Bhavesh S. Barot

Topical delivery of clobetasol propionate loaded microemulsion based gel for effective treatment of vitiligo: Ex vivo permeation and skin irritation studies

The aim of the present investigation was to evaluate microemulsion as a vehicle for dermal drug delivery and to develop microemulsion based gel (MBC) of clobetasol propionate (CP) for the effective treatment of vitiligo. D-Optimal mixture experimental design was adopted to optimize the amount of oil (X(1)), S(mix) (mixture of surfactant and cosurfactant) (X(2)) and water (X(3)) in the microemulsion. The formulations were assessed for globule size (nm) (Y(1)) and solubility of CP in microemulsion (mg/ml) (Y(2)). The microemulsion containing 3% oil, 45% S(mix) and 50% water was selected as the optimized batch (ME). The globule size and solubility of CP in ME were 18.26 nm and 36.42 mg/ml respectively. Transmission electron microscopy showed that ME globules were spherical in shape. Carbopol 934P was used to convert microemulsion containing drug into gel form without affecting its structure. Ex-vivo permeation studies showed that cumulative amount of CP permeated (Q(n)) from ME, MBC and market formulation (MFCP) at 8h after application were 53.6±2.18, 28.43±0.67 and 37.73±0.77 μg cm(-2) respectively. MBC showed greater retention of CP in to skin layers than ME and MFCP. Skin irritation studies showed MBC to be significantly less irritating than MFCP. Photomicrographs and scanning electron micrographs of skin sections treated with MBC showed significant changes in the skin structure, which was attributed to the interaction of microemulsion components with skin resulting in permeation enhancement and retention of CP into skin layers. It was concluded that CP loaded gel could be a promising formulation for effective treatment of vitiligo.

Development of directly compressible metformin hydrochloride by the spray-drying technique

Development of directly compressible metformin hydrochloride by the spray-drying technique Metformin hydrochloride exhibits poor compressibility during compaction, often resulting in weak and unacceptable tablets with a high tendency to cap. The purpose of this study was to develop directly compressible metformin hydrochloride by the spray-drying technique in the presence of polymer. Metformin hydrochloride was dissolved in solutions containing a polymer, namely polyvinylpyrrolidone (PVP K30), in various concentrations ranging from 0-3% (m/V). These solutions were employed for spray-drying. Spray-dried drug was evaluated for yield, flow property and compressibility profile. Metformin hydrochloride spray-dried in the presence of 2% PVP K30 showed an excellent flow property and compressibility profile. From the calculated Heckels parameter (Py = 2.086), it was demonstrated that the treated drug showed better particle arrangement in the initial compression stage. Kawakita analysis revealed better packability of the treated drug compared to the untreated drug. Differential scanning calorimetry and Fourier transform infrared spectroscopy experiments showed that the spray-dried drug did not undergo any chemical modifications. Tablets made from the spray-dried drug (90%, m/m) were evaluated for crushing strength, friability and disintegration time and the results were found satisfactory. Razvoj metformin hidroklorida za izravnu kompresiju metodom sušenja raspršivanjem Metformin hidroklorid se teško komprimira zbog čega nastaju slabe tablete neodgovarajuć e kvalitete s velikom tendencijom kalanja. Cilj ovog rada je prirediti metformin hidroklorid za izravnu kompresiju metodom sušenja raspršivanjem u prisutnosti polimera. Metformin hidroklorid je otopljen uz dodatak različitih količina (0-3% m/V) polivinilpirolidona (PVP K30). Dobivene otopine sušene su raspršivanjem, a tako pripravljenom metformin hidrokloridu određivano je iskorištenje, tečnost i kompresibilnost. Metformin hidroklorid pripravljen u prisutnosti 2% PVP K30 ima izvrsnu tečnost i kompresibilnost. Izračunati Heckelovi parametri (Py = 2,086) pokazuju da tako obrađeni metformin hidroklorid tvori veće čestice na početku kompresije. Analiza po Kawakiti ukazuje na to da se obrađeni lijek bolje preša od neobrađenog. Diferencijalna pretražna kalorimetrija (DSC) i Fourierova transformirana infracrvena spektroskopija (FTIR) pokazuju da sušenje raspršivanjem nije uzrokovalo nikakve kemijske promjene. Iz obrađenog metformina izrađene su tablete (90% m/m) sa zadovoljavajućom lomljivošću, drobivošću i vremenom dezintegracije.

Physicochemical and structural characterization of iron–sucrose formulations: a comparative study

Abstract Intravenous polynuclear iron formulations are vital components in the treatment of iron deficiency anemia associated with chronic kidney disease as well as other diseases associated with gastro-intestinal and cardio-vascular system. Intravenous iron preparations consist of iron–carbohydrate nanoparticles with iron–oxyhydroxide as a core covered by carbohydrate shell. These preparations should be very well characterized in terms of their physicochemical properties and pharmacological profile in order to establish safety and efficacy. The present research work was aimed to physicochemically characterize a new generic iron–sucrose preparation (IS-Claris) and establish its equivalency with the reference product (Venofer®). Various analytical techniques including gel permeation chromatography (GPC), mass spectroscopy (MALDI-TOF), absorption spectroscopy, X-ray diffraction analysis (XRD), nuclear magnetic resonance spectroscopy (proton and 13C NMR), Fourier transform infrared spectroscopy (FTIR) and thermal gravimetric analysis (TGA) were employed. It was observed that the specifications of IS-Claris obtained through these analyses reflect those of Venofer® and hence the two formulations were considered comparable.

Innovation of novel 'Tab in Tab' system for release modulation of milnacipran HCl: optimization, formulation and in vitro investigations.

The study was aimed toward development of modified release oral drug delivery system for highly water soluble drug, Milnacipran HCl (MH). Novel Tablet in Tablet system (TITs) comprising immediate and extended release dose of MH in different parts was fabricated. The outer shell was composed of admixture of MH, lactose and novel herbal disintegrant obtained from seeds of Lepidium sativum. In the inner core, MH was matrixed with blend of hydrophilic (Benecel®) and hydrophobic (Compritol®) polymers. 32 full factorial design and an artificial neuron network (ANN) were employed for correlating effect of independent variables on dependent variables. The TITs were characterized for pharmacopoeial specifications, in vitro drug release, SEM, drug release kinetics and FTIR study. The release pattern of MH from batch A10 containing 25.17% w/w Benecel® and 8.21% w/w of Compritol® exhibited drug release pattern close proximal to the ideal theoretical profile (t50% = 5.92 h, t75% = 11.9 h, t90% = 18.11 h). The phenomenon of drug release was further explained by concept of percolation and the role of Benecel® and Compritol® in drug release retardation was studied. The normalized error obtained from ANN was less, compared with the multiple regression analysis, and exhibits the higher accuracy in prediction. The results of short-term stability study revealed stable chataracteristics of TITs. SEM study of TITs at different dissolution time points confirmed both diffusion and erosion mechanisms to be operative during drug release from the batch A10. Novel TITs can be a succesful once a day delivery system for highly water soluble drugs.

Topical delivery of clobetasol propionate loaded microemulsion based gel for effective treatment of vitiligo – Part II: Rheological characterization and in vivo assessment through dermatopharmacokinetic and pilot clinical studies

Vitiligo is a non contagious acquired pigmentation disorder with limited treatment possibilities. Clobetasol propionate (CP) is the drug-of-choice for vitiligo which suppresses the immune system by reducing immunoglobulin action and causes the restoration of melanocytes leading to repigmentation of skin. However, despite being effective, its low and variable bioavailability prompt for development of novel carrier that could effectively target CP to site of action without producing undesirable side-effects. Low solubility of CP in subsequent poor in vivo bioavailability was overcome by formulating microemulsion based gel of CP (MBC) which would enhance the percutaneous transport of CP into and across the skin barrier. Comprehensive characterization of MBC was carried out for viscosity, gel strength and rheological behavior. In vitro studies revealed much higher drug release, skin penetration and enhanced skin accumulation as compared to control (Cream of CP). In vitro and in vivo occlusion studies demonstrated similar occlusiveness for MBC and control. MBC exhibited 3.16 times higher stratum corneum CP levels compared to control. Visualization of cutaneous uptake in vivo using laser scanning microscopy confirmed targeting of CP to epidermis and dermis. Dermatopharmacokinetic studies of MBC showed enhanced drug deposition of CP in skin layers. MBC was assessed for in vivo efficacy by single blind randomized pilot clinical study. The efficacy was assessed by vitiligo area scoring index (VASI) method. After completion of trial, repigmentation of vitiligo patches in patients were evaluated and scored. MBC was superior in terms of faster repigmentation and efficacy when compared with control (p value<0.5). Hence, it was concluded that CP loaded MBC possess enhanced skin localization as well as therapeutic activity in vitiligo patients.

An overview of recent patents on nanosuspension.

Pharmaceutical scientists involved in drug discovery and drug development are facing serious problems with newer poorly water soluble drugs with respect to their dissolution and bioavailability. Reducing the particle size of active pharmaceutical ingredient has been an efficient and reliable method for improving the bioavailability of insoluble drugs. Nanosuspension has emerged as an efficient and promising strategy for delivery of insoluble drugs due to its unique advantages such as ease of modification, process flexibility, targeting capabilities, altered pharmacokinetic profile leading to safety and efficacy. These unique features of nanosuspension have enabled its use in various dosage forms, including specialized delivery systems such as oral, parenteral, peroral, ocular and pulmonary routes. Currently, efforts are being directed to extend their applications in site-specific drug delivery. Large numbers of products based on nanosuspension are in the market and few are under clinical trials. The commercialization potential of nanosuspension based formulation for oral route is well established and products for other routes will enter the market within short span. Among the various techniques available, only wet milling technique has been successfully used for commercial production of nanosuspension. Nanosuspension based patents have extensive potential of reaching faster in the market as compared to other nanotechnology based formulations. This review covers various aspects of techniques of preparation, route of administration and commercialization of nanosuspension with main focus on the recent patents granted in the field.

QUANTITATIVE DETERMINATION OF MILNACIPRAN HCL IN RABBIT PLASMA BY HPLC AND ITS APPLICATION TO PHARMACOKINETICS STUDY

A simple, sensitive, and specific reverse phase high performance liquid chromatography (RP-HPLC) method was developed and validated for the quantification of Milnacipran HCl in rabbit plasma. Milnacipran HCl and internal standard (IS, Venlafaxine HCl) were extracted by protein precipitation method with chloroform. The separation was performed on a HiQ sil C18 column (250 mm × 4.6 mm i.d., 5 µm). The wavelength was set at 220 nm. The mobile phase was a mixture of potassium dihydrogen phosphate buffer (0.0125 M) and acetonitrile (72:28%, v/v) with 0.20% triethylamine at a flow rate of 1.0 mL/min. The pH of the solution was adjusted to 3.65 with 0.1 M orthophosphoric acid. The calibration curve was linear over the concentration range 0.1–25 µg/mL. The intra-day and inter-day precision was ranged from 3.9 to 7.3% and 5.2 to 10.8%, respectively. Finally, this proposed method was successfully applied to rabbit pharmacokinetics study and yielded the most comprehensive data on systemic exposure of Milnacipran HCl to date.

In vivo performance evaluation and establishment of IVIVC for osmotic pump based extended release formulation of milnacipran HCl

The objective of the present study was to carry out a pharmacokinetics evaluation of an oral modified release formulation [Aquarius EKX 19102 SRX–2 based osmotic pump (OP)] containing highly soluble milnacipran HCl (MH) as a model drug. It was also aimed at developing an in vitro–in vivo correlation (IVIVC) model for a developed OP. In vivo plasma concentration data were obtained from six healthy male New Zealand albino rabbits after administration of immediate‐release milnacipran HCl solution (IRMHSOL) and milnacipran HCl osmotic pump (MHOP). In vitro samples were analysed using an in house developed spectrophotometry method and in vivo samples were analysed using a RP‐HPLC method developed by the author. A deconvolution based Level A model was attempted through a correlation of the percent in vivo input obtained through deconvolution and the percent in vitro dissolution obtained experimentally. A good correlation between the percentages dissolved vs absorbed (R2 = 0.978) was obtained using level A correlation. Evaluation of the internal predictability of level A correlation was calculated in terms of the percent prediction error, which was found to be below 15%. In a nutshell, the success of the present study warrants further studies in patient volunteers to assess the ability of the MHOP to provide an effective therapy for depression. Copyright