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WO2007068287A1 - Préparation vitaminique à libération prolongée - Google Patents

Préparation vitaminique à libération prolongée Download PDF

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Publication number
WO2007068287A1
WO2007068287A1 PCT/EP2005/056833 EP2005056833W WO2007068287A1 WO 2007068287 A1 WO2007068287 A1 WO 2007068287A1 EP 2005056833 W EP2005056833 W EP 2005056833W WO 2007068287 A1 WO2007068287 A1 WO 2007068287A1
Authority
WO
WIPO (PCT)
Prior art keywords
cellulose
sustained release
vitamin
unit dose
matrix material
Prior art date
Application number
PCT/EP2005/056833
Other languages
English (en)
Inventor
Marc Verlinden
Original Assignee
Laboratoria Qualiphar
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratoria Qualiphar filed Critical Laboratoria Qualiphar
Priority to PCT/EP2005/056833 priority Critical patent/WO2007068287A1/fr
Publication of WO2007068287A1 publication Critical patent/WO2007068287A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention relates to a solid sustained release vitamin unit dose for oral administration, comprising a blend of a matrix material and an effective amount of at least one active ingredient comprising at least one vitamin, according to the preamble of the first claim.
  • Commercially available multi vitamin tablets usually take the form of tablets, which comprise multiple, different vitamin species.
  • the problem associated with the known tablets is however that the tablet is administered in one piece, following which it is digested at once into the gastrointestinal system and the full vitamin dose is released at once into the organism.
  • the release of a high vitamin dose at once is undesirable, in particular for water- soluble vitamins as the excess, which is not metabolized, is released from the body rather shortly after intake.
  • compositions which provide a controlled or a sustained release of a drug into the human gastro-intestinal tract. Controlled release may be achieved by encapsulation of the active ingredient in a film, which controls the release of the drug from the composition. Controlled release may also be obtained by coating a drug-containing tablet with a water permeable coating, which permit diffusion of water into the tablet and of active ingredient dissolved in the water from the tablet. Whereas controlled or sustained release of drugs or medicaments has been widely used in the art, controlled or sustained release formulations of vitamins have hitherto not been found on the market.
  • the present invention aims at providing a vitamin preparation which is suitable for oral administration as a solid product, which shows sustained release of the active ingredients incorporated therein with the aim of providing bioavailability of the active ingredients over a desired period of time. This is achieved according to the present invention with a sustained release vitamin unit dose showing the technical features of the characterizing part of the first claim.
  • the matrix material comprises at least one material selected from the group of a cellulose derivative, an acrylic or methacr ⁇ lic acid polymer or co-polymers of those, modified gelatin or a blend of two or more of these materials, to provide a sustained release effect of the at least one active material for a time period of from about 8 to about 24 hours and in that the at least one vitamin active ingredient is present in an effective amount to render a desired effect.
  • the matrix material comprises at least one material selected from the group of alkyl cellulose, gelatin, starch, cross linked starch, alginate, polyvinyl acetate, povidone, polyacrylate, polyethylene glycol polymer or a blend of two or more of these materials, although alkyl cellulose is particularly preferred.
  • the alkyl cellulose matrix material is preferably selected from the group of methylcellulose, carboxymethyl cellulose and salts thereof, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and or a blend of two or more of those materials. These materials have been found to show an optimal sustained release behavior and permit controlling the release period in an optimum way. Amongst those hydroxypropylmethyl cellulose has been found particularly suitable to provide the desired effect.
  • sustained or controlled release is defined as the release of the active ingredient from the unit dose of this invention, at such a rate that variation of the concentration levels of the at least one active ingredient are maintained within a desired range, to provide that the maximum concentration that can be resorbed by the organism for about 2 to 24 hours, preferably from about 4 to 18 hours, more preferably from about 8 tot 16 hours, is present.
  • the controlled release profile can be altered by varying the amount of matrix material, but also by the inclusion of additional ingredients.
  • the functioning of the unit dose of this invention is based on the finding that the matrix material shows optimum solubility in the conditions prevailing in the human gastro-enteritic system, the solubility being only slightly pH dependent and depending mainly on the contact time of the unit dose with water.
  • This effect has been found to be particularly pronounced with alkyl cellulose, more particularly with hydroxypropymethyl cellulose.
  • the inventors have observed that the alkyl cellulose material, in particular the hydroxypropymethyl cellulose when contacted with water, absorbs the water which causes swelling and is followed by gel formation. Following gel formation, the active ingredients partly dissolve in the gel water, after which they can migrate from the tablet and be released into the environment.
  • release of the active ingredients from the unit dose is determined by the contact time with or residence time in the aqueous environment. Release of the matrix material into the aqueous environment and the active ingredients associated with it, has been found to be further partly determined by the erosion rate of the exposed surface layers.
  • release of the material is governed by the cooperating effects of dissolution and erosion of the matrix material, which permits to adapt the release time as desired. In particular with the present invention release may be controlled over an extended period of time for example from 4 to 24 hours or shorter or longer.
  • the length of the period over which the sustained release occurs may be controlled by adapting the concentration of the matrix material in the tablet, or in other words the release time may be increased by increasing the matrix material concentration in the tablet.
  • the amount of matrix material in one unit dose tablet will usually be 10-50 wt. % with respect to the total weight of the unit dose, preferably 20-40 wt. %, more preferably 20-30 wt. %.
  • the sustained release as provided by the unit dose of the present invention ensures that the active ingredient is released in such a way that it is bio-available so that it may be effective for its intended purpose.
  • Bio- available is defined as the total amount of active substance that is dissolved from the unit dose and available for absorption by the organism to provide the desired effect after administration of a unit dosage form.
  • the unit dose of this invention provides release of the active ingredients over a sustained period of time in water or an aqueous medium.
  • aqueous medium means any water- containing medium, for example gastric fluid, intestinal fluid and the like.
  • the permeability of the unit dose of this invention to water vapor may be limited and the resistance to humidity prevailing in the environment be optimized by coating the tablet with a coating comprising an amount of stearic acid, polyvinyl alcohol or any other suitable ingredient.
  • the coating preferably comprises an alkyl cellulose material selected from the group of natural cellulose, microcr ⁇ stalline cellulose, methylcellulose, carboxymethyl cellulose and salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose or a blend of two or more of those materials.
  • the active ingredient to be released from the composition in a sustained manner is preferably at least one active ingredient selected from the group of vitamins, minerals, enzymes, essential amino acids, non-essential amino acids, proteins, hormones, plant extracts or a blend of two or more of those.
  • vitamins include the water-soluble vitamins for example vitamin C, vitamin B1, B2, B6, B5, B12, biotin, folic acid, thiamine nitrate, pyridoxine, nicotinamide and lipophilic or fat soluble vitamins for example vitamin A, D, E. They may be incorporated in the tablet as such or using a derivative or a salt thereof.
  • vitamin And E may be incorporated as their acetate, vitamin B6 as its hydrochloric acid salt, vitamin B5 as its calcium salt.
  • Suitable examples of essential amino acids include isoleucine, leucine, lysine, methionin, phenylalanin, threonin and valin.
  • Suitable examples of non-essential amino acids include cystein, hystidin and tyrosine.
  • the amino acids may be incorporated as such or as salts thereof, for example leucine.HCI, the hydrochloride of lysine, cystein, methionin and histidin.
  • Suitable minerals to be included in the composition of this invention comprise salts of magnesium, iron, zinc, manganese, pyridoxine, copper, for example magnesium oxide, iron fumarate, zinc sulphate, manganese sulphate, copper sulphate although other suitable salts known to the person skilled in the art may be used as well.
  • the concentration of the active ingredient in the unit dose of this invention may vary within wide ranges, but preferably equals at least the recommended daily allowance (RDA). Thereby however care will be taken that the concentration of the active ingredient is not such as to adversely affect the dissolution of the matrix material.
  • the active ingredient will usually be present as a fine solid dispersed distribution of one or more active ingredients in the matrix material.
  • the active ingredient may be dispersed as a solid solution, a fine crystalline form, a glassy amorphous phase or fine amorphous powder. In may cases it will be preferred to have a substantially homogeneous distribution of the active ingredients over the matrix material.
  • a unit dose of this type will be simple to produce and a simple release profile obtained in this manner will usually be sufficient.
  • matrix materials providing direct or non- sustained release include lactose, cellulose, calciumhydrogenposphate dehydrate, calciumphosphate, calciumsulphate, sorbitol, other polyols, saccharose.
  • a sustained-release unit dose may contain other ingredients conventionally used in the field, such as for example one or more lubricants, binders, granulating aids, colorants, flavorings, release agents, in a concentration, which is adapted and sufficient to obtain the desired effect.
  • the present invention also relates to a process for producing the above-described unit dose.
  • the active ingredients are mixed with matrix material and homogenized.
  • the thus obtained mixture is mixed with a liquid, preferably alcohol, preferably ethanol, in an amount sufficient to wet the surface of the particles and to obtain a paste.
  • the paste is dried using an air based fluidized bed, to evaporate the alcohol, as a result of which a dry powder is obtained.
  • a fluidized bed presents the advantage over the known art of melting and extrusion that heating of the mixture and the ensuing risk to decomposition or reaction of the active ingredients may be minimized, while good evaporation of the solvent is achieved at relatively fast drying rates.
  • drying is continued until the remaining moisture content is not more than 1wt. % with respect to the total weight of the composition.
  • the powder dried in the fluidized bed is sieved over a sieve, to obtain a powder with particle size of between 0.2 -1.5 or 2 mm.
  • a lubricant is added, an amount of the mixture is introduced into a dye and shaped using punches.
  • the composition has a geometric shape, which assists in providing a homogeneous release of the active ingredient over the desired period of time.
  • the composition may for example be ball shaped or take the shape of a cylindrical rod or an oval rod.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

Préparation vitaminique à libération prolongée. La présente invention concerne une dose unitaire solide de vitamine à libération prolongée pour l'administration orale, comprenant un mélange d'un matériau de matrice et d'une quantité efficace d'au moins un principe actif comprenant au moins une vitamine. Le matériau de matrice comprend au moins un matériau choisi dans le groupe comprenant un dérivé de cellulose, un polymère d'acide acrylique ou méthacrylique ou des copolymères de ceux-ci, de la gélatine modifiée ou un mélange de deux de ces matériaux ou plus afin d'obtenir un effet de libération prolongée dudit ou desdits matériaux actifs pendant une durée d'environ 8 à environ 24 heures et les principes actifs vitaminique est présent en une quantité efficace afin de produire un effet recherché.
PCT/EP2005/056833 2005-12-15 2005-12-15 Préparation vitaminique à libération prolongée WO2007068287A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2005/056833 WO2007068287A1 (fr) 2005-12-15 2005-12-15 Préparation vitaminique à libération prolongée

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2005/056833 WO2007068287A1 (fr) 2005-12-15 2005-12-15 Préparation vitaminique à libération prolongée

Publications (1)

Publication Number Publication Date
WO2007068287A1 true WO2007068287A1 (fr) 2007-06-21

Family

ID=36694291

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2005/056833 WO2007068287A1 (fr) 2005-12-15 2005-12-15 Préparation vitaminique à libération prolongée

Country Status (1)

Country Link
WO (1) WO2007068287A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE1020198A3 (nl) * 2011-08-25 2013-06-04 Lab Qualiphar Werkwijze voor het produceren van een tablet.
US9408858B2 (en) 2007-04-25 2016-08-09 Opko Renal, Llc Method for treating secondary hyperparathyroidism in CKD
US9861644B2 (en) 2013-03-15 2018-01-09 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
KR101826994B1 (ko) * 2011-10-31 2018-02-08 롯데정밀화학 주식회사 제어된 방출성의 아스코르빈산 함유 경구용 정제 조성물 및 그 분석방법
US9943530B2 (en) 2006-02-03 2018-04-17 Opko Renal, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US10220047B2 (en) 2014-08-07 2019-03-05 Opko Ireland Global Holdings, Ltd. Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
US10302660B2 (en) 2008-04-02 2019-05-28 Opko Renal, Llc Methods useful for vitamin D deficiency and related disorders
US10668089B2 (en) 2006-06-21 2020-06-02 Opko Ireland Global Holdings, Ltd. Method of treating and preventing secondary hyperparathyroidism
US11173168B2 (en) 2016-03-28 2021-11-16 Eirgen Pharma Ltd. Methods of treating vitamin D insufficiency in chronic kidney disease
US11672809B2 (en) 2010-03-29 2023-06-13 Eirgen Pharma Ltd. Methods and compositions for reducing parathyroid levels
US11752158B2 (en) 2007-04-25 2023-09-12 Eirgen Pharma Ltd. Method of treating vitamin D insufficiency and deficiency
US11801253B2 (en) 2007-04-25 2023-10-31 Opko Renal, Llc Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease

Citations (9)

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Publication number Priority date Publication date Assignee Title
GB1081667A (en) * 1965-05-18 1967-08-31 Merck Ag E Method of preparing solid stable preparations of sensitive active substances
GB1444890A (en) * 1974-06-24 1976-08-04 Shinetsu Chemical Co Coating solid dosage forms
WO1992009271A1 (fr) * 1990-11-28 1992-06-11 Sumitomo Pharmaceuticals Co., Ltd. Composition pour des preparations pharmaceutiques solides contenant des vitamines d3 actives et son procede de preparation
JPH05271072A (ja) * 1992-01-28 1993-10-19 Takeda Chem Ind Ltd 安定なビタミン製剤
US5328903A (en) * 1990-04-28 1994-07-12 Taisho Pharmaceutical Co. Ltd. Composition for solid pharmaceutical preparations containing vitamin D3 derivative
CA2181391A1 (fr) * 1995-07-17 1997-01-18 Pankaj Modi Medicament en comprimes a liberation lente
EP0820703A1 (fr) * 1996-07-22 1998-01-28 Valpharma S.A. Compositions pour intégration nutritionelle comprenant des vitamines hydrosolubles à libération prolongée
JPH1036270A (ja) * 1996-07-25 1998-02-10 Taiyo Yakuhin Kogyo Kk 安定なビタミンｂ１２類含有医薬粒子及びこれを用いた安定な固形経口複合医薬製剤
US20030068366A1 (en) * 2001-08-28 2003-04-10 Shubha Chungi Combination dosage form containing individual dosage units of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1081667A (en) * 1965-05-18 1967-08-31 Merck Ag E Method of preparing solid stable preparations of sensitive active substances
GB1444890A (en) * 1974-06-24 1976-08-04 Shinetsu Chemical Co Coating solid dosage forms
US5328903A (en) * 1990-04-28 1994-07-12 Taisho Pharmaceutical Co. Ltd. Composition for solid pharmaceutical preparations containing vitamin D3 derivative
WO1992009271A1 (fr) * 1990-11-28 1992-06-11 Sumitomo Pharmaceuticals Co., Ltd. Composition pour des preparations pharmaceutiques solides contenant des vitamines d3 actives et son procede de preparation
JPH05271072A (ja) * 1992-01-28 1993-10-19 Takeda Chem Ind Ltd 安定なビタミン製剤
CA2181391A1 (fr) * 1995-07-17 1997-01-18 Pankaj Modi Medicament en comprimes a liberation lente
EP0820703A1 (fr) * 1996-07-22 1998-01-28 Valpharma S.A. Compositions pour intégration nutritionelle comprenant des vitamines hydrosolubles à libération prolongée
JPH1036270A (ja) * 1996-07-25 1998-02-10 Taiyo Yakuhin Kogyo Kk 安定なビタミンｂ１２類含有医薬粒子及びこれを用いた安定な固形経口複合医薬製剤
US20030068366A1 (en) * 2001-08-28 2003-04-10 Shubha Chungi Combination dosage form containing individual dosage units of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin

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DATABASE WPI Section Ch Week 199346, Derwent World Patents Index; Class B05, AN 1993-365141 *
DATABASE WPI Section Ch Week 199816, Derwent World Patents Index; Class A96, AN 1998-174827 *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9943530B2 (en) 2006-02-03 2018-04-17 Opko Renal, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US11911398B2 (en) 2006-02-03 2024-02-27 Opko Renal, Llc Treating Vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US11007204B2 (en) 2006-02-03 2021-05-18 Opko Renal, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US10213442B2 (en) 2006-02-03 2019-02-26 Opko Renal, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US10668089B2 (en) 2006-06-21 2020-06-02 Opko Ireland Global Holdings, Ltd. Method of treating and preventing secondary hyperparathyroidism
US11154509B2 (en) 2007-04-25 2021-10-26 Eirgen Pharma Ltd. Methods for controlled release oral dosage of a vitamin D compound
US9498486B1 (en) 2007-04-25 2016-11-22 Opko Renal, Llc Method for controlled release oral dosage of a vitamin D compound
US9918940B2 (en) 2007-04-25 2018-03-20 Opko Renal, Llc Methods for controlled release oral dosage of a vitamin D compound
US9408858B2 (en) 2007-04-25 2016-08-09 Opko Renal, Llc Method for treating secondary hyperparathyroidism in CKD
US11801253B2 (en) 2007-04-25 2023-10-31 Opko Renal, Llc Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease
US11752158B2 (en) 2007-04-25 2023-09-12 Eirgen Pharma Ltd. Method of treating vitamin D insufficiency and deficiency
US9925147B2 (en) 2007-04-25 2018-03-27 Opko Renal, Llc Method for treating secondary hyperparathyroidism in CKD
US10302660B2 (en) 2008-04-02 2019-05-28 Opko Renal, Llc Methods useful for vitamin D deficiency and related disorders
US11672809B2 (en) 2010-03-29 2023-06-13 Eirgen Pharma Ltd. Methods and compositions for reducing parathyroid levels
BE1020198A3 (nl) * 2011-08-25 2013-06-04 Lab Qualiphar Werkwijze voor het produceren van een tablet.
KR101826994B1 (ko) * 2011-10-31 2018-02-08 롯데정밀화학 주식회사 제어된 방출성의 아스코르빈산 함유 경구용 정제 조성물 및 그 분석방법
US9861644B2 (en) 2013-03-15 2018-01-09 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
US10357502B2 (en) 2013-03-15 2019-07-23 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
US11253528B2 (en) 2013-03-15 2022-02-22 Eirgen Pharma Ltd. Stabilized modified release Vitamin D formulation and method of administering same
US10350224B2 (en) 2013-03-15 2019-07-16 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
US10300078B2 (en) 2013-03-15 2019-05-28 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
US10493084B2 (en) 2014-08-07 2019-12-03 Opko Ireland Global Holdings, Ltd. Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
US11007205B2 (en) 2014-08-07 2021-05-18 Eirgen Pharma Ltd. Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
US11738033B2 (en) 2014-08-07 2023-08-29 Eirgen Pharma Ltd. Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
US10220047B2 (en) 2014-08-07 2019-03-05 Opko Ireland Global Holdings, Ltd. Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
US11173168B2 (en) 2016-03-28 2021-11-16 Eirgen Pharma Ltd. Methods of treating vitamin D insufficiency in chronic kidney disease

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