QbD-enabled systematic development of gastroretentive multiple-unit microballoons of itopride hydrochloride.

The objectives of present studies were to develop the systematically optimized multiple-unit gastroretentive microballoons, i.e. hollow microspheres of itopride hydrochloride (ITH) employing quality by design (QbD)-based approach. Initially, the patient-centric QTPP and CQAs were earmarked, and preliminary studies were conducted to screen the suitable polymer, solvent, solvent ratio, pH and temperature conditions. Microspheres were prepared by non-aqueous solvent evaporation method employing Eudragit S-100. Risk assessment studies carried out by constructing Ishikawa cause-effect fish-bone diagram, and techniques like risk estimation matrix (REM) and failure mode effect analysis (FMEA) facilitated the selection of plausible factors affecting the drug product CQAs, i.e. percent yield, entrapment efficiency (EE) and percent buoyancy. A 3(3) Box-Behnken design (BBD) was employed for optimizing CMAs and CPPs selected during factor screening studies employing Taguchi design, i.e. drug-polymer ratio (X1), stirring temperature (X2) and stirring speed (X3). The hollow microspheres, as per BBD, were evaluated for EE, particle size and drug release characteristics. The optimum formulation was embarked upon using numerical desirability function yielding excellent floatation characteristics along with adequate drug release control. Drug-excipient compatibility studies employing FT-IR, DSC and powder XRD revealed absence of significant interaction among the formulation excipients. The SEM studies on the optimized formulation showed hollow and spherical nature of the prepared microspheres. In vivo X-ray imaging studies in rabbits confirmed the buoyant nature of the hollow microspheres for 8 h in the upper GI tract. In a nutshell, the current investigations report the successful development of gastroretentive floating microspheres for once-a-day administration of ITH.

Buccoadhesive films for once-a-day administration of rivastigmine: systematic formulation development and pharmacokinetic evaluation.

CONTEXT: Rivastigmine, an anti-Alzheimer's drug, suffers from major predicaments like low oral bioavailability, severe GI adverse effects related to rapid fluctuations in drug plasma levels, and high frequency of dosing. OBJECTIVE: The present investigation aims at developing buccoadhesive films capable of delivering the drug in vivo in a sustained manner. Augmentation of drug bioavailability by the avoidance of first-pass effect through the buccal route and reduction in GI side effects would be other key advantages of this system. METHODS: Buccoadhesive films of rivastigmine were systematically designed and evaluated for in vitro drug release, ex vivo buccal permeation and ex vivo buccoadhesive strength. Optimal composition of the polymer blends was rationally chosen using a central composite design and overlay plot. In vivo pharmacokinetic studies were carried out in rabbits, and attempts were made to establish in vitro/ in vivo correlations (IVIVC). RESULTS: Besides possessing the requisite drug release regulation, the optimized formulation exhibited excellent buccoadhesion, and buccal permeation. Pharmacokinetic studies indicated extension of plasma drug levels and level A of IVIVC was successfully established. DISCUSSION: Excellent buccal bioadhesion and transmucosal permeation, coupled with drug release control, ratify the potential of the optimized formulation to deliver the drug in a controlled and site-specific manner. Successful establishment of IVIVC substantiated the judicious choice of in vitro dissolution media for simulating the in vivo conditions. CONCLUSION: Besides unraveling the polymer synergism, the study helped in developing an optimal once-a-day buccoadhesive drug delivery system exhibiting excellent trans-buccal permeation and buccoadhesive characteristics with improved bioavailability potential.

Optimized nanoemulsifying systems with enhanced bioavailability of carvedilol.

The current studies entail a novel approach of formulating the solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of carvedilol solely using rational blends of lipidic and emulsifying excipients without using equipment-intensive techniques and/or inert porous carriers. Delineating the nanoemulsion regions, the amounts of Capmul MCM (i.e., lipid) and Nikkol HCO 50 (i.e., emulgent) were selected as the critical factors for systematically formulating the optimized S-SNEDDS employing face centered cube design. The optimized formulation (mean globule size: 40.8 nm) indicated marked improvement in drug release profile vis-à-vis pure drug and marketed formulation. Augmentation in the values of C(max) (134.2%) and AUC (85.2%) indicated significant enhancement in the rate and extent of bioavailability by the S-SNEDDS formulation compared to pure drug. In situ SPIP studies ascribed the significant enhancement in absorptivity parameters of SNEDDS formulations to transport through the lymphatic system and reduced P-gp efflux. Successful establishment of various levels of in vitro/in vivo correlations (IVIVC's) substantiated the judicious choice of the in vitro dissolution milieu for simulating the in vivo conditions. The optimized formulation was found to be quite stable during six months of study period. The current investigations, therefore, report the successful development of systematically optimized S-SNEDDS with enhanced bioavailability potential of carvedilol.

Formulation development of gastroretentive tablets of lamivudine using the floating-bioadhesive potential of optimized polymer blends.

OBJECTIVES: The current studies entail successful formulation of optimized gastroretentive tablets of lamivudine using the floating-bioadhesive potential of carbomers and cellulosic polymers, and their subsequent in-vitro and in-vivo evaluation in animals and humans. METHODS: Effervescent floating-bioadhesive hydrophilic matrices were prepared and evaluated for in-vitro drug release, floatation and ex-vivo bioadhesive strength. The optimal composition of polymer blends was systematically chosen using central composite design and overlay plots. Pharmacokinetic studies were carried out in rabbits, and various levels of in-vitro/in-vivo correlation (IVIVC) were established. In-vivo gamma scintigraphic studies were performed in human volunteers using (99m) Tc to evaluate formulation retention in the gastric milieu. KEY FINDINGS: The optimized formulation exhibited excellent bioadhesive and floatational characteristics besides possessing adequate drug-release control and pharmacokinetic extension of plasma levels. The successful establishment of various levels of IVIVC substantiated the judicious choice of in-vitro dissolution media for simulating the in-vivo conditions. In-vivo gamma scintigraphic studies ratified the gastroretentive characteristics of the optimized formulation with a retention time of 5 h or more. CONCLUSIONS: Besides unravelling the polymer synergism, the study helped in developing an optimal once-a-day gastroretentive drug delivery system with improved bioavailability potential exhibiting excellent swelling, floating and bioadhesive characteristics.

Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential.

Carvedilol, a widely prescribed cardiovascular drug for hypertension and congestive heart failure, exhibits low and variable bioavailability owing to poor absorption and extensive hepatic first-pass metabolism. The current research work, therefore, entails formulation development of liquid self-nano-emulsifying drug delivery systems (SNEDDS) to enhance the bioavailability of carvedilol by facilitating its transport via lymphatic circulation. The formulation constituents, i.e. lipids, surfactants, and co-surfactants, were selected on the basis of solubility studies. Pseudo-ternary phase diagrams were constructed to embark upon the selection of blend of lipidic (i.e. Capmul PG8) and hydrophilic components (i.e. Cremophor EL as surfactant and Transcutol HP as co-surfactant) for efficient and robust formulation of SNEDDS. The SNEDDS, systematically optimized employing a central composite design (CCD), were evaluated for various response variables viz drug release parameters, emulsification time, emulsion droplet size, and mean dissolution time. In vitro drug release studies depicted that the release from SNEDDS systems followed a non-Fickian kinetic behavior. The TEM imaging of the optimized formulation affirmed the uniform shape and nano size of the system. Accelerated studies of the optimized formulation indicated high stability of the formulation for 6 months. The in situ perfusion studies carried out in wistar rats construed several fold augmentation in the permeability and absorption potential of the optimized formulation vis-à-vis marketed formulation. Thus, the present studies ratified the potential of SNEDDS in augmenting the oral bioavailability of BCS class II drugs.

Formulation development and systematic optimization of solid lipid nanoparticles of quercetin for improved brain delivery.

OBJECTIVE: This study aims at formulating solid lipid nanoparticles (SLNs) of quercetin, a natural flavonoid with established antioxidant activity, for intravenous administration in order to improve its permeation across the blood-brain barrier into the CNS, and eventually to improve the therapeutic efficacy of this molecule in Alzheimer's disease. METHODS: The SLNs of quercetin were formulated using Compritol as the lipid and Tween 80 as the surfactant through a microemulsification technique, and optimized employing a 3(2) central composite design (CCD). Selection of the optimized SLN formulation, using brute-force methodology and overlay plots, was based on its efficiency of entrapping quercetin inside the lipophilic core, particle size, surface charge potential and ability of the SLNs to release the entrapped drug completely. The optimized formulation was subjected to various in-vivo behavioral and biochemical studies in Wistar rats. KEY FINDINGS: The optimized formulation exhibited a particle size of less than 200 nm, 85.73% drug entrapment efficiency and a zeta potential of 21.05 mV. In all the in-vivo behavioral and biochemical experiments, the rats treated with SLN-encapsulated quercetin showed markedly better memory-retention vis-à-vis test and pure quercetin-treated rats. CONCLUSIONS: The studies demonstrated successful targeting of the potent natural antioxidant, quercetin, to brain as a novel strategy having significant therapeutic potential to treat Alzheimer's disease.

Developing oral drug delivery systems using formulation by design: vital precepts, retrospect and prospects.

INTRODUCTION: Over the past few decades, the domain of drug formulations has metamorphosed from the conventional tablets and capsules to advanced and intricate drug delivery systems (DDS), both temporal and spatial. Formulation development of the oral DDS, accordingly, cannot be adequately accomplished using the traditional 'trial and error' approaches of one variable at a time. This calls for the adoption of rational, systematized, efficient and cost-efficient strategies using 'design of experiments (DoE)'. The recent regulatory guidelines issued by the key federal agencies to practice 'quality by design (QbD)' paradigms have coerced researchers in industrial milieu, in particular, to use experimental designs during drug product development. AREAS COVERED: This review article describes these principles of DoE and QbD as applicable to drug delivery development using a more apt expression, that is, 'formulation by design (FbD)'. The manuscript describes the overall FbD methodology along with a summary of various experimental designs and their application in formulating oral DDS. The article also acts as a ready reckoner for FbD terminologies and methodologies. Select literature and an extensive FbD case study have been included to provide the reader with a comprehensive portrayal of the FbD precept. EXPERT OPINION: FbD is a holistic concept of formulation development aiming to design more efficacious, safe, economical and patient-compliant DDS. With the recent regulatory quality initiatives, implementation of FbD has now become an integral part of drug industry and academic research.

Design and development of paclitaxel-loaded bovine serum albumin nanoparticles for brain targeting.

Bovine serum albumin (BSA) nanoparticles loaded with paclitaxel (PTX) were prepared using a desolvation technique. A 32 full factorial design (FFD) was employed to formulate nanoparticles. Nanoparticles were characterized for particle size by photon correlation spectroscopy and surface morphology by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Encapsulation efficiency, zeta potential and particle yield were also determined. Response surface linear modelling (RSLM) was used to predict the optimal formulation. Various models were applied to determine the release mechanism from PTX nanoparticles. The effect of drug-polymer ratio on the release profile of formulations was observed and was applied to determine the suitability of the predicted optimal formulation. A preliminary study to determine the feasibility of targeting the prepared nanoparticles to brain was also carried out using mice as in vivo models.

Development and evaluation of in situ gel-forming system for sustained delivery of insulin.

Phase-sensitive in situ gel-forming controlled release formulations of insulin were prepared using poly(lactide-co-glycolide) and a solvent system consisting of various proportions of benzyl benzoate and benzyl alcohol. The in vitro release samples of formulations were assayed for insulin content by enzyme linked immunosorbent assay. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and circular dichroism spectroscopy studies of released insulin confirmed its conformational stability. The stability of insulin in the formulation was assessed using Fourier transform infrared spectroscopy. Rheological properties of the formulations, assessed under isothermal conditions, showed dilatant behavior of all the formulations. In vivo studies were carried out on the optimized formulations vis-à-vis pure insulin in mice and blood glucose levels were monitored for 15 days. Mean percentage reduction in blood glucose levels was calculated in all the animals and the results analyzed using ANOVA. The studies construed better pharmacodynamic response for the two optimized formulations in controlling the blood glucose levels vis-à-vis routine once-a-day administration of insulin. The subcutaneous tissues, further subjected to scanning electron microscopy studies and histopathological examinations, ascertained the biocompatibility of the formulation.

Developing micro-/nanoparticulate drug delivery systems using "design of experiments".

Of late, micro and nanoparticluate drug delivery systems have been gaining immense importance primarily attributed to their improved drug release controlling and targeting efficiencies. Also, the small particle size and desirable surface charge associated with these delivery systems render them suitable for specific applications like lymphatic uptake, pulmonary uptake, tumor targeting, brain targeting, etc. For decades, micro and nanoparticulate systems have been prepared by the conventional "trial and error" approach of changing One Variable at a Time (OVAT). Using this methodology, the solution of a specific problematic formulation characteristic can certainly be achieved, but attainment of the true optimal composition is never guaranteed. Thus, the present manuscript provides an updated account of the systematic approach "Design of Experiments (DoE)" as applicable to formulation development of microparticles and nanostructured systems. Besides providing a bird's eye view of the various experimental designs and optimization techniques employed for DoE optimization of such systems, the present manuscript also presents a copilation of the major micro/nano-structuctred systems optimized through DoE till date. In a nutshell, the article will act both as a ready reckoner of DoE optimization of micro/nano drug delivery systems and a catalyst in providing an impetus to young pharmaceutical "nano & micro" researchers to venture into the rewarding field of systematic DoE optimization.

Formulation optimization of hydrodynamically balanced oral controlled release bioadhesive tablets of tramadol hydrochloride.

The directly compressible floating-bioadhesive tablets of tramadol were formulated using varying amounts Carbopol 971P (CP) and hydroxy-propylmethyl cellulose (HPMC), along with other requisite excipients. In vitro drug release profile, floatational characteristics and ex vivo bioadhesive strength using texture analyzer were determined, and systematically optimized using a 3(2) central composite design (CCD). The studies indicated successful formulation of gastroretentive compressed matrices with excellent controlled release, mucoadhesion and hydrodynamic balance. Comparison of the dissolution profiles of the optimized formulation, with optimal composition of CP:HPMC :: 80.0:125.0, with that of the marketed controlled release formulation other indicated analogy of drug release performance with each other. Validation of optimization study using eight confirmatory experimental runs indicated very high degree of prognostic ability of CCD with mean  SEM of â0.06%  0.37. Further, the study successfully unravels the effect of the polymers on the selected response variables.

Flow, compressive, and bioadhesive properties of various blends of poly(ethylene oxide).

BACKGROUND: Poly (ethylene oxide) (PEO) is nonionic, water soluble, and highly hydrophilic polymer with well-established applications in mucoadhesives, water-soluble films, rheology control agents and thickeners, and additives in pharmaceutical products. METHODS: Different powder blends containing PEO in varying proportions were evaluated for their flow, compressive, and bioadhesive properties and subsequently compressed into gastroretentive tablets. Two optimized formulations, on the basis of above-mentioned examinations, were subjected to gamma scintigraphy studies on human volunteers. RESULTS: The values of bulk and tapped densities, Hausner ratio and Carr index, angle of repose, loss on drying, total moisture content, and particle size distribution provided a fine estimation of flowability and compressibility of the powder blends. Further, apart from the routine pharmacopoeial assessments, the evaluation of compressed tablets for their surface pH in both acidic and basic environments nullified the possibility of any irritation to the membrane where it is intended to adhere. The measurement of swelling index and bioadhesive strength of tablets revealed that both the parameters were a direct function of the concentration of PEO in the tablet. The results of gamma scintigraphy indicated a fourfold increase in the gastric retention time of the optimized formulation vis-à-vis control formulation. CONCLUSION: The results indicate that PEO, in a concentration of 10-50% (w/w), can be successfully employed in manufacturing gastroretentive tablets.

Development and evaluation of in situ gel forming system for sustained delivery of cyclosporine.

Phase-sensitive in situ gel forming controlled release formulations of cyclosporine were prepared using poly (lactide-co-glycolide) and a solvent system consisting of various proportions of benzyl benzoate and benzyl alcohol. Uniformity of content of cyclosporine in the formulation and in vitro release samples was determined by radio immune assay (RIA). FTIR and CD spectroscopy ratified the conformational stability of cyclosporine in the formulation and in vitro release samples, respectively. Rheological properties of the formulations, assessed under isothermal conditions, showed dilatant behavior of all the formulations. In vivo studies were carried out on the optimized formulations vis-à-vis pure cyclosporine in rats and drug levels were monitored for 13 days. Mean plasma concentration of cyclosporine was calculated for all the animals and pharmacokinetic parameters were determined using Win NonLin software. The studies construed better regulation of plasma drug levels with the optimized formulation vis-à-vis routine once-a-day administration of cyclosporine. The subcutaneous tissues, further subjected to histopathological examinations ascertained the biocompatibility of the formulation.

Formulation development of oral controlled release tablets of hydralazine: optimization of drug release and bioadhesive characteristics.

The current study involves development of oral bioadhesive hydrophilic matrices of hydralazine hydrochloride, and optimization of their in vitro drug release profile and ex vivo bioadhesion against porcine gastric mucosa. A 32 central composite design was employed to systematically optimize the drug delivery formulations containing two polymers, viz., carbomer and hydroxypropyl methyl cellulose. Response surface plots were drawn and optimum formulations were selected by brute force searches. Validation of the formulation optimization study indicated a very high degree of prognostic ability. The study successfully undertook the development of an optimized once-a-day formulation of hydralazine with excellent bioadhesive and controlled release characteristics.

Self-emulsifying drug delivery systems (SEDDS): formulation development, characterization, and applications.

Self-emulsifying drug delivery systems (SEDDS) possess unparalleled potential in improving oral bioavailability of poorly water-soluble drugs. Following their oral administration, these systems rapidly disperse in gastrointestinal fluids, yielding micro- or nanoemulsions containing the solubilized drug. Owing to its miniscule globule size, the micro/nanoemulsifed drug can easily be absorbed through lymphatic pathways, bypassing the hepatic first-pass effect. We present an exhaustive and updated account of numerous literature reports and patents on diverse types of self-emulsifying drug formulations, with emphasis on their formulation, characterization, and systematic optimization strategies. Recent advancements in various methodologies employed to characterize their globule size and shape, ability to encapsulate the drug, gastrointestinal and thermodynamic stability, rheological characteristics, and so forth, are discussed comprehensively to guide the formula-tor in preparing an effective and robust SEDDS formulation. Also, this exhaustive review offers an explicit discussion on vital applications of the SEDDS in bioavailability enhancement of various drugs, outlining an overview on myriad in vitro, in situ, and ex vivo techniques to assess the absorption and/ or permeation potential of drugs incorporated in the SEDDS in animal and cell line models, and the subsequent absorption pathways followed by them. In short, the current article furnishes an updated compilation of wide-ranging information on all the requisite vistas of the self-emulsifying formulations, thus paving the way for accelerated progress into the SEDDS application in pharmaceutical research.