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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

• the present invention refers to pharmaceutical compositions in powder form consisting of active substances loaded on cross-linked polymers prepared with the technology of the supercritical fluids.
• the properties of the supercritical fluids may be exploited in the processing of the materials allowing, for example, the production of powders having controlled granulometry (J. W. Tom, P. G. Debenedetti, J. Aerosol. Sci., 22, 555, 1991 ).
• the present invention refers to pharmaceutical compositions in powder form prepared by loading drugs solubilized in supercritical fluids on cross-linked polymers.
• compositions are prepared by: 1 ) solubilization of the drug in a supercritical fluid; 2 ⁇ contacting the supercritical fluid containing the solubilized drug with the cross- linked polymer;
• the fluid consisting of a pure component or mixture, by a pump is taken to the desired pressure conditions. It is sent to a first container and from this one it is passed through a heat exchanger in order to take it to temperature and pressure conditions higher than those at which it can be considered as supercritical.
• carbon dioxide CO 2
• ethylene higher than 9°C and 54.4 bar
• carbon dioxide (CO 2 ) mixed with methanol (7%) it is taken to conditions above 40°C and 80 bar.
• the supercritical fluid is then passed through an extractor containing the drug.
• the supercritical fluid stream consisting of a pure component or mixture, containing certain amount of drug which solubilized at the temperature and pressure conditions fixed in advance, is contacted in a reactor practically set to the same operative conditions, with the polymer, according to a static or a dynamic process.
• a predeterminate volume of the supercritical fluid with the solubilized drug is introduced in an adequate container and left to equilibrate with an adequate quantity of polymer, for a contact time in the range between 5 minutes and 72 hours, preferably between 0.25 hours and 24 hours; this equilibration loading step can be repeated if necessary more times.
• the stream of the supercritical fluid generated by the pump, at the outlet of the extractor is passed through a column, of predetermined size and length, containing the polymer, for a contact time between 5 minutes and 72 hours, preferably between 0.25 hours and 24 hours.
• Said process embodiments, static and dynamic can be combined; for example after passing dynamically a given volume of supercritical fluid with the solubilized drug through a column of predetermined sizes, the stream is stopped, the supercritical fluid is left in static contact with the polymer for a predetermined time and subsequently the stream of the supercritical fluid is passed again through the column.
• the loading of the drug occurs essentially through the effect of the partitioning of the drug itself between the supercritical fluid and the polymer.
• This stage of the operation may be if necessary aided by acting on other factors assisting the release of the drug from the supercritical fluid.
• the fluid stream is passed through an absorber containing activated carbon or other material suitable to remove from the stream itself any trace of the, in case residual, drug.
• the fluid stream may then be brought back to the ambient conditions and drained or if necessary cooled, sent to a reflux receiver and from this one by the pump to the extractor.
• the polymers according to the present invention are cross-linked hydrophilic and hydrophobic polymers.
• cross-linked polymers we can mention, as an however not exhaustive exemplification: the cross-linked polyvinyl pyrrolidone, the cross-linked sodium carboxymethyl cellulose and cross-linked sodium starch glycolate, among the hydrophilic ones; the cross-linked polystyrene, the cross- linked acrylic acid and the sodium salt of cross-linked polymethyl methacrylate among the hydrophobic ones.
• Analgesics and non steroidal antiinflammatories and their salts sodium diclofenac, ibuprofen, naproxen, etc.; antibactericals: amoxicillin, cephalosporins, etc.; antifungals and antipsoriatics: ketoconazole, griseofulvin, itraconazole, thioconazole, etc.; antivirals: acyclovir, gancyclovir, etc.; antineoplastics and immunosuppressives: ciclosporin, etoposide, taxole and derivatives, etc.; anxiolytics, sedatives, hypnotics: lorazepam, oxazepam, temazepam, etc.; sexual hormones: medroxyprogesterone acetate, testosterone, estradiol, progesterone, etc.; peptidic molecules having different activity: LH-RH analogues, calcitonins, glutathione.;
• compositions according to the present invention contain from 0.1 to 99.9% and preferably from 0.1 to 50% by weight of the active principle with respect to the polymer.
• the compositions are formulated as packets or as tables, perles pellets or granules for pharmaceutical use.
• Examples No. 3-6 15 grams of polymeric materials (respectively physically cross-linked polyvinyl pyrrolidone, chemically cross-linked polyvinyl pyrrolidone, cross-linked sodium starch glycolate and acrylic acid cross-linked with allilic esters of sucrose) are put into a 200 ml reactor and contacted with CO2 saturated with the drug.
• the reactor is washed first with CO2 and then a stream of CO2 saturated with different drugs (nimesulide, ketoprofen, piroxicam, cimetidine respectively) is introduced at 160 bar and 60 °C.
• drugs nimesulide, ketoprofen, piroxicam, cimetidine respectively
• the concentrations of drug in the polymers are 22.2; 25.6; 15.3; and 20.4% respectively.

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• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Epidemiology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

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• 1997
  • 1997-11-19 IT IT97MI002571A patent/IT1296464B1/it active IP Right Grant
• 1998
  • 1998-11-16 KR KR1020007005454A patent/KR20010032251A/ko not_active Application Discontinuation
  • 1998-11-16 BR BR9814656-4A patent/BR9814656A/pt not_active IP Right Cessation
  • 1998-11-16 AU AU21531/99A patent/AU738748B2/en not_active Ceased
  • 1998-11-16 EP EP98965674A patent/EP1033977A2/en not_active Withdrawn
  • 1998-11-16 JP JP2000520756A patent/JP2001522873A/ja active Pending
  • 1998-11-16 NZ NZ505290A patent/NZ505290A/xx unknown
  • 1998-11-16 WO PCT/EP1998/007311 patent/WO1999025322A2/en not_active Application Discontinuation
  • 1998-11-16 CA CA002310423A patent/CA2310423A1/en not_active Abandoned

Non-Patent Citations (1)

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