Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-07-27
2003-06-03
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S431000, C424S433000
Reexamination Certificate
active
06572874
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns devices, methods, compositions and formulations for vaginal delivery of a class of drugs in the bisphosphonate group. In particular, the invention concerns a targeted site delivery of bisphosphonates to the vagina using a bisphosphonate comprising vaginal composition or a medicated intravaginal device comprising the bisphosphonate composition formulated for transvaginal delivery. The composition or the device of the invention delivers 10 to 30 times more bisphosphonates intravaginally as can be delivered orally due to the absorption of bisphosphonates from the vagina which far exceeds the absorption of bisphosphonates from the gastrointestinal tract. Vaginal administration generally avoids major problems connected with oral administration, such as gastric and esophageal reflux and ulceration.
The invention also concerns a method for treatment of osteoporosis, Paget's disease, metastatic cancer of bone, and other related diseases of bone and skeleton and for prevention of bone breakdown and loss of bone mass and strength by intravaginal administration of bisphosphonates via the vagina and by transvaginal delivery of bisphosphonates to general circulation. This novel and unique route of administration provides a mechanism for delivering drugs to prevent and treat osteoporosis in a way now only available with considerable side effects.
2. Background and Related Art
Osteoporosis and therewith associated loss of bone mass and strength leading to bone breakdown and fractures is a major medical problem in postmenopausal women.
It is estimated that eight million women in the United States have osteoporosis and that an additional 15.4 million women have low bone mass, placing them at increased risk for development of osteoporosis. These risks are most profound after menopause when the rate of bone loss is accelerated. Osteoporosis leads to fractures in the spine and hips in a significant number of these women, markedly altering their lifestyle and reducing their life expectancy.
In the past decade, hormone replacement therapy with estrogens has been the mainstay in the treatment of post-menopausal women. Recent studies, however, have shown that this treatment is not suitable for all female patients and that it possesses an increasing risk of certain female cancers and the heightened malignancy of cancers once they occur. For that reason, alternate therapies for osteoporosis have been and are continually sought.
A number of approaches for prevention of osteoporosis in this patient group have been proposed. These approaches include the administration of high doses of calcium and vitamin D in conjunction with the administration of estrogens, and the administration of synthetic substances which bind to estrogen receptors such as raloxifen, tamoxifen, etc.
One of the new approaches which has been suggested and investigated is the administration of bisphosphonates. Bisphosphonates prevent the resorption of bone, thereby reducing occurrences of fractures, especially of the spine and hip. Recent studies have demonstrated these compounds act to prevent the loss of bone and to enhance bone density in the postmenopausal female population and in patients with Paget's disease of bone (
Journal of Clinical Endocrinology and Metabolism
, 82(1):265-274 (1997);
Journal of Bone and Mineral Research
. 12(10):1700-1707 (1997);
American Journal of Medicine
, 106(5):513-520 (1997);
Journal of Clinical Endocrinology and Metabolism
. 83(2):396-402 (1998)).
As described in the above references, bisphosphonates have recently been shown to prevent the continuous breakdown of bone in the vulnerable population and lead to strengthening of bone and an increase in bone mass. In several studies, these compounds have been shown to markedly reduce fractures.
In addition to treating osteoporosis and Paget's disease, the clinical use of bisphosphonates for cancer has increased dramatically in recent years.
New England Journal of Medicine
, 335:1785-1791 (1996) reports that treatment with bisphosphonates decreases the frequency of skeletal events for patients with multiple myeloma involving bone and breast cancer with osteolytic metastases. Recent clinical trials have shown that adjunctive treatment with bisphosphonates reduces the incidence and number of new bone and visceral metastases in women with high risk, primary breast cancer (
New England Journal of Medicine
. 339:398-400 (1998)).
There are at least ten bisphosphonates now available for therapy worldwide, but major problems with their administration have been noted.
The main problems with oral administration of bisphosphonates relate to absorption and gastrointestinal tolerability. Absorption is poor and drug administration recommendations must be given to the patient and checked. Etidronate, tiludronate and risedronate need to be taken two hours before or after a meal with a large volume of water, and dairy products or antacids are forbidden within two hours of administration. Alendronate has been given in the early morning, immediately upon rising, while in the upright position, two hours before any food or drink. Upper gastrointestinal adverse effects are reported in 15-20% of patients with orally administered bisphosphonates. Esophagitis has been reported in a small number of patients with osteoporosis treated with 10 mg/day alendronate. (
Drugs
, 58:827 (1999)).
Generally, thus, the bisphosphonates oral administration requires a strict regimen. In most patients, this regimen has proven to be inconvenient and impractical leading to a failure of oral administration.
In addition, a significant number of women taking these compounds develop irritation of esophageal mucosa, esophageal reflux and esophagitis (
Digestive Diseases and Sciences
, 43(9):1998-2002 (1998);
Digestive Diseases and Sciences
, 43(5):1009-1015 (1998)).
Even if these inconveniences and complications could be overcome, to deliver a sufficient amount of bisphosphonates is also problematic because only less than 1% of the bisphosphonates are generally absorbed following oral administration (
Drugs
, 53(3):415-434 (1997). For these reasons, as many as 35% all patients discontinue the oral treatment with bisphosphonates in one year.
Thus, it would be very important to provide an alternative composition and/or drug delivery route which would avoid problems associated with bisphosphonate oral administration and still provide a patient with a therapeutically effective amount of bisphosphonates.
The major difficulties encountered with the administration of bisphosphonate compounds are their poor absorption from the gastrointestinal tract, their interaction with other drugs and foods which alters their absorption, and their tendency to damage mucosa and irritate the esophagus and stomach.
In view of the problems encountered with oral administration of bisphosphonates which limits their utility, it is clear that new delivery mechanisms which would enhance the absorption and bioavailability of these drugs, especially transvaginal administration with sustained-release administration would be extremely advantageous for achieving and increasing a therapeutic potential of bisphosphonates.
It is, therefore, an objective of the present invention to provide devices, methods and compositions for treating osteoporosis, Paget's disease and other related diseases of bone and skeleton or for treating and prevention of cancer by intravaginal delivery of effective doses of bisphosphonates to the vagina and by transvaginal transport of bisphosphonates into the general circulation after absorption of these drugs through a vaginal mucosa.
All references, patents and patent applications cited herein are hereby incorporated by reference in their entirety.
SUMMARY OF THE INVENTION
One aspect of the present invention is a device, a method, a composition, and a formulation for transvaginal delivery of bisphosphonates effective to treat osteoporosis, Paget's disease and other related diseases of bone and skeleton
Harrison Donald C.
Liu James H.
Pauletti Giovanni M.
Ritschel Wolfgang A.
Page Thurman K.
UMD, Inc.
Verny Hana
Ware Todd D
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