Tejal Mehta

Microneedles: an emerging transdermal drug delivery system

Objectives  One of the thrust areas in drug delivery research is transdermal drug delivery systems (TDDS) due to their characteristic advantages over oral and parenteral drug delivery systems. Researchers have focused their attention on the use of microneedles to overcome the barrier of the stratum corneum. Microneedles deliver the drug into the epidermis without disruption of nerve endings. Recent advances in the development of microneedles are discussed in this review for the benefit of young scientists and to promote research in the area.

Formulation strategies for drug delivery of tacrolimus: An overview

Tacrolimus (FK 506) is a potent macrolide lactone immunosuppressive agent used for prophylaxis of organ rejection after transplantation and graft-versus-host disease after bone marrow transplantation in patients. Moreover, tacrolimus is a drug of choice in the treatment of atopic dermatitis for decreasing side effects associated with the use of topical corticosteroids. In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated due to its narrow therapeutic index (between 5 and 15 ng/ml). Tacrolimus has a large inter-/intra-patient variability in pharmacokinetics profile and a poor oral bioavailability because of its poor solubility, P-gp efflux, marked pre-systemic metabolism by CYP3A in the enterocytes and liver first pass effect. Several formulation approaches such as oily solution, solid dispersions, complexation with cyclodextrins, liposomes etc., have been investigated to improve oral delivery of FK 506. In this review, we have discussed various formulation approaches that have been undertaken by various researchers to solve the problems related to the drug delivery of tacrolimus.

Self micro-emulsifying drug delivery system of tacrolimus: Formulation, in vitro evaluation and stability studies

Background: Tacrolimus has poor solubility in water ranging from 4 to 12 μg/mL. The oral bio availabilities of tacrolimus is poor and exhibits high intra and inter-subject variability (4-89%, average 25%) in the liver and the kidney transplant recipients and in patients with renal impairment. Aim: The present study deals with the development and characterization of self-micro-emulsifying drug delivery system to improve the oral bioavailability of poorly soluble drug tacrolimus. Materials and Methods: Solubility of the tacrolimus was estimated in various oils, surfactants, and co-surfactants. Various in vitro tests such as percentage transmittance, emulsification time, cloud point, precipitation, and thermodynamic stabilities were used to find out optimized formulations. Optimized liquid self micro-emulsifying (SMEDDS) were characterized by particle size analysis and converted in solid by using the Florite RE as an adsorbent, which is further characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and particle size analysis. Results: The optimized liquid SMEDDS formulation contained 10% Lauroglycol FCC as an oil, 60% Cremophor RH, and 30% PEG (polyethylene glycol) 400 as a surfactant and co-surfactant respectively. The optimized liquid and solid SMEDDS showed higher drug release than the marketed capsule and pure API (active pharmaceutical ingredient) powder. For optimized liquid SMEDDS and solid SMEDDS, the globule sizes were found 113 nm and 209 nm respectively. The solid state characterization of solid-SMEDDS by SEM, DSC, FTIR, and XRD revealed the absence of crystalline tacrolimus in the solid-SMEDDS. Shelf-lives for liquid SMEDDS and solid SMEDDS were found to be 1.84 and 2.25 year respectively. Conclusions: The results indicate that liquid SMEDDS and solid SMEDDS of tacrolimus, owing to nano-sized, have potential to enhance the absorption of the drug.

Nanocrystal for ocular drug delivery: hope or hype

The complexity of the structure and nature of the eye emanates a challenge for drug delivery to formulation scientists. Lower bioavailability concern of conventional ocular formulation provokes the interest of researchers in the development of novel drug delivery system. Nanotechnology-based formulations have been extensively investigated and found propitious in improving bioavailability of drugs by overcoming ocular barriers prevailing in the eye. The advent of nanocrystals helped in combating the problem of poorly soluble drugs specifically for oral and parenteral drug delivery and led to development of various marketed products. Nanocrystal-based formulations explored for ocular drug delivery have been found successful in achieving increase in retention time, bioavailability, and permeability of drugs across the corneal and conjunctival epithelium. In this review, we have highlighted the ocular physiology and barriers in drug delivery. A comparative analysis of various nanotechnology-based ocular formulations is done with their pros and cons. Consideration is also given to various methods of preparation of nanocrystals with their patented technology. This article highlights the success achieved in conquering various challenges of ocular delivery by the use of nanocrystals while emphasizing on its advantages and application for ocular formulation. The perspectives of nanocrystals as an emerging flipside to explore the frontiers of ocular drug delivery are discussed.

Formulation optimization of gastroretentive drug delivery system for allopurinol using experimental design

Objectives: The objective of the study was to develop gastroretentive dosage form (GRDF) for allopurinol (ALP) using combined approaches of mucoadhesion and floating systems. GRDF was systematically optimized using 32-full factorial design. Methods: Concentrations of sodium carboxymethyl cellulose (X1) and concentration of polyoxyethylene oxide WSR 303 (X2) were selected as independent variables, whereas gastroretentive parameters like total floating time (TFT) (Y1), mucoadhesive force (MF) (Y2), time required for 10% drug release (Y3) and time required for 80% drug release (Y4) were selected as dependent variables in development of robust GRDF of ALP. GRDF was evaluated for gastroretentive parameters such as floating lag time (FLT) and TFT, MF using texture analyzer and ex vivo residence time using modified disintegration test apparatus. Roentgenography study of optimized formulation was conducted to evaluate in vivo gastro retentive behavior using albino rabbits. Results: Developed tablets showed immediate in situ gas generation and exhibited FLT of 1.68 s after placing into simulated gastric fluid, which lead to buoyancy as well as controlled drug release for 24 h with zero-order drug release kinetics. The optimized formulation was selected based on in vitro drug release characteristics. In vivo retention of optimized formulation was corroborated using roentgenography studies. Conclusion: The study concluded that the combination of mucoadhesive and floating approaches for GRDF aids to achieve desired gastroretentive performance and drug release properties for ALP. The formulation scientists may adopt these formulation strategies for drugs suitable for the development of GRDF.

Crosslinking of starch and its effect on viscosity behaviour

Abstract Starch is a widely used component in the food industry. Native starch does not have the desired properties, so it is modified according to the required properties. Out of different methods, crosslinking is one of the widely used ones. There are different crosslinking agents available. The method and mechanism of widely used crosslinking agents like phosphorous oxychloride, adipate and epichlorohydrin are discussed and compared. When starch is crosslinked, its properties vary. The extent of crosslinking can be predicted with the help of properties like viscosity and swelling. They are also compared for crosslinking by different agents.

Formulation, development and characterization of mucoadhesive film for treatment of vaginal candidiasis

Objective: The objective of the present investigation was formulation, optimization and characterization of mucoadhesive film of clotrimazole (CT) which is patient-convenient and provides an effective alternative for the treatment of vaginal candidiasis. CT is an antimycotic drug applied locally for the treatment of vaginal candidiasis. Materials and Methods: Mucoadhesive vaginal films were prepared by solvent casting technique using hydroxyl propylcellulose and sodium alginate as polymers. Propylene glycol and polyethylene glycol-400 were evaluated as plasticizers. The mucoadhesive vaginal films were evaluated for percentage elongation, tensile strength, folding endurance, drug content, in vitro disintegration time, in vitro dissolution study, swelling index, bioadhesive strength, and diffusion study. Results: Among various permeation enhancers used, isopropyl myristate was found to be suitable. To evaluate the role of the concentration of permeation enhancer and concentration of polymers in the optimization of mucoadhesive vaginal film, 3 2 full factorial design was employed. Optimized batch showed in vitro disintegration time, 18 min; drug content, 99.83%; and tensile strength, 502.1 g/mm 2 . In vitro diffusion study showed that 77% drug diffusion occurred in 6 h. This batch was further evaluated by scanning electron microscopy indicating uniformity of the film. In vitro Lactobacillus inhibition and in vitro antifungal activity of optimized batch showed an inhibitory effect against Candida albicans and no effect on Lactobacillus, which is a normal component of vaginal flora. Conclusion: Mucoadhesive vaginal film of CT is an effective dosage form for the treatment of vaginal candidiasis.

Formulation Design and Characterization of an Elementary Osmotic Pump Tablet of Flurbiprofen

Elementary osmotic pumps are well known for delivering moderately soluble drugs at a zero-order rate. The objective of the present study was to develop elementary osmotic pump tablets containing Flurbiprofen using an inclusion complex. Formation of complex was confirmed by Differential Scanning Calorimetry and Fourier Transform Infrared Spectroscopy. A 32 factorial design was applied systematically; the amount of osmotic agent (X1) and size of delivery orifice (X2) were selected as independent variables. Batches were prepared by the direct compression method and evaluated for percent cumulative drug release (%CDR) at 9 h as dependent variables. The amount of osmotic agent and size of the delivery orifice had a significant effect on %CDR. The results of multiple linear regression analysis revealed that elementary osmotic pump tablets should be prepared using an optimum concentration of osmotic agent and size of delivery orifice to achieve a zero-order drug release. Contour plots as well as response surface plots were constructed to show the effects of X1 and X2 on %CDR. A model was validated for accurate prediction of %CDR by performing checkpoint analysis. The computer optimization process, contour plots, and response surface plots were predicted at the concentration of independent variables X1 and X2 (78.38 mg and 0.99 mm, respectively), for maximized response. The drug release from the developed formulation was found to be independent of pH and agitational intensity. The above optimized batch was also evaluated by different pharmacokinetic models like zero-order, first-order, Higuchi, Korsmeyer Peppas, and Hixson Crowell models. Stability study of the optimized batch was conducted at accelerated conditions for 6 months, and was found stable. This study strongly indicates application of osmotic tablets of Flurbiprofen for the treatment of rheumatoid arthritis, as well as osteoarthritis. LAY ABSTRACT: The aim of this study was to develop an elementary osmotic pump tablet of Flurbiprofen and to deliver the drug at a zero-order rate. Elementary osmotic pumps are well known for delivering moderately soluble drugs at a zero-order rate. Elementary osmotic pump tablets containing an inclusion complex of Flurbiprofen was prepared by the direct compression method. The amount of osmotic agent and size of delivery orifice were selected as independent variables. Percent cumulative drug release at 9 h was evaluated for all batches, and it was found that amount of osmotic agent and size of delivery orifice had a significant effect on percent cumulative drug release. The drug release from the developed formulation was found to be independent of pH and agitational intensity. It was also observed that the optimized formulation followed zero-order kinetics and was stable for 6 months at accelerated conditions.

Formulation and Optimization of Multiparticulate Drug Delivery System Approach for High Drug Loading

The aim of the present work was to develop and optimize multiparticulate formulation viz. pellets of naproxen by employing QbD and risk assessment approach. Mixture design with extreme vertices was applied to the formulation with high loading of drug (about 90%) and extrusion-spheronization as a process for manufacturing pellets. Independent variables chosen were level of microcrystalline cellulose (MCC)—X1, polyvinylpyrrolidone K-90 (PVP K-90)—X2, croscarmellose sodium (CCS)—X3, and polacrilin potassium (PP)—X4. Dependent variables considered were disintegration time (DT)—Y1, sphericity—Y2, and percent drug release—Y3. The formulation was optimized based on the batches generated by MiniTab 17 software. The batch with maximum composite desirability (0.98) proved to be optimum. From the evaluation of design batches, it was observed that, even in low variation, the excipients affect the pelletization property of the blend and also the final drug release. In conclusion, pellets with high drug loading can be effectively manufactured and optimized systematically using QbD approach.

Design of experiment approach for formulating multi-unit colon-targeted drug delivery system: in vitro and in vivo studies

Abstract Objective: The objective of the present investigation was to develop systematically optimized multiunit formulation for colon targeted delivery of metronidazole (MTZ) by employing design of experiment (DoE) and evaluate it for in vitro as well as in vivo drug release study. Methods: Core of mini-tablets of MTZ was prepared using drug along with suitable swelling agents to provide pH sensitive pulsatile drug delivery. Eudragit® S 100 (ES) and ethyl cellulose (EC) were used as coating polymers to prevent initial drug release in gastric region. The coating composition was systematically optimized using 32-full factorial design and optimized formulation was evaluated in vitro and then in vivo, to confirm colon targeting ability of the developed system. Stability study of optimized formulation was performed for 6 months as per ICH guidelines. Results: The optimized coating composition was selected from the results of design batches. The optimized formulation showed 6.99 ± 1.5% drug release up to 5 h and 100% drug release within 7.2 ± 0.2 h indicating pH sensitive pulsatile behavior of formulation. Similar drug release profile was observed while performing in vivo study in rabbits with a lag time of 4 h and Cmax of 190 ± 4.9 ng/ml being achieved after 7 h. Stability study indicated insignificant difference in properties of tablets and their drug release patterns. Conclusion: Optimization of coating composition (EC and ES) and thickness could offer pH sensitive pulsatile release of drugs at colon. Furthermore, in vivo results confirmed the successful development of colon targeted formulation of MTZ.