TREATING VITAMIN D INSUFFICIENCY AND DEFICIENCY WITH 25-HYDROXYVITAMIN D2 AND 25-HYDROXYVITAMIN D3

Abstract

Methods and compositions for treating 25-hydroxyvitamin D insufficiency and deficiency in a patient are described herein. The method includes orally administering to the patient a delayed, sustained release formulation including a first ingredient selected from the group consisting of 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3, or it includes gradually administering to the patient a sterile intravenous formulation including a first ingredient selected from the group consisting of 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3.

Claims

1. A method of treating 25-hydroxyvitamin D insufficiency or deficiency in a patient comprising orally administering to the patient a sustained release formulation of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more calcium salts, bisphosphonates, calcimimetics, nicotinic acid, iron, phosphate binders, glycemic control agents, hypertension control agents, and antineoplastic agents.

2. The method of claim 1, comprising orally administering to the patient a sustained release formulation of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more calcium salts.

3. The method of claim 1, comprising orally administering to the patient a sustained release formulation of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more bisphosphonates.

4. The method of claim 1, comprising orally administering to the patient a sustained release formulation of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with nicotinic acid.

5. The method of claim 1, comprising orally administering to the patient a sustained release formulation of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with iron.

6. The method of claim 1, comprising orally administering to the patient a sustained release formulation of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more phosphate binders.

7. The method of claim 1, comprising orally administering to the patient a sustained release formulation of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more glycemic control agents.

8. The method of claim 1, comprising orally administering to the patient a sustained release formulation of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more hypertension control agents.

9. The method of claim 1, comprising orally administering to the patient a sustained release formulation of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more antineoplastic agents.

10. A sustained release oral dosage formulation of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more calcium salts, bisphosphonates, calcimimetics, nicotinic acid, iron, phosphate binders, cholecalciferol, ergocalciferol, active Vitamin D sterols, glycemic and hypertension control agents, and antineoplastic agents.

11. The sustained release oral dosage formulation of claim 10, comprising 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more calcium salts.

12. The sustained release oral dosage formulation of claim 10, comprising 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more bisphosphonates.

13. The sustained release oral dosage formulation of claim 10, comprising 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with nicotinic acid.

14. The sustained release oral dosage formulation of claim 10, comprising 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with iron.

15. The sustained release oral dosage formulation of claim 10, comprising 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more phosphate binders.

16. The sustained release oral dosage formulation of claim 10, comprising 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more glycemic control agents.

17. The sustained release oral dosage formulation of claim 10, comprising 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more hypertension control agents.

18. The sustained release oral dosage formulation of claim 10, comprising 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, or a combination of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 in combination with one or more antineoplastic agents.

19. A sustained release oral dosage formulation of 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3 dispersed within a matrix and encased with a coating material.

20. The sustained release oral dosage formulation of claim 19, having a melting point which is higher than body temperature but lower than the melting temperature of the coating material.

21. The sustained release oral dosage formulation of claim 19, wherein the matrix comprises a lipid.

22. The sustained release oral dosage formulation of claim 21, wherein the lipid comprises one or more glycerides, fatty acids, fatty alcohols, fatty acid esters, or combinations thereof.

23. The sustained release oral dosage formulation of claim 22, wherein the lipid comprises one or more glycerides.

24. The sustained release oral dosage formulation of claim 22, wherein the lipid comprises one or more fatty acids.

25. The sustained release oral dosage formulation of claim 22, wherein the lipid comprises one or more fatty alcohols.

26. The sustained release oral dosage formulation of claim 22, wherein the lipid comprises one or more fatty acid esters.

27. A sustained release oral dosage formulation of 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3 dispersed within a matrix and comprising a permeable overcoating.

28. The sustained release oral dosage formulation of claim 27, wherein the 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3 is released by diffusion.

29. The sustained release oral dosage formulation of claim 27, wherein the 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3 is released by disintegration of the matrix.

30. The sustained release oral dosage formulation of claim 27, wherein the 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3 is released by a combination of diffusion and disintegration of the matrix.

31. A sustained release oral dosage formulation of 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3 dispersed within a matrix which is solid at body temperature.

32. A controlled release formulation comprising a carrier and 25-hydroxyvitamin D.sub.3, wherein the carrier is selected from the group consisting of synthetic wax, microcrystalline wax, paraffin wax, carnauba wax, beeswax; polyethoxylated castor oil derivatives, hydrogenated vegetable oils, glyceryl mono-, di- or tribehenates; long chain alcohols, and mixtures thereof.

33. The formulation according to claim 32 wherein the carrier is present in a weight percentage in a range of 5 to 50% wt/wt.

34. The formulation according to claim 32 further comprising an emulsifier.

35. The formulation according to claim 33 further comprising a lipoidic agent.

36. The formulation according to claim 35 wherein the lipoidic agent is selected from the group consisting of glycerides and derivatives thereof; mixed fatty acid mono-glycerides; 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 monooleate; sorbitan esters including sorbitan monosterate and sorbitan sesquioleate; fatty acids and their soaps including stearic acid, palmitic acid, and oleic acid and mixtures thereof.

37. The controlled release formulation according to claim 35 wherein the lipoidic agent is selected from mono-glycerides or di-glycerides or a combination thereof.

38. A sustained release formulation comprising 25-hydroxyvitamin D.sub.3, an oily component and a carrier.

39. The sustained release formulation according to claim 38 in the form of a capsule.

40. The sustained release formulation according to claim 39 wherein 25-hydroxyvitamin D.sub.3 is present in a dosage range of 10 to 1000 micrograms per capsule.\

41. A sustained release formulation comprising 25-hydroxyvitamin D.sub.3, a carrier and a lipoidic agent.

42. The sustained release formulation according to claim 41 wherein the lipoidic agent comprises an amphiphile.

43. A sustained release formulation comprising 25-hydroxyvitamin D.sub.3, a carrier and an absorption enhancer.

44. A sustained release capsule formulation comprising 25-hydroxyvitamin D.sub.3, an oil, a carrier, a lipophilic emulsifier, and an absorption enhancer.

45. The sustained release formulation according to claim 44 wherein the capsule is a soft capsule.

46. The sustained release formulation according to claim 44 wherein the capsule is a hard capsule.

47. A capsule comprising the sustained release capsule formulation according to claim 44 wherein the capsule is filled with a homogeneous solution of said sustained release capsule formulation.

48. The capsule according to claim 47 wherein the amount of 25-hydroxyvitamin D.sub.3 is in a range of 10 to 1,000 ug.

49. The capsule according to claim 48 further comprising a preservative.

50. The capsule according to claim 48 further comprising an antioxidant.

51. The capsule according to claim 48 further comprising a solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention relates to a method for dosing a subject, an animal or a human patient, in need of Vitamin D supplementation with sufficient 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3 or any combination of these two prohormones to effectively and safely restore blood 25-hydroxyvitamin D levels to optimal levels (defined for human subjects and patients as >30 ng/mL 25-hydroxyvitamin D) and to maintain blood 25-hydroxyvitamin D levels at such optimal levels.

[0023] As used herein, the following definitions may be useful in aiding the skilled practitioner in understanding the invention:

[0024] As used herein, the term “substantially constant” with respect to the serum or blood level of 25-hydroxyvitamin D means that the release profile of any formulation administered as detailed hereinbelow should not include transient increases in total serum or blood levels of 25-hydroxyvitamin D.sub.3 or 25-hydroxyvitamin D.sub.2 of greater than approximately 3 ng/mL after administration of a unit dose.

[0025] As used herein, the term “controlled release” and “sustained release” are used interchangeably, and refer to the release of the administered 25-hydroxyvitamin D at such a rate that total serum or blood levels of 25-hydroxyvitamin D are maintained or elevated above predosing levels for an extended period of time, e.g., 4 to 24 hours or even longer.

[0026] As used herein, the term “Vitamin D toxicity” is meant to refer to the side effects suffered from excessive administration of 25-hydroxyvitamin D and excessively elevated 25-hydroxyvitamin D blood levels, including nausea, vomiting, polyuria, hypercalciuria, hypercalcemia and hyperphosphatemia.

[0027] “Supraphysiologic” in reference to intralumenal, intracelulluar and blood concentrations of 25-hydroxyvitamin D refers to a combined concentration of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3 during a 24-hour post-dose period which is more than 5 ng/mL greater than the generally stable levels observed over the course of the preceding 24-hour period by laboratory measurement.

[0028] “Vitamin D insufficiency and deficiency” is generally defined as having serum 25-hydroxyvitamin D levels below 30 ng/mL (National Kidney Foundation guidelines, NKF, Am. J. Kidney Dis. 42:S1-S202 (2003), incorporated herein by reference).

[0029] Unless indicated otherwise, “25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3” as used herein is intended to encompass 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination thereof.

[0030] Unless indicated otherwise, “25-hydroxyvitamin D” is intended to refer to 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3 collectively. For example, an assayed blood level of 25-hydroxyvitamin D will include both 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3, if present.

[0031] It also is specifically understood that any numerical value recited herein includes all values from the lower value to the upper value, i.e., all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application. For example, if a concentration range or a beneficial effect range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3%, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended.

[0032] The invention includes compositions comprising oral and intravenous formulations of 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 and methods of administering such formulations to treat 25-hydroxyvitamin D insufficiency and deficiency without the potential first pass effects of these prohormones on the duodenum and jejunum; without supraphysiological surges in intralumenal, intracellular and blood levels of 25-hydroxyvitamin D and their consequences; without causing substantially increased catabolism of the administered 25-hydroxyvitamin D; and, without causing serious side effects associated with Vitamin D supplementation, namely Vitamin D toxicity.

[0033] The controlled release compositions intended for oral administration in accordance with the present invention are designed to contain concentrations of the 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 of 1 to 50 mcg per unit dose, and are prepared in such a manner as to effect controlled or substantially constant release of the 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 into the ileum of the gastrointestinal tract of humans or animals over an extended period of time. The compositions ensure a (a) substantially increased absorption of 25-hydroxyvitamin D via transport on DBP and decreased absorption via transport in chylomicrons, and (b) maintenance of substantially constant blood levels of 25-hydroxyvitamin D during the 24-hour post-dosing period. By providing a gradual, sustained and direct release of the 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 preferentially to circulating DBP (rather than to chylomicrons), blood, intralumenal and intracellular 25-hydroxyvitamin D concentration spikes, i.e., supraphysiologic levels and related unwanted catabolism are mitigated or eliminated.

[0034] The compositions intended for intravenous administration in accordance with the present invention are designed to contain concentrations of the 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 of 1 to 25 mcg per unit dose, and are prepared in such a manner as to allow gradual injection, over a period of 1 to 5 minutes, to effect controlled or substantially constant release of the 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 directly to DBP in the blood. The compositions ensure complete bioavailability of the administered 25-hydroxyvitamin D, complete elimination of first pass effects on the duodenum and jejunum, decreased catabolism of 25-hydroxyvitamin D, and maintenance of substantially constant blood levels of 25-hydroxyvitamin D during the 24-hour post-dosing period. By providing a gradual, sustained and direct release of the 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 over time to circulating DBP, intralumenal, intracellular and even blood 25-hydroxyvitamin D concentration spikes, i.e., supraphysiologic levels, are mitigated or eliminated.

[0035] The compositions of the present invention comprise highly stable pharmaceutical formulations into which 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 is incorporated for convenient daily oral administration. The disclosed compositions produce gradual increases in and then sustained blood levels of 25-hydroxyvitamin D with dual unexpected benefits with continued regular administration over a prolonged period of time of unsurpassed effectiveness in restoring blood 25-hydroxyvitamin D to optimal levels, and unsurpassed safety relative to heretofore known formulations of Vitamin D or 25-hydroxyvitamin D.

[0036] The preparation of a controlled, substantially constant release form of 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 suitable for oral administration can be carried out according to many different techniques. For example, the 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 can be dispersed within a matrix, i.e. a unique mixture of rate controlling constituents and excipients in carefully selected ratios within the matrix, and encased with a coating material. Various coating techniques can be utilized to control the rate and/or the site of the release of the 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 from the pharmaceutical formulation. For example, the dissolution of the coating may be triggered by the pH of the surrounding media, and the resulting gradual dissolution of the coating over time exposes the matrix to the fluid of the intestinal environment. After the coating becomes permeable, 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 diffuses from the outer surface of the matrix. When this surface becomes exhausted or depleted of 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3, the underlying stores begin to be depleted by diffusion through the disintegrating matrix to the external solution.

[0037] In one aspect, a formulation in accordance with the present invention provides 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 within a matrix that releasably binds the ingredients in a controlled substantially constant release when exposed to the contents of the ileum.

[0038] The 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 containing matrix is suitably covered with a coating that is resistant to disintegration in gastric juices. The coated controlled release formulation of 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 is then administered orally to subjects, e.g., animals or human subjects and patients. As the formulation travels through the proximal portion of the small intestine, the enteric coating becomes progressively more permeable but, in a suitable embodiment, it provides a persisting structural framework around the 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 containing matrix. The 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 containing matrix becomes significantly exposed to intestinal fluids in the ileum through the permeable overcoating, and the 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 is then gradually released by simple diffusion and/or slow disintegration of the matrix.

[0039] Once released into the lumen of the ileum, the 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 is absorbed into the lymphatic system or into the portal bloodstream where it is bound to and transported by the DBP. The major portion of 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 is absorbed at a point beyond the duodenum and jejunum. These proximal portions of the small intestine can respond to high intralumenal levels of 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 and, in the process, can catabolize significant quantities of the 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3. By substantially delaying 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 release until the ileum, the pharmaceutical composition described herein virtually eliminates these potential first pass effects on the proximal intestine, and reduces unwanted catabolism. Significant catabolism of administered Vitamin D prior to its absorption into the bloodstream significantly lowers its bioavailability. Elimination of first pass effects reduces the risk of Vitamin D toxicity. Substantially delayed release of 25-hydroxyvitamin D (i.e., beyond the duodenum and jejunum) markedly decreases the amount of 25-hydroxyvitamin D that is incorporated and absorbed from the small intestine via chylomicrons (since chylomicron formation and absorption occurs primarily in the jejunum) and correspondingly increases the amount of 25-hydroxyvitamin D that is absorbed directly through the intestinal wall and onto DBP circulating in lymph or portal blood.

[0040] In one embodiment of the invention, the controlled release oral formulation of 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 is prepared generally according to the following procedure. A sufficient quantity of 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 is completely dissolved in a minimal volume of USP-grade absolute ethanol (or other suitable solvent) and mixed with appropriate amounts and types of pharmaceutical-grade excipients to form a matrix which is solid or semi-solid at both room temperature and at the normal temperature of the human body. The matrix is completely or almost entirely resistant to digestion in the stomach and upper small intestine, and it gradually disintegrates in the lower small intestine.

[0041] In a suitable formulation, the matrix binds the 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 and permits a slow, relatively steady, i.e., substantially constant, release of the 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 over a period of four to eight hours or more, by simple diffusion and/or gradual disintegration, into the contents of the lumen of the lower small intestine. The formulation further has an enteric coating that partially dissolves in aqueous solutions having a pH of about 7.0 to 8.0, or simply dissolves slowly enough that significant release of 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 is delayed until after the formulation passes through the duodenum and jejunum.

[0042] As discussed above, the means for providing the controlled release of 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 may be selected from any of the known controlled release delivery systems of an active ingredient over a course of about four or more hours including the wax matrix system, and the Eudragit RS/RL system (of Rohm Pharma, GmbH, Weiterstadt, Germany).

[0043] The wax matrix system provides a lipophilic matrix. The wax matrix system may utilize, beeswax, white wax, cachalot wax or similar compositions. The active ingredient(s) are dispersed in the wax binder which slowly disintegrates in intestinal fluids to gradually release the active ingredient(s). The wax binder that is impregnated with the 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 is loaded into partially crosslinked soft gelatin capsules. The wax matrix system disperses the active ingredient(s) in a wax binder which softens at body temperature and slowly disintegrates in intestinal fluids to gradually release the active ingredient(s). The system suitably includes a mixture of waxes, with the optional addition of oils, to achieve a melting point which is higher than body temperature but lower than the melting temperature of gelatin formulations typically used to create the shells of either soft and hard gelatin capsules or other formulations used to create enteric coatings.

[0044] Specifically, in one suitable embodiment, the waxes selected for the matrix are melted and thoroughly mixed. The desired quantity of oils are added at this time, followed by sufficient mixing. The waxy mixture is then gradually cooled to a temperature just above its melting point. The desired amount of 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3, dissolved in ethanol, is uniformly distributed into the molten matrix, and the matrix is loaded into soft gelatin capsules. The filled capsules are treated for appropriate periods of time with a solution containing an aldehyde, such as acetaldehyde, to partially crosslink the gelatin in the capsule shell. The gelatin shell becomes increasingly crosslinked, over a period of several weeks and, thereby, more resistant to dissolution in the contents of stomach and upper intestine. When properly constructed, this gelatin shell will gradually dissolve after oral administration and become sufficiently porous (without fully disintegrating) by the time it reaches the ileum to allow the 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 to diffuse slowly from the wax matrix into the contents of the lower small intestine.

[0045] Examples of other lipid matrices that may be of value are glycerides, fatty acids and alcohols, and fatty acid esters.

[0046] Another suitable controlled-release oral drug delivery system is the Eudragit RL/RS system in which the active ingredient, 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3, is formed into granules having a dimension of 25/30 mesh. The granules are then uniformly coated with a thin polymeric lacquer which is water insoluble but slowly water permeable. The coated granules can be mixed with optional additives such as antioxidants, stabilizers, binders, lubricants, processing aids and the like. The mixture may be compacted into a tablet which, prior to use, is hard and dry and can be further coated, or it may be poured into a capsule. After the tablet or capsule is swallowed and comes into contact with the aqueous intestinal fluids, the thin lacquer begins to swell and slowly allows permeation by intestinal fluids. As the intestinal fluid slowly permeates the lacquer coating, the contained 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 is slowly released. By the time the tablet or capsule has passed through the small intestine, about four to eight hours or more later, the 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 will have been slowly but completely released. Accordingly, the ingested tablet will release a stream of 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 as well as any other active ingredient.

[0047] The Eudragit system is comprised of high permeability lacquers (RL) and low permeability lacquers (RS). RS is a water insoluble film former based on neutral swellable methacrylic acids esters with a small proportion of trimethylammonioethyl methacrylate chlorides, the molar ratio of the quaternary ammonium groups to the neutral ester group is about 1:40. RL is also a water insoluble swellable film former based on neutral methacrylic acid esters with a small portion of trimethylammonioethyl methacrylate chloride, the molar ratio of quaternary ammonium groups to neutral ester groups is about 1:20. The permeability of the coating and thus the time course of drug release can be titrated by varying the proportion of RS to RL coating material. For further details of the Eudragit RL/RS system, reference is made to technical publications available from Rohm Tech, Inc. 195 Canal Street, Maiden, Mass., 02146. See also, K. Lehmann, D. Dreher “Coating of tablets and small particles with acrylic resins by fluid bed technology”, Int. J. Pharm. Tech. & Prod. Mfr. 2(r), 31-43 (1981), incorporated herein by reference.

[0048] Other examples of insoluble polymers include polyvinyl esters, polyvinyl acetals, polyacrylic acid esters, butadiene styrene copolymers and the like,

[0049] Once the coated granules are either formed into a tablet or put into a capsule, the tablet or capsule is coated with an enteric-coating material which dissolves at a pH of 7.0 to 8.0. One such pH dependent enteric-coating material is Eudragit L/S which dissolves in intestinal fluid but not in the gastric juices. Other enteric-coating materials may be used such as cellulose acetate phthalate (CAP) which is resistant to dissolution by gastric juices but readily disintegrates due to the hydrolytic effect of the intestinal esterases.

[0050] The particular choice of enteric-coating material and controlled release coating material must provide a controlled and substantially constant release over a period of 4 to 8 hours or more so that release is delayed until the formulation reaches the ileum. Moreover, the controlled release composition in accordance with the present invention, when administered once a day, suitably provides substantially constant intralumenal, intracellular and blood 25-hydroxyvitamin D levels compared to an equal dose of an immediate release composition of 25-hydroxyvitamin D.sub.2/25-hydroxyvitamin D.sub.3 administered once a day

[0051] In another embodiment of the invention, sterile, isotonic formulations of 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3 or combinations thereof may be prepared which are suitable for gradual intravenous administration. Such formulations are prepared by dissolving 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 in absolute ethanol, propylene glycol or other suitable solvents, and combining the resulting solutions with surfactants, salts and preservatives in appropriate volumes of water for injection. Such formulations can be administered slowly from syringes via heparin locks or by addition to larger volumes of sterile solutions (e.g., saline solution) being steadily infused over time.

[0052] The dosage forms may also contain adjuvants, such as preserving or stabilizing adjuvants. They may also contain other therapeutically valuable substances or may contain more than one of the compounds specified herein and in the claims in admixture.

[0053] Advantageously, 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3 or combinations thereof together with other therapeutic agents can be orally or intravenously administered in accordance with the above described embodiments in dosage amounts of from 1 to 100 mcg per day, with the preferred dosage amounts of from 5 to 50 mcg per day. If the compounds of the present invention are administered in combination with 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 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 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, and various antineoplastic agents. In addition, one may choose to intravenously administer 25-hydroxyvitamin D.sub.2 and/or 25-hydroxyvitamin D.sub.3 with cholecalciferol, ergocalciferol, active Vitamin D sterols, glycemic and hypertension control agents, and various antineoplastic 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 are generally 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.

[0054] The inclusion of a combination of 25-hydroxyvitamin D.sub.3 and 25-hydroxyvitamin D.sub.2 in the described delivery systems allows the resulting formulations to be useful in supporting both the Vitamin D.sub.3 and Vitamin D.sub.2 endocrine systems. Currently available oral Vitamin D supplements and the previously marketed oral formulation of 25-hydroxyvitamin D.sub.3 have supported just one or the other system.

[0055] The present invention is further explained by the following examples which should not be construed by way of limiting the scope of the present invention.

EXAMPLE 1

One Embodiment of a Controlled Release Formulation For Oral

[0056] Administration

[0057] Purified yellow beeswax and fractionated coconut oil are combined in a ratio of 1:1 and heated with continuous mixing to 75 degrees Celsius until a uniform mixture is obtained. The wax mixture is continuously homogenized while cooled to approximately 45 degrees Celsius. 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3, in a ratio of 1:1, are dissolved in absolute ethanol and the ethanolic solution is added, with continuous homogenization, to the molten wax mixture. The amount of ethanol added is in the range of 1 to 2 v/v %. Mixing is continued until the mixture is uniform. The uniform mixture is loaded into soft gelatin capsules. The capsules are immediately rinsed to remove any processing lubricant(s) and briefly immersed in an aqueous solution of acetaldehyde in order to crosslink the gelatin shell. The concentration of the acetaldehyde solution and the immersion time is selected to achieve crosslinking to the desired degree, as determined by near-infrared spectrophotometry. The finished capsules are washed, dried and packaged.

EXAMPLE 2

One Embodiment of a Formulation For Gradual Intravenous Administration

[0058] TWEEN Polysorbate 20 is warmed to approximately 50 to 60° F. (10 to 16° C.), and 25-hydroxyvitamin D.sub.3, dissolved in a minimal volume of absolute ethanol, is added with continuous stirring. The resulting uniform solution of 25-hydroxyvitamin D.sub.3, absolute ethanol and TWEEN Polysorbate 20 is transferred to a suitable volume of water for injection, which has been thoroughly sparged with nitrogen to remove all dissolved oxygen. Sodium chloride, sodium ascorbate, sodium phosphate (dibasic and monobasic), and disodium edetate are added, followed by sufficient stirring under a protective nitrogen atmosphere, to produce an isotonic homogeneous mixture containing, per 2 mL unit volume: 20 mcg of 25-hydroxyvitamin D.sub.3; <0.01% absolute ethanol; 0.40% (w/v) TWEEN Polysorbate 20; 0.15% (w/v) sodium chloride; 1.00% (w/v) sodium ascorbate; 0.75% (w/v) sodium phosphate dibasic anhydrous; 0.18% (w/v) sodium phosphate monobasic monohydrate; and, 0.11% (w/v) disodium edetate. This mixture is sterilized by filtration and filled, with suitable protection from oxygen contamination, into amber glass ampules having an oxygen headspace of less than 1%.

EXAMPLE 3

Pharmacokinetics Testing in Dogs

[0059] Twenty male beagle dogs are divided randomly into two comparable groups and receive no supplemental Vitamin D for the next 30 days. At the end of this time, each dog in Group #1 receives a single soft gelatin capsule containing 25 mcg of 25-hydroxyvitamin D.sub.2 prepared in a controlled release formulation similar to the one disclosed in Example 1. Each dog in the other group (Group #2) receives a single immediate-release soft gelatin capsule containing 25 mcg of 25-hydroxyvitamin D.sub.2 dissolved in medium chain triglyceride oil. All dogs have received no food for at least 8 hours prior to dosing. Blood is drawn from each dog at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 15, 24, 36, and 72 hours after dose administration. The collected blood is analyzed for the contained levels of 25-hydroxyvitamin D, and the data are analyzed by treatment group. Dogs in Group #1 show a slower rise and a lower maximum (C.sub.max) in mean blood levels of 25-hydroxyvitamin D than dogs in Group #2. However, dogs in Group #1 show a more prolonged elevation of mean blood levels of 25-hydroxyvitamin D.sub.2 relative to dogs in Group #2, despite the fact that the C.sub.max, recorded in Group #1 is lower. The mean area under the curve (AUC), corrected for predose background levels (recorded at t=0), is substantially greater for Group #1 for 25-hydroxyvitamin D. These procedures demonstrate that administration of 25-hydroxyvitamin D.sub.2 in the formulation described in this invention to dogs results in blood levels of 25-hydroxyvitamin D which rise much more gradually and remain more stable than after dosing with the same amount of 25-hydroxyvitamin D.sub.2 formulated for immediate release (in medium chain triglyceride oil). The greater AUC calculated for blood levels of 25-hydroxyvitamin D in Group #1 demonstrates that the bioavailability of 25-hydroxyvitamin D.sub.2 formulated as described herein is markedly improved.

EXAMPLE 4

Pharmacokinetics Testing in Healthy Normal Volunteers

[0060] Sixteen healthy non-obese adults, aged 18 to 24 years, participate in an 11-week pharmacokinetic study in which they receive successively, and in a double-blinded fashion, two formulations of 25-hydroxyvitamin D.sub.2. One of the formulations (Formulation #1) is a soft gelatin capsule containing 100 mcg of 25-hydroxyvitamin D.sub.2 prepared in a controlled release formulation similar to the one disclosed in Example 1. The other formulation (Formulation #2) is an immediate-release soft gelatin capsule of identical appearance containing 100 mcg of 25-hydroxyvitamin D.sub.2 dissolved in medium chain triglyceride oil. For 60 days prior to study start and continuing through study termination, the subjects abstain from taking other Vitamin D supplements. On Days 1, 3 and 5 of the study, all subjects provide fasting morning blood samples to establish pre-treatment baseline values. On the morning of Day 8, the subjects provide an additional fasting blood sample (t=0), are randomly assigned to one of two treatment groups. Both groups are dosed with a single test capsule prior to eating breakfast: one group receives a capsule of Formulation #1 and the other group receives a capsule of Formulation #2. Blood is drawn from each subject at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72 and 108 hours after dose administration. On the morning of Day 70, the subjects provide additional fasting morning blood samples (t=0) and are dosed with a single capsule of the other test formulation prior to eating breakfast. Blood is again drawn from each subject at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72 and 108 hours after dose administration. All collected blood is analyzed for the contained levels of 25-hydroxyvitamin D, and the data are analyzed by treatment formulation after correction for baseline content. Formulation #1 is found to produce a slower rise and a lower C.sub.max in mean blood levels of 25-hydroxyvitamin D than Formulation #2. However, Formulation #1 also produces a more prolonged elevation of mean blood levels of 25-hydroxyvitamin D.sub.2 relative to Formulation #2, despite the fact that the recorded C.sub.max is lower. The mean AUC is substantially greater after administration of Formulation #1 for 25-hydroxyvitamin D. These procedures demonstrate that administration of 25-hydroxyvitamin D.sub.2 in the formulation described in this invention to healthy human adults results in blood levels of 25-hydroxyvitamin D which rise much more gradually and remain more stable than after dosing with the same amount of 25-hydroxyvitamin D.sub.2 formulated for immediate release (in medium chain triglyceride oil). The greater AUC calculated for blood levels of 25-hydroxyvitamin D after dosing with Formulation #1 demonstrates that the bioavailability of 25-hydroxyvitamin D.sub.2 formulated as described herein is better.

EXAMPLE 5

Efficacy Study in Healthy Adult Male Volunteers With Vitamin D Insufficiency

[0061] The effectiveness of three different formulations of Vitamin D in restoring serum 25-hydroxyvitamin D to optimal levels (>30 ng/mL) is examined in a 23-day study of healthy non-obese men diagnosed with Vitamin D insufficiency. One of the formulations (Formulation #1) is a soft gelatin capsule containing 30 mcg of 25-hydroxyvitamin D.sub.3 prepared as illustrated in this invention. The second formulation (Formulation #2) is an immediate-release soft gelatin capsule of identical appearance containing 50,000 IU of ergocalciferol dissolved in medium chain triglyceride oil. The third formulation (Formulation #3) is an immediate-release soft gelatin capsule, also of identical appearance, containing 50,000 IU of cholecalciferol dissolved in medium chain triglyceride oil. A total of 100 healthy Caucasian and African-American men participate in this study, all of whom are aged 30 to 45 years and have serum 25-hydroxyvitamin D levels between 15 and 29 ng/mL (inclusive). All subjects abstain from taking other Vitamin D supplements for 60 days before study start and continuing through study termination, and from significant sun exposure. On Day 1 and 2 of the study, all subjects provide fasting morning blood samples to establish pre-treatment baseline values of serum 25-hydroxyvitamin D. On the morning of Day 3, the subjects provide an additional fasting blood sample (t=0), 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 #1 each receive a single capsule of Formulation #1, and the subjects in Groups #2 and #3 each receive a single capsule of Formulation #2 or Formulation #3, respectively. Subjects in Group #4 receive a matching placebo capsule. Subjects in Group #1 each receive an additional capsule of Formulation #1 on the mornings of Days 4 through 22 before breakfast, but subjects in Groups #2, #3 and #4 receive no additional capsules. A fasting morning blood sample is drawn from each subject, irrespective of treatment group, on Days 4, 5, 6, 10, 17 and 23 (or 1, 2, 3, 7, 14 and 20 days after the start of dosing). All collected blood is analyzed for the contained levels of 25-hydroxyvitamin D, and the data are analyzed by treatment group after correction for baseline values. Subjects in all four treatment groups exhibit mean baseline serum 25-hydroxyvitamin D levels of approximately 16 to 18 ng/mL, based on analysis of fasting blood samples drawn on Days 1 through 3. Subjects in Group #4 (control group) show no significant changes in mean serum 25-hydroxyvitamin D over the course of the study. Subjects in Group #1 show a steadily increasing mean serum 25-hydroxyvitamin D reaching at least 30 ng/mL by Day 23. In marked contrast, subjects in Group #2 exhibit marked increases in mean serum 25-hydroxyvitamin D for the first few days post-dosing, reaching a maximum of just above 25 ng/mL, and then rapidly declining thereafter. By study end, serum 25-hydroxyvitamin D is significantly lower than baseline in Group #2. Subjects in Group #3 exhibit continuing increases in mean serum 25-hydroxyvitamin D through the first 2 weeks after dosing with gradual, but progressive, decreases occurring thereafter. By study end, mean serum 25-hydroxyvitamin D is below 30 ng/mL, being only approximately 11 ng/mL higher than pre-treatment baseline. The data from this study demonstrate that administration of 600 mcg of 25-hydroxyvitamin D.sub.3, formulated as described herein and administered at a dose of 30 mcg per day for 20 days, is substantially more effective in restoring low serum levels of 25-hydroxyvitamin D to optimal levels than immediate-release formulations of 50,000 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.

EXAMPLE 6

Efficacy and Safety Study in End-Stage Renal Disease Patients Exhibiting Vitamin D Deficiency

[0062] The efficacy and safety of intravenous 25-hydroxyvitamin D.sub.3 in restoring serum 25-hydroxyvitamin D to optimal levels (>30 ng/mL) are examined in a 3-month study of patients with end-stage renal disease (ESRD) requiring regular hemodialysis and diagnosed with Vitamin D insufficiency. The formulation examined in this study is an aqueous isotonic and sterile solution containing 20 mcg of 25-hydroxyvitamin D.sub.3 similar to the one disclosed in Example 2. A total of 50 healthy Caucasian, Asian, Hispanic and African-American subjects participate in this study, all of whom are at least 4-months on regular hemodialysis and have serum 25-hydroxyvitamin D levels below 15 ng/mL. Prior to enrolling, all subjects provide two fasting morning blood samples, separated by at least one week, to establish pre-treatment baseline values of serum calcium, plasma intact PTH, and serum 25-hydroxyvitamin D. On the morning of Day 1, the subjects are randomly assigned to one of two treatment groups, and they begin thrice weekly dosing with the test preparation, or with a matching placebo. All dosing occurs during regularly scheduled hemodialysis sessions and is accomplished by gradual injection (over a period of 1 to 5 minutes) into the blood exiting from the hemodialysis machine. Additional fasting blood samples and 24-hour urine collections are obtained from each subject at quarterly intervals for determination of serum calcium, plasma intact PTH and serum 25-hydroxyvitamin D. Throughout the study, all subjects adhere to a daily intake of approximately 1,000 to 1,500 mg of elemental calcium (from self-selected diets and calcium supplements, as needed) under the ongoing guidance of a dietician. At the conclusion of the study, the laboratory data are analyzed by treatment group and by test formulation after appropriate correction for baseline values. Both groups have comparable mean baseline values for serum 25-hydroxyvitamin D (range: 10.7 to 11.9 ng/mL), plasma intact PTH (range: 45.3 to 52.1 pg/mL) and serum calcium (range: 8.72 to 9.31 mg/dL). No significant changes in any of the laboratory mean values are observed in the placebo (control) group over the course of the study. Subjects in the treatment group receiving 25-hydroxyvitamin D.sub.3 exhibit progressively increasing serum 25-hydroxyvitamin D levels during the first 3 months of dosing, reaching steady state levels thereafter. Mean serum calcium increases significantly from baseline in the treatment group receiving 25-hydroxyvitamin D.sub.3, and is significantly higher than those observed in the placebo group. Episodes of hypercalcemia, defined as serum calcium above 9.5 mg/dL, are infrequently observed in both treatment groups. Data from this study demonstrate that the intravenous formulation of 25-hydroxyvitamin D.sub.3 is effective at increasing serum 25-hydroxyvitamin D without causing unacceptable side effects related to calcium and PTH metabolism.

[0063] All patents, publications and references cited herein are hereby fully incorporated by reference. In case of conflict between the present disclosure and incorporated patents, publications and references, the present disclosure should control.

[0064] Embodiments contemplated in view of the foregoing description include the following numbered paragraphs.

[0065] 1. A sustained release oral dosage formulation of 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or a combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3.

[0066] 2. The sustained release oral dosage formulation of paragraph 1, wherein the formulation further provides delayed release of the 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3 after ingestion of the formulation.

[0067] 3. The sustained release oral dosage formulation of paragraph 2, wherein release is substantially delayed until the 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3 reaches the ileum of the intestine.

[0068] 4. The sustained release oral dosage formulation of any one of the preceding paragraphs, comprising the 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3 dispersed within a wax matrix.

[0069] 5. The sustained release oral dosage formulation of paragraph 4, wherein the wax matrix comprises a wax and an oil.

[0070] 6. The sustained release oral dosage formulation of paragraph 4 or 5, further comprising a glyceride.

[0071] 7. The sustained release oral dosage formulation of any one of paragraphs 4 to 6, further comprising a gelatin capsule, the wax matrix being disposed in the gelatin capsule.

[0072] 8. The sustained release oral dosage formulation of paragraph 7, wherein the gelatin capsule is a hard gelatin capsule.

[0073] 9. The sustained release oral dosage formulation of any one of the preceding paragraphs, wherein the formulation is semi-solid at body temperature.

[0074] 10. The sustained release oral dosage formulation of any one of the preceding paragraphs, comprising 1 to 50 mcg per unit dose of the 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3.

[0075] 11. The sustained release oral dosage formulation of any one of the preceding paragraphs, wherein the sustained release is effected over a period of at least four hours.

[0076] 12. The sustained release oral dosage formulation of any one of the preceding paragraphs, comprising 25-hydroxyvitamin D.sub.3.

[0077] 13. A sustained release oral dosage formulation of 25-hydroxyvitamin D.sub.3 dispersed within a wax matrix comprising a wax, an oil, and a glyceride, and disposed within a hard gelatin capsule.

[0078] 14. A method of treating 25-hydroxyvitamin D insufficiency or deficiency in a patient comprising orally administering to the patient a delayed, sustained release formulation according to any one of the preceding paragraphs.

[0079] 15. The method of paragraph 14, wherein the formulation is administered once a day, and provides substantially constant intralumenal, intracellular and blood 25-hydroxyvitamin D levels compared to an equal dose of an immediate release formulation administered once a day.

[0080] 16. The method of paragraph 14, comprising administering 1 to 100 mcg per day of the 25-hydroxyvitamin D.sub.2, 25-hydroxyvitamin D.sub.3, or combination of 25-hydroxyvitamin D.sub.2 and 25-hydroxyvitamin D.sub.3.

[0081] 17. The method of paragraph 14, wherein the administration provides reduced aberrations in PTH compared to an equal dose of an immediate release formulation.