EP1558215A1 - Sterile gelling agents - Google Patents
Sterile gelling agentsInfo
- Publication number
- EP1558215A1 EP1558215A1 EP03748442A EP03748442A EP1558215A1 EP 1558215 A1 EP1558215 A1 EP 1558215A1 EP 03748442 A EP03748442 A EP 03748442A EP 03748442 A EP03748442 A EP 03748442A EP 1558215 A1 EP1558215 A1 EP 1558215A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- gelling agent
- sterile
- organic solvent
- solvent
- water
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- 239000003349 gelling agent Substances 0.000 title claims abstract description 72
- 238000000034 method Methods 0.000 claims abstract description 38
- 230000008569 process Effects 0.000 claims abstract description 21
- 238000012377 drug delivery Methods 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract 2
- 239000002904 solvent Substances 0.000 claims description 50
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 230000001954 sterilising effect Effects 0.000 claims description 27
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 25
- 239000001587 sorbitan monostearate Substances 0.000 claims description 25
- 235000011076 sorbitan monostearate Nutrition 0.000 claims description 25
- 229940035048 sorbitan monostearate Drugs 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 claims description 9
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
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- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 4
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- 125000005907 alkyl ester group Chemical group 0.000 claims description 3
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- 150000003431 steroids Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/04—Oxygen-containing compounds
- C08K5/10—Esters; Ether-esters
- C08K5/101—Esters; Ether-esters of monocarboxylic acids
- C08K5/103—Esters; Ether-esters of monocarboxylic acids with polyalcohols
-
- 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
- Forms of sterile compositions include sterilization by moist heat (autoclaving), sterilization by dry heat, ethylene oxide sterilization (gaseous sterilization), exposure to ultraviolet rays or to gamma irradiation or sterilization by aseptic processing. These and other methods of sterilization are described in detail in Pharmaceutical Dosage Forms: Parenteral Medications (Eds. Avis, Lachman and Lieberman, Volumes 1-3).
- sterile controlled release products for parenteral administration such as the microencapsulated products, in-situ forming implants and the in-situ microcarrier forming gelled polymeric dispersions.
- sterile processing of the in-situ microcarrier forming gelled polymeric dispersions poses the greatest challenge to the formulation scientist because of the complex nature of the delivery composition.
- These gelled polymeric dispersions are comprised of dispersions of organic solvent solutions of biocompatible polymers in a continuous oleaginous phase gelled and stabilized by emulsifiers chosen from sorbitan monostearate or monopalmitate.
- the organic solvents are preferably water-soluble though water-immiscible solvents can also be used.
- the gelling agents of this invention as commercially available are not free from foreign particulate material and contain significant quantities of impurities which add color to the final product making it unacceptable for parenteral use. Further, the use of water for the processing of these gelling agents is not feasible because the gelling agents would degrade during autoclaving for example resulting in a loss of gelling capability. Also, presence of moisture in any of the materials, specially the gelling agent would result in the loss of physical stability of the gelled dispersions. A process to manufacture sterile in-situ microcarrier forming gelled polymeric dispersion compositions would be a tremendous improvement in the current state-of-the- art in the development of commercial products using these compositions.
- a novel method for the manufacture of sterile gelling agent for use in a suitable composition or delivery system for therapeutic administration involves the use of aseptic processing alone or gamma-irradiation alone or a combination of aseptic processing and gamma irradiation to achieve a product of the desired attributes including sterility, freedom from foreign particulates, syringeability, particle formation upon coming in contact with aqueous media, potency of active, and physical stability.
- a in-situ microcarrier forming gelled polymeric dispersion composition prepared using the gelling agents treated as above are subjected to gamma irradiation to prepare a sterile product useful for human administration without any significant loss in potency or behavior of the gelled dispersion composition in physical stability, syringeabihty or particle formation upon coming in contact with aqueous media.
- Another embodiment of the invention describes the administration of this sterile composition to an animal species.
- the gelling agents of the invention viz. sorbitan monostearate or sorbitan monopalmitate are soluble in a variety of organic solvents including volatile organic solvents such as methylene chloride, ethyl acetate, benzene, petroleum ether, carbon tetrachloride, methanol, acetonitrile, acetone, ethanol, tetrahydrofuran and other volatile solvents, at elevated temperatures.
- volatile organic solvents such as methylene chloride, ethyl acetate, benzene, petroleum ether, carbon tetrachloride, methanol, acetonitrile, acetone, ethanol, tetrahydrofuran and other volatile solvents
- Non-volatile organic solvents in which the gelling agents are soluble include NN'-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), triacetin, triethyl citrate, benzyl alcohol, propylene carbonate, decylmethylsulfoxide, dimethylformamide (DMF), glycofural, benzoyl benzoate, alkyl esters of aromatic acids, polyethylene glycols (PEG), propylene glycol and the like, also at elevated temperatures.
- DMA NN'-dimethylacetamide
- DMSO dimethylsulfoxide
- NMP N-methyl-2-pyrrolidone
- triacetin triethyl citrate
- benzyl alcohol propylene carbonate
- decylmethylsulfoxide dimethylformamide (DMF)
- glycofural glycofural
- benzoyl benzoate alkyl esters of aromatic acids
- the solvents for the invention should be biocompatible and not pose toxicity issues. Such solvents may be completely water-miscible, partially water-miscible or completely water-immiscible.
- Water-im niscible organic solvents such as dichloromethane, chloroform, ether, benzene, hexane and the like though otherwise used in the preparation of pharmaceutical compositions are generally toxic and require exotic methods such as lyophilization and the like for removal. Also, there are very strict guidelines for the levels of such residual solvents allowable in pharmaceutical compositions, especially so for parenteral administration. Water-miscible organic solvents are preferred.
- water-miscible organic solvents are chosen from DMA, DMSO, NMP, triacetin, triethyl citrate, benzyl alcohol, propylene carbonate, decylmethylsulfoxide, DMF, glycofural, benzoyl benzoate, alkyl esters of aromatic acids, PEG, propylene glycol, isopropanol, methanol, acetonitrile, acetone, ethanol, tetrahydrofuran and the like.
- a specially preferred volatile water-miscible solvent is ethanol because of its proven antiseptic properties, its complete water-miscibility, its volatile nature, its biocompatibility and low toxicity potential, its solvating capability for the gelling agents of the invention at elevated temperatures and its known use in the pharmaceutical industry for parenteral administration of solution dosage forms.
- Preferred non-volatile water-miscible organic solvents include DMA, DMSO, DMF, NMP, PEG among others.
- the sterile bulk gelling agent is prepared by dissolution in volatile water-miscible organic solvents specifically chosen from ethanol, methanol, acetonitrile, acetone, ethanol, tetrahydrofuran at a temperature above ambient, filtered through a sterilizing grade filter membrane at the elevated temperature and dried under vacuum at the elevated temperature.
- volatile water-miscible organic solvents specifically chosen from ethanol, methanol, acetonitrile, acetone, ethanol, tetrahydrofuran
- the solution of the gelling agent which has been filtered through a sterilizing grade filter membrane is cooled to room temperature or lower to cause gelation of the solvent and the same solvent is added to the gel to cause precipitation of the gelling agent.
- This suspension is then filtered through a further sterilizing grade filter membrane and the wet mass which is substantially free from the organic solvent is then dried under vacuum at an elevated temperature.
- This procedure has the advantage of removal of a large percentage of the organic solvent from the gelled bulk which would otherwise be lost under vacuum.
- This solvent can then further be used in processing of a separate lot of the gelling agent.
- substantially free indicates that a large percentage of the organic solvent is removed when compared with the situation where all of the solvent is bound to the gelling agent in the form of a gel.
- the solution of the gelling agent which has been filtered through sterilizing grade filter membranes at elevated temperatures is then added to a non-solvent to cause precipitation of the gelling agent.
- the non-solvent can be an organic solvent or can be water.
- the precipitated gelling agent is then treated further as in the earlier embodiment described above with the same advantages.
- the water-miscible organic solvent is nonvolatile chosen from DMA, DMSO, NMP, triacetin, triethyl citrate, benzyl alcohol, decylmethylsulfoxide, DMF, glycofural, PEG, propylene glycol and the like.
- the gelling agent is subjected to drying to remove water.
- the residual organic solvent should be chosen advantageously to be the same as the one to be used in the final gelled polymeric dispersion.
- the sterile dried bulk gelling agent is subjected to sterilization by gamma irradiation. Surprisingly, the gelling agents are not degraded by this procedure.
- Other materials in the gelled polymeric dispersion can be processed by other techniques as described above and generally known in the art of preparation of sterile dosage forms.
- the concentration of the gelling agent in the water-miscible solvent can be from 5 %w/w to 80 %w/w, preferably from about 10 %w/w to 70 %w/w and even more preferably from about 20 %w/w to 60 %w/w.
- the concentration of the gelling agent in the final solution will be dependent on the solvent chosen, the gelling agent solvent interactions, the processing temperature and of course the solubility of the gelling agent in the solvent. Of particular importance is the concentration of the gelling agent in the solvent, which allows filtration through a sterilizing grade membrane filter. The higher the concentration of the gelling agent in the solution the greater the yields and smaller the amounts of the expensive solvents that are used.
- the ratio of the solvent to the non-solvent may be adjusted so that complete precipitation occurs to ensure maximum yields.
- the temperature of preparation of the solution and also the processing will of course depend on the solvent to be used with a temperature below the boiling point of the solvent being preferred.
- a clear solution can be prepared at a temperature of 35-40 °C and higher at concentrations as high as 50 %w/w, which can be filtered through a sterilizing grade 0.22 ⁇ m filter at the same temperature.
- a solvent such as DMA a solution with the same concentration needs to be processed at a higher temperature because of the viscosity imparted by the gelling agent.
- the gelling agents of the invention are known to gel the solvents of the invention at high concentrations.
- Each gelling agent-solvent system will have a different temperature range at which the gelation occurs which will also affect the processability of the solution.
- the sterilizing grade filter can be any membrane, which has the capability to remove foreign particulates and also microorganisms to ensure sterility. Such filters usually have a pore size of 0.22 ⁇ m. Any membrane filter is acceptable for the practice of this invention as long as it can filter the solution and is compatible with the solvents of the invention. Such membranes include those made from nylon 66, cellulose acetate, cellulose nitrate, polytetrafluoroethylene (PTFE), silver membrane, gold membrane, polysulfone, polycarbonate and other known in the art and supplied by various manufacturers.
- the sterilizing grade filter could be preceded by a cleaning filter such as a 0.45 ⁇ m, 5 ⁇ m or 8 ⁇ m filter which can take up much of the burden from the sterilization filter. The choice of filters is within the scope of a person skilled in the art of development of pharmaceutical injectable dosage forms.
- Any mode of filtration is acceptable as long as a sterile product is produced.
- Such methods include, vacuum filtration, filtration under positive pressure using compressed air or nitrogen and the like.
- cartridge filters or filter candles and the like are well within the scope of this description.
- the drying of the sterile gelling agent bulk obtained after the above described processes can be conducted by any means known in the art including for example tray drying in an oven with or without the application of vacuum and with or without heating, lyophilization, simple vacuum drying and other methods known to a person skilled in the art of processing pharmaceutical dosage forms. Where heating is required it is preferable to heat at a temperature above the boiling point of the solvent to be evaporated to ensure complete removal of the organic solvent.
- sterile solvents, polymers, oil and bioactive agents can be as per known procedures in the art such as aseptic filtration of the solvents and oil, gamma irradiation of the polymer or aseptic filtration of the polymer solution in a volatile organic solvent followed by evaporation of the solvent and the like and are well known to persons skilled in the art of manufacture of parenteral controlled release dosage forms.
- the bioactive agents which can be incorporated into the sterile in-situ microcarrier fo ⁇ riing gelled polymeric dispersion compositions can be chosen from peptide drugs, protein drugs, desensitizing agents, antigens, vaccines, anti-infectives, antibiotics, antimicrobials, antineoplastics, antitumor, antiallergenics, steroidal anti- inflammatory agents, analgesics, decongestants, miotics, anticholinergics, sympathomimetics, sedatives, hypnotics, antipsychotics,.psychic energizers, tranquilizers, androgenic steroids, estrogens, progestational agents, humoral agents, prostaglandins, analgesics, antispasmodics, antimalarials, antihistamines, cardioactive agents, non- steroidal anti-inflammatory agents, antiparkinsonian agents, antihypertensive agents, beta-adrenergic blocking agents, nutritional agents, antivirals, DNA fragment
- drugs or biologically active agents that can be released in an aqueous environment can be utilized in the described delivery system.
- various forms of the drugs or biologically active agents may be used. These include, without limitation, forms such as uncharged molecules, molecular complexes, salts, ethers, esters, amides, and other chemically modified forms of the biologically active agent which are biologically activated when injected into a body.
- the sterile bioactive agent may also be added to the oil phase as a suspension to enhance the loading of the bioactive agent in the delivery composition. Whatever the final composition that is arrived at the process allows a sterile composition to be prepared.
- parenterally as used herein is intended to include routes such as intramuscular, intravenous, subcutaneous, subdermal, intralesional, intratumoral, intracavitary, peritumoral, intraarticular, vaginal, intraperitoneal, intraabdominal, intrathecal, intraorgan and the like or on open wounds, fractures, ulcers, cancerous lesions and the like and is not to be construed as limiting on the scope of the invention.
- the composition can be used for the immediate or controlled release or both of bioactive agents or bioinactive agents wherever the use of a sterile composition is called for.
- Examples 1-5 describe different methods for preparation of sterile sorbitan monostearate. The same methods can be applied to the preparation of other sterile gelling agents including sorbitan monopalmitate.
- Sorbitan monostearate (Sanyo, Japan) was subjected to sterilization by dry heat at a temperature of 180 °C for 2 hours. A dark brown colored mass was obtained. The material thus obtained though it would pass the test for sterility renders the final product unacceptable for pharmaceutical use because of the dark brown color it imparts.
- Example 1 Preparation of sterile sorbitan monostearate by direct evaporation of the solvent from a solution in a volatile organic solvent
- Sorbitan monostearate (Sanyo, Japan) was dissolved in ethanol (50 %w/v) by heating upto 60 - 65 °C in a water bath to form a clear solution.
- the hot solution was filtered through a 0.2 ⁇ m nylon 66 (Pall German) sterilizing grade membrane filter under vacuum using a specially fabricated jacketed stainless steel filtration assembly, which was also maintained, at the elevated temperature.
- the filtrate was dried in a vacuum oven at 40 °C and 760 mm vacuum for 48 hours. The dried material was crushed and stored in a sterile container free from moisture.
- Example 2 Preparation of sterile sorbitan monostearate by dissolving in a hot volatile water- miscible solvent and precipitating by mixing with the same solvent which is cold
- Sorbitan monostearate (Sanyo, Japan) was dissolved in ethanol (50 %w/v) by heating upto 60 - 65 °C in a water bath to form a clear solution.
- the hot solution was filtered through a 0.2 ⁇ m nylon 66 (Pall German) sterilizing grade membrane filter under vacuum using a specially fabricated jacketed stainless steel filtration assembly, which was also maintained, at the elevated temperature.
- the filtered solution was kept at 37 °C for 60 minutes and was then slowly added into cold, sterile, particulate free ethanol at 2 - 8 °C.
- the sorbitan monostearate precipitated as a fine powder at the bottom of the beaker.
- the precipitated sorbitan monostearate was collected and dried.
- Example 3 Preparation of sterile sorbitan monostearate by dissolving in a volatile water- miscible organic solvent and precipitating from a non-solvent Sorbitan monostearate (Sanyo, Japan) was dissolved in ethanol (50 %w/v) by heating upto 60 — 65 °C in a water bath to form a clear solution.
- the hot solution was filtered through a 0.2 ⁇ m nylon 66 (Pall Gelman) sterilizing grade membrane filter under vacuum using a specially fabricated jacketed stainless steel filtration assembly that was also maintained at the elevated temperature.
- the sorbitan monostearate was precipitated by drop-wise addition of the filtered ethanolic solution into sterile water for injection. The supernatant was decanted off and the precipitated sorbitan monostearate was collected on a filter paper and dried under vacuum at an elevated temperature. The dried material was crushed and stored in a sterile container free from moisture.
- Example 4 Preparation of sterile sorbitan monostearate by dissolving in a non-volatile water- miscible solvent and precipitating from a non-solvent
- Sorbitan monostearate (Sanyo, Japan) was dissolved in DMA (Fluka) by heating upto 60 - 65 °C in a water bath to form a clear solution. This solution was slowly added into sterile water for injection to cause precipitation of sorbitan monostearate, which was collected and dried.
- Sorbitan monostearate prepared in Example 1 was exposed to gamma irradiation at a dose of 25 KGy using a 60 Cobalt source at a contract irradiation laboratory. A dose of 25 KGy is accepted internationally to be sufficient to ensure sterility (British Pharmacopoeia). There was no change in appearance of the gelling agent.
- sterile sorbitan monostearate can be prepared by these techniques without any change in properties.
- the same techniques may be used to prepare sterile sorbitan monopalmitate.
- the further examples describe the use of the sterile sorbitan monostearate in the preparation of the gelled polymeric dispersions.
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- Engineering & Computer Science (AREA)
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Abstract
Description
Claims
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IB2003/004509 WO2005037252A1 (en) | 2003-10-14 | 2003-10-14 | Sterile gelling agents |
Publications (2)
Publication Number | Publication Date |
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EP1558215A1 true EP1558215A1 (en) | 2005-08-03 |
EP1558215A4 EP1558215A4 (en) | 2007-09-12 |
Family
ID=34452204
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP03748442A Withdrawn EP1558215A4 (en) | 2003-10-14 | 2003-10-14 | Sterile gelling agents |
Country Status (3)
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EP (1) | EP1558215A4 (en) |
AU (1) | AU2003267747A1 (en) |
WO (1) | WO2005037252A1 (en) |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2209671A (en) * | 1987-09-15 | 1989-05-24 | Sandoz Ltd | Water soluble monoesters as solubilisers |
EP0712631A2 (en) * | 1994-11-21 | 1996-05-22 | Biogal Gyogyszergyar Rt. | Cyclosporin containing multiple emulsions |
WO1998023226A1 (en) * | 1996-11-26 | 1998-06-04 | The Regents Of The University Of California | Biological tissue transplant coated with stabilized multilayer alginate coating suitable for transplantation and method for preparation thereof |
WO2000044808A1 (en) * | 1999-02-01 | 2000-08-03 | Hubbell Jeffrey A | Biomaterials formed by nucleophilic addition reaction to conjugated unsaturated groups |
WO2000074650A2 (en) * | 1999-06-04 | 2000-12-14 | Alza Corporation | Implantable gel compositions and method of manufacture |
US6165225A (en) * | 1995-10-13 | 2000-12-26 | Islet Sheet Medical Llc | Retrievable bioartificial implants having dimensions allowing rapid diffusion of oxygen and rapid biological response to physiological change, processes for their manufacture, and methods for their use |
WO2002000193A2 (en) * | 2000-06-23 | 2002-01-03 | Battelle Memorial Institute | Multiple stimulus reversible hydrogels |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3133863A (en) * | 1961-03-10 | 1964-05-19 | Strong Cobb Arner Inc | Sustained release therapeutic tablet compositions comprising organic solvent-gelled gums |
US4937081A (en) * | 1988-01-14 | 1990-06-26 | Daicel Chemical Industries Ltd. | Process for producing porous, spherical particles |
-
2003
- 2003-10-14 EP EP03748442A patent/EP1558215A4/en not_active Withdrawn
- 2003-10-14 WO PCT/IB2003/004509 patent/WO2005037252A1/en not_active Application Discontinuation
- 2003-10-14 AU AU2003267747A patent/AU2003267747A1/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2209671A (en) * | 1987-09-15 | 1989-05-24 | Sandoz Ltd | Water soluble monoesters as solubilisers |
EP0712631A2 (en) * | 1994-11-21 | 1996-05-22 | Biogal Gyogyszergyar Rt. | Cyclosporin containing multiple emulsions |
US6165225A (en) * | 1995-10-13 | 2000-12-26 | Islet Sheet Medical Llc | Retrievable bioartificial implants having dimensions allowing rapid diffusion of oxygen and rapid biological response to physiological change, processes for their manufacture, and methods for their use |
WO1998023226A1 (en) * | 1996-11-26 | 1998-06-04 | The Regents Of The University Of California | Biological tissue transplant coated with stabilized multilayer alginate coating suitable for transplantation and method for preparation thereof |
WO2000044808A1 (en) * | 1999-02-01 | 2000-08-03 | Hubbell Jeffrey A | Biomaterials formed by nucleophilic addition reaction to conjugated unsaturated groups |
WO2000074650A2 (en) * | 1999-06-04 | 2000-12-14 | Alza Corporation | Implantable gel compositions and method of manufacture |
WO2002000193A2 (en) * | 2000-06-23 | 2002-01-03 | Battelle Memorial Institute | Multiple stimulus reversible hydrogels |
Non-Patent Citations (1)
Title |
---|
See also references of WO2005037252A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO2005037252A1 (en) | 2005-04-28 |
EP1558215A4 (en) | 2007-09-12 |
AU2003267747A1 (en) | 2005-05-05 |
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