WO2000021542A1 - Methods for stimulating bone formation - Google Patents
Methods for stimulating bone formation Download PDFInfo
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- WO2000021542A1 WO2000021542A1 PCT/US1999/023757 US9923757W WO0021542A1 WO 2000021542 A1 WO2000021542 A1 WO 2000021542A1 US 9923757 W US9923757 W US 9923757W WO 0021542 A1 WO0021542 A1 WO 0021542A1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/88—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving prostaglandins or their receptors
Definitions
- the present invention relates to methods for stimulating bone formation, i.e. osteogenesis, in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP receptor subtype agonist.
- disorders in humans and other mammals involve or are associated with abnormal or excessive bone loss.
- Such disorders include, but are not limited to, osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.
- osteoporosis which in its most frequent manifestation occurs in postmenopausal women.
- Osteoporosis is a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporotic fractures are a major cause of morbidity and mortality in the elderly population. As many as 50% of women and a third of men will experience an osteoporotic fracture. A large segment of the older population already has low bone density and a high risk of fractures. There is a significant need to both prevent and treat osteoporosis and other conditions associated with bone resorption. Because osteoporosis, as well as other disorders associated with bone loss, are generally chronic conditions, it is believed that appropriate therapy will typically require chronic treatment.
- Normal bone physiology involves a process wherein bone tissue is continuously being turned over by the processes of modeling and remodeling. In other words, there is normally an appropriate balance between resorption of existing bone tissue and the formation of new bone tissue. The exact mechanism underlying the coupling between bone reso ⁇ tion and formation is still unknown. However, an imbalance in these processes is manifested in various disease states and conditions of the skeleton.
- osteoblasts Two different types of cells called osteoblasts and osteoclasts are involved in the bone formation and reso ⁇ tion processes, respectively. See H. Fleisch, Bisphosphonates In Bone Disease, From The Laboratory To The Patient, 3rd Edition, Parthenon Publishing (1997), which is inco ⁇ orated by reference herein in its entirety.
- Osteoblasts are cells that are located on the bone surface. These cells secrete an osseous organic matrix, which then calcifies. Substances such as fluoride, parathyroid hormone, and certain cytokines such as protaglandins are known to provide a stimulatory effect on osetoblast cells. However, an aim of current research is to develop therapeutic agents that will selectively increase or stimulate the bone formation activity of the osteoblasts.
- Osteoclasts are usually large multinucleated cells that are situated either on the surface of the cortical or trabecular bone or within the cortical bone. The osteoclasts resorb bone in a closed, sealed-off microenvironment located between the cell and the bone. The recruitment and activity of osteoclasts is known to be influenced by a series of cytokines and hormones. It is well known that bisphosphonates are selective inhibitors of osteoclastic bone reso ⁇ tion, making these compounds important therapeutic agents in the treatment or prevention of a variety of systemic or localized bone disorders caused by or associated with abnormal bone reso ⁇ tion.
- Prostaglandins are alicyclic compounds related to the basic compound prostanoic acid.
- a natural prostaglandin, PGE2 has the following structure.
- Prostaglandins such as PGE2 are known to stimulate bone formation and increase bone mass in mammals, including man. It is believed that four different receptor subtypes, designated EPj, EP2, EP3, and EP4 are involved in mediating the bone modeling and remodeling processes of the osteoblasts and osteoclasts.
- the major prostaglandin receptor in bone is EP4, which is believed to provide its effect by signaling via cyclic AMP.
- the scientific information that is currently known about the prostaglandin mediated bone effect is rather limited, because the exact mechanism of action is not known.
- Prostaglandins and their accosted receptors are more fully described in for example, K.
- agonists of the EP4 subtype receptor are useful for stimulating bone formation. Without being limited by theory, it is believed that these agonists are responsible for upregulating the number and/or activity of the osteoblasts.
- the present invention relates to methods for stimulating bone formation, i.e. osteogenesis, in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype agonist.
- the present invention relates to methods for treating or reducing the risk of contracting a disease state or condition involving bone tissue in a mammal in need of such treatment or risk reduction, composing administering to said mammal a therapeutically effective amount of an EP4 receptor subtype agonist.
- the present invention relates to methods for stimulating bone formation in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of an EP4 receptor subtype agonist and a bisphosphonate active.
- the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of an EP4 receptor subtype agonist.
- the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of an EP4 receptor subtype agonist and a bisphosphonate active. In further embodiments, the present invention relates to a method for identifying agonists of an EP4 receptor subtype.
- the present invention relates to the use of a composition in the manufacture of a medicament for stimulating bone formation, i.e. osteogenesis, in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype agonist.
- the present invention relates to methods for stimulating bone formation, i.e. osteogenesis, in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype agonist.
- Prostaglandins E especially PGE2
- PGE2 stimulate bone formation and increase bone mass in several species, including man.
- the mechanism of this effect, the target cells and the receptors involved are not completely known.
- Specific cell- surface receptors for PGE2 for PGE2,
- EP1.4 which employ distinct secondary messenger systems have been cloned and characterized. It is believed that cyclic AMP may have a role in osteogenesis induced by PGE2.
- EP4 mRNA which peaks at 2 hours.
- systemic administration of an anabolic dose of PGE2 (3-6 g/kg) to young adult rats upregulates the expression of EP4 in tibiae and calvariae, an effect which peaks at 1-2 hours.
- PGE2 3-6 g/kg
- EP4 is expressed in osteoblastic cells in vitro and in bone marrow putative osteoprogenitor cells in vivo and is upregulated by its ligand, PGE2. Given the presence of EP4 expression in the cells examined and in bone tissue, it is found in the present invention that EP4 is the receptor subtype which mediates the anabolic effects of PGE2.
- Prostaglandins have multiple effects on bone, stimulating both reso ⁇ tion and formation.
- Systemic administration of PGE ⁇ or PGE2 to infants and to animals is clearly anabolic, stimulating bone formation and increasing bone mass.
- local administration of PGE2 into long bones stimulates new bone formation, suggesting that PGE2 acts directly on bone tissue to induce osteogenesis.
- Histological analysis of bones treated with PGE2 indicates that PGE2 increases the number of osteoblasts present on the bone surface, suggesting that prostaglandins act by recruiting osteoblasts from their precursors and/or sustaining existing osteoblasts.
- PGEs act on various cells via specific cell-surface receptors divided into 4 subtypes, EP- ., according to their relative sensitivity to selective agonists and antagonists.
- the receptor subtypes all belong to the G-protein-coupled receptor family and activate distinct secondary messenger systems such as adenylate cyclase or phospholipase C.
- EP4 and EP2 activate adenylate cyclase
- EP1 activates phospholipase C
- EP3 either lowers intracellular cAMP levels or activates phospholipase C, depending on the specific spliced variant.
- PGE2 stimulates both phosphatidylinositol and cyclic AMP transduction pathways.
- EP1 and EP4 found in osteoblastic MC3T3-E ⁇ cells are believed to play a role in the biological action of PGE2 in bone tissue.
- PGE1 a potent inducer of bone formation in humans and other species, increases intracellular cyclic AMP but has no effect on phosphatidylinositol turnover in osteoblastic cells. It is therefore believed that PGE receptors coupled to adenylate cyclases, EP2 and/or EP4, are involved in osteogenesis.
- Initial characterization of in vivo expression of EP receptors by in situ hybridization shows that in embryonic and neonatal mice, EP4 is the major form found in bone tissue, especially in preosteoblasts. See Ikeda T, Miyaura C, Ichikawa A, Narumiya S, Yoshiki S and Suda T 1995, In situ localization of three subtypes
- Bone Miner Res 10 (sup 1):S172, which is inco ⁇ orated by reference herein in its entirety. Also, it is found that EP4, but not EP2, mRNA is expressed in adult rat bone tissue and bone-derived cell lines and that expression is stimulated by PGE2.
- EP4 is expressed in total RNA from adult rat tibiae and calvariae.
- EP4 is believed to be the major adenylate cyclase-coupled PGE2 receptor expressed in osteoblastic cells and in bone tissue.
- the EP4 receptor subtype is expressed in the bone tissue of young adult rats, in which PGE2 is strongly anabolic.
- EP4 mRNA is expressed in osteoblast precursor cells. It is also found in less differentiated bone cell lines such as RCT-1, TRAJB-11 and the RP-1 periosteal cells, but not in fibroblasts. It is highly expressed in bone marrow cells that include osteoblast precursor cells, but not in fully mature osteoblasts on the bone surface. It is believed that PGE2 induces osteogenesis via an increase in the number of active osteoblasts present on the bone surface, resulting from the recruitment of osteoblast precursor cells rather than the enhancement of the activity of existing osteoblasts.
- EP4 receptor subtype is believed to be the major receptor which mediates the effects of PGE2 in rat bone tissue. Induction of EP4 by PGE2 further supports its biological role in the bone tissue and points to a mechanism of autoamplification of PGE action. inco ⁇ orated by reference herein in its entirety.
- the present invention relates to methods for stimulating bone formation, i.e. osteogenesis, in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype agonist.
- the methods and compositions of the present invention are useful for both treating and reducing the risk of disease states or conditions associated with abnormal bone reso ⁇ tion.
- disease states or conditions include, but are not limited to, osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.
- the methods comprise administering a therapeutically effective amount of an EP4 receptor subtype agonist and a bisphosphonate active.
- an EP4 receptor subtype agonist and a bisphosphonate active are deemed within the scope of the present invention.
- sequential administration the agonist and the bisphosphonate can be administered in either order.
- the agonist and bisphosphonate are typically administered within the same 24 hour period.
- the agonist and bisphosphonate are typically administered within about 4 hours of each other.
- therapeutically effective amount means that amount of the EP4 receptor subtype agonist, or other actives of the present invention, that will elicit the desired therapeutic effect or response or provide the desired benefit when administered in accordance with the desired treatment regimen.
- a prefered therapeutically effective amount is a bone formation stimulating amount.
- “Pharmaceutically acceptable” as used herein means generally suitable for administration to a mammal, including humans, from a toxicity or safety standpoint.
- the agonist is typically administered for a sufficient period of time until the desired therapeutic effect is achieved.
- the term "until the desired therapeutic effect is achieved”, as used herein, means that the therapeutic agent or agents are continuously administered, according to the dosing schedule chosen, up to the time that the clinical or medical effect sought for the disease or condition being mediated is observed by the clinician or researcher.
- the compounds are continuously administered until the desired change in bone mass or structure is observed. In such instances, achieving an increase in bone mass or a replacement of abnormal bone structure with normal bone structure are the desired objectives.
- the compounds are continuously administered for as long as necessary to prevent the undesired condition. In such instances, maintenance of bone mass density is often the objective.
- Nonlimiting examples of administration periods can range from about 2 weeks to the remaining lifespan of the mammal.
- administration periods can range from about 2 weeks to the remaining lifespan of the human, preferably from about 2 weeks to about 20 years, more preferably from about 1 month to about 20 years, more preferably from about 6 months to about 10 years, and most preferably from about 1 year to about 10 years.
- the present invention also relates to methods for identifying compounds useful as agonists of the EP4 receptor subtype. Compounds so identified are useful for stimulating bone formation.
- the present invention relates to a method for identifying compounds which agonize an EP4 receptor subtype comprising: a). contacting a putative agonist of an EP4 receptor subtype with a cell culture; and b). determining the agonist activity by comparing the agonist activity from the cell culture so contacted (i.e. the cell culture contacted with said putative agonist) with a cell culture not contacted with said putative agonist.
- the present invention also relates to a method for identifying a compound which agonizes an EP4 receptor subtype comprising: a). contacting a putative agonist of an EP4 receptor subtype with an EP4 receptor; and b). determining the agonist activity by comparing the agonist activity from the EP4 receptor so contacted (i.e. the EP4 receptor contacted with said putative agonist) with the agonist activity from an EP4 receptor not contacted with said putative agonist.
- compositions of the present invention comprise a therapeutically effective amount of an EP4 receptor agonist.
- compositions can further comprise a pharmaceutically-acceptable carrier.
- these compositions also comprise a bisphosphonate active.
- compositions of the present invention comprise an EP4 receptor subtype agonist.
- agonist as used herein, is used in its standard meaning to mean a chemical substance that can interact with a receptor and initiate a physiological or pharmacological response characteristic of that receptor.
- the agonists useful herein generally have an EC50 value from about 0.1 nM to about 100 microM, although agonists with activities outside this range can be useful depending upon the dosage and route of administration.
- the agonists have an EC50 vame of from about 0.01 microM to about 10 microM.
- the agonists have an EC50 value of from about 0.1 microM to about 10 microM.
- EC50 is a common measure of agonist activity well known to those of ordinary skill in the art and is defined as the concentration or dose of an agonist that is needed to produce half, i.e. 50%, of the maximal effect.
- Nonlimiting examples of agonists are selected from the group consisting of prostaglandin E1 , prostaglandin E2, misoprostal, 19-hydroxy prostaglandin E2, 9-oxo-8-phenyl-8-(5-phenylpentyl)decanoic acid, 8-acetyl-8- phenyl-13- ⁇ henoxytridecanoic acid, and the pharmaceutically acceptable salts thereof, and mixtures thereof.
- the methods and compositions of the present invention can further comprise a bisphosphonate active.
- the bisphosphonates of the present invention correspond to the chemical formula
- n is an integer from 0 to 7 and wherein A and X are independently selected from the group consisting of H, OH, halogen, NH2, SH, phenyl, C1-C30 alkyl, C3- C30 branched or cycloalkyl, C1-C30 substituted alkyl, C1-C10 alkyl substituted NH2, C3-C10 branched or cycloalkyl substituted NH2, C1-C10 dialkyl substituted NH2, C3-C 10 branched or cycloalkyl disubstituted NH2, C 1 -C 10 alkoxy, C 1 -C 10 alkyl substituted thio, thiophenyl, halophenylthio, C1-C10 alkyl substituted phenyl, pyridyl, furanyl, pyrrolidinyl, imidazolyl, imidazopyridinyl, and benzyl, such
- the alkyl groups can be straight, branched, or cyclic, provided that sufficient atoms are selected for the chemical formula.
- the C1-C30 substituted alkyl can include a wide variety of substituents, nonlimiting examples which include those selected from the group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, NH2, Cl -CIO alkyl or dialkyl substituted NH2, OH, SH, and Cl -CIO alkoxy.
- a non-limiting class of structures useful in the instant invention are those in which A is selected from the group consisting of H, OH, and halogen, X is selected from the group consisting of C1-C30 alkyl, C1-C30 substituted alkyl, halogen, and C1-C10 alkyl or phenyl substituted thio, and n is 0.
- a non-limiting subclass of structures useful in the instant invention are those in which A is selected from the group consisting of H, OH, and Cl, X is selected from the group consisting of C1-C30 alkyl, C1-C30 substituted alkyl, Cl, and chlorophenylthio, and n is 0.
- a non-limiting example of the subclass of structures useful in the instant invention is when A is OH and X is a 3-aminopropyl moiety, and n is 0, so that the resulting compound is a 4-amino-l,-hydroxybutylidene- 1,1 -bisphosphonate, i.e. alendronate.
- salts include those selected from the group consisting alkali metal, alkaline metal, ammonium, and mono-, di, tri-, or tetra-Cl-C30-alkyl-substituted ammonium.
- Preferred salts are those selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts.
- derivatives include those selected from the group consisting of esters, hydrates, and amides.
- bisphosphonate and “bisphosphonates”, as used herein in refeoing to the therapeutic agents of the present invention are meant to also encompass diphosphonates, biphosphonic acids, and diphosphonic acids, as well as salts and derivatives of these materials.
- the use of a specific nomenclature in referring to the bisphosphonate or bisphosphonates is not meant to limit the scope of the present invention, unless specifically indicated. Because of the mixed nomenclature currently in use by those or ordinary skill in the art, reference to a specific weight or percentage of a bisphosphonate compound in the present invention is on an acid active weight basis, unless indicated otherwise herein.
- the phrase "about 5 mg of a bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof, on an alendronic acid active weight basis” means that the amount of the bisphosphonate compound selected is calculated based on 5 mg of alendronic acid. For other bisphosphonates, the amount of bisphosphonate is calculated based on the cooesponding bisphosphonic acid.
- Nonlimiting examples of bisphosphonates useful herein include the following:
- Alendronate also known as alendronate sodium or alendronate monosodium trihydrate
- 4-amino-l-hydroxybutylidene- 1,1 -bisphosphonic acid monosodium trihydrate 4-amino-l-hydroxybutylidene- 1,1 -bisphosphonic acid monosodium trihydrate.
- a non-limiting class of bisphosphonates useful in the instant invention are selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zolendronate, pharmaceutically acceptable salts thereof, and mixtures thereof.
- a non-limiting subclass of the above-mentioned class in the instant case is selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof.
- a non- limiting example of the subclass is alendronate monosodium trihydrate.
- the EP4 receptor subtype agonists, and in further embodiments the bisphosphonate actives and any other additional actives are typically administered in admixture with suitable pharmaceutically acceptable diluents, excipients, or carriers, collectively referred to herein as "carrier materials", suitably selected with respect to the mode of administration.
- suitable pharmaceutically acceptable diluents, excipients, or carriers collectively referred to herein as "carrier materials”
- suitable pharmaceutically acceptable diluents, excipients, or carriers collectively referred to herein as "carrier materials”, suitably selected with respect to the mode of administration.
- suitable pharmaceutically acceptable diluents, excipients, or carriers collectively referred to herein as "carrier materials”
- suitable pharmaceutically acceptable diluents, excipients, or carriers collectively referred to herein as "carrier materials”
- suitable pharmaceutically acceptable diluents, excipients, or carriers collectively referred to herein as "carrier
- the active ingredient can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, croscarmellose sodium and the like.
- an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, croscarmellose sodium and the like.
- the oral drug components can be combined with any oral, non- toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
- suitable binders, lubricants, disintegrating agents and coloring agents can also be inco ⁇ orated.
- Suitable binders can include starch, gelatin, natural sugars such a glucose, anhydrous lactose, free-flow lactose, beta-lactose, and corn sweeteners, natural and synthetic gums, such as acacia, guar, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like.
- Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- An example of a tablet formulation is that described in U.S. Patent No.
- the compounds used in the present method can also be coupled with soluble polymers as targetable drug carriers.
- soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropyl- methacrylamide, and the like. The following Examples are presented to better illustrate the invention.
- 5-week old Sprague-Dawley rats (Charles River) are euthanized by CO2, their tibiae and calvariae are excised, cleaned of soft tissues and frozen immediately in liquid nitrogen.
- 6-week old rats are given a single injection of either vehicle (7% ethanol in sterile water) or an anabolic dose of PGE2 (Cayman Chemical, Ann Arbor, MI), 3-
- Animals are euthanized at several time points post-injection and their tibiae and calvariae, as well as samples from lung and kidney tissues are frozen in liquid nitrogen.
- RP-1 periosteal cells are spontaneously immortalized from primary cultures of periosteal cells from tibae of 4-week old Sprague-Dawley rats and are cultured in DMEM (BRL, Gaithersburg, MD) with 10 % fetal bovine serum (JRH Biosciences, Lenexa, KS). These cells do not express osteoblastic phenotypic markers in early culture, but upon confluence, express type I collagen, alkaline phosphatase and osteocalcin and produce mineralized extracellular matrix.
- RCT-1 and RCT-3 are clonal cell lines immortalized by SV-40 large T antigen from cells released from fetal rat calvair by a cmbination collagenase/hyaluronidase digestion.
- RCT-1 cells derived from cells released during the first 10 minutes of digestion (fraction I), are cultured in RPMI 1640 medium (BRL) with 10% fetal bovine serum and 0.4 mg/ ml G418 (BRL). These cells differentiate and express osteoblastic features upon retinoic acid treatment.
- RCT-3 cells immortalized from osteoblast-enriched fraction III cells, are cultured in F-12 medium (BRL) with 5% Fetal bovine serum and 0.4 mg/ml G418.
- TRAB-11 cells are also immortalized by SV40 large T antigen from adult rat tibia and are cultured in RPMI 1640 medium with 10% FBS and 0.4 mg/ml G418.
- ROS 17/2.8 rat osteosarcoma cells are cultured in F-12 containing 5% FBS.
- Osteoblast-enriched (fraction III) primary fetal rat calvaria cells are obtained by collagenase/hyaluronidase digestion of calvariae of 19 day-old rat fetuses. See Rodan et al., Growth stimulation of rat calvaria osteoblastic cells by acidic FGF, Endocrinology, 121, 1919-1923
- FBS normal rat kidney fibroblasts
- NRK normal rat kidney fibroblasts
- RNA is extracted from the tibial metaphysis or diaphysis and calvaria using a guanidinium isothiocyanate-phenol-chloroform method after pulverizing frozen bone samples by a tissue homogenizer. See P. Chomczynski et al., Single-step method of RNA isolation by acid guanidium thiocyanate-phenol- chloroform extraction., Analyt Biochem, 162, 156-159 (1987), which is inco ⁇ orated by reference herein in its entirety. RNA samples (20 mg) are separated on 0.9% agarose/formaldehyde gels and transferred onto nylon membranes (Boehringer Mannheim, Germany).
- Membranes are prehybridized in Hybrisol I (Oncor, Gaithersburg, MD) and 0.5 mg/ml sonicated salmon sperm DNA (Boehringer) at 42°C for 3 hours and are hybridized at 42°C with rat EP2 and mouse EP4 cDNA probes labeled with [32p]-dCTP (Amersham, Buckinghamshire, UK) by random priming using the rediprime kit (Amersham). After hybridization, membranes are washed 4 times in 2xSSC + 0.1% SDS at room temperature for a total of 1 hour and once with 0.2xSSC + 0.1 % SDS at 55°C for 1 hour and then exposed to Kodak XAR 2 film at -70°C using intensifying screens.
- Frozen tibiae are sectioned coronally at 7 mm thickness and sections are mounted on charged slides (Probe On Plus, Fisher Scientific, Springfield, NJ) and are kept at -70°C until hybridization.
- cRNA probes are labeled with 35s-UTPgS (ICN, Costa Mesa, CA) using a Riboprobe II kit (Promega Madison, WI).
- Hybridization is performed overnight at 50° C. See M. Weinreb et al, Different pattern of alkaline phosphatase, osteopontin and osteocalcin expression in developing rat bone visualized by in-situ hybridization, J. Bone Miner Res., 5, 831-842 (1990) and D. Shinar et al., Expression ofalphav and beta3 integrin subunits in rat osteoclasts in situ, J. Bone Miner. Res., 8, 403-414 (1993), which are both inco ⁇ orated by reference herein in their entirety.
- EP4 and EP2 mRNA are examined in various bone derived cells including osteoblast-enriched primary rat calvaria cells, immortalized osteoblastic cell lines from fetal rat calvaria or from adult rat tibia and an osteoblastic osteosarcoma cell line. Most of the osteoblastic cells and cell lines show significant amounts of 3.8 kb EP4 mRNA, except for the rat osteosarcoma cell line ROS 17/2.8. Consistent with this finding, in ROS 17/2.8 cells PGE2 has no effect on intracellular cAMP, which is markedly induced in RCT-3 and TRAB-11 cells. Treatment of RCT-
- EP4 mRNA 1 cells with retinoic acid, which promotes their differentiation, reduces the levels of EP4 mRNA.
- NRK fibroblasts do not express EP4 mRNA, while P815 mastocytoma cells, used as positive controls, express large amounts of EP4 mRNA.
- EP4 mRNA In contrast to EP4 mRNA, none of the osteoblastic cells and cell lines express detectable amounts of EP2 mRA in total RNA samples. Expression of EP4 mRNA in osteoblastic cells,
- EP4 is also expressed in total RNA isolated from tibiae and calvariae of 5-week-old rats. In contrast, no EP2 mRNA is found in RNA from tibial shafts. 6. PGE2 Induces The Expression Of EP4 mRNA in RP-1 Periosteal Cells And In
- PGE2 enhances its own production via upregulation of cyclooxygenase
- RP-1 cells are immortalized from a primary culture of adult rat tibia periosteum is examined. These cells express osteoblast phenotypic markers upon confluence and form mineralized bone matrix when implanted in nude mice. Similar to the other osteoblastic cells examined, RP-1
- periosteal cells express a 3.8 kb EP4 transcript.
- Treatment with PGE2 (10 M) rapidly increases EP4 mRNA levels peaking at 2 hours after treatment.
- PGE2 has no effect on EP4 mRNA levels in the more differentiated RCT-3 cells pointing to cell- type specific regulation of EP4 expression by PGE2.
- EP2 mRNA is not expressed in RP-1 cells before or after treatment with PGE2.
- PGE2 regulates EP4 mRNA levels in vivo in bone tissue
- five-week-old male rats are injected with PGE2 (3 - 6 mg/Kg).
- Systemic administration of PGE2 rapidly increased EP4 mRNA levels in the tibial diaphysis peaking at 2 h after injection.
- a similar effect of PGE2 on EP4 mRNA is observed in the tibial metaphysis and in calvaria.
- PGE2 induces EP4 mRNA levels in vitro in osteogenic periosteal cells and in vivo in bone tissue in a cell type-specific and tissue- specific manner.
- PGE2 does not induce EP2 mRNA in RP-1 cells nor in bone tissue.
- In situ hybridization is used in order to localize cells expressing EP4 in bone
- In control experiment (vehicle-injected) rats, low expression of EP4 is detected in bone marrow cells.
- Administration of a single anabolic dose of PGE2 increasesd the expression of EP4 in bone maoow cells.
- the distribution of silver grains over the bone marrow is not uniform and occurs in clumps or patches in many areas of the metaphysis.
- EP4 expression is restricted to the secondary spongiosa area and is not seen in the primary spongiosa.
- Hybridization of similar sections with a sense probe does not show any signal.
- EP4 is expressed in osteoblastic cells in vitro and in bone marrow cells in vivo, and is upregulated by its ligand, PGE2.
- prostaglandin E1 prostaglandin E2
- misoprostal 19-hydroxy prostaglandin E2
- 9-oxo- 8-phenyl-8-(5-phenylpentyl)decanoic acid 9-oxo- 8-phenyl-8-(5-phenylpentyl)decanoic acid
- 8-acetyl-8-phenyl-13- phenoxytridecanoic acid 8-acetyl-8-phenyl-13- phenoxytridecanoic acid.
- compositions are prepared using standard mixing and formation techniques.
- Tablets containing about 1 to 100 mg of an EP4 receptor subtype agonist are prepared using the following relative weights of ingredients.
- the resulting tablets are useful for administration in accordance with the methods of the present invention for stimulating bone formation.
- tablets are prepared that also contain 5 or 10 mg of a bisphosphonate active, on a bisphosphonic acid active basis, of a bisphosphonate selected from the group consisting of alendronate cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zolendronate, and pharmaceutically acceptable salts thereof.
- a bisphosphonate active on a bisphosphonic acid active basis, of a bisphosphonate selected from the group consisting of alendronate cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zolendronate, and pharmaceutically acceptable salts thereof.
- Liquid formulations are prepared using standard mixing techniques.
- a liquid formulation containing about 1 to about 100 mg of an EP4 receptor subtype agonist is prepared using the following relative weights of ingredients.
- solutions are prepared also containing 5 or 10 mg of a bisphosphonate active, on a bisphosphonic acid active basis, of a bisphosphonate selected from the group consisting of alendronate cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zolendronate, and pharmaceutically acceptable salts thereof.
- a bisphosphonate active on a bisphosphonic acid active basis, of a bisphosphonate selected from the group consisting of alendronate cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zolendronate, and pharmaceutically acceptable salts thereof.
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Abstract
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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JP2000575518A JP2002527400A (en) | 1998-10-15 | 1999-10-12 | How to stimulate bone formation |
CA002346031A CA2346031A1 (en) | 1998-10-15 | 1999-10-12 | Methods for stimulating bone formation |
AU64275/99A AU6427599A (en) | 1998-10-15 | 1999-10-12 | Methods for stimulating bone formation |
EP99951948A EP1121133A1 (en) | 1998-10-15 | 1999-10-12 | Methods for stimulating bone formation |
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US10437498P | 1998-10-15 | 1998-10-15 | |
US60/104,374 | 1998-10-15 | ||
GB9824573.1 | 1998-11-09 | ||
GBGB9824573.1A GB9824573D0 (en) | 1998-11-09 | 1998-11-09 | Methods for stimulating bone formation |
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WO2000021542A1 true WO2000021542A1 (en) | 2000-04-20 |
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PCT/US1999/023757 WO2000021542A1 (en) | 1998-10-15 | 1999-10-12 | Methods for stimulating bone formation |
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EP (1) | EP1121133A1 (en) |
JP (1) | JP2002527400A (en) |
AU (1) | AU6427599A (en) |
CA (1) | CA2346031A1 (en) |
WO (1) | WO2000021542A1 (en) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2000051585A2 (en) * | 1999-03-05 | 2000-09-08 | The Procter & Gamble Company | Use of a non-naturally-occurring ep1 selective agonist for increasing bone volume |
WO2001037877A1 (en) * | 1999-11-24 | 2001-05-31 | Ono Pharmaceutical Co., Ltd. | Remedies for diseases in association with decrease in bone mass |
EP1110949A1 (en) * | 1999-12-22 | 2001-06-27 | Pfizer Products Inc. | EP4 receptor selective agonists in the treatment of osteoporosis |
JP2002104939A (en) * | 2000-07-28 | 2002-04-10 | L'oreal Sa | Use of non-prostaglandin agonist of prostaglandin ep-2 and/or ep-4 receptor as a cosmetic for lowering, reducing or stopping loss of head and body hair |
WO2002032422A2 (en) * | 2000-10-19 | 2002-04-25 | Pfizer Pharmaceuticals Inc. | Ep4 receptor inhibitors to treat rheumatoid arthritis |
WO2002042268A2 (en) * | 2000-11-27 | 2002-05-30 | Pfizer Products Inc. | Ep4 receptor selective agonists in the treatment of osteoporosis |
WO2002047669A1 (en) * | 2000-12-14 | 2002-06-20 | Glaxo Group Limited | Use of ep4 receptor agonists for treating neuropathic pain |
EP1417975A1 (en) * | 2001-07-23 | 2004-05-12 | Ono Pharmaceutical Co., Ltd. | REMEDIES FOR DISEASES WITH BONE MASS LOSS HAVING EP sb 4 /sb AGONIST AS THE ACTIVE INGREDIENT |
WO2004073589A2 (en) * | 2003-02-24 | 2004-09-02 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with g-protein coupled receptor prostaglandin e2 ep4 (prostaglandin e2 ep4) |
US6849657B2 (en) | 2001-07-16 | 2005-02-01 | Syntex (U.S.A.) Llc | 2-pyrrolidone derivatives as prostanoid agonists |
WO2005027931A1 (en) * | 2003-09-19 | 2005-03-31 | Pfizer Products Inc. | Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin d derivatives and an ep2 or ep4 selective agonist |
US6900336B2 (en) | 2001-07-16 | 2005-05-31 | Syntex (U.S.A.) Llc | 8-aza-11-deoxy prostaglandin analogues |
US7053085B2 (en) | 2003-03-26 | 2006-05-30 | Merck & Co. Inc. | EP4 receptor agonist, compositions and methods thereof |
WO2006122403A1 (en) * | 2005-05-19 | 2006-11-23 | Merck Frosst Canada Ltd. | Quinoline derivatives as ep4 antagonists |
US7179820B2 (en) | 2003-06-06 | 2007-02-20 | Allergan, Inc. | Piperidinyl prostaglandin E analogs |
US7271183B2 (en) | 2003-01-10 | 2007-09-18 | Roche Palo Alto Llc | 2-Piperidone derivatives as prostaglandin agonists |
US7425549B2 (en) | 2001-02-06 | 2008-09-16 | The Royal Alexandra Hospital For Children | Drug for the treatment of osteonecrosis and for the management of patients at risk of developing osteonecrosis |
EP2085088A1 (en) * | 2006-10-26 | 2009-08-05 | ONO Pharmaceutical Co., Ltd. | Adhesive preparation |
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US5730715A (en) * | 1996-06-14 | 1998-03-24 | Becton Dickinson And Company | Method for the iontophoretic administration of bisphosphonates |
US5892099A (en) * | 1997-01-27 | 1999-04-06 | Ono Pharmaceutical Co., Ltd. | 3,7-dithiaprostanoic acid derivative |
-
1999
- 1999-10-12 JP JP2000575518A patent/JP2002527400A/en not_active Withdrawn
- 1999-10-12 EP EP99951948A patent/EP1121133A1/en not_active Withdrawn
- 1999-10-12 AU AU64275/99A patent/AU6427599A/en not_active Abandoned
- 1999-10-12 CA CA002346031A patent/CA2346031A1/en not_active Abandoned
- 1999-10-12 WO PCT/US1999/023757 patent/WO2000021542A1/en not_active Application Discontinuation
Patent Citations (3)
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US5616571A (en) * | 1995-06-06 | 1997-04-01 | Merck & Co., Inc. | Bisphosphonates prevent bone loss associated with immunosuppressive therapy |
US5730715A (en) * | 1996-06-14 | 1998-03-24 | Becton Dickinson And Company | Method for the iontophoretic administration of bisphosphonates |
US5892099A (en) * | 1997-01-27 | 1999-04-06 | Ono Pharmaceutical Co., Ltd. | 3,7-dithiaprostanoic acid derivative |
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Also Published As
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JP2002527400A (en) | 2002-08-27 |
CA2346031A1 (en) | 2000-04-20 |
AU6427599A (en) | 2000-05-01 |
EP1121133A1 (en) | 2001-08-08 |
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