WO2011095388A1 - Microgranule de toltérodine - Google Patents

Microgranule de toltérodine Download PDF

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Publication number
WO2011095388A1
WO2011095388A1 PCT/EP2011/050572 EP2011050572W WO2011095388A1 WO 2011095388 A1 WO2011095388 A1 WO 2011095388A1 EP 2011050572 W EP2011050572 W EP 2011050572W WO 2011095388 A1 WO2011095388 A1 WO 2011095388A1
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WO
WIPO (PCT)
Prior art keywords
bead
tolterodine
controlled release
layer
polymer
Prior art date
Application number
PCT/EP2011/050572
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English (en)
Inventor
Denny Johan Marijn Van Den Heuvel
Original Assignee
Synthon Bv
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Filing date
Publication date
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Publication of WO2011095388A1 publication Critical patent/WO2011095388A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes

Definitions

  • the present invention relates to a controlled release bead comprising tolterodine, a process for preparing it, its use for the manufacturing of a pharmaceutical dosage form, a pharmaceutical dosage form comprising it, and the use of the bead and the
  • controlled release beads comprising an inert core, such as a sugar sphere, coated with a drug-containing layer and an outer membrane layer for controlling the release rate of the drug are well known in the art.
  • An example of such a controlled release bead can be found in WO 96/01621 and its equivalent US 5,783,215.
  • the specifications of these two patents indicate that the presence in certain amounts of a hydrophilic polymer in the drug layer can provide advantageous mechanical properties and may, for the specific drug furosemid, provide for favorable control over dissolution properties below pH 4.
  • WO 00/27364 and corresponding US 6,911 ,217 relate to controlled release beads containing (i) an inert core, (ii) a water-insoluble polymer layer surrounding the core (iii) a drug layer thereon, and (iv) a controlled release polymer layer.
  • the specification teaches that it was previously "not uncommon" to apply a water-soluble polymer layer between the core and the drug layer, known as a "sealcoat,” to the beads as described in US 5,783,215. Such a water- soluble sealcoat would be present in a small amount, e.g. 1-3%.
  • the purpose of the sealcoat was to isolate the drug from the core surface to prevent any possible chemical interaction and/or to provide a smooth surface on the core with more consistent surface area to thereby obtain improved coating quality and reduced lot-to-lot variations.
  • the purported invention in WO 00/27364 and US 6,911,217 relates to the use of a sealcoat made of a water-insoluble material that serves to enhance the drug release profile. As seen in figure 1 of these patents, the in vitro release of tolterodine becomes slower and more zero-order as the amount of the water-insoluble sealcoat increases from 0% to 14%.
  • tolterodine tartrate markets a prolonged-release capsule formulation of tolterodine tartrate under such brand names as DETROL ® LA in the U.S. and DETRUSITOL SRTM in Europe.
  • Tolterodine is a well known pharmaceutical substance and is useful for treatment of urinary disorders such as overactive bladder. Its chemical name is (R)-N,N-disopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine and it has been disclosed in US 5,382,600.
  • tolterodine is typically used in the form of a salt with L-tartaric acid, commonly referred to as tolterodine tartrate.
  • the bead composition is preferably adjusted so that the in vitro dissolution of tolterodine is not more than 30% after 1 hour, from 40 to 85% after 3 hours and not less than 80% after 7 hours.
  • US 6,630,162 and US 6,770,295 also relate to tolterodine-containing beads and capsule formulations. These patents describe controlled-release formulations, similar to those in US 6,911,217, that obtain certain release profiles or blood plasma levels, respectively.
  • the water-insoluble polymer ethylcellulose under the brand name SURELEASE ® (Colorcon, Inc. West Point, PA, U.S.A.), is used as a sealcoat.
  • the same brand name polymer is also used as the sealcoat in the examples of US 6,911,217.
  • WO 2004-105735 teaches that it is possible to obtain the suitable release profile of tolterodine from coated pellets without the use of the intermediary coating (sealcoat). That is, the tolterodine-containing layer coat is directly coated on the inner core. This possibility was also studied in the US 6,911,217, however it was shown that after two hours the release rate failed to maintain the desired zero order release rate and released the tolterodine too quickly.
  • WO 2006/021425 relates to sustained release compositions of tolterodine wherein the release profile has a reduced dependency on pH and/or ionic strength of the dissolution medium.
  • One of the embodiments comprises an inert core having a tolterodine drug layer coated thereon and an outer layer containing a sustained release polymer coated on the drug layer.
  • the sustained release polymer is taught to be hydrophobic and examples of such polymers are reported as neutral polymers of ethyl acrylate/methyl methacrylate, ethylcellulose, polyvinyl acetate (PVAc) and polyvinyl pyrrolidone (PVP) or mixtures thereof.
  • the exemplified dosage forms coat the drug layer directly on the inert core and use either ethyl acrylate/methyl methacrylate copolymer (Eudragit NE 30 D - used in three examples) or ethylcellulose
  • sustained release polymer (Surelease ® - used in one example) as the sustained release polymer.
  • the dissolution of the formulation was compared to the commercial tolterodine beads in several different pH media and shown to have a more pH-independent release than the commercial product.
  • WO 2007/029087 is directed to improved cores for controlled release formulations. It describes a bead which has an inert core comprising ethyl cellulose and optionally one or more water-soluble or -swellable excipients, a first layer comprising the active ingredient and a hydrophilic polymer, and a second layer comprising a polymer which is effective for controlling the release of the active ingredient, wherein tolterodine is specifically mentioned as the active ingredient.
  • US Published application number US 2009/0017111 relates to tolterodine beads.
  • the beads comprise (i) a microcrystalline cellulose core, (ii) a water-soluble polymer layer surrounding the core comprising a vinyl pyrrolidone polymer, (iii) a tolterodine drug layer thereon, and (iv) a controlled release layer comprising a pH independent polymer, which is a polyacrylate polymer.
  • Preferred embodiments have superior pH-independency.
  • the present invention relates to a controlled release bead comprising tolterodine or an acid addition salt thereof as the active substance.
  • a first aspect of the invention is a controlled release bead comprising: i) a microcrystalline cellulose core unit having a diameter of 100-2000 micron which generally constitutes 50-90 wt% of the total weight of the bead composition,
  • a controlled release layer overlying the drug layer and comprising a poly(vinylacetate) polymer.
  • the use of poly(vinylacetate) in the controlled release layer can provide for favorable release characteristics of tolterodine.
  • the controlled release layer constitutes 5 to 50%, more typically 10-30%), such as 14-25%), of the total weight of the bead composition.
  • the poly(vinylacetate) polymer is typically at least 30%>, often at least 35%>, and frequently at least 45%, of the controlled release layer
  • the controlled release layer may further contain an anti- tacking agent such as talc; a plasticizer such as triethylcitrate or propyleneglycol; and/or a pore former such as HPMC or polyvinylpyrrolidone.
  • Another aspect of the invention is a pharmaceutical dosage form comprising a plurality of the above-mentioned beads.
  • a further aspect of the invention is a process for preparing a controlled release bead of the invention comprising the steps:
  • a controlled release layer comprising a poly(vinylacetate) polymer on the drug layer.
  • a still further aspect of the invention relates to the use of the above defined bead, a bead made by the above defined process and/or pharmaceutical dosage forms comprising such bead for use in medicine, such in treatment of urinary or gastrointestinal disorders.
  • Figure 1 represents the dissolution curves for the beads of Example 1 in three different media and the dissolution curves of the commercial product in the corresponding media plotted for comparison.
  • Figure 2 represents the dissolution curves for the beads of Example 2 in three different media and the dissolution curves of the commercial product in the corresponding media plotted for comparison.
  • the present invention relates to the discovery that the use of the pH- independent poly(vinylacetate) in a controlled release coating can surprisingly allow for the pH- dependent release of tolterodine.
  • tolterodine has a pH-dependent release that is typically masked by other pH-independent controlled release polymers.
  • poly(vinylacetate) can facilitate the formation of a bead that can closely match the pH-dependent dissolution performance of the commercial tolterodine beads, such as DETROL LA®, even though the poly(vinylacetate) is itself pH-independent.
  • Tolterodine refers to tolterodine and pharmaceutically acceptable salts thereof, preferably tolterodine tartrate, unless indicated to the contrary.
  • Percentages as used herein refer to weight percentages (wt%) unless otherwise stated.
  • the controlled release beads of the invention are generally comprised of a microcrystalline cellulose core unit, a water-soluble coat surrounding the core unit, a drug layer thereon comprising tolterodine and a pharmaceutically acceptable binder, and a controlled release layer comprising a poly(vinylacetate) polymer. Further layers may additionally be present, i.e., the drug layer "overlying" the water-soluble coat does not necessitate direct contact of the named layers as an additional layer could be in between. But typically no such additional layers are present. A top coat may optionally be applied if desired. Further details of the bead components are set forth below.
  • the microcrystalline cellulose core unit of the beads is any core or seed that contains microcrystalline cellulose and is typically a commercially available microcrystalline cellulose sphere such as Cellets or Celpheres .
  • the size of the core unit typically has a diameter within the range of 100-2000 microns, preferably the diameter of the core unit is within the range of 710-1000 microns.
  • the core unit constitutes 50-90 wt% of the total weight of the bead composition and in some embodiments the core unit is 70-90 wt%.
  • One benefit of using a microcrystalline cellulose unit core is that it is relatively easy to coat; e.g., hardly any erosion or dissolving of the core unit occurs during coating.
  • the coating rate may be increased (e.g., in comparison with known sugar cores) which reduces the process time and hence the production costs without adversely affecting the quality of the beads.
  • the thickness of the coat layers on the bead may be better controlled. The calculated yields of the process are more reliable since hardly any core material is lost during the different coating processes.
  • the cellulose core unit is primarily surrounded by a water-soluble coat which contains a vinyl pyrrolidone polymer.
  • a vinyl pyrrolidone polymer in this context includes both homopolymers and copolymers thereof, the latter generally containing at least 20% by mol of the vinyl pyrrolidone moiety in relation to other co-monomers.
  • a copolymer of vinyl pyrrolidone and vinyl acetate is used.
  • Such a copolymer typically has a molar ratio of about 6:4, respectively (e.g., Kollidon ® VA64 or more generically "PVP VA64").
  • the water-soluble coat can be present in the water-soluble coat as well, though typically no other polymers are present and the water-soluble coat is comprised mainly of one or more vinyl pyrrolidone polymer(s), e.g. at least 70%, typically at least 90%.
  • Other materials that can be included in the water-soluble coating include conventional coating aids such as triethylcitrate and/or talc.
  • the choice of polymer(s) used in the water-soluble coat may have an influence on the lag time during dissolution of the bead, which is preferably a relatively short lag time.
  • the water- soluble coat surrounding the core constitutes l-6%> of the total weight of the bead composition. In some embodiments, the water-soluble coat is 2 to 3%. For clarity, whole numbers whenever recited herein include lesser (and greater) values that are properly rounded to the whole number, e.g., 1.7%) is considered to be "2".
  • the drug layer comprises tolterodine, preferably tolterodine tartrate or another water-soluble pharmaceutically acceptable salt of tolterodine, together with a
  • the binder is a hydrophilic polymer.
  • Convenient hydrophilic polymer binders include hydroxypropyl methyl cellulose (HPMC). Among the commercially available grades, a low viscosity HPMC is generally desired such as Methocel E5 TM . However, practically any hydrophilic polymer having a sufficient binding property such as PVP, starch, hydrophilic cellulose derivatives, hydrophilic acrylate or methacrylate polymers may be used.
  • the "pharmaceutically acceptable binder” includes a singular polymer as well as blends of the same and/or different types of polymers. Additional components may also be present in the drug layer.
  • the drug layer typically constitutes 2-12%, more typically 2-6%, of the total weight of the bead composition. Tolterodine generally constitutes 40-70% of the total weight of the drug layer.
  • the outer controlled release layer comprises a poly(vinylacetate) polymer.
  • KOLLICOAT ® SR30D by BASF (note the "SR” denoting sustained release and the 30 D denoting 30% solids content).
  • This product is reported to be a dispersion of 27% poly(vinylacetate), 2.7% polyvinylpyrrolidone (PVP K30), 0.3%) sodium lauryl sulfate, and 70%> water.
  • PVP K30 2.7% polyvinylpyrrolidone
  • the poly(vinylacetate) polymers used in the present invention have an average molecular weight of at least 250000, typically at least 350000.
  • the poly(vinylacetate) in KOLLICOAT ® SR30D for example, is reported to have an average molecular weight of 450000.
  • the poly(vinylacetate) polymer normally comprises the single largest component of the controlled release layer and typically accounts for at least 30%, more commonly at least 35% and often at least 45% of the controlled release layer. Generally the poly(vinylacetate) polymer is not more than 90%, and typically less than 80% of the controlled release layer. Accordingly, typical ranges for the amount of poly(vinylacetate) relative to the controlled release layer are 35 to 80%, and preferably 45 to 75%.
  • the controlled release layer may contain additional ingredients. For example, an anti-tacking agent such as talc or silicon dioxide, and/or a plasticizer such as triethylcitrate or propyleneglycol may be additionally included.
  • each of these types of excipients can constitute 1 to 55% of the controlled release layer. Often the total of these excipients is 5 to 40% of the controlled release layer and in some embodiments is 25 to 35% of the controlled release layer. In these latter embodiments, talc and/or another anti-tacking agent is usually the majority component while the plasticizer, if present, is only 1 to 10% of the controlled release layer.
  • the controlled release layer can contain a pore former agent.
  • a pore former as is known in the art, is a water-soluble material that facilitates the transport of water through channels or pores in the controlled release layer. Typical pore forming agents include HPMC and polyvinylpyrrolidone.
  • a pore forming agent is typically present in an amount from 1 to 35%, typically 3 to 30%, and often 5-25% of the controlled release layer.
  • the controlled release layer typically constitutes 5 to 50%), more typically 10-30%), and often 14-25%), of the total weight of the bead composition.
  • the bead may further comprise an outermost coating or dusting, i.e., a top coat, for a variety of purposes including improving the mechanical properties, reducing staticity, avoiding agglomeration, and/or improving flow of the bead.
  • a top coat is not a functional coat, i.e., it does not substantially modify the controlled release rate of the bead.
  • Such a top coat can comprise, for example, hydroxypropyl methylcellulose, talc, or silicon dioxide and generally constitutes about 0.0.1 - 2% of the total weight of the bead composition, if present.
  • a top coat can be a film coat or more commonly a dry mixing of silicon dioxide.
  • the beads of the present invention are controlled release beads, meaning in a broad sense that immediate release (i.e., 90%> in 30 minutes) of the tolterodine has been disrupted.
  • preferred embodiments of the invention exhibit the following release rate of tolterodine in a phosphate buffer pH 6.8: not more than 30% (preferably 1-25%) at 1 hour, from 35 to 85% (preferably 40-65%>) at 3 hours and not less than 80%> at 7 hours.
  • the pellets of the invention preferably exhibit a significant pH-dependence in release.
  • the amount of tolterodine released at 3 hours and 7 hours in HC1 medium at pH 1.2 is at least 20%> less than the amount released at 3 and 7 hours, respectively, in phosphate buffer at pH 6.8.
  • the amount released at 3 hours in pH 1.2 medium is 30 to 75%, preferably 30 to 60%, of the corresponding amount released in pH 6.8 medium.
  • the amount released at 7 hours in pH 1.2 medium is typically 40 to 75%, more typically 50 to 75%, of the amount released in pH 6.8 medium. It is believed that such a profile with pH-dependency assists in ensuring that a product would be bioequivalent to the current controlled release capsules of tolterodine, e.g. DETROL ® LA and/or DETRUSITOL SRTM.
  • the process for producing the bead of the present invention can be carried out by any conventional or suitable techniques such as those known in the art and typically comprises the following steps: a) providing a core unit with a diameter size specified as described above,
  • a controlled release layer comprising a poly(vinylacetate) polymer on the drug layer.
  • a step e) of applying a top coat is also carried out.
  • the coating may be performed in a fluid bed coating equipment, wherein the coats are applied stepwise on the material to be coated.
  • the coating operations are performed by spraying a solution or dispersion of the respective coating materials on the particle to be coated.
  • the liquid carriers of the materials to be coated are generally water, a pharmaceutically acceptable organic solvent, such as an aliphatic alcohol (e.g., C1-C3 alcohol), or a combination of both. Any method known in the art to apply coatings on a bead may be used. After any particular coating, the coated material may be dried before applying the next coat.
  • the beads are generally cured, usually in the same fluid bed system or in a tray drier system, by heating to a temperature of about 30-80°C for 1-72 hours.
  • the curing is performed at a temperature of about 30-60 C for 2-48 hours, more typically 10-30 hours at 40°C.
  • the bead of the invention can be formulated into a pharmaceutical dosage form.
  • the pharmaceutical dosage form comprises a plurality of beads according to the invention.
  • the pharmaceutical dosage form may be a capsule or a tablet.
  • the capsule can be filled with the beads in a manner that is known in the art. Typically the capsule dosage form is filled so as to obtain 1 to 10 mg of tolterodine calculated as free base.
  • two or more kinds of the beads e.g., different populations, are used as a mixture together in one capsule. The beads of one population will have a different release of tolterodine than another due to differences in the bead composition.
  • the mixture of bead populations uses beads of a faster release rate ("fast spheres") with beads of a slower release rate (“slow spheres”) in a desired ratio, which may be from 10:90 to 90: 10 wt % ( fast/slow), in order to obtain an overall desired release rate.
  • the release rate of a bead population is typically adjusted/controlled by adjusting the amount and/or composition of the controlled release layer. But preferably a mixture of bead populations is not used, i.e., a single population or kind of bead is employed.
  • the plurality of controlled release beads can also be compressed into a tablet with appropriate excipients in a manner known in the art to obtain a tablet dosage form which contains 1 to 10 mg of tolterodine calculated as free base, preferably 2 to 4 mg of tolterodine tartrate.
  • the tablet upon dissolution disintegrates into the separate controlled release beads.
  • the plurality of beads may be comprised of two or more different bead populations.
  • the beads of the invention and/or beads made by the process of the invention and/or pharmaceutical dosage forms of the invention may be used in medicine, particularly in the treatment of urinary and gastrointestinal disorders.
  • Tolterodine beads were made using a fluidized bed coating apparatus by the following procedure.
  • 153 g tolterodine is suspended in 124 g HPMC in 3837 g demiwater. Coat 2493 g tolterodine suspension onto 3000 g spheres at a product temperature of 30°C.
  • a suspension is prepared by dissolving 9 g triethylcitrate in 249 g demiwater. 14 g Kollidon ® 30 is dissolved and subsequently 311 g Kollicoat ® SR30D is added under continuously stirred. The suspension is sieved over 0.4 mm screen. 531 g suspension is coated on 500 g of drug layered spheres at product temperature of 40°C. Dissolution testing was performed on the spheres at different pH and the results are depicted in Figure 1 along with the results for a commercial batch of tolterodine beads for comparison.
  • the overall composition of the beads is as follows:
  • Kollicoat SR30D and Kollidon 30 listed in the above table refer to the amount of solids from these suspensions that are coated; i.e., the amount does not include the water from the original product suspension, as is conventional in the art. Also, this means that of the 13.98% of Kollicoat ® , only about 90% is poly(vinyl acetate) as the other 10% is polyvinylpyrrolidone according to the manufacturer.
  • Tolterodine beads were made using a fluidized bed coating apparatus by the following procedure.
  • suspension A is prepared by dissolving 3 g triethylcitrate in 100 g demiwater and subsequently adding 220 g Kollicoat ® SR30D under continuously stirring.
  • Suspension B is prepared by dissolving 14 g Kollidon® 30 is dissolved 213 g demiwater. 33 g Talc is added and mixed thoroughly. Suspension B was added to suspension A under stirring. The suspension is sieved over 0.4 mm screen. 531 g suspension was coated on 500 g drug layered spheres at product temperature of 40°C.
  • silicium dioxide was added to the spheres and dry mixed in a free fall mixer. The complete batch was cured for 24 hours at 40°C in oven.
  • Dissolution testing was performed on the spheres at different pH and the results are depicted in Figure 2 along with the results for a commercial batch of tolterodine beads for comparison.
  • the overall composition of the beads is as follows:
  • bead populations A, B, and C are prepared having the following average composition per bead:

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Abstract

La présente invention concerne une microgranule de toltérodine à libération contrôlée formée qui présente un noyau de cellulose microcristalline, et un enrobage hydrosoluble contenant du polyvinylpyrrolidone (PVP), une couche de médicament à base de toltérodine, et une couche à libération contrôlée contenant du poly(vinylacétate).
PCT/EP2011/050572 2010-02-04 2011-01-18 Microgranule de toltérodine WO2011095388A1 (fr)

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US61/301,306 2010-02-04

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Cited By (10)

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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
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

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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
US9918940B2 (en) 2007-04-25 2018-03-20 Opko Renal, Llc Methods for controlled release oral dosage of a vitamin D compound
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US11672809B2 (en) 2010-03-29 2023-06-13 Eirgen Pharma Ltd. Methods and compositions for reducing parathyroid levels
US11253528B2 (en) 2013-03-15 2022-02-22 Eirgen Pharma 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
US10350224B2 (en) 2013-03-15 2019-07-16 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
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US9861644B2 (en) 2013-03-15 2018-01-09 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
US11007205B2 (en) 2014-08-07 2021-05-18 Eirgen Pharma Ltd. Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
US10493084B2 (en) 2014-08-07 2019-12-03 Opko Ireland Global Holdings, 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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