Title of Invention

"SUSTAINED RELEASE PHARMACEUTICAL COMPOSITIONS CONTAINING CURCUMIN AND BETA-CYCLODEXTRIN"

Abstract

A novel gastro-retentive floating drug delivery system for the delivery of curcumin 0-cyclodextrin complex for oral administration is disclosed. The formulation is based on effervescent floating drug delivery system and floats on gastric juice thereby remaining in the stomach for an extended period of time. The present invention also provides process of preparing such dosage form. This novel pharmaceutical dosage form may be used for the treatment of cancer particularly of stomach and other diseases that might benefit from the effects of curcumin p-cyclodextrin complex.

Full Text

TECHNICAL FIELD The present invention relates with the development of gastro-retentive floating composition of curcumin in the form of a solid oral dosage form, preferably a tablet. The present invention also provides process of preparing such dosage form and methods of using such dosage form compositions. The invention relates generally to the field of cancer therapeutics and more specifically, the invention relates to the use of natural dietary phyto-constituent curcumin in a therapeutically effective pharmaceutical dosage form for prophylaxis and treatment of fore-stomach cancers. BACKGROUND Curcumin[(E,E)-l,7-Bis(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3,5-dione] is a phyto-polyphenol pigment isolated from the plant Curcuma longa, commonly known as turmeric, with a variety of pharmacologic properties, chiefly used as a spice and coloring agent in Indian food, as well as a therapeutic agent in traditional Indian medicine for various diseases, including biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism and sinusitis. The novel trends in medicine have led to extensive investigations to establish the wide spectrum of biological and pharmacological actions of this phytochemical. Curcumin possesses anti-inflammatory (Chainani 2003), antioxidant (Chen et al., 2005), anticarcinogenic (Aggarwal et al., 2006), antimutagenic (Shukla et al., 2002), anticoagulant (Srivastava et al., 1995), antiarthritic (Funk et al., 2006), antibacterial (Mishra et al., 2005), antifungal (Wuthi-Udomler et al., 2000), antiprotozoal (Koide et al., 2002), antiviral (De Clercq 2000 and Taher et al., 2000), anti-Alzheimer, anti-psoriatic (Shishodia et al., 2005) and neuroprotective (Vajragupta et al., 2003) activities. The efficacy, pharmacological safety, cost effectiveness of curcumin and no-dose limiting toxicity has also prompted many researchers to further investigate this molecule (Ammon et al., 1991). A study conducted by Cheng et al., in 2001 indicates that curcumin is tolerated in human beings at doses as high as 8g/day. Enthusiasm for curcumin as an anti-cancer agent evolved based on the wealth of epidemiological evidence suggesting a correlation between dietary turmeric and low incidence of gastrointestinal mucosal cancers. A plethora of experimental data has unequivocally established that free curcumin induces cell cycle arrest and/or apoptosis in human cancer cell lines derived from a variety of solid tumors including colorectal, lung, breast, pancreatic and prostate carcinoma amongst others. Curcumin also inhibits the growth of Helicobacter pylori, which causes gastric ulcers and has been linked with gastric cancers. Curcumin can also ameliorate the progression to cancer in a variety of organ sites, reiterating this agent's potential as a tool for chemoprevention. Curcumin's best known therapeutic effect is its anti-cancer effect (Kuttan et al., 1985). In vivo studies in mice demonstrate that curcumin suppresses carcinogenesis of the skin (Conney et al., 1991; Huang et al., 1991; Lu et al., 1994; Limtrakul et al., 1997; Huang et al., 1997), the forestomach (Huang et al., 1994; Singh et al., 1998), the colon (Rao et al., 1995; Kim et al., 1998; Kawamori et al., 1999), and the liver (Chuang et al., 2000). Curcumin has been shown to inhibit the proliferation of a wide variety of tumor cells, including B cell and T cell leukemia (Kuo et al., 1996; Ranjan et al., 1999; Piwocka et al., 1999; Han et al., 1999), colon carcinoma (Chen et al., 1999), epidermoid carcinoma (Korutla and Kumar, 1994) and breast cancer (Aggarwal et al., 2003). Despite the considerable promise that curcumin is an efficacious and safe compound for cancer therapy and chemoprevention; it has by no means been embraced by the cancer community as a "panacea for all ills". The single most important reason for this reticence has been the poor circulation bioavailability and absorption of orally administered curcumin from the gastrointestinal tract. Curcumin's bioavailability after oral administration is poor as it is practically insoluble in water/acidic pH of stomach and although soluble in alkaline pH degrades in intestine. Therefore, the in vivo concentrations of curcumin that are growth inhibitory to tumor cells in vitro cannot be achieved by the oral route. Even intravenous administration of free curcumin has also been found to be ineffective to achieve significant concentrations of curcumin in any tissue, since curcumin appears to be rapidly metabolized in circulation. Many research reports support the fact that although curcumin is exceedingly useful in the treatment of a wide range of pathological conditions, still its practical utility is limited by its rapid clearance from the body. Therefore, the need is to design a novel formulation which increases the systemic bioavailability against various pathological conditions with improved therapeutic potential and responsiveness towards curcumin. The prior work reported regarding bioavailabilty enhancement of curcumin include the use of adjuvant like piperine that interferes with glucuronidation thereby enhancing its systemic circulation (Shoba et al., 1998), liposomal curcumin formulations (US Patent 20060067998), aerosol delivery of curcumin (US Patent 20050181036) curcumin nanoparticles, complexation with betacyclodextrin (Tang et al, 2002 and Tonneson et al., 2002), enhanced solubility and dissolution with hydroxypropyl betacyclodextrin, complexation with water dispersible substances (US Patent 4999205), formulation with phosphatidylcholine (Marczylo et al., 2007). The principle of gastro-retentive controlled release is that these remain intact and buoyant in the gastric fluid while substantially all of the medicament is released there from are described in the art, i.e., the tablets remain buoyant and free floating in the gastric fluid for an extended period of time, during which substantially all of the medicament is released. Although many mechanisms of sustained release are recognized in the art and the concept of a floating tablet is recognized, there is no teaching which recognizes the application of buoyancy as well as its retention (inability to escape the pyloric sphincter) for sustaining the release of curcumin from curcumin 0-CD complex as is taught by the subject invention. US Patent Application No. 20040131669 talks about capsular floating pharmaceutical composition. The key of invention lies in the combination of the coatings using polymers like hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxycellulose, sodium carboxy methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, cellulose acetate phthalate etc. which is sprayed over hydroxypropyl methylcellulose capsule bodies. US Patent Nos. 4140755, 4167558,4424235 cites the two-layered sustained release tablet formulations in which hydrocolloids are incorporated in 'dry' form excluding the wet granulation techniques. These formulations after coming in contact with gastric fluids form soft gelatinous mass with bulk density less than one. US Patent Nos. 4126672 deals with the sustained release delivery of benzodiazepines using hydrodynamically balanced capsules which form an impermeable barrier on their surface after coming in contact with gastric fluid; acquires and maintains a bulk density of less than 1 thereby being buoyant in gastric fluid and remaining buoyant in the gastric fluid of the stomach until substantially all of said benzodiazepine contained therein has been released. US Patent Nos. 6746678 discloses the use of non-absorbable polyamine polymeric coagents such as chitosan, antioxidants (including curcumin) and nutritional agents, fillers like dicalcium phosphate and Magnesium stearate. The formulations may be used orally, intravenously, intramuscularly or subcutaneously to treat the neurodegenerative diseases. US Patent Application Nos. 20060008543, 20060008544 discloses non-buoyant anti-oxidant promoting composition using various extracts of various drugs (including turmeric) to alleviate stress.The invention claims the composition is administered daily as a dietary supplement. Moreover, the invention uses turmeric extract which contains 95% pure curcumin. Shree S. Dave et al. (2004), Gastroretentive Drug Delivery System of Ranitidine Hydrochloride: Formulation and In vitro evaluation, AAPS PharmaSciTech, 5 (2): article 34, focuses on gel forming properties of hydroxypropyl methylcellulose, guar gum and xanthan gum in the gastro retentive drug delivery system using ranitidine hydrochloride. The in vitro buoyancy studies indicate that the system floated for 8 hours only.Also, the study uses citric acid as release rate enhancer and stearic acid as release rate retardant. All of the above cited prior arts discloses and / or envisages bilayer tablets or floating capsules or combined bilayer gastroretentive formulation which are either intended for immediate release, or only for controlled delivery of drugs which pose problems of bioavailability fluctuations. Thus, there is a need to improve the aqueous solubility of curcumin at acidic pH by incorporating it into (3-CD complex and in order to facilitate its absorption and systematic availability from stomach, to target stomach tumors and to prevent likely degradation in alkaline environment of intestine a buoyant dosage form with sustained release characteristics was developed. SUMMARY The present disclosure provides composition of the phyto-phenolic compound curcumin. The compound is practically insoluble at the gastric pH and although soluble but degrades rapidly in alkaline pH of the intestines resulting in only traces in the blood circulation. The composition of the invention is a floating drug delivery system of curcumin with sustained release characteristics which after oral administration is designed to prolong the gastric residence time, increase bioavailability and also stomach specific delivery of curcumin. This invention is based on the fact that the oral administration of gastro-retentive effervescent controlled drug delivery of curcumin formulated as 0-CD complex resulting in improved solubility not only sustains the release of the polyphenolic component but also remains buoyant in the gastric contents for more than 16 hours during which substantially the entire active ingredient contained in the formulation is released in the gastric fluid. BRIEF DESCRIPTION OF THE DRAWINGS Fig .1 : In vitro release characteristics of curcumin in HC1 buffer pH 1-2. Fig. 2 : FT - IR spectrogram of curcumin Fig. 3 : FT - IR spectrogram of 0-CD. Fig. 4 : FT - IR spectrogram of physical mixture of curcumin and 0-CD. Fig. 5 : FT - IR spectrogram of inclusion complex of curcumin and 0-CD. DETAILED DESCRIPTION The present disclosure relates to a controlled release gastro-retentive floating composition useful for the treatment of stomach tumours this composition provides increased bioavailability and solubility, said composition comprising of curcumin beta-cyclodextrin (P-CD) complex as an active ingredient in the range of 3.0% to 23.0% w/w; one or more release controlling material in the range of 29.0% to 62.0% w/w; one or more gas generating component in combination with one or more acidic substances in the range of 6.0% to 18.0% w/w and other pharmaceutically acceptable excipients in the range of 2.0% to 30.0% w/w of the composition. The embodiment of the pharmaceutical composition of the present disclosure is that the composition comprises one or more solubility enhancer selected from a group of cyclodextrin but not limited to it. Another embodiment of the present disclosure is floating drug delivery system which offers sustained drug delivery, drug targeting to stomach and pharmacokinetic advantages. In another embodiment of the composition of the present disclosure is that the controlled release composition is preferably formulated as a gastro-retentive system such that the residence time of curcumin is increased in the stomach, so as to deliver curcumin substantially at the desired site of absorption that is preferably the upper part of the gastrointestinal tract. Further another embodiment of the present disclosure is that the release controlling material is selected from the group consisting of cellulose and cellulose derivatives like methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomers or mixture thereof. Yet another embodiment of the present disclosure is that the release controlling materials are preferably hydrophilic in nature. Another embodiment of the present disclosure is that the release controlling materials comprise materials, which are non-toxic and pharmaceutically acceptable. These may be natural, semi-synthetic, synthetic or man-modified. An another embodiment of the present disclosure is that the gas-generating component is selected from the group consisting of sodium bicarbonate, sodium carbonate,calcium carbonate and potassium carbonate. Yet another embodiment of the composition of present disclosure is that the acidic substance is selected from a group consisting of hydrochloric acid, citric acid, ascorbic acid, tartaric acid, fumaric acid and maleic acid or mixture thereof. Further, another embodiment of the composition of the present disclosure is that the other pharmaceutically acceptable excipients are selected from the group consisting of carrier filler, bulking agent, colorant, glidants, diluents, binders, lubricants, anti-adherants, hydrophilic polymers, solubility enhancing agents, osmotic agents and the like used either alone or in combination thereof. Another embodiment of the present disclosure is that the composition is in the form of compressed or compacted dosage forms like tablets. The present disclosure also relates to the process for preparing controlled release pharmaceutical composition said process comprising of mixing curcumin 0-CD complex in the range of 3.0% to 23.0% w/w of the composition with a release controlling material in the range of 29 % to 62.0% w/w of the composition, a gas forming agent in the range of 6.0% to 18.0% w/w of the composition and other pharmaceutically acceptable excipients in the range of 2.0% to 30.0% w/w of the composition then drying the composition thus obtained and finally compressed this pharmaceutical composition into the tablets. Another embodiment of the pharmaceutical composition of the present disclosure is that the water solubility of curcumin in the acidic pH is improved by inclusion into (i-cyclodextrin. Further, another embodiment of the present disclosure is that the water soluble curcumin complex is formulated into an effervescent floating drug delivery system. This control of placement of curcumin in the acidic medium of the stomach through this gastroretentive form may not only prevent its degradation, help targeting of curcumin to the stomach tumors and enhance systemic availability. This therapeutic efficacy is contemplated to reduce the dose and enhance patient compliance. Example 1: Preparation and evaluation of Curcumin beta cyclodextrin (p-CD) Complex Curcumin [Curcumin - Sigma C7727] was converted into a soluble form using beta cyclodextrin (P-CD). Kneading was employed to prepare 2:1 host-guest molecular complex of curcumin with P-CD. The slurry of P-CD (2.27 g) and curcumin (368.4 mg) was prepared in minimum amount of methanol solution in water (80%) in a mortar and kneaded for 45-60 minutes with intermittent addition of methanol solution. The slurry was dried overnight in vacuum oven at 50°C. The solid powder obtained was washed initially with chloroform and subsequently with water to remove un-entrapped drug and again dried at 50°C under vacuum. Curcumin +2p-CD -> curcumin in (P~CD) 2. The complex formation is confirmed by FT-IR method (See Fig.2-5). The inclusion of curcumin into p-CD may results in non-covalent interactions between them such as Vander Waal's interactions, hydrophobic interactions and hydrogen bonds which may lower the energy of the included part of curcumin and may also reduce the force constants of the corresponding bonds. This may decrease the absorption frequency of curcumin complex. By comparison of the IR spectrograms of curcumin (Fig.2), P-CD (Fig.3), the physical mixture of curcumin and P-CD (Fig.4) and the inclusion complex of curcumin and P-CD (Fig. 5), it was observed that the spectrum of Fig. 4 was essentially the combination of Fig.2 and Fig.3, which indicated that physical mixture, cannot lead to inclusion. It was also found that there were apparent differences between the spectra of Fig.4 and Fig.5 and that some characteristic IR peaks of curcumin had changed in Fig.5. For example, the 1600 cm-1 absorption beak, which could be assigned to the stretching vibration of benzene ring skeleton, was blue-shifted to 1632 cm-1 and 1279 cm-1 absorption beak because of the Ar-O stretching vibration has disappeared in Fig.5. Also delocalization of n electron of the olefinic double bond had resulted in the split in the 1428 cm-1 peak [which might be attributed to the olefinic C-H in-plane bending vibration (8C-H)] and a red-shifted peak at about 1425 cm-1 came into being. These observations were found to be supported by literature reports (Tang et al., 2002) that only aromatic structures at each end of the curcumin molecule may have included into the p-CD cavity and absorption frequency of the alkene part of curcumin (not included directly into the B-CD cavity) may have been influenced indirectly because of its conjugation with the aromatic rings (included into p-CD cavity).Therefore IR spectromettry confirmed the supramolecular inclusion complex formation between curcumin and P-CD (Fig.2-5). Example 2: Preparation of floating tablets of Curcumin (CI) Curcumin (lOOmg), hydroxypropyl methylcellulose (200mg), dicalcium phosphate (20mg), citric acid (50mg), sodium bicarbonate (25mg) were blended and wet granulating using 95% v/v ethanol. Then dried granules of 16-20 # (Mesh number Tyler; 16 mesh per inch is 1 mm sieve aperture and 20 mesh per inch is 0.841 mm sieve aperture) fractions were blended with Carbopol (25mg) and magnesium stearate (lOmg) and lastly, mixture was compressed into the tablets using flat faced, round punches of 13.1 mm diameter in a single punch tableting machine. The prepared tablets were subjected to in vitro evaluation for its drug content, weight variation, hardness, thickness and diameter uniformity and release characteristics. The average weight of tablet for this formulation was found to be 428.15± 1.20 mg. The thickness was 3.22±0.02 mm and hardness was found to be 2.60±0.08 kg/cm2. It was also observed that tablet formulation possessed acceptable physical characteristics. example j: Preparation of floating tablets of Curcumin p-cyclodextrin Complex (CH) Curcumin p-cyclodextrin complex (lOOmg), hydroxypropyl methylcellulose (200mg), dicalcium phosphate (20mg), citric acid (50mg), sodium bicarbonate (25mg) were blended and wet granulating using 95% v/v ethanol. Then dried granules of 16-20 # (Mesh number Tyler; 16 mesh per inch is 1 mm sieve aperture and 20 mesh per inch is 0.841 mm sieve aperture) fractions were blended with Carbopol (25mg) and magnesium stearate (lOmg) and lastly, mixture was compressed into the tablets using flat faced, round punches of 13.1 mm diameter in a single punch tableting machine. The prepared tablets were subjected to in vitro evaluation for its drug content, weight variation, hardness, thickness and diameter uniformity and release characteristics. The average weight of tablet for this formulation was found to be 430.15± 1.39 mg. The thickness was 3.23±0.02 mm and hardness was found to be 2.50±0.06 kg/cm2. It was also observed that tablet formulation possessed acceptable physical characteristics. Example 4: Different proportions of hydrocolloids and tableting agents It was observed that tablets of formulation FI and F2 (See Table 1) containing lower viscosity grade of HPMC (K4M) were buoyant only for 8-12 hours. To further increase the duration of buoyancy the higher viscosity grade of HPMC (K15M) was used. It was observed that with 200 mg of HPMC (K15M) the duration of buoyancy was increased to 16 hours.Duration of buoyancy exhibited an increase with the increase in concentration and viscosity of HPMC. The higher concentration of polymer also helps to retain the generated carbon dioxide (liberated when citric acid reacts with sodium bicarbonate; when the formulation comes in contact with the gastric fluid) for longer period of time thereby conferring good floating properties to the formulation FS as compared to the other formulations. The formulations Fi-Fs contained the filler dicalcium phosphate, due to which these formulations possessed a floating lag time period of 5-12 minutes. Therefore other fillers like lactose and microcrystalline cellulose were added to obtain immediately buoyant dosage forms. Although formulations Fe and FI containing lactose and microcrystalline cellulose respectively were immediately buoyant but these retained their integrity for only 10-12 hours compared with formulation FS which remained intact for 16 hours. Also, the swelling characteristics of formulation FS were examined in pH 1.2 HC1 buffer for 24 h. The size of the tablet was found to increase to 1.5 times the initial diameter after 15 h. This increase in size may also prevent the floating tablet from leaving the pyloric sphincter and help to improve its gastric retention. Table 1: Optimization of the tableting ingredients(Table Removed) [Note: ^represents the optimized formulation composition] Example 5: In vitro studies In vitro release studies were carried out using USP XXIII Dissolution Apparatus II (paddle type). The floating tablets of CI and CII were dropped into 900 ml of HC1 buffer pH 1.2 maintained at a temperature of 37±0.5°C and stirred at a speed of 50 rpm. At different time intervals, 10 ml aliquot was withdrawn and volume was replaced with an equivalent amount of fresh dissolution medium kept at 37°C. The collected samples were filtered and analyzed at A,max 420 nm (Ireson et al., 2002) using UV-visible spectrophotometer against HC1 buffer pH 1.2 taken as blank. Also, pure curcumin and curcumin 0-CD complex (100 mg each) were filled into hard gelatin capsules and subjected to dissolution studies in the manner described above to serve as Control I and Control II respectively. Drug release data were analyzed using ZOREL software (Singh and Singh, 1998) after correcting the values for the drug loss occurred during sampling. Based primarily on the algorithms proposed by Peppas and Sahlin (1989) the software reports the values of the release exponent (ri) indicating the kinetics of drug release, the kinetic constant (&), magnitudinal contributions of the Fickian diffusion (&/) and polymer relaxation (fo), respectively. The time between the introduction of the tablet into the medium and its buoyancy to the upper one-third of the dissolution vessel (buoyancy lag time) and the time for which the formulation constantly floats on the surface of medium (duration of buoyancy) were measured simultaneously as a part of dissolution studies. The results indicate that the critical value of release exponent (n) calculated as per algorithm proposed by Peppas and Sahlin, was 0.75 and 0.77 for formulations CI and CII respectively (See Table 2). In general the release pattern of curcumin from floating tablets was found to be non-Fickian. Much higher values of k\ (1.001-1.133) compared to fo (0.001-0.048) clearly indicate that the drug release was governed predominantly by Fickian diffusion, with varying contribution of polymer relaxation mechanism as well. Table 2: Data showing in vitro dissolution parameters of different curcumin formulations in HC1 buffer pH 1.2 (Table Removed)*Control I indicates pure curcumin; Control II indicates pure curcumin p-CD complex CI indicates curcumin floating tablet; CII indicates curcumin p-CD complex floating tablet Example 6: In vitro release characteristics of Different curcumin tablets The results indicate that the In vitro release pattern of Control I (pure curcumin) and CI (curcumin floating tablets) are almost super imposable.A very low percent drug release value (2.25% in 24 h) indicates the poor solubility characteristics of curcumin in the gastric pH.However, inclusion of curcumin into P-CD drastically improved its solubility in the acidic environment as it is evident from the release pattern of Control II (Curcumin P-CD complex).Almost 50% of curcumin was released in 1 h and more than 80% was released in 2 h from Control II. The overall release rate constant from Control II was observed to be 0.7998 which is significantly different and greater than Control I. Further buoyant Formulation CII containing curcumin P-CD complex could sufficiently sustain release of curcumin from the matrix (k= 0.1347) and only 50% of curcumin was released in 5 h and almost 100% release was achieved in 24 h (See Fig.l). An initial lag time of 10-12 min was observed for floating tablets of both the formulations (CI and CII) of curcumin to come on the surface after that the tablets remained buoyant up to 16 hours without disintegration. Example 7: The ex vivo studies for the antitumor activities in Albino female mice (Balb/C strain) Albino female mice (Balb/C strain) of 8-9 weeks old weighing 20-30 g were used. The animals were kept under standard 12/12 light/dark cycle and were given food and water ad libitum. The animals were administered two doses of 3mg of benzo(a)pyrene [B(a)P] in 0.25 ml of corn oil per oral at the gap of 2 weeks. The vehicle alone in an equal quantity was administered to the control group (Deep et al., 2006; Gangar et al., 2006; Triano et al., 1985). The B(a)P treated mice were divided into 4 groups (n=12 per group). Group I served as non-treatment control, Group II, III and IV were given treatment CI, Control II and CH respectively per orally as 100 mg/kg corn oil suspension of the drug till the end of the study.The mice were sacrificed after 18 weeks of last dose of B(a)P by cervical dislocation. The forestomach was separated and was cut longitudinally and fixed in 10% buffered formalin-phosphate. Stomach papillomas measuring 1.0 mm or larger were counted using magnifying glass (Triano et al., 1985). The relative susceptibility to B(a)P induced tumors was expressed by the tumorigenic index as proposed by Shimkin (1940). Tumorigenic index = Percentage of mice with tumors xMean number of tumors per tumor bearing mouse All the data was statistically analyzed by one way analysis of variance (ANOVA) followed by Dunnett's method. The results indicate that the treatment of mice with benzopyrene [B(a)P] resulted in 100% incidence of fore-stomach tumors after 10 weeks with an average of 2.0 tumors per mouse compared to corn oil-treated control animals.The treatment of mice with CI, Control II and CII after last dose of B(a)P i.e., during the initiation period, resulted in 25%, 35% and 50% reduction in tumor incidence respectively (See Table 3).The overall rate of tumor incidence and number of tumors/mouse were greater in animals which were treated with CI rather than CII. The insignificant reduction in number of tumors by CI may be attributed to low solubility of curcumin in acidic pH of stomach, which might have prevented its solubilisation in stomach fluids to give the required therapeutic concentration in body. Combined effect of complexation of curcumin with (3-CD and formulation of resulting complex into floating dosage form (CII) might have improved its solubility along with site-specific delivery of curcumin to gastric tumor giving the required therapeutic effect in mice. Thus, site-specific delivery of curcumin through floating dosage form produced statistically significant reduction in number of tumors. These results were in agreement with in vitro release studies of curcumin from floating tablets. Due to the low solubility of curcumin at acidic pH (Tonnesen et al., 2002), the formulation CI was found to offer no significant advantage over Control I. The amount of curcumin released from Control I (2.62% in 24 h) and CI (2.44% in 24 h) was very low. However, 98% of curcumin was released in 24 h from CII due to the increase in the water solubility of curcumin by ß-CD. Table 3: Data showing results of anti-tumor studies (Table Removed) " Tumorigenic index obtained by multiplying the percentage of mice with tumors times the mean number of tumors per tumor bearing mouse b Number in parentheses indicate percentage of the control tumorigenic index I/WE CLAIM 1. A controlled release gastro-retentive floating composition useful for the treatment of stomach tumours characterized in that said composition provides increased bioavailability and solubility, said composition comprising: a) curcumin beta-cyclodextrin complex as an active ingredient in the range of 3.0% to 23.0% w/w of the composition; b) one or more release controlling material in the range of 29.0% to 62.0% w/w of the composition; c) one or more gas generating component in combination with one or more acidic substances in the range of 6.0% to 18.0% w/w of the composition and; d) other pharmaceutically acceptable excipients in the range of 2.0% to 30.0% w/w of the composition. 2. The composition as claimed in claim 1, wherein the release controlling material is selected from a group consisting of cellulose and cellulose derivatives like methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and carbomers, or mixture thereof. 3. The composition as claimed in claim 1, wherein the gas-generating component is selected from a group consisting of sodium bicarbonate, sodium carbonate, calcium carbonate and potassium carbonate. 4. The composition as claimed in claim 1, wherein the acidic substance is selected from a group consisting of hydrochloric acid, citric acid, ascorbic acid, tartaric acid, fumaric acid and maleic acid or mixture thereof. 5. The composition as claimed in claim 1, wherein the other pharmaceutically acceptable excipients are selected from the group consisting of diluents, binders, lubricants, anti-adherants, hydrophilic polymers, solubility enhancing agents, osmotic agents and the likes used either alone or in combination thereof. 6. The composition as claimed in claim 1, wherein the composition is in the form of compressed or compacted dosage forms. 7. The composition as claimed in claim 6, wherein the compressed or compacted dosage form is tablet. 8. The composition as claimed in claim 1, wherein the mode of administration is orally. 9. A process for preparing controlled release pharmaceutical composition as claimed in claim 1, said process comprising: a) mixing curcumin P-CD complex in the range of 3.0% to 23.0% w/w of the composition with a release controlling material in the range of 29 % to 62.0% w/w of the composition, a gas forming agent in the range of 6.0% to 18.0% w/w of the composition and other pharmaceutically acceptable excipients in the range of 2.0% to 30.0% w/w of the composition; b) granulating; c) drying; and d) compressing into tablet.

Documents:

353-del-2008-abstract.pdf

353-del-2008-claims.pdf

353-del-2008-Correspondence Others-(14-10-2014).pdf

353-DEL-2008-Correspondence-Others (22-01-2010)--.pdf

353-DEL-2008-Correspondence-Others (22-01-2010).pdf

353-del-2008-correspondence-others.pdf

353-del-2008-description (complete).pdf

353-del-2008-drawings.pdf

353-DEL-2008-Form-1 (22-01-2010).pdf

353-del-2008-form-1.pdf

353-DEL-2008-Form-18 (22-01-2010).pdf

353-DEL-2008-Form-2 (22-01-2010).pdf

353-del-2008-form-2.pdf

353-del-2008-form-3.pdf

353-DEL-2008-Form-5 (22-01-2010).pdf

353-del-2008-form-5.pdf