Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-07-23
2002-07-09
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S433000, C424S489000, C514S899000, C514S937000, C514S944000, C514S945000, C514S967000, C514S969000
Reexamination Certificate
active
06416778
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical preparations, and especially pharmaceutical formulations that can be introduced topically, locally, intrapelvically, intraperitoneally or directly on reproductive organs of interest in amounts effective to treat various conditions, particularly local diseases of the female reproductive system, such as pelvic, uterine, cervical and vaginal diseases which are present in this region of the body.
BACKGROUND OF THE INVENTION
It has long been known that treatment of female reproductive diseases by traditional methods of oral or systemic administration is associated with drug bioavailability problems and concomitant side effect complications from unwanted absorption of drugs into the systemic circulation. For example, normal digestive tract action may break down orally administered active ingredients to decrease effective drug delivery dosages, or the pharmaceutical preparation may be changed by passage through the liver or by systemic circulation or may not achieve adequate levels in the area of interest. To counteract these undesirable actions, the dosage of the active ingredient needs to be increased, oftentimes leading to undesirable side effects.
Danazol, an isoxazolo derivative of 17∝ ethenyltestosterone (an androgen hormone), is commonly administered to women for treatment of endometriosis, range up to 800 mg daily. At high doses, adverse side effects are seen which may include weight gain, voice change, development of facial and chest hair, loss of libido, acne, and central nervous system (“CNS”) symptoms such as depression, anxiety, fatigue, nausea and diarrhea, as well as the inhibition of pregnancy while undergoing treatment. See, for example, Spooner,
Classification of Side Effects to Danazol Therapy
, Winthrop Laboratories, Surrey, England.
It is therefore highly desirable to provide new systems and methods for the administration of pharmaceuticals which would avoid such drawbacks. Mizutani, et al., in
Fertility and Sterility
63, 1184-1189 (1995), describes administration of danazole vaginally by means of a 100 mg suppository, and compared the results with oral administration of a 400 mg dosage. No effect on the hypothalamic-pituitary-ovarian axis was noted, although high concentrations were present in the ovary, uterus and serum, with insignificant serum levels, following vaginal administration. Mizutani, et al., conducted their study following a report by Igarishi,
Asia-Oceania J. Obstet. Gynaecol
. 16(1), 1-12 (1990), that administration of danazole in a silicone vaginal ring reduced endometriotic tissue in the uterus and increased the incidence of pregnancy in treated women to a statistically significant degree. The immediate drawback to both therapies, however, is that the formulation and delivery platform such as vaginal rings and other devices are particularly unsatisfactory for women who already suffer from the cramps and pains associated with endometriosis. The dosages which were used were also quite high and extremely variable and may potentially have a negative and accumulative depot effect.
Igarashi's implant, and other proposed danazole formulations for local release of danazol for treatment of endometriosis, wherein the effect is achieved by direct administration of the danazole to the tissue to be treated, are described in U.S. Pat. No. 4,997,653 to Igarashi and EPA 0 501 056 (col. 2, lines 24-29 of the U.S. patent).
Many other drug delivery systems are available, but have not been developed for this purpose. Examples include U.S. Pat. No. 3,921,636 to Zaffaroni, which describes a drug delivery reservoir for controlled, sustained release of water soluble materials as a function of diffusion of water into the device and dissolution of the drug to be released for systemic or local effect (col. 10, line 46). EPA 0 566 135 by Takeda Chemical Industries describes a preparation for systemic delivery of proteins or peptides via the mucosal regions such as the mouth or vagina, wherein delivery is enhanced by inclusion of a cytidine nucleotide derivative. WO 96 37232 by Universidade de Santiago de Compostela describes complexes of nanoparticules, emulsions or nanocapsules within a matrix formed by ionic complexing of a water soluble positively charged amino polysaccharide and a negatively charged phospholipid, which are useful for topical or transmucosal administration of drugs. WO 95 07071 by Edko Trading describes an ointment or creme for intravaginal administration of antifungal drugs. U.S. Pat. No. 5,510,118 to Nanosystems describes preparation of a powder consisting solely of nanoparticles of drugs, such as danazole, which is highly soluble and therefore advantageous for systemic administration by injection.
It is therefore an object of the present invention to provide formulations which are effective in treating disorders of the reproductive system.
It is therefore an object of the present invention to provide formulations which are effective in treating disorders of the reproductive organs which has high patient compliance and comfort.
It is a further object of the present invention to provide formulations and methods of administration which provide for extremely rapid uptake of drug in the affected region, with low systemic concentrations and few concordant side effects.
It is still another object of the present invention to provide greatly enhanced bioavailability of drug in formulations administered topically or locally, intrapelvically, intraperitoneally or directly on reproductive organs of interest as compared to the drugs administered in controlled release devices.
SUMMARY OF THE INVENTION
Formulations have been developed for topical or local delivery of drugs intrapelvically, intraperitoneally or directly onto organs of interest, to produce a regional effect, with lower systemic drug levels than obtained when an effective dosage is systemically administered. In a preferred embodiment, drug is administered to a region such as the female reproductive system, provide for increased comfort, increased bioavailability, rapid and relatively high blood levels in the region to be treated without causing systemic levels of drug which might cause side effects. The preferred formulations consist of drug micro or nanoparticles, which may be formed of drug alone or in combination with an excipient or polymeric carrier. The excipient or polymer may be used to manipulate release rates and to increase adhesion of the drug to the affected region. The drug formulation can be applied as a dry powder, a liquid suspension or dispersion, a hydrogel suspension or dispersion, sponges, or as a topical ointment, creme, lotion, foam or suppository.
Specific danazole formulations are described. Rat studies demonstrate rapid uptake of danazole into the tissues affected in endometriosis, with serum drug levels that are almost undetectable.
DETAILED DESCRIPTION OF THE INVENTION
The compositions and methods for administration thereof provide for significantly diminished side effects with increased bioavailability and comfort, as compared to conventional drug administration techniques, and avoid the need for oral and parenteral administration, the use of complex and expensive biocompatible polymeric material, and insertion into the body and maintenance therein of potentially infectious foreign objects, such as intrauterine devices, vaginal rings, and suppositories.
I. Formulations
The formulations are designed to provide maximum uptake in the affected tissues with rapid dissemination throughout the region to be treated, with little to no increase in systemic blood levels of the drug. The formulations can consist solely of drug, or drug combined with excipient or polymeric material.
A. Drugs
The term “drug” can refer to any pharmaceutically active substance capable of being administered in a particulate formulation, which achieves the desired effect. Drugs can be synthetic or natural organic compounds, proteins or peptides, oligonucleotides or nucleotides, or polysaccharides or sugars. Drugs may have
DiPiano Gerianne M.
Ragavan Vanaja V.
FemmePharma
Holland & Knight LLP
Pabst Patrea L.
Spear James M.
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