US20100144684A1 - Method of Safely and Effectively Treating and Preventing Secondary Hyperparathyroidism in Chronic Kidney Disease - Google Patents
Method of Safely and Effectively Treating and Preventing Secondary Hyperparathyroidism in Chronic Kidney Disease Download PDFInfo
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- US20100144684A1 US20100144684A1 US12/597,234 US59723408A US2010144684A1 US 20100144684 A1 US20100144684 A1 US 20100144684A1 US 59723408 A US59723408 A US 59723408A US 2010144684 A1 US2010144684 A1 US 2010144684A1
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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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
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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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
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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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
- A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
- A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH
Definitions
- Secondary hyperparathyroidism is a disorder which develops primarily because of Vitamin D deficiency. It is characterized by abnormally elevated blood levels of parathyroid hormone (PTH) and, in the absence of early detection and treatment, it becomes associated with parathyroid gland hyperplasia and a constellation of metabolic bone diseases. It is a common complication of chronic kidney disease (CKD), with rising incidence as CKD progresses. Secondary hyperparathyroidism can also develop in individuals with healthy kidneys, due to environmental, cultural or dietary factors which prevent adequate Vitamin D supply.
- PTH parathyroid hormone
- CKD chronic kidney disease
- Vitamin D is a term that refers broadly to the organic substances named
- Vitamin D 2 Vitamin D 3 , Vitamin D 4 , etc., and to their metabolites and hormonal forms that influence calcium and phosphorus homeostasis.
- “Vitamin D deficiency” is a term that broadly refers to reduced or low blood levels of Vitamin D, as defined immediately above.
- Vitamin D 2 is produced in plants from ergosterol during sunlight exposure and is present, to a limited extent, in the human diet.
- Vitamin D 3 is generated from 7-dehydrocholesterol in human skin during exposure to sunlight and also is found, to a greater extent than Vitamin D 2 , in the human diet, principally in dairy products (milk and butter), brain, certain fish and fish oils, and egg yolk.
- Vitamin D supplements for human use consist of either Vitamin D 2 or Vitamin D 3 .
- Vitamin D 2 and Vitamin D 3 are metabolized into prohonnones by one or more enzymes located in the liver.
- the involved enzymes are mitochondrial and microsomal cytochrome P450 (CYP) isoforms, including CYP27A1, CYP2R1, CYP3A4,CYP2J3 and possibly others.
- CYP mitochondrial and microsomal cytochrome P450
- These enzymes metabolize Vitamin D 2 into two prohormones known as 25-hydroxyvitamin D 2 and 24(S)-hydroxyvitamin D 2
- Vitamin D 3 into a prohormone known as 25-hydroxyvitamin D 3 .
- the two 25-hydroxylated prohormones are more prominent in the blood, and are separately or collectively referred to as “25-hydroxyvitamin D”.
- Vitamin D 2 and Vitamin D 3 can be metabolized into these same prohormones outside of the liver in certain epithelial cells, such as enterocytes, which contain the same (or similar) enzymes, but extrahepatic prohormone production probably contributes little to blood levels of 25-hydroxyvitamin D.
- the rates of hepatic and extrahepatic production of the Vitamin D prohormones are not tightly regulated, and they vary mainly with intracellular concentrations of the precursors (Vitamin D 2 and Vitamin D 3 ). Higher concentrations of either precursor increase prohormone production, while lower concentrations decrease production. Hepatic production of prohormones is inhibited by high levels of 25-hydroxyvitamin D via a poorly understood mechanism apparently directed to prevention of excessive blood prohormone levels. However, there is little evidence of feedback regulation of extrahepatic prohormone production.
- Vitamin D prohormones are further metabolized in the kidneys into potent hormones by an enzyme known as CYP27B1 (or 25-hydroxyvitamin D 3 -1 ⁇ -hydroxylase) located in the proximal kidney tubule.
- the prohormones 25-hydroxyvitamin D 2 and 24(S)-hydroxyvitamin D 2 are metabolized into hormones known as 1 ⁇ ,25-dihydroxyvitamin D 2 and 1 ⁇ ,24(S)-dihydroxyvitamin D 2 .
- 25-hydroxyvitamin D 3 is metabolized into a hormone known as 1 ⁇ ,25-dihydroxyvitamin D 3 (or calcitriol). These hormones are secreted by the kidneys into the blood for systemic delivery.
- Vitamin D prohormones can be metabolized into hormones outside of the kidneys in keratinocytes, lung epithelial cells, enterocytes, cells of the immune system (e.g., macrophages) and certain other cells containing CYP27B1 or similar enzymes, but such extrarenal hormone production is incapable of sustaining normal blood levels of 1,25-dihydroxyvitamin D in advanced CKD. Extrarenal hormone production permits intracellular concentrations of 1,25-dihydroxyvitamin D to exceed and be independent of blood levels of 1,25-dihydroxyvitamin D.
- Blood levels of 1,25-dihydroxyvitamin D are precisely regulated by a feedback mechanism which involves PTH.
- the renal 1 ⁇ -hydroxylase (or CYP27B1) is stimulated by PTH and inhibited by 1,25-dihydroxyvitamin D.
- VDR Vitamin D receptors
- the secreted PTH stimulates expression of renal CYP27B1 and, thereby, increases production of Vitamin D hormones.
- the parathyroid glands attenuate further PTH secretion.
- renal production of Vitamin D hormones decreases.
- Vitamin D hormone production also directly inhibit further Vitamin D hormone production by CYP27B1.
- PTH secretion can be abnormally suppressed in situations where blood 1,25-dihydroxyvitamin D concentrations become excessively elevated, as can occur in certain disorders or more commonly as a result of bolus (usually intravenous) doses of Vitamin D hormone replacement therapies. Oversuppression of PTH secretion can cause or exacerbate disturbances in calcium homeostasis and has been linked to vascular calcification.
- the parathyroid glands and the renal CYP27B1 are so sensitive to changes in blood concentrations of Vitamin D hormones that serum 1,25-dihydroxyvitamin D is tightly controlled, fluctuating up or down by less than 20% during any 24-hour period. In contrast to renal production of Vitamin D hormones, extrarenal production is not under precise feedback control.
- the Vitamin D hormones have essential roles in human health which are mediated by the intracellular VDR.
- the Vitamin D hormones regulate blood calcium levels by controlling intestinal absorption of dietary calcium and reabsorption of calcium by the kidneys.
- the Vitamin D hormones also participate in the regulation of cellular differentiation and growth and normal bone formation and metabolism. Further, Vitamin D hormones are required for the normal functioning of the musculoskeletal, immune and renin-angiotensin systems. Numerous other roles for Vitamin D hormones are being postulated and elucidated, based on the documented presence of intracellular VDR in nearly every human tissue.
- Vitamin D hormones on specific tissues depend on the degree to which they bind to (or occupy) the intracellular VDR in those tissues.
- the three Vitamin D hormones specifically discussed herein have nearly identical affinities for the VDR and, therefore, have essentially equivalent VDR binding when present at the same intracellular concentrations. VDR binding increases as the intracellular concentrations of the hormones rise, and decreases as the intracellular concentrations fall.
- Intracellular concentrations of the Vitamin D hormones change in direct proportion to changes in blood hormone concentrations with the exception that in cells containing CYP27B1 (or similar enzymes), intracellular concentrations of the Vitamin D hormones also change in direct proportion to changes in blood and/or intracellular prohormone concentrations, as discussed above. In such cells, adequate intracellular prohormone concentrations can prevent reductions in intracellular 1,25-dihydroxyvitamin D concentrations due to low blood levels of 1,25-diydroxyvitamin D.
- Vitamin D 2 , Vitamin D 3 and their prohormonal forms have affinities for the VDR which are estimated to be at least 100-fold lower than those of the Vitamin D hormones.
- physiological concentrations of these hormone precursors exert little, if any, biological actions without prior metabolism to Vitamin D hormones.
- supraphysiological levels of these hormone precursors, especially the prohormones, in the range of 10 to 1,000 fold higher than normal, can sufficiently occupy the VDR and exert actions like the Vitamin D hormones.
- Vitamin D 2 and Vitamin D 3 Blood levels of Vitamin D 2 and Vitamin D 3 are normally present at stable, concentrations in human blood, given a sustained, adequate supply of Vitamin D from sunlight exposure and an unsupplemented diet. Slight, if any, increases in blood Vitamin D levels occur after meals since unsupplemented diets have low Vitamin D content, even those containing foods fortified with Vitamin D. The Vitamin D content of the human diet is so low that the National Institutes of Health (NIH) cautions “it can be difficult to obtain enough Vitamin D from natural food sources” [NIH, Office of Dietary Supplements, Dietary Supplement Fact Sheet: Vitamin D (2005)]. Almost all human Vitamin D supply comes from fortified foods, exposure to sunlight or from dietary supplements, with the last source becoming increasingly important.
- NASH National Institutes of Health
- Vitamin D hormone concentrations also remain generally constant through the day in healthy individuals, but can vary significantly over longer periods of time in response to seasonal changes in sunlight exposure or sustained alterations in Vitamin D intake. Marked differences in normal Vitamin D hormone levels are commonly observed between healthy individuals, with some individuals having stable concentrations as low as approximately 20 pg/mL and others as high as approximately 70 pg/mL. Due to this wide normal range, medical professionals have difficulty interpreting isolated laboratory determinations of serum total 1,25-dihydroxyvitamin D; a value of 25 pg/mL may represent a normal value for one individual or a relative deficiency in another.
- Transiently low blood levels of 1,25-dihydroxyvitamin D stimulate the parathyroid glands to secrete PTH for brief periods ending when normal blood Vitamin D hormone levels are restored.
- chronically low blood levels of 1,25-dihydroxyvitamin D continuously stimulate the parathyroid glands to secrete PTH, resulting in a disorder known as secondary hyperparathyroidism.
- Chronically low hormone levels also decrease intestinal calcium absorption, leading to reduced blood calcium concentrations (hypocalcemia) which further stimulate PTH secretion.
- Continuously stimulated parathyroid glands become increasingly hyperplastic and eventually develop resistance to regulation by Vitamin D hormones.
- secondary hyperparathyroidism progressively increases in severity, causing debilitating metabolic bone diseases, including osteoporosis and renal osteodystrophy.
- Appropriate prophylactive therapy for early stage CKD can delay or prevent the development of secondary hyperparathyroidism.
- Kidney Disease Outcomes Quality Initiative K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease [ Am. J. Kidney Dis. 42:S1-S202, 2003)].
- the K/DOQI Guidelines identified the primary etiology of secondary hyperparathyroidism as chronically low blood levels of 1,25-dihydroxyvitamin and recommended regular screening in CKD Stages 3 through 5 for elevated blood PTH levels relative to stage-specific PTH target ranges, which for Stage 3 is 35-70 pg/mL (equivalent to 3.85-7.7 pmol/L), for Stage 4 is 70-110 pg/mL (equivalent to 7.7-12.1 pmol/L), and for Stage 5 is 150-300 pg/mL (equivalent to 16.5-33.0 pmol/L) (defined in K/DOQI Guideline No. 1).
- Vitamin D hormone replacement therapies available for use in CKD patients contain 1,25-dihydroxyvitamin D 3 , 19-nor-1,25-dihdroxyvitamin D 2 , or 1-alpha-hydroxyvitamin D 2 and are formulated for quick or immediate release in the gastrointestinal tract or for bolus intravenous administration.
- these products can effectively restore serum total 1,25-dihydroxyvitamin D to levels above 20 pg/mL and lower iPTH by at least 30% in the majority of patients.
- the present invention provides a method of treating and preventing secondary hyperparathyroidism in CKD by increasing or maintaining blood concentrations of both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in a patient by administering 25-hydroxyvitamin D 3 with or without 25-hydroxyvitamin D 2 and, as necessary, 1,25-dihydroxyvitamin D 2 as a Vitamin D hormone replacement therapy.
- the blood concentrations of 25-hydroxyvitamin D are increased to and maintained at or above 30 ng/mL, with 25-hydoxyvitamin D 3 being the predominant hormone, and blood concentrations of serum total 1,25-dihydroxyvitamin D 2 are increased to or maintained within a patient's normal historical physiological range for serum total 1,25-dihydroxyvitamin D without causing side effects, including hypercalcemia, hyperphosphatemia, hypercalciuria and oversuppression of iPTH, in a significant minority of the patients.
- the invention provides a method of concurrently lowering or maintaining plasma iPTH levels, increasing or maintaining serum calcium levels, maintaining serum phosphorous levels, increasing or maintaining serum 25-hydroxyvitamin D, or increasing or maintaining serum 1,25-dihydroxyvitamin D levels in a human patient by administering to the early stage CKD patient, 25-hydroxyvitamin D 3 with or without 25-hydroxyvitamin D 2 and, as necessary, 1,25-dihydroxyvitamin D 2 , so that the blood concentrations of 25-hydroxyvitamin D are increased to and maintained at or above 30 ng/mL, with 25-hydoxyvitamin D 3 being the predominant hormone, and blood concentrations of 1,25-dihydroxyvitamin D are increased to or maintained within a patient's normal historical physiological range for 1,25-dihydroxyvitamin D.
- the invention provides a method of reducing the risk of over suppression of plasma iPTH levels in a patient undergoing treatment for elevated levels of plasma iPTH, or maintenance/prevention therapy for secondary hyperparathyroidism by administering 25-hydroxyvitamin D 3 with or without 25-hydroxyvitamin D 2 and, as necessary, 1,25-dihydroxyvitamin D 2 , so that the blood concentrations of 25-hydroxyvitamin D are increased to and maintained at or above 30 ng/mL, with 25-hydoxyvitamin D 3 being the predominant hormone, and blood concentrations of 1,25-dihydroxyvitamin D are increased to or maintained within a patient's normal historical physiological range for 1,25-dihydroxyvitamin D, and elevated plasma iPTH levels are decreased or controlled while avoiding an abnormally low bone turnover rate.
- the invention provides a method of proactively administering 25-hydroxyvitamin D 3 with or without 25-hydroxyvitamin D 2 , and/or Vitamin D 3 with or without Vitamin D 2 , to an early stage CKD patient having the potential to develop secondary hyperparathyroidism due to Vitamin D insufficiency or deficiency.
- the present invention relates to treating and preventing secondary hyperparathyroidism and the underlying chronically low blood levels of 1,25-dihydroxyvitamin D by administering safe and effective amounts of Vitamin D repletion therapy with, as necessary, 1,25-dihydrovitamin D 2 . It has been discovered that secondary hyperparathyroidism arising in CKD is frequently unresponsive to Vitamin D repletion therapy unless such therapy specifically elevates serum total 25-hydroxyvitamin D to levels of at least 30 ng/mL and consistently maintains such levels in a manner which ensures that the predominant circulating prohormone is 25-hydroxyvitamin D 3 .
- the present invention consists of increasing and then maintaining blood concentrations of 25-hydroxyvitamin D at or above 30 ng/mL, and blood concentrations of 1,25-dihydroxyvitamin D to within a patient's normal historical physiological range for 1,25-dihydroxyvitamin D by administering 25-hydroxyvitamin D 3 with or without a lesser amount of 25-hydroxyvitamin ID, and/or Vitamin D 3 with or without a lesser amount of Vitamin D 2 .
- many circumstances can lead to chronically low blood levels of 1,25-dihydroxyvitamin D, including the development of CKD, living in northern latitudes and insufficient intake of cholecalciferol and/or ergocalciferol.
- Vitamin D repletion therapy with, as necessary, 1,25-dihydroxyvitamin D 2 , can provide blood concentrations of 25-hydroxyvitamin D consistently at or above 30 ng/mL, with 25-hydroxyvitamin D 3 being the predominant circulating hormone, and blood concentrations of 1,25-dihydroxyvitamin D consistently within the patient's normal historical physiological range, which together can reduce and often normalize elevated plasma PTH levels and subsequently maintain reduced or normalized plasma PTH levels.
- the invention provides a method of concurrently lowering or maintaining plasma iPTH levels, increasing or maintaining serum calcium levels, maintaining serum phosphorous levels, increasing or maintaining serum 25-hydroxyvitamin D levels, and increasing or maintaining serum 1,25-dihydroxyvitamin D levels in a human patient by chronically administering to the patient appropriate, effective and progressively adjusted amounts of Vitamin D repletion therapy with, as necessary, one or more Vitamin D hormone replacement therapies.
- Many diseases manifest abnormal blood levels of one or more prohormones, hormones and minerals.
- CKD for example, patients may experience decreases in serum total 25-hydroxyvitamin D, and/or 1,25-dihydroxyvitamin D, increases in plasma iPTH, decreases in serum calcium and increases in serum phosphorous. Consistent therapeutic and, then, prophylactic treatment in accordance with the present invention presents concurrent leveling and/or maintaining of the prohormone, hormone and mineral levels.
- the invention provides a method of proactively administering 25-hydroxyvitamin D 3 with or without a lesser amount of 25-hydroxyvitamin D 2 , and/or Vitamin D 3 with or without a lesser amount of Vitamin D 2 , to an early stage CKD patient having the potential to develop secondary hyperparathyroidism due to Vitamin D insufficiency or Vitamin D deficiency with the result that blood concentrations of 25-hydroxyvitamin D are maintained consistently at or above 30 ng/mL, with 25-hydroxyvitamin D 3 being the predominant circulating hormone, and blood concentrations of 1,25-dihydroxyvitamin D are maintained consistently within the patient's normal historical physiological range, and plasma PTH is maintained at reduced or normal levels.
- blood concentrations of 25-hydroxyvitamin D are maintained consistently at or above 30 ng/mL, with 25-hydroxyvitamin D 3 being the predominant circulating hormone, for at least 14 days, at least 1 month, at least 30 days, at least 2 months, at least three months, at least 90 days, or at least 6 months.
- blood concentrations of 1,25-dihydroxyvitamin D are maintained consistently within the patient's normal historical physiological range, and plasma PTH is maintained at reduced or normal levels, for at least 14 days, at least 1 month, at least 30 days, at least 2 months, at least three months, at least 90 days, or at least 6 months.
- “Vitamin D insufficiency and deficiency” is generally defined as having serum 25-hydroxyvitamin D levels below 30 ng/mL (equivalent to about 75 nmol/L) (National Kidney Foundation guidelines, NKF, Am. J. Kidney Dis. 42:S1-S202 (2003), incorporated herein by reference).
- vitamin D 2 compound refers to a precursor, analog or derivative of ergocalciferol, 25-hydroxyvitamin D 2 or 1,25-dihydroxyvitamin D 2 .
- vitamin D 3 compound refers to a precursor, analog or derivative of vitamin D 3 (cholecalciferol), 25-hydroxyvitamin D 3 , or 1 ⁇ ,25-dihydroxyvitamin D 3 , including, 1 ⁇ -hydroxyvitamin D 3 , that activates the vitamin D receptor or that can be metabolically converted in a human to a compound that activates the vitamin D receptor.
- the term “patient's normal historical physiological range of serum 1,25-dihydroxyvitamin D” refers to the average blood concentration range of 1,25-dihydroxyvitamin D of a patient based on at least two annual or biannual readings of serum 1,25-dihydroxyvitamin D levels taken while the kidneys are healthy.
- hypocalcemia refers to condition in a patient wherein the patient has corrected serum levels of calcium above 10.2 mg/dL. Normal corrected serum levels of calcium for a human are between about 8.6 to 10.2 mg/dL.
- hypophosphatemia refers to a condition in a patient having normal kidney function, or Stage 1-4 CKD, wherein the patient has serum phosphorous levels above 4.6 mg/dL. In a patient who has Stage 5 CKD, hyperphosphatemia occurs when the patient has serum levels above 5.5 mg/dL. Normal values for serum phosphorous in a human are 2.4-4.5 mg/dL.
- over suppression of plasma iPTH refers to a condition in a patient having adequate kidney function, or Stage 1-3 CKD, wherein the patient has levels of plasma iPTH below 15 pg/mL.
- over suppression of plasma iPTH occurs when the patient has levels of plasma iPTH below 30 pg/mL.
- over suppression of plasma iPTH occurs when the patient has levels of plasma iPTH below 150 pg/mL.
- Vitamin D repletion therapy refers to the administration to a patient of an effective amount of a vitamin D 3 compound with a vitamin D compound, e.g., cholecalciferol with or without a lesser amount of ergocalciferol, and/or 25-hydroxyvitamin D 3 with or without a lesser amount of 25-hydroxyvitamin D 2 via any route of administration.
- a vitamin D 3 compound e.g., cholecalciferol with or without a lesser amount of ergocalciferol, and/or 25-hydroxyvitamin D 3 with or without a lesser amount of 25-hydroxyvitamin D 2 via any route of administration.
- Vitamin D hormone replacement therapy refers to the administration to a patient of an effective amount of 1,25-dihydroxyvitamin D 2 , 1,25-dihydroxyvitamin D 3 , 1,25-dihydroxyvitamin D 4 , or other metabolites and analogs of Vitamin D which can substantially occupy the intracellular VDR.
- a therapeutically effective amount depends on the patient's condition and is an amount effective to achieve a desired clinical effect, e.g. to maintain a laboratory test value within the normal range or the recommended range for that patient's condition, or an amount effective to reduce the occurrence or severity of a clinical sign or symptom of disease.
- a therapeutically effective amount is an amount effective on average to maintain serum 25-hydroxyvitamin D levels or 25-hydroxyvitamin D 3 levels at about 30 ng/mL (equivalent to about 75 nmol/L) or higher. Such levels may be maintained for an extended period, for example at least one month, at least three months, at least six months, nine months, one year, or longer.
- a therapeutically effective amount is an amount effective on average to achieve at least a 15%, 20%, 25% or 30% reduction in serum parathyroid hormone levels (iPTH) from baseline levels without treatment.
- a therapeutically effective amount is an amount effective on average to reach CKD stage-specific iPTH target ranges which for Stage 3 is 35-70 pg/mL (equivalent to 3.85-7.7 pmol/L), for Stage 4 is 70-110 pg/mL (equivalent to 7.7-12.1 pmol/L), and for Stage 5 is 150-300 pg/mL (equivalent to 16.5-33.0 pmol/L) (defined in K/DOQI Guideline No. 1).
- “therapeutically effective” can refer either to the effective amount of vitamin D 3 supplement when administered alone, or to the effective amount of vitamin D 3 compound when administered in combination with a vitamin D 2 compound.
- any numerical value recited herein includes all values from the lower value to the upper value, i.e., all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application.
- a concentration range or a beneficial effect range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3%, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended.
- Ergocalciferol, cholecalciferol, 25-hydroxyvitamin D 2 and/or 25-hydroxyvitamin D 3 , 1,25-dihydroxyvitamin D 2 , and analogs thereof are useful as pharmacologically active compounds of this invention.
- the pharmacologically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce pharmaceutical agents for administration to patients, e.g., in admixtures with conventional excipients such as pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral (e.g., oral), topical or transdermal application which do not deleteriously react with the active compounds.
- Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt (buffer) solutions, alcohols, gum arabic, mineral and vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.
- the pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic active compounds.
- auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic active compounds.
- a pharmaceutically acceptable solid carrier is used, the dosage form of the analogs may be tablets, capsules, powders, suppositories, or lozenges.
- a liquid carrier soft gelatin capsules, transdermal patches, aerosol sprays, topical creams, syrups or liquid suspensions, emulsions or solutions may be the dosage form.
- injectable, sterile solutions preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.
- Ampoules are convenient unit dosages.
- Suitable enteral application particularly suitable are tablets, dragées, liquids, drops, suppositories, or capsules such as soft gelatin capsules.
- a syrup, elixir, or the like can be used wherein a sweetened vehicle is employed.
- Sustained or directed release compositions can be formulated, e.g., liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. It is also possible to freeze-dry the new compounds and use the lypolizates obtained, for example, for the preparation of products for injection. Transdermal delivery of pharmaceutical compositions of the compounds of the invention is also possible.
- viscous to semi-solid or solid forms comprising a carrier compatible with topical application and having a dynamic viscosity preferably greater than water.
- suitable formulations include, but are not limited to, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, aerosols, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g., preservatives, etc.
- the dosage forms may also contain adjuvants, such as preserving or stabilizing adjuvants. They may also contain other therapeutically valuable substances or may contain more than one of the compounds specified herein and in the claims in admixture.
- Vitamin D repletion and Vitamin D hormone replacement therapies are preferably administered to the human patients in oral or intravenous dosage formulations.
- the administration of such therapies can be on an episodic basis, suitably from daily, to 1 to 3 times a week.
- the dosage of Vitamin D replacement therapy or Vitamin D hormone replacement therapy is about 0.5 ⁇ g to about 400 ⁇ g per week, depending on the agent selected.
- such therapies can be given in a unit dosage form between about 0.5 ⁇ g to about 100 ⁇ g, or about 0.5 ⁇ g to about 10 ⁇ g in a pharmaceutically acceptable carrier per unit dosage.
- Episodic doses can be a single dose or, optionally, divided into 2-4 subdoses which, if desired, can be given, e.g., twenty minutes to an hour apart until the total dose is given.
- Dosages for a given patient can be determined using conventional considerations, e.g., by customary comparison of the differential activities of the subject compounds and of a known agent, such as by means of an appropriate conventional pharmacological protocol.
- a physician of ordinary skill can readily determine and prescribe the effective amount of the drug required to counter or arrest the progress of the condition.
- Optimal precision in achieving concentrations of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
- the dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that an efficacious dosage is obtained.
- the active ingredient is administered to patients (animal and human) in need of treatment in dosages that will provide optimal pharmaceutical efficacy.
- compositions, methods and kits of the invention are useful for treating any subject in need of vitamin D supplementation, either prophylactically to prevent vitamin D insufficiency or deficiency, or therapeutically to replete low serum vitamin 25(OH)D levels to normal range or above.
- the compositions and methods of the invention are also useful for preventing or treating secondary hyperparathyroidism resulting from low vitamin D levels.
- serum 25(OH)D values less than 5 ng/mL indicate severe deficiency associated with rickets and osteomalacia.
- 30 ng/mL has been suggested as the low end of the normal range, more recent research suggests that PTH levels and calcium absorption are not optimized until serum total 25(OH)D levels reach approximately 40 ng/mL.
- subject or “patient” as used herein includes humans, mammals (e.g., dogs, cats, rodents, sheep, horses, cows, goats), veterinary animals and zoo animals.
- Patients in need of vitamin D supplementation include healthy subjects and subjects at risk for vitamin D insufficiency or deficiency, for example, subjects with stage 1, 2, 3, 4 or 5 chronic kidney disease; infants, children and adults that do not drink vitamin D fortified milk (e.g.
- lactose intolerant subjects subjects with milk allergy, vegetarians who do not consume milk, and breast fed infants
- subjects with rickets subjects with dark skin (e.g., in the U.S., 42% of African American women between 15 and 49 years of age were vitamin D deficient compared to 4% of white women); the elderly (who have a reduced ability to synthesize vitamin D in skin during exposure to sunlight and also are more likely to stay indoors); institutionalized adults (who are likely to stay indoors, including subjects with Alzheimer's disease or mentally ill); subjects who cover all exposed skin (such as members of certain religions or cultures); subjects who always use sunscreen (e.g., the application of sunscreen with an Sun Protection Factor (SPF) of 8 reduces production of vitamin D by 95%, and higher SPFs may further reduce cutaneous vitamin D production); subjects with fat malabsorption syndromes (including but not limited to cystic fibrosis, cholestatic liver disease, other liver disease, gallbladder disease, pancreatic enzyme deficiency, Crohn's disease,
- compositions and methods of the invention are useful for prophylactic or therapeutic treatment of vitamin D-responsive diseases, i.e., diseases where vitamin D, 25(OH)D or active vitamin D (e.g., 1, 25(OH) 2 D) prevents onset or progression of disease, or reduces signs or symptoms of disease.
- vitamin D-responsive diseases include cancer (e.g., breast, lung, skin, melanoma, colon, colorectal, rectal, prostate and bone cancer).
- 1,25(OH) 2 D has been observed to induce cell differentiation and/or inhibit cell proliferation in vitro for a number of cells.
- Vitamin D-responsive diseases also include autoimmune diseases, for example, type I diabetes, multiple sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Grave's disease, Hashimoto's disease, acute or chronic transplant rejection, acute or chronic graft versus host disease, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosis, Sjogren's Syndrome, eczema and psoriasis, dermatitis, including atopic dermatitis, contact dermatitis, allergic dermatitis and/or chronic dermatitis.
- autoimmune diseases for example, type I diabetes, multiple sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Grave's disease, Hashimoto's disease, acute or chronic transplant rejection, acute or chronic graft
- Vitamin D-responsive diseases also include other inflammatory diseases, for example, asthma, chronic obstructive pulmonary disease, polycystic kidney disease (PKD), polycystic ovary syndrome, pancreatitis, nephritis, hepatitis, and/or infection. Vitamin D-responsive diseases have also been reported to include hypertension and cardiovascular diseases.
- cardiovascular diseases for example, subjects with atherosclerosis, arteriosclerosis, coronary artery disease, cerebrovascular disease, peripheral vascular disease, myocardial infarction, myocardial ischemia, cerebral ischemia, stroke, congestive heart failure, cardiomyopathy, obesity or other weight disorders, lipid disorders (e.g.
- hyperlipidemia dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia hypoalphalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, and low HDL (high density lipoprotein)
- metabolic disorders e.g. Metabolic Syndrome, Type II diabetes mellitus, Type I diabetes mellitus, hyperinsulinemia, impaired glucose tolerance, insulin resistance, diabetic complication including neuropathy, nephropathy, retinopathy, diabetic foot ulcer and cataracts
- thrombosis e.g. Metabolic Syndrome, Type II diabetes mellitus, Type I diabetes mellitus, hyperinsulinemia, impaired glucose tolerance, insulin resistance, diabetic complication including neuropathy, nephropathy, retinopathy, diabetic foot ulcer and cataracts
- thrombosis e.g. Metabolic Syndrome, Type II diabetes mellitus, Type I diabetes mellitus, hyperinsulinemia, impaired glucose tolerance, insulin resistance, diabetic complication including neuropathy, nephropathy, reti
- Vitamin D repletion and Vitamin D hormone replacement therapies has improved efficacy in reducing or preventing elevated blood PTH levels as well as maintaining adequate and appropriate levels of serum calcium, serum phosphorous, serum total 25-hydroxyvitamin D and serum total 1,25-dihydroxyvitamin D.
- the effectiveness of 25-hydroxyvitamin D 3 and, as necessary, 1,25-dihydroxyvitamin D 2 in restoring serum total 25-hydroxyvitamin D to optimal levels (>30 ng/mL) and serum total 1,25-dihydroxyvitamin D to adequate levels (>25 pg/mL) is examined in an open-ended study of adult male and female patients with Stage 4 CKD and secondary hyperparathyroidism associated with vitamin D insufficiency.
- Two formulations are used in the study.
- One of the formulations (Formulation #1) is a soft gelatin capsule containing 30 ⁇ g of 25-hydroxyvitamin D 3 .
- the second formulation (Formulation #2) is a soft gelatin capsule containing 0.25 ⁇ g of 1,25-dihydroxyvitamin D 2 .
- the daily dosage of Formulation #1 is maintained unchanged in patients whose serum total 25-hydroxyvitamin D is between 50 and 90 ng/mL, increased by one capsule in patients whose serum total 25-hydroxyvitamin D is below 50 ng/mL, and decreased by one capsule per day in patients whose serum total 25-hydroxyvitamin D is above 90 ng/mL. Further adjustments in the daily dose are made as needed in order to maintain serum total 25-hydroxyvitamin D between 50 and 90 ng/mL. After 6 months, subjects whose serum iPTH levels are above K/DOQI targets also begin receiving a daily dose of one capsule of Formulation #2.
- the dosage of Formulation #2 is adjusted upwards in one capsule increments at monthly intervals until serum iPTH levels are lowered progressively into K/DOQI targets. Dosing with both Formulation #1 and #2 is continued indefinitely, provided that hypercalcemia, hypercalciuria and hyperphosphatemia do not develop, in which case appropriate adjustments in dosage are made.
- the subjects' ongoing serum total 25-hydroxyvitamin D levels are found to remain stable between 50 and 90 ng/mL
- serum total 1,25-dihydroxyvitamin D levels are found to remain stable at levels that are within the subjects' normal historical range prior to the onset of advanced CKD
- serum iPTH is found to remain stable at levels consistent with targets published in the K/DOQI Guidelines.
- the incidence of hypercalcemia, hypercalciuria and hyperphosphatemia are rare once stable dosing has been achieved.
Abstract
Description
- The benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application Ser. No. 60/913,850 filed Apr. 25, 2007, is hereby claimed.
- Secondary hyperparathyroidism is a disorder which develops primarily because of Vitamin D deficiency. It is characterized by abnormally elevated blood levels of parathyroid hormone (PTH) and, in the absence of early detection and treatment, it becomes associated with parathyroid gland hyperplasia and a constellation of metabolic bone diseases. It is a common complication of chronic kidney disease (CKD), with rising incidence as CKD progresses. Secondary hyperparathyroidism can also develop in individuals with healthy kidneys, due to environmental, cultural or dietary factors which prevent adequate Vitamin D supply.
- “Vitamin D” is a term that refers broadly to the organic substances named
- Vitamin D2, Vitamin D3, Vitamin D4, etc., and to their metabolites and hormonal forms that influence calcium and phosphorus homeostasis. “Vitamin D deficiency” is a term that broadly refers to reduced or low blood levels of Vitamin D, as defined immediately above.
- The most widely recognized fauns of Vitamin D are Vitamin D2 (ergocalciferol) and Vitamin D3 (cholecalciferol). Vitamin D2 is produced in plants from ergosterol during sunlight exposure and is present, to a limited extent, in the human diet. Vitamin D3 is generated from 7-dehydrocholesterol in human skin during exposure to sunlight and also is found, to a greater extent than Vitamin D2, in the human diet, principally in dairy products (milk and butter), brain, certain fish and fish oils, and egg yolk. Vitamin D supplements for human use consist of either Vitamin D2 or Vitamin D3.
- Both Vitamin D2 and Vitamin D3 are metabolized into prohonnones by one or more enzymes located in the liver. The involved enzymes are mitochondrial and microsomal cytochrome P450 (CYP) isoforms, including CYP27A1, CYP2R1, CYP3A4,CYP2J3 and possibly others. These enzymes metabolize Vitamin D2 into two prohormones known as 25-hydroxyvitamin D2 and 24(S)-hydroxyvitamin D2, and Vitamin D3 into a prohormone known as 25-hydroxyvitamin D3. The two 25-hydroxylated prohormones are more prominent in the blood, and are separately or collectively referred to as “25-hydroxyvitamin D”. Vitamin D2 and Vitamin D3 can be metabolized into these same prohormones outside of the liver in certain epithelial cells, such as enterocytes, which contain the same (or similar) enzymes, but extrahepatic prohormone production probably contributes little to blood levels of 25-hydroxyvitamin D.
- The rates of hepatic and extrahepatic production of the Vitamin D prohormones are not tightly regulated, and they vary mainly with intracellular concentrations of the precursors (Vitamin D2 and Vitamin D3). Higher concentrations of either precursor increase prohormone production, while lower concentrations decrease production. Hepatic production of prohormones is inhibited by high levels of 25-hydroxyvitamin D via a poorly understood mechanism apparently directed to prevention of excessive blood prohormone levels. However, there is little evidence of feedback regulation of extrahepatic prohormone production.
- The Vitamin D prohormones are further metabolized in the kidneys into potent hormones by an enzyme known as CYP27B1 (or 25-hydroxyvitamin D3-1α-hydroxylase) located in the proximal kidney tubule. The prohormones 25-hydroxyvitamin D2 and 24(S)-hydroxyvitamin D2 are metabolized into hormones known as 1α,25-dihydroxyvitamin D2 and 1α,24(S)-dihydroxyvitamin D2. Likewise, 25-hydroxyvitamin D3 is metabolized into a hormone known as 1α,25-dihydroxyvitamin D3 (or calcitriol). These hormones are secreted by the kidneys into the blood for systemic delivery. The two 25-hydroxylated hormones, usually far more prominent in the blood than 1α,24(S)-dihydroxyvitamin D2, are separately or collectively referred to as “1,25-dihydroxyvitamin D”. Vitamin D prohormones can be metabolized into hormones outside of the kidneys in keratinocytes, lung epithelial cells, enterocytes, cells of the immune system (e.g., macrophages) and certain other cells containing CYP27B1 or similar enzymes, but such extrarenal hormone production is incapable of sustaining normal blood levels of 1,25-dihydroxyvitamin D in advanced CKD. Extrarenal hormone production permits intracellular concentrations of 1,25-dihydroxyvitamin D to exceed and be independent of blood levels of 1,25-dihydroxyvitamin D.
- Blood levels of 1,25-dihydroxyvitamin D are precisely regulated by a feedback mechanism which involves PTH. The renal 1α-hydroxylase (or CYP27B1) is stimulated by PTH and inhibited by 1,25-dihydroxyvitamin D. When blood levels of 1,25-dihydroxyvitamin D fall, the parathyroid glands sense this change via intracellular Vitamin D receptors (VDR) and secrete PTH. The secreted PTH stimulates expression of renal CYP27B1 and, thereby, increases production of Vitamin D hormones. As blood concentrations of 1,25-dihydroxyvitamin D rise again, the parathyroid glands attenuate further PTH secretion. As blood PTH levels fall, renal production of Vitamin D hormones decreases. Rising blood levels of 1,25-dihydroxyvitamin D also directly inhibit further Vitamin D hormone production by CYP27B1. PTH secretion can be abnormally suppressed in situations where blood 1,25-dihydroxyvitamin D concentrations become excessively elevated, as can occur in certain disorders or more commonly as a result of bolus (usually intravenous) doses of Vitamin D hormone replacement therapies. Oversuppression of PTH secretion can cause or exacerbate disturbances in calcium homeostasis and has been linked to vascular calcification. The parathyroid glands and the renal CYP27B1 are so sensitive to changes in blood concentrations of Vitamin D hormones that serum 1,25-dihydroxyvitamin D is tightly controlled, fluctuating up or down by less than 20% during any 24-hour period. In contrast to renal production of Vitamin D hormones, extrarenal production is not under precise feedback control.
- The Vitamin D hormones have essential roles in human health which are mediated by the intracellular VDR. In particular, the Vitamin D hormones regulate blood calcium levels by controlling intestinal absorption of dietary calcium and reabsorption of calcium by the kidneys. The Vitamin D hormones also participate in the regulation of cellular differentiation and growth and normal bone formation and metabolism. Further, Vitamin D hormones are required for the normal functioning of the musculoskeletal, immune and renin-angiotensin systems. Numerous other roles for Vitamin D hormones are being postulated and elucidated, based on the documented presence of intracellular VDR in nearly every human tissue.
- The actions of Vitamin D hormones on specific tissues depend on the degree to which they bind to (or occupy) the intracellular VDR in those tissues. The three Vitamin D hormones specifically discussed herein have nearly identical affinities for the VDR and, therefore, have essentially equivalent VDR binding when present at the same intracellular concentrations. VDR binding increases as the intracellular concentrations of the hormones rise, and decreases as the intracellular concentrations fall. Intracellular concentrations of the Vitamin D hormones change in direct proportion to changes in blood hormone concentrations with the exception that in cells containing CYP27B1 (or similar enzymes), intracellular concentrations of the Vitamin D hormones also change in direct proportion to changes in blood and/or intracellular prohormone concentrations, as discussed above. In such cells, adequate intracellular prohormone concentrations can prevent reductions in intracellular 1,25-dihydroxyvitamin D concentrations due to low blood levels of 1,25-diydroxyvitamin D.
- Vitamin D2, Vitamin D3 and their prohormonal forms have affinities for the VDR which are estimated to be at least 100-fold lower than those of the Vitamin D hormones. As a consequence, physiological concentrations of these hormone precursors exert little, if any, biological actions without prior metabolism to Vitamin D hormones. However, supraphysiological levels of these hormone precursors, especially the prohormones, in the range of 10 to 1,000 fold higher than normal, can sufficiently occupy the VDR and exert actions like the Vitamin D hormones.
- Blood levels of Vitamin D2 and Vitamin D3 are normally present at stable, concentrations in human blood, given a sustained, adequate supply of Vitamin D from sunlight exposure and an unsupplemented diet. Slight, if any, increases in blood Vitamin D levels occur after meals since unsupplemented diets have low Vitamin D content, even those containing foods fortified with Vitamin D. The Vitamin D content of the human diet is so low that the National Institutes of Health (NIH) cautions “it can be difficult to obtain enough Vitamin D from natural food sources” [NIH, Office of Dietary Supplements, Dietary Supplement Fact Sheet: Vitamin D (2005)]. Almost all human Vitamin D supply comes from fortified foods, exposure to sunlight or from dietary supplements, with the last source becoming increasingly important. Blood Vitamin D levels rise only gradually, if at all, after sunlight exposure since cutaneous 7-dehydrocholesterol is modified by UV radiation to pre-Vitamin D3 which undergoes thermal conversion in the skin to Vitamin D3 over a period of several days before circulating in the blood.
- Blood Vitamin D hormone concentrations also remain generally constant through the day in healthy individuals, but can vary significantly over longer periods of time in response to seasonal changes in sunlight exposure or sustained alterations in Vitamin D intake. Marked differences in normal Vitamin D hormone levels are commonly observed between healthy individuals, with some individuals having stable concentrations as low as approximately 20 pg/mL and others as high as approximately 70 pg/mL. Due to this wide normal range, medical professionals have difficulty interpreting isolated laboratory determinations of serum total 1,25-dihydroxyvitamin D; a value of 25 pg/mL may represent a normal value for one individual or a relative deficiency in another.
- Transiently low blood levels of 1,25-dihydroxyvitamin D stimulate the parathyroid glands to secrete PTH for brief periods ending when normal blood Vitamin D hormone levels are restored. In contrast, chronically low blood levels of 1,25-dihydroxyvitamin D continuously stimulate the parathyroid glands to secrete PTH, resulting in a disorder known as secondary hyperparathyroidism. Chronically low hormone levels also decrease intestinal calcium absorption, leading to reduced blood calcium concentrations (hypocalcemia) which further stimulate PTH secretion. Continuously stimulated parathyroid glands become increasingly hyperplastic and eventually develop resistance to regulation by Vitamin D hormones. Without early detection and treatment, followed by consistent maintenance or preventative therapy, secondary hyperparathyroidism progressively increases in severity, causing debilitating metabolic bone diseases, including osteoporosis and renal osteodystrophy. Appropriate prophylactive therapy for early stage CKD can delay or prevent the development of secondary hyperparathyroidism.
- Chronically low blood levels of 1,25-dihydroxyvitamin D develop when there is insufficient renal CYP27B1 to produce the required supply of Vitamin D hormones, a situation which commonly arises in CKD. The activity of renal CYP27B1 declines as the Glomerular Filtration Rate (GFR) falls below approximately 60 ml/min/1.73 m2 due to the loss of functioning nephrons. In end-stage renal disease (ESRD), when the kidneys fail completely and hemodialysis is required for survival, renal CYP27B1 often becomes altogether absent. Any remaining CYP27B1 is greatly inhibited by elevated serum phosphorous (hyperphosphatemia) caused by inadequate renal excretion of dietary phosphorous.
- Chronically low blood levels of 1,25-dihydroxyvitamin also develop because of a deficiency of Vitamin D prohormones, since renal hormone production cannot proceed without the required precursors. Prohormone production declines markedly when cholecalciferol and ergocalciferol are in short supply, a condition often described in the medical literature by terms such as “Vitamin D insufficiency”, “Vitamin D deficiency” or “hypovitaminosis D”. Therefore, measurement of prohormone (serum total 25-hydroxyvitamin D) levels in blood has become the accepted method among healthcare professionals to monitor Vitamin D status. Recent studies have documented that the great majority of CKD patients have low blood levels of 25-hydroxyvitamin D, and that the prevalence of Vitamin D insufficiency and deficiency increases as CKD progresses.
- It follows that individuals most vulnerable to developing chronically low blood levels of 1,25-dihydroxyvitamin D are those with CKD. Most CKD patients typically have decreased levels of renal CYP27B1 and a shortage of 25-hydroxyvitamin D prohormones. Not surprisingly, most CKD patients develop secondary hyperparathyroidism. Unfortunately, early detection and treatment of secondary hyperparathyroidism in CKD is rare, let alone prevention.
- The National Kidney Foundation (NKF) has recently focused the medical community's attention on the need for early detection and treatment of secondary hyperparathyroidism by publishing Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease [Am. J. Kidney Dis. 42:S1-S202, 2003)]. The K/DOQI Guidelines identified the primary etiology of secondary hyperparathyroidism as chronically low blood levels of 1,25-dihydroxyvitamin and recommended regular screening in CKD Stages 3 through 5 for elevated blood PTH levels relative to stage-specific PTH target ranges, which for Stage 3 is 35-70 pg/mL (equivalent to 3.85-7.7 pmol/L), for Stage 4 is 70-110 pg/mL (equivalent to 7.7-12.1 pmol/L), and for Stage 5 is 150-300 pg/mL (equivalent to 16.5-33.0 pmol/L) (defined in K/DOQI Guideline No. 1). In the event that screening revealed an iPTH value to be above the ranges targeted for CKD Stages 3 and 4, the Guidelines recommended a follow-up evaluation of serum total 25-hydroxyvitamin D to detect possible Vitamin D insufficiency or deficiency. If 25-hydroxyvitamin D below 30 ng/mL was observed, the recommended intervention was Vitamin D repletion therapy using orally administered ergocalciferol. If 25-hydroxyvitamin D above 30 ng/mL was observed, the recommended intervention was Vitamin D hormone replacement therapy using oral or intravenous Vitamin D hormones or analogs.
- Current Vitamin D hormone replacement therapies available for use in CKD patients contain 1,25-dihydroxyvitamin D3, 19-nor-1,25-dihdroxyvitamin D2, or 1-alpha-hydroxyvitamin D2 and are formulated for quick or immediate release in the gastrointestinal tract or for bolus intravenous administration. When administered at chronically high doses (usually 0.25 to 2.0 mcg orally, or 1.0 to 10 mcg intravenously), as is usually required for adequate hormone replacement, these products can effectively restore serum total 1,25-dihydroxyvitamin D to levels above 20 pg/mL and lower iPTH by at least 30% in the majority of patients. However, they cannot be administered in high enough doses to control elevated iPTH in all patients and they sporadically cause side effects, including hypercalcemia, hyperphosphatemia, hyercalciuria and oversuppression of iPTH, in a significant minority of the patients. Health care professionals are cautious in raising the dose of these hormone replacement therapies for purposes of improving the control of secondary hyperparathyroidism in patients with excessive iPTH levels due to the increasing risk of causing such side effects.
- As explained above, all CKD patients eventually develop decreased levels of renal CYP27B1 as kidney insufficiency becomes more severe, making it even more difficult, and eventually impossible, to treat secondary hyperparathyroidism with Vitamin D repletion therapies alone. The safe and effective use of Vitamin D hormone replacement therapies, therefore, is essential in the later stages of CKD.
- Clearly, a novel alternative approach to Vitamin D hormone replacement for the treatment and prevention of secondary hyperparathyroidism in CKD Stages 3-5 is sorely needed, in view of the problems encountered with the currently available oral and intravenous Vitamin D hormone therapies.
- In one aspect the present invention provides a method of treating and preventing secondary hyperparathyroidism in CKD by increasing or maintaining blood concentrations of both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in a patient by administering 25-hydroxyvitamin D3 with or without 25-hydroxyvitamin D2 and, as necessary, 1,25-dihydroxyvitamin D2 as a Vitamin D hormone replacement therapy. The blood concentrations of 25-hydroxyvitamin D are increased to and maintained at or above 30 ng/mL, with 25-hydoxyvitamin D3 being the predominant hormone, and blood concentrations of serum total 1,25-dihydroxyvitamin D2 are increased to or maintained within a patient's normal historical physiological range for serum total 1,25-dihydroxyvitamin D without causing side effects, including hypercalcemia, hyperphosphatemia, hypercalciuria and oversuppression of iPTH, in a significant minority of the patients.
- In another aspect, the invention provides a method of concurrently lowering or maintaining plasma iPTH levels, increasing or maintaining serum calcium levels, maintaining serum phosphorous levels, increasing or maintaining serum 25-hydroxyvitamin D, or increasing or maintaining serum 1,25-dihydroxyvitamin D levels in a human patient by administering to the early stage CKD patient, 25-hydroxyvitamin D3 with or without 25-hydroxyvitamin D2 and, as necessary, 1,25-dihydroxyvitamin D2, so that the blood concentrations of 25-hydroxyvitamin D are increased to and maintained at or above 30 ng/mL, with 25-hydoxyvitamin D3 being the predominant hormone, and blood concentrations of 1,25-dihydroxyvitamin D are increased to or maintained within a patient's normal historical physiological range for 1,25-dihydroxyvitamin D.
- In yet another aspect, the invention provides a method of reducing the risk of over suppression of plasma iPTH levels in a patient undergoing treatment for elevated levels of plasma iPTH, or maintenance/prevention therapy for secondary hyperparathyroidism by administering 25-hydroxyvitamin D3 with or without 25-hydroxyvitamin D2 and, as necessary, 1,25-dihydroxyvitamin D2, so that the blood concentrations of 25-hydroxyvitamin D are increased to and maintained at or above 30 ng/mL, with 25-hydoxyvitamin D3 being the predominant hormone, and blood concentrations of 1,25-dihydroxyvitamin D are increased to or maintained within a patient's normal historical physiological range for 1,25-dihydroxyvitamin D, and elevated plasma iPTH levels are decreased or controlled while avoiding an abnormally low bone turnover rate.
- In another aspect, the invention provides a method of proactively administering 25-hydroxyvitamin D3 with or without 25-hydroxyvitamin D2, and/or Vitamin D3 with or without Vitamin D2, to an early stage CKD patient having the potential to develop secondary hyperparathyroidism due to Vitamin D insufficiency or deficiency.
- Given this invention, which is described in more detail herein, it becomes possible, for the first time, to (1) effectively and safely use 25-hydroxyvitamin D3 with or without 25-hydroxyvitamin D2, and/or Vitamin D3 with or without Vitamin D2, to treat secondary hyperparathyroidism due to Vitamin D insufficiency or deficiency in the early stages of CKD; (2) concurrently apply these Vitamin D repletion therapies and Vitamin D hormone replacement therapies for more effective treatment of secondary hyperparathyroidism in this population; (3) prevent the recurrence of secondary hyperparathyroidism due to Vitamin D insufficiency of deficiency after initial diagnosis and treatment with Vitamin D repletion therapies; and (4) prevent the development of Vitamin D insufficiency and deficiency altogether by proactive administration of Vitamin D repletion therapy.
- A fuller appreciation of the specific attributes of this invention will be gained upon an examination of the following detailed description of preferred embodiments, and the appended claim. Before the embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangements of the components set forth in the following description. The invention is capable of other embodiments and of being practiced or being carried out in various ways. Also, it is understood that the phraseology and terminology used herein are for the purpose of description and should not be regarded as limiting. The use of “including”, “having” and “comprising” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items and equivalents thereof.
- The present invention relates to treating and preventing secondary hyperparathyroidism and the underlying chronically low blood levels of 1,25-dihydroxyvitamin D by administering safe and effective amounts of Vitamin D repletion therapy with, as necessary, 1,25-dihydrovitamin D2. It has been discovered that secondary hyperparathyroidism arising in CKD is frequently unresponsive to Vitamin D repletion therapy unless such therapy specifically elevates serum total 25-hydroxyvitamin D to levels of at least 30 ng/mL and consistently maintains such levels in a manner which ensures that the predominant circulating prohormone is 25-hydroxyvitamin D3. Without ensuring the predominance of circulating 25-hydroxyvitamin D3, adequate production of 1,25-dihydroxyvitamin D by the remaining renal CYP271B is not fully supported, making control of chronically elevated PTH (or secondary hyperparathyroidism) incomplete or unlikely. Current approaches to administering Vitamin D replacement therapies to CKD patients overwhelmingly favor or promote the elevation of serum total 25-hydroxyvitamin D in such a manner that 25-hydroxyvitamin D2 becomes the predominant circulating prohormone, due to its perceived safety advantage.
- It has been further found that elevated levels of circulating either 25- hydroxyvitamin D2 or 25-hydroxyvitamin D4, in the presence of 25-hydroxyvitamin D3, do not strongly support the production of 1,25-dihydroxyvitamin D2 or 1,25-dihydroxyvitamin D4, respectively, and instead support the predominant production of other metabolites, including 24,25-dihydroxyvitamin D2 and 24,25-dihydroxyvitamin D4. Unlike 1,25-dihydroxyvitamin D2 or 1,25-dihydroxyvitamin D4, these alternative metabolites do not potently inhibit the secretion of PTH by the parathyroid glands in secondary hyperparathyroidism.
- In one aspect the present invention consists of increasing and then maintaining blood concentrations of 25-hydroxyvitamin D at or above 30 ng/mL, and blood concentrations of 1,25-dihydroxyvitamin D to within a patient's normal historical physiological range for 1,25-dihydroxyvitamin D by administering 25-hydroxyvitamin D3 with or without a lesser amount of 25-hydroxyvitamin ID, and/or Vitamin D3 with or without a lesser amount of Vitamin D2. As noted hereinbefore, many circumstances can lead to chronically low blood levels of 1,25-dihydroxyvitamin D, including the development of CKD, living in northern latitudes and insufficient intake of cholecalciferol and/or ergocalciferol. It has been found that chronic treatment of those CKD patients in need thereof with appropriate, effective and progressively adjusted Vitamin D repletion therapy with, as necessary, 1,25-dihydroxyvitamin D2, can provide blood concentrations of 25-hydroxyvitamin D consistently at or above 30 ng/mL, with 25-hydroxyvitamin D3 being the predominant circulating hormone, and blood concentrations of 1,25-dihydroxyvitamin D consistently within the patient's normal historical physiological range, which together can reduce and often normalize elevated plasma PTH levels and subsequently maintain reduced or normalized plasma PTH levels.
- In another aspect, the invention provides a method of concurrently lowering or maintaining plasma iPTH levels, increasing or maintaining serum calcium levels, maintaining serum phosphorous levels, increasing or maintaining serum 25-hydroxyvitamin D levels, and increasing or maintaining serum 1,25-dihydroxyvitamin D levels in a human patient by chronically administering to the patient appropriate, effective and progressively adjusted amounts of Vitamin D repletion therapy with, as necessary, one or more Vitamin D hormone replacement therapies. Many diseases manifest abnormal blood levels of one or more prohormones, hormones and minerals. In CKD, for example, patients may experience decreases in serum total 25-hydroxyvitamin D, and/or 1,25-dihydroxyvitamin D, increases in plasma iPTH, decreases in serum calcium and increases in serum phosphorous. Consistent therapeutic and, then, prophylactic treatment in accordance with the present invention presents concurrent leveling and/or maintaining of the prohormone, hormone and mineral levels.
- In yet another aspect, the invention provides a method of proactively administering 25-hydroxyvitamin D3 with or without a lesser amount of 25-hydroxyvitamin D2, and/or Vitamin D3 with or without a lesser amount of Vitamin D2, to an early stage CKD patient having the potential to develop secondary hyperparathyroidism due to Vitamin D insufficiency or Vitamin D deficiency with the result that blood concentrations of 25-hydroxyvitamin D are maintained consistently at or above 30 ng/mL, with 25-hydroxyvitamin D3 being the predominant circulating hormone, and blood concentrations of 1,25-dihydroxyvitamin D are maintained consistently within the patient's normal historical physiological range, and plasma PTH is maintained at reduced or normal levels.
- Preferably blood concentrations of 25-hydroxyvitamin D are maintained consistently at or above 30 ng/mL, with 25-hydroxyvitamin D3 being the predominant circulating hormone, for at least 14 days, at least 1 month, at least 30 days, at least 2 months, at least three months, at least 90 days, or at least 6 months. Further preferably, blood concentrations of 1,25-dihydroxyvitamin D are maintained consistently within the patient's normal historical physiological range, and plasma PTH is maintained at reduced or normal levels, for at least 14 days, at least 1 month, at least 30 days, at least 2 months, at least three months, at least 90 days, or at least 6 months.
- “Vitamin D insufficiency and deficiency” is generally defined as having serum 25-hydroxyvitamin D levels below 30 ng/mL (equivalent to about 75 nmol/L) (National Kidney Foundation guidelines, NKF, Am. J. Kidney Dis. 42:S1-S202 (2003), incorporated herein by reference).
- The term “vitamin D2 compound” as used herein refers to a precursor, analog or derivative of ergocalciferol, 25-hydroxyvitamin D2 or 1,25-dihydroxyvitamin D2.
- The term “vitamin D3 compound” as used herein refers to a precursor, analog or derivative of vitamin D3 (cholecalciferol), 25-hydroxyvitamin D3, or 1α,25-dihydroxyvitamin D3, including, 1α-hydroxyvitamin D3, that activates the vitamin D receptor or that can be metabolically converted in a human to a compound that activates the vitamin D receptor.
- As used herein, the term “patient's normal historical physiological range of serum 1,25-dihydroxyvitamin D” refers to the average blood concentration range of 1,25-dihydroxyvitamin D of a patient based on at least two annual or biannual readings of serum 1,25-dihydroxyvitamin D levels taken while the kidneys are healthy.
- As used herein the term “hypercalcemia” refers to condition in a patient wherein the patient has corrected serum levels of calcium above 10.2 mg/dL. Normal corrected serum levels of calcium for a human are between about 8.6 to 10.2 mg/dL.
- As used herein the term “hyperphosphatemia” refers to a condition in a patient having normal kidney function, or Stage 1-4 CKD, wherein the patient has serum phosphorous levels above 4.6 mg/dL. In a patient who has Stage 5 CKD, hyperphosphatemia occurs when the patient has serum levels above 5.5 mg/dL. Normal values for serum phosphorous in a human are 2.4-4.5 mg/dL.
- As used herein the term “over suppression of plasma iPTH” refers to a condition in a patient having adequate kidney function, or Stage 1-3 CKD, wherein the patient has levels of plasma iPTH below 15 pg/mL. In a patient having Stage 4 CKD, over suppression of plasma iPTH occurs when the patient has levels of plasma iPTH below 30 pg/mL. In a patient having Stage 5 CKD, over suppression of plasma iPTH occurs when the patient has levels of plasma iPTH below 150 pg/mL.
- As used herein, the term “Vitamin D repletion therapy” refers to the administration to a patient of an effective amount of a vitamin D3 compound with a vitamin D compound, e.g., cholecalciferol with or without a lesser amount of ergocalciferol, and/or 25-hydroxyvitamin D3 with or without a lesser amount of 25-hydroxyvitamin D2 via any route of administration.
- As used herein, the term “Vitamin D hormone replacement therapy” refers to the administration to a patient of an effective amount of 1,25-dihydroxyvitamin D2, 1,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D4, or other metabolites and analogs of Vitamin D which can substantially occupy the intracellular VDR.
- The term “therapeutically effective amount” depends on the patient's condition and is an amount effective to achieve a desired clinical effect, e.g. to maintain a laboratory test value within the normal range or the recommended range for that patient's condition, or an amount effective to reduce the occurrence or severity of a clinical sign or symptom of disease. In some embodiments, a therapeutically effective amount is an amount effective on average to maintain serum 25-hydroxyvitamin D levels or 25-hydroxyvitamin D3 levels at about 30 ng/mL (equivalent to about 75 nmol/L) or higher. Such levels may be maintained for an extended period, for example at least one month, at least three months, at least six months, nine months, one year, or longer. In other embodiments, a therapeutically effective amount is an amount effective on average to achieve at least a 15%, 20%, 25% or 30% reduction in serum parathyroid hormone levels (iPTH) from baseline levels without treatment. In yet other embodiments, a therapeutically effective amount is an amount effective on average to reach CKD stage-specific iPTH target ranges which for Stage 3 is 35-70 pg/mL (equivalent to 3.85-7.7 pmol/L), for Stage 4 is 70-110 pg/mL (equivalent to 7.7-12.1 pmol/L), and for Stage 5 is 150-300 pg/mL (equivalent to 16.5-33.0 pmol/L) (defined in K/DOQI Guideline No. 1). When used in reference to an amount of a vitamin D3 compound, “therapeutically effective” can refer either to the effective amount of vitamin D3 supplement when administered alone, or to the effective amount of vitamin D3 compound when administered in combination with a vitamin D2 compound.
- It also is specifically understood that any numerical value recited herein includes all values from the lower value to the upper value, i.e., all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application. For example, if a concentration range or a beneficial effect range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3%, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended.
- Ergocalciferol, cholecalciferol, 25-hydroxyvitamin D2 and/or 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D2, and analogs thereof are useful as pharmacologically active compounds of this invention. The pharmacologically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce pharmaceutical agents for administration to patients, e.g., in admixtures with conventional excipients such as pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral (e.g., oral), topical or transdermal application which do not deleteriously react with the active compounds. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt (buffer) solutions, alcohols, gum arabic, mineral and vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.
- The pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic active compounds. If a pharmaceutically acceptable solid carrier is used, the dosage form of the analogs may be tablets, capsules, powders, suppositories, or lozenges. If a liquid carrier is used, soft gelatin capsules, transdermal patches, aerosol sprays, topical creams, syrups or liquid suspensions, emulsions or solutions may be the dosage form.
- For parenteral application, particularly suitable are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. Ampoules are convenient unit dosages.
- For enteral application, particularly suitable are tablets, dragées, liquids, drops, suppositories, or capsules such as soft gelatin capsules. A syrup, elixir, or the like can be used wherein a sweetened vehicle is employed.
- Sustained or directed release compositions can be formulated, e.g., liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. It is also possible to freeze-dry the new compounds and use the lypolizates obtained, for example, for the preparation of products for injection. Transdermal delivery of pharmaceutical compositions of the compounds of the invention is also possible.
- For topical application, there are employed as nonsprayable forms, viscous to semi-solid or solid forms comprising a carrier compatible with topical application and having a dynamic viscosity preferably greater than water. Suitable formulations include, but are not limited to, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, aerosols, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g., preservatives, etc.
- It is possible, if desired, to produce the metabolites of certain ones of the compounds of the invention, in particular by nonchemical means. For this purpose, it is possible to convert them into a suitable form for administration together with at least one vehicle or auxiliary and, where appropriate, combined with one or more other active compounds.
- The dosage forms may also contain adjuvants, such as preserving or stabilizing adjuvants. They may also contain other therapeutically valuable substances or may contain more than one of the compounds specified herein and in the claims in admixture.
- As described hereinbefore, Vitamin D repletion and Vitamin D hormone replacement therapies are preferably administered to the human patients in oral or intravenous dosage formulations. The administration of such therapies, in accordance with the present invention, can be on an episodic basis, suitably from daily, to 1 to 3 times a week. Suitably the dosage of Vitamin D replacement therapy or Vitamin D hormone replacement therapy is about 0.5 μg to about 400 μg per week, depending on the agent selected. Suitably such therapies can be given in a unit dosage form between about 0.5 μg to about 100 μg, or about 0.5 μg to about 10 μg in a pharmaceutically acceptable carrier per unit dosage. Episodic doses can be a single dose or, optionally, divided into 2-4 subdoses which, if desired, can be given, e.g., twenty minutes to an hour apart until the total dose is given.
- Those of ordinary skill in the art will readily optimize effective doses and co-administration regimens as determined by good medical practice and the clinical condition of the individual patient. Regardless of the manner of administration, it will be appreciated that the actual preferred amounts of active compound in a specific case will vary according to the efficacy of the specific compound employed, the particular compositions formulated, the mode of application, and the particular situs and organism being treated. For example, the specific dose for a particular patient depends on age, sex, body weight, general state of health, on diet, on the timing and mode of administration, on the rate of excretion, and on medicaments used in combination and the severity of the particular disorder to which the therapy is applied. Dosages for a given patient can be determined using conventional considerations, e.g., by customary comparison of the differential activities of the subject compounds and of a known agent, such as by means of an appropriate conventional pharmacological protocol. A physician of ordinary skill can readily determine and prescribe the effective amount of the drug required to counter or arrest the progress of the condition. Optimal precision in achieving concentrations of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug. The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that an efficacious dosage is obtained. The active ingredient is administered to patients (animal and human) in need of treatment in dosages that will provide optimal pharmaceutical efficacy.
- Bulk quantities of Vitamin D and Vitamin D analogs in accordance with the present invention can be readily obtained in accordance with the many widely known processes.
- The compositions, methods and kits of the invention are useful for treating any subject in need of vitamin D supplementation, either prophylactically to prevent vitamin D insufficiency or deficiency, or therapeutically to replete low serum vitamin 25(OH)D levels to normal range or above. The compositions and methods of the invention are also useful for preventing or treating secondary hyperparathyroidism resulting from low vitamin D levels. In general, serum 25(OH)D values less than 5 ng/mL indicate severe deficiency associated with rickets and osteomalacia. Although 30 ng/mL has been suggested as the low end of the normal range, more recent research suggests that PTH levels and calcium absorption are not optimized until serum total 25(OH)D levels reach approximately 40 ng/mL. [See also Vieth, R. Prog Biophys Mol Biol. 2006 Sep; 92(1):26-32.] The term “subject” or “patient” as used herein includes humans, mammals (e.g., dogs, cats, rodents, sheep, horses, cows, goats), veterinary animals and zoo animals.
- Patients in need of vitamin D supplementation include healthy subjects and subjects at risk for vitamin D insufficiency or deficiency, for example, subjects with stage 1, 2, 3, 4 or 5 chronic kidney disease; infants, children and adults that do not drink vitamin D fortified milk (e.g. lactose intolerant subjects, subjects with milk allergy, vegetarians who do not consume milk, and breast fed infants); subjects with rickets; subjects with dark skin (e.g., in the U.S., 42% of African American women between 15 and 49 years of age were vitamin D deficient compared to 4% of white women); the elderly (who have a reduced ability to synthesize vitamin D in skin during exposure to sunlight and also are more likely to stay indoors); institutionalized adults (who are likely to stay indoors, including subjects with Alzheimer's disease or mentally ill); subjects who cover all exposed skin (such as members of certain religions or cultures); subjects who always use sunscreen (e.g., the application of sunscreen with an Sun Protection Factor (SPF) of 8 reduces production of vitamin D by 95%, and higher SPFs may further reduce cutaneous vitamin D production); subjects with fat malabsorption syndromes (including but not limited to cystic fibrosis, cholestatic liver disease, other liver disease, gallbladder disease, pancreatic enzyme deficiency, Crohn's disease, inflammatory bowel disease, sprue or celiac disease, or surgical removal of part or all of the stomach and/or intestines); subjects with inflammatory bowel disease; subjects with Crohn's disease; subjects who have had small bowel resections; subjects with gum disease; subjects taking medications that increase the catabolism of vitamin D, including phenytoin, fosphenytoin, phenobarbital, carbamazepine, and rifampin; subjects taking medications that reduce absorption of vitamin D, including cholestyramine, colestipol, orlistat, mineral oil, and fat substitutes; subjects taking medications that inhibit activation of vitamin D, including ketoconazole; subjects taking medications that decrease calcium absorption, including corticosteroids; subjects with obesity (vitamin D deposited in body fat stores is less bioavailable); subjects with osteoporosis and/or postmenopausal women. According to the Institute of Medicine's report on the Dietary Reference Intakes for vitamin D, food consumption data suggest that median intakes of vitamin D for both younger and older women are below current recommendations; data suggest that more than 50% of younger and older women are not consuming recommended amounts of vitamin D. Optionally excluded from the methods of the invention are therapeutic treatment of subjects suffering from renal osteodystrophy (including osteomalacia and osteitis fibrosa cystica).
- In other aspects, the compositions and methods of the invention are useful for prophylactic or therapeutic treatment of vitamin D-responsive diseases, i.e., diseases where vitamin D, 25(OH)D or active vitamin D (e.g., 1, 25(OH)2D) prevents onset or progression of disease, or reduces signs or symptoms of disease. Such vitamin D-responsive diseases include cancer (e.g., breast, lung, skin, melanoma, colon, colorectal, rectal, prostate and bone cancer). 1,25(OH)2D has been observed to induce cell differentiation and/or inhibit cell proliferation in vitro for a number of cells. Vitamin D-responsive diseases also include autoimmune diseases, for example, type I diabetes, multiple sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Grave's disease, Hashimoto's disease, acute or chronic transplant rejection, acute or chronic graft versus host disease, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosis, Sjogren's Syndrome, eczema and psoriasis, dermatitis, including atopic dermatitis, contact dermatitis, allergic dermatitis and/or chronic dermatitis. Vitamin D-responsive diseases also include other inflammatory diseases, for example, asthma, chronic obstructive pulmonary disease, polycystic kidney disease (PKD), polycystic ovary syndrome, pancreatitis, nephritis, hepatitis, and/or infection. Vitamin D-responsive diseases have also been reported to include hypertension and cardiovascular diseases. Thus, the invention contemplates prophylactic or therapeutic treatment of subjects at risk of or suffering from cardiovascular diseases, for example, subjects with atherosclerosis, arteriosclerosis, coronary artery disease, cerebrovascular disease, peripheral vascular disease, myocardial infarction, myocardial ischemia, cerebral ischemia, stroke, congestive heart failure, cardiomyopathy, obesity or other weight disorders, lipid disorders (e.g. hyperlipidemia, dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia hypoalphalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, and low HDL (high density lipoprotein)), metabolic disorders (e.g. Metabolic Syndrome, Type II diabetes mellitus, Type I diabetes mellitus, hyperinsulinemia, impaired glucose tolerance, insulin resistance, diabetic complication including neuropathy, nephropathy, retinopathy, diabetic foot ulcer and cataracts), and/or thrombosis.
- The present invention is further explained by the following example which should not be construed by way of limiting the scope of the present invention. The following example demonstrates that the concomitant administration of Vitamin D repletion and Vitamin D hormone replacement therapies has improved efficacy in reducing or preventing elevated blood PTH levels as well as maintaining adequate and appropriate levels of serum calcium, serum phosphorous, serum total 25-hydroxyvitamin D and serum total 1,25-dihydroxyvitamin D.
- The effectiveness of 25-hydroxyvitamin D3 and, as necessary, 1,25-dihydroxyvitamin D2 in restoring serum total 25-hydroxyvitamin D to optimal levels (>30 ng/mL) and serum total 1,25-dihydroxyvitamin D to adequate levels (>25 pg/mL) is examined in an open-ended study of adult male and female patients with Stage 4 CKD and secondary hyperparathyroidism associated with vitamin D insufficiency. Two formulations are used in the study. One of the formulations (Formulation #1) is a soft gelatin capsule containing 30 μg of 25-hydroxyvitamin D3. The second formulation (Formulation #2) is a soft gelatin capsule containing 0.25 μg of 1,25-dihydroxyvitamin D2.
- A total of 100 subjects participate in this study, all of whom are aged 30 to 70 years and have serum 25-hydoxyvitamin D levels between 15 and 29 ng/mL (inclusive) and serum intact parathyroid hormone (iPTH) levels above the target levels published in the current K/DOQI Guidelines at the time of enrolment. All subjects abstain from taking other Vitamin D supplements for 60 days before study start and continuing through study termination, and from significant sun exposure. All subjects begin daily dosing with two capsules of Formulation #1. Serum total 25-hydroxyvitamin D is measured at biweekly intervals and serum iPTH is determined at quarterly intervals. After 1 month, the daily dosage of Formulation #1 is maintained unchanged in patients whose serum total 25-hydroxyvitamin D is between 50 and 90 ng/mL, increased by one capsule in patients whose serum total 25-hydroxyvitamin D is below 50 ng/mL, and decreased by one capsule per day in patients whose serum total 25-hydroxyvitamin D is above 90 ng/mL. Further adjustments in the daily dose are made as needed in order to maintain serum total 25-hydroxyvitamin D between 50 and 90 ng/mL. After 6 months, subjects whose serum iPTH levels are above K/DOQI targets also begin receiving a daily dose of one capsule of Formulation #2. The dosage of Formulation #2 is adjusted upwards in one capsule increments at monthly intervals until serum iPTH levels are lowered progressively into K/DOQI targets. Dosing with both Formulation #1 and #2 is continued indefinitely, provided that hypercalcemia, hypercalciuria and hyperphosphatemia do not develop, in which case appropriate adjustments in dosage are made. After 1 year, the subjects' ongoing serum total 25-hydroxyvitamin D levels are found to remain stable between 50 and 90 ng/mL, serum total 1,25-dihydroxyvitamin D levels are found to remain stable at levels that are within the subjects' normal historical range prior to the onset of advanced CKD and serum iPTH is found to remain stable at levels consistent with targets published in the K/DOQI Guidelines. The incidence of hypercalcemia, hypercalciuria and hyperphosphatemia are rare once stable dosing has been achieved.
- All patents, publications and references cited herein are hereby fully incorporated by reference. In case of conflict between the present disclosure and incorporated patents, publications and references, the present disclosure should control.
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Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080261925A1 (en) * | 2006-12-29 | 2008-10-23 | Margaret Clagett-Dame | Compounds, compositions, kits and methods of use to orally and topically treat acne and other skin conditions by administering a 19-nor containing vitamin d analog with or without a retinoid |
US20120157418A1 (en) * | 2009-10-02 | 2012-06-21 | Wisconsin Alumni Research Foundation | 2-Methylene-19-Nor-Vitamin D Analogs and Their Uses |
US9408858B2 (en) | 2007-04-25 | 2016-08-09 | Opko Renal, Llc | Method for treating secondary hyperparathyroidism in CKD |
US9943530B2 (en) | 2006-02-03 | 2018-04-17 | Opko Renal, Llc | Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 |
US10220047B2 (en) | 2014-08-07 | 2019-03-05 | Opko Ireland Global Holdings, Ltd. | Adjunctive therapy with 25-hydroxyvitamin D and articles therefor |
US10302660B2 (en) | 2008-04-02 | 2019-05-28 | Opko Renal, Llc | Methods useful for vitamin D deficiency and related disorders |
US10300078B2 (en) | 2013-03-15 | 2019-05-28 | Opko Ireland Global Holdings, Ltd. | Stabilized modified release vitamin D formulation and method of administering same |
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US10668089B2 (en) | 2006-06-21 | 2020-06-02 | Opko Ireland Global Holdings, Ltd. | Method of treating and preventing secondary hyperparathyroidism |
WO2020161543A1 (en) | 2019-02-06 | 2020-08-13 | Opko Ireland Global Holdings, Limited | Method of controlling progression of hyperparathyroidism with calcifediol, and compositions for use therein |
US11026625B2 (en) | 2017-08-08 | 2021-06-08 | Fresenius Medical Care Holdings, Inc. | Systems and methods for treating and estimating progression of chronic kidney disease |
US11173168B2 (en) | 2016-03-28 | 2021-11-16 | Eirgen Pharma Ltd. | Methods of treating vitamin D insufficiency in chronic kidney disease |
US11672809B2 (en) | 2010-03-29 | 2023-06-13 | Eirgen Pharma Ltd. | Methods and compositions for reducing parathyroid levels |
US11752158B2 (en) | 2007-04-25 | 2023-09-12 | Eirgen Pharma Ltd. | Method of treating vitamin D insufficiency and deficiency |
US11801253B2 (en) | 2007-04-25 | 2023-10-31 | Opko Renal, Llc | Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008134518A2 (en) | 2007-04-25 | 2008-11-06 | Cytochroma Inc. | Methods and compounds for vitamin d therapy |
AU2009214049B2 (en) * | 2008-02-13 | 2014-02-06 | Dsm Ip Assets B.V. | Combination of vitamin D and 25-hydroxyvitamin D 3 |
EP2461815B1 (en) * | 2009-08-03 | 2014-10-22 | Wisconsin Alumni Research Foundation | Method of preventing renal disease and treating symptoms thereof |
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US9539264B2 (en) * | 2014-12-30 | 2017-01-10 | Wisconsin Alumni Research Foundation | Use of 2-methylene-19-nor-(20S)-1-alpha,25-dihydroxyvitamin D3 to treat secondary hyperparathyroidism in patients previously treated with calcimimetics |
CN108370575A (en) * | 2016-01-05 | 2018-08-03 | 富士通株式会社 | Information transferring method, device and system |
JP7106563B2 (en) | 2016-11-29 | 2022-07-26 | スミトモ ファーマ オンコロジー, インコーポレイテッド | Naphthofuran derivatives, their preparation and methods of use |
AU2021285494A1 (en) * | 2020-05-31 | 2022-12-08 | Eirgen Pharma Ltd. | Hard capsule dosage form and uses thereof |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6190695B1 (en) * | 1919-04-09 | 2001-02-20 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition containing osteogenesis-promoting substance |
US20020183288A1 (en) * | 1995-04-03 | 2002-12-05 | Bone Care International, Inc. | Method for treating and preventing hyperparathyroidism |
US20040043971A1 (en) * | 1995-04-03 | 2004-03-04 | Bone Care International, Inc. | Method of treating and preventing hyperparathyroidism with active vitamin D analogs |
US20040101554A1 (en) * | 1999-05-27 | 2004-05-27 | Drugtech Corporation | Nutritional formulations |
US20070122477A1 (en) * | 2005-10-12 | 2007-05-31 | Cytochroma, Inc. | Methods and articles for treating 25-hydroxyvitamin D insufficiency and deficiency |
WO2007092755A2 (en) * | 2006-02-03 | 2007-08-16 | Proventiv Therapeutics, Llc | Treating vitamin d insufficiency and deficiency with 25-hydroxyvitamin d2 and 25-hydroxyvitamin d3 |
US20090176748A1 (en) * | 2007-04-25 | 2009-07-09 | Cytochroma Inc. | Methods and compositions for controlled release oral dosage of a vitamin d compound |
Family Cites Families (159)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3565924A (en) | 1968-07-01 | 1971-02-23 | Wisconsin Alumni Res Found | 25-hydroxycholfcalciferol |
US3833622A (en) | 1969-03-17 | 1974-09-03 | Upjohn Co | Crystalline 25-hydroxycholecalciferol hydrate and structurally related compounds |
US3974272A (en) * | 1972-09-01 | 1976-08-10 | Merck & Co., Inc. | Palatable cholestyramine coacervate compositions |
US3880894A (en) | 1974-05-24 | 1975-04-29 | Wisconsin Alumni Res Found | 1,25-Dihydroxyergocalciferol |
US4004003A (en) | 1974-08-28 | 1977-01-18 | The Upjohn Company | 25-Hydroxycalciferol compounds for treatment of steroid-induced osteoporosis |
US4335120A (en) | 1979-03-21 | 1982-06-15 | Hoffmann-La Roche Inc. | Administration of biologically active vitamin D3 and vitamin D2 materials |
US4230701A (en) | 1979-03-21 | 1980-10-28 | Hoffmann-La Roche Inc. | Administration of biologically active vitamin D3 and vitamin D2 materials |
JPS5832823A (en) | 1981-08-20 | 1983-02-25 | Chugai Pharmaceut Co Ltd | Cancer eliminating agent |
US4721613A (en) | 1982-12-13 | 1988-01-26 | Alza Corporation | Delivery system comprising means for shielding a multiplicity of reservoirs in selected environment of use |
JPS59155309A (en) | 1983-02-22 | 1984-09-04 | Teijin Ltd | Active type vitamin d3 composition and its preparation |
US4684524A (en) | 1984-03-19 | 1987-08-04 | Alza Corporation | Rate controlled dispenser for administering beneficial agent |
US4555364A (en) | 1984-11-01 | 1985-11-26 | Wisconsin Alumni Research Foundation | Method for preparing 1-hydroxyvitamin D compounds |
US4695591A (en) | 1985-03-29 | 1987-09-22 | Schering Corporation | Controlled release dosage forms comprising hydroxypropylmethylcellulose |
US4668517A (en) | 1985-04-04 | 1987-05-26 | Norwich Eaton Pharmaceuticals, Inc. | Furazolidone dosage form |
DE3676235D1 (en) | 1985-06-04 | 1991-01-31 | Teijin Ltd | DRUG PREPARATION WITH DELAYED DELIVERY OF ACTIVE SUBSTANCE. |
JPS61293911A (en) | 1985-06-24 | 1986-12-24 | Teisan Seiyaku Kk | Sustained release preparation |
US5167965A (en) * | 1987-02-09 | 1992-12-01 | The Dow Chemical Company | Palatable cholestyramine granules, tablets and methods for preparation thereof |
US4997824A (en) | 1987-07-22 | 1991-03-05 | Teva Pharmaceutical Industries Ltd. | Combination of cholecalciferol derivatives for the treatment of renal bone disease |
US5602116A (en) | 1988-08-02 | 1997-02-11 | Bone Care International, Inc. | Method for treating and preventing secondary hyperparathyroidism |
US5104864A (en) | 1988-08-02 | 1992-04-14 | Bone Care International, Inc. | Method for treating and preventing loss of bone mass |
US5869473A (en) | 1988-08-02 | 1999-02-09 | Bone Care International, Inc. | Method for treating and preventing hyperparathyroidism |
JP2893191B2 (en) | 1988-11-08 | 1999-05-17 | 武田薬品工業株式会社 | Controlled release matrix agent |
JPH02240024A (en) | 1989-03-13 | 1990-09-25 | Ss Pharmaceut Co Ltd | Composition for active type vitamin d3s preparation |
US5026559A (en) | 1989-04-03 | 1991-06-25 | Kinaform Technology, Inc. | Sustained-release pharmaceutical preparation |
GB9004544D0 (en) | 1990-03-01 | 1990-04-25 | Leo Pharm Prod Ltd | Novel treatment ii |
JP2845342B2 (en) | 1990-04-28 | 1999-01-13 | 大正製薬株式会社 | Vitamin D Lower 3 Derivative-Containing Solid Preparation Composition |
JP2893140B2 (en) | 1990-11-30 | 1999-05-17 | エスエス製薬株式会社 | Stable vitamin D preparation |
JPH04288016A (en) | 1991-03-14 | 1992-10-13 | Tokai Capsule Kk | Production of soft capsule agent of active type vitamin d3s |
IE75709B1 (en) | 1991-04-09 | 1997-09-10 | Takeda Chemical Industries Ltd | Stabilised vitamin D preparation |
US5693615A (en) | 1991-06-05 | 1997-12-02 | The Procter & Gamble Company | Therapeutic compositions for osteoinduction |
US5266331A (en) | 1991-11-27 | 1993-11-30 | Euroceltique, S.A. | Controlled release oxycodone compositions |
US5472712A (en) | 1991-12-24 | 1995-12-05 | Euroceltique, S.A. | Controlled-release formulations coated with aqueous dispersions of ethylcellulose |
US5160742A (en) | 1991-12-31 | 1992-11-03 | Abbott Laboratories | System for delivering an active substance for sustained release |
ES2170069T3 (en) | 1992-06-22 | 2002-08-01 | Bone Care Int Inc | 1-ALFA-HYDROXIPREVITAMINE D FOR ORAL ADMINISTRATION. |
US5795882A (en) | 1992-06-22 | 1998-08-18 | Bone Care International, Inc. | Method of treating prostatic diseases using delayed and/or sustained release vitamin D formulations |
US5354743A (en) | 1992-09-15 | 1994-10-11 | Thys Jacobs Susan | Method for the treatment of premenstrual syndrome with vitamin D |
US5431917A (en) | 1992-10-08 | 1995-07-11 | Japan Elanco Company, Ltd. | Hard capsule for pharmaceutical drugs and method for producing the same |
US5342626A (en) | 1993-04-27 | 1994-08-30 | Merck & Co., Inc. | Composition and process for gelatin-free soft capsules |
JP2684587B2 (en) | 1993-06-21 | 1997-12-03 | 呉羽化学工業株式会社 | Inhibitor of bone loss in renal osteodystrophy |
US6121469A (en) | 1993-12-23 | 2000-09-19 | The Regents Of The University Of California | Therapeutically effective 1α,25-dihydroxyvitamin D3 analogs |
JPH07242550A (en) * | 1994-03-02 | 1995-09-19 | Teijin Ltd | Therapeutic agent for secondary hyperparathyroidism |
IL110117A0 (en) | 1994-06-24 | 1994-10-07 | Univ Ben Gurion | Pharmaceutical compositions comprising vitamin-d analogs |
SE9402422D0 (en) | 1994-07-08 | 1994-07-08 | Astra Ab | New beads for controlled release and a pharmaceutical preparation containing the same |
WO1996003113A1 (en) | 1994-07-22 | 1996-02-08 | G.D. Searle & Co. | Self-emulsifying drug delivery system |
JPH0892098A (en) | 1994-09-27 | 1996-04-09 | Teijin Ltd | Therapeutic medicine for consumption |
US5756123A (en) | 1994-12-01 | 1998-05-26 | Japan Elanco Co., Ltd. | Capsule shell |
US6376479B1 (en) | 1995-04-03 | 2002-04-23 | Bone Care International, Inc. | Method for treating and preventing hyperparathyroidism |
US6242434B1 (en) | 1997-08-08 | 2001-06-05 | Bone Care International, Inc. | 24-hydroxyvitamin D, analogs and uses thereof |
HUP9802303A3 (en) | 1995-09-21 | 1999-05-28 | Wisconsin Alumni Res Found | Calcitriol derivatives and their uses |
DE19549243A1 (en) | 1995-12-21 | 1997-06-26 | Schering Ag | Pharmaceutical preparations containing clathrates of cyclodextrins and unnatural vitamin D analogues |
US5958451A (en) | 1996-09-03 | 1999-09-28 | Yung Shin Pharm Ind. Co., Ltd. | Process for producing porous, controlled-release capsules and encapsulated composition |
JP2002511777A (en) | 1996-10-28 | 2002-04-16 | ゼネラル ミルズ,インコーポレイテッド | Embedding and encapsulation of controlled release particles |
JPH10158171A (en) | 1996-12-02 | 1998-06-16 | Kita:Kk | Intraocular administrating agent formulating vitamin d compound therein |
US20020128240A1 (en) | 1996-12-30 | 2002-09-12 | Bone Care International, Inc. | Treatment of hyperproliferative diseases using active vitamin D analogues |
US6503893B2 (en) * | 1996-12-30 | 2003-01-07 | Bone Care International, Inc. | Method of treating hyperproliferative diseases using active vitamin D analogues |
US20030129194A1 (en) | 1997-02-13 | 2003-07-10 | Bone Care International, Inc. | Targeted therapeutic delivery of vitamin D compounds |
US6034075A (en) | 1997-03-20 | 2000-03-07 | The Trustees Of Columbia University In The City Of New York | Method of treating polycystic ovarian syndrome |
JPH1175863A (en) | 1997-07-10 | 1999-03-23 | Kyowa Hakko Kogyo Co Ltd | 25-hydroxyvitamin d3-1-alpha-hydroxylase and dna encoding the same |
US20020076442A1 (en) | 1997-09-02 | 2002-06-20 | Martin Burke | Vitamin d3 analog loaded polymer formulations for cancer and neurodegenerative disorders |
WO1999049870A1 (en) | 1998-03-27 | 1999-10-07 | Oregon Health Sciences University | Vitamin d and its analogs in the treatment of tumors and other hyperproliferative disorders |
US6197340B1 (en) | 1998-05-28 | 2001-03-06 | Medical Research Institute | Controlled release lipoic acid |
SE9803871D0 (en) | 1998-11-11 | 1998-11-11 | Pharmacia & Upjohn Ab | Therapeutic method and formulation |
HUP0100437A3 (en) | 1998-08-27 | 2002-08-28 | Pharmacia And Upjohn Ab | Therapeutic formulation for administering tolterodine with controlled release |
US6139875A (en) | 1998-09-29 | 2000-10-31 | Eastman Chemical Company | Aqueous enteric coating composition and low gastric permeability enteric coating |
CA2346001C (en) | 1998-10-01 | 2003-12-30 | Elan Pharma International, Limited | Controlled release nanoparticulate compositions |
DE69940821D1 (en) | 1998-10-09 | 2009-06-10 | Gen Mills Inc | Encapsulation of Sensitive Liquid Components in a Matrix for the Recovery of Discrete Particle-Stable Particles |
JP3449253B2 (en) | 1998-10-29 | 2003-09-22 | シオノギクオリカプス株式会社 | Manufacturing method of hard capsule |
JP2000206312A (en) * | 1998-11-12 | 2000-07-28 | Olympus Optical Co Ltd | Optical element |
WO2000035419A2 (en) | 1998-12-17 | 2000-06-22 | Alza Corporation | Conversion of liquid filled gelatin capsules into controlled release systems by multiple coatings |
US6342249B1 (en) | 1998-12-23 | 2002-01-29 | Alza Corporation | Controlled release liquid active agent formulation dosage forms |
US6432936B1 (en) | 1999-01-20 | 2002-08-13 | Wisconsin Alumni Research Foundation | Crystalline 1α-hydroxyvitamin D2 and method of purification thereof |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
WO2000059513A1 (en) | 1999-04-01 | 2000-10-12 | Johns Hopkins University | NON-CALCEMIC, ANTIPROLIFERATIVE, TRANSCRIPTIONALLY ACTIVE SULFUR-CONTAINING ANALOGS OF 1α, 25-DIHYDROXY VITAMIN D¿3? |
DE19916419B4 (en) | 1999-04-08 | 2005-06-16 | Schering Ag | Combination preparation of vitamin D metabolites or vitamin D analogues and an estrogen partial agonist for the treatment of osteoporosis |
US6340473B1 (en) | 1999-07-07 | 2002-01-22 | R.P. Scherer Technologies, Inc. | Film forming compositions comprising modified starches and iota-carrageenan and methods for manufacturing soft capsules using same |
US6051567A (en) | 1999-08-02 | 2000-04-18 | Abbott Laboratories | Low oxygen content compositions of 1α, 25-dihydroxycholecalciferol |
US6274169B1 (en) | 1999-08-02 | 2001-08-14 | Abbott Laboratories | Low oxygen content compostions of 1α, 25-dihydroxycholecalciferol |
DE60045101D1 (en) | 1999-08-31 | 2010-11-25 | Chugai Pharmaceutical Co Ltd | CAPSULES |
US20060034937A1 (en) | 1999-11-23 | 2006-02-16 | Mahesh Patel | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
GB0007419D0 (en) | 2000-03-27 | 2000-05-17 | Smithkline Beecham Gmbh | Composition |
US6375981B1 (en) | 2000-06-01 | 2002-04-23 | A. E. Staley Manufacturing Co. | Modified starch as a replacement for gelatin in soft gel films and capsules |
CA2414407A1 (en) * | 2000-07-18 | 2002-01-24 | Bone Care International, Inc. | Stabilized 1.alpha.-hydroxy vitamin d |
EP1323404B1 (en) | 2000-08-29 | 2013-10-16 | Nisshin Kasei Co.,Ltd. | Hard capsule |
AU2002227383B2 (en) | 2000-10-30 | 2004-07-08 | Euro-Celtique S.A. | Controlled release hydrocodone formulations |
US6479649B1 (en) | 2000-12-13 | 2002-11-12 | Fmc Corporation | Production of carrageenan and carrageenan products |
CA2452577C (en) | 2001-07-05 | 2011-04-19 | Wakunaga Pharmaceutical Co., Ltd. | Soft capsules |
US7033996B2 (en) | 2001-08-31 | 2006-04-25 | University Of Medicine & Dentistry Of New Jersey | Method for the treatment of vitamin D related disease |
ES2283593T3 (en) | 2001-10-12 | 2007-11-01 | Johns Hopkins University | OXIMA LITTLE CALCEMIC ANALOGS OF 1ALFA, 25-DIHIDROXI VITAMIN D3. |
US6524788B1 (en) | 2001-11-02 | 2003-02-25 | Thomas L. Cantor | Methods for monitoring and guiding therapeutic suppression of parathyroid hormone in renal patients having secondary hyperparathyroidism |
US7056655B2 (en) * | 2001-11-02 | 2006-06-06 | Scantibodies Laboratory, Inc. | Methods for monitoring and guiding therapeutic suppression of parathyroid hormone in renal patients having secondary hyperparathyroidism |
ITMI20012366A1 (en) | 2001-11-09 | 2003-05-09 | Farmatron Ltd | THERAPEUTIC SYSTEMS STABILIZED WITH IMMEDIATE RELEASE AND / OR MODIFIED FOR THE ORAL ADMINISTRATION OF ACTIVE AND / OR EXCIPIENT PRINCIPLES AND / OR WINGS |
US7255921B2 (en) | 2001-11-22 | 2007-08-14 | Morishita Jintan Co., Ltd. | Non-gelatinous capsule shell composition and a capsule formed from the same |
CN100391464C (en) | 2001-12-03 | 2008-06-04 | 诺瓦西股份有限公司 | Pharmaceutical compositions comprising active vitamin D compounds |
FR2829142B1 (en) | 2001-12-27 | 2004-02-13 | Ulice | FILMOGENEOUS COMPOSITION OF HETEROXYLANE FOR THE MANUFACTURE OF CAPSULES THUS OBTAINED |
US7632518B2 (en) | 2002-01-15 | 2009-12-15 | Dsm Ip Assets B.V. | 25-hydroxy vitamin D3 compositions |
US6949256B2 (en) | 2002-01-18 | 2005-09-27 | Banner Pharmacaps, Inc. | Non-gelatin capsule shell formulation |
NO20021592D0 (en) | 2002-04-04 | 2002-04-04 | Fmc Biopolymer As | Polysaccharide Capsules and Method of Preparation thereof |
WO2003086415A1 (en) * | 2002-04-05 | 2003-10-23 | Merck & Co., Inc. | Method for inhibiting bone resorption with an alendronate and vitamin d formulation |
JP4490262B2 (en) | 2002-06-13 | 2010-06-23 | ジョンズ ホプキンス ユニバーシティ | 24-sulfoximine vitamin D3 compound |
US20060127484A1 (en) | 2002-07-05 | 2006-06-15 | Speirs Christopher J | Controlled release composition |
US8268352B2 (en) | 2002-08-05 | 2012-09-18 | Torrent Pharmaceuticals Limited | Modified release composition for highly soluble drugs |
AU2002368245A1 (en) | 2002-09-26 | 2004-04-19 | Young-Kweon Choi | Matrix type patch for transdermal administration of vitamin d analog and the use thereof |
US20050101576A1 (en) | 2003-11-06 | 2005-05-12 | Novacea, Inc. | Methods of using vitamin D compounds in the treatment of myelodysplastic syndromes |
US8999372B2 (en) | 2002-11-14 | 2015-04-07 | Cure Pharmaceutical Corporation | Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use |
JP2004175750A (en) | 2002-11-28 | 2004-06-24 | Kose Corp | Dermopathy inhibitor and dermopathy improving agent, and skin care preparation for external use containing them |
DE10393906T5 (en) | 2002-12-16 | 2006-01-12 | Teva Pharmaceutical Industries Ltd. | A method of increasing the bioavailability of alendronate or another bisphosphonate by administering a pre-dose of a vitamin D derivative |
BRPI0409357B8 (en) | 2003-04-14 | 2021-05-25 | Dupont Nutrition Usa Inc | homogeneous thermo-reversible gel film, process for making the gel films, soft capsules, process for making the soft capsules, and solid form |
US7816341B2 (en) | 2003-04-14 | 2010-10-19 | Fmc Corporation | Homogeneous, thermoreversible gel containing reduced viscosity carrageenan and products made therefrom |
WO2004098522A2 (en) * | 2003-04-30 | 2004-11-18 | Bioxell S.P.A. | Gemini vitamin d3 compounds and methods of use thereof |
EP1479677A1 (en) | 2003-05-19 | 2004-11-24 | Aventis Pharma Deutschland GmbH | New indole derivatives as factor xa inhibitors |
JP2007526013A (en) | 2003-06-16 | 2007-09-13 | ソルクス インコーポレイテッド | Shunt device for treating glaucoma |
US20050148557A1 (en) | 2003-07-29 | 2005-07-07 | Jin Tian | Use of Vitamin Ds to treat kidney disease |
US20050124591A1 (en) | 2003-07-29 | 2005-06-09 | Jin Tian | Use of vitamin Ds to treat kidney disease |
WO2005030222A1 (en) * | 2003-09-24 | 2005-04-07 | Bioxell S.P.A. | 1,3-diaclyated,26,27-alkyl/haloalkyl vitamin d3 compounds and methods of use thereof |
US7053075B2 (en) | 2003-11-25 | 2006-05-30 | Deluca Hector F | Methods for reducing body fat using vitamin D compounds |
US20060009425A1 (en) | 2004-05-28 | 2006-01-12 | Leticia Delgado-Herrera | Oral formulations of paricalcitol |
WO2005123120A1 (en) | 2004-06-16 | 2005-12-29 | Smart Drug Systems Inc. | Sustained release vaccine composition |
WO2006007323A2 (en) | 2004-06-28 | 2006-01-19 | Alza Corporation | Dosage forms for low solubility and/or low dissolution rate free acid pharmaceutical agents |
US20060019933A1 (en) | 2004-07-22 | 2006-01-26 | David Boardman | Process for preparing stabilized vitamin D |
JP2008508227A (en) | 2004-07-29 | 2008-03-21 | サノフイ−アベンテイス | Pharmaceutical multilayer tablets for controlled release of active ingredients with high PH-dependent solubility |
EP1809305A4 (en) * | 2004-10-15 | 2009-12-30 | Altairnano Inc | Phosphate binder with reduced pill burden |
US8231896B2 (en) | 2004-11-08 | 2012-07-31 | R.P. Scherer Technologies, Llc | Non-gelatin soft capsule system |
CN101316865B (en) | 2004-12-03 | 2012-01-25 | 科学与工业研究委员会 | Method for preparing biological degradable membrane from semi-refined kappa carrageen glycan |
US8318210B2 (en) | 2005-02-28 | 2012-11-27 | Neos Therapeutics, Lp | Compositions and methods of making sustained release liquid formulations |
US7745226B2 (en) | 2005-04-06 | 2010-06-29 | Quest Diagnostics Investments Incorporated | Methods for detecting vitamin D metabolites |
AU2006236564B2 (en) | 2005-04-15 | 2011-02-17 | Tolmar, Inc. | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
US20060257481A1 (en) | 2005-04-21 | 2006-11-16 | Decode Genetics Ehf. | Sustained release formulation and dosing schedule of leukotriene synthesis inhibitor for human therapy |
US20080134937A1 (en) | 2005-05-25 | 2008-06-12 | Joo Hwan Yang | Cellulose hard capsule enhancing mechanical film strength |
AR055099A1 (en) | 2005-07-28 | 2007-08-08 | Alza Corp | LIQUID FORMULATIONS FOR THE CONTROLLED ADMINISTRATION OF BENCISOXAZOL DERIVATIVES |
JP2009509992A (en) | 2005-09-29 | 2009-03-12 | エフ.ホフマン−ラ ロシュ アーゲー | Antibody to 25-hydroxyvitamin D |
ITFI20050206A1 (en) | 2005-09-30 | 2007-04-01 | Valpharma Sa | PHARMACEUTICAL COMPOSITION OF CONTROLLED RELEASE OF VENLAFAXINE CHLORIDRATE, AND PROCESS FOR ITS PREPARATION |
EP1959935A2 (en) | 2005-10-26 | 2008-08-27 | Banner Pharmacaps Inc. | Hydrophilic vehicle-based dual controlled release matrix system as capsule fill |
EP1951208A2 (en) | 2005-10-26 | 2008-08-06 | Banner Pharmacaps Inc. | Lipophilic vehicle-based dual controlled release matrix system as capsule fill |
AP2008004489A0 (en) | 2005-11-01 | 2008-06-30 | Cpkelco U S Inc | Films and capsules made from modified carboxymethycellulose materials and methods of making same |
WO2007068287A1 (en) | 2005-12-15 | 2007-06-21 | Laboratoria Qualiphar | Sustained release vitamin preparation |
EP2024436A1 (en) | 2006-06-06 | 2009-02-18 | Fmc Corporation | Kappa-2 carrageenan composition and products made therefrom |
ES2497494T3 (en) * | 2006-06-21 | 2014-09-23 | Opko Renal, Llc | Method of treatment and prevention of secondary hyperparathyroidism |
ES2895666T3 (en) | 2006-10-27 | 2022-02-22 | Capsugel Belgium Nv | Hydroxypropylmethylcellulose hard capsules and manufacturing process |
US8501717B2 (en) | 2007-02-09 | 2013-08-06 | Merck, Sharp & Dohme Corp. | Methods to treat and/or prevent mucositis |
WO2008134523A1 (en) | 2007-04-25 | 2008-11-06 | Proventiv Therapeutics, Llc | Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease |
WO2009047644A2 (en) | 2007-04-25 | 2009-04-16 | Cytochroma Inc. | Method of treating vitamin d insufficiency and deficiency |
DE102008006203B4 (en) * | 2008-01-26 | 2011-03-17 | Jost-Werke Gmbh | Vehicle coupling for establishing a mechanical connection between a first and a second vehicle |
AU2009214049B2 (en) | 2008-02-13 | 2014-02-06 | Dsm Ip Assets B.V. | Combination of vitamin D and 25-hydroxyvitamin D 3 |
CN101951916A (en) | 2008-02-13 | 2011-01-19 | 帝斯曼知识产权资产管理有限公司 | Use of 25-hydroxy-vitamin D3 to affect human muscle physiology |
JP6095891B2 (en) | 2008-07-24 | 2017-03-15 | ウイスコンシン アラムナイ リサーチ ファウンデーシヨンWisconsin Alumni Research Foundation | An oral dosage form comprising 25-hydroxyvitamin D3 and a method comprising administering the oral dosage form to a human once a week |
ES2532877T3 (en) | 2008-09-24 | 2015-04-01 | Evonik Röhm Gmbh | PH-dependent controlled release opioid pharmaceutical composition with resistance against the influence of ethanol |
TR201904204T4 (en) | 2009-09-10 | 2019-04-22 | Dupont Nutrition Usa Inc | Jointless alginate capsules. |
US8101203B2 (en) | 2010-01-14 | 2012-01-24 | Karl Wei Cao | Hard capsule composition and method of use |
US8101204B2 (en) | 2010-01-14 | 2012-01-24 | Karl Wei Cao | Hard capsule composition and method of use |
WO2011095388A1 (en) | 2010-02-04 | 2011-08-11 | Synthon Bv | Tolterodine bead |
MX344742B (en) | 2010-08-04 | 2017-01-05 | Scherer Technologies Llc R P | Film-forming composition for soft capsules. |
JP5982695B2 (en) | 2010-12-06 | 2016-08-31 | ディーエスエム アイピー アセッツ ビー.ブイ. | Treatment of symptoms associated with increased eotaxin using 25-hydroxyvitamin D3 |
KR101838328B1 (en) | 2010-12-28 | 2018-03-13 | 퓨처 디아그노스틱스 비.브이. | Release reagent for vitamin d |
GB2502032B (en) | 2011-03-02 | 2015-03-04 | D3 Pharma Ltd | Stable Vitamin D3 Composition |
JP5597770B2 (en) | 2011-04-20 | 2014-10-01 | サフン カプセル カンパニー, リミテッド | Non-animal soft capsule coating composition with improved disintegration and coating hardness |
CN102771688A (en) | 2011-05-13 | 2012-11-14 | 富曼实(上海)商贸有限公司 | Edible liquid-filled polysaccharide capsule |
EP2815745A1 (en) | 2013-06-21 | 2014-12-24 | Swiss Caps Rechte und Lizenzen AG | Soft shell capsule and process for its manufacture |
CN103495176B (en) | 2013-10-26 | 2015-01-28 | 中山市凯博思淀粉材料科技有限公司 | Method for preparing starch-base soft capsules based on co-blending extrusion method |
CN103520133B (en) | 2013-10-26 | 2015-02-04 | 中山市凯博思淀粉材料科技有限公司 | Preparation method of starch-based soft capsules |
-
2008
- 2008-04-25 WO PCT/US2008/061594 patent/WO2008134523A1/en active Application Filing
- 2008-04-25 JP JP2010506524A patent/JP2010525080A/en active Pending
- 2008-04-25 EP EP18155042.7A patent/EP3335712A1/en active Pending
- 2008-04-25 EP EP17158264.6A patent/EP3225243A1/en active Pending
- 2008-04-25 US US12/597,234 patent/US20100144684A1/en not_active Abandoned
- 2008-04-25 CA CA2683514A patent/CA2683514C/en active Active
- 2008-04-25 EP EP08746920A patent/EP2148683A4/en not_active Ceased
-
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- 2014-02-26 JP JP2014034861A patent/JP2014098034A/en active Pending
- 2014-05-30 US US14/291,666 patent/US20140274977A1/en not_active Abandoned
-
2017
- 2017-02-02 JP JP2017017323A patent/JP2017075183A/en active Pending
- 2017-09-29 US US15/720,830 patent/US11801253B2/en active Active
- 2017-10-24 JP JP2017205043A patent/JP2018009040A/en active Pending
-
2019
- 2019-08-06 JP JP2019144447A patent/JP2019196402A/en active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6190695B1 (en) * | 1919-04-09 | 2001-02-20 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition containing osteogenesis-promoting substance |
US20020183288A1 (en) * | 1995-04-03 | 2002-12-05 | Bone Care International, Inc. | Method for treating and preventing hyperparathyroidism |
US20040043971A1 (en) * | 1995-04-03 | 2004-03-04 | Bone Care International, Inc. | Method of treating and preventing hyperparathyroidism with active vitamin D analogs |
US20040101554A1 (en) * | 1999-05-27 | 2004-05-27 | Drugtech Corporation | Nutritional formulations |
US20070122477A1 (en) * | 2005-10-12 | 2007-05-31 | Cytochroma, Inc. | Methods and articles for treating 25-hydroxyvitamin D insufficiency and deficiency |
WO2007092755A2 (en) * | 2006-02-03 | 2007-08-16 | Proventiv Therapeutics, Llc | Treating vitamin d insufficiency and deficiency with 25-hydroxyvitamin d2 and 25-hydroxyvitamin d3 |
US20090311316A1 (en) * | 2006-02-03 | 2009-12-17 | Proventiv Thereapeutics, Llc | Treating vitamin d insufficiency and deficiency with 25-hydroxyvitamin d2 and 25-hydroxyvitamin d3 |
US20090176748A1 (en) * | 2007-04-25 | 2009-07-09 | Cytochroma Inc. | Methods and compositions for controlled release oral dosage of a vitamin d compound |
Non-Patent Citations (9)
Title |
---|
A. Fournier et al. (Kidney International, Vol. 33, Suppl. 24 (1988), pp. S. 178-S189) * |
Blunt et al.(Proc. N. A. S. Biochemistry, pages 1503-1506, August 5, 1968, 892 ref.) * |
Chonchol et al. (Kidney International (2007), 71, 134-139 (Pulished on line November 1, 2006) * |
Editors Jules Traeger, Lyon, Cantarivich F, Olmer M, Present Day Concepts in the treatment of Chronic Renal Failure, Fourier et al., Contributions to Nephrology., Basel, Krager, 1989, vol. 71, pp-64-80. * |
Haddad et al. (J. Clinical Endocrinol Metabolism 42, 284, 1976) * |
Halloran (Plasma vitamin D metabolite concentration in chronic renal failure; effect of oral administration of 25-hydroxyvitamin D3, J. clin endocrinol Metabolism, 1984 Dec 59(6) pages 1063-9) * |
Lips et al. (The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 3, pages 1212-1221) * |
Sebert et al. (Proceedings of the Eighth Workshop on Vitamin D, Paris, France, pp. 765-766, New York, Walter De Gruyter (1991). * |
Zerwekh et al (Extra-renal production of 24,25-dihydroxyvitamin D in chronic renal failure during 25 hydroxyvitamin D3 therapy, Kidney International, Vol. 23, (1983), pages 401-406), * |
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US11026625B2 (en) | 2017-08-08 | 2021-06-08 | Fresenius Medical Care Holdings, Inc. | Systems and methods for treating and estimating progression of chronic kidney disease |
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WO2019193425A1 (en) | 2018-04-03 | 2019-10-10 | Opko Ireland Global Holdings, Ltd. | Use of calcifediol in bariatric surgery patients |
WO2020161543A1 (en) | 2019-02-06 | 2020-08-13 | Opko Ireland Global Holdings, Limited | Method of controlling progression of hyperparathyroidism with calcifediol, and compositions for use therein |
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JP2014098034A (en) | 2014-05-29 |
US20180021355A1 (en) | 2018-01-25 |
CA2683514A1 (en) | 2008-11-06 |
JP2017075183A (en) | 2017-04-20 |
JP2019196402A (en) | 2019-11-14 |
EP2148683A4 (en) | 2012-09-12 |
CA2683514C (en) | 2019-07-09 |
US11801253B2 (en) | 2023-10-31 |
EP3225243A1 (en) | 2017-10-04 |
JP2010525080A (en) | 2010-07-22 |
JP2018009040A (en) | 2018-01-18 |
US20140274977A1 (en) | 2014-09-18 |
WO2008134523A1 (en) | 2008-11-06 |
EP3335712A1 (en) | 2018-06-20 |
EP2148683A1 (en) | 2010-02-03 |
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