BIODEGRADABLE LIQUID CRYSTALLINE POLYMERS

Abstract: Novel thermotropic polymers, typically aromatic poly(ester-anhydride)s, having high modulus and biodegradability, have use as bone fixative materials and may be used in the construction of prosthetic devices and for filling other bone defects.

Description: BIODEGRADABLE LIQUID CRYSTALLINE POLYMERS This invention relates to novel polymers and particularly high performance bioresorbable polymers which have liquid crystalline properties. Thermotropic polyesters are known and such materials generally possess advantageous properties such as, inter alia, high thermostability, low sensitivity to oxidation. However, such polyesters are generally not biodegradable. Although many biodegradable polymers are known, such as those comprising lactic acid or β-hydroxybutyric, they are generally aliphatic in nature. Whilst they find utility in, for example, drug delivery systems or medical sutures, they do not possess the high strength and high modulus required for use in, eg. load bearing implants. Polyester anhydrides are known from European Patent application No.0055527. However, the polyester anhydrides disclosed therein are not sufficiently bioresorbable or do not possess sufficient strength and/or modulus to be suitable as load bearing bioresorbable implants. We have now surprisingly found a novel polymeric material which overcomes or mitigates these disadvantages. Thus according to the invention we provide a polymeric material comprising repeating units of an aromatic mesogenic moiety, a hydroiysabie moiety and a spacer moiety. The polymeric material is preferably a condensation product containing aromatic ester moieties as the mesogenic component, mixed aromatic and aliphatic anhydride moieties as the hydrolysable component and aliphatic chains as the spacer moiety. Suitably these components may be provided by a condensation product comprising both aromatic and aliphatic diacid residues or functional derivatives thereof and residues of polyfunctional nucleophilic species such as a diol or thiol. Thus the preferred polymeric materials of the present invention are poly(ester-anhydride)s. Alternatively the mesogenic component may be derived from aromatic amide moieties. The aromatic mesogenic moiety may be a polyester moiety and is preferably a condensation product of, for example, a terephthaloyl or isophthaloyl moiety and a quinoid such as hydroquinone, methylhydroquinone, phenyihydroquinone, biphenol or dihydroxynaphthalene or derivatives thereof. Thus the aromatic mesogenic moiety aptly comprises a moiety of formula I. OC - R 2 - CO - 0 - Ri - O - OC - R 2 - CO I where R^ is: and R 2 is : or -(Q)~ A preferred mesogenic moiety comprises a moiety of the general formula II The hydrolysable moiety may comprise any conventionally known hydrolysable group. However, a preferred hydrolysable moiety is an anhydride linkage. Such anhydrides may be the condensation product of an aliphatic diacid derivative and an aromatic diacid derivative, such as a terephthaloyi acid derivative, eg. terephthaloyi chloride or an isophthaloyl derivative such as isophthaloyl chloride. The spacer moiety is any inert group and may preferably comprise an aliphatic chain, for example comprising methylene groups from C 2 to C 20 . suitably from C 2 to C 18 , and preferably from C 4 toC 10 . Alternatively, the spacer moiety may comprise alkylene oxide units ethylene oxide, propylene oxide or tetramethyiene oxide units. Thus according to the invention we provide a polymeric material comprising repeating units of formula III, in which: n is an integer from 2 to 20, preferably from 2 to 16, more preferably 4 to 10, R, and R 2 are as defined above and the ratio of x:y is from 1 :99 to 99:1 In a preferred embodiment R, andR 2 is methyl-substitued phenyl. According to a further feature of the invention we provide a method of manufacturing a polymeric material as hereinbefore described which comprises condensing a terephthaloyi or isophthaloyl compound and a quinoid such as hydroquinone, methylhydroquinone, phenylhydroquinone, biphenol or dihydroxynaphthalene or derivatives thereof and an aliphatic diacid or derivative thereof. The terephthaloyi or isophthaloyl derivative is preferably an acid haiide, eg. acid chloride such as terephthaloyi or isophthaloyl chloride. Such materials are generally commercially available. The quinoid derivative is preferably an activated hydroquinone such as the silylated derivative, eg. bis-trimethylsilyl hydroquinone. Bis-trialkylsilyl hydroquinones may be manufactured by, inter alia, reacting the respective quinoid with hexalkyldisiiazane. Similarly, the aliphatic diacid derivative is preferably an activated diacid such as a silylated diacid, eg. comprising silyl groups as hereinbefore described. The polymeric material of the invention is advantageous in that it may be degradable to fragments of low molecular weight, which may in itself facilitate bioresorbability. Such polymeric materials may be processed to produce high strength and high modulus materials which are useful in the manufacture of, inter alia, implantable devices, eg. implantable fixation devices such as bone fixation or prosthetic devices. The desired strength and modulus of the polymeric materials of the invention is evidenced by the presence of liquid crystal properties. Thus according to a further feature of the invention we provide a medical fixation device comprising a polymeric material as hereinbefore described. We further provide the use of a polymeric material as hereinbefore described in the manufacture of a medical fixation device. We also provide a method of bone fixation which comprises attaching a fixation device as hereinbefore described to portions of existing bone. Aptly such fixation devices are preformed to the shape of implantable prosthetic devices, such as femoral head or condylar prostheses or as a filling material, which may be suitably shaped, to replace missing or excised bone portions. The invention will now be described but in no way limited with reference to the following Examples. Example 1 Preparation of Bis-trimethytsilvl Methyl Hydroquinone Methyl hydroquinone (27.53g) and hexamethyldisilazane (48.42g) were refluxed together in toluene (400ml) for 2 hours. The resultant bis-trimethylsilyl hydroquinone (75g) was isolated by vacuum distillation. Preparation of Bis-trimethylsilyl Adipic Acid Adipic acid (36.54g) and hexamethyldisilazane (48.42g) were refluxed in toluene (400ml) for 4 hours. The resultant bis- trimethylsilyl adipate (84g) was isolated by vacuum distillation. Terephthaloyi chloride (4.06g), bis-trimethylsilyl methyl- hydroquinone (4.3g), bis-trimethylsilyl dodecanedioate (1.5g) and benzyltriethylammonium chloride (0.01g) were weighed under nitrogen into a glass reaction vessel. The reaction mixture was heated, with stirring under nitrogen, from 90 ' C to 260 * C over a period of 3 hours after which a vacuum was applied for a further half-hour. The product was washed with dry tetrahydrofuran, dried under vacuum at 60 'C and characterised by FTIR spectral analysis, 13C-NMR spectral analysis and optical scanning under polarised light. Figures 1 and 2, respectively, illustrate the FTIR and NMR spectra of the polymer. Figure 3 is a monochromatic reproduction of a coloured microphotograph of the polymer demonstrating the liquid crystalline properties of the polymer. The micrograph was taken between cross polars whilst the polymer was molten. The coloured region (textured region X shown in Figure 3) is evidence of a birefringent fluid which can only arise if there is molecular order in the liquid, i.e. a liquid crystalline polymer. Also illustrated in Figure 3 are thread-like structures (Y) which are typically associated with nematic type liquid crystals. Examples 2 to 5 Poly(ester-anhydride)s having the compositions shown in the following table were prepared in accordance with the method described in Example 1. Each polymer exhibited thermotropic behaviour (viz. a liquid crystalline phase in the polymer melt). T: Terephthaloyi Chloride M: Bis-trimethylsilyl methylhydroquinone P: Bis-trimethylsilyl phenylhydroquinone A: Bis-trimethyisiyl adipate Su: Bis-trimethylsilyl suberate Se: Bis-trimethylsilyl sebacate D: Bis-trimethylsilyl dodecanedioate Example 6 The method of Example 1 was used to prepare a polyester- anhydride) comprised of residues derived from 50 mole% terephthaloyi chloride, 37.5 mole% bis-trimethylsilyl hydroquinone and 12.5 mole% bis-trimethylsilyl dodecanedioate. A disc of the polymer material was immersed in deionized water, maintained at room temperature, for one month. The structure was analysed by infared spectroscopy to investigate hydrolysis of the anhydride linkage. The FTIR spectra of the original polymer (Curve A) and the degraded polymer (Curve B) is shown in Figure 4 where it will be seen that the strong absorption band near 1790 cm "1 for Curve A has almost disappeared at that point in Curve B.

Claims: CLAIMS 1. A biodegradable polymer comprising repeating units of an aromatic mesogenic moiety, a hydrolysable moiety and a spacer moiety. 2. A polymer as claimed in claim 1 in which the mesogenic moiety comprises aromatic ester residues. 3. A polymer as claimed in claim 1 or claim 2 in which the mesogenic moiety comprises residues of the general formula: OC - R 2 - CO - 0 - RT - 0 - R 2 - CO in which R ή is: and R 2 is -<Q^ °' 4δr 4. A polymer as claimed in any one of the preceding claims in which the hydrolysable moiety comprises anhydride linkages. 5. A polymer as claimed in any one of the preceeding claims in which the hydrolysable moiety comprises residues of mixed aromatic-aliphatic anhydride. 6. A polymer as claimed in any one of the preceding claims formed by the condensation of aromatic and aliphatic diacids or functional derivatives thereof with a nucleophilic compound. 7. A polymer as claimed in claim 6 in which the nucleophilic compound is an aromatic diol or thiol. 8. A polymer as claimed in any one of the preceding claims having repeating units if the general formula: 9. [(-OC-R 2 -CO-0-R r O)Jr\(OC-R 2 -CO-0-OC-{CH 2 ) n -COO) y ] in which n is an integer from 2 to 20; R, and R 2 are as defined in claim 3 and the ratio of x:y is from 1 :99 to 99: 1 , 10. A medical fixation device comprising a biodegradable polymer as defined in any one of the preceding claims. 11. A device as claimed in claim 10 comprising a prosthesis or a bone filling material.

Inventors: ALI SAAD ABOUL MAJEED, ROSE JOHN, SEARLE RICHARD JOHN, ALI, SAAD, ABOUL, MAJEED, ROSE, JOHN, SEARLE, RICHARD, JOHN
Applicants: ALI SAAD ABOUL MAJEED, ROSE JOHN, SEARLE RICHARD JOHN, SMITH & NEPHEW, ALI, SAAD, ABOUL, MAJEED, ROSE, JOHN, SEARLE, RICHARD, JOHN, SMITH & NEPHEW PLC
Application year: 1997
Main classification: C09K19
IPC codes: A61L24, A61L27, C08G63, C08G67