WO1993020126A1 - Biodegradable polycarbonates and their use as drug carriers - Google Patents
Biodegradable polycarbonates and their use as drug carriers Download PDFInfo
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- WO1993020126A1 WO1993020126A1 PCT/EP1993/000699 EP9300699W WO9320126A1 WO 1993020126 A1 WO1993020126 A1 WO 1993020126A1 EP 9300699 W EP9300699 W EP 9300699W WO 9320126 A1 WO9320126 A1 WO 9320126A1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G64/00—Macromolecular compounds obtained by reactions forming a carbonic ester link in the main chain of the macromolecule
- C08G64/42—Chemical after-treatment
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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
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G64/00—Macromolecular compounds obtained by reactions forming a carbonic ester link in the main chain of the macromolecule
- C08G64/02—Aliphatic polycarbonates
- C08G64/0208—Aliphatic polycarbonates saturated
Definitions
- the invention relates to biodegradable and biocompatible polyesters and to pharmaceutical compositions containing them.
- the function of the polyesters in the pharmaceutical compositions is to control the rate of the release of pharmacologically active compounds from the compositions and the duration of the activity in the animal body to which the compositions are administered.
- the polyesters when administered to the body the polyesters can initially screen off the pharmacologically active compounds from the aqueous media, present in the body, whereafter due to biodegradation of the polyesters or to diffusion of the drug compounds through the polyesters, the drug releases and becomes medically active. This may be an interesting mechanism e.g. when the polyesters are water insoluble.
- the drug compound may also be chemically bound to the polyesters, whereafter due to biodegradation of the polyester molecule part, the drug releases from the compositions. This may be an interesting mechanism e.g. when the polyesters are water soluble and the polyester - drug compound combination functions as a water soluble pre-drug.
- the drug compound can be set free e.g. within one or more hours or days if chemically bound to polyesters or within one or more days, weeks or months if screened off by the polyesters.
- the invention provides biodegradable, biocompatible polyesters comprising (C 3-10 ) alkylene carbonic acid ester units, each alkylene group being a C 3 -alkylene group having 1 oxy substituent or a (C 4-10 ) alkylene group having 2-8 oxy substituents, each of the oxy substituents occurring independently as a hydroxyl group, or as a moiety independently comprising an ester or an ortho ester or an acetal group.
- polymers may contain e.g. mixtures of different oxy
- substitutents Preferably the oxy substituents are the same.
- Representative compounds may contain however a hydroxyl group and an oxy substituent, e.g. up to 30 or 20% hydroxyl groups.
- Polyesters containing carbonic acid ester groups are generally known as rather stable polymeric materials. Exceptions reported so far are poly(ethylene carbonate) s, which decompose within approximately 2 - 4 weeks in vivo.
- poly(ethylenecarbonate) and poly(trimethylene carbonate) are polymers, in which the alkylene group is unsubstituted.
- the polyesters of the invention comprise preferably C 3 -alkylene groups or ⁇ C 4-10 ) alkylene groups situated between the carbonic acid ester groups, each having 2 terminal -CH 2 - groups.
- (C 4-10 ) alkylene groups have a (C 2-8 ) alkylene central part carrying at least 2 and at most 8 hydroxyl groups in free form or in a form in which at least one of them is a derivatized hydroxyl group, comprising an ester or an orthoester or an acetal residue.
- a C 3 -alkylene group has a methylene central part, carrying 1 hydroxyl or derivatized hydroxyl group.
- Polyesters having such C 3 -alkylene or (C 4-10 ) alkylene units between the carbonic acid ester groups are novel. They are in principle biodegradable, many quickly, others slowly, depending on their structural type. Preferred are those, which biodegrade within 1-90 days.
- polyesters of the invention can be prepared by methods known per se, e.g. by reacting: - a diol with phosgene
- the invention thus also provides a process for the production of a polyester of the invention by reacting a bifunctionally reactive carbonic acid ester derivative with a bifunctional reactive sugar alcohol or glycerol having one or more protected secondary hydroxyl groups and 2 free primary hydroxyl groups.
- the polyesters may be prepared having a molecular weight of several hundreds up to more million daltons (Da).
- diol or bis (alkyl) carbonate polycondensations give linear polyester chains having lower molecular weights of 1000 - 50,000 Daltons .
- Anionic ring opening polymerizations of cyclic carbonates generally lead to products having higher molecular weights, e.g. up to more than 100,000 Daltons:
- polyesters having the highest molecular weights of e.g. more than 1,000,000 Daltons may be obtained by copolymerization of epoxides with carbon dioxide (12-15).
- the polyesters of the invention have basically molecular weights of the same ranges.
- Typical polyesters have Mw from about 5000 to about 25,000 Da. Typical Mw/Mn are from 1.2 - 1.9.
- a diol may be used for the production of the polyesters. Since preferably all the backbone chain carbon atoms are oxy substituted in the polyesters of the invention, preferably a sugar alcohol (reduced sugar, particularly reduced mono saccharides, e.g. threitol) or glycerol is chosen of which the secondary hydroxyl groups may be protected.
- a sugar alcohol reduced sugar, particularly reduced mono saccharides, e.g. threitol
- glycerol is chosen of which the secondary hydroxyl groups may be protected.
- a preferred process feature is thus using bifunctionally reactive su gar alcohols or glycerol having one or more additional, protected, secondary hydroxyl groups.
- glycerol having one or more additional, protected, secondary hydroxyl groups.
- 2-benzyloxy-1,3-propandiol can be used as a known starting compound.
- Protection in sugar alcohols may occur by methods known per se, e.g. by the pre-protection of the primary terminal hydroxyl groups, e.g. by converting them into benzoic acid ester groups, by converting the secondary hydroxyl groups to e.g. acetals or hemiacetals e.g. with acetone giving rise to O-isopropylidene residues and by splitting off the benzoic acid ester groups with e.g. methanol in the presence of sodium methylate.
- the thus obtained sugar alcohols have two free terminal primary hydroxyl groups and protected secondary hydroxyl groups and can be used as diol starting compounds for the production of the polyesters of the invention.
- polyesters having protected secondary hydroxyl groups in the form of an acetal and/or a hemi-acetal residue, are compounds according to the invention.
- the hemi-acetal or acetal groups may be removed by methods known per se, e.g. by water and trifluoro acetic acid, leading to polyesters having free secondary hydroxyl groups, which are also compounds of the invention.
- the polyesters having free hydroxylic groups are preferably dissolved or suspended in an inert, aprotic solvent e.g. in tetrahydrofuran, methylene chloride, toluene or dimethylformamide and reacted in the presence of a catalyst, e.g. a tertiary amine, with an active carboxylic acid derivative.
- aprotic solvent e.g. in tetrahydrofuran, methylene chloride, toluene or dimethylformamide
- a catalyst e.g. a tertiary amine
- Active carboxylic acid derivatives are e.g. carboxylic acid anhydrides and carboxylic acid chlorides. These derivatives may be obtained by reacting the carboxyclic acid with an activation reagent and can often be brought into contact with the hydroxyl groups when formed in situ. Reaction with ketenes leads also to the introduction of carboxylic acid ester residues.
- activation reagents are dicyclohexyl carbodiimide
- Polyesters according to the invention are those in which the carboxylic acid ester residues comprise those of formic acid and/or saturated or unsaturated (C 2-20 ) fatty acids, e.g. of lauric acid, oleic acid or stearic acid. Conveniently the carboxylic acid residues are unsubstituted.
- polyesters according to the invention include those in which the carboxylic ester residues comprise moieties of a hydroxy carboxylic acid, e.g. those of lactoyl or glycoyl or of polylactoyl, polylactoyl-co-glycoyl or polyglycoyl, such with the pre-fix "poly” however not having chain lengths enabling the polyester to form a hydrogel in an aqueous medium, to exclude hydrogels described in the EP 92918.
- the carboxylic ester residues comprise moieties of a hydroxy carboxylic acid, e.g. those of lactoyl or glycoyl or of polylactoyl, polylactoyl-co-glycoyl or polyglycoyl, such with the pre-fix "poly” however not having chain lengths enabling the polyester to form a hydrogel in an aqueous medium, to exclude hydrogels described in the EP 92918.
- polyesters may be obtained and are in the scope of the invention, in which the derivatized hydroxyl groups comprise substituted carboxylic acid ester residues, e.g. oxo carboxylic acid ester residues, or dicarboxylic acid ester residues.
- polyesters having free hydroxyl groups are reacted with active carbonic acid derivatives, preferably with chloroformic acid esters or
- polyesters according to the invention thus also comprise those in which the derivatized hydroxyl groups are carbonic acid ester residues, e.g. those containing hydroxy carboxylic acid ester residues or being cyclic carbonate residues.
- polyesters according to the invention are such having carbonic acid ester residues, e.g. comprising those containing a steroid alcohol, like cholesterol or a (C 1-20 ) alkanol residue.
- polyesters according to the invention are those in which the derivatized hydroxyl groups comprise such carbonic acid ester residues which contain carbamic acid or a derivative thereof.
- Carbamates of hydroxy compounds are generally made e.g. by their conversion with isocyanates or with carbamoyl chlorides.
- the residues may also comprise ortho ester residues, e.g. those of an ortho carboxylic acid ester or an ortho carbonic acid ester, which are acid sensitive and thus increase the biodegradability of the polyesters of the invention.
- Polyesters according to the invention may be those in which the derivatized hydroxyl groups comprise those of an amino acid or peptide.
- the amino acid residue can be present as a part of a carboxylic acid ester residue or as a part of a carbonic acid ester residue, if the amino acid contains hydroxyl, e.g. serine, or as a part of a carbamic acid ester residue.
- amino acid residue is a carboxylic acid ester or a carbonic acid ester derivative
- the amino group may be present in free condition, in a protected form or in a salt form.
- polyesters of the invention may e.g. thus be obtained by reacting the secondary free hydroxyl groups or a reactive derivative thereof with mono- or bifunctional carboxylic acid or carbonic acid
- terminal groups of the polyesters of the invention are free hy droxyl and/or esterified hydroxyl groups, depending on the preparation method applied. If an anionic ring opening polycondensation is applied, the starter molecule will be incorporated as a terminal group into each polyester chain.
- Terminal esterified hydroxyl groups are e.g. those which have been formed during the preparation step of the polyester back bone chain, e.g. ethoxycarbonyloxy.
- terminal esterified groups are those obtained from terminal hydroxyl groups during the esterification step of the secondary hydroxyl groups.
- terminal hydroxyl groups e.g. esterification agents or by splitting the polycarbonate chain by transesterification reactions, before splitting off the groups protecting the secondary hydroxyl groups, e.g. acetal residues.
- groups protecting the secondary hydroxyl groups e.g. acetal residues.
- lipophilic residues like stearoyl groups can be introduced as terminal groups.
- amphiphilic products are obtained characterized by hydrophilic secondary hydroxyl groups and lipophilic terminal residues.
- the invention thus additionally provides a process for the production of the polyesters of the invention by a) reacting a bifunctionally reactive carbonic acid ester derivative with a bifunctionally reactive sugar alcohol or glycerol having one or more protected secondary hydroxyl groups and 2 free primary hydroxyl groups, and optionally, b) for the production of end-group modified polyesters treating the polyester obtained with an esterification or transesterification reagent and, optionally, c) for the production of polyesters having free secondary hydroxyl groups, deprotecting the secondary hydroxyl groups in the formed polyester, and, optionally, d) for the production of esters and orthoesters reacting the
- a typical sugar alcohol has e.g.4-6 carbon atoms, e.g. threitol or mannitol.
- the invention further provides a process for the production of polyesters having an acetal residue by choosing for reaction step a) a bifunctionally reactive sugar alcohol having secondary hydroxyl groups protected by an acetal residue.
- the polyesters comprise generally alkylene carbonic acid ester units in homopolyester arrangement, although other configurations may be contemplated.
- alkylene parts contain free hydroxyl groups as well as derivatized hydroxyl residues, their distribution over the alkylene units of the polymer chain is preferably random. The arrangement is then that of a randomized homopolycarbonate.
- the number of alkylene carbonic acid ester back bone units, also when partially or completely derivatized is 5 to 1000.
- novel alkylene carbonate units can however also be chemically combined with known ester units e.g. also of the carbonic acid ester type and/or of the hydroxy carboxylic ester type to form a polymer chain. If so, the novel alkylene carbonate units form with the known ester units a polycarbonate or a polyester chain having a randomized co-polyester or a block-co-polyester arrangement respectively.
- the number of ester units, inclusive the known ester units is 5 to 1000, e.g. 5 to 500.
- the polyesters of the invention are preferably prepared from sugar alcohols, particularly those of natural sources, which are optically active and thus are stereomeric isomers. Their chiral, asymmetric centres are the carbon atoms to which secondary hydroxyl groups are bounded. When the sugar alcohol molecules are converted to polyesters and the hydroxyl groups are derivatized, no significant change in the asymmetric arrangement takes place, although the type of
- derivatization may influence the size of optical rotation of each asymmetric carbon atom involved.
- polyesters will have corresponding asymmetric arrangements.
- the sugar alcohols can be used in any stereomeric enantiomer form, in racemate form, in meso form or in mixtures in which one of the enantiomers preponderates over the other.
- optically active sugar alcohols D,L,DL-isomer
- polyesters of the invention contain cleavable bonds and are of a type, biodegradable in neutral or acidic or basic media.
- polyesters which contain only one type of residue.
- polyesters are taken which have only one ester bond type, i.e. the carbonate bond, in their back bones.
- polyesters in homopolyester arrangement, especially in randomized homopolycarbonate arrangement.
- the amino acid and the steroid alcohol residues can be the active part of a drug compound.
- the polyesters thus also include such in which the derivatized hydroxyl groups comprise drug compound residues, e.g. further those of a peptide or a protein.
- the polyester structures have then a pro-drug character. They can be used in pharmaceutical compositions.
- Water soluble polyesters e.g. those of Examples 4-6, are preferred for pro-drug formation, enhancing drug solubilization and/or releasing drugs by cleavage of a labile bond.
- the polyester is capable of being incorporated into liposomes by lipophile - lipophile interaction in an aqueous medium, leaving the main hydrophilic polymer chain in the outer sphere of the liposome.
- the pharmaceutical compositions of the invention preferably contain a polyester of the invention mixed with a drug compound, especially in such manner that the polyester is a solid matrix for the drug compound e.g. in the form of a microparticle or a implant.
- the polyesters can also be used as a capsule wall material, e.g. for normal size or microcapsules.
- polyesters have been described containing alkylene carbonic acid ester units as well.
- the carbon atoms of the alkylene groups art not oxysubstituted and have thus no adjacent hydroxyl nor hydrolysable ester, ortho ester or acetal residues. They are thus less biodegradable.
- the polyesters are used for medical devices, e.g. implants, to aid in tissue regeneration, growth and/or healing and do as medical devices not contain drug compounds.
- polyesters are described, prepared by reacting a) diphenyl carbonate, b) a diol, like neopentyl glycol and c) a triol, e.g. hexanetriol-1,2,6 (Example 40) or a tetrol. They were said to have an undefined structure.
- the polyesters are used for the preparation of weatherproof and ultra-violet light resistant protective coatings.
- the preparation of the pharmaceutical forms according to the invention may be carried out by methods known per se, the microparticles and microcapsules by appropriate spray drying or emulsifying techniques, the implants by mixing the drug compound and the polyesters both in particulated, solid state at higher temperatures at which the polyesters become liquid, followed by cooling the mixture to solid state and modelling it to a suitable shape. It is also possible to mix the drug compound in dissolved or dispersed state with a solution of the polyester and to evaporate the solvent, after which the solid residue is shaped to suitable implant forms.
- compositions containing microparticles may be made by working them up with suitable galenical excipients and optionally bringing them in appropriate dispensers.
- the drug loading content can vary between wide limits, in the order of 0.001 to about 70%, the loading content of microparticles and microcapsules can - due to the method of their production - vary between narrower limits, e.g. 0.001 to 8% of weight.
- pharmacologically active compound to be used in combination with the polyesters of the invention is not critical.
- those types of drug compounds are used, which are pharmacologically active in low amounts and need to have an uninterrupted blood level during extended periods, e.g. peptides or proteins, e.g. somatostatins or
- interleukins but especially such of hormonal types, in particular those that will desintegrate after oral use in the gastro-intestinal system and thus preferably are administered parenterally.
- the depot formulation according to the invention may be used to administer a wide variety of classes of active agents, e.g. pharmacologically active agents such as contraceptives, sedatives, steroids, sulphonamides, vaccines, vitamines, anti-migraine drugs, enzymes, bronchodilators, cardiovascular drugs, analgesics, antibiotics, antigens, anti-convulsive drugs, anti-inflammatory drugs, anti-parkinson drugs, prolaction secretion inhibitors, anti-asthmatic drugs, geriatrics and anti-malarial drugs.
- active agents e.g. pharmacologically active agents such as contraceptives, sedatives, steroids, sulphonamides, vaccines, vitamines, anti-migraine drugs, enzymes, bronchodilators, cardiovascular drugs, analgesics, antibiotics, antigens, anti-convulsive drugs, anti-inflammatory drugs, anti-parkinson drugs, prolaction secretion inhibitors, anti-asthmatic drugs
- the depot formulations may be used for the known indications of the particular drug compound incorporated therein.
- the exact amounts of drug compound and of the depot formulation to be administered depends on a number of factors, e.g. the condition to be treated, the desired duration of treatment, the rate of release of drug compound and the degradability of the polyester matrix.
- the desired formulations may be produced in known manner.
- the amount of the pharmacologically active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, e.g. how long a particular active agent concentration in the blood plasma remains at an acceptable level.
- the degradability of the matrix may also be obtained by in vitro or especially in vivo techniques, for example wherein the amount of matrix materials in the muscle is weighed after particular time periods, e.g. in comparison with other matrix materials.
- the depot formulations of the invention may be administered in the form of e.g. microparticles, e.g. orally or preferably subcutaneously or intramusculary, particularly as a suspension in a suitable liquid carrier or in the form of implants, e.g. sub-cutaneously.
- Repeated administration of the depot formulations of the invention may be effected when the polyester matrix has sufficiently been degraded. e.g. after 1, 2 or 3 weeks or 1 month.
- polyester matrices of the invention are that during and after the release of the drug compound many of them may be quickly degraded to a molecular size, which may be transported by the body fluids from the site of administration.
- the starting material was 1,5-di-O-benzoyl-D-mannitol:
- Hyflo (Super) Cel Karlgur, 2-25 microns, Fluka 56678 was used as filtration aid.
- polystyrene-divinylbenzene crosslinked gels Polymer Laboratories, UK, combination of columns with pores of 10 5 , 10 4 and 500 Angstroms, at 35°C. Calibration with standard polystyrenes. Polymer Laboratories, UK, for a molecular weight range of 1.75 ⁇ 10 6 to 580 Daltons.
- Tg Glass transition temperatures
- Tm melting points
- NMR spectra were obtained on a Bruker AM 360 spectrometer, ( ⁇ ) in NMR-data means the chemical shift delta, given in ppm.
- the assignments of the NMR-signals to the nuclei are not proved. Therefore, some of the assignments may be interchangeable.
- the empirical formulae in the microanalysis results are those of the corresponding monomer units of the polyesters.
- reaction mixture was cooled down to room
- the polyester from (-)-2,3-O-Isopropylidene-D-threitol and Diethyl carbonate
- the polyester from 2,3-O-Isopropylidene-DL-threitol and Diethyl carbonate (Monomer unit 1c)
- the distillate was removed under argon and the pressure was carefully reduced to 50 mbars.
- the temperature was increased stepwise to 100°C during 3 hrs. to distill the excess of diethyl carbonate.
- the pressure was set to atmospheric pressure with argon and the distillate was removed in an argon atmosphere. Then, the pressure was reduced to 8 mbars and the temperature was increased stepwise to 120°C during 1 hr.
- the reaction mixture was stirred for 20 hrs. at 120°C / 8 mbars and for 20 hrs. at 140°C / 0.5 mbars.
- the product mixture was cooled down to 40°C and dissolved in 600 ml of dichloromethane under reflux.
- the solution was treated with 6g Hyflo Cel, stirred for 1 hr. at room temperature and filtered.
- the solvent was evaporated to a final volume of ca. 250 ml under reduced pressure and the polymeric product was precipitated by dropwise addition of the solution to 4000 ml of methanol.
- the brownish-beige precipitate was dissolved in 1500 ml of acetone and 2.2 ml of 30% hydrogen peroxide in water were added slowly to the stirred solution.
- the mixture was stirred at room temperature for 20 hours.
- the solution was then treated with 6 g of Hyflo Cel, stirred for another 1 hr. and filtered.
- the solvent was evaporated at reduced pressure, the residue dissolved in ca. 250 ml of dichloromethane and the product was precipitated by dropweise addition of the
- IR (KBr) : 2990m, 2940m, 2907m, 1757s,broad, 1576w, 1457m, 1385s, 1233s,broad, 1169m, 1092s, 993m, 963m, 845m, 786m, 737w, 607w, 513m [cm -1 ].
- the polyester is soluble in water, dimethyl formamide and dimethyl sulphoxide. It is insoluble or hardly soluble in chloroform,
- IR (KBr) 3468s, broad, 2968w, 2917w, 1751s, broad, 1458m, 1409m, 1284 and 1259s, broad, 1132m, 1075m, 959m, 895w, 787m [cm -1 ].
- Example 5 were acetylated according to the procedure described in example 7) to give the polyester as a fine, white powder.
- ⁇ inh (dl/g) 0.10 in CHCl 3
- IR- and NMR-Spectra of the polymer of 3b were identical to those of the polymer of 3a.
- Tg 32.2°C IR (film): Strong absorptions at 1762, 1246, 1185 and 1125 cm -1 .
- Polyesters having monomer units 2a-2c are alternatively derivatized with glycolic- or lactic acid ester residues by treatment with the corresponding chloroformates, utilizing the hydroxyl groups of glycolic respectively lactic acid residues.
- the conversion of e.g. ethyl lactate into ethyllactyl chloroformate is described in the literature [29]: US Patent 3,742,022 (1973) and [30]: German Patent 26 58 254 (1977).
- Treatment of the polyester having the monomer unit 2c with ethyllactyl chloroformate according to the procedure described in examples 21 or 22 gives the corresponding ethyllactyl carbonate derivative.
- the reaction mixture was stirred for additional 7 hours at this temperature, then dissolved in 300 ml of dichloromethane and the dichloromethane solution was washed with aqeuous 5% sodium bicarbonate (2 ⁇ ) and water. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the residue was dissolved in 20 ml of dichloromethane. The product was precipitated by dropwise addition of the dichloromethane solution into 1500 ml diethyl ether.
- the precipitate was dried in vacuo for 48 hours to give the polyester, in which according to 1 H-NMR ca. 76.5% of the hydroxyl groups were ethoxycarbonylated and ca. 23.5% were in free condition.
- the ratio of di-ethoxycarbonylated units to mono-ethoxycarbonylated units was ca. 53% : 47%, according to the integral ratio of the signals at 5.18 ppm (m, 2 CH of di-ethoxycarbonylated units) and 5.02 ppm (m, 1 CH of mono-ethoxycarbonylated units).
- ⁇ inh (dl/g) 0.10 in CHCl 3
- Tg No Tg was observable from -30°C to +240°C.
- the product comprised 86% di-carbamoylated units (di-units) and 14% mono-carbamoylated units (mono-units). The ratio of
- polyester having the monomer unit 2c of example 6 was dissolved in 8 ml of dimethyl formamide.
- the solution was diluted with 32 ml of tetrahydrofuran.
- To the stirred solution subsequently were added at room temperature 4.78g (18 mmol) of BOC-L-phenylalanin, 3.71g (18 mmol) of N,N'-dicyclohexyl-carbodiimide and 135 mg (1.2 mmol) of 4-dimethylaminopyridine. The mixture was stirred for additional 2 hours at room temperature.
- the tert.-butyloxycarbonyl protecting groups are removed by known methods, e.g. by treatment of the product with an acid, e.g.
- Polyesters having monomer units 2a-2c are alternatively derivatized with amino acid ester residues by treatment with their corresponding isocyanates. Amino groups of amino acid ester are readily converted into isocyanates: [31]: Japanese Patent 53018515 (1978) and [32]:
- the esterification was also performed using Z-L-leucyl-L-alanin, under the same reaction conditions to give the corresponding dipeptide ester derivative.
- the benzyloxycarbonyl protecting groups are removed by known methods, e.g. by hydrogenation on palladium/charcoal, to give a polyester with free amino groups or, if an acid is added, the corresponding ammonium salt.
- dichloromethane solution was washed with 300 ml of aequous 5% sodium bicarbonate by stirring for 15 min. at room temperature.
- the organic layer was separated, dried over anhydrous sodium sulfate, concentrated to a final volume of ca. 20 ml and the product was precipitated by dropwise addition of the solution to 1000 ml of hexane.
- IR (film) Strong absorptions at 2982, 1755, 1266, 1214, 1145 and 1047 cm -1 .
- EXAMPLE 28 a) Synthesis of 2,3:4,5- and 2,4:3,5-di-O-Isopropylidene-D-mannitol
- the crude mixture was dissolved in 5000 ml of chloroform and a solution of 10 g (0.18 mol) sodium methylate in 1500 ml of methanol was added. The mixture was stirred for 20 hrs. at room temperature, then the solvent was evaporated under reduced pressure and the residue was washed several times with light petroleum. The crude product mixture was dissolved in a minimum amount of chloroform and subjected to flash chromatography on silica gel. Elution with diethyl ether containing 0.1% triethylamine gave 45 g of pure
- endgroup-stearoylated polyester 26b 0.85g was dissolved in 7 ml of dichloromethane and treated subsequently with 7 ml of trifluoroacetic acid and 2.3 ml of water. The solution was stirred for 15 minutes at room temperature and poored slowly into 350 ml of ethyl acetate to precipitate the product. The precipitate was washed well with ethyl acetate and with water and dried in vacuo for 48 hours to obtain the amphiphilic polyester 27b. According to 1 H-NMR, the product comprised ca. 16 monomer units 24b per stearate ester endgroup.
- This ratio was calculated from the integrals of the signals at 2.28 ppm (t, 2H of the stearate residue) and at 4.34 ppm (d, 2H of the monomer unit 24b).
- the IR-spectrum (KBr) of 27b showed strong absorptions at 3391, 1740, 1283 and 1076 cm -1 .
- the protecting groups are removed by catalytic hydrogeneration on palladium - charcoal to give a polyester with free hydroxyl
- EXAMPLE 35 Co-polyester from 2,3-O-Isopropylidene-L-threitol and 1,4-Butan-diol, having the monomer units la and 29
- the crude product was dissolved in 50 ml of dichloromethane, the solution was treated with HyfloCel and filtered. The filtrate was evaporated to a final volume of ca. 20 ml and the product was precipitated by dropwise addition of this solution into 500 ml of methanol. The precipitate was further purified by dissolving it in acetone, stirring of the solution with hydrogen peroxide and florisil, and filtration. The solvent was evaporated. The residue was dissolved in dichloromethane and the product was precipitated from methanol. The product, dried in vacuo for 48 hours, gave the
- the co-polyester comprised ca. 52.8% of monomer units 29 and 47.2% of monomer units 1a.
- Tg 25.7°C IR (film): Strong absorptions at 1747 and 1258 cm -1 .
- EXAMPLE 36 a) Degradation of polymers in vitro using sterile conditions
- the remaining implant mass was again dried and weighted to determine the mass loss. If possible, the molecular mass of the remaining implant mass was measured using GPC and polystyrene as standard.
- the degradation kinetics of polyesters in vitro and in vivo are of a comparable level (Fig. 2 and 3).
- the time point for complete mass degradation can be varied between 24 hours and about 90 days (Fig. 1 and 2) depending on the chosen structural polyester type.
- the loss of molecular weight is faster than the loss of polyester mass ( Figure 3) which means that first the polyester chains will be cleaved to a certain degree throughout the whole implant, and thereafter water soluble molecule fragments will be removed.
- the residue was milled in a SPEX-mill at the temperature of liquid nitrogen to give a fine powder which was then compressed at 59°C and 7 bar during 15 min. to implants of 5 mm diameter and ca. 25 mg of weight.
- the drug compound release correlated with the polymer mass loss in a satisfactory manner, although a very simple technique was used to prepare the implants.
- the retardation of the polymer mass loss may be attributed to the presence of the drug compound, since the degradation of the unloaded polymer is faster (see Fig. 4 and 2).
- R 2 R 1 or H 18c:
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5517042A JPH07505420A (en) | 1992-03-27 | 1993-03-23 | Biodegradable polycarbonate and its use as a pharmaceutical carrier |
EP93908849A EP0633905A1 (en) | 1992-03-27 | 1993-03-23 | Biodegradable polycarbonates and their use as drug carriers |
US08/307,754 US5849859A (en) | 1992-03-27 | 1993-03-23 | Polyesters |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB9206736.2 | 1992-03-27 | ||
GB929206736A GB9206736D0 (en) | 1992-03-27 | 1992-03-27 | Improvements of organic compounds and their use in pharmaceutical compositions |
Publications (1)
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WO1993020126A1 true WO1993020126A1 (en) | 1993-10-14 |
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ID=10712983
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/EP1993/000699 WO1993020126A1 (en) | 1992-03-27 | 1993-03-23 | Biodegradable polycarbonates and their use as drug carriers |
Country Status (6)
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---|---|
US (1) | US5849859A (en) |
EP (1) | EP0633905A1 (en) |
JP (1) | JPH07505420A (en) |
CA (1) | CA2128621A1 (en) |
GB (1) | GB9206736D0 (en) |
WO (1) | WO1993020126A1 (en) |
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- 1993-03-23 WO PCT/EP1993/000699 patent/WO1993020126A1/en not_active Application Discontinuation
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Cited By (8)
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US6955822B1 (en) | 1998-11-02 | 2005-10-18 | Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Of Paris | Lactone bearing absorbable polymers |
US7205378B2 (en) | 1998-11-02 | 2007-04-17 | Societe De Conseils De Recherches Et D'applications Scientifiques, Sas | Lactone bearing absorbable polymers |
EP1787658A1 (en) | 2005-11-10 | 2007-05-23 | South Shore Properties Inc. | Sustained release formulations of somatostatin analogue inhibitors of growth hormone |
US8519075B2 (en) | 2007-11-30 | 2013-08-27 | Joseph P. Laurino | Polycarbonate resin, and method of use of, poly (2-octadecyl-butanedioic acid) and the salts and esters thereof |
WO2011002865A2 (en) | 2009-06-30 | 2011-01-06 | Joseph Laurino | Polycarbonate resin, and method of use of, poly (2-octadecyl-butanedioic acid) and the salts and esters thereof |
WO2012051448A1 (en) | 2010-10-13 | 2012-04-19 | Texas A&M University | Degradable polycarbonates |
EP2627691A4 (en) * | 2010-10-13 | 2017-02-15 | Texas A&M University | Degradable polycarbonates |
EP4032931A4 (en) * | 2019-09-20 | 2022-08-24 | Mitsubishi Gas Chemical Company, Inc. | Polycarbonate resin, method for producing same, polycarbonate resin composition and molded body |
Also Published As
Publication number | Publication date |
---|---|
CA2128621A1 (en) | 1993-10-14 |
JPH07505420A (en) | 1995-06-15 |
US5849859A (en) | 1998-12-15 |
EP0633905A1 (en) | 1995-01-18 |
GB9206736D0 (en) | 1992-05-13 |
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