Title of Invention	A MACROMONOMER BASED COPOLYMER SOLUBLE IN AQUEOUS MEDIUM ABOVE PH 6 AND A PROCESS FOR THE PREPARATION THEREOF
Abstract	The present invention provides copolymer synthesized from lactide macromonomers and acidic monomers, comprising an acrylate or methacrylate ester of low molecular weight oligomeric lactide copolymerized with acidic monomer. The copolymers dissolve over extended time period ranging between 30 to 1440 minutes at pH > 6 and are insoluble at pH < 6. Accordingly, these copolymers can be used in drug delivery systems and other applications wherein pH dependent dissolution over extended time period is desirable.

Title of Invention

A MACROMONOMER BASED COPOLYMER SOLUBLE IN AQUEOUS MEDIUM ABOVE PH 6 AND A PROCESS FOR THE PREPARATION THEREOF

Abstract

The present invention provides copolymer synthesized from lactide macromonomers and acidic monomers, comprising an acrylate or methacrylate ester of low molecular weight oligomeric lactide copolymerized with acidic monomer. The copolymers dissolve over extended time period ranging between 30 to 1440 minutes at pH > 6 and are insoluble at pH < 6. Accordingly, these copolymers can be used in drug delivery systems and other applications wherein pH dependent dissolution over extended time period is desirable.

Full Text	FIELD OF THE INVENTION The present invention relates to a macromonomer based copolymer soluble in aqueous medium above pH 6 having the general formula: P [A (x) B (y)] Particularly the invention relates to a composition comprising a lactide macromonomer and an acidic monomer and a process for the preparation thereof. More particularly it refers to a copolymer composition comprising a lactide macromonomer and an acidic monomer having a general formula P [A (x) B (y)] Where A = Acrylate or methacrylate ester of oligomer of lactide (Table 1 Removed) m = 2to5, n = 2to4 AND B = an acidic monomer H Z X X = COOH or C6H5COOH Y=H or COOH Z = H or CH3 Wherein (A) is an acrylate or methacrylate ester containing oligomer of lactide of molecular weight 500 to 1500 and the content (x) of oligomeric ester of lactide varies between 35 to 99.7 % w/w of the copolymer and (B) is an acidic monomer and the content (y) of the acidic monomer varies between 0.30 to 65 % w/w of the copolymer. The copolymers dissolve over extended time period ranging between 30 to 1440 minutes at pH > 6 and are insoluble at pH copolymers can be used in drug delivery systems and other applications wherein pH dependent dissolution over extended time period is desirable. BACKGROUND OF THE INVENTION Smart polymers undergo a conformational change in response to changes in external environment such as pH, temperature, light, and metabolites. (S.I. Kang, Y.H. Bae, Macromolecules (2001), 34, 8173-8178). Among these, pH sensitive polymers have attracted growing interest in both scientific and technological fields (H.C. Chiu, A.T.Wu, Y.F. Lin, Polymer (2001), 42, 1471-1479). pH responsive conformation accompanied by solubility changes is common behavior in biopolymers. These polymers consist of ionizable groups that can accept and donate protons in response to environmental pH. As the environmental pH changes, the degree of ionization in a polymer bearing weakly ionizable groups is dramatically altered. (Eun Seok Gil, Samuel M. Hudson. Prog. Polym. Sci., (2004), 29, 1173-1222). This change in net charge of pendant groups causes an alteration in the hydrodynamic volume of the polymer chains. The transition from collapsed state to expanded state is due to the osmotic pressure exerted by mobile counter ions neutralizing the network charges (S.R. Tonge, B.J. Tighe, Adv Drug Deliv Rev (2001), 53, 109-122). The polymers containing ionizable groups form polyelectrolyte in aqueous medium. There are two types of pH responsive polyelectrolytes; weak polyacids and weak polybases. Weak polyacids such as poly(acrylic acid) are ionized in neutral and basic pH ( O.E. Philippova, D. Hourdet, R. Audebert and A.R. Khokhlov, Macromolecules (1997), 30 , 8278-8285). On the other hand, polybases like poly (4-vinylpyridine) are protonated at low pH. (V.T. Pinkrah, M.J. Snowden, J.C. Mitchell, J. Seidel, B.Z. Chowdhry and G.R. Fern, Langmuir (2003), 19, 585-590). Polyacids bearing carboxylic group with pKa around 5-6 are the most representative weak polyacids. The polymers containing acrylic acid and methacrylic acid have been most frequently reported as pH responsive polymers. Carboxylic pendant groups accept protons at low pH and release at basic pH. Polymers containing methacrylic acid show an abrupt phase transition, compared with the relatively continuous phase transition in case of polymers containing acrylic acid. Polymethacrylic acid has a compact conformation before a critical charge density is attained, because the methyl groups in this polymer induce stronger hydrophobia interactions which lead to aggregation. pH responsive polymers contain functional groups which undergo structural change in response to pH. This property of polymers can be used in drug delivery systems to target the release of drugs to intended sites along the gastrointestinal tract. The concept of using pH as a trigger to release a drug in the colon is based on pH conditions that continuously vary from acidic (1-3) to near neutral and basic (5-8) along the gastrointestinal tract. Pharmaceutical uses of acrylic polymers are widespread and these copolymers are available in the market under different brand names depending on the composition and manufacturer. Applications of acrylic polymers in ocular, nasal, buccal, gastro-intestinal, epidermal and transdermal, vaginal or cervical drug delivery continue to be explored. (Acrylic acid and methacrylic acid copolymers are used as excipients in variety of ways ranging from personal care products to intestinal drug delivery. These copolymers solubilize in intestine and release encapsulated drug. Since the copolymers are insoluble at acidic pH, they protect encapsulated drug in gastric region. Molecular weights of these copolymers are high. Content of acidic monomers like acrylic acid and methacrylic acid which contributes to pH dependent behavior in these copolymers is 25 to 55 % w/w. Lactose-based placebo tablets were coated using various combinations of two methacrylic acid copolymers, Eudragit L100-55 and Eudragit S100. The coated tablets were tested in vitro for their suitability for pH dependent colon targeted oral drug delivery. The same coating formulations were then applied on tablets containing mesalazine as a model drug and evaluated for in vitro dissolution. The dissolution data obtained from the placebo tablets demonstrate that disintegration rate of the tablets is dependent on: (i) the polymer composition used to coat the tablets, (ii) pH of the dissolution media, and (iii) the coating level of the tablets. Dissolution studies performed on mesalazine tablets further confirmed that the release profiles of the drug in the pH range 5.5 to 7.0 could be manipulated by changing Eudragit L100-55 and Eudragit S100 ratios. (Khan, Zahirul I.; Prebeg, eljko; Kurjakovic, Nevenka. Journal of Controlled Release (1999), 58(2), 215-222). The colon-specific drug delivery system containing a drug core along with a solid particulate inter-polymer complex of glucosamine and poly (acrylic) acid and a pH-dependent coating surrounding at least a portion of the core was designed and evaluated. The pH-dependent coating was insoluble in gastric fluid and intestinal fluid below pH 6.0 but became soluble in the colonic environment. (Wilson, Clive; Mukherji, Gour; Rampal, Ashok Kumar. PCT Int. Appl. (2005), WO 2005030173 A1 20050407) pH independent release of the basic model drug Verapamil HCI was achieved by coating with combination of dispersion of polyvinyl acetate and the enteric polymer dispersion of methacrylic acid and ethyl acrylate. Two polymers were applied either as separate layers (enteric polymer + extended release polymer or vice versa) or as a polymer blend. A careful balance of the ratios of the polymers enabled pH independent release. Higher amounts of the enteric polymer in the polymer blend resulted in faster release at pH 6.8 than at pH 1.2. (Dashevsky, A.; Kolter, K.; Bodmeier, R. European Journal of Pharmaceutics and Biopharmaceutics (2004), 58(1), 45-49).Thus, these polymer combinations released the drug both in gastric and intestinal pH. Such polymers are not useful for the delivery of acid labile drugs. Use of pH-responsive, poly (methacrylic-g-ethylene glycol) hydrogels as oral delivery vehicles for insulin was investigated in vivo using healthy and diabetic Wistar rats. In the acidic environment of the stomach, the gels remained collapsed due to the formation of intermolecular polymer complexes. Insulin remained in the gel and was protected from proteolytic degradation. In the basic and neutral environments of the intestine, the complexes dissociated which resulted in rapid swelling of the gel and insulin release. Within two hours of administration of the insulin containing polymers, strong dose-dependent hypoglycemic effects were observed in both healthy and diabetic rats. (Lowman, A. M.; Morishita, M.; Kajita, M.; Nagai, T.; Peppas, N. A. Journal of Pharmaceutical Sciences (1999), 88(9), 933-937). Insulin release from such hydrogels was rapid and swelling dependent. Release could not be extended beyond two hours. Microparticles made from the graft copolymers containing equimolar amounts of methacrylic acid and ethylene glycol were investigated for insulin release. These microparticles exhibited unique pH-responsive characteristics in which interpolymer complexes were formed in acidic media and dissociated in neutral / basic environments. Thus Insulin release from the gel was significantly retarded in acidic media while rapid release occurred under neutral / basic conditions. But as the amount of methacrylic acid in the polymer increased, insulin was readily released from the polymer network in both, the acidic and neutral / basic media. (Morishita, Mariko; Lowman, Anthony M.; Takayama, Kozo; Nagai, Tsuneji; Peppas, Nicholas A. Journal of Controlled Release (2002), 81(1-2), 25-32). Thus, the copolymer composition containing higher amount of methacrylic acid could not protect insulin in acidic media. A novel oral sustained release formulation for delivery of a highly water soluble drug was investigated. Release rates of various drugs in polyacrylic acid / carrageenan (PAA / CA) (1:1) were compared with formulations containing polyacrylic acid / polyethylene oxide (PAA / PEO) (1: 1.5). Drug was released from PAA / CA matrix although at a slower rate in both simulated gastric fluid as well as simulated intestinal fluid as compared to the release from PAA / PEO matrix. (Rogers, Victoria; Dor, Philippe J. M.; Fix, Joseph A.; Kojima, Hiroyuki; Sako, Kazuhiro. PCT Int. Appl. (2003), WO 2003041656 A2 20030522) These matrices can therefore not be used when the release of the drug in the gastric region is not desirable. Linear and star shaped oligolactide macromonomers were synthesized by ring opening oligomerization of L-lactide and subsequent end group functionalization of the oligo lactide with methacrylate moiety. These liquid macromonomers were valuable building blocks for the preparation of biocompatible polymer networks. These polymer networks exhibited excellent biocompatibility and were well suited as scaffolds for bone tissue engineering. (Matthias Schnabelrauch, Sebastian Vogt, Yves Larcher, Ingo Wilke Biomolecular Engineering (2002), 19, 295-298). Thus low molecular weight lactide macromonomers are used in the literature as scaffolds in tissue engineering. These macromonomers alone do not exhibit any pH dependent behavior. Materials combining both bioadhesive and biodegradable components were synthesized using lactide polymers. These polymers were selected from the group consisting of poly (acrylic acid)-graft-poly (lactic acid) (PAA-g-PLA), poly (lactic-co-glycolic acid)-g-poly (acrylic acid) (PLGA-g-PAA). Hydrogen bonded interpolymer complexes were formed between polycarboxylic acids and PEG-PLGA copolymers. Such copolymers were mainly utilized to maintain acidic pH in body cavities like vagina or as mucoadhesive drug delivery components. (Huang, Yanbin; Kim, Jaeho. U.S. Pat. Appl. Publ. (2003), US 20030232088 A1 20031218). These polymeric systems worked on the principle of hydrolysis of biodegradable materials in aqueous system. A biodegradable, biocompatible polymer in the form of solid or porous microcapsules was investigated for insertion into the eye of a patient for treating dry eye symptoms. Treating agents like saline, carboxy methylcellulose sodium, Dextran, hydroxypropyl methylcellulose, propylene glycol and glycerin were released in a patient's eye as polymer microcapsule biodegraded. Copolymers of lactide, copolymers of methacrylic acid and acrylic acid, copolymers of hydroxy ethyl methacrylate and methyl methacrylate were used to design such microcapsules. Such drug delivery system worked by slowly releasing the treatment agent into the eye through the polymer shell or sphere and provided dry eye treatment that was long lasting and easy to apply. (El-Sherif, Dalia M.; EI-Mansoury, Jeylan A. (USA). U.S. Pat. Appl. Publ. (2003) US 20030143280 A1 20030731). Release rate of treatment agent from such formulations was dependent on biodegradation of polymer system in ocular cavity. Thermo-responsive, pH-responsive, and biodegradable nanoparticles comprising of Lactide macromonomer-g-poly (N-isopropyl acrylamide-co-methacrylic acid) (PLA-g-P (NIPAm-co-MAA)) were developed by grafting biodegradable poly (D, L-lactide) onto N-isopropyl acrylamide and methacrylic acid. A core-shell type nano-structure was formed with a hydrophilic outer shell and a hydrophobic inner core, which exhibited a phase transition temperature above 37 °C suitable for biomedical application. The release of 5-Fluorouracil (5-FU) from nanoparticles was controlled by pH in aqueous solution. In acidic surrounding more than 25 % of 5-FU was released from nanoparticles in first hour. This was followed by a sustained release for 4 days by drug diffusion from core or due to PLA degradation. No drug release was observed at pH 7.4. These PLA-g-P (NIPAm-co-MAA) nanoparticles can be used as drug carrier for intracellular delivery of anti-cancer drug. (Chun-Liang Lo, Ko-Min Lin and Ging-Ho Hsiue Journal of Controlled Release, (2005), 104(3), 477-488). Thus these lactide nanoparticles released the drug in acidic pH which is not desirable for acid labile drugs. In case of the references cited above, the drug release profile was not suitable for intestinal drug delivery. There is therefore a need to tailor polymers which dissolve over extended time period. There are three different approaches for drug delivery to intestinal region depending on need of drug release pattern for specific disease conditions. Immediate enteric delivery of drugs is desirable in certain cases to treat acute conditions like pain associated with osteoarthritis (Ibuprofen), or delivery of acid labile cardiovascular drugs (Verapamil, Diltiazem), proteins and peptides. These are called delayed release preparations. Conditions like rheumatoid arthritis need controlled release of therapeutic agent (e.g. Diclofenac Sodium) over prolonged time period. Such preparations are called extended release preparations. Chronotherapeutic delivery is another concept in medicine, which brings out the drug release from a formulation in harmony with patient's natural circadian rhythm. Such a formulation delays release of drug by 4 to 5 hours and makes it available in circulation in the body at predetermined time. This is required in case of antihypertensive, antiasthmatic, analgesic, anti-inflammatory and some anticancer drugs. For intestinal drug delivery, anionic polymers of methacrylic acid and methacrylates containing -COOH group are available in the market which dissolve immediately when they reach near neutral or neutral pH in intestine and release the drug. Other pH independent copolymers of acrylate and methacrylates containing quaternary ammonium group which are being explored, swell both in acidic as well as basic pH. Thus these polymers are not suitable for delivery of acid labile drugs. Other type of copolymers of acrylates and methacrylates containing quaternary ammonium group in combination with sodium carboxymethylcellulose exhibit pH independent dissolution behavior and these too can not protect acid labile drugs. Hence no acrylate or methacrylate polymers are available currently to satisfy the need. From the foregoing it is clear that there is a need to design polymers which unlike conventional enteric polymers will dissolve over extended time periods. Such polymers will be useful for the release of drugs over varying time periods to satisfy needs of a wide variety of intestinal drug delivery systems like delayed and extended release. This invention describes copolymer compositions comprising oligomeric lactide macromonomer and acidic monomer. It demonstrates that even at very low concentration of the acidic monomer (about 0.3 % w/w), the copolymer dissolves at pH > 6 over time periods ranging from 30 to 1440 minutes. These copolymers will satisfy the need for an excipient in intestinal drug delivery, as mentioned earlier. Since the polymers do not dissolve in acidic pH of stomach, they would protect acid labile drugs and release them in intestinal region over an extended time period. Thus these can be used as biocompatible pH sensitive excipients in drug delivery systems. OBJECTIVES OF THE INVENTION The main object of the present invention is to provide a copolymer comprising a lactide macromonomer and an acidic monomer by polymerization of acrylate or methacrylate ester of oligomeric lactide with an acidic monomer. Another object of the present invention is to provide a process for the preparation of the said copolymer. Yet another object of the present invention is to provide a copolymer which dissolve over an extended time period at pH > 6 similar to that present in intestine, but which do not dissolve at acidic pH of the stomach. SUMMARY OF THE INVENTION Accordingly the macromonomer based copolymer soluble in aqueous medium above pH 6 having the general formula: P[(A)x(B)y] wherein, A is an acrylate or methacrylate ester containing oligomer of lactide molecular weight ranging from 500 to 1500; X varies from 35 to 99.7% w/w of the copolymer; B is an acidic monomer; y varies from 0.30 to 65% w/w of the copolymer. In a feature of the invention a macromonomer based copolymer has the following characteristics: a) copolymer is soluble at pH > 6 and insoluble at pH b) copolymer has solubility in aqueous medium over extended time period ranging from 30 to 1440 minutes; c) copolymer has a molecular weight in the range of 1000 to 15000. In an embodiment of the invention the macromonomer (A) used is selected from oligo (lactide) acrylate and oligo (lactide) methacrylate. In an embodiment of the invention the macromonomer (A) used has a molecular weight in the range of 500 to 1500. In an embodiment the acidic macromonomer used is selected from the group consisting of 4-vinyl benzole acid, fumaric acid, maleic acid, acrylic acid and methacrylic acid. Another feature of the invention provides a process for the preparation of the macromonomer based copolymer soluble in aqueous medium above pH 6 having the general formula: P[(A)x(B)y] Wherein, A is an acrylate or methacrylate ester containing oligomer of lactide molecular weight ranging from 500 to 1500; X varies from 35 to 99.7% w/w of the copolymer; B is an acidic monomer; y varies from 0.30 to 65% w/w of the copolymer and is having the following characteristics: i) copolymer is soluble at pH > 6 and insoluble at pH ii) copolymer has a solubility in aqueous medium over extended time period ranging from 30 to 1440 minutes; iii) copolymer has a molecular weight in the range of 1000 to 15000. the said process comprising the steps of: a) preparaing a solution of a macromonomer (A) and an acidic monomer (B) in an organic solvent; b) adding a free radical initiator to above mixture and stirring the resultant reaction mixture for about 10 minutes under inert atmosphere followed by heating at a temperature in the range of 50-70°C, for a period of 16-24 hours; c) concentrating the reaction mixture at reduced pressure in the range of 7-12 mbar followed by precipitation in water to obtain the desired copolymer. In another embodiment of the invention the macromonomer (A) used has molecular weight in the range of 500 to 1500. In another embodiment of the invention the acidic monomer (B) used is selected from 4-vinyl benzoic acid, fumaric acid, maleic acid, acrylic acid and methacrylic acid. In another embodiment of the invention the organic solvent used for polymerization in step (a) is selected from the group consisting of chlorinated hydrocarbon, alcohol, ester, ketone, tetrahydrofuran, dioxane and dimethyl sulphoxide. In another embodiment the free radical initiator used in step (b) is selected from the group consisting of azo compound, peroxide, hydroperoxide, peracid and perester. In another embodiment the azo compound used is selected from the group consisting of azo-bis-cyano-valeric acid, azo-bis-biphenyl methane, azo-bis-methyl isobutyrate and azo-bis-isobutyronitrile. In another embodiment of the invention the molar ratio of macromonomer to acid monomer used in step (a) is in the range of 0.11 to 4.0 In yet another embodiment the concentration of oligomeric lactide macromonomer in the copolymer is in the range of 35 to 99.7% w/w of the copolymer. In still another embodiment the concentration of acidic monomer is in the range of 0.30 to 65% w/w of the copolymer. DETAILED DESCRIPTION OF THE INVENTION Copolymers of acrylic acid and methacrylic acid are being used as enteric coating materials in drug delivery systems. These polymers retain their integrity in acidic pH and dissolve immediately in near neutral or neutral pH. As a result these are not suitable for prolonged release of drugs or chronotherapeutic delivery, which is needed in certain cardiovascular or analgesic, anti-inflammatory treatments. Hence it is desirable to tailor dissolution profile of the excipient to satisfy these needs. We have surprisingly found that copolymers comprising lactide macromonomer and an acidic monomer such as acrylic acid or methacrylic acid undergo dissolution over extended time periods. These copolymers dissolve in near neutral or neutral pH over time period ranging from 30 to 1440 minutes. Thus this invention relates to the synthesis of copolymers which undergo dissolution over extended time period above pH 6. The copolymer compositions of the present invention can be obtained by varying three principal variables. 1. The molecular weight of lactide macromonomer. 2. Type of acidic monomer 3. Composition of the copolymer In the present invention the lactide macromonomer (A) is synthesized by ring opening oligomerization of L-lactide and subsequent end group functionalization of the oligo (lactide) diol with acrylate or methacrylate moiety. (Matthias Schnabelrauch, Sebastian Vogt, Yves Larcher, Ingo Wilke Biomolecular Engineering, (2002), 19, 295- 298). The macromonomer can also be synthesized by coupling oligomeric diol with acrylic acid or methacrylic acid using Dicyclohexyl carbodiimide. Oligomeric lactide diol is an oligomeric lactide having terminal hydroxyl groups which is synthesized from Lactide and 1, 4 Butanediol by ring opening melt polymerization. (Kari Hiltunen, Mika Harkonen, Jukka Seppala, Taito Vaananen Macromolecules (1996), 29, 8677-8682). The oligo (lactide) diol is then dissolved in tetrahydrofuran to which acryloyl chloride is added dropwise under Nitrogen atmosphere. The salt is removed by filtration and mixture is evaporated to concentrate the macromonomer. The macromonomer is precipitated in non-solvent like water and dried at room temperature. The macromonomer is then used for copolymerization with an acidic monomer. The solution polymerization technique is used for polymerization of oligomeric lactide macromonomer with acidic monomers. In solution polymerization the macromonomer and acidic monomer are dissolved in the solvent and the initiator such as Azo-bis-isobutyronitrile is added. The mixture is purged with Nitrogen and the polymerization is carried out under inert atmosphere. After 16 to 24 hours, solvent is evaporated under reduced pressure and the polymer is precipitated from the solution in nonsolvents like water or diethyl ether. The polymer is then dried under vacuum. The dissolution behavior of the polymers synthesized was studied by exposing the polymers to buffer solutions of different pH ranges and the results are tabulated in tables 2 - 5. The invention is illustrated herein below with reference to examples which are representative only and do not in any way limit the scope of the invention in any manner. Example 1 This example provides for the copolymer of oligo (Lactide) acrylate with acrylic acid in which mol. wt. of lactide macromonomer is 555. 1 g (1.8x10-3 moles) oligo (Lactide) acrylate was dissolved in 15 ml Dimethyl formamide, to which 1.167g (1.62 x10~2 moles) of acrylic acid was added. The initiator azo bis Isobutyronitrile 0.0591 g (3.6 x 10"4 moles) was added to it. This reaction mixture was stirred well and nitrogen was purged through it for 10 minutes, and was heated for 24 hours at 65°C in a water bath. The solvent was then removed under reduced pressure and the reaction mixture was precipitated in water. Polymer was dried under vacuum and characterized by NMR and VPO. The copolymer composition was 07:93 (oligo (lactide) acrylate: acrylic acid) on mole basis. Molecular weight of the polymer was 4176. Example 2 All remaining examples describing copolymers of oligo (lactide) acrylate and oligo (lactide) methacrylate with acidic monomers are presented in table 1 Table 1 Examples of copolymers of macromonomer (M1) and acidic monomers (M2) (Table Removed) LAc = oligo (lactide) acrylate M= Acrylic acid LMc=oligo (lactide) methacrylate MAA= Methacrylic acid VBA= 4-vinyl benzole acid Table 2 Dissolution behavior of polymers in buffers Composition - oligo (lactide) acrylate: acrylic acid (Table 2 Removed) indicates the copolymer does not dissolve in given pH buffer Table 3 Dissolution behavior of polymers in buffers (Table 3 Removed) Composition - oligo (lactide) acrylate: methacrylic acid Table 4 Dissolution behavior of polymers in buffers Composition - oligo (lactide) methacrylate: acrylic acid (Table 4 Removed) Table 5 Dissolution behavior of polymers in buffers Composition - oligo (lactide) methacrylate: methacrylic acid (Table 5 Removed) ADVANTAGES OF THE INVENTION 1. The copolymers are low molecular weight which is advantageous for rapid elimination from the body after drug release. 2. The copolymers exhibit pH sensitive dissolution behavior at very low content of acidic monomer (as low as 0.3 % w/w). 3. The copolymers do not dissolve in acidic pH of stomach and thus will protect acid labile drugs from deleterious effects of low pH. 4. The copolymers dissolve in aqueous medium at pH > 6 over varied time periods ranging from 30 to 1440 minutes. 5. The copolymers described herein can find applications in delayed, extended and chronotherapeutic applications depending on their dissolution profile. We Claim: 1. A macromonomer based copolymer soluble in aqueous medium above pH 6 having the general formula: (Formula Removed) wherein , A is an acrylate or methacrylate ester containing oligomer of lactide molecular weight ranging from 500 to 1500; X varies from 35 to 99.7% w/w of the copolymer; B is an acidic monomer; y varies from 0.30 to 65% w/w of the copolymer. 2. A macromonomer based copolymer as claimed in claim 1,has the following characteristics: a) copolymer is soluble at pH > 6 and insoluble at pH b) copolymer has a solubility in aqueous medium over extended time period ranging from 30 to 1440 minutes; c) copolymer has a molecular weight in the range of 1000 to 15000. 3. A copolymer as claimed in claim 1, wherein the macromonomer (A) used is selected from oligo(lactide) acrylate and oligo(lactide) methacrylate. 4. A copolymer as claimed in claim 1, wherein the acidic monomer used is selected from the group consisting of 4-vinyl benzoic acid, fumaric acid, maleic acid, acrylic acid and methacrylic acid. 5. A process for the preparation of a macromonomer based copolymer soluble in aqueous medium above pH 6 having the general formula: (Formula Removed) Wherein, A is an acrylate or methacrylate ester containing oligomer of lactide molecular weight ranging from 500 to 1500; X varies from 35 to 99.7% w/w of the copolymer; B is an acidic monomer; y varies from 0.30 to 65% w/w of the copolymer, the said process comprising the steps of: a) preparing a solution of a macromonomer (A) and an acidic monomer (B) in an organic solvent; b) adding a free radical initiator to above mixture and stirring the resultant reaction mixture for 10 minutes under inert atmosphere followed by heating at a temperature in the range of 50-70°C, for a period of 16-24 hours; c) concentrating the reaction mixture at reduced pressure in the range of 7-12 mbar followed by precipitation in water to obtain the desired copolymer. 6. A process as claimed in claim 5, wherein the organic solvent used for polymerization in step (a) is selected from the group consisting of chlorinated hydrocarbon, alcohol, ester, ketone, tetrahydrofuran, dioxane and dimethyl sulphoxide. 7. A process as claimed in claim 5, wherein the free radical initiator used in step (b) is selected from the group consisting of azo compound, peroxide, hydroperoxide, peracid and perester. 8. A process as claimed in claim 7, wherein the azo compound used is selected from the group consisting of azo-bis-cyano-valeric acid, azo-bis-biphenyl methane, azo-bis-methyl isobutyrate and azo-bis-isobutyronitrile. 9. A process as claimed in claim 5, wherein the molar ratio of macromonomer to acid monomer used in step (a) is in the range of 0.11 to 4.0 10. A process as claimed in claim 5, wherein the concentration of oligomeric lactide macromonomer in the copolymer obtained is in the range of 35 to 99.7% w/w of the copolymer. 11. A process as claimed in claim 5, wherein the concentration of acidic monomer in the copolymer obtained is in the range of 0.30 to 65% w/w of the copolymer.

Full Text

FIELD OF THE INVENTION
The present invention relates to a macromonomer based copolymer soluble in aqueous medium above pH 6 having the general formula:
P [A (x) B (y)]
Particularly the invention relates to a composition comprising a lactide macromonomer and an acidic monomer and a process for the preparation thereof. More particularly it refers to a copolymer composition comprising a lactide macromonomer and an acidic monomer having a general formula
P [A (x) B (y)]
Where A = Acrylate or methacrylate ester of oligomer of lactide
(Table 1 Removed)

m = 2to5, n = 2to4
AND
B = an acidic monomer H Z
X
X = COOH or C6H5COOH Y=H or COOH Z = H or CH3
Wherein (A) is an acrylate or methacrylate ester containing oligomer of lactide of molecular weight 500 to 1500 and the content (x) of oligomeric ester of lactide varies between 35 to 99.7 % w/w of the copolymer and (B) is an acidic monomer and the content (y) of the acidic monomer varies between 0.30 to 65 % w/w of the copolymer.
The copolymers dissolve over extended time period ranging between 30 to 1440 minutes at pH > 6 and are insoluble at pH copolymers can be used in drug delivery systems and other applications wherein pH dependent dissolution over extended time period is desirable.
BACKGROUND OF THE INVENTION
Smart polymers undergo a conformational change in response to changes in external environment such as pH, temperature, light, and metabolites. (S.I. Kang, Y.H. Bae, Macromolecules (2001), 34, 8173-8178). Among these, pH sensitive polymers have attracted growing interest in both scientific and technological fields (H.C. Chiu, A.T.Wu, Y.F. Lin, Polymer (2001), 42, 1471-1479). pH responsive conformation accompanied by solubility changes is common behavior in biopolymers. These polymers consist of ionizable groups that can accept and donate protons in response to environmental pH. As the environmental pH changes, the degree of ionization in a polymer bearing weakly ionizable groups is dramatically altered. (Eun Seok Gil, Samuel M. Hudson. Prog. Polym. Sci., (2004), 29, 1173-1222). This change in net charge of pendant groups causes an alteration in the hydrodynamic volume of the polymer chains. The transition from collapsed state to expanded state is due to the osmotic pressure exerted by mobile counter ions neutralizing the network charges (S.R. Tonge, B.J. Tighe, Adv Drug Deliv Rev (2001), 53, 109-122). The polymers containing ionizable groups form polyelectrolyte in aqueous medium. There are two types of pH responsive polyelectrolytes; weak polyacids and weak polybases. Weak polyacids such as poly(acrylic acid) are ionized in neutral and basic pH ( O.E. Philippova, D. Hourdet, R. Audebert and A.R. Khokhlov, Macromolecules (1997), 30 , 8278-8285). On the other hand, polybases like poly (4-vinylpyridine) are protonated at low pH. (V.T. Pinkrah, M.J. Snowden, J.C. Mitchell, J. Seidel, B.Z. Chowdhry and G.R. Fern, Langmuir (2003), 19, 585-590).
Polyacids bearing carboxylic group with pKa around 5-6 are the most representative weak polyacids. The polymers containing acrylic acid and methacrylic acid have been most frequently reported as pH responsive polymers. Carboxylic pendant groups accept protons at low pH and release at basic pH. Polymers containing methacrylic acid show an abrupt phase
transition, compared with the relatively continuous phase transition in case of polymers containing acrylic acid. Polymethacrylic acid has a compact conformation before a critical charge density is attained, because the methyl groups in this polymer induce stronger hydrophobia interactions which lead to aggregation.
pH responsive polymers contain functional groups which undergo structural change in response to pH. This property of polymers can be used in drug delivery systems to target the release of drugs to intended sites along the gastrointestinal tract. The concept of using pH as a trigger to release a drug in the colon is based on pH conditions that continuously vary from acidic (1-3) to near neutral and basic (5-8) along the gastrointestinal tract.
Pharmaceutical uses of acrylic polymers are widespread and these copolymers are available in the market under different brand names depending on the composition and manufacturer. Applications of acrylic polymers in ocular, nasal, buccal, gastro-intestinal, epidermal and transdermal, vaginal or cervical drug delivery continue to be explored.
(Acrylic acid and methacrylic acid copolymers are used as excipients in variety of ways ranging from personal care products to intestinal drug delivery. These copolymers solubilize in intestine and release encapsulated drug. Since the copolymers are insoluble at acidic pH, they protect encapsulated drug in gastric region. Molecular weights of these copolymers are high. Content of acidic monomers like acrylic acid and methacrylic acid which contributes to pH dependent behavior in these copolymers is 25 to 55 % w/w.
Lactose-based placebo tablets were coated using various combinations of two methacrylic acid copolymers, Eudragit L100-55 and Eudragit S100. The coated tablets were tested in vitro for their suitability for pH dependent colon targeted oral drug delivery. The same coating formulations were then applied on tablets containing mesalazine as a model drug and evaluated for in vitro dissolution. The dissolution data obtained from the placebo tablets demonstrate that disintegration rate of the tablets is dependent on: (i) the polymer composition used to coat the tablets, (ii) pH of
the dissolution media, and (iii) the coating level of the tablets. Dissolution studies performed on mesalazine tablets further confirmed that the release profiles of the drug in the pH range 5.5 to 7.0 could be manipulated by changing Eudragit L100-55 and Eudragit S100 ratios. (Khan, Zahirul I.; Prebeg, eljko; Kurjakovic, Nevenka. Journal of Controlled Release (1999), 58(2), 215-222).
The colon-specific drug delivery system containing a drug core along with a solid particulate inter-polymer complex of glucosamine and poly (acrylic) acid and a pH-dependent coating surrounding at least a portion of the core was designed and evaluated. The pH-dependent coating was insoluble in gastric fluid and intestinal fluid below pH 6.0 but became soluble in the colonic environment. (Wilson, Clive; Mukherji, Gour; Rampal, Ashok Kumar. PCT Int. Appl. (2005), WO 2005030173 A1 20050407)
pH independent release of the basic model drug Verapamil HCI was achieved by coating with combination of dispersion of polyvinyl acetate and the enteric polymer dispersion of methacrylic acid and ethyl acrylate. Two polymers were applied either as separate layers (enteric polymer + extended release polymer or vice versa) or as a polymer blend. A careful balance of the ratios of the polymers enabled pH independent release. Higher amounts of the enteric polymer in the polymer blend resulted in faster release at pH 6.8 than at pH 1.2. (Dashevsky, A.; Kolter, K.; Bodmeier, R. European Journal of Pharmaceutics and Biopharmaceutics (2004), 58(1), 45-49).Thus, these polymer combinations released the drug both in gastric and intestinal pH. Such polymers are not useful for the delivery of acid labile drugs.
Use of pH-responsive, poly (methacrylic-g-ethylene glycol) hydrogels as oral delivery vehicles for insulin was investigated in vivo using healthy and diabetic Wistar rats. In the acidic environment of the stomach, the gels remained collapsed due to the formation of intermolecular polymer complexes. Insulin remained in the gel and was protected from proteolytic degradation. In the basic and neutral environments of the intestine, the complexes dissociated which resulted in rapid swelling of the gel and insulin release. Within two hours of administration of the insulin containing
polymers, strong dose-dependent hypoglycemic effects were observed in both healthy and diabetic rats. (Lowman, A. M.; Morishita, M.; Kajita, M.; Nagai, T.; Peppas, N. A. Journal of Pharmaceutical Sciences (1999), 88(9), 933-937). Insulin release from such hydrogels was rapid and swelling dependent. Release could not be extended beyond two hours.
Microparticles made from the graft copolymers containing equimolar amounts of methacrylic acid and ethylene glycol were investigated for insulin release. These microparticles exhibited unique pH-responsive characteristics in which interpolymer complexes were formed in acidic media and dissociated in neutral / basic environments. Thus Insulin release from the gel was significantly retarded in acidic media while rapid release occurred under neutral / basic conditions. But as the amount of methacrylic acid in the polymer increased, insulin was readily released from the polymer network in both, the acidic and neutral / basic media. (Morishita, Mariko; Lowman, Anthony M.; Takayama, Kozo; Nagai, Tsuneji; Peppas, Nicholas A. Journal of Controlled Release (2002), 81(1-2), 25-32). Thus, the copolymer composition containing higher amount of methacrylic acid could not protect insulin in acidic media.
A novel oral sustained release formulation for delivery of a highly water soluble drug was investigated. Release rates of various drugs in polyacrylic acid / carrageenan (PAA / CA) (1:1) were compared with formulations containing polyacrylic acid / polyethylene oxide (PAA / PEO) (1: 1.5). Drug was released from PAA / CA matrix although at a slower rate in both simulated gastric fluid as well as simulated intestinal fluid as compared to the release from PAA / PEO matrix. (Rogers, Victoria; Dor, Philippe J. M.; Fix, Joseph A.; Kojima, Hiroyuki; Sako, Kazuhiro. PCT Int. Appl. (2003), WO 2003041656 A2 20030522)
These matrices can therefore not be used when the release of the drug in the gastric region is not desirable.
Linear and star shaped oligolactide macromonomers were synthesized by ring opening oligomerization of L-lactide and subsequent end group functionalization of the oligo lactide with methacrylate moiety. These
liquid macromonomers were valuable building blocks for the preparation of biocompatible polymer networks. These polymer networks exhibited excellent biocompatibility and were well suited as scaffolds for bone tissue engineering. (Matthias Schnabelrauch, Sebastian Vogt, Yves Larcher, Ingo Wilke Biomolecular Engineering (2002), 19, 295-298). Thus low molecular weight lactide macromonomers are used in the literature as scaffolds in tissue engineering. These macromonomers alone do not exhibit any pH dependent behavior.
Materials combining both bioadhesive and biodegradable components were synthesized using lactide polymers. These polymers were selected from the group consisting of poly (acrylic acid)-graft-poly (lactic acid) (PAA-g-PLA), poly (lactic-co-glycolic acid)-g-poly (acrylic acid) (PLGA-g-PAA). Hydrogen bonded interpolymer complexes were formed between polycarboxylic acids and PEG-PLGA copolymers. Such copolymers were mainly utilized to maintain acidic pH in body cavities like vagina or as mucoadhesive drug delivery components. (Huang, Yanbin; Kim, Jaeho. U.S. Pat. Appl. Publ. (2003), US 20030232088 A1 20031218). These polymeric systems worked on the principle of hydrolysis of biodegradable materials in aqueous system.
A biodegradable, biocompatible polymer in the form of solid or porous microcapsules was investigated for insertion into the eye of a patient for treating dry eye symptoms. Treating agents like saline, carboxy methylcellulose sodium, Dextran, hydroxypropyl methylcellulose, propylene glycol and glycerin were released in a patient's eye as polymer microcapsule biodegraded. Copolymers of lactide, copolymers of methacrylic acid and acrylic acid, copolymers of hydroxy ethyl methacrylate and methyl methacrylate were used to design such microcapsules. Such drug delivery system worked by slowly releasing the treatment agent into the eye through the polymer shell or sphere and provided dry eye treatment that was long lasting and easy to apply. (El-Sherif, Dalia M.; EI-Mansoury, Jeylan A. (USA). U.S. Pat. Appl. Publ. (2003) US 20030143280 A1 20030731).
Release rate of treatment agent from such formulations was dependent on biodegradation of polymer system in ocular cavity.
Thermo-responsive, pH-responsive, and biodegradable nanoparticles comprising of Lactide macromonomer-g-poly (N-isopropyl acrylamide-co-methacrylic acid) (PLA-g-P (NIPAm-co-MAA)) were developed by grafting biodegradable poly (D, L-lactide) onto N-isopropyl acrylamide and methacrylic acid. A core-shell type nano-structure was formed with a hydrophilic outer shell and a hydrophobic inner core, which exhibited a phase transition temperature above 37 °C suitable for biomedical application. The release of 5-Fluorouracil (5-FU) from nanoparticles was controlled by pH in aqueous solution. In acidic surrounding more than 25 % of 5-FU was released from nanoparticles in first hour. This was followed by a sustained release for 4 days by drug diffusion from core or due to PLA degradation. No drug release was observed at pH 7.4. These PLA-g-P (NIPAm-co-MAA) nanoparticles can be used as drug carrier for intracellular delivery of anti-cancer drug. (Chun-Liang Lo, Ko-Min Lin and Ging-Ho Hsiue Journal of Controlled Release, (2005), 104(3), 477-488). Thus these lactide nanoparticles released the drug in acidic pH which is not desirable for acid labile drugs.
In case of the references cited above, the drug release profile was not suitable for intestinal drug delivery. There is therefore a need to tailor polymers which dissolve over extended time period.
There are three different approaches for drug delivery to intestinal region depending on need of drug release pattern for specific disease conditions. Immediate enteric delivery of drugs is desirable in certain cases to treat acute conditions like pain associated with osteoarthritis (Ibuprofen), or delivery of acid labile cardiovascular drugs (Verapamil, Diltiazem), proteins and peptides. These are called delayed release preparations.
Conditions like rheumatoid arthritis need controlled release of therapeutic agent (e.g. Diclofenac Sodium) over prolonged time period. Such preparations are called extended release preparations.
Chronotherapeutic delivery is another concept in medicine, which
brings out the drug release from a formulation in harmony with patient's
natural circadian rhythm. Such a formulation delays release of drug by 4 to 5 hours and makes it available in circulation in the body at predetermined time. This is required in case of antihypertensive, antiasthmatic, analgesic, anti-inflammatory and some anticancer drugs.
For intestinal drug delivery, anionic polymers of methacrylic acid and methacrylates containing -COOH group are available in the market which dissolve immediately when they reach near neutral or neutral pH in intestine and release the drug. Other pH independent copolymers of acrylate and methacrylates containing quaternary ammonium group which are being explored, swell both in acidic as well as basic pH. Thus these polymers are not suitable for delivery of acid labile drugs. Other type of copolymers of acrylates and methacrylates containing quaternary ammonium group in combination with sodium carboxymethylcellulose exhibit pH independent dissolution behavior and these too can not protect acid labile drugs. Hence no acrylate or methacrylate polymers are available currently to satisfy the need.
From the foregoing it is clear that there is a need to design polymers which unlike conventional enteric polymers will dissolve over extended time periods. Such polymers will be useful for the release of drugs over varying time periods to satisfy needs of a wide variety of intestinal drug delivery systems like delayed and extended release.
This invention describes copolymer compositions comprising oligomeric lactide macromonomer and acidic monomer. It demonstrates that even at very low concentration of the acidic monomer (about 0.3 % w/w), the copolymer dissolves at pH > 6 over time periods ranging from 30 to 1440 minutes. These copolymers will satisfy the need for an excipient in intestinal drug delivery, as mentioned earlier. Since the polymers do not dissolve in acidic pH of stomach, they would protect acid labile drugs and release them in intestinal region over an extended time period. Thus these can be used as biocompatible pH sensitive excipients in drug delivery systems.
OBJECTIVES OF THE INVENTION
The main object of the present invention is to provide a copolymer comprising a lactide macromonomer and an acidic monomer by polymerization of acrylate or methacrylate ester of oligomeric lactide with an acidic monomer.
Another object of the present invention is to provide a process for the preparation of the said copolymer.
Yet another object of the present invention is to provide a copolymer which dissolve over an extended time period at pH > 6 similar to that present in intestine, but which do not dissolve at acidic pH of the stomach.
SUMMARY OF THE INVENTION
Accordingly the macromonomer based copolymer soluble in aqueous medium above pH 6 having the general formula:
P[(A)x(B)y]
wherein,
A is an acrylate or methacrylate ester containing oligomer of lactide molecular weight ranging from 500 to 1500;
X varies from 35 to 99.7% w/w of the copolymer;
B is an acidic monomer;
y varies from 0.30 to 65% w/w of the copolymer.
In a feature of the invention a macromonomer based copolymer has the following characteristics:
a) copolymer is soluble at pH > 6 and insoluble at pH b) copolymer has solubility in aqueous medium over extended time
period ranging from 30 to 1440 minutes;
c) copolymer has a molecular weight in the range of 1000 to 15000.
In an embodiment of the invention the macromonomer (A) used is selected from oligo (lactide) acrylate and oligo (lactide) methacrylate.
In an embodiment of the invention the macromonomer (A) used has a molecular weight in the range of 500 to 1500.
In an embodiment the acidic macromonomer used is selected from the group consisting of 4-vinyl benzole acid, fumaric acid, maleic acid, acrylic acid and methacrylic acid.
Another feature of the invention provides a process for the preparation of the macromonomer based copolymer soluble in aqueous medium above pH 6 having the general formula:
P[(A)x(B)y]
Wherein, A is an acrylate or methacrylate ester containing oligomer of lactide molecular weight ranging from 500 to 1500; X varies from 35 to 99.7% w/w of the copolymer; B is an acidic monomer; y varies from 0.30 to 65% w/w of the copolymer and is having the following characteristics:
i) copolymer is soluble at pH > 6 and insoluble at pH ii) copolymer has a solubility in aqueous medium over extended time period ranging from 30 to 1440 minutes;
iii) copolymer has a molecular weight in the range of 1000 to 15000.
the said process comprising the steps of:
a) preparaing a solution of a macromonomer (A) and an acidic monomer
(B) in an organic solvent;
b) adding a free radical initiator to above mixture and stirring the resultant
reaction mixture for about 10 minutes under inert atmosphere followed
by heating at a temperature in the range of 50-70°C, for a period of
16-24 hours;
c) concentrating the reaction mixture at reduced pressure in the range of
7-12 mbar followed by precipitation in water to obtain the desired
copolymer.
In another embodiment of the invention the macromonomer (A) used has molecular weight in the range of 500 to 1500.
In another embodiment of the invention the acidic monomer (B) used is selected from 4-vinyl benzoic acid, fumaric acid, maleic acid, acrylic acid and methacrylic acid.
In another embodiment of the invention the organic solvent used for polymerization in step (a) is selected from the group consisting of chlorinated hydrocarbon, alcohol, ester, ketone, tetrahydrofuran, dioxane and dimethyl sulphoxide.
In another embodiment the free radical initiator used in step (b) is selected from the group consisting of azo compound, peroxide, hydroperoxide, peracid and perester.
In another embodiment the azo compound used is selected from the group consisting of azo-bis-cyano-valeric acid, azo-bis-biphenyl methane, azo-bis-methyl isobutyrate and azo-bis-isobutyronitrile.
In another embodiment of the invention the molar ratio of macromonomer to acid monomer used in step (a) is in the range of 0.11 to 4.0
In yet another embodiment the concentration of oligomeric lactide macromonomer in the copolymer is in the range of 35 to 99.7% w/w of the copolymer.
In still another embodiment the concentration of acidic monomer is in the range of 0.30 to 65% w/w of the copolymer.
DETAILED DESCRIPTION OF THE INVENTION
Copolymers of acrylic acid and methacrylic acid are being used as enteric coating materials in drug delivery systems. These polymers retain their integrity in acidic pH and dissolve immediately in near neutral or neutral pH. As a result these are not suitable for prolonged release of drugs or chronotherapeutic delivery, which is needed in certain cardiovascular or
analgesic, anti-inflammatory treatments. Hence it is desirable to tailor dissolution profile of the excipient to satisfy these needs.
We have surprisingly found that copolymers comprising lactide macromonomer and an acidic monomer such as acrylic acid or methacrylic acid undergo dissolution over extended time periods. These copolymers dissolve in near neutral or neutral pH over time period ranging from 30 to 1440 minutes.
Thus this invention relates to the synthesis of copolymers which undergo dissolution over extended time period above pH 6. The copolymer compositions of the present invention can be obtained by varying three principal variables.
1. The molecular weight of lactide macromonomer.
2. Type of acidic monomer
3. Composition of the copolymer
In the present invention the lactide macromonomer (A) is synthesized by ring opening oligomerization of L-lactide and subsequent end group functionalization of the oligo (lactide) diol with acrylate or methacrylate moiety. (Matthias Schnabelrauch, Sebastian Vogt, Yves Larcher, Ingo Wilke Biomolecular Engineering, (2002), 19, 295- 298).
The macromonomer can also be synthesized by coupling oligomeric diol with acrylic acid or methacrylic acid using Dicyclohexyl carbodiimide.
Oligomeric lactide diol is an oligomeric lactide having terminal hydroxyl groups which is synthesized from Lactide and 1, 4 Butanediol by ring opening melt polymerization. (Kari Hiltunen, Mika Harkonen, Jukka Seppala, Taito Vaananen Macromolecules (1996), 29, 8677-8682). The oligo (lactide) diol is then dissolved in tetrahydrofuran to which acryloyl chloride is added dropwise under Nitrogen atmosphere. The salt is removed by filtration and mixture is evaporated to concentrate the macromonomer. The macromonomer is precipitated in non-solvent like water and dried at room temperature. The macromonomer is then used for copolymerization with an acidic monomer.
The solution polymerization technique is used for polymerization of oligomeric lactide macromonomer with acidic monomers. In solution polymerization the macromonomer and acidic monomer are dissolved in the solvent and the initiator such as Azo-bis-isobutyronitrile is added. The mixture is purged with Nitrogen and the polymerization is carried out under inert atmosphere. After 16 to 24 hours, solvent is evaporated under reduced pressure and the polymer is precipitated from the solution in nonsolvents like water or diethyl ether. The polymer is then dried under vacuum.
The dissolution behavior of the polymers synthesized was studied by exposing the polymers to buffer solutions of different pH ranges and the results are tabulated in tables 2 - 5.
The invention is illustrated herein below with reference to examples which are representative only and do not in any way limit the scope of the invention in any manner.
Example 1
This example provides for the copolymer of oligo (Lactide) acrylate with acrylic acid in which mol. wt. of lactide macromonomer is 555.
1 g (1.8x10-3 moles) oligo (Lactide) acrylate was dissolved in 15 ml Dimethyl formamide, to which 1.167g (1.62 x10~2 moles) of acrylic acid was added. The initiator azo bis Isobutyronitrile 0.0591 g (3.6 x 10"4 moles) was added to it. This reaction mixture was stirred well and nitrogen was purged through it for 10 minutes, and was heated for 24 hours at 65°C in a water bath. The solvent was then removed under reduced pressure and the reaction mixture was precipitated in water. Polymer was dried under vacuum and characterized by NMR and VPO.
The copolymer composition was 07:93 (oligo (lactide) acrylate: acrylic acid) on mole basis. Molecular weight of the polymer was 4176.
Example 2
All remaining examples describing copolymers of oligo (lactide) acrylate and oligo (lactide) methacrylate with acidic monomers are presented in table 1
Table 1 Examples of copolymers of macromonomer (M1) and acidic monomers (M2)

(Table Removed)
LAc = oligo (lactide) acrylate M= Acrylic acid
LMc=oligo (lactide) methacrylate MAA= Methacrylic acid
VBA= 4-vinyl benzole acid

Table 2 Dissolution behavior of polymers in buffers
Composition - oligo (lactide) acrylate: acrylic acid

(Table 2 Removed)
indicates the copolymer does not dissolve in given pH buffer
Table 3 Dissolution behavior of polymers in buffers

(Table 3 Removed)

Composition - oligo (lactide) acrylate: methacrylic acid

Table 4 Dissolution behavior of polymers in buffers
Composition - oligo (lactide) methacrylate: acrylic acid

(Table 4 Removed)
Table 5 Dissolution behavior of polymers in buffers
Composition - oligo (lactide) methacrylate: methacrylic acid

(Table 5 Removed)
ADVANTAGES OF THE INVENTION
1. The copolymers are low molecular weight which is advantageous for rapid
elimination from the body after drug release.
2. The copolymers exhibit pH sensitive dissolution behavior at very low
content of acidic monomer (as low as 0.3 % w/w).
3. The copolymers do not dissolve in acidic pH of stomach and thus will
protect acid labile drugs from deleterious effects of low pH.
4. The copolymers dissolve in aqueous medium at pH > 6 over varied time
periods ranging from 30 to 1440 minutes.
5. The copolymers described herein can find applications in delayed,
extended and chronotherapeutic applications depending on their dissolution
profile.

We Claim:
1. A macromonomer based copolymer soluble in aqueous medium
above pH 6 having the general formula:
(Formula Removed)
wherein ,
A is an acrylate or methacrylate ester containing oligomer of lactide molecular weight ranging from 500 to 1500;
X varies from 35 to 99.7% w/w of the copolymer;
B is an acidic monomer;
y varies from 0.30 to 65% w/w of the copolymer.
2. A macromonomer based copolymer as claimed in claim 1,has the
following characteristics:
a) copolymer is soluble at pH > 6 and insoluble at pH b) copolymer has a solubility in aqueous medium over extended time period ranging from 30 to 1440 minutes;
c) copolymer has a molecular weight in the range of 1000 to 15000.

3. A copolymer as claimed in claim 1, wherein the macromonomer (A) used is selected from oligo(lactide) acrylate and oligo(lactide) methacrylate.
4. A copolymer as claimed in claim 1, wherein the acidic monomer used is selected from the group consisting of 4-vinyl benzoic acid, fumaric acid, maleic acid, acrylic acid and methacrylic acid.
5. A process for the preparation of a macromonomer based copolymer soluble in aqueous medium above pH 6 having the general formula:
(Formula Removed)
Wherein, A is an acrylate or methacrylate ester containing oligomer of lactide molecular weight ranging from 500 to 1500; X varies from 35 to 99.7% w/w of the copolymer; B is an acidic
monomer; y varies from 0.30 to 65% w/w of the copolymer, the said process comprising the steps of:
a) preparing a solution of a macromonomer (A) and an acidic monomer (B) in an organic solvent;
b) adding a free radical initiator to above mixture and stirring the resultant reaction mixture for 10 minutes under inert atmosphere followed by heating at a temperature in the range of 50-70°C, for a period of 16-24 hours;
c) concentrating the reaction mixture at reduced pressure in the range of 7-12 mbar followed by precipitation in water to obtain the desired copolymer.
6. A process as claimed in claim 5, wherein the organic solvent used for
polymerization in step (a) is selected from the group consisting of
chlorinated hydrocarbon, alcohol, ester, ketone, tetrahydrofuran,
dioxane and dimethyl sulphoxide.
7. A process as claimed in claim 5, wherein the free radical initiator used
in step (b) is selected from the group consisting of azo compound, peroxide, hydroperoxide, peracid and perester.
8. A process as claimed in claim 7, wherein the azo compound used is
selected from the group consisting of azo-bis-cyano-valeric acid, azo-bis-biphenyl methane, azo-bis-methyl isobutyrate and azo-bis-isobutyronitrile.
9. A process as claimed in claim 5, wherein the molar ratio of
macromonomer to acid monomer used in step (a) is in the range of
0.11 to 4.0
10. A process as claimed in claim 5, wherein the concentration of oligomeric lactide macromonomer in the copolymer obtained is in the range of 35 to 99.7% w/w of the copolymer.
11. A process as claimed in claim 5, wherein the concentration of acidic monomer in the copolymer obtained is in the range of 0.30 to 65% w/w of the copolymer.

Documents:

1365-DEL-2006-Abstract-(23-05-2012).pdf

1365-del-2006-abstract.pdf

1365-DEL-2006-Claims-(23-05-2012).pdf

1365-del-2006-claims.pdf

1365-DEL-2006-Correspondence Others-(23-05-2012).pdf

1365-del-2006-correspondence-others.pdf

1365-del-2006-description (complete).pdf

1365-del-2006-form-1.pdf

1365-del-2006-form-2.pdf

1365-DEL-2006-Form-3-(23-05-2012).pdf

1365-del-2006-form-3.pdf

1365-del-2006-form-5.pdf

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Patent Number

253643

Indian Patent Application Number

1365/DEL/2006

PG Journal Number

32/2012

Publication Date

10-Aug-2012

Grant Date

08-Aug-2012

Date of Filing

08-Jun-2006

Name of Patentee

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

Applicant Address

ANUSANDHAN BHAWAN, RAFI MARG, NEW DELHI-110 001, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	SUVARNAPATHAKI RUPALI KEDAR	NATIONAL CHEMICAL LABORATORY DR. HOMI BHABHA ROAD, PUNE-411008 (MAHARASHTRA) INDIA.
2	KULKARNI MOHAN GOPALKRISHNA	NATIONAL CHEMICAL LABORATORY DR. HOMI BHABHA ROAD, PUNE-411008 (MAHARASHTRA) INDIA.

PCT International Classification Number

C08F 299/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA