Design, Synthesis, Evaluation, and Molecular Docking Study of Ascorbic Acid Dual-Coated Omeprazole Pellets and the Antioxidative Effect of Ascorbic Acid on Omeprazole-Induced Renal Injury in an Animal Model.

The present study was carried out to investigate the antioxidant effect of ascorbic acid on omeprazole (O.P.)-induced acute kidney infection (AKI). Design of experiment (DoE) was employed to fabricate formulations (P1-P8) by the extrusion spheronization technique, and they were evaluated using various analytical techniques. P1-P8 formulations have % drug loading ranging from 56.34 ± 1.10 to 98.67 ± 1.05%, encapsulation efficiency from 70.98 ± 0.96 to 98.67 ± 1.05%, percentage drug release varying from 36.56 ± 1.34 to 93.45 ± 1.45%, Hausner's ratio ranging from 1.026 ± 0.05 to 1.065 ± 0.02%, and Carr's index varying from 2.3 ± 0.07 to 6.1 ± 0.06 g/mL. The optimized formulation (P6) was dual-coated with Eudragit L-100 (5% w/v) and ascorbic acid (2% w/v). A smooth uniform morphology was found after coating, and particle size nonsignificantly changed from 85.31 ± 77.43 to 101.99 ± 65.56 µm. IR spectra showed omeprazole characteristic peaks confirming drug loading, and peaks at 1747.40 and 1611.51 cm-1 confirmed ascorbic acid and Eudragit L-100 coating. X-ray diffraction (XRD) analysis confirmed the crystalline nature, and thermal degradation studies until 500 °C demonstrated increased stability after coating. Cytotoxicity analysis with 97% cell viability revealed the nontoxic behavior of pellets. In vitro dissolution studies of coated pellets showed <20% drug release at pH 1.2 and 99.54% at pH 6.8. Animal studies showed that pure omeprazole showed a nonsignificant decrease in weight, urine output, and fecal output compared to rodents on ascorbic acid pellets. Increased uric acid and creatinine levels in the group on pure omeprazole indicated AKI. Histopathological studies of renal cells also supported these results. The integration of experimental pellet formulation with molecular docking simulations has unveiled the potential of ascorbic acid and omeprazole as highly promising therapeutic agents for addressing oxidative stress and inflammation.

Synthesis and characterization of Hyaluronic Acid (HA) modified polymeric composite for effective treatment of wound healing by transdermal drug delivery system (TDDS).

The present study aimed to fabricate a novel polymeric spongy composite to enhance skin regeneration composed of Nystatin (antifungal agent) and Silver Nanoparticles (AgNps). Different formulations (F1-F8) were developed & characterized by using various analytical techniques. AgNps synthesized by chemical reduction method showed spherical morphology 2 µm in size showed by SEM and XRD. A fine porous structure of gel embedded with AgNps having an amorphous structure with 10 % crystallinity due to AgNps was found. IR spectra revealed no chemical interaction between polymers and Nystatin. An increase in thermal stability of formulation was observed till 700 â„ƒ analyzed by Differential Scanning Calorimetry. Cytotoxic analysis on L929 mouse skin fibroblast cells showed a decrease in cell viability as Ag concentration increased (inactivating Fibroblast and keratinocytes) while 10 mg composition was found safest concentration (94%). Optimized formulation (F2) presented in-vitro drug release up to 90.59% ± 0.76 at pH 7.4, swelling studies (87.5% ± 0.57), water retention (26.60 ± 0.34), pH (5.31 ± 0.03). In the animal burn model, the group that received CHG/Ag/Nystatin healed the wound significantly (p < 0.05). These results suggested that optimized carrier can be used for other anti-fungal drugs facilitating the early healing of the wound.

Development and DoE-ANN based optimization of novel swellable matrix-diffusible doxorubicin loaded zinc oxide nanoflowers using sonochemical-precipitation method.

This research aimed to acquire doxorubicin loaded zinc oxide nanoflowers (DOX-ZnO-NFs) for intracellular drug cargo possessing a synergistic in-vitro anticancer activity with minimal toxicity. Zinc is the main inorganic metallic component of various enzyme systems and has the possibility of fabrication into the diverse nano-structural forms. An easy absorption and extensive tissue distribution of zinc have made it unique candidate for drug delivery system. Hence, the zinc oxide nanoflowers were prepared with sonochemical-precipitation. The developed system was characterized using the reported methods and was optimized employing design of experiment, coupled with artificial neural network approach. The optimized nanoflowers (DOX-ZnO-NFV) were anionic with particle size of 24 ± 0.05 nm, polydispersity index of <0.5, a zeta potential of -25.68 ± 0.16 mV, yield of 87.40% and encapsulation efficiency of 85.25%. DOX-ZNO-NFV depicted sustained DOX release, around 65.413% release in 30 h at pH 7.4 and assumed Weibull model with its derived parameters, a and b of 22.77 and 0.918, respectively. DOX-ZnO-NFV remained stable on storage for 3 months at 4° C/50% RH and 25° C/60% RH. DOX-ZnO-NFV displayed a zone of inhibition of 13.50 ± 1.25 mm and 25.50 ± 0.98 mm, respectively against gram-positive Staphylococcus aureus and gram-negative Escherichia coli strains, presenting the nanoflowers as self-preservative. DOX-ZnO-NFV exhibited higher in-vitro anticancer activity in Henrietta Lacks cell line, with least hemolysis compared to the free DOX and ZnO-NF. Thus, doxorubicin loaded zinc oxide nanoflowers envisioned to act as better chemotherapeutic cargos with the maximize anticancer activity and minimal toxicity.

Influence of Quercetin Pretreatment on Pharmacokinetics of Warfarin in Rats.

BACKGROUND: Warfarin (WAR) is an anticoagulant with a narrow therapeutic index and is principally metabolized by CYP3A4 and CYP2C9 enzymes. The inhibitors of these enzymes may alter the systemic exposure to WAR. Quercetin (QUE), a bioflavonoid, may modify the bioavailability of drugs used concurrently by inhibiting CYP3A4, CYP2C8, CYP2C9, CYP1A2, and Pglycoprotein (P-gp). OBJECTIVE: The current study scrutinized the influence of QUE on WAR pharmacokinetics in rats. METHOD: QUE was orally administered to animals for 14 consecutive days, followed by WAR as a single oral dose on the 15th day in the pre-treatment group. The co-administration group received a single dose of QUE and WAR concomitantly. Only carboxymethylcellulose (CMC) 0.5% was administered as a vehicle to control group. RESULTS: In the pre-treated group, WAR's Cmax was increased by 30.43%, AUC0-∞ by 62.94%, and t1/2 by 10.54%, while Cl decreased by 41.35%, relative to control. In co-administered animals, WAR's Cmax increased by 10.98%, AUC0-∞ by 20.20%, and t1/2 by 8.87%, while Cl declined by 16.40%. CONCLUSION: QUE alters the pharmacokinetics of WAR, warranting possibly WAR dose adjustment after confirmatory clinical investigations, specifically in patients with thrombotic disorders and a pre-treatment history of QUE or its product.

Development of Optimized Sumatriptan-Prochlorperazine Combined Orodispersible Films Without Disintegrant: in vitro, ex vivo and in vivo Characterization.

Sumatriptan succinate and prochlorperazine maleate are a clinically proven combination for treating migraine and associated nausea and vomiting. Classical oral dosage forms are not frequently workable in migraine because of the associated nausea/vomiting, and no effective fixed dose combination is available. Thus, the aim of the study was to optimize a combined sumatriptan-prochlorperazine orodispersible film for rapid release of drugs. Orodispersible films were prepared by solvent casting method using varied amounts of polyvinyl alcohol and glycerol as film former and plasticizer, respectively, along with fixed levels of other ingredients employing central composite design. The optimum film (VF) demonstrated disintegration and total dispersion times as 21 s and 2.3 min, respectively. Tensile strength and Young's modulus were 8.86 ± 0.37 MPa and 24.15 ± 0.07 MPa, respectively. The in vitro T80% of both drugs from the ODF was achieved within 4 min. The film was palatable and disintegrated in 2 min in buccal cavity of human volunteers. Permeation study through goat mucosa demonstrated 100% permeation of both drugs within 15 min. X-Ray diffraction and differential scanning calorimetry supported drugs being amorphous and Fourier transform infrared demonstrated drug-excipient compatibility in optimized film. A judicious combination of sumatriptan succinate and prochlorperazine maleate could be prepared in orodispersible films for the possible relief of migraine.

Development of Simple Dissolution Methods for Felodipine and Combined Amlodipine Besylate-Indapamide Extended Release Tablets without Stationary (Felodipine) Basket.

BACKGROUND: The dissolution method for certain drugs needs specialized conditions. Dissolution testing for felodipine extended release (ER) tablets (Plendil® 5 mg) and amlodipine-indapamide fixed dose (Natrilam®, 5/1.5 mg) ER tablets requires the use of a stationary (felodipine) basket in USP Apparatus II. OBJECTIVE: The study aimed to develop simple methods for Plendil® and Natrilam® without the use of a felodipine basket. METHODS: The dissolution profiles obtained from different media and paddle speeds were used to compute miscellaneous dissolution parameters and were compared to those obtained from standard (existing) methods using a felodipine basket. RESULTS: The f1, f2, and bootstrap f2 (5th % percentile) values for Plendil® 2.47, 88.17, and 54.62, respectively, and all other dissolution factors revealed similarity between standard and the selected test method with 1% Tween 20 at 50 rpm. For Natrilam®, f1 and f2 and bootstrap f2 5.13, 72.92, and 62.67, respectively, and all other dissolution parameters showed similarity of the standard and selected test method using 0.1N HCl media having 0.38 gm/L EDTA with a sinker at 100 rpm. Release of products assumed zero-order and Weibull model, respectively. CONCLUSION: Test dissolution methods for Plendil® and Natrilam® tablets produced equivalent dissolution profiles compared to their respective standard methods with stationary basket USP Apparatus II.

Prediction of CYP-mediated silybin A-losartan pharmacokinetic interactions using physiological based pharmacokinetic modeling.

The concomitant use of herbal products and synthetic drugs necessitates the assessment of their interaction potentials. The herbal hepatoprotective medicine, silybin A inhibits cytochrome P450 (CYP) 2C9 and 3A4 enzymes, thus, may interact with the drugs that are substrates of CYP2C9 and 3A4, such as losartan. The three most prominent genotypes, expressed by CYP2C9 are the CYP2C9*1/*1, CYP2C9*1/*2 and CYP2C9*1/*3. This study aimed to assess silybin A-losartan interaction in different CYP2C9 genotypes using physiological-based pharmacokinetic (PBPK) model approach. The individual PBPK models for silybin A and losartan were developed using PK-Sim®. Losartan pharmacokinetics was predicted with or without co-administration of silybin A in individuals of different CYP2C9 genotypes to find herbal-drug interaction. The predicted drug plasma curves and pharmacokinetic parameters were optimized using parameter identification tool and were compared with reported pharmacokinetic parameters from the published clinical studies for model validation. The silybin-losartan interactions were predicted by change in area under the curve (AUC) and peak systemic concentration (Cmax). The co-treatment of silybin A, 420 mg/24 h (140 mg/8 h) with losartan 50 mg/24 h, exhibited a genotype-dependent change in the losartan's AUC and Cmax. In CYP 2C9*1/*1 genotype, AUC and Cmax of losartan were increased 1.16 and 1.37 folds, respectively falling in a range stipulated for negligible interaction. Increase in AUC and Cmax by 0.873 and 0.294 folds, respectively in CYP2C9*1/*3 after co-administration of silybin A exhibited a minor interaction with losartan. However, in individuals with CYP2C9*1/*2 genotype, the losartan's AUC and Cmax were decreased by 0.01 folds, manifesting a moderate interaction. Hence, in CYP2C9*1/*1 and CYP2C9*1/*3 genotypes, silybin A is a weak CYP inhibitor for losartan while in CYP2C9*1/*2 genotype, the co-administration of silybin consequents into a moderate pharmacokinetic interaction with losartan.

Medicinal Plants and Nonsteroidal Anti-inflammatory Drugs (NSAIDs) in Treatment of Arthritis: A Literature Review.

Context: Arthritis is an inflammatory disease of diarthrodial joints and is associated with swollen inflamed joints, disruption of joints, and loss of integrity of articular cartilage and synovial joints. Objective: The current review intended to examine the data on the epidemiology, causes, clinical diagnosis, and prevention and control of different types of arthritis and on the use of medicinal plants in gouty arthritis. Design: The research team performed a literature review, searching relevant literature databases, including bioRxiv, medRxiv, Google Scholar, Embase, PsychINFO, and PubMed. The search terms were arthritis, diarthodial joints, use of medicinal plants in gouty arthritis, and synovial joints. Setting: The study took place in the main library of the University of Sargodha in Sargodha, Pakistan. Results: The research team identified 135 studies, and eventually 92 unique academic publications were included in the analysis. Arthritis can develop and progress in any musculoskeletal joint, and most commonly occurs in knees, hips, shoulders, and hands. Major risk factors for arthritis include age, obesity, trauma, other diseases, and smoking. Arthritis is classified into various types, including rheumatoid arthritis (RA), osteoarthritis (OA), gouty arthritis, septic arthritis, and psoriatic arthritis (PsA). RA and OA are the most common types worldwide. RA is an autoimmune disease in which the body's immune cells attack the joints. OA develops due to damage of cartilage, tissues, and joints due to age, obesity, or stress on joints. Gouty arthritis develops due to hyperuricemia; deposits of monosodium urate crystals can lead to gouty arthritis. Septic arthritis occurs due to a microbial infection in synovial joints because in synovial joints the basement membrane is absent. PsA develops due to the psoriasis-skin disease. Conclusions: The current review showed that different types of arthritis has different causes and pathogeneses. Pain in joints is a major and common symptom in all types of arthritis. Arthritis is managed pharmacologically and nonpharmacologically. Treatment is different for each class of arthritis according to its cause and symptoms.

Appraisal of hypotensive effect of natural monoterpene: Bornyl acetate and in-silico molecular docking analysis.

The modern trend of research is highly focused on finding new bioactive molecules from medicinal plants. As a functional bicyclic monoterpene, Bornyl acetate (BA) has displayed antioxidant and anti-inflammatory properties in different types of cells and tissues. The purpose of this research was to evaluate the probable hypotensive effect of BA, an underlying mechanism(s) backboned by in-silico studies. Mean arterial pressure and heart rate were recorded via invasive blood pressure measuring technique in normotensive Sprague-Dawley rats following the administration of BA (1-80mg/kg). Docking studies were carried out with various targets involved in the pathophysiology of hypertension.RO5 and ADMET properties were also evaluated. In the current study dose-dependent reduction in systolic, diastolic and mean arterial pressure was observed. Pretreatment with atropine and captopril significantly (p<0.001) reduced the hypotensive effect produced by BA. On the other hand docking studies showed pronounced interactions with M2 mAch receptor in an agonistic way and ACE protein in an antagonistic way. BA justified all cut-off limits of RO5 and had an acceptable predicted computational toxicity profile. Results postulate that dose-dependent hypotensive effect of BA is mediated through the muscarinic pathway and ACE inhibitory activity corresponding well with findings of in-silico studies.

Fixed Dose Single Tablet Formulation with Differential Release of Amlodipine Besylate and Simvastatin and Its Pharmacokinetic Profile: QbD and Risk Assessment Approach.

PURPOSE: A differential release fixed dose matrix tablet of amlodipine besylate (AML-B) and simvastatin (SIM) was formulated to enhance patient compliance. MATERIAL AND METHOD: In the first phase, release controlling parameters of AML-B and SIM granules were identified and in the second phase a fixed dose AML-B and SIM tablet formulation was prepared and optimized for a differential release of the drugs using a quality by design (QbD) and risk assessment approach. A validated HPLC method was employed for simultaneous determination of AML-B and SIM for FDC formulation. A pharmacokinetics of the above drugs was studied in healthy dogs in the third phase. RESULTS: In QbD-based optimized formulation, Eudragit® RSPO-dicalcium phosphate (DCP) blend controlled the release of AML-B over 8 h, though this diffusion-controlled release assumed first order kinetics. DCP and Eudragit® RS 100 also retarded release of SIM causing SIM release over 8 h after AML-B release from the optimized FDC tablet formulation. The HPLC retention times of AML-B and SIM were 2.10 and 15.52 min, respectively. Linearity for AML-B was 5.0-50 ng/mL and 0.01-2.0 µg/mL for SIM with percent recoveries of 92.85-101.53% and 94.51-117.75% for AML-B and SIM. AUC0-∞ of AML-B was increased 3 fold, while AUC0-∞ of SIM was decreased 2 fold. The tmax values for AML-B and SIM were 12 and 6 h, respectively. AML-B was absorbed without any lag time (tlag) while tlag was 6.33 ± 0.81 h for SIM, thus met the study objective. CONCLUSION: The pharmacokinetic study showed an immediate absorption of AML-B while that of SIM was withheld for 6 h, close to the desired delay time of 8 h.

Amelioration of physicochemical, pharmaceutical, and pharmacokinetic properties of lornoxicam by cocrystallization with a novel coformer.

OBJECTIVE: The present study was aimed to prepare and characterize new cocrystals of lornoxicam (LORX), a BCS class II drug employing 1,3-dimethyl urea (DMU) as a coformer to improve physicochemical, pharmaceutical, and pharmacokinetic performance. METHODS: A screening study was conducted by employing three techniques viz. neat grinding, liquid-assisted grinding (LAG), and solvent evaporation (SE) using different drug-coformer molar ratios (1:1, 1:2, and 1:3). Samples were characterized by DSC, PXRD, ATR-FTIR, SEM, intrinsic dissolution rate (IDR) studies, compressional studies, and pharmacokinetic studies. In vitro dissolution and stability studies (25 °C/60%RH and 40 °C/75%RH for three months) were carried out for cocrystal tablets. RESULTS: LAG and SE were found successful in ratio 1:3 and IDR showed approximately 28- and 19-fold increase, respectively in 0.1 N HCl (pH 1.2) and buffer (pH 7.4) as compared to pure LORX. The cocrystal exhibited good tabletability and was ∼2.5 times that of LORX at 6000 Psi. Dissolution profiles of tablets of cocrystal increased (56% and 100% at pH 1.2 and 7.4, respectively in contrast to those of physical mixture (PhyMix) (∼35% and ∼10%) and pure LORX (∼17% and ∼7%) within 60 min. The Cmax and AUC0-∞ for the selected cocrystal were significantly increased (p < 0.05) which was 2.4 and 2.5 times, respectively, that of LORX in a single dose oral pharmacokinetic study executed in rabbits. Tablets of cocrystal were found stable at both conditions. CONCLUSION: The study indicates that cocrystallization with DMU can concomitantly improve tabletability, dissolution rate, and in vivo performance of dissolution limited drug LORX.

The Potentially Recommended Pharmacotherapy for COVID-19.

CONTEXT: A completely unique coronavirus (2019-nCoV), formally referred to as severe acute respiratory syndrome (SARS-CoV-2), appeared in China. SARS-CoV-2 is an etiological mediator of coronavirus 2 (COVID-19), characterized by pneumonic contagion in human beings. In spite of forceful suppression, this virus has spread worldwide. No specific drugs have been approved by the FDA for treating COVID-19 patients. OBJECTIVE: The study intended to examine the data from studies on clinical management of COVID-19. DESIGN: The research team performed a literature review, searching relevant literature databases. The sources of data included bioRxiv, medRxiv, Google Scholar, Embase, PsychINFO, WanFang Data, and PubMed. The search terms were treatment of the novel coronavirus, management of nCoV-19, chloroquine, and hydroxychloroquine. SETTING: The study took place in the main library of the University of Sargodha in Sargodha, Pakistan. RESULTS: The study identified 42 unique studies that had reported and confirmed over 1500 cases of nCoV-19 by April 21, 2020. The studies found that clinical management, for patients who presented with symptoms, included supportive care and control measures that comprised mechanical ventilator support and supplementary oxygen. CONCLUSIONS: There have been intensive attempts to explore drug therapy for the prophylaxis and treatment of SARS-CoV-2 infection during this COVID-19 pandemic. Several drugs have been identified which including remdesivir, two antimalarials (chloroquine and hydroxychloroquine) and immunosuppressive agents. The effects of most drug interventions are currently highly uncertain and several drugs and vaccines are under trail for the effective treatment of COVID-19 virus, until an effective treatment will discover social distancing and physical hygiene should be practiced strictly.

Design and In Vitro Characterization of Orally Disintegrating Modified Release Tablets of Naproxen Sodium.

OBJECTIVES: The aim of this study was to prepare orally disintegrating, slow release tablets of naproxen sodium for prompt onset and sustained action required in many types of acute pain. MATERIALS AND METHODS: Tablet formulations containing varying concentrations of croscarmellose sodium (a superdisintegrant) and Soluplus® (as release modifier) were prepared by wet granulation method using a single punch tablet machine. The prepared granules were evaluated for their bulk properties and the tablets were evaluated for hardness, disintegration time, and drug release profiles. RESULTS: The results showed that the granules so prepared have good flow and compressional properties. A disintegration time of tablets <30 s was achieved by selecting an optimum concentration of croscarmellose sodium. The drug release from the tablets was sustained for 2 h by incorporating a suitable amount of Soluplus®. CONCLUSION: This study examined the use of Soluplus® (a novel solubilizer) for the first time as a release modifier of API from tablets.

Artificial Neural Network (ANN) Approach to Predict an Optimized pH-Dependent Mesalamine Matrix Tablet.

BACKGROUND: Severe bleeding and perforation of the colon and rectum are complications of ulcerative colitis which can be treated by a targeted drug delivery system. PURPOSE: Development of colon-targeted delivery usually involves a complex formulation process and coating steps of pH-sensitive methacrylic acid based Eudragit®. The current work was purposefully designed to develop dicalcium phosphate (DCP) facilitated with Eudragit-S100-based pH-dependent, uncoated mesalamine matrix tablets. MATERIALS AND METHODS: Mesalamine formulations were compressed using wet granulation technique with varying compositions of dicalcium phosphate (DCP) and Eudragit-S100. The developed formulations were characterized for physicochemical and drug release profiles. Infrared studies were carried out to ensure that there was no interaction between active ingredients and excipients. Artificial neural network (ANN) was used for the optimization of final DCP-Eudragit-S100 complex and the experimental data were employed to train a multi-layer perception (MLP) using quick propagation (QP) training algorithm until a satisfactory root mean square error (RMSE) was reached. The ANN-aided optimized formulation was compared with commercially available Masacol®. RESULTS: Compressed tablets met the desirability criteria in terms of thickness, hardness, weight variation, friability, and content uniformity, ie, 5.34 mm, 7.7 kg/cm2, 585±5 mg (%), 0.44%, and 103%, respectively. In-vitro dissolution study of commercially available mesalamine and optimized formulation was carried out and the former showed 100% release at 6 h while the latter released only 12.09% after 2 h and 72.96% after 12 h which was fitted to Weibull release model with b value of 1.3, indicating a complex release mechanism. CONCLUSION: DCP-Eudragit-S100 blend was found explicative for mesalamine release without coating in gastric and colonic regions. This combination may provide a better control of ulcerative colitis.

Off-label antibiotic use in a specialized children care hospital in Punjab, Pakistan: Findings and implications.

INTRODUCTION: Most of the antibiotics currently used in pediatrics are either unlicensed or being prescribed outside the specifications of product label (off-label prescribing). The aim of this study was to assess the extent of off-label antibiotic use in pediatrics. METHODOLOGY: A six month longitudinal off-label antibiotic utilization survey was carried out from January to June, 2018. A structured questionnaire was designed to collect detailed information for each pediatric patient admitted to participating health center. The data included basic demographic and clinical diagnosis with details of prescribed antibiotics (formulation, dose, dosage, route of administration and indication for use). Data were analyzed using Social packages for Statistical Sciences (SPSS) version 21.0. RESULTS: Of 1,810 admissions, 1,795 (99.2%) patients received antibiotics. Out of these, a total of 451 (25.1%) patients (326 patients admitted in the medical ward and 125 patients in ICUs) received at least one unlicensed/off-label antibiotic. Antibiotics were predominantly prescribed for the treatment of infections (n = 311, 69.0%). The majority of the pediatric patients who received off-label antibiotic suffered from respiratory tract infections (n = 223, 49.4%), skin and soft tissue infections (n = 53, 11.8%), gastrointestinal tract infections (n = 56, 12.4%) and other infections (n = 46, 10.2%). Co-amoxiclav (n = 190, 42.1%) was the most frequently off-label prescribed antibiotic to pediatric patients. An inappropriate dose for patients (n = 430, 95.3%) was the most frequent cause of prescribing off-label antibiotics. CONCLUSIONS: Further evaluation of health and economic outcomes of off-label prescribing and determinants influencing the drug choice is required.

In Vivo Evaluation of a Novel Chitosan-Polycaprolactone Based Mucoadhesive Gastro-Retentive Sustained Release Drug Delivery System for Milnacipran HCl.

The study was aimed to develop a gastro-retentive mucoadhesive sustained release matrix formulation for milnacipran HCl (MCN) by using the design of experiment (DoE). The gastro-retentive swellable mucoadhesive matrix tablets were prepared by modified solvent-based wet granulation through mixing milnacipran (MCN), chitosan low molecular weight (CH-LM), chitosan medium molecular weight (CH-MM), and polycaprolactone (PCL). Optimization of the formulation was carried out via DoE. Formulations were characterized by DSC, FTIR, and in vitro drug release testing. In vitro mucoadhesive studies were performed on rabbit's intestinal mucosa. In vivo drug release studies were performed on dogs. Optimized matrix formulations showed no significant interaction among the polymers and MCN, confirmed by DSC and FTIR, and were characterized as swellable controlled release matrix systems. The optimized formulations MOPT3 and MOPT4 showed significantly improved adhesion time of 12 h on the gastric mucosa. Based on the in vivo analysis, the elimination half-life of MCN was increased that proved the matrix formulation to be sustained release DDS. The Tmax was extended from 2 to 12 ± 1.63 h for MOPT4. Cmax of matrix was reduced to 121.60 ± 9.496 ng/ml as compared to 149.22 ± 9.942 ng/ml of solution. The bioavailability of the matrix formulation was significantly improved as compared to the MCN solution by 272.20 ± 48.11%. The controlled drug release and strong mucoadhesive properties of the gastro-retentive matrix formulations suggested the potential application of the formulations for the extended oral delivery of MCN.

Effect of cellulose acetate phthalate and polyethylene glycol on physical properties and release of theophylline from microcapsules

ABSTRACT The present study describes the development of theophylline microcapsules by a non-solvent addition method and the effect of plasticizer addition on microencapsulation. The release was studied in distilled water and the data were analysed by various mathematical models for determining the mechanism of release. Prepared microcapsules were found to be spherical, free flowing and having more than 80% entrapped drug. The polymer - cellulose acetate phthalate and plasticizer - polyethylene glycol was considered to be affecting the properties of microcapsules including drug release (time for 50% drug release, T50). The formulation with the highest proportion of polymer and without plasticizer (F3) showed the slowest release with T50 = 4.3 h, while the formulation with lower proportion of polymer and 20% (w/w) plasticizer (F13 &14) showed the fastest release of drug with T50 values of 1.2 h and 1.3 h, respectively. The drug release from most of the formulations was found to be following Higuchi model. It is concluded from the results of the present study that cellulose acetate phthalate significantly affects the sustained release of the drug in water, whereas the addition of polyethylene glycol slightly enhances the drug release.

RESUMO O presente estudo descreve o desenvolvimento de microcápsulas de teofilina pelo método sem adição de solvente e o efeito da adição de plastificante na microencapsulação. A liberação foi estudada em água destilada e os dados foram analisados por vários modelos matemáticos para determinação do mecanismo de liberação. As microcápsulas preparadas mostraram-se esféricas, livres de corrente e com mais de 80% de fármaco encapsulado. O polímero - ftalato de acetato de celulose e o plastificante - polietileno glicol - afetaram as propriedades das microcápsulas, incluindo a liberação do fármaco (tempo para liberação de 50% do fármaco, T50). A formulação com a maior proporção de polímero e sem plastificante (F3) se mostrou como a de liberação mais lenta, com T50 = 4,3 h, enquanto as formulações com menor proporção de polímero e 20% de plastificante (m/m) (F13 &14) apresentaram a liberação mais rápida do fármaco, com T50 de 1,2 h e 1,3 h, respectivamente. A liberação do fármaco para a maioria das formulações seguiu o modelo de Higuchi. Concluiu-se, dos resultados do presente estudo, que o ftalato do acetato de celulose afeta significativamente a liberação controlada do fármaco em água, enquanto que a adição de polietileno glicol aumenta ligeiramente a liberação do fármaco.

Carcinoembryonic antigen (CEA) levels in hookah smokers, cigarette smokers and non-smokers.

OBJECTIVE: To find CEA levels in smokers of different categories (hookah smokers, cigarette smokers smoking different brands of cigarettes and different number of cigarettes per day) and to correlate CEA levels with type and rate of smoking. METHODS: A total of 122 cigarette smokers (115 men and 7 women) and 14 hookah smokers (all men) with age ranging from 16-80 years were studied. CEA levels were also measured in 36 non-smokers who served as controls. Enhanced chemilumiscent immunometeric technique was applied to measure CEA levels in our subjects. RESULTS: The mean CEA levels of cigarette smokers were compared with the mean CEA levels observed in hookah smokers (7.16 +/- 10.4 ng/ml) and non-smokers (2.15 +/- 0.68 ng/ml). The mean value of CEA level observed in cigarette smokers, 9.19 +/- 14.9 ng/ml (n=122) was significantly higher than the levels in non-smokers and hookah smokers (p < 0.0067). It was also observed that CEA levels increased with the number of cigarettes smoked per day. The highest levels were observed in smokers who smoke more than 31 cigarettes per day. The smokers that use relatively cheaper brands of cigarettes had higher levels of CEA compared to those who use high quality brands. CONCLUSION: It was concluded that the brands of cigarettes (which were ranked on the basis of price) and the rate of smoking both play an important role in raising the CEA levels. Further the common belief that hookah also called narghile or shisha is a relatively safe mode of smoking is not completely correct; a significant proportion of hookah smokers have high levels of CEA although mean levels of hookah smokers were low compared to cigarette smokers.