EP0250492A1 - Polypeptide synthetique biodegradable et son utilisation en therapeutique - Google Patents
Polypeptide synthetique biodegradable et son utilisation en therapeutiqueInfo
- Publication number
- EP0250492A1 EP0250492A1 EP87900038A EP87900038A EP0250492A1 EP 0250492 A1 EP0250492 A1 EP 0250492A1 EP 87900038 A EP87900038 A EP 87900038A EP 87900038 A EP87900038 A EP 87900038A EP 0250492 A1 EP0250492 A1 EP 0250492A1
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- EP
- European Patent Office
- Prior art keywords
- polymer
- polymers
- copolymers
- formula
- acid
- 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.)
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Classifications
-
- 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
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
- C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
- C08G69/10—Alpha-amino-carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/2045—Polyamides; Polyaminoacids, e.g. polylysine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
Definitions
- the subject of the present invention is a non-toxic, water-soluble biodegradable polypeptide which can be used in biology and for various therapeutic applications, in particular to serve as a support for medicaments, the latter being then gradually released in the organism as the biochemical degradation of the polymer.
- polyamino acids polyamino acids
- SIDMAN ET AL J. MEMBR. SCI (1980), 7 (3), 277-91
- a copolymer of glutamic acid and ethyl ⁇ -glutamate the degradation rate of which is a function of the composition of the copolymer (molar proportions of the esterified segments relative to the non-esterified segments) and which makes it possible to store numerous products, for example anti-malaria, anticancer and other drugs.
- Such polymers can be used in the form of rods containing, in a mixture, the desired medicament or in the form of capsules containing the medicament if the latter is not miscible with the polymer.
- the polyglutamates and polyaspartates of alkyl are degradable in good time (of an order of magnitude compatible with their pharmaceutical use) only in partially hydrolyzed form (see for example ASANO et al, J. Macromol. Sci. Chem. A21 (5) (1984), 561-582).
- these polyglutamates or polyaspartates must be subjected to a controlled hydrolysis reaction, the conditions of which are very difficult to reproduce.
- very small differences in the degree of hydrolysis considerably influence the rate of subsequent biodegradability, which constitutes an additional problem in the use of such polymers for the aforementioned purposes.
- thermoplastics 1. Excellent solubility in most common harmless solvents suitable for medicines and even in water (indeed, known polyamino acid derivatives are generally only soluble in certain special solvents (DMF, pyridine, F 3 CCOOH) whose use is inconvenient for pharmaceutical preparations). thermoplastics.
- R is any amino acid residue, but preferably hydrogen (glycine), methyl (alanine), benzyl (phenylalanine), etc.
- R can also denote amino acid residues containing OH functions , SH, NH 2 (corresponding to other amino acids), as well as - COOH (corresponding to glutamic and aspartic acids), this carboxylic group possibly being free, partially esterified by a lower alkyl or completely esterified.
- n is 1 or 2
- m is 0 or one integer from 1 to 4
- p is zero
- x is such that the molecular weight of the polymer is at least 5000D.
- the amide bond connecting the lateral carbon of the polyacid and the rest of the side chain is called an "isopeptide" bond.
- the polymer in the case where m equals zero, the polymer is a derivative of polyglutamine and, in particular when p is zero, poly- ⁇ -malonylglutamine.
- p 1, we have poly- ⁇ -succinylglutamine and when p is 2, asymmetric poly- ⁇ -glutarylglutamine.
- the molecule When m is other than zero, the molecule has a mono or oligopeptide link inserted between the CO group of the polyglutamine and the terminal amino-substituted group.
- the existence of one or more peptide groups in the side chain of the present polymer corresponds to the presence of one or more sites of enzymatic hydrolytic attack leading to the degradation of the polymer into resorbable fragments by the organism in which the polymer is incorporated. It is therefore possible, by varying the number and type of amino acids constituting said link, to exercise precise control over the rate of degradation of the polymer in a given application.
- amino acids which are preferred for constituting these links, mention may be made of glycine, alanine, phenylalanine, esterified or non-esterified aspartic and glutamic acids, leucine, tyrosine, methionine and others.
- the polymer of the invention can also be in the form of a copolymer with other polyamino acids. In this case, there will be a copolymer of formula:
- the definition of R 'can therefore correspond to that of R.
- R' it is preferred for R' to have groups such as, for example methyl (alanine), isopropyl ( valine), isobutyl (leucine and isoleucine), benzyl (phenylalanine), etc.
- R ′ can also denote a residue of glutamic or aspartic acid which is not esterified, or partially esterified by any alcohol, for example MeOH or EtOH, that is to say, for example, -CH 2 ) n -COOH or - (CH 2 ) n -COOMe, n being 1 or 2.
- R 'de a residue of free glutamic or aspartic acid
- amino acids of the L or D series we can also have, indifferently, amino acids of the L or D series.
- the amino acids of the L series (or natural) are the most interesting because the polypeptides containing them are degradable by enzymes (proteases) of the human body, so that polypeptides made up of D units are not.
- the molar proportion, in copolymer II, of the other free or partially esterified polyamino acid also makes it possible, to a considerable extent, to regulate the rate of biodegradation of the copolymer as a function of the agents present in the organism at the site of destination of the mixture of copolymer and of the drug to be administered, (that is to say in the organ where the drug must act).
- the copolymer is a copolymer of polyglutamine I and of leucine
- the relative molar proportion of the two constituents will be chosen as a function of the relative rate of degradation, at the place considered, of the polyglutamine and of the polyleucine.
- the z / y ratio can vary from 1 to 30, but these limits can be exceeded if necessary.
- the polymers of the invention can comprise elements of configuration L or D or racemic mixtures or, again, polymers where one of the configurations dominates.
- the biochemical properties of these various assemblies are, of course, not identical, the polymers dominated by the natural forms L being more accessible to enzymatic degradation. It is therefore possible, as already mentioned above, to control its degradability by proportioning, in the copolymer, the relative proportions of one and the other form.
- Polymers I and copolymers II are soluble in water (even at acidic pH, unlike polyglutamic acid) (unless the COOH groups are esterified) and generally soluble in one or more solvents such as dimethylformamide, trifluoroacetic acid, dichloroacetic acid, trifluoroethanol
- the biodegradation of polymer I can be diagrammed as follows:
- reaction (2) is consecutive to the reaction (1) and, therefore, the biodegradation of the polymer will be all the faster the faster the hydrolysis rate of the side chain.
- Polymer I and its copolymer II can be prepared by various routes.
- the desired polyamino acid IV or co-polyamino acid is reacted with an aminomalonate, aspartate or glutamate of alkyl III (of tert-butyl, for example) in the presence of dicyclohexylcarbodiimide (DCC) which provides the corresponding ester of polyacid I or II, the latter being then hydrolyzed by the usual means.
- DCC dicyclohexylcarbodiimide
- polyamino acid IV or co-polyamino acid V used as starting material for the preparation of polymer I or of copolymer II is easily obtained by the usual means comprising the esterification by a lower alcohol of the lateral carboxylate of an acid of formula
- N-carboxyanhydride N-carboxyanhydride
- the starting product (V) that will be used will be a copolymer of H 2 NCHE acid (CH 2 ) n -COOH] -COOH and of ester HN 2 -CHC (CH 2 ) n -COOAlk] -COOH.
- polymers I and II Due to the presence, along the chain, of two carboxylic groups, polymers I and II can fix certain metal ions, such as Ca +2 , more firmly than monocarboxylic acids.
- Such a property is encountered with certain natural polypeptides present in the organism, such as prothrombin, factor Xa of the blood, osteocalcin of bones and cartilages; these compounds have ⁇ -carboxyglutamic residues (Gla) capable of binding Ca +2 (see JP
- osteocalcin has a great affinity for hydroxyapatite and, although its physiological role is still poorly understood, it probably plays an important role in the control of bone growth.
- prothrombin As far as prothrombin is concerned, it has, in its molecule, ten Gla residues allowing prothrombin to bind, in the presence of calcium, to the phospholipids constituting cell membranes. In under such conditions, prothrombin has the property of converting, in the presence of factor Xa, into thrombin which causes the blood to clot by catalyzing the transformation of fibrimogen into fibrin. In the absence of Gla remains the prothrombin loses all activity.
- prostheses can be used for the manufacture of bone prostheses and fully biocompatible and biodegradable cartilage without the formation of toxic residues.
- Such prostheses are mechanically very rigid, but are gradually absorbed as the regeneration of the consolidated bone. Thus, the usual final intervention to remove the prosthesis after healing can be avoided.
- the present carboxylic polypeptides can be used to provide cyclic anhydrides, when p is equal to 1 or 2, for example by treatment of polyacids I or II with a carbodiimide such as DCC, as indicated below:
- This transformation has the effect of providing polymers which are insoluble in water, but soluble in the numerous usual organic solvents, such as acetone, methyl ethyl ketone, THF, dioxane, ethyl acetate, monoglyme and others, which allows their easy transformation into beads. , rods, fibers, filaments, microcapsules etc ... by the processes of extrusion, casting, evaporation etc.
- polymers IA, as well as their HA homolics obtained identically from II, restore polyacids I and II.
- the polymers and copolymers IA and HA are biodegradable and biocompatible when used for the slow and controlled release of drugs, for example from thin films prepared by pouring a solution of polymer and drug onto a support followed by drying. by evaporation of the solvents from the solution.
- Such techniques are described in "Controlled Release of Macromolecules from Polymers by R. LANGER et al., Biomedical Polymers, Ed. GOLDBERG and NAKAJIMA, Académie Press, 1980). After the film has dried, the drug may be in the state dissolved or as a suspension of particles.
- the polymer IA and the copolymer IIA can be used as a drug reservoir in various ways.
- the present polymers IA and copolymers IIA can be used to make microcapsules containing a drug.
- microcapsules comprise a polymeric membrane and contain an aqueous or oily solution in which the medicament is in suspension, or in solution.
- Microspheres can also be made, that is to say solid particles or beads containing the drug in the dispersed state or in the form of a solid solution in the polymer matrix.
- micro sponges microporous products
- solubility of the present polymers in numerous solvents, miscible or not with water is an advantage for their application according to the techniques described in these references. It is also possible to prepare yarns made of these polymers by extruding a solution of these in a die and precipitating the yarn, either by evaporation, or by a non-solvent bath, according to the usual spinning techniques. Filaments prepared in this way can be knitted, knotted or woven to form sutures, ligatures or tubular structures that can serve as artificial arteries, veins, conduits or internal organs with temporary functioning.
- the polymers of the invention can also be used, either directly or as a mixture with a plasticizer, for the manufacture of films or surgical prostheses used, for example, in the consolidation of fractured bones, such as staples, needles, screws, reinforcement plates, buffers etc ..., these materials can be produced by casting or molding a solution, thermoforming or by machining solid polymer blocks. As such prostheses are absorbable, they are gradually eliminated in the body and it is then no longer necessary to provide, as is currently done, a new operation to remove the reinforcement and consolidation material.
- the polymers and copolymers of the invention can also be used for the preparation of biodegradable surgical dressings.
- Such dressings consist of one or more layers successively obtained from solutions of these polymers in a solvent deposited on a support and solidified by evaporation or drying.
- Such dressings consist of one or more layers of suc stops obtained from solutions of these polymers in a hydrocompatible solvent deposited on a support and solidified by extraction with water of the solvent in question. Such extraction can be done by contacting with water, for example by washing or immersion.
- Such dressings can be formed by pouring solutions onto a support (these solutions containing or not containing one or more drugs, for example a disinfectant) under sterile conditions, by treating the whole with water and then detaching the film. insolubilized from the support and possibly drying it before use (or by packaging it in a sterile manner if its immediate use is not foreseen).
- the intrinsic advantage of the IA and IIA polypeptides over the polyalkyglutamates or aspartates of the prior art lies in the unstable character of the anhydride functions, which makes it possible to ensure the dissolution / biodegradation of the polymer in its hydrophobic anhydride form.
- the anhydride compounds IA and IIA are also useful as a "drug vector" for covalently fixing drugs exhibiting a reactive function with this cycle (that of an enzyme, a protein or d 'a polypeptide), for example an amino function, as indicated below where M denotes the molecule of a medicament to be fixed on the present polymer:
- the polymer thus modified by binding to the drug M can in general be handled as described above and administered likewise, so that it acts at its destination in the body. Such a pharmacological action may, in some cases be due to the polymer thus modified itself, but, most often the drug will only be active after having been separated, for example by hydrolysis, from its support.
- the arrows indicate the bonds likely to split by hydrolysis.
- Polyamino acids have also been used as drug carriers, especially in cancer therapy.
- poly L-lysine has been used as a carrier for anticancer drugs (SHEN and RYSER, Molecul. Pharmacol. 16, (1979), 614-622) .
- Polyaspartic acid has also been used (ZUNINO et al, Int. J. Cancer 30, (1982) 465-470) to fix daunorubicin.
- polyglutamic acid has been reported as a support for norethindrone (contraceptive product) (ZUPON et al, J. Pharmac.
- Adriamycin an anticancer drug was also attached to polyglutamic acid (Van Heeswijk et al., Journal of Controlled Release 1, 301 (1985)).
- copolymers of maleic anhydride and another vinyl monomer have often been used for medical applications.
- these polymers have an intrinsic pharmacological activity after hydrolysis (this is particularly the case for the divinylether-maleic anhydride DIVEMA which acts as an activator of macrophages).
- DIVEMA divinylether-maleic anhydride which acts as an activator of macrophages.
- they are capable of serving as drug carriers, in particular by reaction of the anhydride function with an R-OH or R-NH 2 group of an active principle like anhydrides derived from the polyacids of the invention; HIRANO et al, Makromol. Chem. 180 1125 (1979).
- polymers of the invention as well as the corresponding anhydrides can be used to form soluble macromolecules carrying an active ingredient and allowing a slow release of this active ingredient. It will be noted that, compared with the known examples of the technique described above, they have the following advantages:
- dicarboxylic groups -CH- (COOH) 2 capable of chelating calcium, are part of the ⁇ -carboxyglutamic acid found in certain human proteins
- This property of fixing calcium makes the compounds of the invention particularly useful for the manufacture of bone prostheses and cartilages entirely biocompatible and resorbable.
- a prosthesis can for example be produced by molding a mixture of hydroxyapatite Ca 10 (PO 4 ) 6 (OH) 2 in powder form and a binder consisting of the polymer or copolymer of the invention in which p is, preferably zero.
- p is, preferably zero.
- the accompanying drawing is a graph illustrating the complexing power of calcium in the polymers according to the invention.
- polymers and copolymers of the invention are synthesized as follows: firstly, poly-L-glutamic acid or poly-L-aspartic acid is prepared, in a conventional manner, by the method of M -carboxyanhydrides. (See for example patent application CH-5021/84).
- polyglutamic acid of the N-carboxyanhydride of alkyl ⁇ -benzylglutamate ( ⁇ -benzylglutamate NCA) which makes it possible to obtain polymers of high molecular weights.
- ⁇ -benzylglutamate NCA alkyl ⁇ -benzylglutamate
- the poly- ⁇ -benzylglutamate thus obtained is then debenzylated by HBr in benzene to give poly-L-glutamic acid.
- Polyaspartic acid will be prepared in the same way, by polymerization of the ⁇ -benzylaspartate NCA and then debenzylation of the esterified polyacid.
- the molecular weights of the polymers obtained are generally lower in the case of polyaspartate than in that of polyglutamate.
- This copolymer is prepared by incomplete hydrolysis of poly [Glu (OMe)] in aqueous trifluoroacetic acid (this polymer therefore comprises in its backbone 20% of methyl glutamate unit).
- the pellet (dicyclohexylurea) is washed with CHCl 3 (50 ml) and the extract is added to the supernatant. Another 100 ml of CHCl 3 is added thereto and this phase is washed successively with H 2 O (3 times 100 ml), 1N NaHCO 3 (2 times 100 ml), H 2 O (100 ml), 1% HCl (3x100 ml) and H 2 O (2x100 ml). The organic phase is dried over Ma 2 SO 4 and concentrated to 40 ml.
- a polymer sample is hydrolyzed for 12 h in 6N HCl at 120 ° C.
- the NMR spectrum of the polymer in TFA solution corresponds well to the proposed structure.
- the product thus obtained is very hygroscopic and must be stored in a desiccator. 0.927 g of the above poly [Glu (OMe) Glu (OH) Glu (Asp)] are dissolved in 10 ml of DMF and 3 mmol of DCC are added.
- the precipitate is redissolved in chloroform (50 ml) and washed successively with 0.1 N NaHCO 3 , H 2 O, 1% HCl and H 2 O saturated with salt (100 ml). It is centrifuged with each washing to separate the organic and aqueous phases. The organic phase is finally dried over MgSO 4 , filtered and the solution is precipitated by adding an excess of ether.
- the polymer is redissolved in MeOH (20 ml), acetic acid (30 ml) and 5 ml of H 2 O are added; 2 g of palladium on activated carbon are added and hydrogen is bubbled through this solution for 15 hours. After filtration of the activated carbon, the solution is dialyzed for 3 days in distilled water, then lyophilization is carried out, which provides 3.5 g of poly ( ⁇ -L-glutamyl-glutamine].
- the polymer can be stored in its dicarboxylic acid form or it can be cyclized as follows:
- poly [ ⁇ -L-aspartyl-L-aspartamine] is obtained. This can be cyclized to the corresponding anhydride by the above-mentioned means.
- reaction medium a solvent where mixture of solvent such that the reaction of the group -NH 2 of the substance to be fixed is favored compared to that of the hydrolysis of the anhydride cycle.
- the polymer (3 g) is added to 30 ml of KOH N / 10 in MeOH. 25 ml of H 2 O are then added. The polymer gradually dissolves. After 17 hours, the pH is brought back to 7 and the solution is dialyzed for 1 day in H 2 O then HCl at 1%.
- the whole is lyophilized and thus 2.45 g of the polymer of formula is obtained:
- the proportion of amino acids in a sample is measured after complete hydrolysis of the latter in a 6N HCl solution (24 h) from which it is deduced that the rate of fixation of the malonylamido radical is 85%.
- the analysis consists in assaying the glycine which forms, during hydrolysis, by decarboxylation of the aminomalonic residue.
- the purpose of this example is to demonstrate the complexing power of various polymers according to the invention vis-à-vis calcium ions.
- a series of 1 ml aqueous solution containing radioactive Ca +2 100, ⁇ l of 45 Ca 10 -3 M and variable amounts of various polymers according to the invention were introduced into a series of dialysis envelopes (casings) as well as a control).
- the polymers studied were: polyglutamic acid (control A); poly- (malonyl-glutamine) B; poly- (aspartylglutamine) C; poly- (glutaryl-glutamine) D.
- This example is intended to show that the poly ( ⁇ -malonylglutamine) derivative binds in the presence of Ca +2 , to lipid surfaces as does prothrombin - (see for example SP BAJAJ et al., Journal of Biol.
- a liposome suspension was first prepared by dissolving 250 mg of lecithin in 36 ml of CHCl 3 , adding 10 ml of buffer (20 mM Tris, HCl + 40 mMol NaCl, pH 7.5) and subjecting this mixture to ultrasound at 50 ° C. After evaporation of CHCl 3 , 30 ml of buffer were added, the total volume was adjusted to 40 ml and centrifuged for 1/2 hour at 60,000 rpm. The pellet was taken up in 41.6 ml of buffer which provided a liposome suspension at 6 mg / ml.
- a 10 mM aqueous solution of Ca ions was then introduced into a series of test tubes, each containing 2 mg / ml of liposomes and increasing amounts (from 0.025 to 1 mg / ml) of poly ( ⁇ -malonylglutamine) labeled with 14 C.
- poly ( ⁇ -malonylglutamine) labeled with 14 C.
- EEDQ radioactive methyl glycinate 14 C in the presence of EEDQ, (2-ethoxy-1-ethoxy-carbonyl-1,2, dihydroquinoline) so as to replace approximately 1% of the malonic residues with the glycinate and thus obtain a specific activity of 37,000 dpm / mg (disintegrate / min) of polymer.
- the liposomes were centrifuged and the radioactivity present in the supernatant was then measured, this quantity characterizing the percentage of poly ( ⁇ -malonylglutamine) not fixed by the liposomes.
- polymers -poly ( ⁇ -glutamylglutamine); -poly ( ⁇ -aspartylglutamine); - poly ( ⁇ -malonylglutamine) were dissolved in an isotonic NaCl solution at pH 7.4 (0.01 M phosphate) at a concentration of 100 mg / ml.
- the solutions were injected i.p. to white mice (25-30 g) up to a dose of 2000 mg / kg (5 tests per dose). After a 4-week observation period, no lethal effect was observed on the experimental animals, up to the dose of 2000 mg / kg.
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Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH5436/85 | 1985-12-19 | ||
CH5436/85A CH667874A5 (fr) | 1985-12-19 | 1985-12-19 | Polypeptide synthetique biodegradable et son utilisation pour la preparation de medicaments. |
Publications (1)
Publication Number | Publication Date |
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EP0250492A1 true EP0250492A1 (fr) | 1988-01-07 |
Family
ID=4293559
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP87900038A Withdrawn EP0250492A1 (fr) | 1985-12-19 | 1986-12-15 | Polypeptide synthetique biodegradable et son utilisation en therapeutique |
Country Status (5)
Country | Link |
---|---|
US (1) | US4892733A (fr) |
EP (1) | EP0250492A1 (fr) |
JP (1) | JPS63502037A (fr) |
CH (1) | CH667874A5 (fr) |
WO (1) | WO1987003891A1 (fr) |
Families Citing this family (78)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3700128A1 (de) * | 1987-01-03 | 1988-07-14 | Hoechst Ag | Biologisch abbaubare poly- (hydroxyalkyl)- aminodicarbonsaeure-derivate, verfahren zu ihrer herstellung und verwendung derselben fuer depotzubereitungen mit kontrollierter wirkstoffabgabe |
US5141751A (en) * | 1988-06-29 | 1992-08-25 | Daiichi Pharmaceutical Co., Ltd. | Lipid membrane structures |
LU87410A1 (fr) * | 1988-12-20 | 1990-07-10 | Cird | Composition cosmetique ou pharmaceutique contenant des microspheres de polymeres ou de corps gras chargees d'au moins un produit actif |
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- 1986-12-15 WO PCT/CH1986/000177 patent/WO1987003891A1/fr not_active Application Discontinuation
- 1986-12-15 JP JP62500035A patent/JPS63502037A/ja active Pending
- 1986-12-15 US US07/101,298 patent/US4892733A/en not_active Expired - Fee Related
- 1986-12-15 EP EP87900038A patent/EP0250492A1/fr not_active Withdrawn
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Title |
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Also Published As
Publication number | Publication date |
---|---|
CH667874A5 (fr) | 1988-11-15 |
WO1987003891A1 (fr) | 1987-07-02 |
JPS63502037A (ja) | 1988-08-11 |
US4892733A (en) | 1990-01-09 |
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