Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-02-09
2001-02-20
Criares, T. J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C514S108000, C514S324000, C514S428000, C514S443000, C514S448000, C514S319000
Reexamination Certificate
active
06190695
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a preventive (prophylactic) or treating (therapeutic) agent for bone diseases comprising a non-peptide osteogenesis-promoting substance and polyethylene glycol or a derivative thereof.
BACKGROUND ART
There are two types of bone diseases: non-metabolic bone diseases, such as bone fractures, bone/spinal deformation, osteosarcoma, myeloma, bone dysplasia and scoliosis, and metabolic bone diseases, such as osteoporosis, osteomalacia, rickets, fibrous osteitis, renal bone dystrophy and Paget's disease of bone. In recent years, metabolic bone disease has increasingly became a problem. For example, osteoporosis, a metabolic bone disease, is a systemic disease characterized by increased bone fragility and fracturability due to decreased bone mass and change in fine bone tissue structure, its major clinical symptoms including spinal kyphosis, and fractures of dorsolumbar bones, vertebral centra, femoral necks, lower end of radius, ribs, upper end of humerus, and others. In bone tissue, bone formation and destruction due to bone resorption occur constantly with a good balance; osteoblasts and osteoclasts play key roles in osteogenesis and bone resorption, respectively. Upon deterioration of the balance between bone formation and bone destruction due to bone resorption, a quantitative reduction in bone occurs. Traditionally, bone resorption suppressors such as estrogens, calcitonin and bisphosphonates have been mainly used to treat osteoporosis.
Japanese Patent Unexamined Publication No. 232880/1991 describes a compound represented by the formula:
wherein ring A represents a benzene ring which may be substituted; R represents a hydrogen atom or a hydrocarbon group which may be substituted; B represents a carboxyl group which may be esterified or amidated; X represents —CH(OH)— or —CO—; k represents 0 or 1; and k′ represents 0, 1 or 2; or a salt thereof, which is useful as a drug for treating osteoporosis.
Japanese Patent Unexamined Publication No. 364179/1992 describes a compound represented by the formula:
wherein ring A represents an optionally substituted benzene ring; R represents a hydrogen atom or an optionally substituted hydrocarbon group; B represents a carboxyl group which may be esterified or amidated; X represents CH(OH)— or —CO—; and n represents 0, 1 or 2; or a salt thereof, which is useful as a drug for treating osteoporosis.
EP-719782 describes an optically active compound represented by the formula:
wherein R represents a lower alkyl group; R
1
and R
2
each represent a lower alkyl group, or may bind together to form a lower alkylene group, which compound is useful as a drug for treating osteoporosis.
On the other hand, the International Journal of Pharmaceutics, 118 (1995), pp. 221-227 describes a pharmaceutical preparation comprising a leukotriene B4 antagonist of the formula:
and polyethylene glycol 3350.
In the International Journal of Pharmaceutics, 126 (1995), pp. 155-160, a preparation for hypoglycemic agent comprising Glybride and polyethylene glycol 4000 or 6000 is described.
In the Clinical Orthopedics and Related Research, 294 p. 333 (1993), an implant comprising bone morphogenic protein (BMP) and polyethylene glycol 200 or 600 or a block polymer of polyethylene glycol and lactic acid is described.
Currently available pharmaceuticals used clinically to treat bone diseases fail to have a satisfactory effect in clinical situations, due to limitation on the subject of administration associated with the mechanism of action, or to problems in terms of side-effects and efficacy. Also, long and continuous administration is necessary in the prevention and treatment of osteoporosis; there is therefore a need for an easily administered oral preparation. However, some osteogenesis-promoting substances need to be improved as to bioavailability, stability and other aspects when administered as oral preparations. Therefore, a therapeutic drug for bone diseases that permit practical clinical use and that is effective not only in non-oral administration but also in oral administration is desired.
DISCLOSURE OF INVENTION
After extensive investigation aiming at resolving the above problems, the present inventors found that a pharmaceutical composition of a non-peptide osteogenesis-promoting substance containing polyethylene glycol or a derivative thereof has higher bioavailability than does one not containing polyethylene glycol, and that it surpasses conventional osteogenesis-promoting pharmaceutical compositions in terms of pharmaceutical properties, such as greater stability in blood. The present inventors made further investigation based on these findings, and developed the present invention. Accordingly, the present invention relates to:
(1) a pharmaceutical composition which comprises a non-peptide osteogenesis-promoting substance and a polyethylene glycol or a derivative thereof,
(2) the pharmaceutical composition according to term (1), which is used for oral administration,
(3) the pharmaceutical composition according to term (1), which is used for preventing or treating a bone disease,
(4) the pharmaceutical composition according to term (3), wherein the bone disease is osteoporosis,
(5) the pharmaceutical composition according to term (1), wherein the non-peptide osteogenesis-promoting substance is a compound represented by the formula or salt thereof:
wherein ring A is an optionally substituted benzene ring; R is a hydrogen atom or an optionally substituted hydrocarbon group; B is an optionally esterified or amidated carboxyl group; X is —CH(OH)— or —CO—; k is 0 or 1; and k′ is 0, 1 or 2,
(6) the pharmaceutical composition according to term (5), wherein the ring A is a benzene ring which may be substituted by 1 or 2 substituents selected from the group consisting of halogen atoms, C
1-10
alkyl groups, C
1-10
alkoxy groups, alkylendioxy groups represented by the formula: —O—(CH
2
)
n
—O—, wherein n is an integer from 1 to 3 and C
1-10
alkylthio groups,
(7) the pharmaceutical composition according to term (5), wherein B is an optionally substituted carbamoyl group of the formula: —CON(R
1
)(R
2
) wherein R
1
and R
2
are independently a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted 5 to 7 membered heterocyclic group,
(8) the pharmaceutical composition according to term (5), wherein R
1
is a hydrogen atom or a C
1-10
alkyl group, and R
2
is (i) a phenyl or phenyl-C
1-3
alkyl group which may be substituted by a halogen atom, a C
1-6
alkoxy group, a mono- or di-C
1-6
alkoxyphosphoryl group, a mono- or di-C
1-6
alkoxyphosphoryl-C
1-3
alkyl, a moiety of the formula:
wherein p is an integer from 2 to 4, or a C
1-6
alkoxy-carbonyl group or (ii) a 5- or 6-membered heterocyclic group containing 1 or 2 nitrogen atom(s) or 1 nitrogen atom and 1 sulfur atom, which may be substituted by a phenyl group,
(9) the pharmaceutical composition according to term (5), wherein R is a hydrogen atom, a C
1-6
alkyl group or a phenyl group,
(10) the pharmaceutical composition according to term (5), wherein k is 1 and k′ is 0,
(11) the pharmaceutical composition according to term (1), wherein the non-peptide osteogenesis-promoting substance is an optically active compound represented by the formula:
wherein R
3
is a lower alkyl group; and R
4
and R
5
are independently a lower alkyl group or bind together to form a lower alkylene group,
(12) the pharmaceutical composition according to term (11), wherein R
3
, R
4
and R
5
are independently a C
1-6
alkyl group,
(13) the pharmaceutical composition according to term (1), wherein the non-peptide osteogenesis-promoting substance is (2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepine-2-carboxamide,
(14) the pharmaceutical composition according to term (1), wherein the weight ratio of the polyethylene glycol or a derivative thereof relative to the non-peptide osteogenesis-promoting substance is from about 0.5 to about 2,000 times,
(
Hoshino Tetsuo
Iwasa Susumu
Saito Kazuhiro
Criares T. J.
Foley & Lardner
Takeda Chemical Industries Ltd.
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