Compositions and methods for preventing and treating heterotopic ossification and pathologic calcification
Inventors
Assignees
Publication Number
US-10456409-B2
Publication Date
2019-10-29
Expiration Date
2037-09-13
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Abstract
The present invention is directed to compositions and methods for the prevention or treatment of treatment of heterotopic ossification, vascular calcification, or pathologic calcification.
Core Innovation
The invention is directed to methods and compositions for the prevention or treatment of heterotopic ossification, vascular calcification, or other forms of pathologic calcification by administering drug combinations that include an antagonist of the Hedgehog (Hh) signaling pathway, vitamin D or its analogs (including cholecalciferol), and statins. The approach is based on the concept that these agents can inhibit osteogenesis in mesenchymal stem cells and prevent pathological calcification either alone or more effectively in combinations.
The problem being addressed is the lack of generally effective treatments for ectopic bone formation and related pathological calcifications, which can arise due to trauma, surgery, genetic diseases, and other conditions. Existing preventive treatments such as NSAIDs and radiation therapy have serious limitations and side effects. There is a need for improved treatment methods that can reduce or prevent heterotopic ossification and pathological calcification more effectively and safely.
The invention provides various methods for inhibiting osteogenesis by using combinations of Hh pathway antagonists with vitamin D or statins, combinations of vitamin D with statins, or all three agents together. These combinations, administered in a co-timely manner, produce greater inhibition of osteogenesis than individual agents alone, showing dose-dependent and synergistic effects. The treatments can be applied to patients with ectopic bone formation or calcification from various causes, and pharmaceutical compositions are also disclosed with defined dosages and formulations.
Claims Coverage
The patent contains multiple independent claims covering methods of preventing or treating heterotopic ossification, vascular calcification, or other pathological calcifications using combinations of therapeutic agents.
Combination of Hedgehog pathway antagonist and vitamin D or analogs
A method comprising administering a combination of a Hedgehog (Hh) pathway antagonist with vitamin D, cholecalciferol, or a vitamin D analog in an effective amount to prevent or treat heterotopic ossification, vascular calcification, or other pathological calcifications.
Combination of Hedgehog pathway antagonist and statin
A method comprising administering a combination of a Hedgehog (Hh) pathway antagonist with a statin in an effective amount to prevent or treat heterotopic ossification, vascular calcification, or other pathological calcifications.
Co-timely administration with specified dosages
Administration of the therapeutic agents in a co-timely manner, preferably concomitantly or essentially simultaneously, at specified dosages: Hh antagonists at 1-500 mg/day, vitamin D forms at 300-3000 IU/day, and statins at 1-500 mg/day, or adjusted dosages based on route of administration.
Specific selections of Hedgehog pathway antagonists and statins
Use of specific Hh pathway antagonists selected from a large group including arsenic trioxide, cyclopamine, GANT-58, GANT-61, among others, and statins selected from Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, Simvastatin, Pitavastatin, Cerivastatin, Lovastatin, and Mevastatin in the therapeutic combinations to treat or prevent pathological calcifications.
Single unit dosage form containing combination of agents
Pharmaceutical compositions in unit dosage form comprising the combination of a Hedgehog pathway antagonist, vitamin D or analog, and/or statin, wherein the components are present in amounts effective for treatment or prevention, and are suitable for oral or transdermal administration.
The independent claims cover methods for preventing or treating heterotopic ossification, vascular calcification, or pathological calcification by co-timely administering therapeutic combinations of Hedgehog pathway antagonists with vitamin D forms and/or statins, employing specific agent selections, dosages, and pharmaceutical formulations including single unit dosage forms to achieve synergistic therapeutic effects.
Stated Advantages
The combination therapies produce a greater degree of inhibition of osteogenesis and pathological calcification than any single agent alone, exhibiting synergistic effects.
The dose-dependent synergy allows minimizing the quantity of each agent, thereby reducing the toxicity and side effects associated with higher doses of individual compounds.
Treatment methods may reduce the frequency or severity of side effects such as weakness, fatigue, nausea, liver and kidney damage, cardiac arrhythmias, and others compared to treatment with individual agents.
Documented Applications
Prevention and treatment of heterotopic ossification and pathologic calcification following traumatic injuries, spinal cord damage, brain and head injuries, burns, fractures, muscle injuries, and surgery, especially arthroplasty.
Treatment of patients with diseases or conditions predisposing to ectopic bone formation or vascular calcification such as atherosclerosis or myocardial infarction.
Treatment of rare genetic diseases associated with ectopic bone formation or calcification including osseous heteroplasia, fibrodysplasia ossificans progressiva, and Albright's hereditary osteodystrophy.
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