WO2005047339A1 - Esters de cellulose oxydes biodegradables et leurs utilisations sous forme de microspheres - Google Patents

Esters de cellulose oxydes biodegradables et leurs utilisations sous forme de microspheres Download PDF

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WO2005047339A1
WO2005047339A1 PCT/US2004/036004 US2004036004W WO2005047339A1 WO 2005047339 A1 WO2005047339 A1 WO 2005047339A1 US 2004036004 W US2004036004 W US 2004036004W WO 2005047339 A1 WO2005047339 A1 WO 2005047339A1
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cooh
drug
group
microspheres
ocr
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PCT/US2004/036004
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Vijay Kumar
Yang Dong
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University Of Iowa Research Foundation
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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
    • A61K9/14—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
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes

Definitions

  • OC containing 16-24% carboxylic acid groups is used in humans as a hemostatic agent and as a postsurgical adhesion barrier.
  • OC has found little use in pharmaceutical applications. This is because it is practically insoluble in water and common organic solvents and, hence, offers little or no formulation flexibility. Accordingly, it is a primary objective of the present invention to provide novel, biodegradable polymers for potential applications as biodegradable polymers in drug delivery, tissue engineering, and related areas. It is a further objective of the present invention to provide oxidized cellulose esters, and novel dosage forms of the same.
  • the present invention relates to the use of oxidized cellulose esters (OCE) as a new class of biodegradable polymers for use as biomaterials and as drug carriers in medicine, pharmaceutics, agriculture, and veterinary fields.
  • OCCAE oxidized cellulose carboxylate alkyl/aryl esters
  • OCE oxidized cellulose carboxylate alkyl/aryl esters
  • OCCAE are prepared by first forming oxidized cellulose esters (OCE).
  • OCE are formed by first treating oxidized cellulose with an organic acid, organic acid/acid anhydride combination, or an organic acid chloride.
  • the OCCAE are then prepared by reacting the OCE with an alcohol in the presence of a carbodiimide coupling agent, and a basic catalyst, such as 4-(dimethylamino) pyridine (DMAP).
  • a carbodiimide coupling agent such as 4-(dimethylamino) pyridine (DMAP).
  • DMAP 4-(dimethylamino) pyridine
  • the OCE and OCCAE described maybe used for a variety of purposes, including entrapment of various water soluble and insoluble drugs to produce controlled release microspheres or other dosage forms, such as gels, implantable devices, tablets, etc.
  • the OCE and/or OCCAE selected will depend upon the time period of drug release desired. In this regard, the nature of alkyl or aryl groups, and their degree of substitution determine their release time. In general, the substitution of a more hydrophobic group and increase in degree of substitution prolong the duration of release.
  • FIG. 2 shows the 'H-NMR spectra of OCA-14 (DS - 2.2), OCAM-14, and OCAE- 14, as described in Example 5.
  • FIG. 4 shows the powder X-ray diffraction patterns of cotton linter, OC-14, OCA- 14, OCAM-14, and OCAE- 14, as described in Example 5.
  • FIG. 5 shows the pH vs.
  • FIG. 6 shows the intrinsic viscosity and molecular weight measurement of OCA-14, as described in Example 5.
  • FIG. 7 shows the histograms of diameter distribution of CPT microspheres, as described in Example 6.
  • FIG. 8 shows the powder X-ray diffraction patterns of CPT, OCA-CPT, and OCAM-CPT microspheres, as described in Example 6.
  • FIG. 9 shows the dissolution/release profiles of CPT, OCA-CPT, and OCAM-CPT microspheres in pH 7.4 PBS at 37.0°C.
  • FIG. 10 shows the l+2F-3(F) A (2/3) model fitting for OCAM-CPT microsphere release.
  • the present invention relates to the development of novel biodegradable oxidized cellulose esters (OCE) and oxidized cellulose carboxylate alkyl esters (OCCAE).
  • OCE oxidized cellulose esters
  • OCCAE oxidized cellulose carboxylate alkyl esters
  • U.S. Serial No. 10/007,866 the disclosure of which is specifically incorporated herein by reference, the inventors synthesized OCE.
  • These novel modified oxidized celluloses exhibit solubility in aqueous alkaline solution, water, and/or common organic solvents, such as acetone and alcohol, depending on the nature of the ester groups and degree of substitution.
  • the new OCCAE polymers are biodegradable and are useful as biomaterials and as drug carriers.
  • the present invention also relates to the discovery that OCE may be modified to include an alkyl or an aryl group in place of hydrogen in the carboxylic acid group located on carbon 6, which depending on the degree of substitution and its physical/chemical properties, determines the use of the polymer as a drug carrier or a biomaterial.
  • OCE may be modified to include an alkyl or an aryl group in place of hydrogen in the carboxylic acid group located on carbon 6, which depending on the degree of substitution and its physical/chemical properties, determines the use of the polymer as a drug carrier or a biomaterial.
  • X is H, Na, K, Ca, NH 4 , or NEt 3 H; R is H; CF ; (CH 2 ) n CH 3 , where n is from 0 to 18, and preferably 0 to 5; (CH 2 ) n COOH, where n is from 1 to 8, and preferably 2 to 4;
  • X is H, Na, K, Ca, NH 4 , or NEt 3 H;
  • R' and R" are each selected from the group consisting of: H; CF 3 ; (CH ) n CH 3 , where n is from 0 to 18, preferably 0 to 2; (CH 2 ) n COOH, where n from 1 to 8, preferably 2 to 4;
  • CY CZCOOH, where Y and Z are independently selected from the group consisting of hydrogen, methyl, branched alkyl having from 1 to 20 carbon atoms and from one to three cis or trans double bonds; branched alkenyl having from 1 to 20 carbon atoms and having from one to three cis or trans double bonds;
  • Oxidized cellulose containing at least 3% by weight of carboxylic acid (COOH) content, and preferably 3-25% content, is used as the starting material in the manufacture of the OCE compounds.
  • COOH carboxylic acid
  • Various methods of preparing oxidized celluloses are well known in the art, and are described in the following publications, the disclosures of which are hereby expressly incorporated by reference: Heinze et al. (1998); Netherland Patent 77, 111, 034 (1979); U.S. Patent, 2,756,112 (1956); U.S. Patent, 6,627,749 (2003); Walimbe et al. (1978); C. Bertocchi et al. (1995); E. V. Gert et al.
  • the cellulose used in the preparation of oxidized cellulose, the starting cellulose material for OCE can be from any source, including cotton linters, alpha cellulose, hard and soft wood pulp, regenerated cellulose, amorphous cellulose, low crystallinity cellulose, powdered cellulose, mercerized cellulose, bacterial cellulose and microcrystalline cellulose.
  • Illustrative methods can be found in the following publications, the disclosures of which are hereby incorporated by reference: Powdered cellulose: U.S. Patent Nos. 4,269,859, 4,438,263, and 6,800,753; Low crystallinity cellulose: U.S. Patent 4,357,467; U.S.
  • the oxidized cellulose is preferably treated with a swelling agent for 5-120 minutes, and preferably for about 30-60 minutes, at room temperature.
  • the swelling agent should be used in an amount sufficient to soak the oxidized cellulose.
  • Use of the swelling agent prior to esterification increases the rate of reaction and allows the reaction to occur at a lower temperature (by about 5-25°C).
  • pretreatment with a swelling agent allows the esterification reaction to be conducted at a lower temperature.
  • suitable swelling agents include, but are not limited to phosphoric acid, isopropyl alcohol, aqueous zinc chloride solution, water, amines, etc.
  • the swelled oxidized cellulose is preferably washed with water, and then with the solvent of the reaction as described below.
  • the oxidized cellulose source may then be acylated in one of two manners.
  • Method (1) involves treating the cellulose with an organic acid, either alone or in the presence of an acid anhydride.
  • Organic acids and acid anhydrides suitable for this purpose are -Cs organic acids and/or anhydrides, with about CrC 3 being preferred. If an anhydride is used, it may be the anhydride corresponding to the organic acid (i.e. acetic acid/acetic anhydride), or a different anhydride. If a non-corresponding anhydride is used, the resulting oxidized cellulose ester product will be a mixed ester.
  • organic acids that can be used alone include formic acid, trifluroacetic acid, and acetic acid.
  • organic acids and their corresponding anhydrides include, but are not limited to, acetic acid/acetic anhydride, propionic acid/propionic anhydride, or butyric acid/butyric anhydride, valeric acid/valeric anhydride, caproic acid/caproic anhydride, caprylic acid/caprylic anhydride, nonanoic acid/nonanoic anhydride, capric acid/capric anhydride, lauric acid/lauric anhydride, myristic acid/myristic anhydride, palmitic acid/palmitic anhydride, heptadecanoic acid/heptadecanoic anhydride, stearic acid/stearic anhydride, arachidic acid/arachidic anhydride, behenic acid/behenic anhydride, maleic acid/maleic anhydride, succinic acid/succinic anhydride, mellitic acid/mellitic anhydride, phthallic acid/phthallic anhydride
  • the oxidized cellulose is preferably treated in the presence of an acid catalyst, for e.g. sulfuric acid, o-phosphoric acid, perchloric acid, and zinc chloride solution.
  • an acid catalyst for e.g. sulfuric acid, o-phosphoric acid, perchloric acid, and zinc chloride solution.
  • the acid catalyst should be present in a concentration ranging from about 0.1-10%, preferably 0.5-2%, by weight of the organic acid anhydride. In general, the higher the reaction temperature the lower the concentration of the acid catalyst, and vice versa, is required.
  • Method (2) involves treatment of the oxidized cellulose with an excess of an organic acid chloride or organic acid anhydride in an organic solvent such as dimethylsulfoxide (DMSO), N,N'-dimethylacetamide (DMA), NN'-dimethylformamide (DMF), dioxane, or the like, in the presence of a base catalyst.
  • organic acid chlorides are C -C 20 compounds, with about - s being preferred.
  • organic acid chlorides include, but are not limited to, caproyl chloride, heptanoyl chloride, octanoyl chloride, capryl chloride, undecanoyl chloride, lauroyl chloride, tridecanoyl chloride, myristoyl chloride, pentadecanoyl chloride, palmitoyl chloride, heptadecanoyl chloride, steroyl chloride, arachidoyl chloride, and behenoyl chloride.
  • Examples of unsaturated acid chlorides include palmitileoyl chloride (cis-9), oleoyl chloride (cis-9), linoleoyl chloride (cis-9, 12), linolelaidoyl chloride (trans-9,12), ⁇ -linolenoyl chloride (cis- 6,9,12), etc.
  • Examples of unsaturated acids that can be converted to the corresponding acid chlorides by the method known in the art include undecylenic acid, myristoleic acid (cis-9), myristelaidic acid (trans-9), palmitelaidic acid (trans-9), sterolic acid (9-ynoic), etc.
  • Examples of appropriate base catalysts include, but are not limited to pyridine, triethylamine, pyridine derivatives, etc.
  • the amount of the base catalyst that can be used varies from reaction to reaction, typically ranging from 2% to 20% by weight of the amount of the anhydride or acid chloride used in the reaction. In some reactions, it could also be used both as a solvent and as a catalyst.
  • the acylating reaction should occur at a temperature ranging from about 5-125°C, and preferably between about 15-75°C. The reaction should be allowed to continue for a time period of 0.5-12 hours, and preferably between about 2-6 hours.
  • the resulting solid is then preferably filtered, washed with water to a neutral pH range of between about pH 6-8, and then dried using conventional methods such as air- drying, vacuum drying, etc. Yields of the various OCE prepared by these methods range between about 70-95%.
  • the hydrophobic character of the OCE increases with increasing length of the carbon chain in the ester moiety.
  • the OCE are soluble in alcohols, ketones, aqueous alcohol, aqueous acetone, DMSO, DMA, DMF, or mixtures thereof. Owing to the presence of free carboxylic groups, OCE are soluble in mild to strong aqueous alkali solutions.
  • the pH at which the dissolution occurs depends on the nature of the ester moiety present in the polymer and degree of substitution.
  • oxidized cellulose acetate is insoluble in water and acidic aqueous solutions, but swells in pH 7 and higher buffer solutions, and eventually dissolves.
  • oxidized cellulose maleate or other unsaturated alkyl or alkenyl substituted esters containing one or more free carboxylic groups on the ester moiety as pendant groups hydrate in water and dissolve to give a viscous solution.
  • the aryl substituted esters of oxidized cellulose irrespective of the absence or presence of the free carboxylic group, neither swell nor dissolve in water.
  • the mixed oxidized cellulose esters exhibit solubility intermediate to those of the parent alkyl and aryl cellulose esters.
  • the OCE are reacted with an alcohol. Any Ci-C 16 alcohol may be used for this purpose, ultimately depending on the length of the alkyl chain or aryl group desired. Alcohol can be used in excess. Temperature is not critical in this step, and the reaction can occur in a broad range from about -5°C to as high as the boiling/melting point of the alcohol being used. For cost and practical reasons, room temperature is preferred.
  • the OCE Prior to reaction with the alcohol, the OCE is dissolved in an organic solvent. Any organic solvent will work for this purpose so long as it is effective in dissolving the OCE and does not contain a hydroxyl or carboxylic acid group. Examples of appropriate organic solvents for this purpose include, but are not limited to, halogenated aliphatic hydrocarbons and methylene dichloride. Persons skilled in the art can readily determine an appropriate organic solvent for this purpose.
  • the alcohol is added in excess. A carbodiimide coupling agent and a basic catalyst (what concentrations?), as solids or as solutions in the reaction solvent, are then added.
  • the amount of OCE to carbodiimide should range from about 1:0.1 to about 0.1-10 OCE to carbodiimide, with a range of about 1 :0.5-l :3 being preferred.
  • Any carbodiimide may be used as a coupling agent including, but not limited to, (S)-l,r-binaphthyl-2,2'-diylcarbodiimide, bis[(S)-l,l'-binaphthyl-2,2'- diyl] bis(carbodiimide), 2,2'-biphenylenecarbodiimide, bis(2,2'- bi ⁇ henylene)bis(carbodiimide), and 1,3-dicyclohexylcarbodiimide (DCC), with DCC being preferred.
  • Any basic catalyst will work for purposes of this step including, but not limited to, magnesium oxide, calcium oxide, mixed oxides obtained by calcination of layered double hydroxides, zeolites, hydrotalcites, and 4-(dimethylamino) pyridine (DMAP). Persons skilled in the art are well familiar with such catalysts.
  • the preferred basic catalyst is DMAP.
  • the amount of coupling agent to catalyst is not critical, except that at least a slight excess of coupling agent should be used. A range of about 2:1-10:1 coupling agent to catalyst is preferred.
  • the mixture is preferably stirred for a period of time sufficient to produce the desired OCCAE. This time period from about 15 minutes to about 48 hours, and preferably about 4-24 hours.
  • OCCAE may be used for the same purposes and in the same manner as OCE, i.e. as biomaterials and as drug carriers in medicine, pharmaceutics, agriculture, and veterinary fields. Both OCE and OCCAE may be used in the manufacture of sustained release dosage forms, such as granules, microspheres, tablets, capsules, gels, etc. They can be used as coating materials.
  • sustained release dosage forms such as granules, microspheres, tablets, capsules, gels, etc. They can be used as coating materials.
  • the formulation of pharmaceutically-acceptable dosage forms is well known in the art. As used herein, the term "pharmaceutically-acceptable" refers to the fact that the preparation is compatible with the other ingredients of the formulation and is safe for administration to humans and animals. Oral dosage forms encompass tablets, capsules, and granules.
  • Preparations which can be administered rectally include suppositories.
  • Other dosage forms include suitable solutions for administration parenterally or orally, and compositions which can be administered buccally or sublingually.
  • the pharmaceutical preparations of the present invention are manufactured in a manner which is itself well known in the art.
  • the pharmaceutical preparations maybe made by means of conventional mixing, granulating, dissolving, and lyophilizing processes. The processes to be used will depend ultimately on the physical properties of the active ingredient used.
  • Suitable excipients are, in particular, fillers such as sugars for example, lactose or sucrose, mannitol, sorbitol, cellulose, and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch, paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone, and powdered oxidized cellulose as described in U.S. Pat. No. 6,627,749.
  • fillers such as sugars for example, lactose or sucrose, mannitol, sorbitol, cellulose, and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch, paste, using, for example, maize starch, wheat star
  • disintegrating agents maybe added, such as the above-mentioned starches as well as carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are flow-regulating agents and lubricants, for example, such as silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate and/or polyethylene glycol.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • microspheres of this invention may be generally prepared by conventional emulsion/solvent evaporation method by suspending/dissolving the drug in an appropriate solvent system in an amount sufficient to suspend/dissolve the drug being used.
  • solvent systems for particular types of drugs are well known in the art.
  • dichloromethane/methanol is preferred, while dichloromethane is preferred for 5-fluorouracil (5-FU).
  • the drug suspension/solution is then combined with a solution of OCE, OCCAE, or OCE/OCCAE mixture (drug concentration of about 1-10%) in the same solvent system, which is then added dropwise to an aqueous solution containing an emulsifying agent.
  • emulsifying agents include without limitation various emulsifiers, surfactants, and wetting agents known in the pharmaceutical arts, such as polyvinylalcohol, sodium lauryl sulfate, dodecyl sodium sulfate, docusate salts such as the sodium salt thereof, alkyl carboxylates, acyl lactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acyl glutamates, fatty acid, polypeptide condensates, sulfuric acid esters, non-ionic surfactants and/or cationic surfactants such as, for example, polyoxyethylene compounds, lecithin, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols, ethoxylated/propoxylated block polymers, propoxylated esters, alkanolamides
  • Suitable pharmaceutically- acceptable surfactants include acacia, benzalkonium chloride, cholesterol, emulsifying wax, glycerol monostearate, lanolin alcohols, lecithin, poloxamer, polyoxyethylene, and castor oil derivatives.
  • a 1% solution of polyvinylalcohol (PVA) is preferred.
  • the mixture is stirred with vigorous agitation to form an O/W emulsion.
  • the agitation is continued for a period of time sufficient to form microspheres, which are formed as the organic solvent is evaporated. This time period will generally range from about 0.5-48 hours.
  • the temperature at which this occurs will depend upon the temperature necessary to evaporate the organic solvent chosen.
  • the amount and vigor of the stirring will determine the size of the microspheres formed, which can range in size from micrometers to nanometers in diameter.
  • the microspheres are then filtered and dried.
  • Double emulsion and other conventional formulation methods can also be used to prepare microspheres in accordance with this invention.
  • Microspheres that include OCE will release drug over a time period of between about 24-150 hours, depending on the degree of oxidation, i.e. carboxylic acid content and the nature of the ester group.
  • Microsphere formulations that include OCCAE will release drug over a much longer time period of between about 150 hours to 6 months or longer, again depending on the nature of drug, the types of ester groups, and/or degree of substitution of alkyl or aryl-substituted carboxylic acid ester group.
  • a drug dosing strategy can be formed depending on the drug release time desired by selecting a particular OCE, OCCAE, or combination of the two types of polymers, to achieve this result.
  • a higher proportion of OCE in the microsphere will provide a faster release of drug because of increased hydrophilicity.
  • a higher proportion of OCCAE in the microsphere will provide a slower release of drug because of increased hydrophobicity.
  • the OCCAE of this invention have the following general structures I and II:
  • X is H, alkyl (d-C 16 ) or an aryl group; R is H; CF 3 ; (CH 2 ) n CH 3 , where n is from 0 to 18, and preferably 0 to 5; (CH 2 ) n COOH, where n is from 1 to 8, and preferably 2 to 4;
  • the new OCCAE is nearly amorphous. Like OCE, it is soluble in common organic solvents. In contrast, oxidized cellulose can only be dissolved in alkaline aqueous solutions.
  • the carboxylic acid content of OCCAE is significantly reduced compared to oxidized cellulose and OCE, indicating the substitution of carboxylic acid group to carboxylic alkyl or aryl ester group.
  • the carboxylic content of OCCAE will depend upon the degree of substitution of the carboxylic acid alkyl or aryl ester group, but is generally much lower than for OCE.
  • the degree of polymerization (DP) of the new product was determined according to the procedure described in the U.S. Pharmacopeia/National Formulary (USP 24/NF 19), page 2432. The value ranged between 25 and 750.
  • oxidized cellulose acetate was prepared from oxidized cellulose (OC) by treatment with a mixture of acetic acid and acetic acid anhydride in the presence of catalytic amounts of concentrated sulfuric acid, in accordance with U.S. Serial number 10/007,866, filed December 6, 2001.
  • OC was prepared from a reaction between cotton linter sheet (Grade R 270; Southern Cellulose Products, Inc., Chattanooga, TN) and a mixture of phosphoric acid (85% w/w), nitric acid (69.9% w/w) and sodium nitrite at room temperature for different time periods (See U.S.
  • DMAP was added first to the reaction mixture and then DCC was slowly added drop-wise to the solution.
  • DMAP facilitates the conversion of the activated OCE-DCC complex intermediate into the DMAP-OCE intermediate, which is then attacked by the alcohol to give the product.
  • OCAM-20 prepared after 2 hr. showed only a slight decrease in the intensity of the v(O-H) vibration band in the region between 2500 and 3500 cm "1 compared to the corresponding peak in the spectrum of OCA-20.
  • the peaks at 100.4, 71.7, 72.4, 72.7, 76.0, and 63.4 ppm are attributed to Cl, C2, C3, C4, C5, and C6, respectively.
  • the peak at -170 ppm is due to carbonyl carbons belonging to the acetyl and carboxyl acid groups.
  • the peaks at 53.4 ppm and 61.3 ppm belong to CH 3 O- and -CH 2 O- carbons.
  • the methyl carbon in the ethyl group is identified at 14.1 ppm.
  • the resulting solution was then added drop-wise using a syringe over a period of 15 minutes to 300 ml of 1% (w/v) solution of poly(vinyl alcohol) (PVA) in water with vigorous stirring (-715 r.p.m.) at room temperature. The stirring was continued at the same speed for an additional 5 minutes. The mixture was then allowed to stir at a slower speed ( ⁇ 30 r.p.m.) for 4 hours to remove the organic solvents. The microspheres formed were separated by filtration, washed with 3x50 ml distilled water and then dried under vacuum (25 inches Hg) at 50°C for 12 hours.
  • PVA poly(vinyl alcohol)
  • OCAM14-Camptothecin Microspheres The preparation of OCAM14-CPT microspheres was achieved following the same procedure as described in above section, except for that the amounts of CPT and OCAM employed in the experiment were 40 mg and 450 mg, respectively, and they were dissolved in 10 ml of a 8:2 (v/v) mixture of methylene chloride-.methanol.
  • the emulsion was prepared using 100 ml of 1% (w/v) aqueous PVA solution and an agitation rate of 400 r.p.m. The mixture was then allowed to stir at a slow speed ( ⁇ 200 r.p.m.) for 4 hours.
  • OCA14-OCAM14 (l:l -Camptothecin Microspheres
  • OCA14-OCAM14 (1:1)-CPT microspheres was achieved following the same procedure as described in above section, the amount of CPT is 30.0 mg, and OCAM and OCAM14 employed in the experiment were 200 mg and 200 mg. They were dissolved in 10 ml of a 8:2 (v/v) mixture of methylene chloride:methanol.
  • the emulsion was prepared using 100 ml of 1% (w/v) aqueous PVA solution and an agitation rate of 400 r.p.m. The mixture was then allowed to stir at a slow speed ( ⁇ 200 r.p.m.) for 4 hours. The microspheres formed were separated by filtration, washed with 3x50 ml distilled water and then dried under vacuum at 50°C for 12 hours.
  • Preparation of OCAM20-Camptothecin Microspheres About 1 g of CPT which particle size had been reduced was accurately weighed and suspended in 20 ml of methylene dichloride:methanol (8:2). To this mixture, 2.0 g of OCA-20 was added. The mixture was stirred until OCAM20 completely dissolved in the solution.
  • the resulting solution was then added drop-wise using a syringe to 300 ml of 1% (w/v) solution of poly(vinyl alcohol) (PVA) in water with vigorous stirring ( ⁇ 400 r.p.m.) at room temperature. The stirring was continued at the same speed for an additional 5 minutes. The mixture was then allowed to stir at a slower speed ( ⁇ 200 r.p.m.) for 4 hours to remove the organic solvents. The microspheres formed were separated by filtration, washed with 3 x 50 ml distilled water and then dried under vacuum at 50°C for 12 hours.
  • PVA poly(vinyl alcohol)
  • OCAM20-OCA20 (1:1) - Camptothecin Microspheres About 1 g of CPT which particle size had been reduced was accurately weighed and suspended in 20 ml of methylene dichloride: methanol (8:2). To this mixture, 1.0 g of OCAM20 and 1.0 g of OCA20 were added. The mixture was stirred until OCA20 and OCAM20 completely dissolved in the solution. The resulting solution was then added drop- wise using a syringe to 200 ml of 1% (w/v) solution of poly(vinyl alcohol) (PVA) in water with vigorous stirring ( ⁇ 400 r.p.m.) at room temperature. The stirring was continued at the same speed for an additional 5 minutes.
  • PVA poly(vinyl alcohol)
  • the mixture was then allowed to stir at a slower speed ( ⁇ 200 r.p.m.) for 4 hours to remove the organic solvents.
  • the microspheres formed were separated by filtration, washed with 3 x 50 ml distilled water and then dried under vacuum at 50°C for 12 hours.
  • 5-Fluorouracil was introduced 30 years ago as a synthesized anticancer agent. It still continues to be widely used in the treatment of several common malignancies including colon cancer, breast cancer, and skin cancer. It is an analog of the naturally occurring pyrimidine uracil. It is more acidic than its natural pyrimidine analog and is also more soluble in aqueous solutions. It is stable in solution at physiological pH for weeks. It is a poorly absorbed drug after oral administration with erratic bioavailability. The parenteral preparation is the major dosage form, used intravenously (bolus or continuous infusion). After parenteral administration of 5-fluorouracil, there is a rapid distribution of the drug and rapid elimination with an apparent terminal half-life of approximately 8 to 20 minutes.
  • Oxidized cellulose esters containing methyl, octyl, and cetyl substituted carboxylic acid ester groups were used to study the substitution effect on the release characteristics of the drug. The release studies were performed in pH 7.4 phosphate buffer-saline (PBS) solution (ionic strength - 0.165 M). Preparation of OCAM20.
  • PBS pH 7.4 phosphate buffer-saline
  • OCAOCT20, and OCACET20 - 5 FU Microspheres About 1.0 g of 5-fluorouracil with reduced particle size was accurately weighed and suspended in 10.0 ml of methylene dichloride. To this mixture, 1.0 g of polymer (OCAM20, OCAOCT20, or OCACET20) was added. The mixture was stirred until the polymer completely dissolved in the solution. The resulting solution was then added drop- wise using a syringe to 50 ml of 1% (w/v) solution of poly(vinyl alcohol) (PVA) in water with vigorous stirring ( ⁇ 400 r.p.m.) at room temperature.
  • PVA poly(vinyl alcohol)
  • the mixture was then allowed to stir at a slower speed ( ⁇ 200 r.p.m.) to remove the organic solvents.
  • the microspheres formed were separated by filtration, washed with 3 x 50 ml distilled water and then dried under vacuum at 50°C for 12 hours.
  • the drug loading and drug loading efficiencies are presented in Table 1.
  • OCAM20-5FL appeared to have a smoother surface. Since these microspheres were prepared using the same experimental conditions, the morphology difference of the microspheres can be attributed to the different alkyl ester groups present. That is, microspheres prepared from long chain ester derivatives had a rougher surface than those made from methyl ester. The mean particle size diameter of the microspheres is listed in Table 2.
  • X is the fraction of drug released at time t
  • k is a rate constant
  • m is a constant.
  • Oxidized cellulose acetate was prepared from oxidized cellulose (OC) by treatment with a mixture of Ac 2 O/HAC/H 2 SO 4 .
  • the methyl and ethyl esters of OCA (OCAM and OCAE, respectively) were prepared by reacting OCA with methanol or ethanol using dicyclohexylcarbodumide and dimethylaminopyridine as the catalysts.
  • the new esters were characterized by FT-IR, 1H and 13 C NMR, 1H- 13 C HQMC NMR, and powder X-ray diffraction methods.
  • the weight loss studies on OCA were performed in pH 7.4 phosphate buffer-saline (PBS).
  • OCAM and OCAE ranged from 45% to 78, respectively.
  • the carboxylic acid contents (w/w) of OCAM and OCAE were 1.35, and 0.97 %, respectively.
  • the moisture contents determined by drying over P 2 O 5 were 2.16 and 1.36%, respectively.
  • the IR and NMR spectra showed peak patterns conforming to the structures of OCAM, and OCAE.
  • the OCAM and OCAE prepared in Example 2 were characterized as follows.
  • Carboxylic Acid Content Determination The carboxylic acid content was determined according to the USP methods (USP 26: Acid value determination, 391; Oxidized cellulose, 2068).
  • FT-IR Fourier-Transform Infrared
  • Moisture Content Determination The moisture content was determined using a Perkin Elmer Thermogravimetric Analyzer (TGA 7, temperature range: 25-200°C; heating rate: 10°C/min), or by drying the sample over P 2 O 5 to a constant weight.
  • the apparent pKa of OC-14 and OCA-14 are 3.45 and 4.34, respectively. (FIG. 5).
  • the moisture content of the compounds are set forth in Table 4.
  • the average viscosity molecular weight of OCA-14 is about 50,000, corresponding to the degree of polymerization (DP) of 194.
  • the molecular weight of OCAM and OCAE were not determined, but they are expected to have the same molecular weight ( ⁇ 50,000) because of the mild non-hydrolyzing reaction condition used in their preparation. (FIG. 6).
  • OCA can be prepared from OC by treatment with Ac 2 O/HOAc/H 2 SO 4 .
  • the preparation of OCAM and OCAE can be achieved from reaction between OCA and MeOH or EtOH in the presence of DCC and DMAP.
  • OCA and its methyl/ethyl esters are soluble in commonly used organic solvents.
  • OCA and its methyl and ethyl esters are low crystallinity materials.
  • the apparent pKa of OC-14 and OCA-14 are 3.5 and 4.3, respectively (FIG. 3).
  • the viscosity average molecular weight of OCA-14 is about 5.13 X IO 4 , which corresponds to a degree of polymerization (DP) of 194.
  • OCA oxidized cellulose acetate
  • OCAM oxidized cellulose methyl
  • OCA and OCAM microspheres containing CPT were prepared by the emulsion/solvent evaporation method using the CH 2 Cl 2 -CH 3 OH mixture as a solvent and polyvinyl alcohol as an emulsifier. Microspheres were characterized by IR, scanning electron and confocal microscopes, and powder X-ray diffractometry. Dissolution studies were performed in pH 7.4 phosphate buffer-saline (PBS) at 37°C. Results OCA-CPT microspheres ranged in size 86 ⁇ 31 ⁇ m and showed discontinuous and rough surfaces. OCAM-CPT microspheres, compared to those made using OCA, were smaller in size (68 + 17 ⁇ m) and had smoother surfaces.
  • OCA oxidized cellulose acetate
  • OCAM oxidized cellulose methyl
  • OCA and OCAM microspheres containing CPT were prepared by the emulsion/solvent evaporation method using the CH 2 Cl 2 -CH 3 OH mixture as a solvent and polyvinyl alcohol as an emulsifier. Microspheres were characterized by ER, scanning electron and confocal microscopes, and powder X-ray diffractometry. Dissolution studies were performed in pH 7.4 phosphate buffer-saline (PBS) at 37°C.
  • PBS pH 7.4 phosphate buffer-saline
  • SEM Scanning Electron Microscopy
  • the X-ray data were processed by DiffracPlus diffraction software (EVA, Version 2.0, Siemens Energy and Automation, Inc., Madison, WI).
  • EVA DiffracPlus diffraction software

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Abstract

L'invention porte sur un nouvel excipient de cellulose, l'OCCAE, approprié pour être utilisé comme liant, charge de remplissage et/ou délitant dans le développement de formes galéniques solides et comme agent biologique ou vecteur de médicament dans la préparation de formulations topiques. L'excipient de cellulose est obtenu par la réaction d'un ester de cellulose oxydé avec un alcool en présence d'un catalyseur. L'invention porte également sur la formation de microsphères à libération contrôlée utilisant des esters OCCAE et/ou des esters de cellulose oxydés pouvant être utilisés pour réguler la libération de médicament dans le corps d'un patient sur une période allant de plusieurs heures à plusieurs jours.
PCT/US2004/036004 2003-10-28 2004-10-28 Esters de cellulose oxydes biodegradables et leurs utilisations sous forme de microspheres WO2005047339A1 (fr)

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WO2009134746A1 (fr) * 2008-04-30 2009-11-05 Xyleco, Inc. Glucides
US7649089B2 (en) 2001-12-06 2010-01-19 University Of Iowa Research Foundation Biodegradable oxidized cellulose esters and their uses as microspheres
US20130323315A1 (en) * 2012-05-31 2013-12-05 Confluent Surgical, Inc. Microspheres Including Oxidized Cellulose
US9138489B2 (en) 2012-05-31 2015-09-22 Covidien Lp Oxidized cellulose miczrospheres including visualization agents
US9168227B2 (en) 2012-05-31 2015-10-27 Covidien Lp Multi-encapsulated microspheres made with oxidized cellulose for in-situ reactions
US9447197B2 (en) 2012-06-28 2016-09-20 Covidien Lp Dissolution of oxidized cellulose and particle preparation by dispersion and neutralization
US9447196B2 (en) 2012-06-28 2016-09-20 Covidien Lp Dissolution of oxidized cellulose and particle preparation by solvent and non-solvent precipitation
US9499636B2 (en) 2012-06-28 2016-11-22 Covidien Lp Dissolution of oxidized cellulose and particle preparation by cross-linking with multivalent cations
US9522963B2 (en) 2011-06-29 2016-12-20 Covidien Lp Dissolution of oxidized cellulose
US9782430B2 (en) 2013-03-15 2017-10-10 Covidien Lp Resorbable oxidized cellulose embolization solution
US10040871B2 (en) 2012-06-28 2018-08-07 Covidien Lp Medical devices based on oxidized cellulose
US10328095B2 (en) 2013-03-15 2019-06-25 Covidien Lp Resorbable oxidized cellulose embolization microspheres
US10413566B2 (en) 2013-03-15 2019-09-17 Covidien Lp Thixotropic oxidized cellulose solutions and medical applications thereof
US10449152B2 (en) 2014-09-26 2019-10-22 Covidien Lp Drug loaded microspheres for post-operative chronic pain

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DE3346204A1 (de) * 1983-12-21 1985-07-11 Council Of Scientific And Industrial Research, New Delhi Verfahren zur herstellung von 17ss-((l-oxoheptyl)oxy)19-norpregn-4-en-20-in-3on norethisteronoenanthat) und estern davon und diese enthaltende arzneimittel
DD267497A1 (de) * 1987-11-11 1989-05-03 Akad Wissenschaften Ddr Verfahren zur bindung von methotrexat an polysaccharide
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US7649089B2 (en) 2001-12-06 2010-01-19 University Of Iowa Research Foundation Biodegradable oxidized cellulose esters and their uses as microspheres
WO2009134746A1 (fr) * 2008-04-30 2009-11-05 Xyleco, Inc. Glucides
US9522963B2 (en) 2011-06-29 2016-12-20 Covidien Lp Dissolution of oxidized cellulose
US11873350B2 (en) 2011-06-29 2024-01-16 Covidien Lp Dissolution of oxidized cellulose
US10982012B2 (en) 2011-06-29 2021-04-20 Covidien Lp Dissolution of oxidized cellulose
US10561744B2 (en) 2012-05-31 2020-02-18 Covidien Lp Multi-encapsulated formulations made with oxidized cellulose
CN110200924A (zh) * 2012-05-31 2019-09-06 柯惠Lp公司 包含氧化纤维素的微球体
US20130323315A1 (en) * 2012-05-31 2013-12-05 Confluent Surgical, Inc. Microspheres Including Oxidized Cellulose
CN110200925B (zh) * 2012-05-31 2022-01-28 柯惠Lp公司 氧化纤维素微球体和组合物
US9271937B2 (en) 2012-05-31 2016-03-01 Covidien Lp Oxidized cellulose microspheres
AU2013206105B2 (en) * 2012-05-31 2017-03-16 Covidien Lp Microspheres including oxidized cellulose
US9687450B2 (en) 2012-05-31 2017-06-27 Covidien Lp Oxidized cellulose microspheres
US11065204B2 (en) 2012-05-31 2021-07-20 Covidien Lp Oxidized cellulose microspheres
US9138489B2 (en) 2012-05-31 2015-09-22 Covidien Lp Oxidized cellulose miczrospheres including visualization agents
US10188608B2 (en) 2012-05-31 2019-01-29 Covidien Lp Oxidized cellulose microspheres
US9168227B2 (en) 2012-05-31 2015-10-27 Covidien Lp Multi-encapsulated microspheres made with oxidized cellulose for in-situ reactions
US10426730B2 (en) 2012-05-31 2019-10-01 Covidien Lp Oxidized cellulose microspheres
CN110200925A (zh) * 2012-05-31 2019-09-06 柯惠Lp公司 氧化纤维素微球体和组合物
US9447197B2 (en) 2012-06-28 2016-09-20 Covidien Lp Dissolution of oxidized cellulose and particle preparation by dispersion and neutralization
US10584184B2 (en) 2012-06-28 2020-03-10 Covidien Lp Medical devices based on oxidized cellulose
US10040871B2 (en) 2012-06-28 2018-08-07 Covidien Lp Medical devices based on oxidized cellulose
US11053323B2 (en) 2012-06-28 2021-07-06 Covidien Lp Dissolution of oxidized cellulose and particle preparation by cross-linking with multivalent cations
US9499636B2 (en) 2012-06-28 2016-11-22 Covidien Lp Dissolution of oxidized cellulose and particle preparation by cross-linking with multivalent cations
US9447196B2 (en) 2012-06-28 2016-09-20 Covidien Lp Dissolution of oxidized cellulose and particle preparation by solvent and non-solvent precipitation
US10413566B2 (en) 2013-03-15 2019-09-17 Covidien Lp Thixotropic oxidized cellulose solutions and medical applications thereof
US10328095B2 (en) 2013-03-15 2019-06-25 Covidien Lp Resorbable oxidized cellulose embolization microspheres
US9782430B2 (en) 2013-03-15 2017-10-10 Covidien Lp Resorbable oxidized cellulose embolization solution
US11872244B2 (en) 2013-03-15 2024-01-16 Covidien Lp Thixotropic oxidized cellulose solutions and medical applications thereof
US10449152B2 (en) 2014-09-26 2019-10-22 Covidien Lp Drug loaded microspheres for post-operative chronic pain

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