations in female white New Zealand rabbits after intravenous administration. Drug solution of 0.5 mg was prepared in sterile saline (0.9%; w/w) and injected into the systemic circulation through the marginal ear vein. Plasma samples were collected for six hours and analyzed for the drug using HPLC. Results are presented as means plasma+SEM (n=4) FIG. 2B shows normalized metoclopramide plasma concentrations in white female New Zealand rabbits after vaginal administration. Plasma samples were analyzed for the drug using a selective HPLC method and normalized to metoclopramide concentrations measured at the same time points after intravenous injection. Experiments were performed in three individual animals and results are presented as mean.+-.SEM.

Three female white New Zealand rabbits were dosed at 0.05-0.1 mg/kg body weight intravenously, orally, and vaginally. Blood samples were removed at various time points, and plasma concentrations were quantified using a selective HPLC method described in Int. J. Clin. Pharmacol. Ther., 40: 169-174 (2002). Model-dependent pharmacokinetic parameters were calculated from time/plasma concentration data using WinNonlin 4.1.

Intravenous injection of a metoclopramide solution prepared in 0.9% saline immediately reaches average plasma concentrations around 60 ng/mL (FIG. 2A). First-order distribution and elimination phases result in a monophasic decline of plasma concentrations with an apparent t.sub.1/2 of 84.+-.38 min. Total body exposure as measured by the AUC.sub..infin. was 3845.+-.1415 ng.times.min/mL. Oral administration of the same dose resulted in peak plasma concentration that were on average 30-fold lower than measured after parenteral administration (data not shown) This implied that the transfer of this anti-nausea drug from the gastrointestinal tract into the systemic circulation is inefficient. Considering the additional complication that patients who are vomiting experience great difficulties, in general, to swallow oral dosage forms, it becomes apparent that oral delivery of anti-nausea drugs such as metoclopramide appears therapeutically undesirable. However, inclusion of this drug into a vaginal delivery device consisting of a lipophilic base such as SUPPOCIRE AS2, the mucoadhesive hydroxypropyl methylcellulose, and the permeation enhancer ethoxydiglycol provides a unique opportunity to bypass the irritated gastrointestinal tract in female patents and deliver therapeutically sufficient amounts into the systemic circulation.

Results of the vaginally administered metoclopramide depicted in FIG. 2B demonstrate that plasma levels of metoclopramide delivered vaginally using a device such as described above are close to the respective drug levels measured after intravenous injection. The profile shown in FIG. 2B was generated by normalizing the actual plasma levels measured for metoclopramide after vaginal administration to the time-equivalent levels after parenteral administration. Consequently, the initial concentrations appearing after 10 minutes following vaginal dosing are equivalent within intersubject variability to plasma levels after parenteral administration. Therapeutically, this may offer great benefit to the patient suffering from vomiting without the requirement to inject the drug.

The above described studies clearly demonstrate feasibility and benefits of vaginally delivered anti-migraine and anti-nausea drugs. Clearly, such vaginal delivery provides much larger dosage of the drug delivered more rapidly and for longer time than that achieved by oral administration. Advantages of the vaginal delivery of anti-migraine and anti-nausea drugs compared to requirements, inconveniences and invasiveness of the intravenous administration are obvious.

II. Devices for Vaginal Delivery of Anti-Migraine and Anti-Nausea Drugs

The vaginal device of the invention, such as a tampon, foam, tampon-like foam, sponge, pessary or ring provides an improvement against previously described devices. In particular, the device of the invention, which is preferably the vaginal tampon or a degradable or non-degradable tampon-like foam is coated completely or, preferably, only partly at its proximal end with a layer of a fluid impermeable material.

The fluid impermeable material may be applied to the device as one layer or several layers interspaced with a layer or layers of different material, it may form a cap or cup covering a proximal portion of the tampon or a strip or rim of a fluid impermeable material encircling the tampon. Since the vaginal tampon or vaginal foam is made of porous material, usually a cotton or polymer, the fluid impermeable material covering at least a proximal portion, typically the proximal end of the tampon, separates the porous material from the material coated with the impermeable layer and sequesters the proximal portion of such porous material within the fluid impermeable coating. The fluid impermeable coating, whether the layer, layers, strip, strips, cap or cup, is incorporated with a mucoadhesive composition or such composition is attached to such fluid impermeable coating by various means.

The coating of the entire device prevents the absorption of the mucoadhesive composition into the porous portion of the device. The partial coating of the device permits sequestration of the drug to a smaller area and prevents the absorption of the mucoadhesive composition into the porous portion of the device. Thus, the loss of the drug due to reabsorption into the porous portion of the device is either eliminated or substantially decreased. Additionally, since the mucoadhesive composition comprising the anti-migraine or anti-nausea drug is sequestered within the fluid impermeable coating applied to the proximal end of the device, it is preferentially released from the device into the vicinity of uterus where the mucosal epithelia is more apt to drug absorption. The drug is therefore delivered more quantitatively to the vaginal mucosa to which it adheres due to the presence of the mucosal agent and is transported through the mucosa to the uterus and/or to the general systemic circulation due to the presence of the sorption promoter and/or penetration enhancer. The lipophilic or hydrophilic carrier additionally modifies the drug affinity to the mucosal surface and enhances the drug surface exposure.

A. Coated Vaginal Devices

The vaginal device of the invention is a vaginal tampon, degradable or non-degradable vaginal tampon-like shaped foam, vaginal foam, vaginal sponge, vaginal ring or vaginal pessary, all coated or at least partially coated with an impermeable layer of coating separating the body of the device from the mucosal composition incorporated into or attached to said coating. The most preferred embodiment is a vaginal tampon or the tampon-like shaped foam.

1. Vaginal Tampon

One preferred embodiment for vaginal drug delivery is the vaginal tampon. The vaginal tampon is typically a commercially available vaginal tampon that is coated, according to the invention, in its upper proximal portion, typically to about one third or one half, that is a portion coming in contact with the vaginal wall. The proximal end of the tampon is coated with a fluid impermeable coating forming a layer, layers, cap, cup or strip around the upper proximal top portion of the tampon or attached to the tampon as a fluid impermeable layer, cap or cup or strip prepared separately. However, the whole tampon may also be coated with the fluid impermeable coating, if desirable and the composition is then attached to the whole, to the proximate part, or to the tip of the tampon.

2. Vaginal Foam

Another preferred embodiment is a tampon-like shaped vaginal foam that may be fully or partially degradable in the vagina or it may be non-degradable. However, the foam may also be shaped differently than a tampon-like structure.

The foam used as a vaginal device is preformed into a specific shape of a solid structure or a semi-solid or liquid preparation. The latter two may be used as a receptacle for the mucoadhesive composition which forms a foam layer, strip, cup or cap coating into which the composition may be conveniently incorporated.

The vaginal foams, whether degradable or non-degradable and whether used as a vaginal device or a coating therefore, are prepared by processes known in the art that introduce porosity in a polymer matrix, namely by lyophilization, aeration, freeze drying, hydrocarbon templating, salt or particulate leaching, gel or solvent casting, gas expansion, sintering, polymerization of high internal phase emulsions, and free form fabrication techniques such as three-dimensional polymer printing. The most preferred process to fabricate foams is lyophilization, which is described in detail in the copending application Ser. No. 10/600,849 filed Jun. 30, 2003.

Lyophilized foams are open cell, high-surface-area, biodegradable or non-degradable constructs that can be manufactured from a variety of polymers, preferably from hydrophilic polymers. The foam materials are characterized by controlled chemical and physical properties that can be tailored according to their intended application. Tuneable properties include hydrophilicity, rate of fluid absorption, degradation profile and dissolution rate, a measure of which is the time needed to complete dissolution of the foam.

Typically, the lyophilized foam is prepared by dissolving an appropriate polymer, preferably a hydrophilic polymer, or a mixture thereof, serving as a substrate material, as listed below, in an amount needed to prepare solution from 1 to 10% (w/w) in an aqueous or non-aqueous solvent, such as methanol, ethanol, glycerine, methylene, chloride, propylene glycol, propylene carbonate, glycofurol, cetyl alcohol, difluroethane and isopropyl alcohol, preferably a purified water. Alternatively, polymeric solutions with the drug and additives may be prepared in acetic acid, cyclohexane, acetonitrile, tert-butanol, ethanol, and isopropanol or in mixtures of aqueous and non-aqueous solvents.

Substrate materials for preparation of foam compositions of the invention are hydrophobic or, preferably, hydrophilic polymers. These polymers may be used singly or in combination with each other. They may be used in variable concentrations and ratios to each other when in admixture of two or several polymers.

Non-exclusive list of substrate polymers comprises cellulose and cellulose derivatives, microcrystalline cellulose, polyacrylic acid, polyethylene glycol, polypropylene glycol, divinyl glycol, polyethylene oxide, polypropylene oxide. Other possible polymers include the cellulose derivatives such as carboxymethyl cellulose, hydroxyethyl cellulose, polylactide, polyglycolide, polymethacrylic acid, poly-.gamma.-benzyl-L-glutamate, polypropylene fumarate, poly-.epsilon.-caprolactone, poly-butylene terephthalate, polyvinyl alcohol, polyvinyl ether, poly-1-vinyl-2-pyrrolidinone, 2,5-dimethyl-1,5-hexadiene, divinyl benzene, polystyrene-divinyl benzene, polyanhydrides such as poly-bis-p-carboxy-phenoxypropane-co-sebacic acid, polyhydroxyalkanoates such as poly-.beta.-hydroxybutyrate or poly-.beta.-butyrolactone, and alkyl-substituted silica gel such as tetraethylorthosilicate and dimethyldiethoxysilane.

Examples of hydrophilic polymers suitable for a foam manufacture include hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose, polyethylene glycol (PEG), alginic acid, alginic acid sodium salt, pectin, gelatin, collagen, polyvinyl pyrrolidone, poloxamer, acrylic-acid based polymers, such as carbopol, noveon, polyurethanes, polyvinyl alcohol, chitosan, hydroxypropyl cellulose, polyethylene oxide, fibronectin, hyaluronic acid, polysaccharide gums such as karaya gum, polyacrylamide, polycarbophil, dextran, xanthan gum, polyacrylamide, polyacrylamide, crosslinked polymethyl vinyl ether-co-maleic anhydride, commercially available as Gentrez.TM., gelatin, corn starch and mixtures thereof.

Examples of hydrophobic polymers suitable for formation of the foam are, among others, polypropylene oxide, polyamides, polystyrene, and polymethacrylic acid.

Tampon-like vaginal foams that undergo degradation in the vagina into smaller units or polymers by various mechanisms are classified as degradable foam. This type of the foam is preferred as long as their degradation is controlled and coincides with or exceeds the time needed for a complete release of the drug from the coating attached to the degradable vaginal foam.

Non-degradable vaginal foams are the foams resisting a degradation of the three-dimensional structure. Representative but not limiting examples of non-biodegradable polymers that may be used exclusively, or in alternative that may be also coated with biodegradable polymeric foams, include polyamides, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polymethacrylic acid, and derivatives thereof alone or as co-polymeric mixtures thereof.

Both degradable or non-degradable foams may be prepared in a range of sizes and a variety of shapes suitable for use as a vaginal device or the coating thereof, including foam pillows, tubes, cylinders, spheres, tablets or rings (devices) or films, sheets or beads or any other desirable shape (coating) using an appropriate processes known in the art that introduce porosity in a polymer matrix.

The foam as a vaginal device is preformed into a device such as a tampon, tampon-like cylinder, strip, pad, pillow, tube, sphere, tablet or ring or any other shape as might be desirable or it may be applied as a film, sheet or beads, as a coating to a surface of a more complex vaginal device made of a different material, such as, for example, a conventional vaginal tampon, tampon-like device, pessary, ring, strip, pad, pillow, sheet, tube, sphere or tablet covered by said coating foam. In this configuration the foam is applied as a receptacle for the mucoadhesive composition as described in greater detail in the coating section below.

3. Vaginal Sponge

Another example of the tampon-like device is the vaginal sponge. The mucosal composition comprising a desired anti-migraine or anti-nausea drug can be incorporated into a fluid impermeable silicone matrix which is coated onto a cylindrical drug-free polyurethane vaginal sponge.

4. Vaginal Ring

Another example of a suitable controlled release drug delivery system for the present invention is the vaginal ring. Vaginal rings usually consist of an inert elastomer ring coated by another layer of elastomer containing the drug to be delivered. The rings can be easily inserted, left in place for the desired period of time, up to 7 days, then removed by the user. The ring may be solid or hollow containing the anti-migraine and/or anti-nausea drug and it may be coated with a porous material releasing the drug therefrom. The ring can optionally include a third, outer, rate-controlling elastomer layer which contains no drug. Optionally, the third ring can contain a second drug for a dual release ring. The drug can be incorporated into polyethylene glycol throughout the silicone elastomer ring to act as a reservoir for drug to be delivered.

5. Other Vaginal Devices

Vaginal pessaries, vaginal cylinders, vaginal tablets, vaginal capsules, vaginal pads, vaginal patches, vaginal suppositories or vaginal tubes are other examples of drug delivery systems which can be used in the present invention. These systems have been previously used for delivery of vaginal contraceptives, and have been described extensively in the literature.

These other types of vaginal devices are similarly coated on the side or on the end facing the uterus with the fluid impermeable coating. For example the pessary or ring can be coated on the side facing the uterus with the other side remaining non-coated, sponge or pad may be coated at the portion closest to the uterus while the other side may be porous and adsorbent for, for example, the menstrual blood.

The vaginal device is provided in dry or wet form or may be wetted prior to insertion.
 

Claim 1 of 13 Claims

1. A vaginal device for delivering an anti-migraine or anti-nausea drug to a female subject, said device comprising the vaginal device; the anti-migraine or anti-nausea drug formulated as a mucoadhesive composition; and a fluid impermeable coating comprising said composition; wherein said vaginal device is a tampon, foam, ring, pessary, sponge, cylinder, tablet, capsule, pad, suppository, pellet or tube; wherein said anti-migraine drug is selected from the group of compounds consisting of ergotamine, dihydroergotamine, ergostine, butalbital, phenobarbital, acetaminophen, diclofenac sodium, ketoprofen, ketorolac, ibuprofen, piroxicam, naproxen, acetylsalicylic acid, flurbiprofen, tolfenamic acid, butorphanol, meperidine, methadone, sumatriptan, naratriptan, razatriptan, zolmitriptan, almotriptan, eletriptan, dexamethasone, hydrocortisone, isometheptene, chlorpromazine, diazepam, droperidol, valproic acid, gabapentin, topiramate and divalproex sodium, each alone or in combination, or in combination with the anti-nausea drug, and wherein said anti-nausea drug is selected from the group consisting of metoclopramide, prochlorperazine, domperidone, ondansetron, tropisetron, dolasetron, nabilone, dronabinol, levonantradol, aprepitant, cyclizine, promethazine, each alone or in combination or in combination with the anti-migraine drug; wherein said fluid impermeable coating is a degradable or non-degradable water soluble or non-soluble polymer selected from the group consisting of wax, plastic polymeric film, coated gauze, synthetic polymer, dextran, cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, polyethylene, polyethylene oxide, alginate, chitosan, copolymer of ethylene oxide and propylene oxide, polyethylene oxide-co-propylene oxide, polyacrylic acid, collagen, albumin, gelatin, polylactide, polyglycolide, polyethylene terephthalate, polybutyric acid, polyvaleric acid, polylactide-co-caprolactone, polyanhydride, polyorthoester, polyamide, polypropylene, polystyrene, polyvinyl chloride, polymethacrylic acid and a derivative thereof, alone, or in combination, wherein said coating is attached to said device as a film, foil, sheet, beads or xerogel and is either incorporated into said device, attached to said device or inserted into said device.

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