Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-04-28
2002-10-22
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S456000, C424S457000, C424S458000, C424S459000, C424S463000, C424S496000, C424S498000, C424S502000, C424S460000, C424S461000, C424S462000, C514S102000, C514S104000, C514S108000, C514S962000
Reexamination Certificate
active
06468559
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to drug delivery, and more specifically relates to novel enteric coated pharmaceutical dosage forms that for oral administration of bisphosphonic acid compounds. The invention additionally relates to methods for administering a bisphosphonic acid compound using the novel dosage forms.
BACKGROUND
A number of bisphosphonic acids are known as pharmaceutical agents, particularly in the diagnosis and treatment of disorders and conditions related to bone resorption, calcium metabolism and phosphate metabolism. Such disorders and conditions include, for example, osteoporosis, Paget's disease, periprosthetic bone loss or osteolysis, metastatic bone disease, hypercalcemia of malignancy, multiple myeloma, periodontal disease, and tooth loss. The bisphosphonic acids, or “bisphosphonates,” which are known to be useful in treating such disorders and conditions fall into three categories: a first generation of drugs, including etidronate, which have significant activity but do not reliably suppress bone resorption, and result in undesirable side effects (etidronate, for example, can give rise to osteomalacia, resulting in a decrease in bone mineralization; see Boyce et al. (1984)
Lancet
1(8381):821-824, and Gibbs et al. (1986)
Br. Med. J
. 2:1227-1229); a second generation of drugs, e.g., pamidronate, which reliably suppress bone resorption when administered parenterally, but are not orally active; and a third generation of drugs typified by alendronate and risedronate, that exhibit both oral and parenteral efficacy.
The known bisphosphonic acids include 1-hydroxyethane-1,1-diphosphonic acid (etidronic acid, salts of which are referred to as “etidronate”), 1,1-dichloromethylene-1,1-bisphosphonic acid (clodronic acid, salts of which are is referred to as “clodronate”), 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronic acid, salts of which are referred to as “pamidronate”), 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (alendronic acid, salts of which are referred to as “alendronate), 6-amino-1-hydroxy-hexylidene-1,1-bisphosphonic acid (neridronic acid, salts of which are referred to as “neridronate”), (4-chlorophenyl)-thiomethane-1,1-diphosphonic acid (tiludronic acid, salts of which are referred to as “tiludronate”), 2-(3-pyridinyl)-1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid (risedronic acid, salts of which are referred to as “residronate”), cycloheptylaminomethylene-1,1-bisphosphonic acid (cimadronic acid, salts of which are referred to as “cimadronate”), 1-hydroxy-3-(N-methyl-N-pentylamino)-propylidene-1,1-bisphosphonic acid (ibandronic acid, salts of which are referred to as “ibandronate”), 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid (olpadronic acid, salts of which are referred to as “olpadronate”), [2-(2-pyridinyl)-ethylidene]-1,1-bisphosphonic acid (piridronic acid, salts of which are referred to as “piridronate”) and 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (zoledronic acid, salts of which are referred to as “zoledronate”). Although the bisphosphonic acids are therapeutically effective, oral administration of the drugs is problematic, primarily because of adverse gastrointestinal effects, particularly irritation of the esophagus. Pamidronate has been associated with esophageal ulcers, as has alendronate, although to a lesser extent. See, for example, Lufkin et al. (1994)
Osteoporosis International
4:320-322; De Groen et al. (1996),
N. Eng. J. Med
. 335(124):1016-1021; Castell et al. (1996)
N. Eng. J. Med
. 335(124):1058-1059; and Lieberman et al. (1996)
N. Eng. J. Med
. 3(124):1069-1070. Even with risedronate, which because of its potency can be administered at relatively low doses, complaints such as heartburn and esophageal burning are frequent.
Although efforts have been made to reduce the adverse gastrointestinal effects of bisphosphonic acids, there is a continuing need for dosage forms containing these active agents wherein undesirable side effects are minimnized and patient compliance and thus therapeutic efficacy are improved.
The following references pertain to one or more aspects of the invention and may provide useful background information:
U.S. Pat. No. 4,621,077 to Rosini et al. describe biphosphonic acids as therapeutic agents, the acids including alendronate, difluoromethanebiphosphonic acid, and 5-amino-1-hydroxypentane-1,1-biphosphonic acid. U.S. Pat. Nos. 5,358,941 and 5,681,590 to Bechard et al. describe immediate release tablets of bisphosphonic acids and salts thereof, for the treatment of disturbances involving calcium or phosphate metabolism, e.g., treatment and prevention of diseases involving bone resorption, particularly osteoporosis, Paget's disease, malignant hypercalcemia and metastatic bone disease.
International Patent Publication WO 93/09785, U.S. Pat. No. 5,622,721 to Dansereau et al., and U.S. Pat. No. 5,935,602 to Dansereau et al. disclose enterically coated dosage forms of the drug risedronate. The '602 patent describes delayed release risedronate formulations comprised of compressed tablets that are enterically coated, compressed tablets that contain enterically coated drug particles, or capsules containing enterically coated drug particles. U.S. Pat. No. 5,431,920 to Bechard describes an enterically coated dosage form comprising a core tablet containing a therapeutically effective amount of a bisphosphonic active agent, a stability-enhancing subcoat designed to minimize migration of active agent from the core tablet to the surface of the enteric coating, and an enteric film formulated to rapidly and completely dissolve once the dosage form enters the proximal portion of the lower gastrointestinal tract. U.S. Pat. No. 6,015,801 to Daifotis et al. pertains to a method for administering a bisphosphonic acid compound while minimizing gastrointestinal side effects, the method involving administering a high unit dosage of the active agent at relatively infrequent dosing intervals, e.g., on a once-weekly or biweekly basis.
U.S. Pat. No. 5,462,932 to Brenner et al. describes an oral alendronate formulation in the form of a liquid, for administration to individuals who have difficult in swallowing tablets and other solid dosage forms.
U.S. Pat. No. 4,627,850 to Deters et al. and U.S. Pat. No. 5,413,572 to Wong et al. pertain to osmotic dosage forms in which a drug-containing composition is contained within a semipermeable outer wall, i.e., a membrane that is permeable to the passage of fluid, is impermeable to any influx of drug, and contains an orifice that allows delivery of the drug-containing composition from the capsule.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the invention to address the above-mentioned need in the art by providing an enterically coated dosage form for the administration of a bisphosphonic acid compound.
It is another object of the invention to provide such a dosage form comprised of a capsule housing the drug in a liquid or semi-solid carrier.
It is still another object of the invention to provide such a dosage form comprised of an osmotically activated device in which a semipermeable membrane encapsulates a drug-containing formulation.
It is an additional object of the invention to provide a method for treating an individual having a condition that is responsive to administration of a bisphosphonic acid compound, by administering a dosage form as provided herein within the context of an effective dosing regimen.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one aspect of the invention, then, a pharmaceutical formulation for oral administration is provided which comprises an enterically coated capsule housing a therapeutically effective amount of an active agent selected from bisphosphonic acids and pharmacologically ac
Chen Feng-Jing
Patel Mahesh V.
Channavajjala Lakshmi
Lipocine Inc.
Page Thurman K.
Reed Dianne E.
Reed & Associates
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