Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1998-05-15
2001-03-06
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S431000, C424S432000, C424S434000, C424S443000
Reexamination Certificate
active
06197327
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns devices, methods, and compositions for treating dysmenorrhea by intravaginal administration of therapeutic and/or palliative drugs 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 to account for the pain, whereas only a biochemical imbalance is responsible for primary dysmenorrhea. Primary dysmenorrhea affects 50 percent of postpubescent women, and absenteeism among severe dysmenorrheics has been estimated to cost about 600 million lost working hours or over 2 billion dollars annually. Thus, an effective, simple, and safe treatment of primary dysmenorrhea over a period of several days during menstruation will not only enhance the quality of life for sufferers of dysmenorrhea, but will have a positive economic impact.
The pain of dysmenorrhea originates in the uterus. Systemic administration of analgesic drugs generally by the oral route to the patient has not successfully relieved the condition in many women and the administration is frequently limited by side effects. We believe this failure is the result of a failure to achieve an effective dosage level of the analgesic to the muscle in the uterus.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide devices, methods and compositions for treating dysmenorrhea by intravaginal delivery of effective doses of drug to the uterus by transvaginal transport to the uterus, that is, into the uterus via lymphatic and venous channels after absorption through the vaginal mucosa.
It is another object of the present invention to provide safe and convenient devices, methods, and compositions which will promote effective localized transvaginal delivery of drugs which are effective to treat dysmenorrhea.
It is another object of this invention to provide pharmaceutically acceptable compositions which will promote effective intravaginal delivery for the purpose of preventing or treating dysmenorrhea.
In one aspect, the present invention provides a method for treating a human female suffering from dysmenorrhea comprising contacting the vaginal epithelium of the female with a pharmaceutical agent selected from the group consisting of nonsteroidal anti-inflammatory drugs, anti-prostaglandins, prostaglandin inhibitors, local anesthetics, calcium channel blockers, potassium channel blockers, &bgr;-adrenergic agonists, leukotriene blocking agents, smooth muscle inhibitors, vasodilators, and drugs capable of inhibiting dyskinetic muscle contraction. 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 attain a therapeutically effective amount of the agent in the uterine muscle of the individual upon intravaginal application of the combination. In the preferred embodiment, the agent is absorbable through the vaginal mucosa and thereby transmitted via venous and lymphatic channels to the uterus.
Non-limiting examples of nonsteroidal anti-inflammatory drugs suitable for use in the method of the invention include Aspirin, Ibuprofen, Indomethacin, Phenylbutazone, Bromfenac, Fenamate, Sulindac, Nabumetone, Ketorolac, and Naproxen. Examples of local anesthetics include Lidocaine, Mepivacaine, Etidocaine, Bupivacaine, 2-Chloroprocaine hydrochloride, Procaine, and Tetracaine hydrochloride. Examples of calcium channel antagonists include Diltaizem, Israpidine, Nimodipine, Felodipine, Verapamil, Nifedipine, Nicardipine, and Bepridil. Examples of potassium channel blockers include Dofetilide, E4031, Almokalant, Sematilide, Ambasilide, Azimilide, Tedisamil, RP58866, Sotalol, Piroxicam, and Ibutilide. Examples of &bgr;-adrenergic agonists include Terbutaline, Salbutamol, Metaproterenol, and Ritodrine. Vasodialtors, which are believed to relieve muscle spasm in the uterine muscle, include nitroglycerin, isosorbide dinitrate and isosorbide mononitrate.
In another aspect, the method of the invention includes combining the pharmaceutical agent with a drug delivery system for intravaginal delivery of the agent. Examples of the drug 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 delivery 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 6000, polyethylene glycol having an average molecular weight of 1500, polyethylene glycol having an average molecular weight of 400 or mixtures thereof. The biocompatible excipient can also include a muco-adhesive agent such as alginate, pectin, or cellulose derivative. The biocompatible excipient can 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 about 60 to 90% by weight lipophilic carrier, between about 5 to 25% muco-adhesive agent, and between about 5 to 20% penetration enhancer.
In another embodiment of the invention, the excipient comprises between about 60 to 90% by weight hydrophilic carrier, between about 5 to 25% muco-adhesive agent, and between about 5 to 20% penetration enhancer.
In another embodiment of the invention, the drug delivery system comprises a standard fragrance free lotion formulation sold under the trademark JERGENS® lotion.
In another embodiment, the biocompatible excipient can 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% SUPPOCIRE® AS2, 10% hydroxypropyl methylcellulose, and 15% TRANSCUTOL®.
In another aspect, the invention provides a device for delivering an effective amount of a pharmaceutical agent to the uterus for treating a human female suffering from dysmenorrhea. The device is an absorbent vaginal tampon device having a proximal and a distal end. Located at the distal end is a means for delivery of the agent to the epithelium of the vagina. The device also includes a means for preferentially conveying fluid discharged from the uterus near the proximal end to the tampon and thereby preventing contact of the fluid with the agent. The device also has a means for retrieval of the device, such as a string or tape as used in tampons, vaginal rings and diaphragms.
In one embodiment, the invention provides a tampon device for delivering a pharmaceutical agent to the uterus comprising an absorbent vaginal tampon having a proximal end and a distal end. A cup-shaped porous foam portion at the distal end fits around the cervix of the uterus and contains a pharmaceutical agent for delivery to the cervix. The device may also include a nonabsorbing axial tube having a distal opening and extending through the porous foam cup into the tampon for conducting blood flow to the absorbent material. A retrieval string or tape connected to the tampon device is also included.
In another embodiment of a tampon device, the distal porous foam cup has a rim which encircles the cervix. The rim has high concentrations of medication and is positioned away from the direct flow of blood which exudes from the cervix during menstruation.
In another embodiment of a tampon device, the distal porous foam up has a rim which encircles the cervix. The rim has fingers extending into the fornix areas around the cervix and the tips of the fingers have high concentr
Harrison Donald C.
Liu James H.
Ritschel Wolfgang A.
Stern Roger A.
Azpuru Carlos A.
UMD, Inc.
Verny Hana
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