| Title of Invention | "POLYURETHANE ELASTOMERS" |
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| Abstract | A linear polymer is obtained by reacting together a polyethylene glycol or polypropylene glycol; PEG-PPG-PEG or PPG-PEG-PPG bloek copolymer; a difunctional amine or diol; and a diisocynnatc. A controJlccl rclcalc compstition comprises the polymer together with on active agent. Active agents of molecular wcigtil 200 to 20,000 rnay be used. |
| Full Text | POLYURETHANE ELASTOMERS The present invention relates to hydrophilic thermoplastic polyurethane elastomer polymers, suitable for the production of controlled release compositions for release of phannaceutically active agents over a prolonged period of time Their clastomeric nature provides better comfort in use, for example, in pessaries, suppositories or vaginal rings. Certain cross-linked poiyurethane hydrogel polymers are known from European Patent Publications EP0016652 and EP0016654. Tliese patent specifications describe cross-linked polyurethanes formed by reacting a polyethylene oxide of equivalent weight greater than 1500 with a polyfunctional isocyanate and a trifimctional compound reactive therewith, such as an alkane trial. The resultant cross-linked poiyurethane polymers ore water-swellable to form a hydrogel but are water-insoluble and may be loaded with water-soluble pharmaceutically active agents. One particular poiyurethane polymer is the reaction product of polyethylene glycol 8000, Desmodur (DMDI i.e. dicyclohexylmethane-4,4-diisocyanate) and 1,2,6-hexane triol and which has been used commcrciaily for vaginal delivery of prostaglandins. However, such poiyurethane polymers possess a number of practical disadvantages. Whilst the use of a triol cross-linking agent is effective in providing polymers of relatively reproducible swelling characteristics, the percent swelling is typically 200-300% (i.e. the increase in weight of the swollen polymer divided by the weight of the dry polymer). Pharmaceutically active agents are loaded by contacting the polymer with an aqueous solution of phannaceutically active agent, such that the solution becomes absorbed into the polymer, forming a hydrogc. The swoilen polymer is then dried back to the chosen water content before use. A consequence is that with the conventional cross-linked poiyurethane, the degree of swelling limits the molecular weight of the pharmaceuticaily active agent which can be absorbed into the hydrogel structure to below about 3000 g/mol. A further disadvantage is that only water-soluble pharmaceutically active agents may be used. Finally, since the conventional cross-linked polyurethane polymer is essentially a non-thennoplastic polymer (thermosct), insoluble in both water and organic solvents, ihe further processing of the formed polymer into other solid forms, such as films, monolithic devices, foams, wafers, composites, sandwich structures, particles, pellets, foams or coatings, is not possible. In addition, the thermosct nature of the conventional cross-linked polyurethane polymer rules out the possibility of melt mixing drug with the polymer, in order to load the polymer with a suitable active agent without using solvents or water. Certain thermoplastic polyurethane hydrogel polymers arc known from patent Publication WO2004029125. This patent specification describes linear thermoplastic polyurethanes formed by reacting a polyethylene glycol of molecular weight of greater than 4000 g/mol vdth a polyftinctional socyanate and a bxfunctioral compound reactive therewith, such as an alkane diol or diamine, The resultant thermoplastic polyurethane polymers are water-swellable to form a hydrogel but are water-insoluble and may be loaded with water-soluble pharmaceuticaily active agents. One particular polyurethane polymer is the reaction product of polyethylene glycol 8000, Dcsmodur (DMDI i.e. dicyclohexylmethane-4,4-diisocyanate) and 1,10-decane diol, which has shown percentage-swelling from 600% up to 1700% or even above This type of polymer has shown a suitability for diffusion loading and short-term delivery of relatively water-soluble drugs e.g. clindamycin phosphate, oxytocin, aiid misopfostol. However, such a high-swelling thermoplastic polyurethanc polymer possesses many practical disadvantages. Due to the high weight content and block length of PEG, the polymer is only suitable for relatively short-term release (i.e. controlled release from 10 rnin to only a few hours) of active agents, especially in the case oi highly water-soluble drags. In addition, the low hydrophobic content, i.e. low amount of hydrophobic compound e,g. dccanediol (DD) or dodecancdio) (DDD) makes the polymer inappropriate for hydrophobic drugs and thus restricts its use Hydropluiic and hydrophobic drugs need to have interactions with both of the phages in order for their release to be controlled by the polymer structure. Further, the imbalance between hydrophobic and hydrophilic compounds hampers raicrophase separation, which reducpes the mechanical strength of the polymer in both the dry and wet state. In addidon, due to the high crystallinity of polymer and the formation of hard blocks, the final polymer is rigid and the processing temperature relatively high. The swelling percentage of high-swelling thermoplastic polyurethanes is typically 200-1700% and is dependent on the PEG content and/or the leagtli of PEG block. Phamiaceutically active agents can be loaded by using (the same method as described above for the conventional cross-linked polyurethane, as well as melt mixing drug and polymer. The release time and profiles obcaiced for the high swelling and crosslinked polyurethane polymers are, however, very similar. Patent specification WO 94/22934 discloses the production of a linear random block copolymer from polyethylene oxide (number average molecular weight 1000 lo 12,000), a diamine and a diisocyanate. Yu et ai. Biomaterials 12 (1991) March, No.2, page 119-120 discloses the use of polyurethane hydrogcis formed of polyethylene glycol (number average molecular weight of 5830) and a low molecular weight polypropylene glycol (molecular weight 425) and a diisocyanate. Patent specification US 4,202,880 discloses the production of polytwethanes from polyethylene glycol (molecular weight 400-20,000), an alkaline glycol containing from 2-6 carbon atoms and a diisocyanate. Patent specification US 4,235,988 is a similar disclosure, although the preferred PEG range is 600-6,000. The object of the present invention is to provide a hydrophilic thermoplastic polyurethane elastomer, which can be processed arid mixed with an active agent at the temperature below the degradation temperature of the active agent by using conventional polymer processing systems, e.g. melt mixer, extruder and injection moulding machine. An additional objective of the present invention is to enhance the melt viscosity, to increase elasticity and to lower the crystallinity of the polymer in order to apply conventional melt processing techniques e.g. extrusion and injection moulding, as well as different types of solvents to the formation of drug loaded resilient controlled release devices of any chosen shape. The present invention is based on the discovery that thermoplastic polyurethane elastomers having suitable melt processing properties for drug loading and elasticity at body temperature, as well as suitable drug release characteristics, may be obtamcd by reacting a polyethylene glycol or polypropylene glycol with a dioi or other difunctional compound, and a PPG-PEG-PPG or PEG-PPG-PHG blocic copolymer and a difunctional isocyanate. PEG stands for polyethylene glycol; and PPG stands for polypropylene glycui In particular, the present invention provides a hydrophiJic thermoplastic polyTurethane elastomer polymer obtainable by reacting together; (a) a polyethylene glycol or polypropylene glycol; (b) a PEG-PPG-PEG or PPG-PEG-PPG block copolymer; (c) a difunctional compound; arid (d) adifunctionai isocyanate, The thermoplastic polyuiethane elastomer produced is swellable in water to a specific degree, depending upon the ratio of the four components (a), (b), (c) and (d), for example from 1% up to 200% (e.g. 20 to 100%) thus better controiiing the release of pharmaceutically active agents from the high-swelling, PBG-based Unear polyuiethane. The polymer of the invention is also soluble in cenain organic-solvents, such as dichloromethane, l-methyl-2-pyrrolidofte (NMP) aad tetiahydroftirau, which allows tiie polymer to be dissolved and cast inio films or coatings. It also allows thermally unstable active agents of poor water soiubil5t> but which are soluble in orgawc solvents, to be loaded into the polymer. Due to the unique combination of starting components, these polyurethane elastomers have a composition that can control the release of active compounds from a few days up to a few months. Polyether polyols contain the repeating ether linkage -R-O-R- and have two or more hydroxyl groups as terminal functional groups. They are manufactured by the catalysed addition of epoxides to an initiator (anionic ring-opening polymerisation). The most important of the cyclic ethers by far are ethylene oxide and propylene oxide. These oxides react with active hydrogen-containing compounds (initiators), such ns water, glycols, polyols and amines. A catalyst may or may not be used. Potassium hydroxide or sodium hydroxide is the basic catalyst most often employed. After the desired degree of polymerisation has been achieved, the catalyst is neutralized, removed by filtration and additives such as antioxidants are added. A wide variety of compositions of varying structures, chain lengths and molecular weights is possible. By selecting the oxide or oxides, initiator, and react on conditions and catalysts, it is possible tc polymerise a series of polyether polyols that range from low-molecuiar-weight polygiycols to high-moiccular-weight polymers. Since these polymers contain repeating alkylene oxide units, they are often referred tc as polyaikylcne glycols or polygiycols. Most potyether polyois are produced for polyurcthane applications. Polyethylene glycols (PEG) contain the repeat unit ( CH2CH2O-) and are conveniently prepared fay the addition of ethylene oxide to ethylene glycol to produce a difunotional polyethylene glycol structure HO(CH2CH2O)nH wherein n is an integer of varying size depending on the molecular weight of the polyethylene glycol, Polyethyleae glycols used in the present invention are generally linear polyethylene glycols i.e. diols having molecular weights of 200 to 35,000 g/moL (generally 400 to 2000), Polypropylene glycols (PPG) are polymers of propylene oxide and thus contain the repeat unit (-CH2(CH3)CH2O-). Polypropylene glycol has unique physical and chemical properties due to the co-occurance of both primary and secondary hydroxyl groups during poiymerisation, and to the rauitiplicity of methyl side chains on the polymers. Conventional polymerisation of propylene glycol results in an atactic polymer. The isotactic polymers mainly exist m the labomlti.'-y. Mixtures of atactic and isotactic polymers may also occur, PPG has many properties in common with polyethylene glycol. Polypropylene glycols of all molecular weights are clear, viscous liquids with a low pour point, and which show an inverse temperature-solubility relationship, along wth a rapid decrease in water solubility 'is the molecular weight increases. The terminal hydroxy! groups undergo the typical reactions of primary and secondary alcohols. I'he secondary hydroxyl group of polypropylene glycols is not as reactive as the primary hydroxy! .group in polyethylene glycols. PPG is used m many ibrmulations for polyuietlianes Polypropylene glycols used in the present invention are generally linear having molecular weights of 200 to 4000 g/mol, (generally 400 to 2000), The invention also provides a method of producing the linear polymer, which comprises melting and drying PEG or PPG, and the block copolymer, together witii the difunctional compound at a temperature of 85°C to 100°C under vacuum; and then adding the difunctional isocyanate. The production of block copolymers (b), based on propylene oxide and ethylene oxide, can be initiated with ethylene glycol, glycerine, trimethyiolethane, trimethjylolpropane pentaerythroitol-sorbitol, sucrose and several other compounds. Mixed and alternating block copolymers can also be produced. When the secondary hydrojcyl groups of PPG are capped with ethylene oxides, block copolymers of PEG and PPG with terminal primary hydroxyl groups arc yield. The primary hydroxyl groups arc more reactive with isocyanates than secondary hydroxyl groups. PEG-PPG-PEG and PPG-PEG-PPG copolymers used in the present invention are generally linear having molecular weight of 200 to 14,000 g/mol. The block copolymer appears to contribute to the non-crystalline elastomeric nature of the polymer of the invention. The difunctional compound (c) is reactive with the difunctional isocyanate, and is typically a difunctional amine or diol. Diols in the range C5 to C20, preferably C8 to C15 are preferred. Thus, decanediol has been found to produce particulefly good results. The diol may be a satuurated or unsaturated diol. Branched diols may be used but straight chain diols are preferred The two hydroxyl groups are generally on terminal carbon atoms. Preferred diols include 1,6-hexancdiol, 1,10-decanediol, 1,12-dodecanedioland 1,16-hexadecanedioI, The difunctional isocyanate (d) is generally one of the conventional diisocyanates, such as dicyclohexylmcthane-4,4-diisocyanatc, diphcnylmethane-4,4-diisocyanate, 1,6-hexamethylene diisocyanate etc. The equivalent weight ratio of the components (a), (b), (c) and (d) is generally in the range 0.01-1 to 0.01-1 to 1 to 1.02-3 respectively. Of course, the skilled man through reasonable experimentation would detemine the best ratio of ingredients to give the desired properties. The amount of component (d) is generally equal to the combined amounts of (a), (b) and (c) to provide the correct stoichiomstiy. The polymers arc generally produced by melting and drying PEG or PPG, and PEG-PPG-PEG or PPG-PEG-PPG block copolymer together with the difiinctjonal compound and a typical polyurethane catalyst (if used), e.g. ferric chloride, DABCO and/or tin (II) octoatc, at a temperature of 85°C to 100°C (e.g. 95°C) under vacuum to remove excess moisture; before the diisocyanate, e.g. DMDI or HMDI is added thereto. The polymerisation is carried out in a batch or alternatively a continuous reactor; or the reaction mixture is fed into moulds and reacted for a specified time. After polymerisation the polymer is cooled down, pelletised or granulated and stored in a freezer for furthcr analysis and processing. The elastomeric properties of the thennoplastic polyurethane elastomers of the invention are due to two factors; microphase separation of hard and soft blocks; and the scmicrystalline nature of the polymer, whose amorphous phase has a low glass transition temperature. Hard blocks form from the difunctional compound and diisocyanate. Soft blocks are PEG, PPG or copolymer, The elasticity may depend on the ratio of hard to soft blocks and may be represented by Shore hardness measurements. The linear polymers of the present invention are soluble in certain organic solvents. This allows the polymer to be dissolved and the resultant solution cast to form films. The solution may also be employed for coating granules, tablets etc, in order to modify the polymer release properties. Alternatively, the solution can be poured into a non-solvent so as to precipitate polymer/active microparticles. In addition, the polymer can be ground, chopped, pelletiscd and melted by using conventional techniques used for processing thermoplastic polymers. Thus, the invention also provides a controlled release composition comprising the linear polymer together with an active agent. Any type of plastic processing equipment, e.g. extruder, injection moulding machine, compression moulding equipment and melt mixer can be used for mixing the polymer and active agent together and forming or reshape into any type of drug loaded device, e.g. a ring, pessary, patch, rod, spring or cone, The active agent may be a pharmaceutically active agent for human or animal use. It may also be any other agent where sustained release properties (e.g. algicidcs, fertilisers etc.) are required. The pharmaceutical solid dosage forms include supositories, rings and pessaries for vaginal use, buccal insects for oral administratioa, patches for transdermal administration etc. These dosage forms are generally administered to the patient, retained in place until delivery of active agent has occurred and the spent polymer is then removed. The polymer may also be used for implants, which remain in the body; or for coating such implants (e.g. stents). The polymer of the present invention is an amphiphilic thermoplastic polymer and is thus suitable for the uptake of hydrophilic and hydrophobic, low and high molecular weight pharmaceutically active agents (up to and exceeding a molecular weight of 3000 e.g. up to 10,000, up to 50,000, up to 100,000 or even up to 200,000), Generally, the molecular weight of the active agent is in the range 200 to 20,000. A wide variety of water-soluble pharmaceutically active substances such as those listed in EP00I6652 may thus be incorporated. Furthermore, the linear polymers of the present invention may be loaded with phaimaceutically active hydrophilic and hydrophobic agents, which are poorly water-soluble, provided that these can be dissolved in a common solvent with the polymer. The resultant solution can then be cast into amy desired solid form. In addition, the linear polymers of the present invention may be extrusion loaded or melt mixed with phannaceutically active agents, which are thermally stable at the polymer processing temperature. The release time of the present polymers may exceed 12 hrs, 24 hrs, 5 days, i 0 days, 20 days or even 80 days for substantially complete release of available active agent. The polyether polyol blends and copolymers used in the present invention arc internal and melt rhcology, softness and release rate modifiers. These types of low melting amphiphilic thermoplastic polyurethane polymers are particularly suitable for the melt loading of pharmaccutically active agent and melt processing of loaded polymer to pharmaceutical devices. Phannaceutically active agents of particular interest include: Proteins e.g. interferon alpha, beta and gamma, insulin, human growth hormone, leuprolide; benzodiazepines e.g. midazolam; anti-migraine agents eg. tnptophans, ergotamine and its derivatives; anti-infective agents e.g. azoles, bacterial vaginosis, Candida; and ophthalmic agents e.g. latanoprost. A detailed list of active agent includes H2 receptor antagonist, antimuscaririe, prostaglandin analogue, proton pump inhibitor, aminosalycilatc, corticosteroid, chelating agent, cardiac glycoside, phosphodiesterase inhibitor, thiazide, diuretic, carbonic anhydrase inhibitor, antihypertensive, anti-camcer, anti-depressant, calcium channel blocker, analgesic, opioid antagonist, antiplate!, anticoagulant, fibrinolytic, statin, adrenoceptor agonist, beta blocker, antihistamine, respiratory stimulant, micolytic, cxpertotant, benzodiazepine, barbiturate, anxiolytic, antipsychotic, tricyclic anti depressant, 5HT1 antagonist, opiate, 5HT, agonist, antiemetic, anliepileptic, dopaminergic, antibiotic, antifungal, anthelmintic, antiviral, antiprotozoal, antidiabetic, insulin, thyrotoxin, femal sex honnone, male sex hormone, antiocstrqgec, hypothalamic, pituitary hormone, posterior pituitary hormone antagonist, antidiuretic honnone antagonist, bisphosphonate, dgpamine receptor stimulant, androgen, non-steroidal anti-inflammatory, iramuno suppressant local anaesthetic, sedative, antipsioriatic, silver salt, topical antibacterial vaccine. Embodiments of the present invention will now be described by way of examples below. The effects of type and ratios of PEG or PPG, PEG-PPG-PEG or PPG-PEG-PPG copolymer, diols and diisocyanaitcs on the properties of polymers can be seen in the following Tables, Examples and Figures. Figure 1 shows molecular weight as a function of polymerisation time for certain polymers; and Figure 2 to 5 show various active agent release profiles. Various types of polyethylene glycols, polypropylene glycols, PEG-PPG-PEGs, PPG-PEG-PPGs, diols and diisocyaaates, in a range of stoichiometric ratios were used to demonstrate their effect on the properties of the hydrophilic linear polyurcthanc elastomer polymers. PEG400, PEG900, PEG1000 and PEG2000 are polyethylene glycols having a molecular weight of 400, 900, 1000 and 2000 g/mol, respectively; PPGIOOO and PPG2000 are polypropylene glycols having a molecular weight of 1000 and 2000g/mol; PEG-PPG-PEG11OO and PEG-PPG-PEG4400 are block copolymers having a molecular weight of 1100 and 44(X) g/tnol; PPG-PEG-PEG2000 is a block copolymer having a molecular weight of 2000 g/xnol; DD is 1,10-dccancdiol and DDD is 1,12-dodecanediol; DMDI is dicyciok5xylmcthanc-4,4. diisocyanate and HMDI is 1 ,6-hexanethylene diisocyanate; FeCl3 is Ferric chloride, DABCO is triethylene diamine and SnOct2 is Stannous octoate. Polymers were produced by applying the polymerisation method desscribed in WO patent Publication WO2004029125. The PEG, PPG, PEG-PPG-PEG and/or PPG-PEG-PPG were melted and vacuum dried at 95°C along with the diol and the catalyst (if used) in a rotary-evaporator for an hour at a pressure below 1 mbar. At this point the dried mixture was fed into a reactor prior to the diisocyanate addition. The manufactured polymers are shown in Table 1. Tabic 1. Manufectured hydrophilic thennaplastic polyurethane elastomers- (Table Removed) EXAMPLE 2. Polymerisation reaction as a function of time The effect of polymerisation time on the polymer produced was investigated using triple detection Size Exclusion Chromatography (SEC). Molecular weight determination as a function of polymerisation time was carried out for Polymers B and C, see Figure 1 below. The molecular weight of the polymer will determine the rheology, melt flow and mechanical properties of the polymer. Therefore the importance of determining molecular weight values is evident. EXAMPLE3, The effect of the catalyst on the polymerisation reactions The polymerisations were performed as in Example I but the ferric chloride was replaced by DABCO and SnOct2 for Polymer N (Table 1); while DABCO alone was used fcx" Polymer M (Tabic 1). Polymer H (Table 1) was prepared in tte absence of a catalyst EXAMPLE 4 The use of different diisocvaaates The polymcdsations were performed as in Example I but the DMDI was replaced by HMDI for polymers F, G, H, I, K, L, M, N, O, P, Q and R in Table 1. EXAMPLE 5, Solubility of polymers in different solvents A number of polymers from Table I were dissolved in different solvents in order to find suitable solvents. The solubility tests were carried out for 24 hours at room temperature (RT). The solubility results for the selected polymers are shown in Table 2. Table 2. Polymer solubility in selected solvents. (Table Removed) EXAMPLE 6. Swelling capacity of polymers in different solvents The swelling detennlnations for a number of selected polymers were carried out in water, ethanol, isopropyl alcohol (IPA) and in a 50% mixture of IPA/water in order to measure the amount of solvent absorbed by the polymer. The results were calculated based on the average swelling of 10 specimens and are shovvn in Table 3. The formula used for the calculations is shown below: (Formula Removed) Table 3. Percent swelling of the selected polymers in different swelling media (water, ethanol, IPA and 50% IPA/water). (Table Removed) EXAMPLE 7, Shore hardness testing relasticitv measurement) The manufactured polymers were tested for Shore hardness using durometers A and D. Durometers A and D are generally used to measure elasticity of soft and hard rubber, respectively. These measurements are well known to the skilled person in the field. The results are presented as the average of four measurements and are presented in Table 4. Table 4. Shote hardness values determined for the manufactuxed polymers. (Table Removed) . Experimental conditions: Temperature 2rC Relative Humidity %RH 39 EXAMPLE 8.. Polymer films manufactuered compression moulding A number of seleted polymers from Table 1 were dried over night under vacuum prior to the processing. The upper and lower plate temperatures of the compression moulding machine were set at the target processing temperature. Two Teflon sheets were placed between the mould and the hot plates. The melting time was 3-5 minutes followed by a 30 -120 seconds holding under pressure (170-200 bars). A pfedetennined amount of polymer was used to fill the mould. After cooling to room temperature the samples (pessary devices with dimensions 30mm x 10mm x 1mm) were mechanically punched out and kept in the freezer for further analysis. The film processing conditions are shown in Table 5. Table 5. Thermal processing of the manufiactured polymers using compression moulding. (Table Removed) EXAMPLE 9. Prug loading- extniaion Selected polymers were loaded with two different active ctHnpounds: fluconazole and oxybutynin. A 16mm co-rotating twin-screw laboratory extruder was used for loading the polymers. Table 6 shows the drug loading conditions. Table 6, Extrusion loading conditions used for the fluconazole loaded devices. (Table Removed) Two different batches of the same polymer composition (Polymer A and A*) were loaded with fluconazole in two different drug amounts in order to prove the reproducibility of the polymerisation process. Release results were found to be reproducible. The quantity of the active compound loaded into the polymers was based on the required therapeutic dosage. EXAMPLE 10. Drue release studies - Effect of polymer In vitro drug release properties of the extrusion loaded polymers were determined by dissolution studies. The amount of fluconazole and oxybutynin released from the extiusion loaded polymers was investigated by using dissolution method based on the USP paddle method for short term release and incubator shaker method with Erlenmeyer bottles for long term release. USP paddle technique is comprised of an automated UV dissolution system where a Distek (2100C model) dissolution paddle (speed 50rpm) is connected to a Unicam UV 500 spectrophotometer via an Icalis peristaltic pump. The system is operated using Dsolve software. In the incubator shaker method the samples were taken manually and the Unicam UV 500 spectrophotometer was used to analyse the samples. Experimental conditions: Temperature 37°C Dissolution media 500ml of deionised degassed water In this example the effect of the polymer structure on the release of fluconazole was investigated. Polymer A and C were loaded with 20wt% fluconazole and Polymer A, B and C were loaded with 5% of oxybutynin using extrusion techniques. The release of fluconazole and oxybutynin varied depending on the polymer matrix, see Figure 2a and 2b. EXAMPLE 11. Drug release studies - Effect of drug When the drug type was changed different release profiles were obtained. Fluconazole and oxybutynin were loaded into Polymer A. Normalised dissolution profiles are shown in Figure 3. The same dissolution method as in Example 10 was used to determine the release curves. EXAMPLE 12. Drug release studies - Effect of drug amount The effect of increasing loading content was investigated by dissolution studies. The effect of different drug contents on the release properties of Polymer A was investigated and is shown in Figure 4. The fluconazole loading was increased from 20wt% to 50wt%. The same dissolution method as in Example 10 was used to determine the release curves. EXAMPLE 13. Drug release studies - Comparison with high-swelling polymers The fluconazole release profile obtained for Polymer A and Polymer C were compared with the release profiles obtained for a crosslinked and a linear high-swelling polyurethane polymer, see Figure 5. The diffusion loaded crosslinkcd polymer (crosslinked 17wt% fluconazole) was from patent EP0016652/EP0016654. While the linear high swelling polymer was from patent WO2004029125 and was loaded using diffusion (high %SW 17wt% fluconazole) as well as extnision techniques (high %SW 20wt% fluconazole). The same dissolution mcdiod as in Example 10 was used to determine the release curves. These new polymers can provide an excellent control over drug release, see Figure 5 WE CLAIM: 1) A pharmaceutical controlled release composition in solid dosage form which comprises (i) a linear polymer obtainable by reacting together (a) a dried polyethylene glycol or polypropylene glycol; (b) a dried PEG-PPG-PEG or PPG-PEG-PPG block copolymer; (c) a dried difunctional compound, which is a C5 to C20 diol; and (d) a difunctional isocyanate; together with (ii) a releasable pharmaceutically active agent. 2. A composition according to claim 1, wherein the polyethylene glycol is a linear polyethylene glycol having a molecular weight of 400 to 2000. 3. A linear polymer according to claim 1, wherein the polypropylene glycol is a linear polypropylene glycol having a molecular weight of 400 to 2000. 4. A linear polymer according to any preceding claim, wherein the block copolymer has a molecular weight of 200 to 14,000. 5. A linear polymer according to any preceding claim, wherein the diol is a C5 to C15 diol. 6. A linear polymer according to any preceding claim wherein the diol is a C8 to C15 diol. 7. A linear polymer according to claim 1 wherein the diol is 1,6-hexanedrol, 1,10-decanediol, 1,12-dodecanediol or 1,16-hexadecanediol. 8. A linear polymer according to any preceding claim, wherein the difunctional isocyanate (d) is dicyclohexylmethane-4,4-diisocyanate, diphenyimethane -4,4- diisocyanate, or 1,6-bexamethylene diisocyanate 9. A linear polymer according to any preceding claim, wherein the equivalent weight ratio of the components (a), (b), (c) and (d) is in the range 0.01-1 to 0.01 - 1 to 1 to 1.02-3 respectively. 10. A composition according to any preceding claim in the form of a suppository, ring or pessary for vaginal use, a buccal insert, or a transdermal patch. 11. A composition according to claim 13 in the form of an implant. 12. A composition according to any preceding claim, wherein the active agent has a molecular weight of up to 200,000, 13. A composition according to claim 12, wherein the active agent has a molecular weight of 200 to 20,000. 14 A method of producing a linear polymer according to any preceding claim, which comprises melting and drying PEG or PPG and the block copolymer, together with the drfunctional compound at a temperature of 85X to 100oC under vacuum; and then adding the difunctional isocyanate. |
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| Patent Number | 272129 | |||||||||||||||
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| Indian Patent Application Number | 10326/DELNP/2008 | |||||||||||||||
| PG Journal Number | 13/2016 | |||||||||||||||
| Publication Date | 25-Mar-2016 | |||||||||||||||
| Grant Date | 18-Mar-2016 | |||||||||||||||
| Date of Filing | 15-Dec-2008 | |||||||||||||||
| Name of Patentee | FERRING B.V. | |||||||||||||||
| Applicant Address | POLARIS AVENUE 144, 2132 JX HOOFDDORP, THE NETHERLANDS | |||||||||||||||
Inventors:
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| PCT International Classification Number | C08G 18/48 | |||||||||||||||
| PCT International Application Number | PCT/GB2007/002415 | |||||||||||||||
| PCT International Filing date | 2007-06-27 | |||||||||||||||
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