WO2002089768A1 - Liquid injectable formulation of disodium pamidronate - Google Patents
Liquid injectable formulation of disodium pamidronate Download PDFInfo
- Publication number
- WO2002089768A1 WO2002089768A1 PCT/CA2001/001617 CA0101617W WO02089768A1 WO 2002089768 A1 WO2002089768 A1 WO 2002089768A1 CA 0101617 W CA0101617 W CA 0101617W WO 02089768 A1 WO02089768 A1 WO 02089768A1
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- WIPO (PCT)
- Prior art keywords
- solution
- process according
- group
- pamidronate
- physiologically acceptable
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Classifications
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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
- A61K9/0012—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
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
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- 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
- A61K47/02—Inorganic compounds
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
- A61K9/08—Solutions
Definitions
- the present invention relates to an improved injectable ready to use preparation of pamidronate salts of the formula given by
- 3-amino-l-hydroxypropane-l,l-diphosphonate disodium, the disodium salt of pamidronic acid is a well-known compound useful as a bone resorption inhibitor.
- pamidronate pamidronate disodium or disodium pamidronate
- the compound is part of the therapeutic class of compounds called bisphosphonates.
- Bisphosphonates used as inhibitors of bone resorption all contain two phosphonate groups attached to a single carbon atom, forming a "P- C-P" structure.
- the bisphosphonates are therefore stable analogues of naturally occurring pyrophosphate-containing compounds, which now helps to explain their intracellular as well as their extracellular modes of action.
- bisphosphonates inhibit bone resorption by being selectively taken up and adsorbing to mineral surfaces in bone, where they interfere with the action of osteoclasts. It is likely that bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes and induce apoptosis.
- bisphosphonates including etidronate, clodronate, pamidronate, alendronate, and risedronate are established as effective treatments in clinical disorders such as Paget's disease of bone, hypercalceamia of a malignancy, and bone metastases. Bisphosphonates are also now well established as successful antiresorptive agents for the prevention and treatment of osteoporosis. Additional indications include the reduction of bone pain associated with certain illnesses and to treat bone loss due to breast cancer.
- U.S. Patents 4,71 1,880 and 4,639,338 to Stahl et al. disclose the preparation of the crystalline pentahydrate form of disodium pamidronate from pamidronic acid.
- a heated aqueous suspension of pamidronic acid is partially neutralized with aqueous sodium hydroxide (NaOH) to pH 7 to 7.5. Crystallization is then initiated and the disodium pamidronate is collected by filtration.
- the pentahydrate comprises about 24.1 to 25% water and the product is stable to storage under approximately normal ambient conditions.
- the commercially available formulation, AREDIATM contains the lyophilized form of pamidronate disodium pentahydrate
- disodium pamidronate converts to the pentahydrate depending upon humidity and amount of water present (Stahl et al.) resulting in varying compositions of hydrates. Accordingly, it is difficult to use preformed disodium salts of pamidronic acid (such as anhydrous or partially hydrated forms other than pentahydrate) for further processing into sterile pharmaceuticals due to the interconversion of other crystalline forms of disodium pamidronate.
- pamidronic acid such as anhydrous or partially hydrated forms other than pentahydrate
- pamidronate is usually administered intravenously, due to the poor absorption from the gastrointestinal system.
- Pamidronate is supplied commercially as a lyophilized powder that must be reconstituted with a pharmaceutically acceptable solvent before administration to a patient.
- a lyophilized formulation problems associated with a lyophilized formulation include a risk of microbial contamination during reconstitution and an inability to terminally sterilize the drug product. Double handling of the drug is required, as the lyophilized drug is first required to be reconstituted and then administered. Additionally, time is needed to dissolve the powder and prolonged shaking may be required.
- Pamidronate in a liquid formulation has been shown to be unstable/reactive during long-term storage (Canadian patent application 2,141 ,964). In addition, current guidelines for storage of reconstituted solutions state that the solution should not be kept for more than 24 hours.
- Another liquid formulation of disodium pamidronate is disclosed in U.S. 6,160,165 to Shinal.
- This formulation is prepared by making a stirred slurry of pamidronic acid in water (pamidronic acid is not soluble in water); adding an aqueous solution of sodium hydroxide to the slurry in an about 2:1 molar ratio of sodium hydroxide to pamidronic acid to yield a solution having visual clarity.
- the solution is packaged in a sealed container to yield a liquid dosage form of pamidronate. No data is given on its stability. No information is provided on sterilization of the solution to yield a pharmaceutically acceptable product.
- the patent further discloses a lyophilized form of pamidronate, made by the steps above, filtering the solution and freezing and lyophilizing the filtered solution to yield amorphous, essentially anhydrous disodium pamidronate.
- This process has the disadvantage of a number of manufacturing steps. Additionally, the liquid composition cannot be stored for long periods of time as reaction of the pamidronate with polyvalent cations will occur when stored in glass vials.
- the pharmaceutically acceptable water soluble alkaline salt is the disodium salt.
- an injectable, sterile, ready to use, pyrogen-free pamidronate solution comprising a physiologically acceptable water soluble alkaline salt and a physiologically acceptable aqueous solvent having a concentration of between 0.1 and 100 mg/mL which has not been reconstituted from a lyophilizate wherein the solution is provided in a sealed non-reactive container.
- a prbcess for producing a sterile, injectable, pyrogen-free, ready-to-use pamidronate solution comprising (1) adding pamidronic acid to an aqueous solvent wherein the aqueous solvent contains sodium hydroxide, potassium hydroxide, or water soluble organic amines and (2) sterilizing the solution.
- sodium hydroxide is mixed with pamidronic acid in a 2 to 1 molar ratio in an aqueous solvent to make pamidronate disodium.
- the solution is stored in plastic vials, with non-reactive stoppers such as TeflonTM coated/faced stoppers.
- the invention provides for use of the solution to treat diseases selected from the group of tumour-induced hypercalcemia, Paget's disease, osteoporosis, bone metastases, and breast cancer.
- Any physiologically acceptable alkaline salt that is water-soluble may be used for preparing the solution of the invention.
- Preferred salts are sodium and potassium.
- the disodium salt is the most preferred salt.
- aqueous sodium hydroxide is added to a non-reactive mixing tank such as a polypropylene tank.
- Pamidronic acid is mixed with sodium hydroxide, in a 1 :2 molar ratio, in an aqueous environment.
- Any aqueous solvent that is physiologically acceptable in which pamidronate remains soluble may be used.
- the solution of the invention may also contain one or more additional components such as a preservative, a co-solublizing agent, or any other desired agent. Suitable solvents include those that have acceptable paniculate counts, such as water, or physiological saline.
- Tonicity adjustment agents in an amount that does not cause precipitation may be added, such as sodium chloride, dextrose,,lactose, mannitol and the like.
- preservatives suitable for a physiological administration such as hydroxybenzoic acid esters, chlorobutanol and benzyl alcohol may be added.
- pH adjustment is not necessary for stability purposes, optionally, the pH may be adjusted within the range of from 6 to 10 using any known method of pH adjustment.
- the concentration of the solution may be anywhere from 0.1 mg/mL to
- Non-reactive when used herein means that the packaging material must not contain multivalent metal cations that can react with the pamidronate entity.
- the preferred packaging material is plastic such as polypropylene, polyolefin, cycloolefin, polycarbonate, ABS resin, polyethylene, or PVC.
- the containers are vials with non-reactive stoppers.
- Preferred stoppers are TeflonTM coated/faced. Silicone rubber stoppers or other non- reactive stoppers are contemplated.
- non-reactive intravenous bags and non-reactive ampoules, such as zirconium ampoules or form seal ampoules.
- Sterility of the product may be assured through making the product in aseptic conditions, or other methods for sterilization may be used.
- An advantage of the present invention is the ability to use terminal sterilization processes such as autoclavmg.
- Terminal sterilization when used herein, means steam sterilization by autoclaving using a using a process validated to deliver a minimum end of exposure Fo of 8 minutes and a maximum Fo of 15 minutes.
- the solution may be autoclaved according to methods known in the art. Alternatively, the solution may be passed through a sterilizing filter, such as a 0.22 micron Supor DCF capsule.
- solutions of the invention are characterized by good stability. Solutions have been found to be stable for long periods at room temperature. This is illustrated in the examples which follow.
- compositions of the present invention are useful for treating any bone resorption disorders or conditions. Examples of these indications are tumor-induced hypercalcemia, conditions associated with increased osteoclast activity, predominantly lytic bone metastases and multiple myeloma as well as symptomatic Paget's disease of bone.
- the composition of the present invention is designed to be diluted and administered as a slow intravenous infusion.
- the injectable solutions of the invention are administered according to a variety of possible dose schedules. Suitable dose schedules are for example 90 mg as a 2 hour infusion in 250 ml infusion solution or a maximum of 90 mg in 500 ml over 4 hours for patients with multiple myeloma or tumor induced hypercalcemia.
- the total dose for a treatment course may be given as a single infusion, or in multiple infusions spread over 2-4 consecutive days.
- the maximum dose should be 90 mg.
- the recommended total dose of pamidronate disodium injection for a treatment _ course for Paget's disease of the bone is 180-210 mg either administered as 6 doses of 30 mg once a week or 3 doses of 60 mg every second week following initiation with a 30 mg dose.
- Water for injection USP was collected in a clean, non-reacting polypropylene mixing tank at room temperature. Sodium hydroxide NF was added to the water and mixed thoroughly until completely dissolved. Pamidronic acid was then added and mixed until completely dissolved. Mannitol USP was then added and completely dissolved. The pH was then adjusted to between 6.4 and 6.6 with 10% phosphoric acid. Water for injection USP was added to the final required volume.
- the solution was filtered through a sterilizing 0.22 micron Supor-DCF filter. Volumes of 10 ml of the solution were distributed into plastic vials. The vials were then closed with TeflonTM-faced coated rubber stoppers and sealed, and steam sterilized by autoclaving using a using a process validated to deliver a minimum end of exposure Fo of 8 minutes and a maximum Fo of 15 minutes.
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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CA2,347,330 | 2001-05-10 | ||
CA002347330A CA2347330C (en) | 2001-05-10 | 2001-05-10 | Liquid injectable formulation of disodium pamidronate |
Publications (1)
Publication Number | Publication Date |
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WO2002089768A1 true WO2002089768A1 (en) | 2002-11-14 |
Family
ID=4169021
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/CA2001/001617 WO2002089768A1 (en) | 2001-05-10 | 2001-11-15 | Liquid injectable formulation of disodium pamidronate |
Country Status (3)
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US (2) | US20040147486A1 (en) |
CA (2) | CA2372450A1 (en) |
WO (1) | WO2002089768A1 (en) |
Cited By (1)
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WO2005025551A3 (en) * | 2003-09-18 | 2006-01-12 | Novartis Ag | Pharmaceutical products comprising bisphosphonates |
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JP5243789B2 (en) * | 2004-03-15 | 2013-07-24 | シティ・オブ・ホープ | Methods and compositions for specific inhibition of gene expression by double stranded RNA |
US8071574B2 (en) * | 2005-02-22 | 2011-12-06 | John Dennis Bobyn | Implant improving local bone formation |
WO2006100687A1 (en) * | 2005-03-24 | 2006-09-28 | Dabur Pharma Ltd. | Disodium pamidronate aqueous formulation |
US20070166187A1 (en) * | 2006-01-18 | 2007-07-19 | Song Jing F | Stabilization of paricalcitol using chlorobutyl or chlorinated butyl stoppers |
WO2013171763A1 (en) * | 2012-04-27 | 2013-11-21 | Sun Pharmaceutical Industries Ltd | Ready to be infused gemcitabine solution |
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2001
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- 2001-11-15 WO PCT/CA2001/001617 patent/WO2002089768A1/en not_active Application Discontinuation
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2003
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2005
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005025551A3 (en) * | 2003-09-18 | 2006-01-12 | Novartis Ag | Pharmaceutical products comprising bisphosphonates |
JP2007505861A (en) * | 2003-09-18 | 2007-03-15 | ノバルティス アクチエンゲゼルシャフト | Pharmaceutical products containing bisphosphonates |
AU2004271731B2 (en) * | 2003-09-18 | 2008-07-24 | Novartis Ag | Pharmaceutical products comprising bisphosphonates |
KR101015718B1 (en) * | 2003-09-18 | 2011-02-22 | 노파르티스 아게 | Pharmaceutical products comprising bisphosphonates |
US7932241B2 (en) | 2003-09-18 | 2011-04-26 | Novartis Ag | Pharmaceutical products comprising bisphosphonates |
JP4802096B2 (en) * | 2003-09-18 | 2011-10-26 | ノバルティス アーゲー | Pharmaceutical products containing bisphosphonates |
Also Published As
Publication number | Publication date |
---|---|
US20040147486A1 (en) | 2004-07-29 |
US20050182030A1 (en) | 2005-08-18 |
CA2347330C (en) | 2002-03-12 |
CA2347330A1 (en) | 2001-09-19 |
CA2372450A1 (en) | 2001-09-19 |
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