WO2000064516A1 - Administration regulee de bisphosphonates - Google Patents

Administration regulee de bisphosphonates Download PDF

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Publication number
WO2000064516A1
WO2000064516A1 PCT/US2000/010696 US0010696W WO0064516A1 WO 2000064516 A1 WO2000064516 A1 WO 2000064516A1 US 0010696 W US0010696 W US 0010696W WO 0064516 A1 WO0064516 A1 WO 0064516A1
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WO
WIPO (PCT)
Prior art keywords
drug delivery
bisphosphonates
delivery device
bisphosphonate
drug
Prior art date
Application number
PCT/US2000/010696
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English (en)
Inventor
Petr Kuzma
Agis Kydonieus
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Hydromed Sciences A Division Of Gp Strategies Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hydromed Sciences A Division Of Gp Strategies Corporation filed Critical Hydromed Sciences A Division Of Gp Strategies Corporation
Priority to AU46521/00A priority Critical patent/AU4652100A/en
Priority to CA002370769A priority patent/CA2370769A1/fr
Priority to EP00928260A priority patent/EP1210138A4/fr
Publication of WO2000064516A1 publication Critical patent/WO2000064516A1/fr

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Classifications

    • 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
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes

Definitions

  • This invention relates generally to the controlled delivery of drugs and more specifically to the delivery of drugs from long term polymeric implanted devices.
  • Bisphosphonates are chemical compounds that have C-P bonds, especially P-
  • Some bisphosphonates that have been commercialized include: alendronate, clodronate, pamidronate and etidronate. Others such as cimadronate, ibandronate, neridronate, olpadronate, tiludronate, risedronate, and zoledronate are in different stages of pharmaceutical development. Due to the affinity that bisphosphonates exhibit in binding to bone, they have been used to treat bone diseases such as osteoporosis, Paget's disease, hypercalcemia and bone cancer. Osteoporosis is a disease where reduction in bone mass takes place and specifically when that bone mass is 2.5 standard deviations less than that of young adults. This bone-brittling disease affects 20 million Americans, with only about 2 million currently being treated.
  • Bisphosphonates have been used to treat both post-menopausal osteoporosis as well as corticosteroid-induced osteoporosis and have been shown to increase both the mineral density, as well as the mechanical strength of bone.
  • the lumbar spine density of patients with osteoporosis was increased by 7% over a two year period when patients were treated with 150 mg pamidronate orally, while the lumbar spine density of the placebo group decreased by 1 % over the baseline [L. Reid, et al., J. Clin. Endocrinol. Metab.. 1__ : 1595 (1994)].
  • Etidronate has also been used to treat calcification, i.e, deposition of calcium phosphate in areas that are not normally calcified (soft tissue).
  • Bisphosphonates therefore may have use in the prevention of kidney stones, dental calculi, ectopic bone formation and calcification of heart valves.
  • Other applications for bisphosphonates include treatment for Paget's disease (localized foci of increased bone turnover), osteolytic tumor bone diseases and non-tumor induced hypercalcemia.
  • the oral dose bioavailability of bisphosphonates in animals as well as humans is low, between 1% and 10% [H. Fleisch., Bisphosphonates in Bone Disease, The Parthenon Publishing Group, New York, p.57 (1995)].
  • Bisphosphonates can also cause esophageal irritation to the upper gastrointestinal mucosa. Esophageal adverse reactions such as esophagitis, esophageal ulcers, and esophageal erosions with bleeding have been reported in patients receiving treatment with Fosamax [Fosamax package insert]. With Fosamax, rare events of gastric and duodenal ulcers, some severe and with complications, have also been reported. Additionally, oral bisphosphonates have been known to produce other gastrointestinal side effects such as nausea, dyspepsia, vomiting, gastric pain and diarrhea.
  • the dosage required to decrease bone abso ⁇ tion is similar to the dose causing inhibition of bone calcification or mineralization. This can cause osteomalacia, where the amount of bone is normal but the percent of mineral is reduced causing softening of the bones, which then allows bones to also fracture. Osteomalacia is distinct from osteoporosis, because in osteoporosis the amount of bone is decreased but the percent mineral is normal.
  • bisphosphonates When large doses of bisphosphonates are delivered (i.v. delivery) they can form metal aggregates which deposit on non-calcified tissues and can cause renal failure and hypocalcemia. In patients with renal insufficiency, bisphosphonates are contraindicated because bone abso ⁇ tion can increase in a non-predictable fashion.
  • the present invention provides a drug delivery device useful in a method for controlled delivery of bisphosphonates to a patient over an extended time period.
  • This method provides a pharmaceutically effective amount of bisphosphonates, while avoiding metal aggregation sometimes associated with prior art intravenous administration of bisphosphonates and the undesirable gastrointestinal side effects associated with oral delivery.
  • the present invention provides an implantable drug delivery device containing bisphosphonate.
  • the device delivers at least one bisphosphonate at a daily dose that is less than 50% of its oral dose for an extended period of time, e.g., three to twelve months.
  • the device is a hydrogel polymer material and the bisphosphonate is alendronate.
  • the present invention provides a method of delivering bisphosphonate to a patient.
  • This method involves implanting the patient with a drug delivery device as described herein.
  • the bisphosphonates are released at zero or near zero order kinetics and the drug delivery device is a biodegradable polymer.
  • the invention provides a device useful in a method for treating veterinary and human patients with bone diseases by delivering bisphosphonates.
  • This device is particularly well suited to treatment of such chronic illnesses as osteoporosis and Paget's disease, avoids the gastrointestinal problems associated with oral medications containing bisphosphonates and provides a continuous low dosage which avoids metal aggregate formation, renal failure and hypocalcemia.
  • the reduction in dosage provided by the use of the present invention is also effective in eliminating the problems associated with inhibition of bone mineralization.
  • the present invention pertains to the parenteral delivery of low amounts of bisphosphonates in a continuous, slow and controlled administration.
  • the present invention pertains to an implantable device which delivers over an extended period of time from three months to one year, a bisphosphonate at a daily dose which is from 0.5% to 50%, and preferably 0.5% to 25%, and most preferably, 0.5% to 10%, of current oral doses of these compounds.
  • bisphosphonate for use in the device and method of the invention.
  • Such bisphosphonates may be produced using conventional methods or may be purchased commercially.
  • alendronate ((4-amino-l-hydroxybutylidene)-bis-phosphonate) is commercially available from Gentili and Merck Sha ⁇ & Dohme.
  • a suitable daily oral of alendronate dose for a human or non-human animal of about 80 kg (hereinafter adult) is in the range of 20 to 40 mg.
  • Cimadronate [(cycloheptylamino)- methylene]bis-phosphonate) is available from Yamanouchi.
  • Clodronate ((dichloromethylene)-bis-phosphonate) is available from Astra and Boehringer Mannheim, among others, and is typically administered in an amount of 400 to 1660 mg/daily adult oral dose.
  • EB-1053 [l-hydroxy-3-(l-pyrrolidinyl)-propylidene]bis- phosphonate is available from Leo.
  • Etidronate, (l-Hydroxyethylidene)-bis- phosphonate is available from Procter & Gamble and Gentili and is typically administered at 400 to 800 mg/ daily adult oral dose.
  • Ibandronate [l-Hydroxy-3- (methylpentylamino)propylidene]bis-phosphonate is available from Boehringer Mannheim. Neridronate, (6-Amino-l-hydroxyhexylidene)bis-phosphonate, is available from Gentili. Olpadronate, [3-(Dimethylamino)-l- hydroxypropylidene]bis-phosphonate, is available from Gador and is typically administered at 200 mg/daily adult oral dose. Pamidronate, (3-Amino-l- hydroxypropylidene)bis-phosphonate, is available from Ciba-Geigy and Gador and is typically administered at a daily adult oral dose of 250 to 300 mg.
  • the device and method of the invention are particularly well suited to extended delivery of bisphosphonates at a level which is lower than the oral dose.
  • doses of the bisphosphonate or combinations thereof, selected for delivery can readily be selected by one of skill in the art.
  • the doses are 0.5% to 50%, preferably, 0.5% to 25%, and most preferably 0.5% to 10%, of the oral doses identified above.
  • the dose may be adjusted as needed, depending upon a number of factors, including the age, weight, and condition of the veterinary or human patient. For example, doses in the range of 1% to 5% of oral doses, or other alternative doses, may be desirable.
  • the doses delivered by the method of the invention are also lower than current intravenous doses of bisphosphonate.
  • the delivery devices may contain more than one bisphosphonate and/or may contain additional ingredients.
  • a bisphosphonate in combination with a vitamin compound (e.g., Vitamin D and analogs thereof), calcium, an anti-inflammatory agent (including, but not limited to corticosteroids), prostaglandin inhibitors, calcitonin, or another active agent.
  • a vitamin compound e.g., Vitamin D and analogs thereof
  • an anti-inflammatory agent including, but not limited to corticosteroids
  • prostaglandin inhibitors including, but not limited to corticosteroids
  • calcitonin calcitonin
  • the novel drug delivery device of the invention is designed for implantation into the body of the animal to which the bisphosphonate formulation is to be delivered.
  • the drug delivery devices of the invention are desirably implants containing bisphosphonate in a reservoir, optionally together with another active agent and/or a pharmaceutically acceptable carrier.
  • Such reservoir devices may be composed of hydrophobic or hydrophilic polymers, co-monomers, metals, or other suitable materials.
  • the drug delivery devices may be hydrogels, or other polymeric or co-monomer materials, made up of a matrix having the bisphosphonates and any other optional active agents or carriers interspersed throughout.
  • the bisphosphonates are dispersed homogeneously throughout the matrix.
  • suitable implants are known to those of skill in the art and may be readily selected.
  • novel implant drug delivery devices of the invention are highly useful in the delayed/sustained and the immediate/sustained release of bisphosphonates to animals, e.g., humans, sheep, dogs, cats, turkeys, cattle, etc.
  • "Delayed/sustained release” is defined as delaying the release of an active agent until after placement in a delivery environment, followed by a sustained, preferably zero-order, release of the agent at a later time.
  • this type of release is preferably achieved using a hydrogel delivery device, which may be implanted in a dry or partially hydrated state.
  • the release of an active agent may be delayed for several weeks.
  • Immediate/sustained release is defined as the commencement of the release of bisphosphonate or other active agent immediately or soon thereafter after placement in a delivery environment, followed by sustained release of the active agent.
  • the bisphosphonates will be present in the delayed/sustained release compositions in varying amounts, depending upon the effect desired.
  • the amount of bisphosphonates and any other agents employed in the drug delivery devices of the invention will depend not only on the desired daily dose but also on the number of days that dose level is to be maintained. While this amount can be calculated empirically, the actual dose delivered is also a function of any interaction with materials and the carrier, if employed in the device.
  • the drug delivery device may contain a pharmaceutically acceptable carrier which may be in the form of suspending media, solvents, aqueous systems, and solid substrates or matrices. These carriers are known to those of skill in the art and are not intended to be a limitation on the present invention.
  • suspending media and solvents useful as the carrier include, for example, oils such as silicone oil (particularly medical grade), corn oil, castor oil, peanut oil and sesame oil; condensation products of castor oil and ethylene oxide combining about 30 to 35 moles of ethylene oxide per mole of castor oil; liquid glyceryl triesters of a lower molecular weight fatty acid; lower alkanols; glycols; polyalkylene glycols.
  • oils such as silicone oil (particularly medical grade), corn oil, castor oil, peanut oil and sesame oil; condensation products of castor oil and ethylene oxide combining about 30 to 35 moles of ethylene oxide per mole of castor oil; liquid glyceryl triesters of a lower molecular weight fatty acid; lower alkanols; glycols; polyalkylene glycols.
  • the aqueous systems include, for example, sterile water, saline, dextrose, dextrose in water or saline, and the like. The presence of
  • the solid substrates or matrices include, for example starch, gelatin, sugars (e.g. glucose), natural gums (e.g. acacia, sodium alginate, carboxymethyl cellulose), and the like.
  • the carrier may also contain adjuvants such as preserving, stabilizing, wetting and emulsifying agents, and the like.
  • hydrogels are suited as implantable delivery vehicles for use in delivery of bisphosphonates according to the present invention.
  • One particularly desirable hydrogel is prepared by mixing about 60 weight percent to about 95 weight percent comonomers, at least one of which is hydrophilic, and sufficient amounts of a crosslinker and a liquid diffusion enhancer which is miscible with the comonomers, to yield a homogenous copolymer hydrogel having the equilibrium water content (EWC) value in the range from about 20% to about 85%.
  • EWC equilibrium water content
  • the polymerizable liquid mixture contains about 1 weight percent to about 50 weight percent diffusion enhancer which may be readily selected from among C1-C4 alkyl alcohol, allyl alcohol, tetrahydrofuryl alcohol, cyclohexyl alcohol, diethylene glycol, polyethylene glycols, glycerol, acetone, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, glyceryl isopropylidene ether dioxane, tetrahydrofuran; ethyl acetate; dimethyl sulfoxide; water, and mixtures thereof.
  • the crosslinker and comonomers may be readily selected by one of skill in the art.
  • hydrogel as well as details on its preparation, are provided in preferred hydrogel is described in co-pending International Patent Application Number PCT/US00/01664, filed January 26, 2000 for "HYDROGEL COMPOSITIONS USEFUL FOR THE SUSTAINED RELEASE OF MACROMOLECULES AND METHODS OF MAKING SAME".
  • Other suitable hydrogels may be readily selected by one of skill in the art. See, e.g., US 5,266,325; US 4,959,217; and US 5,292,515.
  • the hydrating liquid useful in the hydrogels used in the invention is typically a liquid simulating the environment in which the active compound will be released, e.g., body fluid, sterile water, tear fluid, physiological saline solution, phosphate buffer solution, and the like. While liquids other than water are useful as the hydrating liquid, the degree to which a hydrophilic membrane is hydrated is referred to as its "water content".
  • the implants may be in the form of an osmotic pump, such as described by Alza [see, e.g., U. S. Patent No. 4,285,987 and U. S. Patent No. 5,273,752] or Merck [see, e.g., European Patent No. 314,206], among others.
  • the implant device may be composed of a hydrophobic membrane material, such as ethylenemethacrylate (EMA) and ethylenevinylacetate (EVA).
  • EMA ethylenemethacrylate
  • EVA ethylenevinylacetate
  • Other suitable implant delivery devices include bioresorbable polymer systems [see, e.g., International Patent Application No. WO98/44964, Bioxid and Cellomeda; U. S. Patent No. 5,756,127 and U. S. Patent No. 5,854,382].
  • Suitable bioresorbable implant devices have been described in the literature and may be composed of, for example, polyesters, polyanhydrides, or lactic acid/glycolic acid copolymers [see, e.g., U. S. Patent No. 5,817,343 (Alkermes Inc.)].
  • the devices useful in the invention(s) provide sustained release of bisphosphonates over extended periods of time.
  • This time period may range from a month to a year or several years, depending on the desired administration regimen.
  • the bisphosphonates will be released in daily doses, over a period of about 1 week or longer, and preferably over a period of about three months to one year, it being understood that this time factor is a variable depending on the rate-releasing membrane of choice, its interconnecting pore structure, the bisphosphonates of choice, the solubility of the active compound(s) in the liquid medium, and other considerations well known to those skilled in the art.
  • the delivery device is composed of a hydrogel
  • it may be prepared such that the hydrogel forms the walls of a cavity which contain the active agent.
  • the void in the core is thereafter sealed to prevent leakage into or out of the vesicle.
  • this can be accomplished by introducing sufficient polymerizable material into the void to cover the layer of inert material or to substantially or completely fill the void and thereafter effecting a polymerization reaction to form a plug of water-swellable, water-insoluble polymer which seals the opening of the vesicle.
  • the hydrophilic polymer plug upon maximum hydration, will have an equilibrium water content value of the hydrophilic vesicle.
  • polymerizable material comprising ethylenically unsaturated monomer(s) and desirably crosslinking agent(s)
  • a polymer plug grafted to the inner surface of the vesicle can be obtained.
  • hydrophilic cartridges are prepared by the rotational casting of polymerizable material in a tubular mold, as described in US Patent 5,266,325 and 5,292,515, which are inco ⁇ orated herein by reference.
  • the internal radius of the tube is approximately 1.2 to 1.3 mm, and may be larger.
  • the tube is rotated about its longitudinal axis which is maintained parallel to the ground. Rotational speeds are of the order of 2150 ⁇ m, though greater or lesser speeds could be used, e.g., 1000 ⁇ m or less to 3000 ⁇ m and more.
  • the tubes are fabricated of polyethylene, polypropylene, glass, or other suitable materials. When the polymerizable mixture within the spinning tube stabilizes to the predetermined shape, UN. light at a distance of less than one foot is then directed at the spinning tube for several minutes, e.g., about 7 minutes, to polymerize the mixture to the shaped product. The shaped product is cured and annealed as follows: Thermal Cure: 60 minutes at 65° C; Postcure: 30 minutes at 95 °C; Annealing: 30 minutes at 115 °C with gradual cooling to about 25 °C.
  • the dimensions of the cartridges are as follows: internal radius 0.98 mm; external radius 1.3mm; length 25mm.
  • Smooth, unscored cylindrically-shaped objects of various lengths can also be prepared in accordance with the teachings herein.
  • Such objects in a hydrated state or plasticized with a non-toxic, biocompatible material, can be formed into desired shapes.
  • a ring shape for use as pessaries, surgical implants, etc.
  • Yet other drug delivery devices and implant shapes may be prepared using techniques known to those of skill in the art or purchased from commercial sources.
  • the invention provides a method of delivering bisphosphonates, alone or in combination with other active agents, to a veterinary or human patient in need thereof.
  • a veterinary or human patient in need thereof.
  • a patient has a bone disease or condition such as osteoporosis, Paget's disease, hypercalcemia or bone cancer.
  • a delivery device as described herein can be implanted subcutaneous ly in an animal by perforation.
  • Such devices are characterized by a length of 10 to 50 mm, or less (e.g., 6 to 9 mm), an external diameter of 2 to 5 mm, or less (e.g., 1.5 to 1.9 mm).
  • the dimensions of the device e.g., a cartridge
  • Animals such as sheep, cows, goats, cattle, and large animals, in general, can tolerate implantation by perforation of larger dimensional drug delivery devices. Implantation can be effected by other means, e.g., open surgery.
  • the drug delivery device is a biodegradable matrix, which is bioresorbed and eliminated from the body following completion of the course of therapy, e.g., three to twelve months, or more.
  • a selected delivery device may be removed by surgical means.
  • treatment of bone conditions using the drug delivery devices of the invention may be readily combined with other therapies administered by routes other through the use of an implantable devices.
  • treatment with bisphosphonates according to the invention may be combined with other treatments or therapies, including, for example, calcium supplements, radiation, chemotherapy.
  • An implant cartridge was prepared essentially as described in US 5,266,325. More particularly, the mixture was deoxygenated by bubbling nitrogen through it for 10 minutes. To avoid premature polymerization the mixture was shielded from light. One end of a polypropylene tube (65 mm in length and d, of 2.5 mm) was plugged with a silicone sealant; the other end of the tube was sealed with a plug made by injecting a small amount of the above mixture, which was cured under a UV lamp for 5 minutes.
  • the silicone plug was punctured and the tube was filled with the mixture to a height of about 10 mm from the top.
  • the tube was inserted in a spin casting apparatus and spun (spinning axis parallel to the ground) at about 2200 ⁇ m.
  • the centrifugal force created by the spinning tube caused the radially outward displacement of the mixture to assume a predetermined hollow cylindrical liquid configuration (i.e., a hollow tube of polymerizable liquid mixture).
  • the spinning tube was then exposed to UV light for 7 minutes to polymerize the "liquid tube” to a solid hydrophilic tube (cartridge).
  • the cartridge within the polypropylene tube was postcured for 14 hours at 65 ° C, followed with an additional 40 minutes at 105° C, and annealed at 116° C for 40 minutes, and then slowly cooled to 22° C.
  • the cartridge was ejected from the tube, inspected for defects, and cut to a length of 30 mm. There was obtained a precisely dimensional plastic cartridge fabricated of crosslinked homogeneous polymers characterized by recurring hydrophilic units. The weight of the cartridge was recorded.
  • This cartridge is available for filling with alendronate sodium (4-amino-l- hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate, by tightly packing it to a 20 mm height.
  • the filled cartridge is weighed again to determine the weight of active agent bisphosphonates.
  • the empty space of the cartridge is filled with the aforesaid monomeric mixture.
  • Part of the cartridge containing the active agent is covered with aluminum foil.
  • the cartridge is then placed in the lathe and spun slowly (spinning axis of cartridge parallel to ground) under a UV lamp for 5 minutes to effect polymerization of the mixture. Postcuring of the polymer plug was effected by maintaining the cartridge at 50° C for 18 hours.
  • the end product is an implantable drug delivery device containing bisphosphonates.
  • the bisphosphonates used for evaluation of these devices were etidronic acid and pamidronic acid.
  • the solubility of etidronic acid is relatively high, therefore the delivery devices for this compound were prepared from lower % EWC polymers as shown in examples 1 and 2.
  • Pamidronic acid was used in examples 3, 4, 5 and 6.
  • In vitro release rates were evaluated by placing the implants in individual glass vials containing 10 ml of physiological saline. The vials and their contents were placed in a shaker waterbath maintained at 37 °C and agitated at 60 strokes/minute. The elution media were changed weekly, and assayed for their drug contents.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
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  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un procédé d'administration régulée de bisphosphonates dans le traitement de l'ostéoporose, la maladie de Paget et autres maladies osseuses. Ce procédé consiste à utiliser un dispositif implantable pour administrer des quantités efficaces, d'un point de vue pharmaceutique, de bisphosphonate, sans manifestation de nombreux effets secondaires associés à l'administration par voie orale.
PCT/US2000/010696 1999-04-22 2000-04-19 Administration regulee de bisphosphonates WO2000064516A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU46521/00A AU4652100A (en) 1999-04-22 2000-04-19 Controlled delivery of bisphosphonates
CA002370769A CA2370769A1 (fr) 1999-04-22 2000-04-19 Administration regulee de bisphosphonates
EP00928260A EP1210138A4 (fr) 1999-04-22 2000-04-19 Administration regulee de bisphosphonates

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US13072899P 1999-04-22 1999-04-22
US60/130,728 1999-04-22

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EP1129714A1 (fr) * 2000-01-12 2001-09-05 Ceva Sante Animale Utilisation de l'acide tiludronique et de ses dérivés chez la volaille pour la préparation d'un médicament destiné à prévenir et à traiter l'ostéoporose
WO2002062352A2 (fr) * 2001-02-07 2002-08-15 Durect Corporation Dispositifs et methodes de gestion de la densite osseuse
KR20020080018A (ko) * 2001-04-10 2002-10-23 한국화학연구원 비스포스포네이트 골 흡수억제제의 이식형 서방성제제
US6719998B1 (en) 1998-07-14 2004-04-13 Yissum Research Development Company Of The Hebrew University Of Jerusalem Treatment of restenosis
WO2005009496A1 (fr) * 2003-07-31 2005-02-03 Bioretec Oy Dispositif d'implant multifonctionnel
WO2005018699A1 (fr) * 2003-08-21 2005-03-03 Optovent Ab Dispositif de type implant recouvert de bisphosphonate et procede associe
US6984400B2 (en) 1998-07-14 2006-01-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Method of treating restenosis using bisphosphonate nanoparticles
US7008645B2 (en) 1998-07-14 2006-03-07 Yissum Research Development Company Of The Hebrew University Of Jerusalem Method of inhibiting restenosis using bisphosphonates
WO2010111627A1 (fr) * 2009-03-26 2010-09-30 Psivida Us, Inc. Formulations implantables d'acides bisphosphoniques
WO2011103307A1 (fr) * 2010-02-17 2011-08-25 Georgia Tech Research Corporation Compositions et procédés pour modifier la calcification in vivo d'hydrogels
US8372422B2 (en) 2000-11-14 2013-02-12 Nektar Therapeutics Hydroxyapatite-targeting poly(ethylene glycol) and related polymers
US8399023B2 (en) 2009-07-31 2013-03-19 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
WO2016003284A1 (fr) * 2014-07-04 2016-01-07 Osteo-Pharma B.V. Compositions et produits destinés à être utilisés dans le traitement de fractures et de défauts osseux
US9340565B2 (en) 2010-11-24 2016-05-17 Thar Pharmaceuticals, Inc. Crystalline forms
US9498488B2 (en) 2003-06-27 2016-11-22 Biorest Ltd. Method of treating acute coronary syndromes
US9993427B2 (en) 2013-03-14 2018-06-12 Biorest Ltd. Liposome formulation and manufacture
US10093691B2 (en) 2009-07-31 2018-10-09 Grunenthal Gmbh Crystallization method and bioavailability
US10195218B2 (en) 2016-05-31 2019-02-05 Grunenthal Gmbh Crystallization method and bioavailability
US20210205459A1 (en) * 2018-06-01 2021-07-08 The University Of North Carolina At Chapel Hill Injectable thermoresponsive hydrogels as a combinatory modality for controlled drug delivery, biomaterial implant and 3d printing bioink

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EP1129714A1 (fr) * 2000-01-12 2001-09-05 Ceva Sante Animale Utilisation de l'acide tiludronique et de ses dérivés chez la volaille pour la préparation d'un médicament destiné à prévenir et à traiter l'ostéoporose
US8784849B2 (en) 2000-11-14 2014-07-22 Nektar Therapeutics Hydroxyapatite-targeting poly(ethylene glycol) and related polymers
US8372422B2 (en) 2000-11-14 2013-02-12 Nektar Therapeutics Hydroxyapatite-targeting poly(ethylene glycol) and related polymers
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WO2002062352A2 (fr) * 2001-02-07 2002-08-15 Durect Corporation Dispositifs et methodes de gestion de la densite osseuse
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US10519176B2 (en) 2010-11-24 2019-12-31 Thar Pharma, Llc Crystalline forms
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US9993427B2 (en) 2013-03-14 2018-06-12 Biorest Ltd. Liposome formulation and manufacture
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US10265269B2 (en) 2013-03-14 2019-04-23 Biorest Ltd. Liposome formulation and manufacture
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WO2016003284A1 (fr) * 2014-07-04 2016-01-07 Osteo-Pharma B.V. Compositions et produits destinés à être utilisés dans le traitement de fractures et de défauts osseux
JP2020143096A (ja) * 2014-07-04 2020-09-10 オステオ−ファルマ・ベー・フェー 骨折及び骨欠損の治療において使用するための組成物及び製品
US11541063B2 (en) 2014-07-04 2023-01-03 Osteo-Pharma B.V. Compositions and products for use in the treatment of bone fractures and defects
JP2017522373A (ja) * 2014-07-04 2017-08-10 オステオ−ファルマ・ベー・フェー 骨折及び骨欠損の治療において使用するための組成物及び製品
US10195218B2 (en) 2016-05-31 2019-02-05 Grunenthal Gmbh Crystallization method and bioavailability
US20210205459A1 (en) * 2018-06-01 2021-07-08 The University Of North Carolina At Chapel Hill Injectable thermoresponsive hydrogels as a combinatory modality for controlled drug delivery, biomaterial implant and 3d printing bioink

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EP1210138A1 (fr) 2002-06-05
CA2370769A1 (fr) 2000-11-02
EP1210138A4 (fr) 2003-05-07
AU4652100A (en) 2000-11-10

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