WO2011024208A1 - Forme posologique mixte contenant de l’acide acétylsalicylique, du calcitriol et du calcium - Google Patents

Forme posologique mixte contenant de l’acide acétylsalicylique, du calcitriol et du calcium Download PDF

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Publication number
WO2011024208A1
WO2011024208A1 PCT/IS2010/000011 IS2010000011W WO2011024208A1 WO 2011024208 A1 WO2011024208 A1 WO 2011024208A1 IS 2010000011 W IS2010000011 W IS 2010000011W WO 2011024208 A1 WO2011024208 A1 WO 2011024208A1
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WIPO (PCT)
Prior art keywords
calcitriol
calcium
tablet
pharmaceutical composition
asa
Prior art date
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PCT/IS2010/000011
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English (en)
Inventor
Torfi E. Kristjansson
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Colotech A/S
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Filing date
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Publication of WO2011024208A1 publication Critical patent/WO2011024208A1/fr

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    • 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
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the present invention relates to a stable pharmaceutical composition suitable for administration to mammals comprising acetylsalicylic acid (ASA), 1,25 dihydroxycholecalciferol (calcitriol) and calcium.
  • ASA acetylsalicylic acid
  • calcitriol 1,25 dihydroxycholecalciferol
  • the invention also relates to a process for the preparation of such compositions and their use.
  • Calcitriol is known to be extremely sensitive to oxidation
  • acetylsalicylic acid is very sensitive to humidity and hydrolytic degradation to salicylic acid and acetic acid.
  • EP1220676 does not disclose or suggest any suitable particular compositions and appears to suggest that the ingredients can be provided as individual doses, to be administered simultaneously.
  • each active ingredient will have its own optimal matrix conditions that affect stability, dissolution and absorption characteristics. This can be difficult with two active ingredients and even more so with three active ingredients.
  • compositions comprising ASA, calcitriol and calcium, together in a single dosage form.
  • the present invention relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising acetylsalicylic acid (ASA), 1,25 dihydroxycholecalciferol (calcitriol) and calcium, all in a single dosage form, such as but not limited to a pill or capsule.
  • ASA acetylsalicylic acid
  • calcitriol 1,25 dihydroxycholecalciferol
  • calcium all in a single dosage form, such as but not limited to a pill or capsule.
  • the invention also relates to a process for the preparation of such compositions and their use.
  • the compositions and dosage forms of the invention exhibit excellent stability, shelf-life and dissolution characteristics. DEETAILED DESCRIPTION
  • EP1220676 discloses the general clinical benefits of the combination of the three active ingredients of the present invention, calcitriol, acetylsalicylic acid (ASA) and calcium. This document is incorporated by reference in its entirety.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising in a single dosage form calcitriol, acetylsalicylic acid or a salt thereof and calcium, wherein the calcitriol has been solubilised in a lipophilic carrier and the acetylsalicylic acid is separated from the calcitriol and preferably also separated from the calcium.
  • compound A can be granulated whereas compound B is not granulated, and preferably the granules of A are coated, subsequently the granules are mixed with compound B and optionally and typically further excipients.
  • the calcitriol is solubilised in a lipophilic carrier.
  • the lipophilic carrier may be selected from suitable low viscosity di- or triglycerides, such as di- and/or triglycerides comprising substantially C8 and/or ClO fatty acids, or mixtures of triglycerides of C8, ClO fatty acids and linoleic acid.
  • suitable lipophilic carriers include fractionated triglycerides sold under the trade name Miglyol® (Sasol, Germany) such as Miglyol 810, Miglyol 812 and Miglyol 818.
  • Miglyol 840 is a diglyceride (glycol diester) with C8 and ClO fatty acids, such diglycerides are also contemplated as a useful lipophilic carrier. Miglyol 810 and Miglyol 812 are particularly preferred. Other lipophilic carriers include dimethyl sulphoxide and suitable lipophilic alcohols, including isopropyl alcohol, ethylene glycol, propylene glycol or glycerol; or a mixture of any of those.
  • the dosage form of the invention comprises preferably the calcitriol component in the amount of about 0.1 ⁇ g (microgram) to about 2 ⁇ g, including about 1 ⁇ g or 1.2 ⁇ g, more preferably in the range of about 0.1 to about 0.5 ⁇ g, including about 0.25 ⁇ g and about 0.35 ⁇ g.
  • This small amount makes stringent requirements on the process for preparing the composition, in order to ensure uniformity of the calcitriol amount between individual dosage forms.
  • calcitriol can be added in the manufacturing process in 20-60% overage, which means that in the manufacturing process 120 - 160% is added of the intended amount, to allow for certain degradation, in particular during the processing, which is hard to fully prevent.
  • calcitriol is added in 20-30% overage.
  • calcitriol is added in overage such that the tablets right after manufacturing comprise 90-130% measured amount of the target amount of calcitriol.
  • the calcium is most preferably in the form of calcium carbonate.
  • other calcium salts are used such as calcium phosphate, calcium chloride, calcium phosphate and calcium sulphate.
  • the dosage form of the invention will comprise in the range of about 200 mg to 3000 mg calcium carbonate, more preferably in the range of about 300 mg to 2000 mg, and even more preferably in the range of about 500 mg to 1000 mg, including about 500 mg, about 625 mg, about 650 mg or about 750 mg.
  • Acetyl salicylic acid is generally in the dosage form in the amount of about 20 mg to about 500 mg, or in the range of about 25 mg to about 400 mg, more preferred in the range of about 25 to 300 mg, including the range of about 50 to 150 mg, or the range of about 25 mg to 100 mg, and including about 25 mg, 37 mg and about 50 mg.
  • the pharmaceutical composition of the invention comprises the above mentioned three ingredients in a single dosage form, where the ASA is chemically separated from the calcitriol and calcium.
  • the dosage form of the invention are instant release tablets, i.e. tablets that dissolve and/or disintegrate readily after intake so as to allow rapid adsorption of the active compounds.
  • the disintegration is less than 30 min and more preferably less than 15 min, yet more preferably less than 10 min, as measured by standards protocols described in Ph. Eur. Dissolution of the active components is preferably within similar ranges of time.
  • the dosage form of the invention is an inlay tablet comprising an inner tablet which comprises the ASA, and one or more outer tablet layer which comprises the calcitriol and the calcium.
  • the inner tablet will generally be coated, preferably film coated, in order to provide the desirable separation of the ASA from the other active ingredients.
  • the term "inlay tablet” is used herein in the conventional meaning, referring to a tablet having an inner tablet which is generally not fully enclosed by an outer layer, but rather the inner tablet sits embedded in the top (or bottom) surface of the compressed outer tablet.
  • compression coated tablet refers herein to a tablet comprising an inner layer/tablet, fully surrounded by an outer layer, referred to as a "mantle layer".
  • the ASA is suitably compressed in an inner tablet as further described herein, and the calcitriol component and calcium components are placed in one or more outer layer, preferably such that the calcitriol and calcium are separated.
  • Tablets according to the invention have good friability and desired hardness, as illustrated in the accompanying Examples.
  • the hardness is in the range of about 20-200 N, more preferably in the range 30-150 N, and even more preferably in the range 40-90 N, wherein hardness is measured by a method as describred in Ph. Eur.
  • a moisture barrier coating is preferred, such as for example polyvinylalcohol based coatings, including a polyvinyl alcohol-based coating with lecithin, such as Opadry AMB (Colorcon, USA) (See US patent No. 5,885,617).
  • a tablet core i.e. uncoated tablet
  • the coating will generally add about 1-8 mg to the tablet core, corresponding to a weight increase of about 2-8%.
  • the moisture barring coat is from 3-7% and most preferably it is about 6%.
  • a moisture barrier coat in this invention may also be based on other ingredients such as but not limited to hydroxypropyl methylcellulose and polyvinyl pyrrolidone (PVP) or polyvinyl alcohol (PVA).
  • the inner tablet preferably comprises suitable pharmaceutical excipients compatible with ASA, such as a carrier/diluent which in some embodiments is selected from microcrystallised cellulose, dextrose, mannitol, sorbitol, corn starch, modified corn starch or mixtures of two or more thereof.
  • a carrier/diluent which in some embodiments is selected from microcrystallised cellulose, dextrose, mannitol, sorbitol, corn starch, modified corn starch or mixtures of two or more thereof.
  • the amount of carrier/diluent can be in the range of about 10-75 wt% of the uncoated core of the inner tablet, such as in the range of about 20-65 wt%, including the range of about 25-50 wt%.
  • a disintegrant such as but not limited to
  • the disintegrant is preferably included in the inner tablet in an amount in the range of about 5-25% based on weight of the uncoated inner tablet, such as in the range of 10-20%, including about 10%, about 15% and about 18%.
  • a lubricant is preferably added to the inner tablet, which is in certain embodiments is one or more of magnesium stearate, sodium stearyl fumarate, stearic acid, colloidal anhydrous silica, synthetic aluminum silicate, magnesium oxide, calcium stearate, talc, hydrogenated castor oil, glyceryl dibehenate and mixtures thereof.
  • Lubricant will generally be present in the amount in the range from about 0.1% to about 4% by weight of the uncoated tablet, preferably from about 0.5 % to about 2% by weight.
  • magnesium stearate or stearic acid is selected as the most preferred lubricant.
  • the dosage amounts of the calcium and ASA are substantial amounts as indicated above, it is preferred to not add too much of inert excipients to the dosage form, so as to not making the dosage form too large and difficult to ingest orally.
  • the total weight of the active ingredients i.e. calcitriol, ASA, and calcium, including their salts if applicable
  • the active ingredients is 60% or more of the total weight of the dosage form. More preferably the active ingredients comprise at least 70% of the total weight of the dosage form.
  • the calcitriol and calcium can be mixed to form a suitable homogeneous mix as will be further described herein.
  • the calcitriol and calcium can be added in separate layers.
  • calcitriol is solubilised in a lipophilic carrier such one or more of those mentioned above.
  • a further lipid compound is added in some embodiments, such as but not limited to hydrogenated vegetable oil (e.g. as sold under the trade name Lubritab (JRS), or Sterotex® (ABITEC) which is hydrogenated cottonseed oil, or castor wax, which is hydrogenated castor oil), or glycerol behenate (e.g. Compritol® (Gatte Fosse)).
  • JRS Lubritab
  • ABS Sterotex®
  • glycerol behenate e.g. Compritol® (Gatte Fosse)
  • an antioxidant may be added to the calcitriol mix, preferably BHA (tert-butyl-4- hydroxyanisole) or BHT (butylated hydroxytoluene).
  • a suitable uniform mix with calcitriol and calcium suitably separated from each other can be made by first solubilising calcitriol in the lipophilic carrier, optionally with the added antioxidant. If a further lipid component is used, this component is suitably dissolved in another portion of the lipophilic carrier, heated as needed to dissolve the lipid compound, and the two portions are combined.
  • a calcitriol lipid solution as described is in certain embodiments Filled in small capsules (such s size 5 capsules, according to standardized sizes well known to the skilled person).
  • the lipid solution is kept at a temperature in the range of about 40-45 0 C to maintain homogeneous pouring solution.
  • the dissolved calcitriol with the optional antioxidant and/or further lipid component such as those mentioned, is mixed with a suitable carrier, such as but not limited to dextrose, mannitol, sorbitol, lactose or microcrystalline cellulose, which is preferred.
  • a suitable carrier such as but not limited to dextrose, mannitol, sorbitol, lactose or microcrystalline cellulose, which is preferred.
  • This resulting mixture is well mixed, such as in a high shear mixer, and dried.
  • the calcitriol solution and carrier can be mixed in a suitable ratio such as in the range of about 1:8 to about 1:20, e.g. about 1: 10 or 1: 12.
  • the obtained calcitriol granules according to the above procedure are found to be stable. These granules can be combined with a calcium carbonate component.
  • the calcium carbonate is preferably pre-mixed with a disintegrant, such as preferably
  • croscarmelose, crospovidone, or sodium starch glycolate which can be mixed with the calcium carbonate in a weight ratio of about 1: 10 to about 1:20, such as about 10, 12 or 15% of the disintegrant.
  • the calcium carbonate or calcium carbonate disintegrant premix can be compacted with roller compaction.
  • a surfactant such as a poloxamer copolymer (triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol), e.g. Poloxamer 407, such as Pluronic F127 (BASF, Germany).
  • Calcium carbonate component and calcitriol granules as described above are mixed together in one embodiment.
  • a lubricant is added, such as one of those mentioned above with respect to the inner ASA tablet.
  • the calcitriol-calcium mix can be suitable compressed on to an inner tablet with the ASA as described above.
  • the obtained inlay tablet with inner ASA tablet and outer inlay layer with calcitriol and calcium can be suitably coated, such as with a coating as mentioned above.
  • a similar embodiment to the above described involves the initial preparation of ASA inner tablets as just described, preferably film coated, which are fed into a suitable modified compression machine in which calcitriol granules such as described above and the calcium component are fed.
  • a tablet is provided with a surrounding mantle around the inner ASA tablet, wherein the surrounding mantle comprises the calcitriol and calcium.
  • the inner tablet is first partially compressed, e.g. at a pressure in the range from 0.5-5 tons, to form a partially- compressed core. This partial compression holds the components of the core together, but is not compressed to its final hardness/thickness.
  • the final tablets may be formed by a process wherein both the core and mantle blends are placed onto the two sides of a single machine (e.g. a Manesty Dry-Cota tablet press).
  • the core blend is again partially compressed (compressed, but not to its final hardness/thickness, only sufficient to hold together until it is transferred) on the core side of the press and then transferred to the mantle side of the press where it is sandwiched in the mantle blend.
  • This core/mantle blend is then compressed into the final, compression-coated tablet.
  • the ASA can also be granulated in granules which are suitably coated, preferably with a suitable film coating material such as but not limited to HPMC based coatings, Kollidon (copovidone) or the like.
  • Calcitriol is provided in granule form preferably as described above and the two respective types of granules are mixed with the calcium component. The resulting mix is subsequently compressed into tablets, which may be further coated, for enhanced stability and/or aesthetic appeal.
  • the solubilised calcitriol with the optional stabilising antioxidant(s) and/or further lipid component can be added to small capsules.
  • an inner tablet with ASA, a small capsule with calcitriol solution and calcium component as described above are placed in a sufficiently large capsule.
  • Such capsule is preferably packed in Alu-alu blister packaging, to give long-term stability. It is found that large such large capsule dosage forms including all three active ingredients readily dissolve to release all ingredients as clinically desired.
  • An inner tablet with ASA can be prepared as described above and used in illustration (i), this inner tablet is one embodiment film coated as described above and placed in a capsule together with calcitriol granules such as described above, and the calcium component.
  • potency as used herein referring to calcitriol refers to the measured amount of calcitriol and the active derivative pre-calcitriol, as measured by established assay.
  • the following method to measure calcitriol can be used.
  • a column such as Tracer Inertsphere, ODS, 5 ⁇ , 250mm x 4.6 mm or equivalent at 25°C, having the detection set at UV at 265 nm, injecting 200 ⁇ L samples, using the mobile phase Water: Acetonitrile: Methanol in the following ratio 30:45:25 (v/v/v) at flow rate of 1.5 mlVmin.
  • the size of the pharmaceutical dosage form can optionally be further decreased by roller compacting or other techniques of one or more of the active ingredients with or without additional excipients.
  • roller compacting or other techniques of one or more of the active ingredients with or without additional excipients In particular it may be advantageous to roller compact calcium prior to making the final dosage form.
  • the dosage form is packaged in stabilising packaging material especially chosen to protect the dosage form from moisture, including Duma containers, preferably with desiccant.
  • the dosage form is provided in aluminium blister packaging (alu-alu).
  • the pharmaceutical composition and dosage form of the invention is useful for prevention and/or treatment of colon cancer in mammals, in particular in humans.
  • the composition and dosage forms are also useful in the prevention of epithelial cancer such as lung, bladder, prostate or gynaecological cancer or the initiation and/or progression of epithelial cancer such as lung, bladder, prostate or gynaecological cancer in a human.
  • the pharmaceutical composition can further be used to treat conditions such as the treatment of swelling, osteoporosis, headache and calcium deficiency in mammals such as humans.
  • the mammal is a human.
  • Example 1 Inner tablet with ASA
  • An ASA tablet was prepared by combining the following ingredients, mixing them in a drum mixer and pressing them together in a tablet press using 6 mm punches. For optimal results the tablets were then coated with about 6 wt% PVA based coating (Opadry AMB).
  • Calcitriol granules were created by using the following ingredients and techniques. Butylated hydroxyanisole (BHA) was dissolved in isopropyl alcohol. Calcitriol was dissolved in the BHA - isopropyl alcohol solution, and sterotex is melted and added to the mix. The resulting mixture was then mixed with mannitol in high shear mixer and dried in fluidised bed processor at 40 0 C.
  • BHA Butylated hydroxyanisole
  • Calcium carbonate component was created by combining calcium carbonate with crosslinked povidone.
  • Example 4 Inlet tablet with inner ASA tablet overlaid with calcitriol and calcium
  • Calcitriol granules and calcium carbonate from examples 2 and 3 were mixed along with sodium stearyl fumarate. They were then compressed into a tablet over the ASA tablet from example 1 thus creating an inlay tablet. The tablets can then optionally be coated. The tablets were then packed into aluminum blisters.
  • the tablets had measured hardness 49-75 N, friability of 0.1% and disintergation time 8 min 20 sek (measured dissolution of calcium).
  • Example 5 Inner tablet with ASA
  • ASA tablet was created by combining the following ingredients, mixing them in a drum mixer and pressing them together in a tablet press using 6 mm punches. For optimal results the tablets were then coated with 6% PVA based coating (Opadry AMB).
  • Butylated hydroxyl anisole and butylated hydroxyl toluene were dissolved in miglyol. Calcitriol in solid form is then added to the solution which was heated to 40-45 0 C to get a clear solution. Lubritab was then melted at 50-70 0 C and allowed to cool until 40-45 0 C before adding it to the Miglyol solution. The above solution was then added to small capsules. A 40-45 0 C temperature was maintained while filling the capsules.
  • Calcium carbonate, starch and poloxamer were sifted and mixed together.
  • a part of the magnesium stearate can be added.
  • the blend was then roller compacted and sieved to reduce its volume. Magnesium stearate was then added to the blend as lubricant followed by a short mixing.
  • Dissolution of the prepared component was assayed with standard methods, after 30 min in 900 mL 0.1N HCL dissolution was 95.8%.
  • Example 8 Capsule with calcitriol in inner capsule
  • Calcitriol potency is measured in samples according to the following HPLC procedure.
  • the potency of calcitriol is defined as the assayed combined amount of calcitriol and the active derivative pre- calcitriol.

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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)
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Abstract

La présente invention a pour objet une composition pharmaceutique stable comprenant de l’acide acétylsalicylique (AAS), du 1,25 dihydroxycholécalciférol (calcitriol) et du calcium, présentant les trois principes actifs sous une seule forme posologique mais de telle sorte que les ingrédients soient chimiquement sensiblement séparés. L’invention concerne aussi un procédé pour la préparation de ces compositions. Les formes posologiques selon l’invention comprennent des comprimés multicouches comprenant des comprimés à incrustations et des comprimés enrobés par compression, des capsules contenant différents granules avec des ingrédients respectifs, des capsules contenant une capsule interne et une capsule contenant un comprimé interne contenant de l’AAS et une matrice comprenant du calcitriol et du calcium.
PCT/IS2010/000011 2009-08-24 2010-08-24 Forme posologique mixte contenant de l’acide acétylsalicylique, du calcitriol et du calcium WO2011024208A1 (fr)

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IS8845 2009-08-24

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103784419A (zh) * 2012-10-31 2014-05-14 成都国弘医药有限公司 一种含有骨化三醇的软胶囊及其制备方法
WO2014207317A1 (fr) * 2013-06-26 2014-12-31 Mas-Metabolic Analytical Services Oy Combinaison pharmaceutiquement possible et sûre pour son utilisation dans le traitement de maladies importantes
US9433583B2 (en) 2011-04-22 2016-09-06 Frank J. Farrell Colon vitamin

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4305935A (en) * 1978-08-09 1981-12-15 Teijin Limited Bone formation stimulant
WO2001022974A1 (fr) * 1999-09-29 2001-04-05 Colotech A/S Prevention du cancer colorectal
WO2001028564A1 (fr) * 1999-10-20 2001-04-26 Yuyu Industrial Co., Ltd. Compositions pharmaceutiques et preparations utiles pour le traitement des maladies metaboliques des os
WO2006074226A2 (fr) * 2005-01-05 2006-07-13 Novacea, Inc. Prevention de troubles thrombotiques a l'aide de composes de vitamine d active ou de mimetiques de ceux-ci
US20090004229A1 (en) * 2007-06-28 2009-01-01 Osmotica Costa Rica Sociedad Anonima rupturing controlled release device comprising a subcoat
WO2009087652A2 (fr) * 2007-10-19 2009-07-16 Usv Limited Compositions pharmaceutiques de calcitriol et de suppléments minéraux

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4305935A (en) * 1978-08-09 1981-12-15 Teijin Limited Bone formation stimulant
WO2001022974A1 (fr) * 1999-09-29 2001-04-05 Colotech A/S Prevention du cancer colorectal
WO2001028564A1 (fr) * 1999-10-20 2001-04-26 Yuyu Industrial Co., Ltd. Compositions pharmaceutiques et preparations utiles pour le traitement des maladies metaboliques des os
WO2006074226A2 (fr) * 2005-01-05 2006-07-13 Novacea, Inc. Prevention de troubles thrombotiques a l'aide de composes de vitamine d active ou de mimetiques de ceux-ci
US20090004229A1 (en) * 2007-06-28 2009-01-01 Osmotica Costa Rica Sociedad Anonima rupturing controlled release device comprising a subcoat
WO2009087652A2 (fr) * 2007-10-19 2009-07-16 Usv Limited Compositions pharmaceutiques de calcitriol et de suppléments minéraux

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9433583B2 (en) 2011-04-22 2016-09-06 Frank J. Farrell Colon vitamin
CN103784419A (zh) * 2012-10-31 2014-05-14 成都国弘医药有限公司 一种含有骨化三醇的软胶囊及其制备方法
WO2014207317A1 (fr) * 2013-06-26 2014-12-31 Mas-Metabolic Analytical Services Oy Combinaison pharmaceutiquement possible et sûre pour son utilisation dans le traitement de maladies importantes

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