DE4224401A1 - New biodegradable homo- and co-polymer(s) for pharmaceutical use - produced by polycondensation of prod. from heterolytic cleavage of aliphatic polyester with functionalised (cyclo)aliphatic cpd. - Google Patents
New biodegradable homo- and co-polymer(s) for pharmaceutical use - produced by polycondensation of prod. from heterolytic cleavage of aliphatic polyester with functionalised (cyclo)aliphatic cpd.Info
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- DE4224401A1 DE4224401A1 DE19924224401 DE4224401A DE4224401A1 DE 4224401 A1 DE4224401 A1 DE 4224401A1 DE 19924224401 DE19924224401 DE 19924224401 DE 4224401 A DE4224401 A DE 4224401A DE 4224401 A1 DE4224401 A1 DE 4224401A1
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- aliphatic
- substituted
- cycloaliphatics
- aliphatic polyester
- biodegradable
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- 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
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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)
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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
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
- C08G63/08—Lactones or lactides
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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
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
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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
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/91—Polymers modified by chemical after-treatment
- C08G63/912—Polymers modified by chemical after-treatment derived from hydroxycarboxylic acids
Abstract
Description
Die Erfindung betrifft ein Verfahren zur Herstellung neuer modifizierter biologisch abbaubarer Homo- und Copolymere. Diese Polymere können vorzugsweise als Matrixmaterialien in parenteralen Langzeitabgabesystemen für spezielle Phar maka, wie Peptide, Steroide, Cytostatika und Antibiotika, in der Human- und Veterinärmedizin sowie für diverse re sorbierbare medizinische Hilfsmittel, insbesondere in der chirurgischen Praxis, eingesetzt werden.The invention relates to a method for producing new modified biodegradable homo- and copolymers. These polymers can preferably be used as matrix materials in long-term parenteral delivery systems for special pharmaceuticals maka, such as peptides, steroids, cytostatics and antibiotics, in human and veterinary medicine as well as for various re sorbable medical aids, especially in the surgical practice.
Der Einsatz biologisch abbaubarer Polymere in Depotarznei formen mit retardierter bzw. kontrollierter Wirkstoff freisetzung wird vor allem durch ihr in vivo Freisetzungs- und Resorptionsverhalten bestimmt. Beides hängt in kom plexer Weise von der chemischen Struktur des Wirkstoffs und des polymeren Matrixmaterials, von Molmasse und Mol massenverteilung des Polymeren sowie von seiner Morpholo gie ab. Biologisch abbaubare Polymere für die Arzneistoff galenik sind vor allem aus der Gruppe der aliphatischen Polyester und - in wesentlich geringerem Umfang - der aliphatischen Polyamide bekannt. Die medikamentöse Thera pie mit solchen Depotarzneiformen erfordert ein breites Spektrum unterschiedlichen Freisetzungsverhaltens, das man vor allem über die chemische Struktur zu steuern sucht.The use of biodegradable polymers in depot drugs mold with delayed or controlled active ingredient Release is primarily due to their in vivo release and Absorption behavior determined. Both depend in com plexer way of the chemical structure of the active ingredient and the polymeric matrix material, molar mass and mol mass distribution of the polymer and its morpholo cast off. Biodegradable polymers for the drug galenics are mainly from the group of aliphatic Polyester and - to a much lesser extent - the aliphatic polyamides known. The drug Thera Pie with such depot pharmaceuticals requires a wide range Spectrum of different release behavior, the one mainly to control the chemical structure is looking for.
Üblicherweise werden für diese pharmazeutischen Applika tionen binäre Copolyester, beispielsweise der Glykol- und der Milchsäure eingesetzt (G.W. Hastings, P. Dualaque, Macromolecular Materials, CRC Press, Boca Raton, Florida 1984). Auch andere Kombinationen von α- bzw. ω-Hydroxycar bonsäuren werden in der Fachliteratur beschrieben (vgl. beispielsweise R. Mank, G. Rafler, B. Nerlich, Pharmazie 46 (1991), 9). Wie in der DE-OS 34 30 852 beschrieben, läßt sich die Palette der aliphatischen Polyester durch Verwendung von binären oder ternären Copolymeren, die neben Milch- oder Glykolester bzw. Milch- und Glykolsäure hydroxylgruppenhaltige Verbindungen, vor allem Monsaccha ride bzw. ihre Reduktionsprodukte enthalten, beträchtlich erweitern.Usually for these pharmaceutical applications binary copolyesters, for example the glycol and lactic acid (G.W. Hastings, P. Dualaque, Macromolecular Materials, CRC Press, Boca Raton, Florida 1984). Other combinations of α- or ω-hydroxycar bonic acids are described in the specialist literature (cf. for example R. Mank, G. Rafler, B. Nerlich, Pharmacy 46: 9 (1991). As described in DE-OS 34 30 852, the range of aliphatic polyesters can be Use of binary or ternary copolymers that in addition to lactic or glycolic ester or lactic and glycolic acid compounds containing hydroxyl groups, especially monsaccha ride or their reduction products, considerable expand.
Die Homo- und Copolymeren der α- bzw. ω-Hydroxycarbonsäu ren können durch Ringöffnungspolymerisation der cyclischen Diester (Lactide bzw. Lactone) oder durch Polykondensation der Hydroxycarbonsäuren selbst synthetisiert werden. Im Fall der α-Hydroxycarbonsäuren führt die Polykondensation aufgrund der thermodynamischen Stabilität ihrer cyclischen Ester und des Ringkettengleichgewichts jedoch nur zu rela tiv niedermolekularen Produkten mit einem mittleren Mole kulargewicht n 5000. Hochmolekulare Polyester der α-Hy droxycarbonsäuren erhält man ausschließlich durch Ring öffnungspolymerisation der cyclischen Diester. Sowohl bei der Polykondensationsreaktion als auch der Ringöffnungs polymerisation werden Stern-Polymere gebildet, d. h. ein Polyolrest als Zentralstelle ist von mehreren Säurerest- Ketten umgeben.The homo- and copolymers of α- and ω-hydroxycarboxylic acids can be synthesized by ring-opening polymerization of the cyclic diesters (lactides and lactones) or by polycondensation of the hydroxycarboxylic acids themselves. In the case of α-hydroxycarboxylic acids, however, due to the thermodynamic stability of their cyclic esters and the ring chain equilibrium, the polycondensation only leads to relatively low-molecular-weight products with an average molecular weight n 5000. High-molecular-weight polyesters of α-hydroxycarboxylic acids are obtained exclusively by ring-opening polymerization of the cyclic diesters . Star polymers are formed in both the polycondensation reaction and the ring opening polymerization, ie a polyol residue as the central point is surrounded by several acid residue chains.
Insbesondere für die Darstellung modifizierter Polylactide bzw. Poly(glycolid-co-lactid)e bedeuten die bekannten Syntheseverfahren Ringöffnungspolymerisation für höher- und hochmolekulare und Polykondensation für niedermoleku lare Materialien eine erhebliche Beschränkung hinsichtlich Art und Konzentration der Modifizierungskomponenten, wie dies aus der DE-OS 43 08 852 auch ersichtlich ist. Werden die modifizierten Polylactide oder Poly(lactid-co-glyco lid)e wie üblich durch Ringöffnungspolymerisation synthe tisiert, so wirken die hydroxylhaltigen Comonomeren als Coinitiatoren in der Initiierungsreaktion, und sie können deshalb infolge der bekannten Zusammenhänge zwischen mitt leren Molekulargewicht und Coinitiatorkonzentration nur in geringen Mengen von weniger als 1 Mol% zugesetzt werden (vgl. beispielsweise H.-G. Elias: "Makromoleküle", Basel/ Heidelberg: Hüthig & Wepf, 1975). Dementsprechend werden in der DE-OS 43 08 852 im allgemeinen auch nur 0,2% an Modifizierungskomponente im Vergleich zu Dilactid bzw. Dilactid-Diglycolid-Gemischen zugesetzt. Derartige geringe Mengen an Modifizierungskomponente können den chemischen Charakter, der von der Natur der im Makromolekül vorhande nen Bindungen determiniert wird, nicht signifikant gegen über dem unmodifizierten Polymeren verändern. Möglich sind nur gewisse Beeinflussungen des Löse- bzw. Quellverhaltens durch die Bildung vernetzter Strukturen mit der hydroxyl gruppenhaltigen Komponente als Ausgangsstelle der Verzwei gung. Werden, wie galenisch häufig gewünscht, größere Mengen an Modifizierungskomponente eingesetzt, so werden in Übereinstimmung mit den bekannten Gesetzmäßigkeiten zum Einfluß von Coinitiatoren auf den Verlauf von Polymerisa tionsprozessen auch nur niedermolekulare Produkte mit Molmassen unter 3500 g/Mol erhalten, wie in der DE-OS 43 08 852 ausgeführt.Especially for the representation of modified polylactides or poly (glycolide-co-lactide) s mean the known ones Synthesis process ring opening polymerization for higher and high molecular and polycondensation for low molecular weight materials have a significant limitation in terms of Type and concentration of the modification components, such as this is also evident from DE-OS 43 08 852. Will the modified polylactides or poly (lactide-co-glyco lid) e as usual by ring opening polymerization tized, the hydroxyl-containing comonomers act as Coinitiators in the initiation reaction and they can therefore due to the known relationships between mitt molecular weight and coinitiator concentration only in small amounts of less than 1 mol% are added (see, for example, H.-G. Elias: "Macromolecules", Basel / Heidelberg: Hüthig & Wepf, 1975). Accordingly in DE-OS 43 08 852 in general only 0.2% Modification component compared to dilactide or Dilactid-diglycolide mixtures added. Such minor Amounts of modification component can be chemical Character that is inherent in the macromolecule ties are determined, not significantly against change over the unmodified polymer. Possible are only certain influences on the dissolving or swelling behavior through the formation of cross-linked structures with the hydroxyl group-containing component as the starting point of the branch supply. Become larger, as is often desired by galenics Amounts of modification component are used in accordance with the known laws on Influence of coinitiators on the course of Polymerisa processes with only low molecular weight products Molar masses below 3500 g / mol obtained, as in DE-OS 43 08 852 executed.
Weiterhin ist bei dem Einsatz von Coinitiatoren als Modi fizierungskomponente nicht nur die Konzentration begrenzt, sondern vor allem auch die chemische Struktur der Kompo nente. Gefordert ist Kompatibilität mit dem Initiator und den der jeweiligen Polymerisation zugrundeliegenden Wachs tumsreaktionen. Im Falle der Ringöffnungspolymerisation können nur hydroxylgruppenhaltige Verbindungen eingesetzt werden, da nur sie als Coinitiatoren wirken (vgl. auch F.E. Kohn et al., J. Appl. Polymer Sci. 29(1984) 3265).Furthermore, when using coinitiators as modes processing component not only limits the concentration, but above all the chemical structure of the compo nente. Compatibility with the initiator and the wax on which the respective polymerization is based growth reactions. In the case of ring opening polymerization can only use compounds containing hydroxyl groups because only they act as coinitiators (see also F.E. Kohn et al., J. Appl. Polymer sci. 29 (1984) 3265).
Auch für die Darstellung durch Polykondensation gelten erhebliche Einschränkungen. Hier muß vor allem die Stö chiometrie der Endgruppen durch den Comonomereinsatz ge wahrt bleiben. Bei Verwendung von höherfunktionellen Mono meren besteht darüber hinaus bereits bei relativ niedrigen Umsetzungsgraden die Gefahr der Vernetzung im Reaktions verlauf. Derartige Materialien sind unlöslich und schwer schmelzbar und können daher nach den üblichen Methoden nicht mit Arzneistoffen beladen und zu einer applizier baren Arzneiform verarbeitet werden.Also apply to the representation by polycondensation significant restrictions. Above all, the interference chiometry of the end groups through the use of comonomers stay true. When using more functional mono Meren also exists at relatively low Implementation levels the risk of cross-linking in the reaction course. Such materials are insoluble and heavy fusible and can therefore be made according to the usual methods not loaded with drugs and applied to an cash drug form can be processed.
Aufgabe der Erfindung ist die Entwicklung eines Verfahrens für parenteral applizierbare Polymere, das von resorbier baren Polyestern ausgehend die Darstellung beliebiger biologisch abbaubarer Copolymerer mit Heterokettenstruktur gestattet. Das Verfahren soll bezüglich der Struktur und der Konzentration der Modifizierungskomponente nicht den Einschränkungen der bekannten Verfahren, wie z. B. Ringöff nungspolymerisation und Gleichgewichtspolykondensation, unterliegen.The object of the invention is to develop a method for parenterally applicable polymers, that of resorbier possible polyesters based on the representation of any biodegradable copolymer with heterochain structure allowed. The procedure is intended in terms of structure and the concentration of the modification component not the Limitations of the known methods, such as. B. ring opening polymerization and equilibrium polycondensation, subject to.
Weitere Aufgabe der Erfindung ist die Darstellung neuer, speziell modifizierter biologisch abbaubarer Polymere, die als Matrixmaterialien für pharmazeutische Depotarzneifor men bzw. für Systeme mit gesteuerter Wirkstofffreisetzung angewendet werden können.Another object of the invention is to present new, specially modified biodegradable polymers that as matrix materials for pharmaceutical depot medicines men or for systems with controlled drug release can be applied.
Unter "biologisch abbaubar" ist im Zusammenhang mit der biomedizinischen Applikation von Polymeren die Biokompati bilität der Polymeren und ihrer Abbauprodukte sowie die vollständige Resorbierbarkeit des Polymeren in einem über schaubaren Zeitraum von einigen Tagen bis zu einigen Mona ten zu verstehen. Die erfindungsgemäß als Ausgangsstoffe eingesetzten aliphatischen Homo- und Copolyester weisen sowohl die erforderliche Biokompatibilität als auch die rückstandsfreie Resorbierbarkeit auf, wie umfangreiche klinische Studien sowie der jahrelange erfolgreiche Ein satz als resorbierbare chirurgische Nahtmaterialien ge zeigt haben.Under "biodegradable" is in connection with the biomedical application of polymers the biocompati bility of the polymers and their degradation products and the complete resorbability of the polymer in an over manageable period from a few days to a few months to understand. According to the invention as starting materials aliphatic homo- and copolyesters used both the required biocompatibility and the residue-free absorbability on how extensive clinical trials and years of successful use set as resorbable surgical sutures shows.
Erfindungsgemäß wird die Aufgabe dadurch gelöst, daß hoch molekulare biologisch abbaubare Homo- und Copolyester zunächst mit einer bi- bzw. höherfunktionellen Verbindung alkoholytisch, aminolytisch oder acidolytisch gespalten und anschließend in einem zweiten Reaktionsschritt unter Einbau der Modifizierungskomponente wieder zu einem hoch molekularen Heterokettenpolymeren, wie Polyestern, Poly esteramiden, Polyetherestern oder Polyesteranhydriden, polykondensiert werden.According to the invention the object is achieved in that high molecular biodegradable homo- and copolyesters initially with a bi- or higher-functional connection split alcoholic, aminolytic or acidolytic and then in a second reaction step Installation of the modification component back to a high molecular hetero-chain polymers, such as polyesters, poly ester amides, polyether esters or polyester anhydrides, be polycondensed.
Als bi- bzw. höherfunktionelle Modifizierungskomponente eignen sich alle Stoffe, die als funktionelle Gruppen Hydroxyl-, Amino- oder Carboxylgruppen allein oder in beliebiger Kombination enthalten. Beispiele für solche Modifizierungskomponenten sind Polyole, wie z. B. Diole, Triole und Hexole (Zuckeralkohole), Diamine, Aminoalkoho le, Dicarbonsäuren, Hydroxycarbonsäuren, Hydroxypolycar bonsäuren sowie bi- und trifunktionelle Aminosäuren.As a bi- or higher functional modification component all substances are suitable as functional groups Hydroxyl, amino or carboxyl groups alone or in any combination included. Examples of such Modification components are polyols, such as. B. diols, Triols and hexols (sugar alcohols), diamines, amino alcohol le, dicarboxylic acids, hydroxycarboxylic acids, hydroxypolycar bonic acids and bi- and trifunctional amino acids.
Bevorzugte Polyole sind die Hexole, besonders bevorzugt sind die Hexole Mannit und Sorbit. Bevorzugte Aminosäuren sind bi- und trifunktionelle Aminosäuren, hier vor allem die α-Aminosäuren, insbesondere die α-L-Aminosäuren. Ganz besonders bevorzugt sind die natürlich vorkom menden α-L-Aminosäuren, wie zum Beispiel L-Glycin, L-Ala nin, L-Glutaminsäure, L-Lysin. Bevorzugte Hydroxycarbon säuren sind Milch-, Glykol-, Hydroxybutter- und Hydroxyca pronsäure sowie als polyfunktionelle Vertreter Wein- und Zitronensäure. Als reine Dicarbonsäuren können als Modifi zierungskomponenten Bernstein- und Sebacinsäure eingesetzt werden.Preferred polyols are the hexols, particularly preferred are the hexols mannitol and sorbitol. Preferred amino acids are bifunctional and trifunctional amino acids, especially here the α-amino acids, especially the α-L-amino acids. All naturally occurring are particularly preferred α-L-amino acids such as L-glycine, L-Ala nin, L-glutamic acid, L-lysine. Preferred hydroxycarbon Acids are milk, glycol, hydroxy butter and hydroxyca pronic acid and as a polyfunctional representative wine and Citric acid. As pure dicarboxylic acids can as Modifi Decorative components used succinic and sebacic acid become.
Erfindungsgemäß geeignete biologisch abbaubare Polymere sind z. B. Polyester, wie z. B. Polyglycolid, Polylactid, Polyhydroxybuttersäure und Polycaprolacton sowie alle Copolymeren dieser Polyester in beliebiger Zusammenset zung. Besonders geeignete biologisch abbaubare Polymere sind die die Homo- und Copolyester der Glykol und der D-, L- bzw. L-Milchsäure.Biodegradable polymers suitable according to the invention are z. B. polyester, such as. B. polyglycolide, polylactide, Polyhydroxybutyric acid and polycaprolactone and all Copolymers of these polyesters in any composition tongue. Particularly suitable biodegradable polymers are the homo- and copolyesters of glycol and D-, L- or L-lactic acid.
Gegenstand der Erfindung sind auch die bei der Alkoholyse der Aminolyse bzw. der Acidolyse der Polymeren gemäß den Reaktionsgleichungen (1) bis (3) gebildeten, die Modifi zierungskomponente als terminale Endgruppe enthaltenden Reaktionsprodukte I bis III.The invention also relates to those in alcoholysis the aminolysis or the acidolysis of the polymers according to the Reaction equations (1) to (3) formed, the Modifi ornamental component containing terminal end group Reaction products I to III.
R₁ = Polyesterrest mit einer mittleren Molmasse von 500 g/mol n 50 000 g/mol
mit einer Methylengruppenzahl der Monomereinheit von nCH₂=1 bis nCH₂=
5, wobei eine CH₂-Gruppe durch einen Alkylrest substituiert sein kann.
R₂ = R₂ weist die gleiche chemische Struktur wie R₁ auf, unterscheidet sich jedoch -
ausgenommen den speziellen Fall R₁=R₂ bei gleicher Kettenlänge - in der
mittleren Molmasse.
R₃ = mono- bzw. polyfunktioneller hydroxy-, amino- oder/und carboxysubstituierter
aliphatischer oder cycloaliphatischer Rest.R₁ = polyester radical with an average molecular weight of 500 g / mol n 50,000 g / mol with a number of methylene groups in the monomer unit from n CH₂ = 1 to n CH₂ = 5, where a CH₂ group can be substituted by an alkyl radical.
R₂ = R₂ has the same chemical structure as R₁, but differs - except for the special case R₁ = R₂ with the same chain length - in the average molecular weight.
R₃ = mono- or polyfunctional hydroxy-, amino- and / or carboxy-substituted aliphatic or cycloaliphatic radical.
R₁, R₂, R₃ entsprechend Gleichung (1)R₁, R₂, R₃ according to equation (1)
R₁, R₂ entsprechend Gleichung (1), R₃ aliphatischer oder cycloaliphatischer RestR₁, R₂ according to equation (1), R₃ aliphatic or cycloaliphatic radical
Die mittleren Molekulargewichte der primären Spaltungs produkte sind der Konzentration der Modifizierungskompo nente und ihrer Funktionalität direkt porportional. Die Molekulargewichte der kettenverknüpfend behandelten primä ren Spaltungsprodukte sind vor allem von der Art der funk tionellen Gruppen und ihrer Reaktivität sowie dem Grad der Desorption der flüchtigen Reaktionsprodukte abhängig.The average molecular weights of the primary cleavage products are the concentration of the modification compo elements and their functionality are directly proportional. The Molecular weights of the chain-linking treated primary Their fission products are primarily of the type of radio tional groups and their reactivity as well as the degree of Desorption of the volatile reaction products dependent.
Nicht nur die bekannte polykondensationsfähige Kombination von Carboxyl- und Hydroxylgruppen ergibt hochmolekulare Kondensationsprodukte (Reaktionsgleichungen (4) und (6)), sondern auch die ether- und aminhaltigen Polymeren weisen hohe Molekulargewichte auf (Reaktionsgleichungen 5, 7 und 8). Not just the well-known combination capable of polycondensation of carboxyl and hydroxyl groups results in high molecular weight Condensation products (reaction equations (4) and (6)), but also have the ether and amine-containing polymers high molecular weights (reaction equations 5, 7 and 8th).
R₁, R₂, R₃ jeweils entsprechend Gleichung (1)R₁, R₂, R₃ each according to equation (1)
Die erfindungsgemäßen Verfahren erlauben die Herstellung biologisch abbaubarer Polymere mit einem beliebigen Gehalt einer Modifizierungskomponente. Vorzugsweise beträgt der Gehalt der Modifizierungskomponente 0,005 bis 0,1 mol pro mol Monomereinheit. Auf diese Weise läßt sich das Abbau verhalten gezielt der gewünschten Anwendung anpassen und in beliebiger Weise steuern.The methods according to the invention allow production biodegradable polymers with any content a modification component. The is preferably Content of the modification component 0.005 to 0.1 mol per mol of monomer unit. In this way, the breakdown adapt the behavior to the desired application and control in any way.
Die erfindungsgemäßen Polymere zeichnen sich dadurch aus, daß sie die Modifizierungskomponente oder -komponenten statistisch über die Polymerketten verteilt enthalten. Es handelt sich um lineare Moleküle und nicht um Stern-Poly mere, wie sie aus dem Stand der Technik bekannt sind.The polymers according to the invention are notable for that they are the modification component or components included statistically over the polymer chains. It are linear molecules and not star poly mere, as they are known from the prior art.
Durch die Wahl der Art und Menge der Modifizierungskom ponente läßt sich das Löslichkeitsverhalten der biologisch abbaubaren Polymere in bisher nicht gekannter Breite be einflussen. Auf diese Weise werden Polymere zugänglich, die - im Gegensatz zu den bekannten Polymeren - in physio logisch unbedenklichen Lösungsmitteln löslich sind, so daß die Verwendung chlorierter Kohlenwasserstoffe bei der Beladung mit Arzneistoffen vermieden werden kann. Diese Eigenschaft macht die erfindungsgemäßen Polymere besonders als Matrix für lösungsmittelempfindliche Arzneistoffe interessant.By choosing the type and amount of Modificationkom component, the solubility behavior of the biological degradable polymers in a previously unknown width influence. In this way, polymers become accessible which - in contrast to the known polymers - in physio logically harmless solvents are soluble, so that the use of chlorinated hydrocarbons in the Loading with drugs can be avoided. This Properties make the polymers according to the invention special as a matrix for solvent-sensitive drugs Interesting.
Im folgenden wird die Erfindung anhand von Beispielen erläutert.In the following the invention will be explained with the aid of examples.
14,4 g Poly-D,L-Lactid mit einer relativen Lösungs viskosität von ηrel = 1,62 (wenn nicht anders ange geben, beziehen sich alle ηrel-Werte auf eine 0,5%ige Lösung in Dimethylformamid (DMF) bei 20°C) werden bei 180°C unter Stickstoff und intensivem Rühren mit 0,182 g Mannit umgesetzt. Nach vier Stunden wird die Reaktion beendet und das Reaktionsprodukt in Dime thylformamid gelöst, in Ethanol gefällt und im Vakuum bei Raumtemperatur getrocknet. Das Material weist ei ne relative Lösungsviskosität von ηrel = 1,43 auf. Das membranosmometrisch ermittelte Molekulargewicht n beträgt 40 500 g/mol.14.4 g poly-D, L-lactide with a relative solution viscosity of η rel = 1.62 (unless stated otherwise, all η rel values refer to a 0.5% solution in dimethylformamide (DMF) at 20 ° C) are reacted with 0.182 g mannitol at 180 ° C under nitrogen and vigorous stirring. After four hours, the reaction is ended and the reaction product is dissolved in dimethylformamide, precipitated in ethanol and dried in vacuo at room temperature. The material has a relative solution viscosity of η rel = 1.43. The molecular weight n determined by membrane osmometry is 40,500 g / mol.
Das entsprechend (1.1) hergestellte primäre Spal tungsprodukt wird bei 180°C und 0,1 bis 0,2 Torr unter intensiver Durchmischung der Schmelze zwei Stunden lang polykondensiert. Nach beendeter Polykon densation wird in DMF gelöst, in Ethanol gefällt und im Vakuum getrocknet. Das mannithaltige Poly-D,L- Lactid weist eine relative Lösungsviskosität von ηrel = 1,58 auf. The primary cleavage product prepared in accordance with (1.1) is polycondensed at 180 ° C. and 0.1 to 0.2 torr with intensive mixing of the melt for two hours. When the polycondensation is complete, it is dissolved in DMF, precipitated in ethanol and dried in vacuo. The mannitol-containing poly-D, L-lactide has a relative solution viscosity of η rel = 1.58.
Entsprechend Beispiel 1 werden Poly-D,L-Lactide (PLA) unterschiedlicher Molekulargewichte alkoholysiert und die mannithaltigen primären Spaltungsprodukte wieder polykon densiert.According to Example 1, poly-D, L-lactides (PLA) of different molecular weights and the alcohol mannitol-containing primary cleavage products again polycon densifies.
28,8 g D,L-PLA mit einer relativen Lösungsviskosität von ηrel = 1,62 werden mit 1,82 g Sorbit innerhalb von einer Stunde gespalten und anschließend im Vakuum bei 180°C polykondensiert. Das sorbithaltige Polylactid wird in DMF gelöst, in Ethanol gefällt und im Vakuum getrocknet. In Abhängigkeit von den Polykondensationszeiten werden die in Tabelle 2 zusammengestellten relativen Lösungsviskositäten erhalten. 28.8 g of D, L-PLA with a relative solution viscosity of η rel = 1.62 are split with 1.82 g of sorbitol within one hour and then polycondensed in vacuo at 180 ° C. The sorbitol-containing polylactide is dissolved in DMF, precipitated in ethanol and dried in vacuo. Depending on the polycondensation times, the relative solution viscosities shown in Table 2 are obtained.
26,0 g Poly(glycolid(50)-co-lactid(50)) mit einer relati ven Lösungsviskosität von ηrel = 1,35 werden entsprechend Beispiel 1 mit 1,82 g Sorbit gespalten und anschließend entsprechend Beispiel 2 polykondensiert. Die Reaktionszeit für die heterolytische Spaltung beträgt 1 h und für die anschließende Polykondensation 2 h. Der sorbithaltige äqui molar zusammengesetzte Copolyester weist eine relative Lösungsviskosität von ηrel = 1,29 auf.26.0 g of poly (glycolide (50) -co-lactide (50)) with a relative solution viscosity of η rel = 1.35 are cleaved in accordance with Example 1 with 1.82 g of sorbitol and then polycondensed as in Example 2. The reaction time for the heterolytic cleavage is 1 h and for the subsequent polycondensation 2 h. The sorbitol-containing equimolar copolyester has a relative solution viscosity of η rel = 1.29.
28,8 g D,L-PLA mit einer relativen Lösungsviskosität von ηrel = 1,78 werden analog Beispiel 1 mit 0,75 g L-Glycin bei 180°C umgesetzt und aufgearbeitet. Das Reaktions produkt weist in DMF einen ηrel-Wert von 1,38 auf. Nach Polykondensation analog Beispiel 2 wird ein glycinhaltiges Polylactid mit einem ηrel-Wert von 1,69 erhalten. Die Reak tionszeit für die heterolytische Spaltung beträgt 1 h und für die anschließende Polykondensation 2 h.28.8 g of D, L-PLA with a relative solution viscosity of η rel = 1.78 are reacted with 0.75 g of L-glycine at 180 ° C. and worked up as in Example 1. The reaction product has a η rel value of 1.38 in DMF. After polycondensation as in Example 2, a glycine-containing polylactide with an η rel value of 1.69 is obtained. The reaction time for the heterolytic cleavage is 1 h and for the subsequent polycondensation 2 h.
Analog Beispiel 8 werden zur Modifizierung von Polylactid bi- und trifunktionelle Aminosäuren eingesetzt. Die erhal tenen aminosäure-terminierten bzw. aminosäurehaltigen Produkte sind in Tabelle 3 beschrieben.Analogous to Example 8 for the modification of polylactide bi- and trifunctional amino acids used. The receive ten amino acid-terminated or amino acid-containing Products are described in Table 3.
17,2 g PHB mit einer relativen Lösungsviskosität von = 2,60 werden entsprechend Beispiel 1 mit 0,364 g Sorbit umgesetzt und anschließend entsprechend Beispiel 2 poly kondensiert und aufgearbeitet. Die Reaktionszeit für die heterocyclische Spaltung beträgt 1 Stunde und für die an schließende Polykondensation 2 Stunden. Die sorbithaltige PHB weist eine relative Lösungsviskosität von ηrel = 1,88 auf. 17.2 g of PHB with a relative solution viscosity of = 2.60 are reacted with 0.364 g of sorbitol as in Example 1 and then polycondensed and worked up as in Example 2. The reaction time for the heterocyclic cleavage is 1 hour and for the subsequent polycondensation 2 hours. The sorbitol-containing PHB has a relative solution viscosity of η rel = 1.88.
Die entsprechend Beispiel 1 bis 12 hergestellten biolo gisch abbaubaren Polymeren weisen in Abhängigkeit von der Art und der Konzentration der Modifizierungskomponente in organischen Lösungsmitteln unterschiedliche Löslichkeiten auf. Damit lassen sich die Polymeren den vom jeweiligen Arzneistoff geforderten günstigsten Verformungsbedingun gen, beispielsweise zu Mikrosphären oder zu Filmen optimal anpassen.The biolo prepared according to Examples 1 to 12 Degradable polymers show depending on the Type and concentration of the modification component in organic solvents different solubilities on. This allows the polymers to be modified by the respective Drug required the most favorable deformation conditions conditions, for example to microspheres or films to adjust.
Zur Charakterisierung des Quell- und Abbauverhaltens wurden aus den erfindungsgemäß hergestellten Polymeren durch Lösungsmittelverdamp fung Mikropartikel hergestellt und diese in einer Phosphatpufferlö sung von pH = 7 bei 37°C gelagert. Für diese Untersuchungen wurde ein Verhältnis der Pufferlösung zum Polymeren von 200 : 1 gewählt.To characterize the swelling and degradation behavior, the Polymers produced according to the invention by solvent evaporation microparticles and these in a phosphate buffer solution solution of pH = 7 stored at 37 ° C. For these examinations a ratio of the buffer solution to the polymer of 200: 1 was chosen.
Claims (28)
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DE19924224401 DE4224401A1 (en) | 1992-07-21 | 1992-07-21 | New biodegradable homo- and co-polymer(s) for pharmaceutical use - produced by polycondensation of prod. from heterolytic cleavage of aliphatic polyester with functionalised (cyclo)aliphatic cpd. |
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DE19924224401 DE4224401A1 (en) | 1992-07-21 | 1992-07-21 | New biodegradable homo- and co-polymer(s) for pharmaceutical use - produced by polycondensation of prod. from heterolytic cleavage of aliphatic polyester with functionalised (cyclo)aliphatic cpd. |
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