MXPA99011480A - Device and method for treatment of dysmenorrhea - Google Patents

Abstract

Los métodos, dispositivos y composiciones para el tratamiento de la dismenorrea comprenden un sistema de distribución intravaginal de medicamento conteniendo un agente farmacéutico adecuado incorporado a un portador farmacéuticamente aceptable por medio del cual el agente farmacéutico es liberado a la vagina y absorbido a través de la mucosa vaginal para proporcionar alivio de la dismenorrea. El sistema de distribución de medicamento puede ser un dispositivo de tampón, anillo vaginal, pesario, tableta, supositorio, esponja vaginal, tableta bioadhesiva, micropartícula bioadhesiva, crema, loción, espuma, ungüento, pasta, solución, o gel. El sistema distribuye una concentración más alta al músculo delútero, el sitio principal para la contracción discinética de músculos, la cual es la causa patofisioiógica de la dismenorrea.

Description

DEVICE AND METHOD FOR THE TREATMENT OF DISMENORRHEA FIELD OF THE INVENTION The present invention relates to devices, methods and compositions for treating dysmenorrhea by intravaginal administration or therapeutic- and / or palliative medicaments to the uterus. BACKGROUND OF THE INVENTION Dysmenorrhea, which may be primary or secondary, is the occurrence of painful uterine cramps during menstruation. In secondary dysmenorrhea, there is a visible pelvic lesion that explains pain, whereas only a lack of biochemical balance is responsible for primary dysmenorrhea. Primary dysmenorrhea affects 50 percent of women after puberty and it has been estimated that absenteeism among women with severe dysmenorrhea costs around 600 million lost work hours or more than 2 billion dollars a year. In this way, an effective, simple and safe treatment of primary dysmenorrhea during a period of several days during menstruation will not only improve the quality of life of women suffering from dysmenorrhea, but will also have a positive economic impact. The pain of dysmenorrhea originates in the uterus. The systemic administration of analgesic drugs generally via the oral route to the patient has not alleviated the condition of many women with success and the administration is often limited by side effects. We believe that this deficiency is the result of not achieving an effective dose level of the analgesic to the muscle in the uterus. SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide devices, methods and compositions for treating dysmenorrhea by the intravaginal distribution of effective doses of medicament to the uterus by transvaginal transport to the uterus, i.e. to uterus a. through the lymphatic and venous channels after absorption by the vaginal mucosa. Another object of the present invention is to provide. safe, convenient devices, methods, and compositions that promote effective localized transvaginal delivery of medications that are effective in treating dysmenorrhea. Another objective of this invention is to provide pharmaceutically acceptable compositions that promote effective intravaginal delivery for the purpose of preventing or treating dysmenorrhea. "In one aspect, the present invention provides a method for treating a woman suffering from dysmenorrhea comprising contacting the vaginal epithelium of a woman with a pharmaceutical agent selected from the group consisting of anti-inflammatory drugs" non-spheroids, antiprostaglandins, "inhibitors of prostaglandins, local anesthetics, "calcium channel blockers, potassium channel blockers, β-adrenergic agonists, agents" leukotriene blockers, smooth muscle inhibitors, vasodilators and drugs capable of inhibiting "the dyskinetic contraction of muscles. The agent is in combination with a biocompatible excipient acceptable for application of the agent to the vaginal epithelium. The agent is present in the combination in an amount sufficient to achieve a therapeutically effective amount of the agent in the uterine muscle of the person in the vaginal application of the combination In the preferred embodiment, the agent can be absorbed through the vaginal mucosa. and therefore it is transmitted via the venous and lymphatic channels to the uterus.Non-restrictive examples of non-steroidal anti-inflammatory drugs suitable for use in the method of the invention include Aspirin, Ibuprofen, Indomethacin, Phenylbutazone, Bromfenac, Fenamate, Sulindac, Nabumetone, Cetorolac and Naproxen Examples of local anesthetics include Lidocaine, Mepivacaine, Etidocaine, Bupivacaine 2-Chloroprocaine Hydrochloride, Procaine and Tetracaine Hydrochloride Examples of calcium channel antagonists include Diltiazem, Israpidine, Nimodipine, Felodipine, Verapamil, Nifedipine, Nicardipine and Bepridil. Examples of potassium channel blockers include Dofetilide, E-4031, Almokalant, Sematilide, Ambasilide, Azimilide, Tedisamilo, RP58866, Sot-Alol, Piroxicam and Ibutilide. Examples of β-adrenergic agonists include Terbutaline, Salbutamol, Metaproterenol and Ritodrine. Vasodilators, which are thought to relieve spasm in the uterine muscle, include nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate. In another aspect, the method of the invention includes the combination of the pharmaceutical agent with a drug delivery system for intravaginal delivery of the agent. Examples of the medicament delivery system include a tampon device, vaginal ring, pessary, tablet, vaginal suppository, vaginal sponge, bioadhesive tablet, bioadhesive microparticle, cream, lotion, foam, ointment, solution and gel. In one embodiment, the distribution system can be a controlled release drug delivery system. Non-limiting examples of a suitable biocompatible excipient for applying the agent include a lipophilic carrier or a hydrophilic carrier. An example of a suitable carrier is a lipophilic carrier such as semi-synthetic glycerides of saturated fatty acids. Non-limiting examples of a hydrophilic carrier include polyethylene glycol having an average molecular weight of 1500, polyethylene glycol having an average molecular weight of 400 or mixtures thereof. The biocompatible excipient may also include a mucoadhesive agent such as alginate, pectin, or cellulose derivative. The biocompatible excipient may also include a penetration enhancer such as bile salts, organic solvents, ethoxydiglycol, or interesterified stone oil. In one embodiment of the invention, the excipient comprises between 60 to 90% by weight of lipophilic carrier, between 5 to 25% of mucoadhesive agent and between 5 to 20% of penetration enhancer. In another embodiment of the invention, the excipient comprises between 60 to 90% by weight of hydrophilic carrier, between 5 to 25% of mucoadhesive agent and between 5 to 20% of penetration enhancer. In another embodiment of the invention, the medicament delivery system comprises a fragrance-free standard lotion formula sold under the brand name JERGENS® lotion. ~~ In another embodiment, the biocompatible excipient may include glycerin, mineral oil, polycarbophil, carbomer 934P, hydrogenated palm oil, glyceride, sodium hydroxide, sorbic acid and purified water.

In another embodiment of the invention, the drug delivery system can be a vaginal suppository which includes 75% of SUPPOCIRE® AS2, 10% of hydroxypropyl methylcellulose and 15% of TRANSCUTOL®. In another aspect, the invention provides a device for delivering an effective amount of a pharmaceutical agent to the uterus to treat a woman suffering from dysmenorrhea. The device is an absorbent vaginal tampon having a proximal end and a distal end. Located at the distal end is a means to deliver the agent to the epithelium of the vagina. The device also includes a means for preferentially carrying the fluid discharged from the uterus-close to the proximal end of the tampon and thereby preventing contact of the fluid with the agent. The device also has a means for recovering the device, such as a thread or ribbon as used in tampons, vaginal rings and diaphragms. In one embodiment, the invention provides a buffer device for delivering a pharmaceutical agent to the uterus comprising an absorbent vaginal buffer having a proximal end and a distal end. A portion of porous foam cup-shaped at the distal end fits around the cervix of the uterus and contains a pharmaceutical agent that will be distributed to the cervix. The device may also include a non-absorbent axial tube having a distal opening and extending through the porous foam cup to the tampon to conduct blood flow to the absorbent material. A recovery thread or ribbon connected to the tampon device is also included. In another embodiment of a tampon device, the distal porous foam cup has a contour surrounding the cervix. The contour has large concentrations of medication and is placed far from the direct flow of blood which exudes from the cervix during menstruation. In another embodiment of a "tampon" device, the cup of distal porous foam has a contour surrounding the cervix.The contour has fingers that extend to the areas of the fornix around the cervix and the tips of the fingers have large concentrations of medicament and are positioned away from the direct flow of menstrual blood In another embodiment of a tampon device, a section of distal porous foam has the shape of a spoon, which only partially surrounds the cervix.The porous foam spoon is shaped of a spout which is designed to fit the posterior fornix.The porous foam spoon is designed to distribute the medication to the vaginal wall along the entire length of the porous foam spoon. - - "In another embodiment of a buffer device, the distal fibers of the tampon that have contact with the cervix have large concentrations of pharmaceutical agent to distribute it to the cervical tissue. In another embodiment of a tampon device, the tampon device has an outer tube z having perforations, the outer tube is concentric about an axial tube. The device has a section of distal porous foam which in its dehydrated state is tightened around the outer tube A bag is located proximal to the porous foam and is filled with liquid pharmaceutical agent The bag is connected to the outer tube. outer sheath covers the tampon The sheath has an annular contraction distal to the bag such that the deployment of the tampon through the distal end of the sheath causes the liquid in the bag to be forcibly removed distally through the outer tube perforated and toward the porous foam In another embodiment of a tampon device, the tampon device has an annular distribution composition around the distal end. The composition has contact with the vaginal epithelium for distribution of the agent. A non-absorbent axial tube opens distally and extends toward the tampon to conduct blood flow to the absorbent material proximal to the porous foam. The annular composition can be a suppository, foam, paste, or gel.

Embodiments of the invention may include buffer devices of a standard length, or may be longer than standard buffers to facilitate placement of the tampon device closer to or in contact with the cervix. In another aspect, the invention provides a pharmaceutically acceptable composition, in unit dose form, for intravaginal distribution to a woman for the purpose of treating dysmenorrhea. The composition consists essentially of a combination of an effective amount of a pharmaceutical agent selected from the group consisting of non-steroidal anti-inflammatory drugs, antiprostaglandins, prostaglandin inhibitors, local anesthetics, calcium channel blockers, potassium channel blockers, beta agonists. -adrenergic agents, leukotriene blocking agents, smooth muscle inhibitors and drugs capable of inhibiting the dyskinetic contraction of the muscles.The agent is combined together with a non-toxic pharmaceutically acceptable carrier.The pharmaceutically acceptable composition can be a vaginal suppository, bioadhesive tablet, bioadhesive microparticle, cream, lotion, foam, ointment, solution or gel Non-limiting examples of non-steroidal anti-inflammatory drugs suitable for use in the composition of the invention include Aspirin, Ibuprofen, Indomethacin, Phenylbutazone, Bromfenac, Fenamate, Suli ndac, Nabumetone, Cetorolac and Naproxen. Examples of local anesthetics include Lidocaine, Mepivacaine, Etidocaine, Bupivacaine, 2-Chloroprocaine Hydrochloride, Procaine and Tetracaine Hydrochloride. Examples of calcium channel antagonists include Diltiazem, Israpidin, Nimodipine, Felodipine, Verapamil, Nifedipine, Nicardipine, Piroxicam and Bepridil. Examples of potassium channel blockers include Dofetilide, E-4031, Almokalant, Sematilide, Ambasilide, Azimilide, Tedisamilo, RP58866, Sotálol and Ibutilida. Examples of β-adrenergic agonists include Terbutaline, Salbutamol, Metaproterenol and Ritodrine. Vasodilators, which are thought to relieve spasm in the uterine muscle, include nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate. In one embodiment of the invention, the composition comprises a sustained release gel. In another embodiment, the composition comprises a sustained release suppository. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a transverse representation of a part of the female reproductive organ including the uterus and the vagina in the vertical orientation.

FIG. 2 is a cross-sectional view of the side view of a part of the female reproductive organ including the uterus and the vagina. FIG. 3 is the representation of the FXG. 1 showing the placement of a vaginal suppository in a first embodiment of a drug delivery system according to the present invention. FIG. 4 is a cross-sectional representation of the side view of the vaginal area adjacent to the cervix showing the placement of a first embodiment "of a buffer medication distribution system incorporating an annular distribution composition." FIG. 5 is the representation of FIG. 2 showing the coTLocation of a second embodiment of a buffer medication distribution system according to the present invention, Figure 6 is the representation of Figure 2 showing the placement of a third embodiment of a distribution system of tampon medication incorporating a distal porous foam section Figure 7 is the representation of Figure 2 showing the placement of a fourth embodiment of a "tampon medication distribution system incorporating a distal porous foam cup. FIG. 7A is a cross-sectional view of the embodiment shown in FIG. 7, taken in the direction indicated by the Jíiechas labeled 7A in FIG. 7. FIG. 8 is an alternative to the embodiment shown in FIG. 7 in which the medicament is contained in the entire porous foam cup. FIG. 9 is the representation of FIG. 2 showing the coloration of a fifth embodiment of a buffer medication distribution system incorporating a distal suppository or a gel capsule. FIG. 9A is a cross-sectional view of the embodiment shown in FIG. 9, taken in the direction indicated by the arrows labeled 9A in FIG. 9. FIG. 10 is the representation of FIG. 2 showing the placement of a sixth embodiment of a tampon medication distribution system incorporating a cup of distal porous foam having "fingers". FIG. 10A is a side view of the distal porous foam cup. FIG. 11 is the representation of FIG. 2 showing the placement of a seventh embodiment of a "" buffer medication distribution system incorporating a porous foam section in the form of a spoon. FIG. 12 is a side view of the embodiment shown in FIG. 11. FIG. 13 is a front view of the embodiment shown in FIG. 11. FIG. 14 is the representation of FIG. 2 showing the placement of an eighth embodiment of a buffer medication distribution system incorporating distal fibers containing concentrated medicament. FIG. 15 is the representation of FIG. 2 showing the placement of a ninth embodiment of a tampon medication distribution system incorporating the nonabsorbent tube having a distal opening. FIG. 16 is the buffer medication distribution system of FIG. 15 is a dehydrated, lined state. FIG. 17 is the buffer medication distribution system of FIG. 16 showing the deployment of the tampon. DETAILED DESCRIPTION OF THE INVENTION When studying the condition of dysmenorrhoea and the lack of treatments based on drugs applied to this condition, we conclude that the limitations due to the side effects of the drugs prevented any attempt to overcome the condition by administration via standard of higher levels of medication to the patient. We believed that the problem could be overcome by focusing the delivery of drug therapy directly to the uterus via the vaginal mucosa, since the uterus is the origin of the painful symptoms of cramping of the condition. We hypothesized and now we have found that the excessively increased concentrations of therapeutic drugs suitable for treating dysmenorrhea can be obtained through the transvaginal distribution through the vaginal mucosa and we have achieved this distribution by the intravaginal application of the drugs thanks to the distribution systems of this invention. In general, the device of the invention comprises an agent for the treatment of dysmenorrhea in a non-toxic pharmaceutically acceptable carrier combined with a suitable device or distribution system which will effect the transvaginal distribution of the medicament to the uterus through the vaginal mucosa. The systems and methods of the invention have the following advantages over the oral administration of drugs: greater concentration of the drug distributed to the uterine muscle due to the localized distribution; reduction of the first pass metabolism in the liver avoiding the gastrointestinal system; provision of a continuous medication reservoir which will provide a constant distribution of medication over a long period of time; and reduction of side effects due to the low systemic concentration. For example, well-established gastrointestinal side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) do not arise with transvaginal administration as described herein. The vaginal delivery system of the drug must provide a sustained distribution of the medication to the vaginal epithelium for the treatment of dysmenorrhea. The distribution system can be a solid object distribution system such as a vaginal ring, pessary, tablet or suppository. Alternatively, it may be a paste or gel having a thickness sufficient to maintain prolonged contact with the vaginal epithelium. Alternatively, it may be a coating on a suppository wall or a sponge or other absorbent material impregnated with a liquid medicament containing, for example, solution, lotion, or suspension of bioadhesive particles. Any form of the drug delivery system that effectively delivers the treatment agent to the vaginal endothelium will be included within the scope of this invention. For the purpose of simplifying the description of the invention and not by way of limitation, a suppository medication delivery system will be described hereinafter, it being understood that all effective distribution systems will be included "within the scope of this invention. The pharmaceutical agents for use in the invention can be absorbed through the vaginal mucosa.The pharmaceutical agent is preferably selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs), prostaglandin inhibitors, local anesthetics, channel blockers. of calcium, potassium channel blockers, β-adrenergic agonists, leukotriene-blocking agents, smooth muscle inhibitors and drugs capable of inhibiting the dyskinetic contraction of muscles.The preferred NSAIDs include Aspirin, Ibuprofen, Indomethacin, Phenylbutazone, Bromfenac, Sulindac, Nabumetone, Cetorolac and Naproxen. Examples of local anesthetics include Lidocaine, Mepivacaine, Etidocaine, Bupivacaine, 2-Chloroprocaine Hydrochloride, Procaine and Tetracaine Hydrochloride. Preferred calcium channel antagonists include Diltiazem, Israpidine, Nimodipine, Felodipine, Verapamil, Nifedipine, Nicardipine and Bepridil. Preferred potassium channel blockers include Dofetilide, E-4031, Imokalant, Sematilide, Ambasilide, Azimilide, Tedisamilo, RP58866, Sotalol, Piroxicam and Ibutilide. Examples of β-adrenergic agonists include Terbutaline, Salbutamol, Metaproterenol and Ritodrine. Vasodilators, which are thought to relieve spasm in the uterine muscle, include nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate.

In order to achieve the desired release of the medicament, the active ingredient will be incorporated into an excipient (i.e., vehicle or carrier) for which the medicament has little affinity. Therefore, hydrophilic drugs will be incorporated into lipophilic carriers and lipophilic drugs will be incorporated into hydrophilic carriers. Preferred lipophilic carriers for use with hydrophilic medicaments include semi-synthetic glycerides of saturated fatty acids, particularly C8 to C18, such as SUPPOCIRE® AS2 (Gattefosse, Westwood, NJ). Preferred hydrophilic carriers, to promote the synergistic distribution of medicament, include polyethylene glycol or mixtures thereof, such as PEG 6000 / PEG 1500, or PEG 6000 / PEG 1500 / PEG 400, or PEG 6000 / PEG 400 (Sigma / Aldrich, St.

Louis, MO). The system of the invention preferably also comprises a mucoadhesive agent for bringing the drug released into solution in prolonged contact, close to the surface of the mucosa. The mucoadhesive agent is preferably a polymer such as an alginate, pectin, or cellulose derivative. Hydroxypropyl methylcellulose is particularly preferred for use in the present invention. The system of the invention may also include a penetration enhancer or absorption promoter to improve the impregnation of the medicament through the uterine mucosal barrier.The preferred absorption promoters include nonionic surfactants, bile salts, organic solvents, particularly ethoxydiglycol (for example, TRANSCUTOL® available from Gattefosse) and interesterified stone oil (for example, LABRAFIL® M 944CS available from Gattefosse). Preferred formulas for hydrophilic medicaments comprise between 60-90% by weight of lipophilic carrier, between 5-25% mucoadhesive agent and between 5-2% Absorption promoter. In a general method for preparing a formula including a hydrophilic medicament, the lipophilic carrier is melted at 45-50 ° C in a heated vessel. The mucoadhesive agent is added to the carrier with agitation. The preferred hydrophilic medicament is dissolved in the absorption promoter and the drug solution / absorption promoter is added to the carrier / mucoadhesive agent solution. The final formula is poured into molds of the desired size and shape, which are then placed in a refrigerator at 4-6 ° C. Preferred formulas for lipophilic medicaments comprise between 50-90% of hydrophilic carrier, between 5-2% of mucoadhesive agent and between 5-25% of absorption promoter. In a general method for preparing a formula including a lipophilic medicament, the hydrophilic carrier is melted at a temperature suitable for the particular PEG used in a heated container. The mucoadhesive agent is added to the carrier with agitation. The preferred lipophilic drug is dissolved in the absorption promoter and the drug / absorption promoter solution is added to the carrier / mucoadhesive agent solution. The final formula is poured into molds of the desired size and shape, which are then placed in a refrigerator at 4-6ºC. The controlled-release drug delivery system must be capable of controlled release of a drug in the vagina for several hours or more. During the menstrual cycle, the pH of the vagina changes. Drug delivery systems with stoppers for -improving absorption are included in the present invention. The distribution system should be able to function in the presence of "menstrual blood and should be easily removable, for example, attached to a thread or tape." Solid-phase drug carriers are preferred, since carriers that dissolve or they can be diluted by menstrual blood.The advantages of a solid carrier include: 1) it does not increase the sucredad; 2) the carrier will not encourage the overgrowth of bacteria with the menstrual blood present; 3) the carrier can be washable or reusable (eg, vaginal ring). The controlled release drug delivery system can be in the form of, for example, a tampon-like device, vaginal ring, pessary, tablet, paste, suppository, vaginal sponge, bioadhesive tablet, bioadhesive microparticles, cream, lotion, foam, ointment, or gel. Later each of these systems is discussed. FIG. 1 is a transverse representation of a part of the female reproductive organ, including the uterus and vagina in the vertical orientation and FIG. 2 is a transverse representation of the side view thereof. The uterus 2 is a muscular organ that surrounds the matrix 4 and opens in the cervix 5 through the cervical canal or cervical orifice 6. The vagina 8 is defined by a muscular tube 10 that goes from the lower lips 12 and the lips greater 14 to the cervix 5. The local vasculature associated with the walls of the vagina 8 communicate with the vascular and lymphatic systems of the uterine muscle (not illustrated). FIG. 3 is a transverse representation of FIG. 1 showing the placement of a suppository 16 in the vagina 8 in a position that introduces the drugs intravaginally to the uterus "72 by means of the vascular and vascular lymphatic systems (not illustrated). Referring now to FIGS. 4-12, various embodiments of tampon-like devices being described which can be used to deliver medicaments for the treatment of dysmenorrhea according to the invention. If a device similar to the buffer is used, there are numerous methods by which a drug can be incorporated into the device. For example, the medicament can be incorporated into a bioadhesive reservoir similar to a gel at the tip of the device. Alternatively, the medicament may be in the form of a powder material placed at the tip of the tampon. The drug can also be absorbed into fibers at the tip of the buffer, for example, by dissolving the drug in a pharmaceutically acceptable carrier and absorbing the drug solution in the buffer fibers. The medication can also be dissolved in a coating material which is applied to the tip of the tampon. Alternatively, the drug can be incorporated into a insertable suppository which is placed in association with the tip of the tampon. The tampon-like device can be constructed to improve drug distribution. For example, the tampon can be molded to fit the area of the posterior fornix and pubic symphysis and constructed to open up to have a maximum surface area of contact for drug distribution. If the medication is in a reservoir on the surface of the device, the shape of the device should be such that it can maintain the reserve towards an orientation of the vaginal mucosa for better predictable characteristics of the release of the medication. The tampon device may also be constructed to have a variable absorption profile. For example, the drug array at the tip of the tampon device could be different from the area of the proximal area in order to force the medicament to diffuse to the tissue and not to the absorbent part of the tampon. Alternatively, there could be a non-absorbent channel around the cervix for the first centimeter or in order to prevent the menstrual flow from taking the composition of the medication. The release of medication from the tampon device must be synchronized to provide "an adequate concentration of the medicament to the uterus during a normal period of use of a tampon device, generally 1-8 hours." Fig. 4 is a transverse representation of the vaginal area, adjacent to the cervix 5, with a first embodiment of a tampon medication distribution system according to the invention The tampon device 22 comprises an absorbent cylindrical tampon 24 consisting of fibrous material, for example cotton, having around its distal end 26 an annular distribution composition 28. The tampon device 22 places the annular distribution composition 28, maintained around the distal end 26 of the tampon device 22, against the "superior" epithelium. of the vagina 8 and posterior fornix 20 for "distribution through the vaginal surfaces in which the annular composition 28 is in contact. The annular composition 28 can be an annular suppository, foam, paste, or gel composed of "suitable distribution components." Since dysmenorrhea occurs "adjust before and" during menstruation, the discharge from the uterus is absorbed by the tampon 24 thereby avoiding The composition of the treatment is carried out, FIG.5 is a transverse representation of the vaginal area adjacent to the cervix 5 with a second embodiment of a buffer medication distribution system according to the invention. buffer 32 includes a non-porous tube 34 which communicates with the cervical orifice 6 for distribution of the menstrual discharge from the cervical orifice to an absorbent cylindrical tampon 36 comprised of fibers, eg cotton, to absorb the discharge. The tube 34 prevents contact of the discharge with an annular medicament distribution composition 38. FIG. 6 is a transverse representation of the vaginal area adjacent to the cervix 5 with a third embodiment of a buffer medication distribution system according to the invention. In FIG. 6, the tampon device 42 includes a section of distal porous foam 43 which has the shape of a cup in the expanded state. At the center of the porous foam section 43 is a non-porous tube 44 which will conduct the blood flow to the absorbent pad 45 proximal to the porous foam section 43. The porous foam is preferably a soft, lightweight foam material Physiologically inert polyurethane, polyester, polyether (eg, as described in U.S. Patent Number 4,309,997) or other material such as collagen (e.g., as described in U.S. Patent No. 5,201,326). The axial tube is preferably a physiologically inert non-absorbent material, such as rubber or plastic and can be coated on its inner surface with an anticoagulant The proximal end 46 of the tube 44 has a plastic clip 47 to which a wire 48 can be tied. for removing the tampon device 42. The porous cup-shaped foam section 43 fits around cervix 5 of uterus 2 and contains medicament which can be distributed to the cervical tissue.

FIG. 7 is a cross-sectional representation of the vaginal area adjacent to cervix 5 with a fourth embodiment of a buffer medication distribution system according to the invention. In FIG. 7, the tampon ce 52 includes a cup of distal porous foam 54 and a proximal absorbent pad 56. The porous foam cup 54 has a contour 58 which surrounds the cervix 5 and which contains high concentrations of medicament. The contour area 58 of the porous foam cup 54 is far from the direct flow of blood. The tampon ce 52 includes a wire 59 for removing the tampon ce 52. FIG. 7A is a cross-sectional view of the embodiment shown in FIG. 7, taken in the direction indicated by the arrows labeled 7A in FIG. 7. As illustrated in FIG. 7A, the contour area 58 forms a ring which contains a large concentration of medicament. Alternatively, as illustrated in FIG. 8, the entire porous foam cup 55 may contain medicament, not only in the area of the ringed tip 59 near the cervix 5. FIG. 9 is a transverse representation of the vaginal area adjacent to cervix 5 with a fifth embodiment of a buffer medication distribution system according to the invention. In FIG. 9, the tampon ce 62 includes a proximal absorbent pad 64 and a distal section 66 which comprises a suppository or dissolvable gel capsule 67 filled with liquid medicament. The medicament prior to the dissolution or release of the liquid is "threaded" to allow blood to pass through the center of the buffer 64. The buffer ce 62 includes annular is only an approximate description of the shape created by the dispensing ces of liquid or semi-solid medication placed around a cylinder and in contact with the epithelium of the adjacent vaginal wall and all forms that conform to the vaginal epithelium and external cervical surfaces will be included within the term "annular" and will be indicated by it. In addition, the use of the term "annular" does not restrict the invention to the use of said ces which surround the entire cervix (i.e., 360 degrees). ces that cover an angle of less than 360 degrees, but that have sufficient contact with the vaginal epithelium to supply sufficient amount of the medicament are within the scope of the invention. The medicament distribution annular composition 28, 38 may be an absorbent material that expands in the presence of body fluid or heat to completely fill the space between tampon 22, 32 and vaginal epithelium 18. FIG. 11 illustrates the drug delivery ce having an annular shape which does not completely surround the entire cervix. FIG. 11 is the representation of FIG. 2 showing the positioning of a seventh embodiment of a tampon ce 80 incorporating a porous foam section in the shape of a spoon 85. FIG. 12 is a side view of the tampon ce 80 and FIG. 13 is a front view of the tampon ce 80. The porous spoon-shaped foam section 85 is annular in shape, but does not completely encircle the cervix 5. Rather, the porous foam section in the form of a spoon has a pointed tip in it. peak shape 81 which is designed to fit the posterior fornix 20. The porous foam section 85 is designed to distribute the medicament to the vaginal wall along the entire length of the porous foam section of spoon 85. FIG. 14 is a cross-sectional representation of the vaginal area adjacent to cervix 5 with an eighth embodiment of a buffer medication distribution system according to the invention. In FIG. 14, "the tampon ce 82 comprises an absorbent pad 84. The section 86 of the tampon 84 which rests against the cervix 5 contains high concentrations of medicament." When the fibers absorb the fluid, the buffer 84 expands around the cervix 5 and distributes the medicament to the tissue. The blood will be taken to proximal sections of the tampon 84 when the fibers become more absorbent in this area. The buffer device 82 includes a wire 88 for removing the tampon device 82. The cylindrical carton boxes or suitable inserter tubes which aid in the insertion and storage of the buffer systems of the present invention will be apparent to experienced persons. in the technique of tampon construction. The examples are described in Patent Numbers 4,3178,447; 3,884,233; and 3,902 / 93 of the "U.S.A. In general practice, a drug delivery buffer device as described herein is placed in the vagina and the inserter tube is removed." The tampon device touches the inner wall of the device. The vagina and penetration enhancer and mucoadhesive act to facilitate the absorption of the drug into the local vasculature, which results in a higher concentration of the drug that is delivered to the uterine muscle where it acts to decrease the pain of dysmenorrhea. 15 is a transverse representation of the vaginal area adjacent to the cervix 5 with a ninth embodiment of a tampon medication distribution system according to the invention In Fig. 15, the tampon device 92 includes a distal foam section porous 93 which, in its dehydrated, lined state (FIG 16), is tightened around a perforated outer tube 94. The outer tube pierces 94 is connected to a proximally located bag 96 which is filled with liquid medicament (not illustrated). Inside the perforated outer tube 94 is a concentric inner tube 95 which provides a path for blood to flow to an absorbent pad 97 which is proximal to the porous foam section 93. Prior to insertion, the buffer device 92 is covered in a sheath 98 which is narrow at the bottom 99 between the porous foam section 93 and the bag 96 so that, when the tampon device 92 is unfolded and the sheath 98 moves over the bag 96, the medicament is forcibly removed 101 through perforated outer tube 94 to porous foam section 93 (FIG 17). The buffer device 92 includes a wire 102 for removing the "buffer 92" device. Another example of a controlled release drug delivery system for the present invention is the vaginal ring.The vaginal rings generally consist of an inert elastomer ring. covered by another layer of elastomer containing the drug that will be supplied The rings can be easily inserted, left in place for the desired period of time (for example, up to 7 days) and then removed by the user. Optionally, a third outer layer of elastomer which controls the variation which does not contain medicament.Optionally, the third ring may contain a second medicament for a double release ring.The medicament can be incorporated into the polyethylene glycol throughout the silicone elastomer ring to act as a reserve for the medication to be delivered. etas and suppositories are other examples of drug delivery systems which can be used in the present invention. These systems have been used to deliver vaginal medications and steroids and have been widely described in the literature. Another example of a distribution system is the vaginal sponge. The desired pharmaceutical agent can be incorporated into a silicone matrix which is coated on a cylindrical vaginal sponge of drug-free polyurethane, as "described in the literature." Bioadhesive tablets are another drug delivery system. hydroxypropyl and polyacrylic acid.They release drugs for up to five days once they are placed in the proper formula.The bioadhesive microparticles are still another drug delivery system suitable for use in the present invention.This system is a liquid or semi-solid preparation of multiple phases which does not drain from the vagina like many current suppository formulas.

The substances adhere to the vaginal wall and release the medication for a period of several hours.

Many of these systems were designed for "nasal use but may also be used in the vagina (for example, US Pat. No. 4,756,907) .The system may comprise microspheres with an active medicament and a surfactant to improve the absorption of the medicament. Microparticles have a diameter of 10-100 μm and can be prepared from starch, gelatin, albumin, collagen, or dextran.The drug can also be incorporated into creams, lotions, foams, pastes, ointments and "gels" which can be applied to the vagina using an applicator The processes for preparing pharmaceutical products in cream, lotion, foam, paste, ointment and gel can be found throughout the literature. An example of a suitable system is a standard formula of fragrance-free lotion containing glycerol, ceramides, mineral oil, petrolatum, parabens, fragrance and water as the product sold under the trademark JERGENS® (Andrew Jergens Co., Cincinnati, OH) . This formula was used by Hargrove et al. (Extract Number 97,051, American Menopause Society, Boston, MA, September 1997) for transcutaneous estradiol and progesterone delivery. Pharmaceutically acceptable non-toxic systems suitable for use in the compositions of the present invention will be apparent to those skilled in the art of pharmaceutical formulations and the examples are described in REMINGTON 'S PHARMACEUTICAL SCIENCES, 19th Edition, A.R. Gennaro, ed. 1995. The choice of suitable carriers will depend on the exact nature of the particular vaginal dosage form desired, for example, whether the active ingredient or ingredients are formulated in a cream, lotion, foam, ointment, paste, solution, or gel, as well as the identity of the active ingredients. In practice, the drug delivery systems of the invention are applied several hours before or just after the onset of menstruation in order to treat or prevent dysmenorrhea. Treatment would continue for a few hours to 2 or 3, as needed, to relieve and prevent painful menstruation and symptoms such as "nausea, fatigue, diarrhea, low back pain and headache." Other characteristics of the invention will be apparent in the course of the following descriptions "of" exemplary embodiments which are provided for "illustration of the invention and are not intended to limit same. All references cited herein are incorporated by reference herein in their entirety. The procedures described in the past tense in the following examples have been carried out in the laboratory. The procedures described in the present tense have not been carried out in the laboratory and are constructively reduced in practice with the presentation of this application. EXAMPLE 1 Preparation of Verapamil Vaginal Suppository The dose of Verapamil (Sigma / Aldrich, St. Louis, MO) was Q.15-0.6 mg / kg body weight. Radiolabeled Verapamil (4-7 μCi) was added to the unlabeled compound. Vaginal suppositories were formulated and prepared 24 hours before each experiment. The three basic ingredients for the suppositories were SUPPOCIRE® AS2 (Gattefosse, Westwood, NJ) (75% by weight); hydroxypropyl methylcellulose (e.g., METHOCEL® K, HPMC K15M) (Dow Chemical, Midland, MI) (10% by weight), a mucoadhesive agent; and TRANSCUTOL® (Gattefosse) (15% by weight). To make eight suppositories, we weighed 4.5 grams of SUPPOCIRE, 600 mg of HPMC, 900 mg of TRANSCUTOL, the calculated dose of the drug and its labeled counterpart. SUPPOCIRE was melted in a disposable 100 mL polypropylene laboratory beaker suspended in 50 ° C water. The solution was stirred until it completely melted. Then HPMC and TRANSCUTOL were added and mixed. Finally, the unlabeled drug and the radioactively labeled drug were added to the hot solution. The hot mix was quickly poured into TYGON® tube molds (available from Fisher Scientific, Pittsburgh, PA) (2-c lengths), the tube held upright on an ice-cooled glass plate.

The suppositories were kept refrigerated until their use. The suppository was weighed before each experiment to determine the actual dose of the medication. EXAMPLE 2 Preparation of Indomethacin Vaginal Suppository 1.3C-Indomethacin was obtained from Amersham Life Science, Arlington Hts., IL. The dose of cold indomethacin (Sigma / Aldrich) was 0.2 mg / kg body weight. The labeled Indomethacin (4-7 μCi) was added to the cold compound. All the other steps in the preparation of the Indometacin suppository are identical to the steps in Example 1, replacing Verapamil with Indomethacin. EXAMPLE 3 Verapamil Pharmacokinetic Experiments 3H-Verapamil was obtained from DuPont / NEN, Boston, MA. Before intravenous injection, cold Verapamil (Sigma / Aldrich, St. Louis, MO) (0.15-0.6 mg / kg body weight, intravenously) was dissolved in 0.5 mL dimethyl sulfoxide sulfoxide (Syntex, West Des Moines, IA ). Then the labeled Verapamil (4-7 μCi) was added to the cold compound just before the intravenous injection. They obtained cspe "j" ace white from New Zealand weighing 2. 8 to 3.5 kg of Myrtle Rabbitry (Thompson Station, TN). The rabbits were kept in a facility approved by the National Institutes of Health and acclimated to their environment at least 48 hours before each experiment. Pharmacokinetic studies of the drug were carried out by means of both intravenous and transvaginal administration. During the first series of experiments, the intravenous route of administration was used to "determine the initial half-lives of the experimental compound.In the second series of experiments, the intravenous and transvaginal routes of administration were compared in the same rabbit. After 18 hours, each rabbit was given ketamine (35 mg / kg, intramuscular), xylazine (5 mg / kg, intramuscular) and atropine (0.5 mg, intramuscular), each rabbit was intubated and anesthesia was maintained with isoflurane ( 1-3%) The vital signs were monitored throughout the experiment by means of an impulse oximeter, the body temperature of the rabbits was kept constant by a recirculating heating pad, and intravenous access was achieved by placement of a catheter. caliber 22 TEFLON in the peripheral vein of the ear, intra-arterial access was achieved by placing a 22-gauge TEFLON catheter in the peripheral artery in the ear A heat lamp was used to warm the ears in order to promote peripheral blood flow. After the rabbit was anesthetized, the mixture containing the labeled and unlabeled drug was injected through the vein of the ear for a period of 10 seconds to 2 minutes. The blood samples were taken through the arterial line in 0.1, 0.25, 0.5, 0.7"5, 2, 4, 6, 8, 10, 12 and 24 hours" in relation to the injection time. Blood samples (1 mL) were placed in a polypropylene tube containing EDTA. The blood was centrifuged at 2000 rpm for 10 minutes and 0.5 mL of plasma was placed in a scintillation vial. Biopsies of uterine muscle were obtained. 0.1 to 0.2 gm in 0.2, 0.35, 0.5, 0.75, 2, 4 and 6 hours in relation to the administration of the medicine of the uterine horn through a transverse laparotomy. For comparative purposes, biopsies of the internal rectus muscle of the thigh were taken in 1.5 and 6 hours in relation to the administration of the drug.The tubes were sacrificed with pentobarbital at the end of this experiment.

(Packard, Meridian, CT) to the plasma samples and the samples were shaken for 30 seconds. 10 mL of Hionic-Fluor scintillation cocktail (Packard) were added and the samples were shaken for 1 minute. 1 mL of tissue solubilizer was added to the tissue samples which were then placed in a water bath at 50 ° C for incubation overnight. 10 mL of scintillation cocktail (Packard) was added and the samples were shaken for 1 minute, after all the samples were put on the scintillation counter. After the rabbit was anesthetized, the marked drug was injected through the vein of the ear as described above and blood samples were taken at 0.1, 0.25, 0.5, 0.75, 2, 4 and 6 hours in relation to "the" intravenous injection, the rabbit was allowed to recover "and ~" a 7-day wash was performed before vaginal administration, vaginal suppositories were formulated and kept on ice, the suppository was introduced into the vagina of the rabbit using the body of a plastic transfer pipette (Baxter, McGaw Park, IL) and a tuberculin syringe as the plunger to load the suppository into the vagina at a depth of 7 to 8 cm. in 0.1, 0.25, 0.5, 0.75, 2, 4 and 6 hours in relation to the administration of the suppository Biopsies of the uterine muscle and internal rectus muscle of the thigh were also obtained during the same time intervals using techniques as previously described. ad performed Verapamil as in Example 3. As shown in Table 1, blood levels persisted for a prolonged period of time and the effect of concentration on the uterine muscle averaged up to 3.5 times the effect on the internal rectus muscle of the thigh in several intervals. Table 1 is a summary of mean concentration ratios after intravaginal administration of Verapamil or Indomethacin. TABLE 1 Relationships Median Concentration (mcg / mL) After Vaginal Administration Medication O.? 5 hours: 1.5 hours: 6 hours: Verapamil (n = 5) Blood / Uterus 0.72 0.67"" 1.51" Blood / Leg 1.52 1.58"" 1.75" Uterus / Leg 2.67 3.16 1.40 Indomethacin (n = 2) Blood / Uterus 2.20 2.30 2.30 Blood / Leg 10.40 9.10 10.70 Uterus / Leg 4.75 4.00 4.70 Indomethacin was administered by means of the methods described above, replacing Verapamil with Indomethacin. The results (Table 1) showed that the ratio of the concentration of uterus and internal rectus muscle of the thigh was 4 or 5 showing that after vaginal administration there were higher concentrations in uterine tissue than in skeletal muscle (internal rectus muscle). of the thigh). The results support the concept of selective and local distribution and absorption. - - - EXAMPLE 4 Preparation of a Solution Containing Naproxen for Intravaginal Application Combine 120 mg of Naproxen with 10 mg of Tween 80.

That mixture is then combined with an amount of isotonic saline solution sufficient to bring the total volume of the solution to 50 mL. The solution is sterilized by being passed through a Millipore filter of 0.2 mi eras. EXAMPLE 5 Preparation of a Gel Containing Naproxen for Intravaginal Application _ 250 mL of isotonic saline is heated at 80 ° C and 1.50 grams of Methocel are added with stirring. The resulting mixture is allowed to stand at room temperature for 2 hours. Then 120 mg of Naproxen are mixed together with 10 mg of Tween 80. The mixture of Naproxen / Tween and an amount of isotonic saline sufficient to bring the total volume to 500 mL are added to the gel and mixed well. EXAMPLE 6 Preparation of a Lotion Containing Indomethacin for Intravaginal Application Indometacin (1-7378, Sigma / Aldrich, St. Louis, MO) (50 mg) is added to 1 mL of JERGENS® fragrance-free standard lotion. EXAMPLE 7 Preparation of Gel Containing Ibuprofen for Intravaginal Application Ibuprofen (1-4883, Sigma / Aldrich, St. Louis, MO) (200 mg) to 1 mL of gel consisting of the following ingredients: glycerin, mineral oil, polycarbophil, carbomer 934P, hydrogenated palm oil, glyceride, sodium hydroxide, sorbic acid and purified water.

EXAMPLE 8 Preparation of Vaginal Suppositories A vaginal suppository is prepared for intravaginal administration of each of the following medications at the indicated dose: Aspirin (975 mg), Piroxicam (20 mg), Indomethacin (50 mg), Fenamate (500 mg), Sulindac_ (200 mg), Nabumetone (750 mg), Cetorolac (10 mg), Ibuprofen (200 mg), Phenylbutazone (50 mg, P-8386, Sigma), Bromfenac (50 mg), Naproxen (550 mg), Lidocaine ( 100 mg), Mepivacaypa (0.2 mg), Etidocaine (200 mg), Bupivacaine (100 mg), 2-chloroprocaine hydrochloride (100 mg), Procaine (200 mg, P-9879, Sigma), tetracaine hydrochloride (20 mg). mg, T-7508, Sigma) / Diltiazem (60 mg), Israpidine (10 mg), Nimodipine (30 mg), Felodipine (450 mg), Nifedipine (90 mg), Nicardipine (30 mg), Ritodrine (150 mg) , Bepridil (300 mg), Dofetilide (1 mg), "E-4031 (1 mg), Almokalant (1 mg), Sematilide (1 mg), Ambasilide (1 mg), Azimilide (1 mg), Tedisamil (100 mg) ), RP58866 (100 mg), Sotalol (240 mg), I Butylide (1 mg), Terbutaline (5 mg), Salbutamol (1 mg), Metaproterenol sulfate (20 mg), Nitroglycerin (3 mg), Isosorbide dinitrate (40 mg) and Isosorbide mononitrate (120 mg). All steps in the preparation of the medicament suppository are identical to the steps of Example 1 except that no radiolabelled compound is used and the indicated amount of medicament is used in place of Verapamil.

The amount of the vaginal dosage form required to deliver the desired dose will of course depend on the concentration of the active ingredient in the composition.The range of therapeutic doses for vaginal administration of the compositions of the present invention will vary with the size of the composition. EXAMPLE 9 Preparation of Other Compositions A "composition for vaginal administration of each of the following medications in the indicated dose will be prepared: Aspirin (975 mg), Piroxicam (20 mg), Indomethacin (50 mg), Fenamate (500 mg), Sulindac (200 mg), Nabumetone (750 mg), Cetorolaa _ (10 mg), Ibuprofen (200 mg), Phenylbutazone (50 mg, " P-8386, Sigma), Bromfenac (50 mg), Naproxen (550 mg), Lidocaine (100 mg), Mepivacaine. (0.2 mg), Etidocaine (200 mg), Bupivacaine (100 mg), 2-chloroprocaine hydrochloride ( 100 mgf, Procaine (200 mg, "P-9879, Sigma), tetracaine hydrochloride (20 mg, T-7508, Sigma), Diltiazem (60 mg), Israpidine (10 mg), Nimodipine (30 mg), Felodipine ( 450 mg), Nifedipine (90 mg), Verapamil (120 mg), Nicardipine (30 mg), Rittoin (150 mg), Bepridil (300 mg), Dofetilide (1 mg), E-4031 (1 mg), Almokalant ( 1 mg), Sematilide (1 mg), Ambasilide (1 mg), Azimilide (1 mg), Tedisamil (100 mg), RP58866 (100 mg), Sotalol '"(240 mg), Ibutilide (1 mg), Terbutaline ( 5 mg), Salbutamol (1 mg), Metaproterenol sulfate (20 mg), nitroglycerin (3 mg), isosorbide dinitrate (40 mg) and isosmon mononitrate rbide (120 mg). Each of the medicaments included in this example is substituted in Example 4, 5, 6 or 7, unless previously described, and the repetition of the procedures detailed therein provides other compositions "according to the invention. The form of vaginal dosage required to deliver the desired dose will of course depend on the concentration of the active ingredient in the composition.The range of therapeutic doses for intravaginal administration of the compositions of the present invention will vary with the size of the patient. invention has been described in terms of several preferred embodiments, the experienced creator will appreciate that various modifications, substitutions, omissions and additions can be made without deviating from his spirit.Accordingly, it is intended that the scope of the present invention is limited only by the scope of the following claims.

Claims (1)

1. CLAIMS A method for treating a woman suffering from "dysmenorrhea comprising: contact of the vaginal epithelium of a woman with a composition" consisting essentially of a pharmaceutical agent and a non-toxic pharmaceutically acceptable excipient which promotes the delivery of the pharmaceutical agent to through the vaginal epithelium, the selected pharmaceutical agent, from the group consisting of non-steroidal anti-inflammatory drugs, antiprostaglandins, prostaglandin inhibitors, local anesthetics, calcium channel blockers, potassium channel blockers, β-adrenergic agonists, leukotriene-blocking agents , smooth muscle inhibitors, vasodilators and drugs capable of inhibiting the dyskinetic contraction of the muscles, the amount of the composition applied to the vaginal epithelium being sufficient to deliver a therapeutically effective dose of the agent to the uterine muscle of the female. A method of claim 1 wherein the pharmaceutical agent can be absorbed through the vaginal mucosa. A method of claim 1 wherein the non-steroidal anti-inflammatory drugs are selected from the group consisting of Aspirin, Ibuprofen, Indomethacin, Phenylbutazone, Bromfenac, Fenamate, Sulindac, Nabumetone, Cetorolac and Naproxen; wherein the local anesthetics are selected from the group consisting of Lidocaine, Mepivacaine, Etidocaine, Bupivacaine, 2-Chloroprocaine Hydrochloride, Arocaine "and Tetracaine Hydrochloride, wherein the calcium channel antagonists are selected from the group consisting of Diltiazem , Israpidine, Nimodipine, Felodipine, Verapamil, Nifedipine, Nicardipine and Bepridil, where the potassium channel blockers are selected from the group consisting of Dofetilide, E-4031, Almokalant, Sematilide, Ambasilide, Azimilide, Tedisamilo, RP58866, Sotalol, Piroxicam and Ibutilida, wherein the β-adrenergic agonists are selected from the group consisting of Terbutaline, Salbutamol, Metaproterenol and Ritodrine, and wherein the vasodilators are selected from the group consisting of nitroglycerin, isosorbide dinitrate and isosorbide mononitrate. The method of claim 1 wherein the agent is combined with a selected drug delivery system. of the group consisting of a tampon device, vaginal ring, pessary, tablet, suppository, vaginal sponge, bioadhesive tablet, bioadhesive microparticle, cream, lotion, foam, paste, ointment, solution and gel. 5. A method of claim 4 wherein the drug delivery system is a controlled release drug delivery system. 6. A method of claim 1 wherein the excipient comprises a carrier selected from a lipophilic carrier and a hydrophilic carrier. 7. A method of claim 6 wherein the lipophilic carrier comprises semi-synthetic glycerides of saturated fatty acids. 8. A method of claim 6 wherein the hydrophilic carrier is selected from the group consisting of 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 and mixtures thereof. 9. A method of claim 6 wherein the excipient includes a mucoadhesive agent selected from the group consisting of alginate, pectin and cellulose derivative. 10. A method of claim 6 wherein the excipient includes a penetration enhancer selected from the group consisting of bile salts, organic solvents, ethoxydiglycol and interesterified stone oil. 11. A method of claim 1 wherein the excipient comprises between 60 to 90% by weight of lipophilic carrier, between 5 to 25% of mucoadhesive agent and between 5 to 20% of penetration enhancer. A method of claim 1 wherein the excipient comprises between 60 to 90% by weight of hydrophilic carrier, between 5 to 25% of mucoadhesive agent and between 5 to 20% of penetration enhancer. A method of claim 4 wherein the medicament distribution system comprises a lotion formula consisting of glycerol, ceramides, mineral oil, petrolatum, parabens, fragrance and water. A method of claim 1 wherein the excipient is composed of glycerin, mineral oil, polycarbophil, carbomer 934P, hydrogenated palm oil, glyceride, sodium hydroxide, sorbic acid and purified water. The medicament distribution system comprises a vaginal suppository consisting of 75% hydrophilic carrier, 10% hydroxypropyl methylcellulose and 15% penetration enhancer, A method of claim 13 wherein the pharmaceutical agent is Verapamil. Claim 13 wherein the pharmaceutical agent is Indomethacin. A method of claim 13 wherein the pharmaceutical agent is Naproxen. A method of claim 13 wherein the pharmaceutical agent is nitroglycerin. A pharmaceutically acceptable composition, in dosage unit form, for intravaginal distribution to a woman for the purpose of treating dysmenorrhea, the composition consisting essentially of a combination of an effective amount of a pharmaceutical agent selected from the group consisting of non-steroidal anti-inflammatory drugs , antiprostaglandins, prostaglandin inhibitors, local anesthetics, calcium channel blockers, potassium channel blockers, β-adrenergic agonists, leukotriene-blocking agents, smooth muscle inhibitors, vasodilators and drugs capable of inhibiting the dyskinetic contraction of muscles, together with a non-toxic pharmaceutically acceptable carrier therefor, the composition selected from the group consisting of a vaginal suppository, bioadhesive tablet, bioadhesive microparticle, cream, lotion, foam, ointment, paste, solution and gel. A composition according to claim 20 wherein the non-spheroidal anti-inflammatory drugs are selected from the group consisting of Aspirin, Ibuprofen, Indomethacin, Phenylbutazone, Bromfenac, Fenamate, Sulindac, Nabumetone, Cetorolac and Naproxen; wherein the local anesthetics are selected from the group consisting of Lidocaine, Mepivacaine, Etidocaine, Bupivacaine, 2-Chloroprocaine Hydrochloride, Procaine and Tetracaine Hydrochloride; wherein the calcium channel antagonists are selected from the group consisting of Diltiazem, Israpidin, Nimodipine, Felodipine, Verapamil, Nifedipine, Nicardipine and Bepridil; wherein the potassium channel blockers are selected from the group consisting of Dofefilide, E-4031, Almokalant, Sematilide, Ambasilide, Azimilide, Tedisamilo, RP58866, Sotalol, Piroxicam and Ibutilida; wherein the β-adrenergic agonists are "selected from the group consisting of Terbutaline, Salbutamol, Metaproterenol and Ritodrine, and wherein the vasodilators are selected from the group consisting of nitroglycerin, isosorbide dinitrate and isosorbide mononitrate. claim 20, the composition comprising a sustained release gel, a composition according to claim 20, the composition comprising a sustained release vaginal suppository. 24. A device for distributing a pharmaceutical agent to a female uterus, the device comprising a tampon, a porous foam cup, attached to the tampon and configured to fit around the cervix of the uterus, and a non-absorbent axial tube extending through the cup. of porous foam towards the buffer, the tube having a first opening arranged to receive the flow of the uterus and a second opening arranged to distribute the flow to the tampon. 25. A composition according to claim 24, wherein the porous foam cup has a contour which, in use, surrounds the cervix. 26. A device according to claim 25, wherein the contour comprises fingers extending toward the fornix areas around the cervix. 27. A device according to claim 24, wherein the contour contains the pharmaceutical agent. 28. A device according to claim 24, wherein the contour is positioned away from the direct flow of fluid from the uterus. 29. A device according to claim 29, wherein the porous foam cup contains the pharmaceutical agent when the device is inserted into the vagina of a woman. A device according to claim 24, comprising an injection means for injecting the pharmaceutical agent into the porous foam after the device has been inserted into the vagina of a woman. A device according to claim 31, wherein the injection means comprises a reservoir containing the pharmaceutical agent. A non-absorbent dispensing tube having a first opening connected to the reservoir for receiving the reservoir pharmaceutical agent and at least one second reservoir. opening arranged to distribute the pharmaceutical agent to the porous foam cup and Medium to force the pharmaceutical agent from the reserve, through the distribution tube, to the porous foam. A device according to claim 31, wherein the dispensing tube comprises a wall having a plurality of perforations arranged to distribute the pharmaceutical agent to the porous foam cup. A device according to claim 24, wherein the pharmaceutical agent is selected to prevent or treat dysmenorrhea. 34. A device for distributing a pharmaceutical agent to the female uterus, the device comprising a buffer configured to have physical contact with the cervix of the uterus, the buffer containing the pharmaceutical agent. 35. A device according to claim 34, wherein the tampon comprises absorbent fibers which contain the pharmaceutical agent and, in use, have contact with the cervix. 36. A device according to claim 34, wherein the pharmaceutical agent is selected to prevent or treat dysmenorrhea. 37. A device for distributing a pharmaceutical agent to the female uterus, the device comprising a buffer, the buffer including an annular distribution means for touching the epithelium of the vagina for distribution of the pharmaceutical agent. 38. A device according to claim 37, comprising a non-absorbent axial tube extending towards the tampon, the tube having a first opening arranged to receive the flow of the uterus and a second opening arranged to distribute the flow to the tampon. 39. A device according to claim 37, wherein the annular distribution means comprises one of the following: annular suppository, foam, paste and gel. A device according to claim 37, wherein the pharmaceutical agent is selected to prevent or treat dysmenorrhea. A device for distributing a pharmaceutical agent to the female uterus, the device comprising absorbing medium to absorb the fluid discharged from the uterus, distribution means for distributing the pharmaceutical agent and transfer medium to carry preferably the fluid discharged from the uterus to the absorption medium and in this way avoid contact of the fluid with the pharmaceutical agent. A device according to claim 41, wherein the absorption means comprises a buffer. A device according to claim 42, wherein the distribution means comprises one of the following: suppository, foam, paste and gel annularly arranged around the tampon and configured to distribute the pharmaceutical agent to the epithelium of the vagina. A device according to claim 42, wherein the transfer means comprises a non-absorbent axial tube extending towards the tampon, the tube having a first opening arranged to receive the