Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1998-10-29
2002-04-16
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
Reexamination Certificate
active
06372728
ABSTRACT:
TECHNICAL FIELD
The present invention relates to pharmaceutical formulations comprising bisphosphonates. The invention also relates to a process for preparing such pharmaceutical formulations, to the use of such pharmaceutical formulations for inhibition of bone resorption and for the treatment and prevention of osteoporosis.
BACKGROUND ART
Bisphosphonates
Bisphosphonates are carbon-substituted pyrophosphate analogues that include potent inhibitors of bone resorption, such as alendronate (4-amino-1-hydroxybutylidene-1,1-biphosphonic acid) (Sato et al. (1991) J. Clin. Invest. 88, 2095-2105).
The oral bioavailability of bisphosphonates (etidronate; clodronate; pamidronate; alendronate) in humans lies between 1% and 10% according to Lin (Bone 18, 75-85, 1996) and absorption is diminished when given with meals, especially in the presence of calcium. Therefore bisphosphonates should never be given at mealtime and never together with milk or diary products according to Fleisch (Bisphosphonates in bone disease, Stampli & Co., Bern 1993, p.50, and references cited therein).
The oral bioavailability of alendronate has been studied by Gertz et al. (Clinical Pharmacology & Therapeutics, vol. 58, pp. 288-298, 1995). It was found that taking alendronate either 60 or 30 minutes before breakfast reduced bioavailability by 40% relative to a 2-hour wait before a meal. Taking alendronate either concurrently with or 2 hours after breakfast drastically (>85%) impaired availability. A practical dosing recommendation, derived from these findings was that patients should take the drug with water after an overnight fast and at least 30 min before any other food or beverage.
Consequently, there is a need for pharmaceutical formulations comprising bisphosphonates, such as alendronate, which reduces the above mentioned drawbacks and allows the patient to take the medicament more conveniently, e.g. together with food intake.
Lipid Absorption Enhancers
The use of absorption enhancers of lipidic origin in pharmaceutical formulations is known in the art. For reviews, see e.g.:
van Hoogdalem et al., Pharmac. Theor., vol 44, 407-443 (1989);
Muranishi, Crit. Rev. Ther. Drug Carrier Syst., vol 7, 1-33 (1990);
Swenson and Curatolo, Adv. Drug Deliv. Rev., vol 8, 39-92 (1992);
Drug Absorption Enhancement (Ed.: A B G de Boer), Harwood Academic Publishers, 1994.
Specifically, medium chain glycerides have been studied and reported as absorption enhancers in a number of papers, see reference above and references therein. The main interest has been to utilize mixtures of mono-, di-, and triglycerides with 6 to 12 carbon atoms in the chains. More or less well defined samples of glycerides have been used, e.g. glyceryl mono-octanoate (Tramedico), Nikkol MGK (Nikko Chemicals), Sunsoft (Taiyo Kagaku), Imwitor (Hüls), Labrasol (Gattefosseé), and Labrafac Lipo (Gattefossé). Akoline MCM® (formerly called Capmul MCM) in a mono/diglyceride of medium chain fatty acids, primarily caprylic (n-octanoic) and capric (n-decanoic) acids.
Only a few reports deal with effects obtained when glycerides have been perorally administered (Sekine et al. (1985) J. Pharmacobio-Dyn. 8, 826; Beskid et al. (1988) Chemotherapy 34, 77).
Several other studies report results when liquid formulations of glycerides have been administered rectally (Matsumoto et al. (1989), Chem Pharm Bull. 37, 2477), or directly as solutions or emulsions by infusion or bolus into different parts of the small intestine (Constantinides et al. (1995) Pharm. Res. 12, 1561). The glycerides were used either as such, or in mixtures with dispersing agents like lecithins and surfactants to form aggregates like mixed micelles, microemulsions, dispersed lamellar phases etc, or to form self-emulsifying systems. A few patent publications have also disclosed the use of such glycerides in formulations, e.g. as components in microemulsions (WO 94/19003 and references therein), and in self-emulsifying systems with lecithins (WO 92/05771 and references therein).
REFERENCES:
patent: 5133972 (1992-07-01), Ferrini et al.
patent: 5391743 (1995-02-01), Ebetino et al.
patent: 5958908 (1999-09-01), Dohi et al.
patent: 9205771 (1992-04-01), None
patent: 9419003 (1994-09-01), None
van Hoogdalem et al. “Intestinal Drug Absorption Enhancement: An Overview.” Pharmac. Ther. 44:407-443, 1989.
Swenson et al. “Means to Enhance Penetration: Intestinal Permeability Enhancement . . . ” Adv. Drug Deliv. Reviews 8:39-92, 1992.
Sato et al. Bisphosphonate Action. (1991) J. Clin. Invest. 88,2095-2105.
Lin, J.H., Bisphosphonates: A Review of their Pharmacokinetic Properties. Bone 18:75-85, 1996.
Fleisch, H. Bisphosphonates in bone disease, Stampli & Co., Bern (1993) p. 50-54.
Gertz et al. Studies of the oral bioavailability of Alendronate. Clinical Pharmacology & Therapeutics, 58:288-298, 1995.
Muranishi, S. Absorption Enhancers. Crit. Rev. Ther. Drug Carrier Syst. 7:1-33 (1990).
Sekine et al. Improvement of Bioavaliability of Poorly Absorbed Drugs . . . (1985) J. Pharmacobio-Dyn 8:286-295.
Beskid et al. (1988) enteral, Oral, and Rectal Absorption of Ceftriaxone Using Glyceride Enhacers. Chemotherapy 34, 77-84.
Matsumoto et al. Enhancing Effects of Glyceryl-1-monooctanoate on Rectal Absorption . . . (1989), Chem. Pharm. Bull. 37:2477-2480.
Constantinides et al. (1995) Lipid Microemulsion for Improving Drug Dissolution and Oral Absorption: Physical and Biopharmaceutical Aspects 12:1561-1572.
Fleisch, H. Bisphosphonates: A New Class of Drugs in Diseases of Bone and Calcium Metabolism. Recent Results Cancer Res. 116:1-28 (1989).
Drug Absorption Enhancement (ed.: A B G de Boer), Harwood Academic Pub., 1994, p. 155-175.
AstraZeneca AB
Criares Theodore J.
White & Case LLP
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