The delivery and device application of bioactive drugs is a rapidly expanding area of research. The development of a polymeric form of aspirin ('Polyaspirin', K. Uhrich, Abstr. Pap. Am. Chem. Soc.

1998, U322 part 2) has recently received much media attention.

This polymer system provides aspirin in the form of a material other than a crystalline solid and also avoids potential overdosing side effects such as gastric ulceration. However, because the active component (aspirin) is covalently bound into the polymeric structure, dosing will continue to be reliant upon the immediate environment of the polymer and breakdown to an unpredictable distribution of oligomeric fragments will still occur. Even so, the inventors claim that degradation of such a material results in a 60-70% release of active as a proportion of the total initial mass.

The present invention proposes a new class of materials which enable 100% of a biocompatible component, for example a pharmacologically active material to be delivered in situ. This objective is met by the provision of an amphiphilic compound in the form of an organic glass including a region comprising the bioactive material and an amorphous region.

A glass is commonly defined as an undercooled liquid (A. Paul, Chemistry of Glasses, 2nd Edition, Chapman and Hall, London, 1990..) Structurally, glasses lack the long range order of a crystalline solid, while maintaining the physical manifestations of the solid state i. e having a viscosity at least1013 poise (10~12kg. m-s~'). Organic glasses differ from the more common inorganic variety in that they are composed of non-ionic species interacting via non-covalent intermolecular forces. For example, many polymers are considered to be organic glasses (A. Bondi in Glass : Science and Technology, Volume 1, Glass-forming Systems, D. R. Uhlmann and N. J. Kreidl Eds., Academic Press NY, 1983,339). The most well known small molecule organic glass is glucose, a material capable of fibre- formation from the molten state (candy-floss). The capacity to form a thermodynamically stable glass is not thought to be an atomic or molecular dependent property but rather one of a state of aggregation.

Thus a normally crystalline bioactive drug may be covalently functionalised such that the product is capable of existing as a stable glass at ambient and body temperatures nd yet bioactive region of the molecule remains unfunctionalised such that the drug is not deactivated. The derivatised bioactive material can be processed into structural devices or applied as a coating and will dissolve into the immediate aqueous environment until total mass loss occurs.

There is no chemical wastage since the device is comprised entirely of the active. Judicious choice of the glass-inducing amorphous region allows control over water solubility and thus rate of release.

We envisage that this approach will be of broadest application in the area of small molecule drugs (e. g. aspirin, paracetamol) in which specific functionalisation can be readily achieved.

The amorphous phase can be stabilized via intermolecular hydrogen bonding between molecules or the mixing of several molecular

components. For example, the major metabolite of aspirin, gentisic acid (2,5-dihydroxybenzoic acid CAS [490-79-9]), may be functionalised wherby the bioactive region comprises a biocompatible moiety containing hydrogen bond donor and acceptor moieties, and a glass-inducing amorphous region, comprised of a hydrophobic moiety to modulate water solubility.

Thus the present invention seeks to provide a class of materials which are capable of being formed, from small-molecule organic- glasses, into artefacts that can be degraded, in a predictable manner to yield predictable fragments, on a timescale appropriate for the desired application.

According to the present invention there are provided amphiphilic compounds of the general formula: A-L- (B) n wherein A is a biocompatible hydrophilic organic moiety containing at least one hydrogen bond donor and at least one hydrogen bond acceptor and each B is a hydrophobic organic moiety which contains no hydrogen bond donors, n is an integer having a value of greater than 1 and, preferably, less than 5 and L is a chemical bond or divalent linking group,.

Aptly A is a bioactive moiety, preferably one which exhibits a pharmaceutical or pharmacological activity. Suitably the moiety A is an alcohol or amine, for example a derivitised or functionalised form of aspirin or its major metabolite, gentisic acid (2,5-dihydroxybenzoic acid CAS [490-79-9]). Other A moieties include derivitised or functionalised forms of paracetamol, morphine, adrenaline or tetrahydrocannabinol

The present invention also provides organic glasses formed by the aggregation of compounds of the general formula A-L- (B) n and which exhibit a thermodynamically stable glass phase at ambient temperature The glass materials of the present invention are characterised in that although they exhibit the polymer-like propensity to form a thermodynamically stable organic glass at ambient temperature, they are composed of simple, low molecular weight organic species.

Cohesive forces between each individual unit enable these materials to be fibre-forming from the molten state.

Aptly L is an ester linkage.

Preferably the moiety B contains an aromatic moiety. More preferably B contains at least one carboxylic acid functionality (which will provide the linking grouping L) and may be derived from methoxybenzoic acid, trimethoxybenzoic acid, an alkylbenzoic acid or cinnamic acid. Suitably, the moiety B (rather-L-B) is derived from a benzoic acid substituted in the 2-position for example with halide or alkoxy groups. Preferably the 2-substituent is an alkoxy group such as methoxy Most preferred are compounds of the formula A-L- (B) n (herein) where A is derived from a dihydoxy benzoic acid such as 2,5- or 3,5- dihydroxy benzoic or a mixture thereof since upon degradation the degradation products will exhibit pharmacological activity.

Thus preferred compounds of the present invention have the general formula (I) :

where: Ri is a moiety containing no hydrogen bond donating functionalities and Rn is a hydrophilic moiety containing at least one hydrogen bond donating functionality and at least one hydrogen bond accepting functionality, Preferred forms of Ri include methoxybenzoyl, cinnamyl and trimethoxybenzoyl Preferred Rn include carboxylic acids and alcohols The amphiphilic molecule (I) is synthesised by known preparative methods. For example, hydrophobic Ri may be attached to the aromatic ring to which Rn are attached by condensation of an acid chloride with an alcohol.

Compounds and mixtures, comprised in at least one part of the compounds of formula (I), are not only capable of exhibiting a thermodynamically stable glassy state at ambient temperature but also exhibit the ability to form fibres from the molten state. These abilities have been correlated with IR and 3C NMR spectroscopic observations of a high degree of hydrogen bond mobility in viscous melts and in the solid-glass state when compared to a systematic series of similar species.

Hence, preferred examples of formula (I) include 3-carboxy-4- hydroxyphenyl-2-methoxybenzoate (II), 3-carboxy-4-hydroxyphenyl- 3,4,5-trimethoxybenzoate (III) and 3-carboxy-4-hydroxyphenyl-trans- cinnamoate (IV) Compounds were characterised by IR and NMR spectroscopies and high resolution CI+MS (see examples). These compounds may be composed of biocompatible and/or therapeutically active components (e. g. 2,5-dihydroxybenzoic acid) that are water soluble.

Alternatively, the compounds themselves may be biocompatible and/or therapeutically active and water soluble.

The objects of this invention are small-molecule organic glasses, as defined above, the manufacture of these compounds and their applications According to a preferred embodiment of the present invention there is provided a composition of matter comprising an aggregate of at least one compound of formula (I) herein. Preferably, such aggregates decompose, via hydrogen bond cleavage, to water soluble compounds. Thus they may be used as structural devices, drug-delivery vehicles, adhesives and, preferably, medical devices.

The organic glasses of the invention when formed into fibres may be used as padding materials for the treatment topical lesions such as ulcers, donor sites and wounds. When formed as solid'glasses', the materials of the invention may be formed in to implant devices such as plates or as shaped implantable prosthetic devices.

The invention will now be further described with reference to the following examples and the accompanying drawings: Example 1: 3-carboxy-4-hydroxyphenyl-2-

methoxybenzoate (II) A magnetically stirred melt of 2, 5-dihydroxybenzoic acid (2.040 g, 13.2 mmol) and o-anisoyl chloride (2.258 g, 13.2 mmol) was heated to 130 °C. When effervescence subsided, the viscous, fibre-forming, transparent yellow melt was poured from the reaction vessel, cooling to a yellow glass. The glass was dissolved in CHCI3 and reprecipitated into n-hexane; the first fraction was discarded. A 50% yield was recovered. Mp. 160-162 °C. High resolution CI+MS (M+NH4) + : 289. 710. IR 1721 (ester), 1685 (acid) cm-1. 13C NMR (67.5 MHz, d6-acetone) carbonyl resonances: 165.75 (ester), 172.53 (acid) ppm. NMR (270 MHz; d8-THF) : 2-methoxybenzoate Ar-H, 87. 94 (1 H, dd, J 8, 2 Hz); Ar-H, 57. 61 (1 H, m); Ar-H, 57. 21 (1 H, d, J 9 Hz); Ar-H, 87. 03 (1 H, d, J 9 Hz) ;-OCH3, 83. 91 (3H, s): gentisyl, 6- H, 87. 70 (1 H, d, J 3 Hz); 4-H, 87. 33 (1 H, dd, J 9 J 3 Hz); 3-H, 87. 03 (1 H, d, J 9 Hz).

Example 2: 3-carboxy-4-hydroxyphenyl-3, 4,5-

trimethoxybenzoate (III) A magnetically stirred melt of 2, 5-dihydroxybenzoic acid (3.913 g, 25.4 mmol) and 3,4,5-trimethoxybenzoyl chloride (5.856 g, 25.4 mmol) was heated to 130 °C. When effervescence subsided, the viscous, fibre-forming, transparent yellow melt was poured from the reaction vessel, cooling to a yellow glass. The glass was dissolved in CHC13 and reprecipitated three times into n-hexane; the first fraction was discarded in each case. A 25% yield was recovered.

Mp. 182-185 °C. High resolution CI+MS (MH) + : 348.085. IR 1731 (ester), 1687 (acid) crrT'. C NMR (67.5 MHz, d6-acetone) carbonyl resonances: 165.75 (ester), 172.53 (acid) ppm. 1H NMR (270 MHz, d6-acetone) : 3,4,5-trimethoxybenzoate, Ar-H, 88. 05 (2H, s); 3,5- OCH3, 83. 92 (6H, s); 4-OCH3, 83. 84 (3H, s): gentisyl, 6-H, 87. 70 (1H, d, J 3 Hz); 4-H, 87. 33 (1 H, dd, J 9 J 3 Hz); 3-H, 87. 03 (1 H, d, J 9 Hz).

Example 3: 3-carboxy-4-hydroxyphenyl-trans-cinnamoate (IV)

A magnetically stirred melt of 2, 5-dihydroxybenzoic acid (3.936 g, 25.5 mmol) and trans-cinnamoyl chloride (4.255 g, 25.5 mmol) was heated to 130 °C. When effervescence subsided, the viscous, fibre- forming, transparent yellow melt was poured from the reaction vessel, cooling to a yellow glass. The glass was dissolved in CHCb and reprecipitated three times into n-hexane; the first fraction was discarded in each case. A 30% yield was recovered. Mp. 135-137 °C. High resolution CI+MS (M+NH4) + : 302.103. IR 1724 (ester), 1690 (acid) cm~1. 3C NMR (67.5 MHz, CDC13) carbonyl resonances: 166.10 (ester), 173.45 (acid) ppm.'H NMR (270 MHz, CD13) : cinnamoate,-OOC-CH=, 87. 87 (1H, d, J 16 Hz); =CH-Ar, 86. 61 (1H, d, J 16 Hz); Ar-H, 87. 58 (2H, m); Ar-H, 87. 43 (3H, m): gentisyl, 6-H, 87. 70 (1 H, d, J 3 Hz); 4-H, 87. 33 (1 H, dd, J 9 J 3 Hz); 3-H, 87. 03 (1 H, d, J 9 Hz):-OH, 810. 34 (1 H, s);-COOH, 84. 50 (1 H, s (broad)).

Example 4: Device dip-coating procedure A solution of Compound II (1.00 g), dissolved in THF (10 ml) was used for the dip-coating of of the following devices: 1. Poly Lactic Acid woven braid, 2. Poly Lactic Acid interference screw and

3. Stainless steel plate fixation screw.

The device was immersed in the solution for approximately 1 second and removed to allow evaporation of solvent. In each case, the coating supplied was uniform and amorphous as can be seen in Figures 1 a-c of the accompanying drawing. When aspirin or gentisic acid was applied in the same manner, crystallization occurred as can be seen in Figure 1 d. Dissolution of the coated devices overnight in deuterated water allowed analysis of extracts by NMR spectroscopy. The spectrum resulting from the stainless steel coating extract, consistent with intact 11, is shown in figure 2.