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WO1996036340A1 - FORMULATIONS AQUEUSES STABLES DE 1α,25-DIHYDROXYCHOLECALCIFEROL POUR ADMINISTRATION PARENTERALE - Google Patents

FORMULATIONS AQUEUSES STABLES DE 1α,25-DIHYDROXYCHOLECALCIFEROL POUR ADMINISTRATION PARENTERALE Download PDF

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Publication number
WO1996036340A1
WO1996036340A1 PCT/US1996/007074 US9607074W WO9636340A1 WO 1996036340 A1 WO1996036340 A1 WO 1996036340A1 US 9607074 W US9607074 W US 9607074W WO 9636340 A1 WO9636340 A1 WO 9636340A1
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WO
WIPO (PCT)
Prior art keywords
dihydroxycholecalciferol
accordance
sodium
aqueous solution
buffer
Prior art date
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Ceased
Application number
PCT/US1996/007074
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English (en)
Inventor
Luk C. Li
Edward A. Pec
Jagdish Parasrampuria
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Abbott Laboratories
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Abbott Laboratories
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Publication date
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Priority to AU58613/96A priority Critical patent/AU5861396A/en
Publication of WO1996036340A1 publication Critical patent/WO1996036340A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/59—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • This invention relates to aqueous formulations of 1 ⁇ ,25- dihydroxycholecalciferol in parenteral solutions.
  • the compound has a molecular weight of 416.647, a molecular formula of C27H44O3, is soluble in organic solvents and is practically insoluble in water.
  • the generic name of 1 ⁇ ,25-dihydroxycholecalciferol is calcitriol.
  • 1 ⁇ ,25-dihydroxycholecalciferol stimulates intestinal calcium and phosphorus absorption and, with parathyroid hormone, stimulates bone calcium resorption or mobilization.
  • 1 ⁇ ,25-dihydroxycholecalciferol meets the criteria of a classic steroid hormone in that it is synthesized in one organ under closely regulated conditions, and is then transported by the circulation to another organ where it exerts its biological effects.
  • the discovery that the kidney is the exclusive site for the production of 1 ⁇ ,25-dihydroxycholecalciferol from 20- hydroxycholecalciferol provided an explanation for the vitamin D-resistant state observed in patients with chronic uremia. Blood levels of 1 ⁇ ,25-dihydroxycholecalciferol in patients with chronic renal failure are low or undetectable.
  • the successful chemical synthesis of 1 ⁇ ,25-dihydroxycholecalciferol made this metabolite available for replacement therapy, and its clinical use for the treatment of hypocalcemia in patients on renal dialysis has recently been approved.
  • 1 ⁇ ,25-dihydroxycholecalciferol uses of 1 ⁇ ,25-dihydroxycholecalciferol include the treatment of renal osteodystrophy, hypoparathyroidism, osteomalacia, osteoporosis, hepatic osteodystrophy, vitamin D-resistant rickets, vitamin D-dependent rickets, childhood renal failure and neonatal hypocalcemia.
  • Neonatal hypocalcemia is the most prevalent hypocalcemic state encountered in pediatrics and can be divided into two main groups: (1) "early” neonatal hypocalcemia beginning in the first 48 hours of life and (2) "late” neonatal hypocalcemia beginning at the end of the first week of life.
  • Late neonatal hypocalcemia usually occurs in full term or premature infants who have been started on feedings and who show signs or symptoms of hypocalcemia only after several days or weeks of feedings.
  • the hypocalcemia appears to be precipitated by the high phosphate load of most feedings other than human milk.
  • the high phosphate serum concentration in serum of infants in the first few weeks is associated with low parathyroid hormone levels and with a low glomerular filtration rate.
  • Calcijex® (Abbott Laboratories, Abbott Park, IL. 60034), a formulation containing 1 ⁇ , 25 - dihydroxycholecalciferol in an aqueous formulation, is one example suitable for parenteral administration for both neonatal hypocalcemia and hemodialysis.
  • hemodialysis patients can be treated with initial doses of 1 ⁇ , 25 - dihydroxycholecalciferol approximately every other day. Serum calcium and phosphorus levels are obtained regularly to monitor the patient until normal calcium levels are observed.
  • patient dosage of 1 ⁇ , 25 - dihydroxycholecalciferol is limited to a total of 9 micrograms per week.
  • Chelating agents including but not limited to citric acid, tartaric acid, amino acids, thioglycolic acid, and edetate disodium (EDTA), and buffers, including but not limited to acetate, citrate, glutamate, and phosphate buffers, are often used to stabilize formulations containing drugs such as 1 ⁇ , 25 - dihydroxycholecalciferol.
  • buffers including but not limited to acetate, citrate, glutamate, and phosphate buffers
  • these additives are found to impart aluminum levels in products to over 3.5 parts per million at the expiration date of the product.
  • the source of aluminum may be partially due to the buffer itself.
  • the use of buffers and chelating agents may also increase aluminum levels by extracting aluminum from the glass ampoule which contains the formulation.
  • EDTA is a chelating agent which is not an acceptable injectable excipient in some international markets, such as Japan.
  • the formulations of the present invention are essentially free of EDTA and buffers which results in a reduction of aluminum levels in the formulations.
  • some of the formulations of the present invention may be terminally sterilized by autoclaving, which imparts a 1 ⁇ 3 fold increase in sterility assurance level (SAL) of the final product over aseptic filling techniques.
  • SAL sterility assurance level
  • the present invention provides pharmaceutical formulations having a pH of from about 5.8 to about 7.8 comprising a therapeutically effective amount of 1 ⁇ , 25 dihydroxycholecalciferol, a solubilizing agent, an antioxidant, and are essentially free of a buffer and a chelating agent wherein at least a two fold decrease in aluminum content results.
  • the present invention also provides for sterile, aqueous solutions having a pH of from about 5.8 to about 7.8 comprising 1 ⁇ , 25-dihydroxycholecalciferol, a solubilizing agent and an antioxidant wherein the aqueous solution has at least a two fold decrease in aluminum content as compared to solutions also containing a buffer and/or a chelating agent. Processes for preparing such sterile, aqueous solutions are also disclosed.
  • the present invention provides a dilute, stable, sterile, aqueous formulation of 1 ⁇ , 25-dihydroxycholecalciferol suitable for parenteral administration.
  • parenteral administration the intramuscular route is preferred.
  • the dilute, stable, sterile, aqueous formulations comprise 1 ⁇ , 25-dihydroxycholecalciferol, a solubilizing agent, and an antioxidant and are essentially free of a buffer and a chelating agent thereby providing at least a two fold decrease in aluminum content.
  • the formulations of the present invention are completely free of buffers and chelating agents.
  • the pH of the formulation may be controlled by the addition of hydrochloric acid and/or sodium hydroxide.
  • the pH of the final product can range from about 5.8 to about 7.8.
  • the solubilizing agents which may be used in the formulations of the present invention comprise dimethylacetamide, polyethylene glycol 400 (PEG 400), polyethylene glycol 200 (PEG 200), ethanol, isopropanol, 1 ,3- butanediol, propylene glycol, dimethylsulfoxide, glycerin, water, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80. It is to be understood by those skilled in the arts that the solubilizing agents used in the formulations of the present invention must be of a pharmaceutically acceptable grade.
  • the solubilizing agents used in the formulations of the present invention are nonionic surfactants which generally comprise the polyoxalkylene compounds, e.g., the mono-fatty acid esters of polyethylene glycol, the partial esters of fatty acids and polyhydric alcohols, or the anhydrides of such alcohols, etherified with polyalkylene oxides.
  • nonionic surfactants which generally comprise the polyoxalkylene compounds, e.g., the mono-fatty acid esters of polyethylene glycol, the partial esters of fatty acids and polyhydric alcohols, or the anhydrides of such alcohols, etherified with polyalkylene oxides.
  • compounds such as polyoxyethylenesorbitan monolaureate (Tween® 20) and analogous compounds work well due to their solubilizing effectiveness and low toxicity.
  • Other polyoxyethylene ester solubilizing agents which can be used include those listed in, but not intended to be limited to, the 1994 Sigma® Chemical Company catalog on pages 850-852. Those skilled in the
  • solubilizing agent used with formulations containing 1 ⁇ , 25-dihydroxycholecalciferol will depend on the particular solubilizing agent used in the formulation. Generally, the solubilizing agent is used to help solubilize the 1 ⁇ , 25- dihydroxycholecalciferol but is not toxic at the concentrations used.
  • the solubilizing agents are used in making aqueous formulations containing the potent and toxic compound 1 ⁇ , 25- dihydroxycholecalciferol. In the formulations of the present invention, a concentrate of 1 ⁇ , 25-dihydroxycholecalciferol and solubilizing agent was made to provide a form of 1 ⁇ , 25- dihydroxycholecalciferol which was easier to formulate.
  • Antioxidants are used to help prevent oxidation of the drug in the product.
  • the antioxidant is quickly oxidized thereby minimizing oxidation of 1 ⁇ , 25-dihydroxycholecalciferol.
  • Antioxidants and some final concentrations, that can be used with the formulations of the present invention include, but are not intended to be limited to, ascorbic acid (0.01-0.5%), metal ascorbates (0.2-1.0%), sodium bisulfite (0.05-1.0%), sodium metabisulfite (0.025-0.2%), ascorbyl palmitate (0.01-1.0%), sodium sulfite (0.01-1.0%), sodium formaldehyde sulfoxylate (0.005-0.15%), acetone sodium bisulfite (0.2%), tocophenol (0.05-0.5%), cysteine (0.1 -0.5%), thioglycerol (0.1-0.5%), monothioglycerol (0.1-0.5%), nordhydroguaianetic acid (0.01%), ascorbic acid est
  • the preferred antioxidants are the metal ascorbates such as the alkali or alkaline earth metal ascorbates.
  • the metal ascorbate is sodium ascorbate (Aldrich Chemical Company, Inc., Milwaukee, Wl., 53233).
  • terminal sterilization generally includes, but is not intended to be limited to, autoclaving, gamma radiation and electron beam sterilization techniques.
  • terminal sterilization will primarily refer to autoclaving processes.
  • formulations employing higher concentrations of sodium ascorbate, such as 10 mg/ml employ aseptic fill techniques.
  • Terminal sterilization provides a much desirable SAL (10" 6), than that of aseptic filling (10" 3 ).
  • Terminal sterilization of formulations containing higher sodium ascorbate concentrations may result in discoloration of product due to sodium ascorbate degradation.
  • the American Public Health Association (APHA) publishes guidelines for products including color standards.
  • the APHA color standard for such products are well known to those skilled in the pharmaceutical arts. Color standard information may be found in the 1995 US Pharmacopiea/National Formulary, Edition No. 23, pages 1779-1780..
  • an APHA of less than 300 is desirable.
  • compositions of the present invention such as 10 mg/ml
  • concentrations of sodium ascorbate in the formulations of the present invention such as 10 mg/ml
  • concentrations of 10 mg/ml may require aseptic filling and a less desirable SAL.
  • the formulations of the present invention contain lower sodium ascorbate levels to allow for terminal sterilization of the end product. Concentrations of sodium ascorbate in formulations of the present invention can be controlled to provide an APHA of less than 300.
  • Stable aqueous formulations of the present invention comprise 1 ⁇ , 25-dihydroxycholecalciferol, a solubilizing agent, an antioxidant, and are essentially free of a buffer and a chelating agent.
  • Two examples of the preferred formulations of the present invention are presented in Table 1 :
  • Solution comprising 1 Solution comprising 2 microg rams/mi I liliter micrograms/milliliter ( ⁇ g/ml) of 1 ⁇ , 25- ( ⁇ g/ml) of 1 ⁇ , 25- dihydroxycholecalciferol dihydroxycholecalciferol
  • formulations of the present invention are the elimination of chelating agents and buffers which are often used as product stabilizers.
  • Buffers often used in formulations include, but are not limited to, acetate, citrate, glutamate, and phosphate buffers.
  • the formulations of the present invention are essentially free of chelating agents and buffers which result in at least a two fold or greater decrease in aluminum levels in the final product.
  • the formulations of the present invention are completely free of chelating agents and buffers.
  • aluminum content levels exceed 1000 parts per billion (ppb) in formulations which include buffers and/or chelating agents. As storage time of the formulation increases, the aluminum content in the formulation may increase as well. Aluminum from the glass ampoule may be extracted into the formulation over time. Generally, buffers themselves contain substantial quantities of aluminum so that when they are used in pharmaceutical formulations, they impart aluminum as well.
  • the formulations of the present invention have initial aluminum content levels of less than 1000 ppb. More preferably, the formulations of the present invention have less than 100 ppb of aluminum. Most preferably, the formulations of the present invention have less than 10 ppb of aluminum.
  • the term "initial” in this disclosure with respect to testing parameters refers to testing the end product after sterile filtration or autoclaving.
  • the stable, aqueous, dilute, sterile 1 ⁇ ,25-dihydroxycholecalciferol solution for parenteral administration may be supplied in unit dose 1 ml amber glass ampoules, having the headspace filled by an inert atmosphere such as nitrogen or argon, and which are stored at temperatures of from about 15° to 30° C. in a darkened area.
  • an inert atmosphere such as nitrogen or argon
  • Each 1 ml of solution preferably contains 1.0 or 2.0 ⁇ g of 1 ⁇ ,25-dihydroxycholecalciferol, 4.0 mg of TWEEN®20 (Polysorbate 20, Sigma Chemical Co., St. Louis, Mo., 63178) nonionic surfactant, 2.5 mg of sodium ascorbate, hydrochloric acid q.s., sodium hydroxide q.s., and water for injection q.s.
  • the pH of the final product is from about 5.8 to about 7.8 and most preferably from about 5.8 to about 7.0. It is understood by those skilled in the art that all components of the present formulations are of a pharmaceutically acceptable grade and quality.
  • Ampoules containing the formulations of the present invention may be aseptically filled using a series of filters to assure a sterility assurance level (SAL) of 1 X 10 " 3 . More preferably, ampoules containing the formulations of the present invention may be filled and then terminally sterilized to provide a SAL of 1 X 10"6. For example, an aqueous solution of a formulation of the present invention may be filtered, using a 0.45 micrometer ( ⁇ m) or finer membrane filter (Millipore Corporation, Bedford, MA. 01730), into ampoules. The ampoules may be sealed under a nitrogen blanket and terminally sterilized.
  • SAL sterility assurance level
  • Terminal sterilization of the final product may be done at a Fo of 8 or a Fo of 16.
  • Fo relates to the degree of sterilization and is well known to those skilled in the art.
  • a Fo of 8 denotes a sterilization cycle run at 121.11° C, with saturated steam for 8 minutes
  • a Fo of 16 denotes a cycle at 121.11 ° C, with saturated steam for 16 minutes.
  • the stabilized, aqueous solution of the present invention may be prepared under an inert atmosphere, such as nitrogen or argon, in order to insure that oxidation of sodium ascorbate and 1 ⁇ ,25-dihydroxycholecalciferol is minimized during terminal sterilization and end product storage.
  • concentration of oxygen in the headspace is in the range of ⁇ 3- 7%. More preferable is a headspace oxygen concentration of ⁇ 3- 4%. The higher the percentage of oxygen in the headspace may result in a larger pH change upon terminal sterilization and end product storage.
  • aqueous solution "A” containing 2 ⁇ g/ml of 1 ⁇ ,25- dihydroxycholecalciferol, 15.7 mg/ml of citrate buffer, and 2.5 mg/ml of sodium ascorbate was prepared.
  • a second solution “B” was prepared that was identical to solution “A” but also contained the chelating agent, EDTA (1.1 mg/ml). Samples were tested initially and at 3 and 4 months storage at 25° C for aluminum content. Aluminum content was determined by using atomic absorption spectrophotometry. Aluminum content is reported in parts per billion (ppb).
  • aqueous solution "A” containing 2 ⁇ g/ml of 1 ⁇ ,25- dihydroxycholecalciferol with 2.5 mg/ml sodium ascorbate was prepared.
  • a second solution “B” was prepared that was identical to solution “A” but also contained the chelating agent, EDTA (1.1 mg/ml).
  • the solutions for storage were aseptically filled into ampoules.
  • the samples were tested for aluminum content initially and at 3, 6, and 12 months storage at 25° C. Aluminum content was determined by using atomic absorption spectrophotometry. Aluminum content is reported in parts per billion (ppb). The results are presented in Table 3.
  • the aluminum content in solution "B” at initial testing and at 3, 6, and 12 and 24 months storage was at least 2 times greater than solution "A".
  • Solution “A” was terminally sterilized at an Fo of 8.
  • Solution “C” was the same as solution “A” but was terminally sterilized at an Fo of 16.
  • Solution “B” was terminally sterilized at an Fo of 8 and solution “D” was the same as solution “B” but was terminally sterilized at an Fo of 16.
  • the lots containing EDTA showed approximately a 2- 5.5 times increase in aluminum content over the non-EDTA containing samples (solution “A” and solution “C”).
  • a drop in pH in all samples was seen which may be attributed to oxidation of sodium ascorbate.
  • the pH of solution “A” and “C” were consistently lower than solutions “B” and “D” which was probably due to the buffering capability provided by EDTA. Results are shown in Table 4.
  • the value for solution "A” at 18 months is the average of 2 readings.
  • the headspace of the ampoules were nitrogen gassed to provide the different 02 concentrations. Gassing is done by standard operating practices well known to those skilled in the arts.
  • the instrument used to measure percent oxygen headspace was an Oxygen Headspace Analyzer from Toray, Model No. LF-700 (Toray Engineering Co. Ltd., Japan). Three different O2 concentrations were tested (6 ⁇ 1%, 3+1 %, and ⁇ 3%) with an in- process pH level of 6.5.
  • the in-process pH level was determined by adjusting the final pH of the formulation with dilute sodium hydroxide and/or hydrochloric acid. The in-process pH was taken prior to terminal sterilization.
  • the solubilizing agent, Tween® 20 was heated in a glass- lined or 316 or higher temper grade stainless steel vessel to a temperature of between 50° to 75° C. Nitrogen gas protection was maintained in the vessel headspace throughout the preparation. After the solubilizing agent was heated to the desired temperature, the 1 ⁇ ,25-dihydroxycholecalciferol was added to the heated solubilizing agent with mixing. Mixing was continued until the 1 ⁇ ,25-dihydroxycholecalciferol dissolved (approximately 10-15 minutes) and the mixture was uniform thereby providing a concentrate containing 575 ⁇ g 1 ⁇ ,25- dihydroxycholecalciferol/gram of Tween® 20. The concentrate was then allowed to cool.
  • an aqueous solution was prepared by heating approximately 110% of the total volume of water for injection in a mixing tank to a temperature of not less than 85° C. The water was cooled to a temperature of between 30° to 45° C while nitrogen bubbling was continued. Before the water reached 30° C, 20% of the final volume in the mixing tank was transferred to a separate covered tank that had been pregassed with nitrogen. The water in the separate covered tank was used to q.s the aqueous solution in the mixing tank.
  • the aqueous solution in the mixing tank was q.s. to its final volume with water from the separate covered tank.
  • the water was mixed gently into the aqueous solution to provide a uniform solution.
  • the pH was adjusted with the addition of hydrochloric acid and/or sodium hydroxide.
  • the mixing tank was sealed and the contents nitrogen sparged.
  • the aqueous solution was then transfer filtered with a 0.45 ⁇ m membrane into a glass-lined holding tank.
  • the fill lines were flushed with nitrogen gas to prevent oxidation of the product prior to filtering.
  • the aqueous solution in the holding tank was filtered with a 0.45 ⁇ m (or finer) membrane filter under an inert atmosphere and then filled in the desired volume into sterile, dry one ml ampoules.
  • Each ampoule was flushed with nitrogen gas prior to filling.
  • the ampoules were filled and headspace nitrogen gassed prior to sealing the container.
  • the ampoules were then terminally sterilized at a Fo of 8.
  • the 1 ⁇ ,25-dihydroxycholecalciferol/polysorbate 20 concentrate (575 ⁇ g 1 ⁇ ,25-dihydroxycholecalciferol/g of polysorbate 20) was prepared as described in Example 5.
  • an aqueous solution was prepared by heating approximately 110% of the total volume of water for injection in a mixing tank to a temperature of not less than 85° C. The water was cooled to a temperature of between 30° to 45° C while nitrogen bubbling was continued. Before the water reached 30° C, 20% of the final volume in the mixing tank was transferred to a separate covered tank that had been pregassed with nitrogen. The water in the separate covered tank was used to q.s the aqueous solution in the mixing tank.
  • the aqueous solution in the mixing tank was q.s. to its final volume with water from the separate covered tank.
  • the water was mixed gently into the aqueous solution to provide a uniform solution.
  • the pH was adjusted with the addition of hydrochloric acid and/or sodium hydroxide.
  • the mixing tank was sealed and the contents nitrogen sparged.
  • the aqueous solution was then transfer filtered with a 0.45 ⁇ m membrane into a glass-lined holding tank.
  • the fill lines were flushed with nitrogen gas to prevent oxidation of the product prior to filtering.
  • the aqueous solution in the holding tank was further filtered with a 0.45 ⁇ m (or finer) membrane filter.
  • the headspace in the holding tank was sparged with nitrogen gas.
  • Each ampoule was flushed with nitrogen gas prior to filling.
  • the ampoules were filled and headspace nitrogen gassed prior to sealing the container.
  • the ampoules were then terminally sterilized at a Fo of 8.

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Abstract

1α,25-dihydroxycholecalciférol est une forme naturelle de la vitamine D3. Celle-ci est convertie en 1α,25-dihydroxycholecalciférol dans le foie et dans les reins avant de stimuler le calcium intestinal et l'absorption phosphoreuse. Les solutions parentérales de 1α,25-dihydroxycholecalciférol sont appropriées pour une thérapie de remplacement.
PCT/US1996/007074 1995-05-19 1996-05-16 FORMULATIONS AQUEUSES STABLES DE 1α,25-DIHYDROXYCHOLECALCIFEROL POUR ADMINISTRATION PARENTERALE Ceased WO1996036340A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58613/96A AU5861396A (en) 1995-05-19 1996-05-16 Stable aqueous formulations of 1alpha,25-dihydroxycholecalci ferol for parenteral administration

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US44498295A 1995-05-19 1995-05-19
US08/444,982 1995-05-19

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WO1996036340A1 true WO1996036340A1 (fr) 1996-11-21

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6051567A (en) * 1999-08-02 2000-04-18 Abbott Laboratories Low oxygen content compositions of 1α, 25-dihydroxycholecalciferol
US6136799A (en) * 1998-04-08 2000-10-24 Abbott Laboratories Cosolvent formulations
US6211169B1 (en) 1999-09-29 2001-04-03 Aesgen, Inc. Stable calcitriol solution for packaging into vials
WO2000061112A3 (fr) * 1999-04-13 2002-09-26 Leo Pharm Prod Ltd Composition pharmaceutique solubilisee a administration parenterale
JP2006502185A (ja) * 2002-09-18 2006-01-19 ボーン ケア インターナショナル インコーポレイテッド 親油性の薬剤のための組成物
WO2006051106A1 (fr) 2004-11-12 2006-05-18 Bioxell Spa Emploi combiné de dérivés de vitamine d et d'agents antiproliférants pour le traitement de cancers de la vessie

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US4308264A (en) * 1981-01-28 1981-12-29 Abbott Laboratories Stabilized, dilute aqueous preparation of 1α,25-dihydroxycholecalciferol for neonatal administration
JPH05238936A (ja) * 1992-02-27 1993-09-17 Dainippon Pharmaceut Co Ltd カルシトリオールの水性液剤
EP0651994A1 (fr) * 1993-11-08 1995-05-10 Hans Dr. Dietl Préparations liquides orales contenant des composés, solubles dans l'huile

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4308264A (en) * 1981-01-28 1981-12-29 Abbott Laboratories Stabilized, dilute aqueous preparation of 1α,25-dihydroxycholecalciferol for neonatal administration
JPH05238936A (ja) * 1992-02-27 1993-09-17 Dainippon Pharmaceut Co Ltd カルシトリオールの水性液剤
EP0651994A1 (fr) * 1993-11-08 1995-05-10 Hans Dr. Dietl Préparations liquides orales contenant des composés, solubles dans l'huile

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Title
DATABASE WPI Section Ch Week 9342, Derwent World Patents Index; Class A96, AN 93-331356, XP002010495 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6136799A (en) * 1998-04-08 2000-10-24 Abbott Laboratories Cosolvent formulations
JP2014129360A (ja) * 1998-04-08 2014-07-10 Abbvie Inc 共溶媒処方物
US6361758B1 (en) * 1998-04-08 2002-03-26 Abbott Laboratories Cosolvent formulations
JP2002510652A (ja) * 1998-04-08 2002-04-09 アボット・ラボラトリーズ 共溶媒処方物
AU768785B2 (en) * 1999-04-13 2004-01-08 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) Solubilized pharmaceutical composition for parenteral administration
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JP2006502185A (ja) * 2002-09-18 2006-01-19 ボーン ケア インターナショナル インコーポレイテッド 親油性の薬剤のための組成物
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