Development and In Vitro Evaluation of Long Circulating Liposomes for Targeted Delivery of Gemcitabine and Irinotecan in Pancreatic Ductal Adenocarcinoma.

The classically used nontargeted chemotherapeutic approach to pancreatic cancer has a dual drawback of suboptimal drug delivery at the target site and the systemic side effects produced by the unfettered exposure of the drug to healthy tissue. This study has the objective of developing novel poly(2-ethyl-2-oxazoline) (PETOX)-based long circulating liposomes loaded with gemcitabine and irinotecan for the treatment of pancreatic ductal adenocarcinoma, with a juxtaposition to PEGylated and uncoated liposomes. A PETOX-cholesteryl chloroformate lipopolymer conjugate (PETOX-ChC) with a carbonate linkage was prepared and characterized by 1H NMR, FTIR, and DSC. Liposomes were prepared using the thin film hydration technique followed by freeze-thaw and membrane extrusion methods. Liposome characterization includes particle size determination, zeta potential determination using a zetameter, and structural elucidation using 31P NMR and cryo-TEM. The PETOXylated liposomes showed a particle size of 180.1 ± 2.2 nm and a zeta potential of - 33.63 ± 1.23 mV. The liposomal combination therapy of gemcitabine and irinotecan was found to have an IC50 value 39 times lower in comparison to the drug combination in solution, while the PEGylated and PETOXylated liposomes showed IC50 values 1.6 times lower and 2 times lower than that of uncoated liposomes, respectively, against Mia PaCa II pancreatic cancer cell line. The PEGylated and PETOXylated liposomes showed 4.1 and 5.4 times slower macrophagial uptake in vitro in comparison to the uncoated liposomes respectively. The PEGylated liposomes showed 11% higher in vitro macrophagial uptake in comparison to PETOXylated liposomes.

Subclinical atherosclerosis and silent myocardial ischaemia in patients with type 2 diabetes: a protocol of a clinico-observational study.

INTRODUCTION: Atherosclerotic cardiovascular disease is a significant modifiable complication in patients with diabetes and subclinical atherosclerosis is considered a surrogate marker of future vascular events. The clustering of cardiometabolic-risk factors in patients with diabetes and cardiovascular disease is increasingly being recognised. Recent evidence indicates that 20-50% of asymptomatic patients with diabetes may have silent coronary heart disease. However, the identification of subclinical atherosclerosis and silent myocardial ischaemia in patients with diabetes has been less well-explored, especially in low-resource population settings where cost-effective non-invasive clinical tools are available. The objective of this study is to identify patients with physician-diagnosed diabetes who are at risk of developing future cardiovascular events measured as subclinical atherosclerosis and silent myocardial ischaemia in an urban population of Eastern India. METHODS AND ANALYSIS: This is a cross-sectional clinico-observational study. A convenience sampling of approximately 350 consecutive patients with type 2 diabetes based on predefined inclusion and exclusion criteria will be identified at an urban diabetes center. This estimated sample size is based on an expected prevalence of silent myocardial ischaemia of 25% (± 5%), we computed the required sample size using OpenEpi online software assuming an α level of 0.05 (95% CI) to be 289. On factoring 20% non-response the estimated sample size is 350. Previously validated questionnaire tools and well-defined clinical, anthropometric and biochemical measurements will be utilised for data collection. The two primary outcomes-subclinical atherosclerosis and silent myocardial ischaemia will be measured using carotid intima-media thickness and exercise tolerance testing, respectively. Descriptive and multivariate logistic regression statistical techniques will be employed to identify 'at risk' patients with diabetes, and adjusted for potential confounders. ETHICS AND DISSEMINATION: Ethical approval was granted by the institutional review board of Kalinga Institute of Medical Sciences, Bhubaneshwar, India. Data will be presented at academic fora and published in peer-reviewed journals.

Effect of obesity on cardiometabolic risk factors in Asian Indians.

OBJECTIVES: To determine the prevalence of overweight and obesity and their effects on cardiometabolic risk factors in a representative sample of urban population in Eastern India. MATERIALS AND METHODS: A population-based survey was conducted among a randomly selected study population aged 20-80 years in an urban population of Berhampur city of Eastern India. Both anthropometric and biochemical information were collected, in addition to detailed information on classical cardiometabolic risk factors. Both descriptive and inferential statistical analyses were performed. Obesity and overweight were defined based on the revised Asian-Pacific population criteria (Body mass index [BMI] ≥25 kg/m(2) and ≥23 kg/m(2), respectively). RESULTS: The age-standardized rates of obesity and overweight are 36.8% (Males: 33.2%; Females: 40.8%) and 17.6%, (Males: 20.4%; Females: 15.1%) respectively, i.e., over half are either obese or overweight in this study population. Compared to the World Health Organization (WHO) standard cutoff criteria of overweight [BMI ≥25 kg/m(2)] and obesity [BMI >30 kg/m(2)], the cardiometabolic risk factors studied showed a significant incremental rise even with the lower cutoffs of the revised Asia-Pacific criteria. Older age, female gender, family history of diabetes, being hypertensive, hypertriglyceridemia, hypercholesterolemia, physical inactivity and middle to higher socioeconomic status significantly contributed to increased obesity risk among this urban population. CONCLUSION: One-third of the urban populations are obese in Eastern India - an underestimate compared to the standard BMI cutoff criteria. Nevertheless, significant associations of the classical cardiometabolic risk factors with obesity were observed using the revised Asia-Pacific criteria clearly indicating a more aggressive cardiovascular prevention strategy for Asian Indians.

Appropriate anthropometric indices to identify cardiometabolic risk in South Asians.

BACKGROUND: South Asians show an elevated cardiometabolic risk compared to Caucasians. They are clinically metabolically obese but are considered normal weight based on current international cut-off levels of several anthropometric indices. This study has two main objectives: (i) to predict the most sensitive anthropometric measures for commonly studied cardiometabolic risk factors, and (ii) to determine optimal cut-off levels of each of the anthropometric indices in relation to these cardiometabolic risk factors in South Asians. METHODS: The study was conducted on a random sample of 1178 adults of 20-80 years of age from an urban population of eastern India. Obesity, as evaluated by standard anthropometric indices of BMI (body mass index), WC (waist circumference), WHpR (waist-to-hip ratio) and WHtR (waist-to-height ratio), was individually correlated with cardiometabolic risk factors. Receiver operating characteristic (ROC) curve analyses were performed which includes: (i) the area under the receiver operating characteristic curve (AUROC) analysis to assess the predictive validity of each cardiometabolic risk factor; and (ii) Youden index to determine optimal cut-off levels of each of the anthropometric indices. RESULTS: Overall, AUROC values for WHtR were the highest, but showed variations within the sexes for each of the cardiometabolic risk factors studied. Further, WHpR cut-offs were higher for men (0.93-0.95) than women (0.85-0.88). WC cut-offs were 84.5-89.5 cm in men and 77.5-82.0 cm in women. For both sexes the optimal WHtR cut-off value was 0.51-0.55. The optimal BMI cut-offs were 23.4-24.2 kg/m2 in men and 23.6-25.3 kg/m2 in women. CONCLUSION: WHtR may be a better anthropometric marker of cardiometabolic risks in South Asian adults than BMI, WC or WHpR.

Prevalence and risk factors for diabetes and impaired glucose tolerance in Asian Indians: a community survey from urban eastern India.

OBJECTIVES: To determine the prevalence of diabetes and impaired glucose tolerance (IGT) and to identify risk factors for the same specific to an underdeveloped urban locale of Eastern India. METHODS: Study design. Population based cross-sectional study, with multistage random sampling technique. Setting. Urban city-dwellers in Orissa one of the poorest states of Eastern India bordering a prosperous state of Andhra Pradesh of Southern India. Participants. 1178 adults of 20-80 years age randomly selected from 37 electoral wards of urban populace. Definition and diagnosis of diabetes mellitus and IGT. These were based on a Report of a World Health Organization/International Diabetes Federation Consultation of 2006. Main outcome measure. Prevalence and significant risk factors for Diabetes and IGT. Statistical analysis. Both descriptive and multivariable logistic regression analyses. RESULTS: The crude rates of diabetes and IGT in the study population were 15.7% and 8.8%, respectively. Similarly age-standardized rates of diabetes and IGT were 11.1% and 6.7%, respectively. Both diabetes and IGT had shown a male preponderance. CONCLUSION: Diabetes and IGT were very highly prevalent in this urban populace. Cardiometabolic risk factors like older age, central obesity, inadequate fruit intake, hypertension, hypertriglyceridemia and socio economic status were found to be significant predictors of diabetes in this study.

Prevalence and risk factors for metabolic syndrome in Asian Indians: A community study from urban Eastern India.

OBJECTIVES: To determine the prevalence of metabolic syndrome and to identify predictors for the same, specific to an underdeveloped urban locale of Eastern India. STUDY DESIGN: Population-based cross-sectional study, with multistage random sampling technique. SETTING: Urban city-dwellers in Orissa one of the poorest states of Eastern India bordering a prosperous state of Andhra Pradesh of Southern India. PARTICIPANTS: 1178 adults of age 20-80 years randomly selected from 37 electoral wards of the urban city. Definition of Metabolic Syndrome: We followed a unified definition of the metabolic syndrome by joint interim statement of five major scientific organizations - the International Diabetes Federation, the National Heart, Lung, and Blood Institute, the American Heart Association, the World Heart Federation, the International Atherosclerosis Society, and the International Association of the Study of Obesity. Individuals who meet at least three of five clinical criteria of abdominal obesity, hypertriglyceredimia, low HDL, hypertension, and hyperglycemia are diagnosed as having the condition; presence of none of these criteria is mandatory. Explicit cut points are defined for all criteria, except elevated waist circumference, which must rely on population and country-specific definitions. MAIN OUTCOME MEASURE: Prevalence and significant predictors of metabolic syndrome. STATISTICAL ANALYSIS: Both descriptive and multivariable logistic regression analyses. RESULTS: Age-standardized prevalence rates of metabolic syndrome were 33.5% overall, 24.9 % in males and 42.3% in females. Older age, female gender, general obesity, inadequate fruit intake, hypercholesterolemia, and middle-to-high socioeconomic status significantly contributed to increased risk of metabolic syndrome. CONCLUSION: Metabolic syndrome is a significant public health problem even in one of the poorest states of India that needs to be tackled with proven strategies.

Abdominal obesity, an independent cardiovascular risk factor in Indian subcontinent: A clinico epidemiological evidence summary.

Evidence is emerging that obesity-associated cardiovascular disorders (CVD) show variations across regions and ethnicities. However, it is unclear if there are distinctive patterns of abdominal obesity contributing to an increased CVD risk in South Asians. Also, potential underlying mechanistic pathways of such unique patterns are not comprehensively reported in South Asians. This review sets out to examine both. A comprehensive database search strategy was undertaken, namely, PubMed, Embase and Cochrane Library, applying specific search terms for potentially relevant published literature in English language. Grey literature, including scientific meeting abstracts, expert consultations, text books and government/non-government publications were also retrieved. South Asians have 3-5% higher body fat than whites, at any given body mass index. Additional distinctive features, such as South Asian phenotype, low adipokine production, lower lean body mass, ethno-specific socio-cultural and economic factors, were considered as potential contributors to an early age-onset of obesity-linked CVD risk in South Asians. Proven cost-effective anti-obesity strategies, including the development of ethno-specific clinical risk assessment tools, should be adopted early in the life-course to prevent premature CVD deaths and morbidity in South Asians.

The in vitro sub-cellular localization and in vivo efficacy of novel chitosan/GMO nanostructures containing paclitaxel.

PURPOSE: To determine the in vitro sub-cellular localization and in vivo efficacy of chitosan/GMO nanostructures containing paclitaxel (PTX) compared to a conventional PTX treatment (Taxol). METHODS: The sub-cellular localization of coumarin-6 labeled chitosan/GMO nanostructures was determined by confocal microscopy in MDA-MB-231 cells. The antitumor efficacy was evaluated in two separate studies using FOX-Chase (CB17) SCID Female-Mice MDA-MB-231 xenograph model. Treatments consisted of intravenous Taxol or chitosan/GMO nanostructures with or without PTX, local intra-tumor bolus of Taxol or chitosan/GMO nanostructures with or without PTX. The tumor diameter and animal weight was monitored at various intervals. Histopathological changes were evaluated in end-point tumors. RESULTS: The tumor diameter increased at a constant rate for all the groups between days 7-14. After a single intratumoral bolus dose of chitosan/GMO containing PTX showed significant reduction in tumor diameter on day 15 when compared to control, placebo and intravenous PTX administration. The tumor diameter reached a maximal decrease (4-fold) by day 18, and the difference was reduced to approximately 2-fold by day 21. Qualitatively similar results were observed in a separate study containing PTX when administered intravenously. CONCLUSION: Chitosan/GMO nanostructures containing PTX are safe and effective administered locally or intravenously. Partially supported by DOD Award BC045664.

Smoking and cardiovascular health: a review of the epidemiology, pathogenesis, prevention and control of tobacco.

The causal associations between cigarette smoking and human diseases are irrefutable. In this review, we focus on the epidemiological pattern of cigarette smoking on cardiovascular risk, the underlying mechanistic process of such a causal link, how to prevent premature cardiovascular morbidity and mortality particularly through smoking cessation, and the health benefits of such cessation measures. Finally, we conclude our review summarizing a few of the proven evidence-based tobacco control strategies and policies from across the globe. We did not conduct a systematic review but followed a similar structure. We abstracted the most relevant published literature on the electronic databases, namely, PubMed, Embase and the Cochrane Library applying specific search terms. We also searched gray literature and consulted experts in the field for cross-references. Smoking has been estimated to cause about 11% of all deaths due to cardiovascular disease. Smoking contributes to the pathogenesis of coronary artery disease and sudden death through a variety of mechanisms, including the promotion of atherosclerosis, the triggering of coronary thrombosis, coronary artery spasm, and cardiac arrhythmias, and through reduced capacity of the blood to deliver oxygen. Smoking cessation also confers substantial benefits on people with serious heart disease. Smoking cessation should be viewed as therapeutic rather than preventive intervention, similar to treating asymptomatic hypertension. Smoking cessation is highly cost-effective relative to other frequently used medical and surgical interventions. Tobacco related illnesses are important public health issues worldwide. It has been estimated that there are 1.1 billion smokers worldwide and 250 million of them live in India.

Clinical Applications of PET and PET-CT.

Positron emission tomography (PET) and PET/ computed tomography (CT) are emerging as important imaging techniques and their popularity is growing within the medical fraternity. Though PET has been a useful research tool for many decades its real growth into clinical applications has occurred in the last one decade or so. Currently its major use is in oncologic imaging. However it has a multitude of clinical applications in cardiology, neurology and psychiatry as well. In oncologic imaging, a major advantage of PET is that a single whole-body examination can provide accurate assessment of disease activity and spread. PET/CT amalgamates the functional information of PET with the structural details of the CT scan, thus greatly aiding in accurate staging, therapy response assessment and early detection of recurrent disease.

A novel nanoparticle formulation for sustained paclitaxel delivery.

PURPOSE: To develop a novel nanoparticle drug delivery system consisting of chitosan and glyceryl monooleate (GMO) for the delivery of a wide variety of therapeutics including paclitaxel. METHODS: Chitosan/GMO nanoparticles were prepared by multiple emulsion (o/w/o) solvent evaporation methods. Particle size and surface charge were determined. The morphological characteristics and cellular adhesion were evaluated with surface or transmission electron microscopy methods. The drug loading, encapsulation efficiency, in vitro release and cellular uptake were determined using HPLC methods. The safety and efficacy were evaluated by MTT cytotoxicity assay in human breast cancer cells (MDA-MB-231). RESULTS: These studies provide conceptual proof that chitosan/GMO can form polycationic nano-sized particles (400 to 700 nm). The formulation demonstrates high yields (98 to 100%) and similar entrapment efficiencies. The lyophilized powder can be stored and easily be resuspended in an aqueous matrix. The nanoparticles have a hydrophobic inner-core with a hydrophilic coating that exhibits a significant positive charge and sustained release characteristics. This novel nanoparticle formulation shows evidence of mucoadhesive properties; a fourfold increased cellular uptake and a 1000-fold reduction in the IC(50) of PTX. CONCLUSION: These advantages allow lower doses of PTX to achieve a therapeutic effect, thus presumably minimizing the adverse side effects.

Mycobacterium avium intracellularae complex associated extrapulmonary axillary lymphadenitis in a HIV-seropositive infant--a rare case report.

Opportunistic infections by Mycobacterium avium intracellulare complex in HIV infected patients, though common in adults, are rarely seen in infants. We herewith report an interesting case of an eight month old infant presenting with isolated axillary lymphadenitis, later on diagnosed to be tubercular lymphadenitis by Mycobacterium avium intracellulare and finally proved to be seropositive for HIV infection born to previously undetected HIV seropositive parents.

X-ray powder diffractometric method for quantitation of crystalline drug in microparticulate systems. I. Microspheres.

Ethylcellulose microspheres containing tolnaftate (I) were prepared by the emulsion-solvent evaporation technique. An X-ray powder diffractometric method was developed to quantify the content of crystalline I in these microspheres. X-ray lines of I with d-spacings of 5.5 and 4.2 A were chosen for the quantitative analyses. Physical mixtures containing various weight fractions of I and blank (empty) microspheres were prepared and lithium fluoride (20% w/w) was added as the internal standard. The 5.5 and 4.3 A lines of I and the 2.3 A line of lithium fluoride were used for the quantitative analysis. A plot of the intensity ratio (intensity of the 5.5 A line of I/intensity of 2.3 A line of lithium fluoride) as a function of the weight percent of I in the mixture, resulted in a straight line. The crystalline content of I in the tolnaftate-loaded microspheres was determined using this standard curve. A second independent determination of the content of I was possible from the intensities of the 4.3 A line. The enthalpy of fusion of I, determined by differential scanning calorimetry (DSC), was also used as a measure of the crystalline content of I in the microspheres. The X-ray and DSC methods measure the content of crystalline I in the microspheres at room temperature ( approximately 25 degrees C) and at the melting point of I (111 degrees C), respectively. The total content of I in the microspheres was determined by HPLC. The DSC and X-ray results indicated that a substantial fraction of the incorporated I was dissolved in the ethylcellulose matrix.

Evaluation of creatine transport using Caco-2 monolayers as an in vitro model for intestinal absorption.

Creatine is a nutraceutical that has gained popularity in both well-trained and casual athletes for its performance-enhancing or ergogenic properties. The major disadvantages of creatine monohydrate formulations are poor solubility and oral bioavailability. In the present study, creatine transport was examined using Caco-2 monolayers as an in vitro model for intestinal absorption. Confluent monolayers of Caco-2 cells (passage 25-35) were used for the permeability studies. Monolayers were placed in side-by-side diffusion chambers. (14)C-Creatine (0.1-0.5 microCi/mL) was added to either the apical or basolateral side, and the transport of the creatine across the Caco-2 monolayer was measured over a 90-min period. The apical to basolateral transport of (14)C-creatine was small, ranging from 0.2-3% of the original amount appearing on the receiver side in a 90-min period. Interestingly, the basolateral to apical permeability of radiolabeled creatine was substantially greater than that observed in the apical to basolateral direction. Studies with drug efflux transport inhibitors indicate that neither the P-glycoprotein nor multidrug resistance-associated protein is involved in the enhanced basolateral to apical transport of creatine.

Cerebrospinal fluid penetration and pharmacokinetics of levofloxacin in an experimental rabbit meningitis model.

This study was designed to investigate the penetration across the blood-brain barrier of three doses of levofloxacin using a microdialysis probe implanted into the cerebrospinal fluid (CSF) of a rabbit pneumococcal meningitis model. The microdialysis guide cannula was implanted into rabbit subarachnoid space using a stereotaxic frame. After 3 days, 10(4) cfu Streptococcus pneumoniae serotype 3 in 0.3 mL saline was injected via intracisternal puncture and animals were allowed to incubate the organisms for 16-18 h. Groups of animals (n = 5) then received 7, 10.5 or 14 mg/kg iv of the drug over 10 min. Plasma samples were obtained via an ear vein 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 h after the antibiotic infusion. CSF microdialysis effluent samples were collected every 0.5 h for the entire experiment. Plasma and microdialysis effluent samples were analysed by HPLC. AUC(0-8) in plasma and CSF were computed using the trapezoid rule. The elimination half-life in plasma and CSF was calculated using non-linear regression analysis. The unbound peak plasma concentrations for the three doses studied were 3.9, 6.4 and 10.3 mg/L, respectively. There was a significant increase in the plasma AUC(0-8) [29.7 +/- 6.3, 49.1 +/- 19.1 and 67.6 +/- 8.9 mg x h/L (P < 0.005)]. The unbound peak CSF concentrations were 3.8, 5.7 and 8.6 mg/L and occurred at 0-0.5 h after the administration of the dose. The AUC(CSF(0-8)) was significantly higher as the dose was increased (7 mg/kg, 15.8 +/- 6.6; 10.5 mg/kg, 37.3 +/- 7.8; and 14 mg/kg, 46.4 +/- 20.9 mg x h/L; P < 0.03). The penetration of levofloxacin averaged 53% for the 7 mg/kg dosage group, 76% for the 10.5 mg/kg group and 68% for the 14 mg/kg group. Our results demonstrate that levofloxacin penetration into the CSF averages 66% for the doses that would be used in clinical practice.

Effect of cross-linking on the in vitro release kinetics of doxorubicin from gelatin implants.

Doxorubicin is one of the most potent anti-tumor agents used generally in the treatment of bone cancer. Like other cancer chemotharepeutics, it produces undesirable side effects such as cardiotoxicity, which is especially severe when administrated via the conventional intravenous route. In order to minimize the systemic toxicities and to make this drug more suitable for the treatment of bone cancer, an implantable delivery system with cross-linked gelatin as the biodegradable matrix material was developed. This delivery system could possibly improve targeting of the drug as well as sustain the rate of release of the drug to the tumor. Glutaraldehyde was used as a cross-linking agent. Incorporation of glutaraldehyde in the matrix was needed to maintain the mechanical strength of the implant and to sustain the rate of release of the drug from the implant. Besides cross-linking the gelatin matrix, glutaraldehyde was found to cross-link the free amino group of doxorubicin. The effect of cross-linker concentration on the stability of the drug in the implant and on the rate and extent of release were also evaluated. In conclusion, cross-linked gelatin implants were developed for the local delivery of doxorubicin.

Evaluation of an acetic acid ester of monoglyceride as a suppository base with unique properties.

The objective of this investigation was to evaluate an acetic acid ester of monoglycerides made from edible, fully hydrogenated palm oil (AC-70) as a suppository base and compare it with a commercially available semisynthetic base (Suppocire AI). Benzocaine and miconazole were used as model drugs. Suppositories were prepared by the fusion method. The drug loads in the suppositories were kept at 2% to 5% (wt/wt). In vitro release of drug from the suppositories into Sorensen's phosphate buffer (pH 7.4) was studied using a US Pharmacopeia dissolution apparatus 1 and a spectrophotometer. The melting behavior of the bases and the physical state of the drug in the suppositories were studied using a differential scanning calorimeter (DSC). Powder x-ray diffractometry was used to study any possible polymorphic changes in the AC-70 base during formulation and storage. In vitro release studies revealed that the release of benzocaine from the AC-70 suppository was substantially slower than that of the commercial AI base. At a 2.5% (wt/wt) benzocaine load, the release of drug from the AC-70 suppositories was found to be linear. This slow and linear release was attributed to the physical property of the base, which forms liquid crystalline phases in the aqueous dissolution medium. The lyotropic liquid crystalline phase has the ability to incorporate drug into its structure and can control the release kinetics of the drug from such a system. The apparent pH of the release medium (water) was decreased by 1 to 1.5 pH units when the AC-70 base was used. The DSC studies revealed that the melting range of the AC-70 base is 36 degrees C to 38 degrees C, which is ideal for suppository formulations. The results of these studies support the possibility of using this new base for slow-release suppository formulations. This base may be of particular interest for a drug that requires an acidic environment to maintain its activity.

Evaluation of quick disintegrating calcium carbonate tablets.

The purpose of this investigation was to develop a rapidly disintegrating calcium carbonate (CC) tablet by direct compression and compare it with commercially available calcium tablets. CC tablets were formulated on a Carver press using 3 different forms of CC direct compressed granules (Cal-Carb 4450, Cal-Carb 4457, and Cal-Carb 4462). The breaking strength was measured using a Stokes-Monsanto hardness tester. The disintegration and dissolution properties of the tablets were studied using USP methodology. The calcium concentration was determined by an atomic absorption spectrophotometer. Scanning electron microscopy was used to evaluate the surface topography of the granules and tablets. Breaking strength of Cal-Carb 4450, Cal-Carb 4457, and Cal-Carb 4462 tablets was in the range of 7.2 to 7.7 kg, as compared with a hardness of 6.2 kg and 10 kg for the commercially available calcium tablets Citracal and Tums, respectively. The disintegration time for the tablets presented in the order earlier was 4.1, 2.1, 1.9, 2.9, and 9.7 minutes, respectively. The dissolution studies showed that all formulations released 100% of the elemental calcium in simulated gastric fluid in less than 20 minutes. In summary, this study clearly demonstrated that quick disintegrating CC tablets can be formulated without expensive effervescence technology.

Development of a rectal nicotine delivery system for the treatment of ulcerative colitis.

The aims of this investigation were: i. to develop a rectal nicotine delivery system with bioadhesives for the treatment of ulcerative colitis and ii. to evaluate nicotine transport and cytotoxicity of the delivery system using Caco-2 cell culture systems. Rectal nicotine suppository formulations were prepared in semi-synthetic glyceride bases (Suppocire AM and AI, Gattefosse Inc.) by fusion method. The in vitro release of nicotine was carried out in modified USP dissolution apparatus 1. Differential scanning calorimetry (DSC) and powder X-ray diffraction were used to study the polymorphic changes if any in the formulations. An LC method was used for the assay of nicotine. The effect of bioadhesives (glyceryl monooleate (GMO), and Carbopol) on the nicotine flux was evaluated using Caco-2 cell permeability studies and Caco-2 cell viability was determined using the MTT toxicity assay. In vitro release studies indicated that the low melting AI base was superior to that of the AM base. Presence of GMO in the formulation enhanced the release of nicotine whereas Carbopol showed an opposite effect. The enhanced release of nicotine in the presence of GMO was found to be partly due to the melting point lowering effect of this compound. Caco-2 cell absorption studies showed that there was a decrease in the flux of nicotine in the presence of both the bioadhesives. The flux of the fluorescein marker which is used to study the integrity of the cell monolayers was found to be slightly higher only in the presence of 10% (w/w) Carbopol. Nicotine, Carbopol, and GMO do not have any cytotoxic effect on these cell monolayers within the concentration range used in the formulations. Rectal nicotine formulations containing bioadhesives were developed and characterized. Both in vitro release and cell culture studies have indicated that one can manipulate the nicotine release from these rectal delivery systems by incorporation of various bioadhesives or the use of different bases in the formulation. Nicotine concentration below 2% (w/v) and bioadhesive concentration below 10% (w/w) do not have any cytotoxic effect on Caco-2 cells.