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WO1996000074A1 - Composition pharmaceutique contenant des analogues de la vitamine d - Google Patents

Composition pharmaceutique contenant des analogues de la vitamine d Download PDF

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Publication number
WO1996000074A1
WO1996000074A1 PCT/US1995/008005 US9508005W WO9600074A1 WO 1996000074 A1 WO1996000074 A1 WO 1996000074A1 US 9508005 W US9508005 W US 9508005W WO 9600074 A1 WO9600074 A1 WO 9600074A1
Authority
WO
WIPO (PCT)
Prior art keywords
vitamin
preparation according
cancer
matrix
analog
Prior art date
Application number
PCT/US1995/008005
Other languages
English (en)
Inventor
Joseph Kost
Shraga Shany
Sergio A. Lamprecht
Carmen Segal
Original Assignee
Ben-Gurion University Of The Negev
Kopeika, Norman, S.
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 Ben-Gurion University Of The Negev, Kopeika, Norman, S. filed Critical Ben-Gurion University Of The Negev
Priority to AU29980/95A priority Critical patent/AU2998095A/en
Publication of WO1996000074A1 publication Critical patent/WO1996000074A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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

Definitions

  • the present invention relates to the field of pharmacy. More particularly, the invention relates to novel slow-release pharmaceutical preparations containing Vitamin-D analogs.
  • Vitamin-D hormone 1,25-dihydroxyvitamin D 3
  • the Vitamin-D hormone is known to be active anti-proliferation agents which is active against a variety of cancer cells, including cells of the large intestine [A. Belelli et al., Carcinogenesis, 13, 2293-2298, 1992].
  • the activity of 1,25-dihydroxyvitamin D 3 was tested in rats colon cancer and it was found that once weekly administration for 5 weeks reduced by 50% the number of DMH-induced murine colon cancer.
  • the potentially useful therapeutic activity of 1,25- dihydroxyvitamin D 3 has so far been hampered by its high calcemic activity. Treatment of rats with higher doses of 1,25-dihydroxyvitamin D 3 , by subcutaneous injection, which could potentially be beneficial in cancer treatment, led to hypercalcemia and death.
  • the primary objects of the invention are achieved by providing controlled- release pharmaceutical preparations comprising a Vitamin-D analog in a supporting matrix, typically a polymeric matrix.
  • Fig. 1 shows the kinetics of 1,25-dihydroxyvitamin D 3 release from an EVA-based matrix, dependent on fetal calf serum concentrations
  • Fig. 2 shows the effect of 1,25-dihydroxyvitamin D 3 loading in the matrix of Fig. 1, on its released fraction;
  • Fig. 3 shows the effect of implantation site in- ⁇ i ⁇ o on the serum concentration of 1,25-dihydroxyvitamin D 3 , following two weeks post-implantation, with a load of 0.0050% of 1,25-dihydroxyvitamin D 3 ;
  • Fig. 4 shows the effect of implantation site in- ⁇ i ⁇ o on the serum concentration of Ca +2 , after two weeks post-implantation, with the same matrix as in Fig. 3;
  • Fig. 5 shows the effect of 1,25-dihydroxyvitamin D 3 released on the activity of ornithine decarboxylase (ODC) in DMH-treated rats (Example 3); and
  • Fig. 6 shows the effect of 1,25-dihydroxyvitamin D 3 released according to the invention, and injected (prior art), on the activity of ornithine decarboxylase (ODC) in DMH-treated rats.
  • ODC ornithine decarboxylase
  • the invention is directed to controlled- release pharmaceutical preparations comprising a Vitamin-D analog in a supporting matrix, alone or together with pharmaceutically acceptable additives or active agents.
  • Vitamin analogs are many, and will be recognized by the skilled person. Illustrative and non-limitative examples of such analogs include 1,25-(OH) 2 D 3 (calcitrol), 26,27-F 6 -1,25-(OH) 2 D 3 (ST-630), 1 ⁇ -(OH)D 2 , 1 ⁇ -(OH)D 3 , 1,24-(OH) 2 D 3 (TV-02), 22-oxacalcitriol (OCT), calcipotriol (MC 903), 1,25-(OH) 2 -16-ene-23-yne-D 3 (Ro 23-7553), EB 1089 and ED-71.
  • the term "analog”, in the context of the present invention, is meant to include synthetic analogs as well as Vitamin-D metabolites.
  • the matrix is a polymeric matrix.
  • Polymeric materials and matrices useful in drug delivery systems are well known in the art, and need not be discussed in detail.
  • Rea detailed discussion of such systems reference is made to Robert Langer, SCIENCE, Vol. 249, pp. 1527-1533, 28 September, 1990, and to Richard L. Dunn, "Polymeric Matrices", in POLYMERIC DRUG AND DRUG DELIVERY SYSTEMS, R. L. Dunn and R. M. Ottenbrite Eds., American Chemical Society, Washington, D.C., 1991.
  • the polymeric matrix may be of a variety of types.
  • water-soluble polymers may be employed, such as polyethylene glycol, poly (vinyl alcohol), poly (vinyl pyrrolidone), poly(2- hydroxymethyl methacrylate), poly(acrylamide), hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, gelatin, starch, dextran, sodium alginate, poly(acrylic acid), poly(methacrylic acid), poly(maleic acid half esters), poly(sodium styrene sulfonate), poly(dimethylaminoethyl methacrylate), poly(vinyl pyridine), cellulose acetate N,N-diethylaminoacetate; other suitable polymers include biodegradable polymers, such as poly(meleic anhydride copolymers), gelatine-formaldehyde, acrylamide-N,N'-methylenebisacrylamide, fumaric acid/polyethylene glycol-N-vinyl-pyrrolidone, poly(vin
  • polymeric matrix is a matrix based on a poly-ethylene-vinyl-acetate copolymer.
  • This matrix will be used in the examples to follow, it being understood that this is only an illustrative matrix and the invention is in no way limited to this or any other matrix.
  • the inventors have found that, in order to obtain an optimal release effect of the vitamin-D analog, it is important that release from the polymeric matrix be effected through the formation of a complex between the vitamin-D analog and the vitamin-D binding protein (DBP) which is found in body fluids. Only the complex is substantially soluble in aqueous media, and thus only the complex is immediately and gradually bioavailable.
  • the pharmaceutical preparation is such that the release of the Vitamin-D analog is permitted or promoted by the presence of the Vitamin-D binding protein (DBP).
  • the invention also encompasses preparations wherein the DBP is provided in the polymeric matrix, to overcome a DBP deficiency at the site of administration, or to promote vitamin-D - DBP complex release.
  • Vitamin-D analog to be used in conjunction with the invention is 1,25-dihydroxyvitamin D 3 .
  • the invention is in no way meant to be hmited to this specific compound, and any other suitable and pharmaceutically valuable analog thereof can be used.
  • the invention is also directed to a pharmaceutical composition for the treatment of cancer, comprising an effective amount of a preparation according to the invention. While the invention is useful in the treatment of a variety of cancers, one particularly difficultly treated cancer, which can be treated according to the invention, is colon cancer.
  • the invention provides a method of treating a cancer patient, comprising administering to the patient in need thereof an anti-cancer effective amount of a preparation as described herein.
  • the slow-release pharmaceutical preparations of the invention may be administered orally, transdermally or by implantation. Suitable slow-release compositions of the type described above will be recognized by the skilled person.
  • the pharmaceutical composition is implanted. Preferably, but non limitatively, the implantation is effected intraperitoneal.
  • the invention further provides a method of treating patients suffering from imbalanced mineral homeostasis, who need constant correction of their serum vitamin D levels.
  • An example is the group of uremic patients, but of course the invention is not limited to this group.
  • Drug delivery matrices based on poly(ethylene-vinyl-acetate) copolymer (EVA) were prepared by solvent casting as described by Rhine et al. [J. of Pharmaceutical Sciences, 69, 265-270, 1980].
  • 1,25-dihydroxyvitamin D 3 - ethanol solution was added to the EVA-methylene chloride solution and casted on dry ice. Loading was calculated as dry weight of 1,25- dihydroxyvitamin D 3 to dry weight of the matrix.
  • Part of the 1,25- dihydroxyvitamin D 3 (1:70,000) was radiolabeled as 1,25-dihydroxy[26,27- methyl- 3 H]cholecalciferol. This was used in the in ⁇ itro experiments. Radiolabeled 1,25-dihydroxyvitamin D 3 was not included in matrices used in in ⁇ i ⁇ o experiments.
  • the release of the radiolabeled 1,25-dihydroxy[26,27-methyl- 3 H]cholecalciferol was detected by ⁇ -counter as a function of time.
  • the matrices were immersed in fetal calf serum (FCS) medium, containing the Vitamin-D binding protein (DBP).
  • FCS fetal calf serum
  • DBP Vitamin-D binding protein
  • Figs. 1 and 2 show the effect of serum concentration in the medium. It can easily be seen that virtually no 1,25-dihydroxyvitamin D 3 release occurs in the absence of DBP (buffer and FCS 0%), and that the release rate increases with increasing FCS (and hence DBP) concentrations.
  • Fig. 2 shows the percentage of released 1,25-dihydroxyvitamin D 3 as a function of its load in the matrix (at 50% FCS). At high loads a lower percentage is released, in contrast to known diffusion dependent EVA systems, and suggesting that the release of 1,25(OH) 2 D 3 depends on the ratio between DBP and 1,25(OH) 2 D 3 .
  • the rats were treated with 1,2-dimethylhydrazine (DMH), after 2 weeks, according to the procedure of Belleli et al., to induce colon cancer.
  • DMH 1,2-dimethylhydrazine
  • the matrices were implanted i.p.. Blood samples were withdrawn after two weeks, and the concentration of 1,25-dihydroxyvitamin D 3 and of Ca +2 were measured. In all cases EVA matrices were used, with a load of 0.0050% of 1,25-dihydroxyvitamin D 3 .
  • ODC activity is believed to be associated with the initiation stage of colon carcinogenesis. [D.H. Russell et al., Drug. Metab. Rev., 16, 1-88, 1981. G.D. Luk et al., Cancer Res., 46, 4449-4452, 1986]. If so, the ODC activity peak may serve as a reliable marker for colon carcinogenesis.
  • a radiometric technique which measures the amount of 14 CO 2 stoichiometrically released from labeled ornitine substrate during the decarboxylation reaction was used. The matrix was implanted i.p. two weeks before DMH induction.
  • Example 3 was repeated, but additionally two additional rat groups were treated with DMH for another 4 weeks until frank colon cancer.
  • the 1st group served as control and the 2nd group consisted of animals with implanted EVAc matrices (about 0.1g) loaded with 0.0050% 1,25-(OH) 2 D 3 .

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Une composition pharmaceutique à libération contrôlée contient un analogue de la vitamine D dans une matrice de support, seul ou en combinaison avec des agents actifs et des additifs acceptables sur le plan pharmaceutique.
PCT/US1995/008005 1994-06-24 1995-06-22 Composition pharmaceutique contenant des analogues de la vitamine d WO1996000074A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29980/95A AU2998095A (en) 1994-06-24 1995-06-22 Pharmaceutical compositions comprising vitamin-d analogs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL110117 1994-06-24
IL11011794A IL110117A0 (en) 1994-06-24 1994-06-24 Pharmaceutical compositions comprising vitamin-d analogs

Publications (1)

Publication Number Publication Date
WO1996000074A1 true WO1996000074A1 (fr) 1996-01-04

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/008005 WO1996000074A1 (fr) 1994-06-24 1995-06-22 Composition pharmaceutique contenant des analogues de la vitamine d

Country Status (3)

Country Link
AU (1) AU2998095A (fr)
IL (1) IL110117A0 (fr)
WO (1) WO1996000074A1 (fr)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998036754A1 (fr) * 1997-02-20 1998-08-27 Paul Trouillas Utilisation du 9,10-secocholesta-5,7,10(19)-trien-1,3-ol, ou alfacalcidol
US6521608B1 (en) 1998-03-27 2003-02-18 Oregon Health & Science University Vitamin D and its analogs in the treatment of tumors and other hyperproliferative disorders
WO2004012743A1 (fr) * 2002-08-01 2004-02-12 Chugai Seiyaku Kabushiki Kaisha Agent antipsoriasis
WO2004028515A1 (fr) * 2002-09-26 2004-04-08 Young-Kweon Choi Timbre de type matriciel pour administration transdermique d'un analogue de la vitamine d et utilisation de ce dernier
KR100438254B1 (ko) * 2001-03-29 2004-07-02 아이큐어 주식회사 비타민 ｄ 유사체를 포함하는 매트릭스형 경피흡수제제
WO2006120682A3 (fr) * 2005-05-10 2007-01-25 Dermipsor Ltd Compositions et methodes pour traiter des maladies epidermiques hyperproliferatives
CN100345547C (zh) * 1996-12-30 2007-10-31 骨疗国际公司 使用延迟和/或持续释放的维生素d制剂治疗前列腺疾病的方法
US20080234239A1 (en) * 2007-03-15 2008-09-25 Derek Wheeler Topical composition
US8207149B2 (en) 2007-04-25 2012-06-26 Cytochroma, Inc. Method for treating secondary hyperparathyroidism in CKD
US8329677B2 (en) 2006-06-21 2012-12-11 Cytochroma, Inc. Method of treating and preventing secondary hyperparathyroidism
US8426391B2 (en) 2006-02-03 2013-04-23 Proventiv Therapeutics, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US8592401B2 (en) 2007-04-25 2013-11-26 Proventiv Therapeutics, Llc Methods and compounds for vitamin D therapy
WO2014143941A1 (fr) * 2013-03-15 2014-09-18 Opko IP Holdings II, Inc. Formulation de vitamine d à libération modifiée stabilisée et son procédé d'administration
US20160038514A1 (en) * 2014-08-07 2016-02-11 Opko Ireland Global Holdings, Ltd. Adjunctive Therapy With 25-Hydroxyvitamin D and Articles Therefor
US20160184329A1 (en) * 2013-07-13 2016-06-30 Aphios Corporation Formulations and Compositions of Vitamin D Analogs for Treating and Preventing Cancer and other Diseases
US9610245B2 (en) 2011-03-14 2017-04-04 Drug Delivery Solutions Limited Ophthalmic composition
US10302660B2 (en) 2008-04-02 2019-05-28 Opko Renal, Llc Methods useful for vitamin D deficiency and related disorders
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
US11696919B2 (en) 2018-03-19 2023-07-11 MC2 Therapeutics Limited Topical composition
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
US12440499B2 (en) 2018-03-19 2025-10-14 MC2 Therapeutics Limited Topical composition

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990009179A1 (fr) * 1989-02-16 1990-08-23 University Of Georgia Research Foundation, Inc. Traitement de la dyschondroplasie tibiale d'allien
EP0567353A1 (fr) * 1992-04-24 1993-10-27 Wisconsin Alumni Research Foundation Utilisation d'1-alpha,25-dihydroxy-22(E)-déhydro-Vitamine 3D pour la fabrication d'un médicament pour le traitement de l'ostéoporose

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990009179A1 (fr) * 1989-02-16 1990-08-23 University Of Georgia Research Foundation, Inc. Traitement de la dyschondroplasie tibiale d'allien
EP0567353A1 (fr) * 1992-04-24 1993-10-27 Wisconsin Alumni Research Foundation Utilisation d'1-alpha,25-dihydroxy-22(E)-déhydro-Vitamine 3D pour la fabrication d'un médicament pour le traitement de l'ostéoporose

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
C. SEGAL ET AL.: "POLYMERIC CONTROLLED DELIVERY SYSTEM OF 1,25-DIHYDROXYVITAMIN D3:DEVELOPMENT,CHARACTERIZATION AND APPLICATION IN CHEMOPREVENTION OF COLON CANCER", PROC. INT. SYMP. CONTROLLED RELEASE BIOACT. MATER., 1994, pages 525 - 526 *
CHEMICAL ABSTRACTS, vol. 122, no. 14, 3 April 1995, Columbus, Ohio, US; abstract no. 169978 *

Cited By (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100345547C (zh) * 1996-12-30 2007-10-31 骨疗国际公司 使用延迟和/或持续释放的维生素d制剂治疗前列腺疾病的方法
WO1998036754A1 (fr) * 1997-02-20 1998-08-27 Paul Trouillas Utilisation du 9,10-secocholesta-5,7,10(19)-trien-1,3-ol, ou alfacalcidol
US6521608B1 (en) 1998-03-27 2003-02-18 Oregon Health & Science University Vitamin D and its analogs in the treatment of tumors and other hyperproliferative disorders
KR100438254B1 (ko) * 2001-03-29 2004-07-02 아이큐어 주식회사 비타민 ｄ 유사체를 포함하는 매트릭스형 경피흡수제제
WO2004012743A1 (fr) * 2002-08-01 2004-02-12 Chugai Seiyaku Kabushiki Kaisha Agent antipsoriasis
WO2004028515A1 (fr) * 2002-09-26 2004-04-08 Young-Kweon Choi Timbre de type matriciel pour administration transdermique d'un analogue de la vitamine d et utilisation de ce dernier
US9173835B2 (en) 2005-05-10 2015-11-03 Dermipsor Ltd. Compositions and methods for treating hyperproliferative epidermal diseases
JP2008540514A (ja) * 2005-05-10 2008-11-20 ダーミプソル リミテッド 過剰増殖表皮疾患の治療用組成物及び方法
WO2006120682A3 (fr) * 2005-05-10 2007-01-25 Dermipsor Ltd Compositions et methodes pour traiter des maladies epidermiques hyperproliferatives
CN101193641B (zh) * 2005-05-10 2013-05-29 德米普瑟尔有限公司 用于治疗表皮过度增殖疾病的组合物和方法
US9603861B2 (en) 2005-05-10 2017-03-28 Dermipsor Ltd. Compositions and methods for treating hyperproliferative epidermal diseases
US8906410B2 (en) 2006-02-03 2014-12-09 Opko Health, Inc. Oral dosage form of 25-hydroxyvitamin D
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
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
US8426391B2 (en) 2006-02-03 2013-04-23 Proventiv Therapeutics, 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
US9402855B2 (en) 2006-06-21 2016-08-02 Opko Renal, Llc Method of treating and preventing secondary hyperparathyroidism
US8329677B2 (en) 2006-06-21 2012-12-11 Cytochroma, Inc. Method of treating and preventing secondary hyperparathyroidism
US9913852B2 (en) 2006-06-21 2018-03-13 Opko Ireland Global Hodlings, Ltd. Method of treating and preventing secondary hyperparathyroidism
US10265265B2 (en) * 2007-03-15 2019-04-23 Drug Delivery Solutions Limited Topical composition
US20080234239A1 (en) * 2007-03-15 2008-09-25 Derek Wheeler Topical composition
US11065195B2 (en) 2007-03-15 2021-07-20 MC2 Therapeutics Limited Topical composition
US9918940B2 (en) 2007-04-25 2018-03-20 Opko Renal, Llc Methods for controlled release oral dosage of a vitamin D compound
US11752158B2 (en) 2007-04-25 2023-09-12 Eirgen Pharma Ltd. Method of treating vitamin D insufficiency and deficiency
US8207149B2 (en) 2007-04-25 2012-06-26 Cytochroma, Inc. 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
US9498486B1 (en) 2007-04-25 2016-11-22 Opko Renal, Llc Method 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
US9925147B2 (en) 2007-04-25 2018-03-27 Opko Renal, Llc Method for treating secondary hyperparathyroidism in CKD
US8778373B2 (en) 2007-04-25 2014-07-15 Opko IP Holdings II, Inc. Methods for controlled release oral dosage of a vitamin D compound
US8592401B2 (en) 2007-04-25 2013-11-26 Proventiv Therapeutics, Llc Methods and compounds for vitamin D therapy
US11154509B2 (en) 2007-04-25 2021-10-26 Eirgen Pharma Ltd. Methods for controlled release oral dosage of a vitamin D compound
US8361488B2 (en) 2007-04-25 2013-01-29 Cytochroma Inc. Methods and compositions for controlled release oral dosage of a vitamin D compound
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
US10154959B1 (en) 2011-03-14 2018-12-18 Drug Delivery Solutions Limited Ophthalmic composition containing a polyaphron dispersion
US9610245B2 (en) 2011-03-14 2017-04-04 Drug Delivery Solutions Limited Ophthalmic composition
US10357502B2 (en) 2013-03-15 2019-07-23 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
EP3888638A1 (fr) * 2013-03-15 2021-10-06 EirGen Pharma Ltd. Formulation de vitamine d à libération modifiée stabilisée et son procédé d'administration
WO2014143941A1 (fr) * 2013-03-15 2014-09-18 Opko IP Holdings II, Inc. Formulation de vitamine d à libération modifiée stabilisée et son procédé d'administration
US10350224B2 (en) 2013-03-15 2019-07-16 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
US9861644B2 (en) 2013-03-15 2018-01-09 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
KR101847947B1 (ko) * 2013-03-15 2018-05-28 옵코 아이피 홀딩스 Ⅱ 인코포레이티드 안정화되고 변형된 비타민 ｄ 방출 제형
EP3650016A1 (fr) * 2013-03-15 2020-05-13 OPKO Ireland Global Holdings, Limited Formulation de vitamine d à libération modifiée stabilisée et son procédé d'administration
US11253528B2 (en) 2013-03-15 2022-02-22 Eirgen Pharma Ltd. Stabilized modified release Vitamin D formulation and method of administering same
EA038867B1 (ru) * 2013-03-15 2021-10-29 Опко Айэлэнд Глобал Холдингз, Лтд. Стабилизированный состав витамина d с модифицированным высвобождением
EP3332773A1 (fr) * 2013-03-15 2018-06-13 OPKO Ireland Global Holdings, Limited Formulation de vitamine d à libération modifiée stabilisée et son procédé d'administration
AU2014228069B2 (en) * 2013-03-15 2019-01-31 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administring 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
US20160184329A1 (en) * 2013-07-13 2016-06-30 Aphios Corporation Formulations and Compositions of Vitamin D Analogs for Treating and Preventing Cancer and other Diseases
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IL110117A0 (en) 1994-10-07

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