Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2003-12-12
2004-08-31
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S468000, C424S469000, C424S471000, C424S172100, C424S484000, C424S488000
Reexamination Certificate
active
06783772
ABSTRACT:
This invention relates to pharmaceutical preparations. In particular, this invention relates to pharmaceutical preparations containing alendronate sodium.
Alendronate sodium is a white, crystalline, non-hygroscopic powder. It is soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform. Typically, alendronate sodium Tablets for oral administration contain either 6.53, 13.05 mg or 52.21 mg of alendronate monosodium salt trihydrate, which is the molar equivalent of 5.0, 10.0 mg and 40.0 mg, respectively, of free acid, and the typically, the following inactive ingredients: microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, and magnesium stearate.
Alendronate sodium belongs to a class of chemical compounds known as Bisphosphonates, which are synthetic analogs of pyrophosphate that binds to bone hydroxyapatite. Alendronate sodium is chemically described as (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate. The empirical formula of alendronate sodium is C
4
H
12
NNaO
7
P
2
.3H
2
O and its formula weight is 325.12. Alendronate sodium is therefore an aminobisphosphonate that acts on osteoclasts, the bone-resorbing cells. Alendronate inhibits bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover. Alendronate sodium thus reduces the elevated rate of bone turnover observed in postmenopausal women to the levels found in premenopausal women. As a specific inhibitor of osteoclast-mediated bone resorption. Overall therefore alendronate Sodium reduces the amount of calcium lost from bones and increases the density of bones.
Normally bones are being rebuilt all the time. First, old bone is removed (resorbed). Then a similar amount of new bone is formed. This balanced process keeps the skeleton healthy and strong.
Osteoporosis is a condition that strikes postmenopausal women as a result of estrogen withdrawal and the consequential depletion of calcium via the kidneys, which is hitherto retained by the mechanism of estrogen and the phosphorus calcium ion exchange mechanism. Osteoporosis causes a thinning and weakening of the bones. It is common in women after menopause. Menopause happens when the ovaries stop producing the female hormone, estrogen, or is removed (which may occur, for example, at the time of a hysterectomy). After menopause, bone is removed faster than it is formed, so bone loss occurs and bones become weaker. Therefore, maintaining bone mass is important to keep bones healthy.
In Postmenopausal Women, therefore osteoporosis is characterized by low bone mass that leads to an increased risk of fracture. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis, indicative of vertebral fracture. Osteoporosis occurs in both males and females but is most common among women following the menopause, when bone turnover increases and the rate of bone resoprtion exceeds that of bone formation. These changes result in progressive bone loss and lead to osteoporosis in a significant proportion of women over age 50. Fractures, usually of the spine, hip, and wrist, are the common consequences. From age 50 to age 90, the risk of hip fracture in women increases 50-fold and the risk of vertebral fracture 15- to 30-fold. It is estimated that approximately 40% of 50-year-old women will sustain one or more osteoporosis-related fractures of the spine, hip, or wrist during their remaining lifetimes. Hip fractures, in particular, are associated with substantial morbidity, disability, and mortality.
Paget's Disease is a chronic, focal skeletal disorder characterized by greatly increased and disorderly bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.
Clinical manifestations of Paget's disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures, and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy.
Alendronate sodium is a suggested treatment in osteoporosis and Paget's disease Alendronate sodium decreases the rate of bone resorption directly, which leads to an indirect decrease in bone formation. In clinical trials, alendronate sodium 40 mg once daily for six months produced highly significant decreases in serum alkaline phosphotase as well as in urinary markers of bone collagen degradation. As a result of the inhibition of bone resorption, alendronate sodium induced generally mild, transient, decreases in serum calcium phosphate. The reduction in serum phosphate may reflect not only the positive bone mineral balance due to alendronate sodium but also a decrease in renal phosphate reabsorption.
Alendronate sodium specifically inhibits Osteoclast-mediated bone resorption thereby preventing resorption. Its mode of action is suggested as follows: At the cellular level, alendronate shows preferential localization to bone resorption sites, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclastic recruitment or attachment, but it does inhibit osteoclast activity. Bones examined 6 and 49 days after alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover. In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.
For the treatment of osteoporosis, the recommended daily dose is 10 mg. For the prevention of osteoporosis the recommended dose is 5 mg daily. And for the treatment of Paget's disease the dose recommended is 40 mg daily for 6 months.
The Pharmacokinetics of alendronate sodium is as follows:
Relative to an intravenous (IV) reference dose, the mean oral bioavailability in women was 0.7% for conventionally available doses ranging from 5 to 40 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10 mg tablet in men (0.59%) was similar to that in women (0.78%) when administered after an overnight fast and 2 hours before breakfast.
Bioavailability is decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast.
Bioavailability is negligible whether alendronate is administered with or up to two hours after a standardized breakfast. Simultaneous administration of alendronate with coffee or orange juice reduces bioavailability by approximately 60%.
Alendronate transiently distributes to soft tissues following 1 mg/kg IV administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28:1 in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 mg/ml) for analytical detection. Protein binding in human plasma is approximately 78%.
Daily oral doses of alendronate sodium 5, 20, and 40 mg for six weeks) in postmenopausal women produce biochemical changes indicative of dose-dependent inhibition of
Khandelwal Sanjeev
Omray Pratibha
Muserlian Lucas and Mercanti
Page Thurman K.
Tran S.
LandOfFree
Pharmaceutical preparations containing alendronate sodium does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical preparations containing alendronate sodium, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical preparations containing alendronate sodium will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3330028