Development of Pulsatile Systems for Targeted Drug Delivery of Celecoxib for Prophylaxis of Colorectal Cancer

The aim of the present study was to formulate fast release enteric-coated tablets for drug delivery to the colon. Two different approaches were used for the preparation of these tablets. The first included making use of superdisintegrant (SD) in the tablet. The amount of super disintegrant (cross-linked PVP) in the tablet and the coat weight were varied to formulate a suitable time-controlled release system, that would provide colon-specific drug delivery. The second approach consisted of development of osmogen-based tablets for drug delivery into the tracts of the colon. Two different osmogens, sodium chloride and potassium chloride, were used. These also were coated at different coat levels. Celecoxib was used as a model drug. In vitro drug release studies showed that superdisintegrants were more effective in showing burst effect in the tablets and therefore showed a rapid drug release as compared with osmogens, which would show a sustained drug release all through the colon. Osmotic tablets were formulated making use of a high concentration of osmogen sodium chloride (OM-SC) and potassium chloride (OM-KC) were further enteric-coated. These also were found to be useful in providing a sustained delivery of nearly 80–90% of the drug into the colonic region. The coat weight required in these tablets for protection in the upper gastrointestinal conditions varied from 9.69% in OM-KC tablets to 4.65% in OM-SC tablets.     

Evaluation of guar gum as a compression coat for drug targeting to colon

Colon-specific drug delivery systems based on a polysaccharide, guar gum, were evaluated using in vitro and in vivo methods. In vitro drug release studies have shown that guar gum in the form of compression coat applied over indomethacin core tablets protects the drug from being released under conditions mimicking mouth to colon transit. Studies in pH 6.8 phosphate buffered saline (PBS) containing 4% w/v rat caecal contents have demonstrated the susceptibility of guar gum to the colonic bacterial enzyme action with consequent drug release. gamma-scintigraphic studies in human volunteers with technetium-99m-DTPA as a tracer in sodium chloride core tablets compression coated with guar gum have shown that the gum coat protect the drug (tracer in the present study) from being released in the stomach and small intestine. On entering the ascending colon, the tablets commenced to release the tracer indicating the breakdown of the gum coat by the enzymatic action of colonic bacteria. The tablets disintegrated in the ascending colon of all the volunteers, except one, resulting in the distribution of released tracer across the entire colon. The study clearly established that guar gum, in the form of compression coat, is a potential carrier for drug targeting to colon.     

Colon-specific drug delivery for mebeverine hydrochloride

Mebeverine Hydrochloride (MB-HCl), an effective spasmolytic drug, was formulated as CODES. A colon-specific drug delivery technology CODES was designed to avoid the inherent problems associated with pH- or time-dependent systems. To achieve more protection and control of drug release, MB-HCl was prepared as microspheres and compressed as core tablets of CODES (modified CODES). The core tablets contained the drug either in free form [Formula 1 (F(1))], or as microspheres with 2 different polymer:drug:lactulose ratios (1:1:0.5 [Formula 2 (F(2))] and 2:1:0.5 [Formula 3 (F(3))]. The release profiles of the coated CODES systems were compared with uncoated compressed tablets. The uncoated tablet showed a drug release of 94% after 1 h in simulated gastric condition (pH = 1.2). The release characteristics of the coated systems revealed that the enteric coating (Eudragit L(100)) prevented any drug release in simulated gastric or duodenal conditions in the first 3 h (pH 1.2-6.1), after which drug was slightly liberated in simulated intestinal fluid (pH 7.4) {Phase 1 (P1)}. After 4 h the pH was adjusted to 7 and beta-glucose-oxidase was added, which is an enzyme produced by enterobacteria present in the colon. The acid-soluble coat (Eudragit)E(100)) dissolved and the drug release suddenly increased to reach 95, 72 and 60.4% for F(1)-F(3), respectively. IR spectrum study showed a covalent bond between the drug and the polymer in the formulae F(2) and F(3) resulting in the sustained drug release from the microspheres with a significant difference (p>0.05) to F(1). The findings were confirmed by in vivo investigation using X-ray images for Guinea pigs ingested tablets containing barium sulphate (F(4)), where the tablet began to disintegrate after 10 h of tablet intake. The results of the study indicated that MB-HCl CODES colon-specific drug delivery can act as a successful trigger for drug targeting in the colon. Furthermore, a sustained release of the drug can be achieved from modified CODES containing the drug in the form of microspheres.     

Composite film-coated tablets intended for colon-specific delivery of 5-aminosalicylic acid: using deesterified pectin

Combinations of Eudragit RS and deesterified pectin, polygalacturonic acid (PGA), or its potassium and sodium salts, when applied as a film coat, has a potential value as a colon-specific delivery system. Dispersions of PGA in Eudragit RS were used as the film former for coating of 5-aminosalicylic acid (5-ASA) tablet cores. Drug release behavior was assessed, in vitro, under simulating conditions in term of pH and time to in vivo during their transit to the colon. Negligible drug release occurred during first 5 hr where the coated tablets were in the stomach and small intestine. After that, the pectinolytic enzymes were added into the pH 6.8 medium to simulate the in vivo condition where there is the digestion of bacteria in the colon. The release of 5-ASA from the coated tablets occurred linearly as a function of time. Drug release depended on the composition of the mixed film, as well as the ratio of Eudragit RS to PGA or its salts. The highest drug release from the coated tablets of about 40% was obtained when the ratio of Eudragit RS to potassium salt of PGA was 2.5 to 1. Drug release profiles seemed to conform to the mechanism involving the osmotically driven release and formation of channels in the film caused by dissolution of PGA salts. Channel formation was, in most cases, activated by the presence of pectinolytic enzymes, showing that the PGA in the mixed film was subjected to enzymic breakdown. In conclusion, PGA could be used as an additive in Eudragit RS films to control the release of colonic delivery system.     

结肠定位释药双氯芬酸钠包衣片体内外相关性

目的研制时间依赖型口服结肠定位释药双氯芬酸钠包衣片。方法用释放度测定法研究双氯芬酸钠包衣片体外释放行为 ,用HPLC法测定包衣片在家犬体内的血药浓度 ,并计算出相关参数 ,进行体内外相关性考察。结果体外平均延迟释放时间为 4～ 5h时 ,体内平均时滞为 3～ 6h ,达到预期结果。结论本文研制的双氯芬酸钠片有进一步开发的价值     

Citric acid as excipient in multiple-unit enteric-coated tablets for targeting drugs on the colon

Delivery of drugs to the large bowel has been extensively investigated during the last decade. The aim of this study was to investigate whether enteric-coated tablets could be made from enteric-coated matrix granules and drug release targeted to the colon. Whether in vitro drug release rate and in vivo absorption could be delayed by adding citric acid to the granules and/or to the tablet matrix was also studied. Ibuprofen was used as model drug because it is absorbed throughout the gastrointestinal tract. Eudragit S and Aqoat AS-HF were used as enteric polymers. Drug release rates were studied at different pH levels and drug absorption was studied in bioavailability tests. The conclusion was that citric acid retarded in vitro drug release when used in multiple-unit tablets. In vivo absorption of ibuprofen was markedly delayed when citric acid was included in both granules and tablet matrix. Further studies are needed to determine the optimal amount of citric acid in formulations.     

甲壳素-双氯灭痛缓释片的研制

以甲壳系作为辅料采用湿颗粒压片法制备了双氯灭痛缓释片。体外溶出实验显示了双氯灭痛在0.1mol/L盐酸中极少溶出。在磷酸盐缓冲液（pH 6.8）中 0～10 h释药呈一级线性相关。含量测定等结果符合中国药典各有关规定,动物实验结果表明本品比其肠溶片抗炎作用延长且毒性较小,可望作为临床的更新产品。     

Design,Development and Optimization of S (-) Atenolol Floating Sustained Release Matrix Tablets Using Surface Response Methodology

The objective of this present investigation was to develop and formulate floating sustained release matrix tablets of s (-) atenolol, by using different polymer combinations and filler, to optimize by using surface response methodology for different drug release variables and to evaluate the drug release pattern of the optimized product. Floating sustained release matrix tablets of various combinations were prepared with cellulose-based polymers: Hydroxypropyl methylcellulose, sodium bicarbonate as a gas generating agent, polyvinyl pyrrolidone as a binder and lactose monohydrate as filler. The 3² full factorial design was employed to investigate the effect of formulation variables on different properties of tablets applicable to floating lag time, buoyancy time, % drug release in 1 and 6 h (D_{1 h,}D_{6 h}) and time required to 90% drug release (t_90%). Significance of result was analyzed using analysis of non variance and P < 0.05 was considered statistically significant. S (-) atenolol floating sustained release matrix tablets followed the Higuchi drug release kinetics that indicates the release of drug follows anomalous (non-Fickian) diffusion mechanism. The developed floating sustained release matrix tablet of improved efficacy can perform therapeutically better than a conventional tablet.     

Preparation and in vitro evaluation of enteric-coated tablets of rosiglitazone sodium

The aim of this study was to prepare the rosiglitazone sodium enteric-coated tablets and investigate its release rate. The rosiglitazone sodium enteric-coated tablet was prepared by single punch tablet press using substituted hydroxypropyl cellulose and polyvinylpyrrolidone (PVP). The release rate from the enteric-coated tablet of rosiglitazone sodium was evaluated. The release rate study showed that few rosiglitazone sodium was released from enteric coated formulation within 2 h in simulated gastric juice, while it released more than 80% of the labeled amount in 30 min in simulated intestinal juice. The preparing method of rosiglitazone sodium enteric-coated tablets was simple and had a good reproducibility. The release condition and determined methods could be used for the routine determinations of rosiglitazone sodium enteric-coated tablets.     

Formulation,Bioavailability, and Pharmacokinetics of Sustained-Release Potassium Chloride Tablets

The release of potassium chloride incorporated into hydrogenated vegetable oil and hydroxypropyl methylcellulose matrix tablets was studied in vitro. The formulations containing 20% hydrogenated vegetable oil and hydroxypropyl methylcellulose showed a sustained-release profile comparable to that of a standard commercially available sustained-release preparation, containing 8 mEq potassium chloride embedded in a wax material. The formulated and standard sustained-release potassium chloride tablets were compared to a conventional enteric-coated potassium chloride tablet in 10 healthy subjects. Mean recoveries in 24-hr urine potassium levels from four dosage forms (after subtracting normal urine potassium excretion levels) were 76 ± 32% from hydroxypropyl methylcellulose, 95 ± 22% from hydrogenated vegetable oil-incorporated matrix tablets, 91 ± 29% from commercially available sustained-release tablets, and 97 ± 13% from enteric-coated tablets. There was no significant difference (P > 0.05) in the time to reach maximum excretion rates among the three sustained-release tablets. No significant adverse effect was experienced with any of the preparations.     

泮托拉唑钠肠溶微丸型片剂的制备

研究泮托拉唑钠肠溶微丸型片剂制备方法。采用流化床包衣法制备泮托拉唑钠肠溶微丸, 将肠溶微丸与适合的辅料混合采用直接压片法制备泮托拉唑钠微丸型片剂。用体外释放度法及扫描电镜法观察压片前后药物的体外累计释放量及微丸形态。结果表明, 优化处方: 衣膜增重55%, 增塑剂含量20%, Eudragit L30D-55/ NE30D为8∶2, 肠溶微丸/辅料 (MCC/PPVP/PEG 6000, 2∶1∶1) 为5∶5时, 肠溶片在0.1 mol·L⁻¹盐酸中2 h累积释放百分数<10%, pH 6.8磷酸盐缓冲液中1 h累积释放百分数>85%。制备的泮托拉唑钠肠溶微丸片的释药行为较好, 有望应用于工业生产。     

The physicodynamic properties of mucoadhesive polymeric films developed as female controlled drug delivery system

Phenoporlamine hydrochloride is a novel compound that is used for the treatment of hypertension. The purpose of this study was to develop a sustained release tablet for phenoporlamine hydrochloride because of its short biological half-life. Three floating matrix formulations of phenoporlamine hydrochloride based on gas forming agent were prepared. Hydroxypropyl methylcellulose K4M and Carbopol 971P NF were used in formulating the hydrogel drug delivery system. Incorporation sodium bicarbonate into matrix resulted in the tablet floating over simulated gastric fluid for more than 6 h. The dissolution profiles of all tablets showed non-Fickian diffusion in simulated gastric fluid. Moreover, release of the drug from these tablets was pH-dependent. In vivo evaluations of these formulations of phenoporlamine hydrochloride were conducted in six healthy male human volunteers to compare the sustained release tablets with immediate release tablets. Data obtained in these studies demonstrated that the floating matrix tablet containing more Carbopol was capable of sustained delivery of the drug for longer periods with increased bioavailability and the relative bioavailability of formulation (containing 25% Carbopol 971P NF, 8.3% HPMC K4M) showed the best bioequivalency to the reference tablet (the relative bioavailability was 1.11 ± 0.19).     

Colon-specific drug delivery for mebeverine hydrochloride

Mebeverine Hydrochloride (MB-HCl), an effective spasmolytic drug, was formulated as CODES?. A colon-specific drug delivery technology CODES? was designed to avoid the inherent problems associated with pH- or time-dependent systems. To achieve more protection and control of drug release, MB-HCl was prepared as microspheres and compressed as core tablets of CODES? (modified CODES?). The core tablets contained the drug either in free form [Formula 1 (F₁)], or as microspheres with 2 different polymer:drug:lactulose ratios (1:1:0.5 [Formula 2 (F₂)] and 2:1:0.5 [Formula 3 (F₃)]. The release profiles of the coated CODES? systems were compared with uncoated compressed tablets. The uncoated tablet showed a drug release of 94% after 1 h in simulated gastric condition (pH = 1.2). The release characteristics of the coated systems revealed that the enteric coating (Eudragit®L₁₀₀) prevented any drug release in simulated gastric or duodenal conditions in the first 3 h (pH 1.2–6.1), after which drug was slightly liberated in simulated intestinal fluid (pH 7.4) {Phase 1 (P1)}. After 4 h the pH was adjusted to 7 and β-glucose-oxidase was added, which is an enzyme produced by enterobacteria present in the colon. The acid-soluble coat (Eudragit®E₁₀₀) dissolved and the drug release suddenly increased to reach 95, 72 and 60.4% for F₁–F₃, respectively. IR spectrum study showed a covalent bond between the drug and the polymer in the formulae F₂ and F₃ resulting in the sustained drug release from the microspheres with a significant difference (p>0.05) to F₁. The findings were confirmed by in vivo investigation using X-ray images for Guinea pigs ingested tablets containing barium sulphate (F₄), where the tablet began to disintegrate after 10 h of tablet intake. The results of the study indicated that MB-HCl CODES? colon-specific drug delivery can act as a successful trigger for drug targeting in the colon. Furthermore, a sustained release of the drug can be achieved from modified CODES containing the drug in the form of microspheres.     

In vivo evaluation of time and site of disintegration of polysaccharide tablet prepared for colon-specific drug delivery

Compression coating has been found to be useful for colonic drug delivery. The aim of the present investigation was to evaluate a formulation with a considerably reduced coat weight and gum concentration for colonic drug delivery in vivo using gamma scintigraphy. In vitro studies have found this formulation to be useful for delivery of 5-fluorouracil to the colon. Rapidly disintegrating core tablets containing (99m)Tc-DTPA were prepared and compression coating with 150 mg of granules containing a mixture of xanthan (XG), guar gum (GG) and starch. The ratios of the two gums XG:GG in the coat was kept 10:20. In vitro dissolution studies on XG:GG::10:20 tablets containing (99m)Tc-DTPA were carried out in simulated upper GIT conditions and also in presence of colonic contents. Cumulative percent release of technetium in the upper GIT conditions and transit time amounted to 4%. The total amount of technetium released in the 24 h of the dissolution study was 53+/-3.23%. Upon introduction of cecal content into the dissolution medium (4%), the release of technetium from the compression-coated tablet increased to 78.34+/-5.34%. Gamma scintigraphy studies carried out in six healthy human volunteers showed that the tablet remained intact during its transit through the upper GIT. The anatomical site of disintegration was found to be the ascending colon/hepatic flexure and the disintegration of the tablet started between 4 and 6 h post-dose in all the volunteers with a further spread of tracer into the ascending, transverse, descending and sigmoidal colon.     

Optimization and pharmacotechnical evaluation of compression‐coated colon‐specific drug delivery system of triphala using factorial design

The purpose of the present investigation was to achieve successful delivery specifically to the colon using guar gum as a compression coat over a core tablet of triphala. In this study, guar gum along with hydroxy propyl methyl cellulose (HPMC) was used as a compression‐coating polymer. The drug delivery system was based on the gastrointestinal transit time concept, assuming colon arrival time to be 6 h. Rapidly disintegrating core tablets containing 100‐mg triphala extract were compression coated with guar gum and HPMC. A 3² full factorial design was applied for optimization of the formulation. Both variables, the proportion of guar gum in polymer blend (X₁) and coat weight of the tablet (X₂), had an influence on the percent drug release after 4 h of dissolution of tablet in the presence of rat cecal content (Y240) and difference in percent drug release between 4 h and 10 h of dissolution of tablet in the presence of rat cecal content (YD).The results revealed that for protecting the rapidly disintegrating core of triphala in the physiological conditions of stomach and upper intestine, the core tablet should be coated with 50% of guar gum in coat formulation and higher coat weight. The proportion of guar gum exhibited predominant action as compared to coat weight. In vivo performance was assessed via an x‐ray roentgenography study by placing barium sulfate as an x‐ray opaque material instead of triphala. The guar gum–HPMC coating was found to be a promising drug delivery system for drugs such as triphala and sennosides to be delivered to the colon. Drug Dev. Res. 65:34–42, 2005. © 2005 Wiley‐Liss, Inc.     

Design and in vitro evaluation of oral colon targeted drug delivery systems for tinidazole

The aim of the present investigation is to develop colon targeted drag delivery sytems for tinidazole using guar gum as a carrier in the treatment of amoebiasis. Fast-disintegrating tinidazole core tablets were compression-coated with 55, 65 and 75% of guar gum. All the formulations were evaluated for the hardness, drug content uniformity, and subjected to in vitro drug release studies. The amount of tinidazole released from tablets at different time intervals was estimated by HPLC method. The compression-coated formulations released < 0.5% of tinidazole in the physiological environment of stomach and small intestine. When the dissolution study was continued in simulated colonic fluids, the compression coated tablet with 55% of guar gum coat released 99% of tinidazole after degradation by colonic bacteria at the end of 24 h of the dissolution study. The compression coated tablets with 65 and 75% of guar gum coat released about 67 and 20% of tinidazole, respectively in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that compression coated tinidazole tablets with either 55 or 65% of guar gum coat is most likely to provide targeting of tinidazole for local action in the colon owing to its minimal release of the drug in the first 5 h of physiological environment of stomach and small intestine. The tinidazole compression coated tablets showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/75% RH for 6 months.     

Microporous bilayer osmotic tablet for colon-specific delivery

Microporous bilayer osmotic tablet bearing dicyclomine hydrochloride and diclofenac potassium was developed using a new oral drug delivery system for colon targeting. The tablets were coated with microporous semipermeable membrane and enteric polymer using conventional pan-coating process. The developed microporous bilayer osmotic pump tablet (OPT) did not require laser drilling to form the drug delivery orifice. The colon-specific biodegradation of pectin could form in situ delivery pores for drug release. The effect of formulation variables like inclusion of osmogen, amount of HPMC and NaCMC in core, amount of pore former in semipermeable membrane was studied. Scanning electron microscopic photographs showed formation of in situ delivery pores after predetermined time of coming in contact with dissolution medium. The number of pores was dependent on the amount of the pore former in the semipermeable membrane. In vitro dissolution results indicated that system showed acid-resistant, timed release and was able to deliver drug at an approximate zero order up to 24 h. The developed tablets could be effectively used for colon-specific drug delivery to treat IBS.     

Formulation development and optimization of bilayer tablets of aceclofenac

Objective: The objective of the present study was to develop bilayer tablets of aceclofenac that are characterized by initial burst drug release followed by sustained release of drug. Methods: The fast-release layer of the bilayer tablet was formulated using microcrystaline cellulose (MCC) and HPMC K4M. The amount of HPMC E4M (X(1)) and MCC (X(2)) was used as independent variables for optimization of sustained release formulation applying 3(2) factorial design. Three dependent variables were considered: percentage of aceclofenac release at 1 h, percentage of aceclofenac release at 12 h, and time to release 50% of drug (t(50%)). The composition of optimum formulation of sustained release tablets were employed to formulate double layer tablets. Results: The results indicate that X(1) and X(2) significantly affected the release properties of aceclofenac from sustained release formulation. The double layer tablets containing fast-release layer showed an initial burst drug release of more than 30% of its drug content during first 1 h followed by sustained release of the drug for a period of 24 h. Conclusion: The double layer tablets for aceclofenac can be successfully employed as once-a-day oral-controlled release drug delivery system characterized by initial burst release of aceclofenac for providing the loading dose of drug.     

Linseed hydrogel based floating drug delivery system for fluoroquinolone antibiotics: Design,in vitro drug release and in vivo real-time floating detection

Herein, we designed a novel gastroretentive drug delivery system as floating matrix tablets based on a polysaccharide material from linseeds (Linum usitatissimum L.) for fluoroquinolone antibiotics. A number of formulations were designed with a combination of linseed hydrogel (LSH) and different excipients to obtain a desired sustained release profile of moxifloxacin. The drug release study was performed basically at pH 1.2. However, the tablet may pass through the stomach to intestine due to certain reasons then it also offered sustained drug release at intestinal pH 4.5, 6.8 and 7.4, as well. Results indicated that sustained moxifloxacin release was directly proportional to the concentration of LSH and the release of drug followed non-Fickian diffusion. SEM of the tablets indicated porous nature of LSH with elongated channels which contributed to the swelling of the tablet and then facilitated the discharge of moxifloxacin from the core of the tablet. In vivo X-ray study was performed to assess disintegration and real-time floating of tablet that confirmed its presence for 6 h in the stomach. These findings indicated that LSH can be used to develop novel gastroretentive sustained release drug delivery systems with the double advantage of sustained drug release at all pH of GIT.     

Gastrointestinal transit of an enteric-coated delayed-release 5-aminosalicylic acid tablet

Gastrointestinal transit of an enteric-coated, delayed-release 5-aminosalicylic acid tablet radiolabelled with indium-111 has been monitored in a preliminary study with eight healthy subjects using gamma scintigraphy. Gastric emptying of the tablet was delayed by the presence of food in the stomach. Disintegration occurred about 5 hours after the tablet left the stomach. There was close agreement between the tablet disintegration times and the initial detection of drug in the blood. The site of disintegration could be established in most instances; approximately 80% of the doses resulted in drug dispersion within the ascending colon. The coated tablets provide an effective means of drug delivery to the proximal colon.