Patent Description:
Cholecalciferol and ergocalciferol (collectively are referred to as "Vitamin D") are fat-soluble seco-steroid precursors to Vitamin D prohormones. The Vitamin D metabolites known as <NUM>-hydroxyvitamin D<NUM> and <NUM>-hydroxyvitamin D<NUM> (collectively referred to herein as "<NUM>-hydroxyvitamin D") are fat-soluble steroid prohormones to Vitamin D hormones that contribute to the maintenance of normal levels of calcium and phosphorus in the bloodstream.

Cholecalciferol and ergocalciferol are normally present at stable, low concentrations in human blood. 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. Almost all human Vitamin D supply comes from fortified foods, exposure to sunlight or from dietary supplements, with the latter source becoming increasingly important. Blood Vitamin D levels rise only gradually, if at all, after sunlight exposure since cutaneous <NUM>-dehydroxycholesterol is modified by ultraviolet (UV) radiation to pre-Vitamin D<NUM>, which undergoes thermal conversion in the skin to cholecalciferol over a period of several days before circulating in the blood. In contrast, supplements such as those currently available, do cause rapid and marked increases in intraluminal, blood and intracellular levels of Vitamin D proportional to the dose administered.

Both cholecalciferol and ergocalciferol are metabolized into prohormones by enzymes primarily located in the liver of the human body. Cholecalciferol is metabolized into a prohormone <NUM>-hydroxyvitamin D<NUM>, and ergocalciferol is metabolized into two prohormones, <NUM>-hydroxyvitamin D<NUM> and <NUM>(S)-hydroxyvitamin D<NUM>. Cholecalciferol and ergocalciferol also can be metabolized into prohormones outside of the liver in certain cells, such as enterocytes, by enzymes which are identical or similar to those found in the liver. Elevating concentrations of either precursor increases prohormone production; similarly, lowering precursor concentrations decreases hormone production. Surges in the blood levels of cholecalciferol and/or ergocalciferol ("cholecalciferol/ergocalciferol") can transiently raise intracellular Vitamin D concentrations, accelerating prohormone production and elevating intracellular and blood prohormone concentrations. Surges in the blood levels of cholecalciferol and/or ergocalciferol also can saturate the enzymes which produce the prohormones, causing the excess Vitamin D to be catabolized or shunted to long-term storage in adipose tissue. Vitamin D stored in adipose tissue is less available for future conversion to prohormones, due to local catabolism. Surges in intraluminal levels of Vitamin D after ingestion of current oral supplements can directly boost Vitamin D and prohormone concentrations in the local enterocytes, thereby exerting "first pass" effects on calcium and phosphorus metabolism in the small intestine.

The Vitamin D prohormones are further metabolized in the kidneys into potent hormones. The prohormone <NUM>-hydroxyvitamin D<NUM> is metabolized into a hormone 1α,<NUM>-dihydroxyvitamin D<NUM> (or calcitriol); likewise, <NUM>-hydroxyvitamin D<NUM> and <NUM>(S)-hydroxyvitamin D<NUM> are metabolized into hormones known as 1α,<NUM>-dihydroxyvitamin D<NUM> and 1α,<NUM>(S)-dihydroxyvitamin D<NUM>, respectively. Production of these hormones from the prohormones also can occur outside of the kidney in cells which contain the required enzyme(s).

Surges in blood or intracellular prohormone concentrations can promote excessive extrarenal hormone production, leading to local adverse effects on calcium and phosphorus metabolism. Such surges also can inhibit hepatic prohormone production from subsequent supplemental Vitamin D and promote catabolism of both Vitamin D and <NUM>-hydroxyvitamin D in the kidney and other tissues.

Blood Vitamin D hormone concentrations 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 changes in Vitamin D intake. Normally, blood levels of cholecalciferol, ergocalciferol and the three Vitamin D prohormones are also constant through the day, given a sustained, adequate supply of Vitamin D from sunlight exposure and an unsupplemented diet. Blood levels of cholecalciferol and ergocalciferol, however, can increase markedly after administration of currently available Vitamin D supplements, especially at doses which greatly exceed the amounts needed to prevent Vitamin D deficiency, rickets or osteomalacia.

The Vitamin D hormones have essential roles in human health which are mediated by intracellular Vitamin D receptors (VDR). In particular, the Vitamin D hormones regulate blood calcium levels by controlling the absorption of dietary calcium by the small intestine and the reabsorption of calcium by the kidneys. Excessive hormone levels can lead to abnormally elevated urine calcium (hypercalciuria), blood calcium (hypercalcemia) and blood phosphorus (hyperphosphatemia). The Vitamin D hormones also participate in the regulation of cellular differentiation and growth, parathyroid hormone (PTH) secretion by the parathyroid glands, 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.

Secondary hyperparathyroidism is a disorder which develops primarily because of Vitamin D insufficiency. It is characterized by abnormally elevated blood levels of 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.

As to secondary hyperparathyroidism and its occurrence in CKD, there is a progressive loss of cells of the proximal nephrons, the primary site for the synthesis of the vitamin D hormones (collectively "<NUM>,<NUM>-dihydroxyvitamin D") from <NUM>-hydroxyvitamin D<NUM> and <NUM>-hydroxyvitamin D<NUM>. In addition, the loss of functioning nephrons leads to retention of excess phosphorus which reduces the activity of the renal <NUM>-hydroxyvitamin D-1α-hydroxylase, the enzyme which catalyzes the reaction to produce the D hormones. These two events account for the low serum levels of <NUM>,<NUM>-dihydroxyvitamin D commonly found in patients with moderate to severe CKD when Vitamin D supply is adequate.

Reduced serum levels of <NUM>,<NUM>-dihydroxyvitamin D cause increased, and ultimately excessive, secretion of PTH by direct and indirect mechanisms. The resulting hyperparathyroidism leads to markedly increased bone turnover and its sequela of renal osteodystrophy, which may include a variety of other diseases, such as, osteitis fibrosa cystica, osteomalacia, osteoporosis, extraskeletal calcification and related disorders, e.g., bone pain, periarticular inflammation and Mockerberg's sclerosis. Reduced serum levels of <NUM>,<NUM>-dihydroxyvitamin D also can cause muscle weakness and growth retardation with skeletal deformities (most often seen in pediatric patients).

Blood levels of <NUM>,<NUM>-dihydroxyvitamin D are precisely regulated by a feedback mechanism which involves PTH and vitamin D hormone. The renal 1α-hydroxylase (or CYP27B <NUM>) is stimulated by PTH and inhibited by <NUM>,<NUM>-dihydroxyvitamin D. When blood levels of <NUM>,<NUM>-dihydroxyvitamin D fall, the parathyroid glands sense this change via intracellular Vitamin D receptors and secrete PTH. The secreted PTH stimulates expression of renal CYP27B1 and, thereby, increases production of Vitamin D hormones. As blood concentrations of <NUM>,<NUM>-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 <NUM>,<NUM>-dihydroxyvitamin D also directly inhibit further Vitamin D hormone production by CYP27B1.

PTH secretion can be abnormally and excessively suppressed in situations where blood <NUM>,<NUM>-dihydroxyvitamin D concentrations become excessively elevated, as can occur in certain disorders such as sarcoidosis or as a result of bolus doses of Vitamin D hormone replacement therapies. Oversuppression of PTH secretion can cause or exacerbate disturbances in calcium homeostasis. The parathyroid glands and the renal CYP27B1 are exquisitely sensitive to changes in blood concentrations of Vitamin D hormones such that serum <NUM>,<NUM>-dihydroxyvitamin D is tightly controlled, fluctuating up or down by less than <NUM>% during any <NUM>-hour period. In contrast to renal production of Vitamin D hormones, extrarenal production is not under precise feedback control.

Blood levels of <NUM>,<NUM>-dihydroxyvitamin D and substrate <NUM>-hydroxyvitamin D prohormone, and regulation thereof, can also be affected by vitamin D hormone analogs, such as 1α-hydroxyvitamin D<NUM> and <NUM>-nor-<NUM>,<NUM> dihydroxyvitamin D<NUM>.

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. Cholecalciferol and ergocalciferol have affinities for the VDR which are estimated to be at least <NUM>-fold lower than those of the Vitamin D hormones. As a consequence, physiological concentrations of cholecalciferol and ergocalciferol exert little, if any, biological actions without prior metabolism to Vitamin D hormones. However, supraphysiologic levels of cholecalciferol and ergocalciferol, in the range of <NUM> to <NUM>,<NUM> fold higher than normal, can sufficiently occupy the VDR and exert actions like the Vitamin D hormones. Similarly, the prohormones <NUM>-hydroxyvitamin D<NUM> and <NUM>-hydroxyvitamin D<NUM> have essentially identical affinities for the VDR which are also estimated to be at least <NUM>-fold lower than those of the Vitamin D hormones. As a consequence, physiological concentrations of <NUM>-hydroxyvitamin D<NUM> and <NUM>-hydroxyvitamin D<NUM> have little, if any, biological actions without prior metabolism to Vitamin D hormones. However, supraphysiologic levels of <NUM>-hydroxyvitamin D<NUM> and <NUM>-hydroxyvitamin D<NUM>, in the range of <NUM> to <NUM>,<NUM> fold higher than normal, can sufficiently occupy the VDR to exert actions like the Vitamin D hormones.

Production of Vitamin D prohormones declines when Vitamin D is in short supply, as in conditions such as Vitamin D insufficiency or Vitamin D deficiency (alternatively, hypovitaminosis D). Low production of Vitamin D prohormones leads to low blood levels of <NUM>-hydroxyvitamin D. Inadequate Vitamin D supply often develops in individuals who are infrequently exposed to sunlight, have chronically inadequate intakes of Vitamin D, or suffer from conditions that reduce the intestinal absorption of fat soluble vitamins (such as Vitamin D). It has recently been reported that most individuals living in northern latitudes have inadequate Vitamin D supplies. Left untreated, inadequate Vitamin D supply can cause serious bone disorders, including rickets and osteomalacia.

The Institute of Medicine (IOM) of the National Academy of Sciences has concluded that an Adequate Intake (AI) of Vitamin D for a healthy individual ranges from <NUM> to <NUM> IU per day, depending on the individual's age and sex (see <NPL>). The AI for Vitamin D was defined primarily on the basis of a serum <NUM>-hydroxyvitamin D level sufficient to prevent Vitamin D deficiency, rickets or osteomalacia (or at least <NUM> ng/mL). The IOM also established a Tolerable Upper Intake Level (UL) for Vitamin D of <NUM>,<NUM> IU per day, based on evidence that higher doses are associated with an increased risk of hypercalciuria, hypercalcemia and related sequelae, including cardiac arrhythmias, seizures, and generalized vascular and other soft-tissue calcification.

Currently available oral Vitamin D supplements are far from ideal for achieving and maintaining optimal blood <NUM>-hydroxyvitamin D levels. These preparations typically contain <NUM> IU to <NUM>,<NUM> IU of Vitamin D<NUM> or <NUM>,<NUM> IU of Vitamin D<NUM> and are formulated for quick or immediate release in the gastrointestinal tract. When administered at chronically high doses, as is often required for Vitamin D repletion, these products have significant and, often, severe limitations which are summarized below.

High doses of immediate release Vitamin D supplements produce marked surges in blood Vitamin D levels, thereby promoting: (a) storage of Vitamin D in adipose tissue, which is undesirable because stored Vitamin D is less available for later hepatic conversion to <NUM>-hydroxyvitamin D; (b) hepatic catabolism of Vitamin D to metabolites, which are less useful or no longer useful for boosting blood <NUM>-hydroxyvitamin D levels, via <NUM>- and/or <NUM>-hydroxylation; and, (c) excessive intracellular <NUM>- or <NUM>-hydroxylation of Vitamin D, which leads to increased risk of hypercalciuria, hypercalcemia and hyperphosphatemia.

High doses of immediate release Vitamin D supplements also produce surges or spikes in blood and intracellular <NUM>-hydroxyvitamin D levels, thereby promoting: (a) excessive extrarenal production of Vitamin D hormones, and leading to local aberrations in calcium and phosphorus homeostasis and increased risk of hypercalciuria, hypercalcemia and hyperphosphatemia; (b) accelerated catabolism of both Vitamin D and <NUM>-hydroxyvitamin D by <NUM>-and/or <NUM>-hydroxylation in the kidney and other tissues; (c) down-regulation of hepatic production of Vitamin D prohormones, unnecessarily impeding the efficient repletion of Vitamin D insufficiency or deficiency; and, (d) local aberrations in calcium and phosphorus homeostasis mediated by direct binding to VDR.

Furthermore, high doses of immediate release Vitamin D supplements produce supraphysiologic pharmacological concentrations of Vitamin D, e.g., in the lumen of the duodenum, promoting: (a) <NUM>-hydroxylation in the enterocytes and local stimulation of intestinal absorption of calcium and phosphorus, leading to increased risk of hypercalciuria, hypercalcemia and hyperphosphatemia; (b) catabolism of Vitamin D by <NUM>- and/or <NUM>-hydroxylation in the local enterocytes, causing decreased systemic bioavailability; and (c) absorption primarily via chylomicrons, leading to increased hepatic catabolism.

Vitamin D supplementation above the UL is frequently needed in certain individuals; however, currently available oral Vitamin D supplements are not well suited for maintaining blood <NUM>-hydroxyvitamin D levels at optimal levels given the problems of administering high doses of immediate release Vitamin D compounds.

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 among healthy individuals, with some individuals having stable concentrations as low as approximately <NUM> pg/mL and others as high as approximately <NUM> pg/mL. Due to this wide normal range, medical professionals have difficulty interpreting isolated laboratory determinations of serum total <NUM>,<NUM>-dihydroxyvitamin D; a value of <NUM> pg/mL may represent a normal value for one individual or a relative deficiency in another.

Transiently low blood levels of <NUM>,<NUM>-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 <NUM>,<NUM>-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, secondary hyperparathyroidism progressively increases in severity, causing debilitating metabolic bone diseases, including osteoporosis and renal osteodystrophy.

Chronically low blood levels of <NUM>,<NUM>-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 <NUM>/min/<NUM><NUM> 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 CYP27B <NUM> is greatly inhibited by elevated serum phosphorous (hyperphosphatemia) caused by inadequate renal excretion of dietary phosphorous.

Chronically low blood levels of <NUM>,<NUM>-dihydroxyvitamin D also develop because of an insufficiency 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 by terms such as "Vitamin D insufficiency," "Vitamin D deficiency," or "hypovitaminosis D. " Therefore, measurement of <NUM>-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 <NUM>-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 <NUM>,<NUM>-dihydroxyvitamin D are those with CKD. Most CKD patients typically have decreased levels of renal CYP27B1 and a shortage of <NUM>-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 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 [<NPL>] and, subsequently, the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) [<NPL>]. Of the two Guidelines, the former offered the most detailed guidance to physicians. The K/DOQI Guidelines identified the primary etiology of secondary hyperparathyroidism as chronically low blood levels of <NUM>,<NUM>-dihydroxyvitamin D and recommended regular screening in CKD Stages <NUM> through <NUM> for elevated blood PTH levels relative to stage-specific PTH target ranges, which for Stage <NUM> is <NUM>-<NUM> pg/mL (equivalent to <NUM>-<NUM> pmol/L), for Stage <NUM> is <NUM>-<NUM> pg/mL (equivalent to <NUM>-<NUM> pmol/L), and for Stage <NUM> is <NUM>-<NUM> pg/mL (equivalent to <NUM>-<NUM> pmol/L) (defined in K/DOQI Guideline No. <NUM>). In the event that screening revealed an iPTH value to be above the ranges targeted for CKD Stages <NUM> and <NUM>, the Guidelines recommended a follow-up evaluation of serum total <NUM>-hydroxyvitamin D to detect possible Vitamin D insufficiency or deficiency. If <NUM>-hydroxyvitamin D below <NUM> ng/mL was observed, the recommended intervention was Vitamin D repletion therapy using orally administered ergocalciferol. If <NUM>-hydroxyvitamin D above <NUM> ng/mL was observed, the recommended intervention was Vitamin D hormone replacement therapy using known oral or intravenous Vitamin D hormones or analogs. The Guidelines did not recommend the concurrent application of Vitamin D repletion and Vitamin D hormone replacement therapies, consistent with warnings mandated by the Food and Drug Administration in package inserts for Vitamin D hormone replacement products.

The NKF K/DOQI Guidelines defined Vitamin D sufficiency as serum <NUM>-hydroxyvitamin D levels ≥ <NUM> ng/mL. Recommended Vitamin D repletion therapy for patients with "Vitamin D insufficiency," defined as serum total <NUM>-hydroxyvitamin D of <NUM>-<NUM> ng/mL, was <NUM>,<NUM> IU per month of oral Vitamin D<NUM> for <NUM> months, given either in single monthly doses or in divided doses of approximately <NUM>,<NUM> IU per day. Recommended repletion therapy for patients with "Vitamin D deficiency" was more aggressive: for "mild" deficiency, defined as serum total <NUM>-hydroxyvitamin D of <NUM>-<NUM> ng/mL, the Guidelines recommended <NUM>,<NUM> IU per week of oral Vitamin D<NUM> for <NUM> weeks, followed by <NUM>,<NUM> IU per month for another <NUM> months; for "severe" deficiency, defined as serum <NUM>-hydroxyvitamin D below <NUM> ng/mL, the Guidelines recommended <NUM>,<NUM> IU/week of oral Vitamin D<NUM> for <NUM> weeks, followed by <NUM>,<NUM> IU/month for another <NUM> months. Doses of <NUM>,<NUM> IU per week are approximately equivalent to <NUM>,<NUM> IU per day. <CIT> describes a clinical study with stage <NUM> Chronic Kidney Disease patients administered daily a modified release composition comprising <NUM>-hydroxyvitamin D<NUM>, thereby achieving iPTH levels consistent with K/DOQI guidelines.

The claimed invention provides a modified release composition comprising <NUM>-hydroxyvitamin D<NUM>, <NUM>-hydroxyvitamin D<NUM>, or a combination thereof, for use in a method for reducing serum parathyroid levels in a Chronic Kidney Disease patient, the method comprising orally administering an effective amount of the composition to the patient, who is a human subject suffering from hyperparathyroidism secondary to Chronic Kidney Disease, said composition being administered at a frequency in a range of every six weeks to every other day, wherein the composition provides a rise in serum total <NUM>-hydroxyvitamin D within the first <NUM> hours after said administering of at least <NUM> ng/ml and no greater than <NUM> ng/ml, as assayable using solid-phase extraction (SPE) with high performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) detection, wherein the composition lowers the subject's serum intact parathyroid hormone (iPTH) level by at least <NUM>% compared to baseline.

The claimed invention further provides the use of a modified release composition comprising <NUM>-hydroxyvitamin D<NUM>, <NUM>-hydroxyvitamin D<NUM>, or a combination thereof in the manufacture of a medicament for the reduction of serum parathyroid levels in a Chronic Kidney Disease patient by orally administering an effective amount of the composition to the patient, who is a human subject suffering from hyperparathyroidism secondary to Chronic Kidney Disease, said composition being administered at a frequency in a range of every six weeks to every other day, wherein the composition provides a rise in serum total <NUM>-hydroxyvitamin D within the first <NUM> hours after said administering of at least <NUM> ng/ml and no greater than <NUM> ng/ml, as assayable using solid-phase extraction (SPE) with high performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) detection, wherein the composition lowers the subject's serum intact parathyroid hormone (iPTH) level by at least <NUM>% compared to baseline.

The present disclosure also describes, but does not claim, methods and compositions. The skilled person will understand that the described methods and compositions are relevant to, and aid the understanding of, the modified release composition for use in a method and the use of a modified release composition in the manufacture of a medicament as provided by the present claimed invention.

Optionally, the amount of the modified release dosage form administered is effective to provide a rise in serum total <NUM>-hydroxyvitamin D of at least <NUM> ng/ml and no greater than <NUM> ng/ml within the first <NUM> hours after dosing. Optionally, the amount of the modified release dosage form administered is effective to provide a rise in serum total <NUM>-hydroxyvitamin D of at least <NUM> ng/ml and no greater than <NUM> ng/ml within the first <NUM> hours after dosing.

Optionally the patient's serum total <NUM>-hydroxyvitamin D can be raised to at least <NUM> ng/ml.

Optionally the patient's iPTH level can be lowered by at least <NUM>% compared to baseline.

Optionally the patient's iPTH level remains lowered for at least <NUM> hours.

Optionally the patient's iPTH level remains lowered for at least <NUM> days.

According to the claimed invention, the administering step is performed on a frequency in a range of every six weeks to every other day. Optionally the frequency is weekly. Optionally the frequency is monthly.

Optionally the bioavailable amount of the <NUM>-hydroxyvitamin D administered is greater than <NUM>µg, optionally in a range of <NUM> to <NUM>µg.

According to the claimed invention, the patient suffers from hyperparathyroidism secondary to chronic kidney disease (CKD). Optionally the CKD is Stage <NUM>, Stage <NUM>, Stage <NUM>, or Stage <NUM> CKD. Optionally the CDK is Stage <NUM> or Stage <NUM>.

Optionally the amount of the modified release dosage form administered can be further effective to provide a rise in serum total <NUM>,<NUM>-dihydroxyvitamin D of greater than <NUM> pg/ml and further less than <NUM> pg/ml within the first <NUM> hours after dosing. Optionally the rise in serum total <NUM>,<NUM>-dihydroxyvitamin D can be at least <NUM> pg/ml and further can be less than <NUM> pg/ml within the first <NUM> hours after dosing.

Optionally the Tmax of serum total <NUM>-hydroxyvitamin D following the administering step can be at least <NUM> hours. Optionally the Tmax of serum total <NUM>-hydroxyvitamin D following the administering step can be at least <NUM> hours.

Optionally the patient can be one who also suffers from vitamin D insufficiency or deficiency, as defined by serum total <NUM>-hydroxyvitamin D of less than <NUM> ng/ml.

Optionally the modified release dosage form can include, consist of, or consist essentially of <NUM>-hydroxyvitamin D<NUM>.

Preferred steps, preferred components, preferred compositional ranges thereof, and preferred combinations of the foregoing, can be selected from the various examples provided herein.

Further aspects and advantages will be apparent to those of ordinary skill in the art from a review of the following detailed description, taken in conjunction with the drawings.

For further facilitating the understanding of the present invention, thirty-one drawing figures are appended hereto.

The present claimed invention provides a modified release composition comprising <NUM>-hydroxyvitamin D<NUM>, <NUM>-hydroxyvitamin D<NUM>, or a combination thereof, for use in a method for reducing serum parathyroid levels in a Chronic Kidney Disease patient. The composition for use in a method according to the invention is as defined in claim <NUM>. The present claimed invention also provides the use of a modified release composition comprising <NUM>-hydroxyvitamin D<NUM>, <NUM>-hydroxyvitamin D<NUM>, or a combination thereof in the manufacture of a medicament. The use according to the invention is as defined in claim <NUM>.

While the compositions for use and the uses as described and claimed herein are susceptible of embodiments in various forms, the description hereafter includes various embodiments with the understanding that the disclosure is illustrative, and is not intended to limit the invention to the embodiments described herein. It will be appreciated by the skilled artisan that various of the embodiments described herein are non-exclusive, such that the features of one embodiment can be optionally combined with the features of another embodiment, and all such combinations are contemplated for use in the methods and compositions of the present disclosure.

As used herein, the term "Vitamin D toxicity" is meant to refer to the side effects suffered from excessively elevated Vitamin D blood levels, including one or more of nausea, vomiting, polyuria, hypercalciuria, hypercalcemia and hyperphosphatemia.

"Vitamin D insufficiency and deficiency" is generally defined as having serum <NUM>-hydroxyvitamin D levels below <NUM> ng/mL (see <NPL>)).

As used herein the term "hypercalcemia" refers to a condition in a patient wherein the patient has corrected serum levels of calcium above <NUM>/dL. Normal corrected serum levels of calcium for a human are between about <NUM> to <NUM>/dL.

As used herein the term "hyperphosphatemia" refers to a condition in a patient having normal kidney function, or Stage <NUM>-<NUM> CKD, wherein the patient has serum phosphorous levels above <NUM>/dL. In a patient who has Stage <NUM> CKD, hyperphosphatemia occurs when the patient has serum levels above <NUM>/dL. Normal values for serum phosphorous in a human are <NUM>-<NUM>/dL.

As used herein the term "over suppression of plasma iPTH" refers to a condition in a patient having normal kidney function, or Stage <NUM>-<NUM> CKD, wherein the patient has levels of plasma iPTH below <NUM> pg/mL. In a patient having Stage <NUM> CKD, over suppression of plasma iPTH occurs when the patient has levels of plasma iPTH below <NUM> pg/mL. In a patient having Stage <NUM> CKD, over suppression of plasma iPTH occurs when the patient has levels of plasma iPTH below <NUM> pg/mL.

As used herein, the term "Vitamin D hormone replacement therapy" refers to the administration to a patient of an effective amount of an active vitamin D hormone such as <NUM>,<NUM>-dihydroxyvitamin D<NUM> and/or <NUM>,<NUM>-dihydroxyvitamin D<NUM>, optionally together with or other metabolites and analogs of Vitamin D which can substantially occupy the intracellular VDR.

The term "substantially constant" with respect to the serum or blood level of <NUM>-hydroxyvitamin D prohormones means that the release profile of any formulation administered as detailed hereinbelow should not include transient increases in total serum or blood levels of <NUM>-hydroxyvitamin D of greater than approximately <NUM> ng/mL within <NUM> hours after administration of a unit dose, optionally not greater than about <NUM> ng/ml in the first <NUM> hours, or about <NUM> ng/ml in the first <NUM> hours, or not greater than about <NUM> ng/ml in the first <NUM> hours, or about <NUM> ng/ml in the first <NUM> hours after administration of a unit dose. The term "substantially constant" with respect to the serum or blood level of an active vitamin D hormone preferably means that the release profile of the controlled release formulation should not include increases in total serum or blood levels of <NUM>,<NUM>-dihydroxyvitamin D of greater than <NUM> pg/ml each after administration of a unit dose, optionally not greater than <NUM> pg/mL, optionally over a period of the initial <NUM> hours, <NUM> hours, <NUM> hours, <NUM> hours, <NUM> hours, <NUM> hours, or <NUM> hours post-dose.

As used herein, the terms "controlled release," "sustained release," and "modified release" are used interchangeably. Such dosage forms release the administered vitamin D compound in a way that deviates from immediate release. A sustained release formulation releases <NUM>-hydroxyvitamin D from the formulation over time, such that it is absorbed at various levels in the gastrointestinal tract. For example, the release of a <NUM>-hydroxyvitamin D compound will preferably be at such a rate that total serum or blood levels of <NUM>-hydroxyvitamin D are maintained or elevated above predosing levels for an extended period of time, e.g. <NUM>, <NUM>, or <NUM> hours, or even longer. The terms optionally also include delayed release characteristics. For example, a delayed, sustained release type of formulation can include a coating such as an enteric coating such that the formulation substantially releases the <NUM>-hydroxyvitamin D in the intestines, or a relatively specific part of the intestines, rather than the stomach.

"Supraphysiologic" in reference to intraluminal, intracellular and blood levels of Vitamin D refers to a total concentration of the vitamin D compound markedly greater than the generally stable levels observed in a Vitamin D-replete subject, animal or human patient over the course of any <NUM>-hour period by laboratory measurement when Vitamin D supplementation has been withheld for at least <NUM> days. "Adverse supraphysiologic surge" refers to a local or serum concentration of a vitamin D compound that elicits adverse effects such as excessive extrarenal hormone production, leading to local adverse effects on calcium and phosphorus metabolism, inhibition of hepatic <NUM>-hydroxylation of vitamin D, increased catabolism of both Vitamin D and <NUM>-hydroxyvitamin D, hypercalciuria, hypercalcemia and/or hyperphosphatemia, with possible cardiovascular sequelae.

As used herein, the term "hyperparathyroidism" refers to primary hyperparathyroidism, secondary hyperparathyroidism and hyperparathyroidism secondary to chronic kidney disease (Stage <NUM>, Stage <NUM>, or Stage <NUM>).

The term "subject" as used herein generally includes humans, mammals (e.g., dogs, cats, rodents, sheep, horses, cows, goats), veterinary animals and zoo animals.

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 <NUM>% to <NUM>%, it is intended that values such as <NUM>% to <NUM>%, <NUM>% to <NUM>%, or <NUM>% to <NUM>%, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended.

Administration of <NUM>-hydroxyvitamin D<NUM> in an immediate release oral formulation has been tried as an alternative method of Vitamin D supplementation. This approach, which was subsequently abandoned, caused problems as do the currently used Vitamin D supplements. Specifically, it produced surges or spikes in blood and intracellular <NUM>-hydroxyvitamin D levels. Without intending to be bound by any particular theory, it is believed that surges or spikes in blood and intracellular <NUM>-hydroxyvitamin D levels promote (a) competitive displacement of Vitamin D hormones from the serum Vitamin D Binding Protein (DBP) and excessive delivery of the displaced hormones to tissues containing VDR, and (b) transiently excessive renal and extrarenal production of Vitamin D hormones, which together led to local aberrations in calcium and phosphorus metabolism. In addition, these surges in blood <NUM>-hydroxyvitamin D levels are believed to promote catabolism of both Vitamin D and <NUM>-hydroxyvitamin D by <NUM>-and/or <NUM>-hydroxylation in the kidney and other tissues, down-regulation of hepatic production of Vitamin D prohormones, unnecessarily impeding the efficient repletion of Vitamin D insufficiency or deficiency, and, additional local aberrations in calcium and phosphorus homeostasis mediated by direct binding to VDR. Importantly, immediate release of <NUM>-hydroxyvitamin D<NUM> is believed to promote its intestinal absorption via a mechanism substantially involving transport to the liver in chylomicrons, rather than bound to the serum DBP. Delivery of <NUM>-hydroxyvitamin D to the liver via chylomicrons is believed to significantly increase the likelihood of its catabolism.

The claimed invention involves a modified release composition comprising <NUM>-hydroxyvitamin D<NUM>, <NUM>-hydroxyvitamin D<NUM>, or a combination thereof. One aspect of the disclosure provides a solid or semi-solid, waxy pharmaceutical formulation for controlled release of <NUM>-hydroxyvitamin D in the gastrointestinal tract of a subject which ingests the formulation. The formulation includes a waxy controlled release carrier agent, a lipoidic agent, an oily vehicle for <NUM>-hydroxvitamin D, and <NUM>-hydroxyvitamin D. The formulation provides for controlled release of <NUM>-hydroxyvitamin D incorporated therein. The formulation can be free of or essentially free of disintegrants.

The waxy controlled release carrier provides for a formulation which is solid or in the alternative semi-solid at room temperature. The formulation can be solid, semi-solid, or liquid at body temperature. In one embodiment, the formulation will be semi-solid at body temperature. In another embodiment, the formulation will be liquid at body temperature. In another embodiment, the formulation will be solid at body temperature. Examples of carriers suitable for use include waxes, such as synthetic wax, microcrystalline wax, paraffin wax, carnauba wax, and beeswax; polyethoxylated castor oil derivatives, hydrogenated vegetable oils, glyceryl mono-, di- or tribehenates; long-chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol; and mixtures of any of the foregoing. Non-digestible waxy substances, such as hard paraffin wax, are preferred.

The waxy carrier preferably is present in an amount greater than about <NUM> % of the formulation, based on the total weight of the formulation excluding any additional coatings or shells (wt%). For example, the waxy carrier can comprise greater than <NUM> wt% of the formulation, greater than <NUM> wt% of the formulation, greater than <NUM> wt% of the formulation, greater than <NUM> wt% of the formulation, and greater than <NUM> wt% of the formulation. The waxy carrier is preferably present in an amount less than <NUM> wt%, less than <NUM> wt%, less than <NUM> wt%, or less than <NUM> wt. Suitable ranges include <NUM> wt% to <NUM> wt%, <NUM> wt% to <NUM> wt% and <NUM> to <NUM> wt%. Examples include <NUM> wt%, <NUM> wt%, <NUM> wt%, <NUM> wt%, <NUM> wt%, <NUM> wt%, <NUM> wt%, <NUM> wt%, <NUM> wt%, <NUM> wt%, <NUM> wt%, <NUM> wt%, <NUM> wt%, <NUM> wt%, <NUM> wt%, and <NUM> wt%.

The lipoidic agent provides for release of <NUM>-hydroxyvitamin D from the formulation in the gastrointestinal tract of the subject being treated. Without intending to be bound by any particular theory of operation, it is believed that the lipoidic agent can serve one or more preferred functions such as creating a micro-emulsion of the oily vehicle in gastrointestinal fluid; providing prolonged gastric retention, for example by bioadhesive properties such that the formulation interacts with the mucous layer of the stomach and/or intestine; and in enhancing absorption of <NUM>-hydroxyvitamin D. However, regardless of the mechanism of action, the invention is not limited by any particular mode of operation.

The lipoidic agent components preferably are amphiphiles, in which the molecule or ion contains both hydrophilic and lipophilic portions. These components can be defined by a numerical value based on the Hydrophile/Lipophile Balance system ("HLB system"). The HLB scale is a numerical scale, extending from <NUM> to approximately <NUM>, where lower numbers denote more lipophilic and hydrophobic substances, and higher numbers denote more hydrophilic and lipophobic substances. The affinity of a compound for water, or for oily substances, is determined and its HLB value is assigned experimentally. The HLB of the hydrophobic carrier employed herein preferably will be in a range of about <NUM> to about <NUM>.

A variety of pharmaceutically acceptable lipoidic agents may be incorporated in the formulation. The quantity of lipoidic agent present in the formulation is preferably at least <NUM> wt%, at least <NUM> wt%, at least <NUM> wt%, at least <NUM> wt% or at least <NUM> wt%. Suitable ranges include about <NUM> wt% to about <NUM> wt%, about <NUM> wt% to about <NUM> wt% and about <NUM> wt% to about <NUM> wt%.

In one embodiment, the lipoidic agent is a lipophilic emulsifier which has an HLB of less than <NUM> and comprises a member selected from the group consisting of mixed fatty acid monoglycerides; mixed fatty acid diglycerides; mixtures of fatty acid mono- and diglycerides; lipophilic polyglycerol esters; glycerol esters including glyceryl monooleate, glyceryl dioleate, glyceryl monostearate, glyceryl distearate, glyceryl monopalmitate, and glyceryl dipalmitate; glyceryl-lacto esters of fatty acids; propylene glycol esters including propylene glycol monopalmitate, propylene glycol monostearate, and propylene glycol monooleate; sorbitan esters including sorbitan monostearate, sorbitan sesquioleate; fatty acids and their soaps including stearic acid, palmitic acid, and oleic acid; and mixtures thereof glyceryl monooleate, glyceryl dioleate, glyceryl monostearate, glyceryl distearate, glyceryl monopalmitate, and glyceryl dipalmitate; glyceryl-lacto esters of fatty acids; propylene glycol esters including propylene glycol monopalmitate, propylene glycol monostearate, and propylene glycol monooleate; sorbitan esters including sorbitan monostearate, sorbitan sesquioleate; fatty acids and their soaps including stearic acid, palmitic acid, and oleic acid; and mixtures thereof.

A preferred lipoidic agent is selected from glycerides and derivatives thereof. Preferred glycerides are selected from the group consisting of medium or long chain glycerides, caprylocaproyl macrogolglycerides, and mixtures thereof.

Preferred medium chain glycerides include, but are not limited to, medium chain monoglycerides, medium chain diglycerides, caprylic/capric triglyceride, glyceryl monolaurate, glyceryl monostearate, caprylic/capric glycerides, glycerylmonocaprylate, glyceryl monodicaprylate, caprylic/capric linoleic triglyceride, and caprylic/capric/succinic triglyceride.

Monoglycerides having a low melting point are preferred for making the formulation. Preferred monoglycerides include but are not limited to, glyceryl monostearate, glyceryl monopalmitate, glyceryl monooleate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate, etc., preferably glyceryl monostearate (GMS). GMS is a natural emulsifying agent. It is oil soluble, but poorly soluble in water. GMS has an HLB value of <NUM>. Another preferred monoglyceride is glyceryl monooleate (GMO). GMO is also a natural emulsifying agent; it is oil soluble, but poorly soluble in water, and it has an HLB value of <NUM>.

In another embodiment, the glyceride is an absorption enhancer selected from caprylocaproyl macrogolglycerides. Caprylocaproyl macrogolglycerides which may be employed include, but are not limited to, polyethylene glycosylated glycerides, also known as polyglycolized glycerides or PEGylated glycerides. PEGylaed glycerides which may be employed in the composition include, but are not limited to, mixtures of monoglycerides, diglycerides, and triglycerides and monoesters and diesters of polyethylene glycol, polyethylene glycosylated almond glycerides, polyethylene glycosylated corn glycerides, and polyethylene glycosylated caprylic/capric triglyceride. The absorption enhancer preferably has an HLB value from <NUM> to <NUM>, more preferably from <NUM> to <NUM>.

One preferred absorption enhancer is known under the trade name GELUCIRE, and is commercially available from Gattefossé Corporation, Paramus, New Jersey, USA. GELUCIRE is a well known excipient which is a family of fatty acid esters of glycerol and PEG esters, also known as polyglycolized glycerides. GELUCIRE is used in various applications including preparing sustained release pharmaceutical compositions. GELUCIRE compounds are inert, semi-solid waxy materials which are amphiphilic and are available with varying physical characteristics such as melting point, HLB, and solubilities in various solvents. They are surface active in nature and disperse or solubilize in aqueous media forming micelles, microscopic globules or vesicles. They are identified by their melting point/HLB value. The melting point is expressed in degrees Celsius. One or a mixture of different grades of GELUCIRE excipient may be chosen to achieve the desired characteristics of melting point and/or HLB value. The preferred GELUCIRE composition is GELUCIRE <NUM>/<NUM>, a semisolid waxy material with a melting point of <NUM> and a HLB of <NUM>.

Another preferred polyglycolyzed glyceride absorption enhancer is caprylocaproyl macrogol-<NUM>-glyceride (<NPL> and <NPL>). This is a mixture of mono-, di- and triesters of glycerol and of PEG <NUM> with medium-chain fatty acids (C<NUM>-C<NUM>) which is marketed, for example, by Gattefossé Corporation, Paramus, New Jersey, USA under the trade name LABRASOL. LABRASOL has a HLB value of <NUM> and has the following composition by weight: C<NUM>-C<NUM> monoglycerides approximately <NUM>%; C<NUM>-C<NUM> diglycerides approximately <NUM>%; C<NUM>-C<NUM> triglycerides approximately <NUM>%; C<NUM>-C<NUM> monoesters of PEG <NUM> approximately <NUM>%; C<NUM>-C<NUM> diesters of PEG <NUM> approximately <NUM>%; free PEG <NUM> approximately <NUM>%; free glycerol approximately <NUM>%.

Preferably, the lipoidic agent includes a mixture of a lipophilic emulsifier which has an HLB of less than <NUM> and an absorption enhancer that preferably has an HLB value from <NUM> to <NUM>. The lipophilic emulsifier is preferably present in an amount in a range of about <NUM> wt% to about <NUM> wt%, preferably about <NUM> wt% to about <NUM> wt%, and the absorption enhancer is preferably present in an amount of about <NUM> to about <NUM> wt%, preferably about <NUM> to about <NUM> wt%.

The low melting points of many of the solid lipoidic compositions provide a means of incorporating the pharmaceutically active ingredients in them at temperatures from about <NUM> to about <NUM> above their respective melting points, and then filling the melt (solution and/or dispersion) in animal or vegetable gelatin capsules. The melt solidifies inside the capsules upon cooling to room temperature.

The oily component serves as a vehicle, preferably the main vehicle, for <NUM>-hydroxyvitamin D. Any pharmaceutically-acceptable oil can be used. Examples include animal (e.g., fish), vegetable (e.g., soybean), and mineral oils. The oil preferably will readily dissolve <NUM>-hydroxyvitamin D. Preferred oily components include non-digestible oils, such as mineral oils, particularly liquid paraffins, and squalene. The oil vehicle preferably comprises about <NUM> wt% to about <NUM> wt% of the formulation, more preferably about <NUM> wt% to about <NUM> wt% about <NUM> wt% to about <NUM> wt%, or about <NUM> wt% to about <NUM> wt%. In one preferred embodiment, the liquid paraffin can be characterized by one or more of the following parameters: specific gravity about <NUM> to <NUM>; kinematic viscosity (<NUM>) about <NUM> to about <NUM> cSt; molecular weight <NUM>; % paraffinic hydrocarbons about <NUM>; and pour point -<NUM>. The ratio between the waxy component and the oily component can be optimized in order to achieve the desired rate of release of <NUM>-hydroxyvitamin D. Thus, if a heavier oil component is used, relatively less of the waxy component can be used, and if a lighter oil component is used, then relatively more waxy component can be used.

<NUM>-hydroxyvitamin D compounds include <NUM>-hydroxyvitamin D<NUM>, <NUM>-hydroxyvitamin D<NUM>, analogs thereof, and combinations of any of the foregoing. These compounds and combinations are generally referred to herein under the generic term <NUM>-hydroxyvitamin D. The claimed invention involves a modified release composition comprising <NUM>-hydroxyvitamin D<NUM>, <NUM>-hydroxyvitamin D<NUM>, or a combination thereof. In one embodiment, <NUM>-hydroxyvitamin D includes one or more hydroxy forms, such as a combination of <NUM>-hydroxyvitamin D<NUM> and <NUM>-hydroxyvitamin D<NUM>.

Optionally, the present invention will have one or more advantages including avoiding supraphysiological surges in intraluminal, intracellular and blood levels of <NUM>-hydroxyvitamin D and their consequences; avoiding substantially increased catabolism of the administered <NUM>-hydroxyvitamin D; and, avoiding serious side effects associated with Vitamin D supplementation, namely Vitamin D toxicity.

The modified release compositions used in the claimed invention preferably are designed to contain concentrations of the <NUM>-hydroxyvitamin D of <NUM> to <NUM>µg per unit dose and are prepared and delivered in such a manner as to effect controlled or substantially constant release of the <NUM>-hydroxyvitamin D, optionally into the ileum of the gastrointestinal tract, of humans or animals over an extended period of time. Preferred dosages include <NUM> to <NUM>µg per unit dose, <NUM> to <NUM>µg, <NUM> to <NUM>µg, <NUM> to <NUM>µg, <NUM> to <NUM>µg, <NUM> to <NUM>µg, <NUM> to <NUM>µg, <NUM> to <NUM>µg, <NUM> to <NUM>µg, <NUM> to <NUM>µg, <NUM> to <NUM>µg, and <NUM> to <NUM>µg, for example <NUM>µg, <NUM>µg, <NUM>µg, <NUM>µg, <NUM>µg, <NUM>µg, <NUM>µg, <NUM>µg, <NUM>µg, and <NUM>µg. The invention may provide substantially increased absorption of <NUM>-hydroxyvitamin D via transport on DBP and decreased absorption via transport in chylomicrons. The modified release compositions used in the claimed invention may provide maintenance of substantially constant blood levels of <NUM>-hydroxyvitamin D during the <NUM>-hour post-dosing period, and preferably <NUM> hours post-dosing, and further preferably to <NUM> hours post-dosing. By providing a gradual, sustained and direct release of the <NUM>-hydroxyvitamin D and absorption preferentially to circulating DBP (rather than to chylomicrons), blood, intraluminal and intracellular <NUM>-hydroxyvitamin D concentration spikes, i.e., supraphysiologic levels, and related unwanted catabolism can be mitigated or eliminated. Furthermore, by providing a gradual and sustained release, serum levels of <NUM>-hydroxyvitamin D can be increased and maintained more predictably and reliably than by administration of immediate release oral formulations, allowing for a consistent dosage and reducing or eliminating the need for frequent patient monitoring.

It will be recognized that such dosage forms can have bioavailabilities less than <NUM>%. Accordingly, viewed one way a dosage amount is a nominal dosage, not accounting for bioavailability, and viewed another way a dosage amount is the effective dosage amount, accounting for bioavailability.

In one preferred class of embodiments, the modified release composition used in the claimed invention releases at least <NUM>-<NUM>%, for example at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, at least <NUM>%, or at least <NUM>% of <NUM>-hydroxyvitamin D within the first <NUM> hours after dosing.

The modified release composition used in the claimed invention is administered on a frequency in a range of every six weeks to every other day, as defined in claim <NUM> and claim <NUM>. The frequency may be at intervals of once every other day, three times a week, twice a week, weekly, every <NUM> weeks, every <NUM> weeks, every <NUM> weeks, every <NUM> weeks, or every <NUM> weeks, for example, wherein higher effective doses generally permit for less frequent dosing and lower effective doses generally permit for more frequent dosing.

Advantageously, <NUM>-hydroxyvitamin D together with other optional therapeutic agents can be orally administered in accordance with the invention in nominal dosage amounts equivalent to a range of <NUM> to <NUM>µg per day, with the preferred dosage amounts in a range of <NUM> to <NUM>µg per day, for example about <NUM> to <NUM>µg. Examples contemplated include <NUM>µg per day, <NUM>µg per day, <NUM>µg per day, <NUM>µg per day, and <NUM>µg per day. Viewed from an effective dose perspective, accounting for bioavailability, it is contemplated that one type of preferred dosage amount will be in a range of about <NUM>µg per day to about <NUM>µg per day, or about <NUM>µg per day to about <NUM>µg per day, for example about <NUM>µg, about <NUM>µg, about <NUM>µg, <NUM>µg, or <NUM>µg effective dose per day based on bioavailability of <NUM>% in the first <NUM> hours following dosing. For a formulation having <NUM>% bioavailability calculated over a range of <NUM> days post-dose, preferred effective doses would be in a range of <NUM> to <NUM>µg per day, for example about <NUM> to <NUM>µg. Examples contemplated include <NUM>µg per day, <NUM>µg per day, <NUM>µg per day, <NUM>µg per day, and <NUM>µg per day.

In one embodiment, the <NUM>-hydroxyvitamin D can be orally administered in accordance with the above described embodiments in nominal dosage amounts of at least <NUM>µg, or at least <NUM>µg, or at least <NUM>µg, or at least <NUM>µg, for example in a range of <NUM>µg to <NUM>µg, or <NUM>µg to <NUM>µg, or <NUM>µg to <NUM>µg and on a frequency in a range of every six weeks to every other day, for example every other day, every third day, every fourth day, weekly, every two weeks, every three weeks, every four weeks, monthly, every five weeks, or every six weeks. Viewed from an effective dose perspective, accounting for bioavailability, a range of about <NUM>µg to <NUM>µg is contemplated, and can be delivered on a frequency in a range of every six weeks to every other day, for example every other day, every third day, every fourth day, weekly, every two weeks, every three weeks, every four weeks, monthly, every five weeks, or every six weeks. From an effective dose perspective, accounting for bioavailability, it is contemplated that one type of preferred dosage amount for less frequent dosing will be in a range of about <NUM>µg to about <NUM>µg, based on bioavailability in the first <NUM> hours following dosing. For a formulation having <NUM>% bioavailability calculated over a range of <NUM> days post-dose, preferred effective doses would be greater than <NUM>µg, at least <NUM>µg, at least <NUM>µg, at least <NUM>µg, at least <NUM>µg, or at least <NUM>µg, for example in a range of <NUM>µg to <NUM>µg or a range of <NUM>µg to <NUM>µg. Preferred dosing regimens (amount and frequency) will provide an average rise in serum <NUM>-hydroxyvitamin D<NUM> of about <NUM> to <NUM> ng/mL at <NUM> days post-dose. It will be understood that the aforementioned dosage amounts described in equivalent amounts per day will be administered according to the invention described herein in intervals longer than once per day; thus, for example, a nominal dose equivalent of <NUM>µg per day can be administered as <NUM>µg every other day, or <NUM>µg per week.

In any of the foregoing embodiments the daily dose described can be delivered on a less frequent dosing regimen to result in an average daily dose within the ranges described above.

In the claimed invention, the composition provides a rise in serum total <NUM>-hydroxyvitamin D within the first <NUM> hours after said administering of at least <NUM> ng/ml and no greater than <NUM> ng/ml, as assayable using solid-phase extraction (SPE) with high performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) detection, wherein the composition lowers the subject's serum intact parathyroid hormone (iPTH) level by at least <NUM>% compared to baseline. In one type of embodiment, a preferred dose will provide an maximum rise in serum total <NUM>-hydroxyvitamin D of at least <NUM> ng/mL, or at least <NUM> ng/mL, or at least <NUM> ng/mL, or at least <NUM> ng/mL, or at least <NUM> ng/mL, or at least <NUM> ng/mL, or at least <NUM> ng/mL, or at least <NUM> ng/mL, and at most <NUM> ng/mL, or <NUM> ng/mL, or <NUM> ng/mL, or <NUM> ng/mL, for example in a range of <NUM> to <NUM> ng/mL, or <NUM> to <NUM> ng/mL, or <NUM> to <NUM> ng/mL, for example <NUM> ng/mL within <NUM> hours post-dose in a dose interval. Optionally, the maximum rise just described can be measured within <NUM> hours post-dose. Still further optionally, the limit on rise in serum total <NUM>-hydroxyvitamin D achieved by the invention will conform to the <NUM>-hours post dose period, or also the <NUM>-hours post-dose period.

In one embodiment, a preferred dose will provide an average rise in serum <NUM>-hydroxyvitamin D of at least about <NUM> ng/mL, or in a range of about <NUM> to <NUM> ng/mL within <NUM> hours post-dose in a dose interval. In another embodiment, a preferred dose will provide an average rise in serum total <NUM>-hydroxyvitamin D in a range of about <NUM> to <NUM> ng/mL within <NUM> hours post-dose in a dose interval.

In embodiments, the invention may include administering a composition described herein to raise and preferably also maintain blood <NUM>,<NUM>-dihydroxyvitamin D levels at <NUM> pg/mL, <NUM> pg/mL, or higher, e.g. <NUM>-<NUM> pg/mL for an extended period, for example at least one month, at least three months, at least six months, or longer. In another embodiment, a preferred dose will provide an average rise in serum total <NUM>,<NUM>-dihydroxyvitamin D of greater than about <NUM> pg/mL and less than about <NUM> pg/mL within the first <NUM> hours of dosing, or at least about <NUM> pg/mL and less than about <NUM> pg/mL within the first <NUM> hours post-dose in a dose interval.

The claimed invention may include administering to human patients an effective amount of a modified release dosage form comprising <NUM>-hydroxyvitamin D to lower or maintain lowered serum parathyroid hormone levels, in an amount that lowers iPTH levels by at least <NUM>%, <NUM>%, <NUM>%, or <NUM>%, compared to baseline, or alternatively the amount needed to reduce serum levels of PTH to the target range for the CKD stage (e.g., for Stage <NUM> is <NUM>-<NUM> pg/mL (equivalent to <NUM>-<NUM> pmol/L), for Stage <NUM> is <NUM>-<NUM> pg/mL (equivalent to <NUM>-<NUM> pmol/L), and for Stage <NUM> is <NUM>-<NUM> pg/mL (equivalent to <NUM>-<NUM> pmol/L) (defined in K/DOQI Guideline No. <NUM>)). In embodiments, the patient's iPTH remains lowered for at least <NUM> hours, at least <NUM> hours, at least <NUM> hours, at least <NUM> days, at least <NUM> days, at least <NUM> days, or at least <NUM> days post-dose in a dose interval.

The claimed invention may involve lowering or maintaining lowered serum parathyroid hormone in human patients and include administering to said patients an effective amount of a modified release dosage form comprising <NUM>-hydroxyvitamin D according to the disclosure herein to lower or maintain lowered serum parathyroid hormone levels, to within K-DIGO guidelines (i.e. for Stages <NUM>, <NUM>, or <NUM> CKD patients not on dialysis, one times the upper limit of normal for the assay used; for Stage <NUM> CKD patients on dialysis, about two to nine times the assay's upper-normal limit, or about <NUM> pg/mL to <NUM> pg/mL), or in the alternative to <NUM> pg/mL iPTH or less.

The claimed invention may include administering an amount of one or more <NUM>-hydroxyvitamin D compounds to a patient such that the time for the plasma concentration of total <NUM>-hydroxyvitamin D to reach its maximum in a dose interval following administration (Tmax) is increased as compared to Tmax for an equivalent amount of <NUM>-hydroxyvitamin D administered by bolus IV injection. In another embodiment the invention includes administering an amount of one or more <NUM>-hydroxyvitamin D compounds to a patient such that the time for the plasma concentration of total <NUM>-hydroxyvitamin D to reach its maximum in a dose interval following administration (Tmax) is increased as compared to Tmax for an equivalent immediate-release, oral dosage form. Practice of a method described herein with a modified release dosage form comprising <NUM>-hydroxyvitamin D preferably will result in a Tmax of serum <NUM>-hydroxyvitamin D at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or greater than <NUM> hours and up to <NUM> hours, for example in a range of <NUM> hours to <NUM> hours, <NUM> hours to <NUM> hours, <NUM> hours to <NUM> hours, or <NUM> hours to <NUM> hours, for example at least about <NUM> or <NUM> hours post-dose.

The claimed invention may include administering an amount of one or more <NUM>-hydroxyvitamin D compounds to a patient such that the time for the plasma concentration of serum total <NUM>,<NUM>-dihydroxyvitamin D to reach its maximum in a dose interval following administration (Tmax) is increased as compared to Tmax for an equivalent amount of <NUM>-hydroxyvitamin D administered by bolus IV injection. In an alternative embodiment the method will involve administering an amount of one or more <NUM>-hydroxyvitamin D compounds to a patient such that the time for the plasma concentration of serum total <NUM>,<NUM>-dihydroxyvitamin D to reach its maximum in a dose interval following administration (Tmax) is increased as compared to Tmax for an equivalent immediate-release, oral dosage form. Practice of a method described herein with a modified release dosage form comprising <NUM>-hydroxyvitamin D preferably will result in a Tmax of serum <NUM>,<NUM>-dihydroxyvitamin D at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or at least <NUM> hours post-dose, or greater than <NUM> hours and up to <NUM> hours, for example in a range of <NUM> hours to <NUM> hours, <NUM> hours to <NUM> hours, or <NUM> hours to <NUM> hours, for example about <NUM> or <NUM> hours post-dose.

The dosages described herein are contemplated for any of the therapeutic methods described herein. It will be appreciated that the actual preferred amount of <NUM>-hydroxyvitamin D in a specific case will vary according the particular compositions formulated, the mode of application, and the particular situs being treated. Dosages can be determined using conventional considerations, e.g., by customary comparison of the differential activity of the hormone and of a known agent, e.g. by means of an appropriate conventional pharmacological protocol.

The specific doses for each particular patient can depend on a wide variety of factors, for example, on the age, body weight, general state of health, sex, on the 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.

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 <NUM>, <NUM>, <NUM>, <NUM> or <NUM> CKD; 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. , <NUM>% of African American women between <NUM> and <NUM> years of age were vitamin D deficient compared to <NUM>% of white women); the elderly (who have a reduced ability to synthesize vitamin D 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 a Sun Protection Factor (SPF) value of <NUM> reduces production of vitamin D by <NUM>%, and higher SPF values may further reduce vitamin D); 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 <NUM>% of younger and older women are not consuming recommended amounts of vitamin D. In the claimed invention, the patient is a human subject suffering from hyperparathyroidism secondary to Chronic Kidney Disease.

Optionally excluded from the compositions for use and the use according to the invention described herein are therapeutic treatment of subjects suffering from renal osteodystrophy (including osteomalacia and osteitis fibrosa cystica).

The compositions of the disclosure, which are described but not claimed, are useful for prophylactic or therapeutic treatment of vitamin D-responsive diseases, i.e., diseases where vitamin D, <NUM>-hydroxyvitamin D or active vitamin D (e.g., <NUM>,<NUM>-dihydroxyvitamin D) 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). <NUM>,<NUM>-dihydroxyvitamin 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. Vitamin D-responsive diseases also include other inflammatory diseases, for example, asthma, chronic obstructive pulmonary disease, polycystic kidney disease, 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 disclosure 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. In the claimed invention, the patient is a human subject suffering from hyperparathyroidism secondary to Chronic Kidney Disease.

Diseases which can benefit from a modulation in the levels of vitamin D compounds, include, but are not limited to: (i) in the parathyroid-- hypoparathyroidism, Pseudohypo-parathyroidism, secondary hyperparathyroidism; (ii) in the pancreas--diabetes; (iii) in the thyroid--medullary carcinoma; (iv) in the skin--psoriasis; wound healing; (v) in the lung--sarcoidosis and tuberculosis; (vi) in the kidney--chronic kidney disease, hypophosphatemic VDRR, vitamin D dependent rickets; (vii) in the bone--anticonvulsant treatment, fibrogenisis imperfecta ossium, osteitis fibrosa cystica, osteomalacia, osteoporosis, osteopenia, osteosclerosis, renal osteodytrophy, rickets; (viii) in the intestine--glucocorticoid antagonism, idopathic hypercalcemia, malabsorption syndrome, steatorrhea, tropical sprue; and (ix) autoimmune disorders. In the claimed invention, the patient is a human subject suffering from hyperparathyroidism secondary to Chronic Kidney Disease.

The claimed invention involves a modified release composition comprising <NUM>-hydroxyvitamin D<NUM>, <NUM>-hydroxyvitamin D<NUM>, or a combination thereof. A modified release formulation can be prepared by procedures well known to one of ordinary skill in the art. Pharmaceutically acceptable waxes, lipoidic agents, and oils can be melted, if necessary, to provide a flowable liquid thereby making it easier to obtain a homogeneous mixture. <NUM>-hydroxyvitamin D can be added to the thus liquid carrier, for example dissolved in an alcohol such as anhydrous ethanol, and the ingredients can be mixed to provide a homogeneous mixture. The mixture can be cooled and stored prior to later division into unit dosage forms, such as filled gelatin capsules.

In one preferred method, a portion of the oil vehicle, solid wax, and a lipophilic emulsifier are heated to a relatively high temperature (e.g., <NUM>) and mixed prior to adding an absorption enhancer, followed by additional mixing until homogenous, then cooling to an intermediate elevated temperature (e.g., <NUM> to <NUM>). In a separate vessel, an antioxidant preservative and the remainder of the oil vehicle are mixed and heated to an intermediate elevated temperature (e.g., <NUM>), then combined and mixed with the wax mixture until a homogenous solution is obtained. Next, a solution of <NUM>-hydroxyvitamin D in alcohol is combined with the homogenous waxy solution, mixed until a homogenous solution is obtained, preferably filled into capsules, and then cooled to room temperature. In another preferred method, a portion of the oil vehicle, solid wax, and a lipophilic emulsifier are heated at a temperature of <NUM> to <NUM> and mixed prior to adding an absorption enhancer, followed by additional mixing until homogenous. In a separate vessel, an antioxidant preservative and the remainder of the oil vehicle are mixed and heated to a temperature of <NUM> to <NUM>, then combined and mixed with the wax mixture until a homogenous solution is obtained. Next, a solution of <NUM>-hydroxyvitamin D in alcohol is combined with the homogenous waxy solution, mixed until a homogenous solution is obtained, preferably filled into capsules, and then cooled to room temperature.

The formulation preferably is placed in capsules prior to administration to the patient in need of treatment. Such capsules may be hard or soft, and soft capsules are preferred. The formulation may be filled into gelatin capsules using standard capsule filling machinery, such as by melting the formulation and injection filling it into soft capsule shells.

The claimed invention and the disclosed formulation and methods of use and making are contemplated to include embodiments including any combination of one or more of the additional optional elements, features, and steps further described below, unless stated otherwise.

Thus, in one type of embodiment, the formulation further includes a preservative, such as an antioxidant. Butylated hydroxytoluene (BHT) is preferred.

In another type of embodiment, <NUM>-hydroxyvitamin D is administered in combination with one or more other therapeutic agents.

If <NUM>-hydroxyvitamin D is administered in combination with one or more other therapeutic agents, the proportions of each of the compounds in the combination being administered will be dependent on the particular disease state being addressed. For example, one may choose to orally administer <NUM>-hydroxyvitamin D with one or more calcium salts (intended as a calcium supplement or dietary phosphate binder), bisphosphonates, calcimimetics, nicotinic acid, iron, phosphate binders, cholecalciferol, ergocalciferol, active Vitamin D sterols, glycemic and hypertension control agents, various antineoplastic agents and inhibitors of CYP24 and other cytochrome P450 enzymes that can degrade vitamin D agents. In addition, one may choose to intravenously administer <NUM>-hydroxyvitamin D<NUM> and/or <NUM>-hydroxyvitamin D<NUM> with cholecalciferol, ergocalciferol, active Vitamin D sterols, glycemic and hypertension control agents, various antineoplastic agents and inhibitors of CYP24 and other cytochrome P450 enzymes that can degrade vitamin D agents. In practice, higher doses of the compounds of the present invention are used where therapeutic treatment of a disease state is the desired end, while the lower doses can be used for prophylactic purposes, it being understood that the specific dosage administered in any given case will be adjusted in accordance with the specific compounds being administered, the disease to be treated, the condition of the subject and the other relevant medical facts that may modify the activity of the drug or the response of the subject, as is well known by those skilled in the art.

As described above, the formulation is preferably filled into gelatin capsules, but it may also be administered in neat form, or with one or more external coating layers, such as an enteric coating. It is also contemplated that the formulation can be pressed into tablets, and in such cases one or more tablet pressing excipients may be included.

In the invention described herein, preferred steps, preferred components, preferred compositional ranges thereof, and preferred combinations of the foregoing, can be selected from the various specific examples provided herein. For example, a preferred formulation includes <NUM>-hydroxyvitamin D (e.g. <NUM>-hydroxyvitamin D<NUM>, for example about <NUM> wt% (e.g.. <NUM> wt%)), about <NUM> wt% (e.g., <NUM> wt%) ethanol, about <NUM> wt% (e.g., <NUM> wt%) GELUCIRE <NUM>/<NUM>, about <NUM> wt% (e.g., <NUM> wt. %) hard paraffin, about <NUM> wt% (e.g., <NUM> wt%) GMS, about <NUM> wt% (e.g., <NUM> wt%) mineral oil, and optionally a small amount of preservative (e.g., <NUM> wt% BHT). A variation on this formulation will include about <NUM>% hard paraffin and about <NUM>% mineral oil.

Specifications for still another preferred embodiment of a capsule, and a <NUM>µg embodiment, are shown in Table <NUM> below.

The following Examples illustrate specific formulations and methods for their preparation. The Examples are provided for illustration and are not intended to limit the scope of the invention, which is defined by the claims. It will be appreciated that not all of the Examples necessarily fall within the scope of the present claimed invention. However, the following Examples do all aid the understanding of the claimed invention.

Nine oral vitamin D formulations were prepared according to Table <NUM> below by homogeneously mixing the identified components in the amounts shown and filling the mixtures into hard gelatin capsules. Formulation <NUM> is an immediate-release formulation according to the prior art, wherein MIGLYOL 812N is the trade name for caprylic/capric triglycerides, available from CONDEA Chemie GmbH of Cranford, New Jersey, USA. The formulations were administered to groups of Yucatan miniature swine (about <NUM>), in single doses equivalent to <NUM>µg of <NUM>-hydroxyvitamin D<NUM>. Each group included five animals. An equivalent <NUM>µg of <NUM>-hydroxyvitamin D<NUM> was administered to a tenth group of five Yucatan miniature swine via intravenous injection.

Blood was collected pre-dose, and at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> hours post dosing. Serum <NUM>-hydroxyvitamin D<NUM> levels were assayed by Liquid Chromatography/Mass Spectrometry/Mass Spectrometry (LC MS/MS).

Plots of the change in serum <NUM>-hydroxyvitamin D<NUM> levels over the first <NUM> hours for Groups <NUM>-<NUM> are shown in <FIG>. In addition, the data for the Group <NUM> immediate release control are plotted with the Group <NUM> data in <FIG> The concentration profiles show that the Group <NUM> formulation according to the invention (a) produced a gradually increasing and sustained rise in serum <NUM>-hydroxyvitamin D<NUM> levels over the first <NUM> hours, and (b) avoided a surge in <NUM>-hydroxyvitamin D<NUM> levels.

<FIG> show plots of the change in serum <NUM>-hydroxyvitamin D<NUM> levels over the period of the study for Groups <NUM>, <NUM>, and <NUM>, respectively. <FIG> shows an overlay plot of the data in <FIG> and <FIG> for Groups <NUM> and <NUM>, respectively.

The concentration profiles shows that the Group <NUM> formulation according to the invention produced a gradually increasing rise in serum <NUM>-hydroxyvitamin D<NUM> levels, avoided a surge in <NUM>-hydroxyvitamin D<NUM> levels, and produced a sustained increase of serum <NUM>-hydroxyvitamin D<NUM> over a long period of time.

In vitro dissolution tests of the same formulations (dissolution media: <NUM> lipase in Ctab/NaH<NUM>PO<NUM> buffer, pH <NUM>) over a period of <NUM> minutes showed results generally consistent with the in vivo data (e.g., formulations <NUM> and <NUM> showed a more gradual and incomplete rise in % dissolution, whereas the immediate release control showed <NUM>% release within <NUM> minutes).

The data in Table <NUM> below show various pharmacokinetic parameters produced in the test subjects by administration of the Group <NUM> formulation according to the invention compared to the Group <NUM> prior art immediate release formulation and the Group <NUM> IV injection administration. The data demonstrate that the Group <NUM> formulation according to the invention avoided a concentration spike, provided a maximum concentration at a time much later than the immediate release dosage form and the intravenous injection, and provided a longer clearance half life than the comparable immediate release dosage form. The Group <NUM> formulation according to the invention resulted in a slower elimination of the <NUM>-hydroxyvitamin D<NUM> administered from systemic circulation compared to Group <NUM>.

A single dose of <NUM>µg <NUM>-hydroxyvitamin D<NUM> administered according to the Group <NUM> formulation of the invention to mini-pigs (about <NUM>) resulted in an approximately <NUM> ng/ml rise in serum <NUM>-hydroxyvitamin D<NUM>. A single dose of <NUM>µg <NUM>-hydroxyvitamin D<NUM> to a human (about <NUM>) is expected to increase serum levels of <NUM>-hydroxyvitamin D<NUM> by about <NUM> ng/ml.

Comparative Cmax, Tmax, and bioavailability data for the formulations of Groups <NUM>-<NUM> and <NUM> are shown in Table <NUM> below.

The purpose of the study was to assess the systemic absorption of <NUM>-hydroxyvitamin D<NUM> in male Yucatan swine (about <NUM> body weight) following the administration of: a) <NUM> x <NUM>µg <NUM>-hydroxyvitamin D<NUM> modified release (MR) capsule, b) <NUM> x <NUM>µg MR capsules, c) <NUM> x <NUM>µg MR capsules, d) <NUM> x <NUM>µg MR capsule, e) <NUM> x <NUM>µg immediate release (IR) <NUM>-hydroxyvitamin D<NUM> capsule, and f) <NUM> x <NUM>µg MR capsule administered on <NUM> consecutive days.

The MR formulations were prepared based on the formulation of Example <NUM>, Group <NUM>, above. In the case of the <NUM>µg MR capsule, the higher concentration of <NUM>-hydroxyvitamin D<NUM> was offset by a relative decrease in ethanol.

To prepare the IR formulation <NUM>-hydroxyvitamin D<NUM> (<NUM>% wt/wt; <NUM>µg per capsule) was dissolved in ethanol USP (<NUM>% wt/wt; solublizer) and mixed with corn oil USP, (<NUM>% wt/wt; main vehicle) and butylated hydroxytoluene (<NUM>% wt/wt; antioxidant). The corn oil solution (<NUM>) was filled into size <NUM> two piece hard gelatin capsules.

Eight male Yucatan miniature swine per group were each administered a dose based on the dosing schedule in Table <NUM> below. Blood was collected from animals prior to first dose and at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> hrs following first dose. Animals in Group <NUM> were administered a second and third dose immediately following the collection of the <NUM> and <NUM> hr blood samples, respectively. <NUM>-hydroxyvitamin D<NUM> was assayed in all the collected samples. Ionized calcium and total calcium were determined in samples collected from animals in Group <NUM> and Group <NUM> at the following time points: pre dose and at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> hrs following first dose.

<NUM>-hydroxyvitamin D<NUM> in swine serum was assayed using solid-phase extraction (SPE) with high performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) detection. Serum samples were baseline corrected to exclude endogenous concentrations of <NUM>-hydroxyvitamin D<NUM> from the pharmacokinetic analysis. To achieve this pre-dose <NUM>-hydroxyvitamin D<NUM> concentration of each animal were subtracted from each of its post dose concentrations. Serum samples below the <NUM> ng/ml (lower limit of quantitation) were assigned a value of zero.

Pharmacokinetic parameters are reported in Table <NUM>.

Dose normalized pharmacokinetic parameters for Groups <NUM> to <NUM> are reported in Table <NUM>.

For the groups administered <NUM>, <NUM> and <NUM> capsules (<NUM>µg MR capsules), there was an increase in exposure as a function of dose. Dose proportional exposure occurred at the <NUM> x <NUM>µg and <NUM> x <NUM>µg doses, while slightly less than proportional exposure was observed between <NUM> x <NUM>µg and <NUM> x <NUM>µg doses. The mean time at which maximum concentration was achieved (Tmax) was between <NUM> to <NUM> hrs.

Comparison of exposure from a single capsule (<NUM> x <NUM>µg) versus four capsules (<NUM> x <NUM>µg) indicated higher exposure in animals dosed with multiple capsules. Dose independent parameters, such as mean Tmax, were similar for both dosing strategies.

The comparison of the modified release formulation of <NUM>-hydroxyvitamin D<NUM> (MR) (Group <NUM>) to the IR formulation (Group <NUM>), indicated that the MR formulation avoided a spike in the concentration of serum <NUM>-hydroxyvitamin D<NUM>. The relative bioavailability of the MR formulation when compared to the IR formulation was approximately <NUM>%. Animals receiving the MR formulation exhibited a mean Tmax of <NUM> hrs which indicated a significant delay compared to the animals receiving the IR formulation (Tmax = <NUM> hrs).

Exposure was assessed in animals receiving <NUM> x <NUM>µg MR capsules on Days <NUM>, <NUM> and <NUM>. The mean increase in concentration of <NUM>-hydroxyvitamin D<NUM> over baseline <NUM> following dosing was <NUM>, <NUM> and <NUM> ng/mL following the first, second and third dose respectively.

<FIG> show the mean pharmacokinetic profile for animals in Groups <NUM>-<NUM>, respectively. <FIG> shows a comparison of pharmacokinetic profiles for MR and IR formulations of <NUM>µg <NUM>-hydroxyvitamin D<NUM>.

The purpose of this study was to assess the increase in systemic <NUM>-hydroxyvitamin D<NUM> concentrations in healthy normal male Yucatan swine (~<NUM>-<NUM> body weight) maintained on a diet including an adequate intake of Vitamin D, following the daily administration of the following: a) <NUM>µg immediate release (IR) <NUM>-hydroxyvitamin D<NUM> capsules (Group <NUM>), b) <NUM>µg modified release (MR) <NUM>-hydroxyvitamin D<NUM> capsules (Group <NUM>), and c) <NUM>µg MR <NUM>-hydroxyvitamin D<NUM> capsules (Group <NUM>), for <NUM> days.

The MR formulations were prepared based on the formulation of Example <NUM>, Group <NUM>, above. The differences in concentration of <NUM>-hydroxyvitamin D<NUM> were offset by relative changes in ethanol.

Eight male Yucatan miniature swine per group were each administered a daily dose based on the dosing schedule in Table <NUM>, below.

Blood was collected from animals prior to the first dose and daily at <NUM> following daily dose, prior to subsequent dose. The concentration of serum <NUM>-hydroxyvitamin D<NUM> was assayed using solid-phase extraction (SPE) with high performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) detection. Total serum calcium was determined in samples collected from animals at the following time points: pre dose (Day <NUM>) and <NUM> following last dose (Day <NUM>).

In all three groups, pre-dose mean serum <NUM>-hydroxyvitamin D<NUM> concentrations were approximately <NUM> ng/mL. After <NUM> doses, an increase in serum <NUM>-hydroxyvitamin D<NUM> was observed in all animals. Following the repeat administration of <NUM>µg MR or IR capsules, the concentration of serum <NUM>-hydroxyvitamin D<NUM> increased to levels above <NUM> ng/mL and began to plateau at approximately <NUM> and <NUM> ng/mL, respectively at approximately Day <NUM> to <NUM>. Upon the administration of a single dose, the increase in serum <NUM>-hydroxyvitamin D<NUM> between the two regimens was comparable (<NUM> versus <NUM> ng/mL). On the other hand, at the completion of dosing the increase was approximately <NUM>% greater for animals administered the IR formulation. This finding indicates that the bioavailability from the MR capsule is comparable to that of the IR following a single dose, but that the MR capsules present a method for repeat dosing of <NUM>-hydroxyvitamin D<NUM> in which systemic <NUM>-hydroxyvitamin D<NUM> can be gradually increased.

Animals administered <NUM>µg MR capsules exhibited higher levels of serum <NUM>-hydroxyvitamin D<NUM>. The administration of a <NUM> fold greater dose (<NUM>µg versus <NUM>µg MR capsules) resulted in approximately <NUM> fold greater increase in <NUM>-hydroxyvitamin D<NUM> following single and repeated dose. This finding indicates that exposure from MR capsules is dose proportional from <NUM> to <NUM>µg.

The effect of the administration of IR and MR capsules on the concentration of serum calcium was investigated. After the administration of <NUM> doses of either IR or MR, the levels of calcium in serum did not change from pre-dose baseline levels. This finding indicates that <NUM>-hydroxyvitamin D<NUM> MR capsules can be utilized to increase serum <NUM>-hydroxyvitamin D<NUM> levels to above <NUM> ng/mL without causing an increase in serum calcium.

Mean uncorrected serum <NUM>-hydroxyvitamin D<NUM> concentration versus time profiles for Groups <NUM> to <NUM> are illustrated in <FIG>. Mean baseline corrected serum <NUM>-hydroxyvitamin D<NUM> concentration versus time profiles for Groups <NUM> to <NUM> are illustrated in <FIG>, <FIG> and <FIG>, respectively.

<FIG> shows the mean change in parathyroid hormone levels for Group <NUM> animals from predose to day <NUM>, and <FIG> shows the mean change in parathyroid hormone levels for Group <NUM> animals from predose to day <NUM>. The immediate release and modified release formulations as administered in this study both raised serum <NUM>-hydroxyvitamin D<NUM>; however, the immediate release formulation resulted in undesirable pharmacological decreases in PTH in these subjects. The modified release formulation as administered did not effect acute supraphysiological reductions in PTH and allows for gradual PTH lowering, believed to be associated with physiological adaptation to markedly rising <NUM>-hydroxyvitamin D<NUM> levels. The MR formulation should permit attainment of higher serum <NUM>-hydroxyvitamin D<NUM> levels without safety concerns associated with undesirable pharmacological lowering of PTH.

Modified release <NUM>-hydroxyvitamin D<NUM> capsules were administered daily to Beagle dogs (<NUM>) for <NUM> consecutive weeks. The MR formulations were prepared based on the formulation of Example <NUM>, Group <NUM>, above. The differences in concentration of <NUM>-hydroxyvitamin D<NUM> were offset by relative changes in ethanol.

The capsules were administered orally, as shown in Table <NUM> below.

Dogs were bled prior to the first dose and at specific time points following the first dose, up to <NUM> weeks (<NUM> days). Serum was generated and <NUM>-hydroxyvitamin D<NUM> was assayed in the serum using a liquid chromatography tandem mass spectrometry method.

Mean serum <NUM>-hydroxyvitamin D<NUM> concentration versus time profiles for Groups <NUM> to <NUM> are illustrated in <FIG>.

<FIG> shows a dissolution release profile for <NUM>µg capsules according to Example <NUM> above, which showed an average release of about <NUM>% of <NUM>-hydroxyvitamin D<NUM> at <NUM> hours. As described above, preferably the modified release formulation releases about <NUM>% of the drug in the first <NUM> hours.

The effectiveness of three different formulations of Vitamin D in restoring serum <NUM>-hydroxyvitamin D to optimal levels (> <NUM> ng/mL) is examined in a <NUM>-day study of healthy non-obese men diagnosed with Vitamin D insufficiency. One of the formulations (Formulation #<NUM>) is a soft gelatin capsule containing <NUM>µg of <NUM>-hydroxyvitamin D<NUM> prepared as described in Example <NUM>, Group <NUM>, above. The second formulation (Formulation #<NUM>) is an immediate-release soft gelatin capsule of identical appearance containing <NUM>,<NUM> IU of ergocalciferol dissolved in medium chain triglyceride oil. The third formulation (Formulation #<NUM>) is an immediate-release soft gelatin capsule, also of identical appearance, containing <NUM>,<NUM> IU of cholecalciferol dissolved in medium chain triglyceride oil. A total of <NUM> healthy Caucasian and African-American men participate in this study, all of whom are aged <NUM> to <NUM> years and have serum <NUM>-hydroxyvitamin D levels between <NUM> and <NUM> ng/mL (inclusive). All subjects abstain from taking other Vitamin D supplements for <NUM> days before study start and continuing through study termination, and from significant sun exposure. On Day <NUM> and <NUM> of the study, all subjects provide fasting morning blood samples to establish pre-treatment baseline values of serum <NUM>-hydroxyvitamin D. On the morning of Day <NUM>, the subjects provide an additional fasting blood sample (t=<NUM>), are randomly assigned to one of four treatment groups, and are dosed with a single test capsule prior to eating breakfast: the subjects in Group #<NUM> each receive a single capsule of Formulation #<NUM>, and the subjects in Groups #<NUM> and #<NUM> each receive a single capsule of Formulation #<NUM> or Formulation #<NUM>, respectively. Subjects in Group #<NUM> receive a matching placebo capsule. Subjects in Group #<NUM> each receive an additional capsule of Formulation #<NUM> on the mornings of Days <NUM> through <NUM> before breakfast, but subjects in Groups #<NUM>, #<NUM> and #<NUM> receive no additional capsules. A fasting morning blood sample is drawn from each subject, irrespective of treatment group, on Days <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> (or <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> days after the start of dosing). All collected blood is analyzed for the contained levels of <NUM>-hydroxyvitamin D and PTH, and the data are analyzed by treatment group after correction for baseline values. Subjects in all four treatment groups exhibit mean baseline serum <NUM>-hydroxyvitamin D levels of approximately <NUM> to <NUM> ng/mL, based on analysis of fasting blood samples drawn on Days <NUM> through <NUM>. Subjects in Group #<NUM> (control group) show no significant changes in mean serum <NUM>-hydroxyvitamin D over the course of the study. Subjects in Group #<NUM> show a steadily increasing mean serum <NUM>-hydroxyvitamin D reaching at least <NUM> ng/mL by Day <NUM> and decreases in plasma PTH. In marked contrast, subjects in Group #<NUM> exhibit marked increases in mean serum <NUM>-hydroxyvitamin D for the first few days post-dosing, reaching a maximum of <NUM> ng/ml and then rapidly declining thereafter. By study end, serum <NUM>-hydroxyvitamin D is significantly lower than baseline in Group #<NUM>. and plasma PTH is not decreased. Subjects in Group #<NUM> exhibit continuing increases in mean serum <NUM>-hydroxyvitamin D through the first <NUM> weeks after dosing with gradual, but progressive, decreases occurring thereafter. By study end, mean serum <NUM>-hydroxyvitamin D is below <NUM> ng/mL, being only approximately <NUM> ng/mL higher than pre-treatment baseline and plasma PTH is only marginally decreased. The data from this study demonstrate that administration of <NUM>µg of <NUM>-hydroxyvitamin D<NUM>, formulated as described herein and administered at a dose of <NUM>µg per day for <NUM> days, is substantially more effective in restoring low serum levels of <NUM>-hydroxyvitamin D to optimal levels than immediate-release formulations of <NUM>,<NUM> IU of either ergocalciferol or cholecalciferol administered in single doses, as currently recommended by the NKF and other leading experts on oral Vitamin D replacement therapy.

The effectiveness of oral immediate-release and modified-release <NUM>-hydroxyvitamin D<NUM> in restoring serum total <NUM>-hydroxyvitamin D to optimal levels (> <NUM> ng/mL) is examined in a <NUM>-month study of adult male and female patients with Stage <NUM> CKD and secondary hyperparathyroidism associated with vitamin D insufficiency. Two formulations are used in the study. One of the formulations (Formulation #<NUM>) is a soft gelatin capsule containing <NUM>µg of <NUM>-hydroxyvitamin D<NUM> in a modified-release formulation. The second formulation (Formulation #<NUM>) is a soft gelatin capsule containing <NUM>µg of <NUM>-hydroxyvitamin D<NUM> in an immediate-release formulation. A total of <NUM> subjects participate in this study, all of whom are aged <NUM> to <NUM> years and have serum <NUM>-hydoxyvitamin D levels between <NUM> and <NUM> 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 <NUM> days before study start and continuing through study termination, and from significant sum exposure. All subjects begin daily dosing with two capsules of either Formulation #<NUM> or Formulation #<NUM>. Serum total <NUM>-hydroxyvitamin D is measured at biweekly intervals and serum iPTH is determined at quarterly invervals. After <NUM> month, the daily dosage of both Formulations is maintained unchanged in patients whose serum total <NUM>-hydroxyvitamin D is between <NUM> and <NUM> ng/mL, increased by one capsule in patients whose serum total <NUM>-hydroxyvitamin D is below <NUM> ng/mL, and decreased by one capsule per day in patients whose serum total <NUM>-hydroxyvitamin D is above <NUM> ng/mL. Further adjustments in the daily dose are made in order to maintain serum total <NUM>-hydroxyvitamin D between <NUM> and <NUM> ng/mL. Dosing with both Formulation #<NUM> and #<NUM> is continued indefinitely, provided that hypercalcemia, hypercalciuria and hyperphosphatemia do not develop, in which case appropriate adjustments in dosage are made. After <NUM>-months, the subjects' serum total <NUM>-hydroxyvitamin D levels are found to remain stable between <NUM> and <NUM> ng/mL with treatment with Formulation #<NUM> and serum iPTH is found to remain stable at levels consistent with or closer to targets published in the K/DOQI Guidelines. The incidence of hypercalcemia, hypercalciuria and hyperphosphatemia are rare once stable dosing has been achieved. In contrast after <NUM>-months, the subjects' serum total <NUM>-hydroxyvitamin D levels are not found to remain stable between <NUM> and <NUM> ng/mL with treatment with Formulation #<NUM> and serum iPTH does not reach levels consistent with or closer to targets published in the K/DOQI Guidelines. The incidence of hypercalcemia, hypercalciuria and hyperphosphatemia are substantial.

Data from this study demonstrate that the modified release formulation of <NUM>-hydroxyvitamin D<NUM> is effective at increasing serum <NUM>-hydroxyvitamin D without causing unacceptable side effects related to calcium and PTH metabolism.

In this randomized open label single-dose study, <NUM> subjects with baseline serum total <NUM>-hydroxyvitamin D between <NUM> and <NUM> ng/mL and serum iPTH above K/DOQI targets were dosed with a modified release oral dosage form according to the disclosure herein (<NUM> or <NUM>µg) or IV calcifediol (<NUM>-hydroxyvitamin D<NUM>) (<NUM>µg) to evaluate bioavailability, pharmacokinetics, pharmacodynamics, safety and tolerability. The modified release dosage formulation was the same as formulation <NUM> in Table <NUM> herein, with the following exceptions: (<NUM>) a vegetable-based capsule was used in place of a gelatin capsule; (<NUM>) hard paraffin content was reduced to <NUM>%; and (<NUM>) liquid paraffin (light mineral oil) content was increased to <NUM>%. The amount of <NUM>-hydroxyvitamin D<NUM> per capsule was <NUM>µg. The bioavailability was estimated to be about <NUM>% measured over the first <NUM> hours post-dose and about <NUM>% over the total <NUM>-day follow-up period.

Serum calcium (Ca), phosphorus (P), iPTH, <NUM>-hydroxyvitamin D<NUM> and total <NUM>,<NUM>-dihydryoxyvitamin D were monitored for <NUM> weeks. Mean (±SD) baseline <NUM>-hydroxyvitamin D<NUM> and iPTH were <NUM>±<NUM> ng/mL and <NUM>±<NUM> pg/mL, respectively. IV calcifediol rapidly raised mean <NUM>-hydroxyvitamin D<NUM> to <NUM>±<NUM> ng/mL. The modified release capsules produced gradual increases in <NUM>-hydroxyvitamin D<NUM> to a mean of <NUM>±<NUM> ng/mL (<NUM>µg) and <NUM>±<NUM> ng/mL (<NUM>µg). Serum <NUM>-hydroxyvitamin D<NUM> Tmax for the IV calcifediol was <NUM>±<NUM> hours , whereas Tmax for the modified release dosage forms was <NUM>±<NUM> hours (<NUM>µg) and <NUM>±<NUM> hours (<NUM>µg). The bioavailability of the modified release dosage form was about <NUM>% measured over the duration of the study (<NUM> days). No confirmed hypercalcemia (><NUM>/dL) was observed in any treatment group.

Serum total <NUM>,<NUM>-dihydroxyvitamin D reached an increase of <NUM> pg/mL at <NUM> hrs after IV calcifediol, and of <NUM> and <NUM> pg/mL at <NUM> to <NUM> hrs after <NUM> and <NUM>µg of the modified release capsules, respectively. IV calcifediol and <NUM>µg of the modified release capsules had no clinically meaningful effect on mean iPTH. The modified release capsules dosed at <NUM>µg reduced iPTH from baseline by a mean of <NUM>% at <NUM> hrs. The rapid increase in serum total <NUM>,<NUM>-dihydroxyvitamin D after IV calcifediol may have triggered excessive expression of the vitamin D catabolic enzyme, CYP24, in the parathyroid glands, leading to local hormone resistance and limited iPTH suppression.

The elimination half-life (t<NUM>/<NUM>) of the absolute <NUM>-hydroxyvitamin D<NUM> levels were substantially increased following administration of the modified release capsules (<NUM> and <NUM> hours) compared to that following IV calcifediol (<NUM> hours). The elimination half-life (t<NUM>/<NUM>) of the absolute <NUM>,<NUM>-hydroxyvitamin D levels also were substantially increased following administration of the modified release capsules (<NUM> and <NUM> hours) compared to that following IV calcifediol (<NUM> hours).

Table <NUM> and Table <NUM> show a summary of the observed and baseline-adjusted pharmacokinetic parameters, respectively, for <NUM>-hydroxyvitamin D<NUM> by treatment group. Table <NUM> and Table <NUM> show a summary of the observed and baseline-adjusted pharmacokinetic parameters, respectively, for <NUM>,<NUM>-dihydroxyvitamin D<NUM> by treatment group.

These findings demonstrate that the modified release capsules gradually normalized <NUM>-hydroxyvitamin D<NUM> levels and suppressed elevated iPTH in this patient population, and that the mechanism to lower iPTH may be more complex than simply boosting serum total <NUM>-hydroxyvitamin D.

<FIG> shows a plot of the change in serum <NUM>-hydroxyvitamin D<NUM> levels over <NUM> hours in Stage <NUM> and <NUM> Chronic Kidney Disease subjects with vitamin D insufficiency and secondary hyperparathyroidism that were intravenously (N=<NUM>) or orally (N=<NUM>) administered a single dose of <NUM>µg of <NUM>-hydroxyvitamin D<NUM> in a modified release dosage form as described herein or orally administered (N = <NUM>) a single dose of <NUM>µg of <NUM>-hydroxyvitamin D<NUM> in a modified release dosage form as described herein. The orally administered doses of <NUM>-hydroxyvitamin D<NUM> gradually increased levels of serum <NUM>-hydroxyvitamin D<NUM>, sustained this increase for over <NUM> hours, and avoided a surge in <NUM>-hydroxyvitamin D<NUM> serum levels. The orally administered dose having <NUM>µg of <NUM>-hydroxyvitamin D<NUM> increased levels of serum <NUM>-hydroxyvitamin D<NUM> by approximately <NUM> ng/ml at <NUM> hours versus only <NUM> ng/ml using the dose having <NUM>µg of <NUM>-hydroxyvitamin D<NUM>.

<FIG> shows a plot of the change in serum <NUM>,<NUM>-hydroxyvitamin D<NUM> levels over <NUM> hours in Stage <NUM> and <NUM> Chronic Kidney Disease subjects with vitamin D insufficiency and secondary hyperparathyroidism that were intravenously (N=<NUM>) or orally (N=<NUM>) administered a single dose of <NUM>µg of <NUM>-hydroxyvitamin D<NUM> in a modified release dosage form as described herein or orally administered (N=<NUM>) a single dose of <NUM>µg of <NUM>-hydroxyvitamin D<NUM> in a modified release dosage form as described herein. The orally administered doses of <NUM>-hydroxyvitamin D<NUM> gradually increased levels of serum <NUM>,<NUM>-hydroxyvitamin D<NUM>, sustained this increase for over <NUM> hours, and avoided a surge in <NUM>,<NUM>-hydroxyvitamin D<NUM> serum levels. The orally administered dose having <NUM>µg of <NUM>-hydroxyvitamin D<NUM> increased levels of serum <NUM>,<NUM>-hydroxyvitamin D<NUM> to a greater extent than the orally administered dose having <NUM>µg of <NUM>-hydroxyvitamin D<NUM>, which increased <NUM>,<NUM>-hydroxyvitamin D<NUM> by only about <NUM> pg/ml.

<FIG> shows the mean percent change in parathyroid hormone levels for Stage <NUM> and <NUM> Chronic Kidney Disease subjects with vitamin D insufficiency and secondary hyperparathyroidism that were orally administered a single dose of <NUM>µg of <NUM>-hydroxyvitamin D3 in a modified release dosage form as described herein (N=<NUM>) compared to subjects intravenously administered a single dose of <NUM>µg of <NUM>-hydroxyvitamin D3 (N=<NUM>). The latter group served as a control (<NUM>% of baseline).

<FIG> shows the mean % change in iPTH levels for Stage <NUM> and <NUM> Chronic Kidney Disease subjects with vitamin D insufficiency and secondary hyperparathyroidism that were intravenously administered a single dose of <NUM>µg of <NUM>-hydroxyvitamin D3 (N=<NUM>) or orally administered a single dose of <NUM>µg (N=<NUM>) or <NUM>µg (N=<NUM>) of <NUM>-hydroxyvitamin D3 in a modified release dosage form. The orally administered single dose of <NUM>µg produced a steady decline with a sustained reduction in iPTH with a final mean % reduction of <NUM>%.

Claim 1:
A modified release composition comprising <NUM>-hydroxyvitamin D<NUM>, <NUM>-hydroxyvitamin D<NUM>, or a combination thereof, for use in a method for reducing serum parathyroid levels in a Chronic Kidney Disease patient, the method comprising orally administering an effective amount of the composition to the patient, who is a human subject suffering from hyperparathyroidism secondary to Chronic Kidney Disease,
said composition being administered at a frequency in a range of every six weeks to every other day,
wherein the composition provides a rise in serum total <NUM>-hydroxyvitamin D within the first <NUM> hours after said administering of at least <NUM> ng/ml and no greater than <NUM> ng/ml, as assayable using solid-phase extraction (SPE) with high performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) detection,
wherein the composition lowers the subject's serum intact parathyroid hormone (iPTH) level by at least <NUM>% compared to baseline.