Abstract: The carboxylic group responsible for the gastric side-effects of the propionic acid derivative, flurbiprofen, was masked temporarily to overcome these side-effects and to accomplish colon-specific delivery of the drug. An amide prodrug (FLU-GLY) was synthesized by coupling flurbiprofen with L-glycine. Confirmation and characterization of the structure of the synthesized prodrug included elemental analysis, Fourier transform (FT)-IR, FT-NMR, mass (FAB) spectroscopy, and determinations of R(f), R(t) and R(M) values, respectively. Aqueous solubility and lipophilicity (logP) value were determined at pH 1.2, 4.0, 6.8 and 7.4. In-vitro reversion of FLU-GLY to flurbiprofen was measured at different pHs and in a simulated colonic environment. Acute toxicity and ulceration potential were evaluated in-vivo in albino rats. Pre-formulation studies showed increased hydrophilicity but a non-significant increase in lipophilicity of the prodrug. In-vitro reversion studies suggested that the prodrug remained intact until colonic pH was attained, when the colonic microfloral enzymes (amidase) hydrolysed the FLU-GLY amide linkage, releasing the free drug. In-vivo evaluation indicated that the prodrug was much less toxic and had less ulcerogenic activity than the parent drug. Selective delivery of drugs to the colon can be useful in terms of reducing the dose administered and reducing undesirable side-effects.

Abstract: In the present study, the aim was to optimize an orodispersible formulation of indomethacin using a combined approach of subliming agent and superdisintegrant. The tablets were made by non-aqueous wet granulation technique with superdisintegrant incorporated both intragranularly and extragranularly. A 2(3) factorial design was used to investigate the effects amount of subliming agents namely camphor and ammonium bicarbonate and taste masking and soothening hydrophilic agent mannitol as independent variables and disintegration time and crushing strength as dependent responses. The volatilization time of eight hours at 50 degrees C was optimized by conducting solid-state kinetic studies of optimized formulations. Optimized orodispersible tablets were evaluated for wetting time, water absorption ratio, porosity and in vitro and in vivo disintegration tests. Results show that higher levels of camphor and mannitol and a lower level of ammonium bicarbonate is desirable for orodispersion. Scanning electron microscopy (SEM) revealed the porous surface morphology and kinetic digital images substantiated the orodispersible property. Differential Scanning Calorimetry (DSC) studies exhibited physiochemical compatibility between indomethacin and various excipients used in the tablet formulation. Stability studies carried out as per ICH Q(1) A guidelines suggested the stable formulations for the tested time period of 6 months. The systematic approach of using subliming and disintegrating agents helped in achieving a stable, optimized orodispersible formulation, which could be industrially viable.

Abstract: The present investigation studied a novel extended release system of promethazine hydrochloride (PHC) with acrylic polymers Eudragit RLPO and Eudragit RS100 in different weight ratios (1 : 1 and 1 : 5) using coevaporation and coprecipitation techniques. Solid dispersions were characterized by Fourier-transformed infrared spectroscopy (FT-IR), Differential scanning calorimetry (DSC), Powder X-ray diffractometry (PXRD), Nuclear magnetic resonance (NMR), Scanning electron microscopy (SEM) as well as solubility and in vitro dissolution studies in 0.1 n HCl (pH 1.2), double distilled water and phosphate buffer (pH 7.4). Adsorption test from drug solution to solid polymers were also performed. Selected solid dispersion system was subjected to direct compression and compressed tablets were evaluated for in vitro dissolution studies. The progressive disappearance of drug peaks in thermotropic profiles of coevaporates were related to increasing amount of polymers while SEM studies suggested homogenous dispersion of drug in polymer. Eudragit RLPO had a greater adsorptive capacity than Eudragit RS100 and thus its coevaporates in 1 : 5 ratio exhibited higher dissolution rate with 91.90% drug release for 12 h. Among different formulations, tablets prepared by Eudragit RLPO coevaporates (1 : 5) displayed extended release of drug for 12 h with 90.87% release followed by zero order kinetics (r(2)=0.9808).

Abstract: The objective of the present work was to improve the dissolution properties of the poorly water-soluble drug meloxicam by preparing solid dispersions with hydroxyethyl cellulose (HEC), mannitol and polyethylene glycol (PEG) 4000 and to develop a dosage form for geriatric population. Differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy and scanning electron microscopy were used to investigate the solid-state physical structure of the prepared solid dispersions. Higher in vitro dissolution of solid dispersions was recorded compared to their corresponding physical mixtures and the pure drug. PEG 4000 in 1: 9 drug to carrier ratio exhibited the highest drug release (100.2%), followed by mannitol (98.2%) and HEC (89.5%) in the same ratio. Meloxicam-PEG 4000 solid dispersion was formulated into suspension and optimization was carried out by 23 factorial design. Formulations containing higher levels of methyl cellulose and higher levels of either sodium citrate or Tween 80 exhibited the highest drug release.

Abstract: In the present study, both disintegrating and non-disintegrating polymeric capsular system in achieving delayed as well as improved osmotic flow for the model drug cefadroxil was developed. Asymmetric membrane in membrane capsule (AMMC) was prepared on a glass mold pin via phase inversion process in two steps. Step 1 included formation of a non-disintegrating, asymmetric membrane capsule (AMC) and step 2 involved formation of a pH sensitive, disintegrating, asymmetric membrane (AM) formed over the non-disintegrating membrane. The effects of different formulation variables were studied namely, level of osmogen, membrane thickness, and level of pore former. Effects of varying osmotic pressure, agitational intensity and intentional defect in the inner membrane on drug release were also studied. Membrane characterization by scanning electron microscopy showed dense regions with less pores on the outer surface of the disintegrating membrane and porous regions on the inner surface of the non-disintegrating asymmetric membrane. In vitro release studies for all the prepared formulations were done (n=6). The drug release was independent of pH, agitational intensity and intentional defect on the membrane but dependent on the osmotic pressure of the dissolution medium. The release kinetics followed the zero order and the mechanism of release was Fickian diffusion.

Abstract: The aim of this study is to carry out preformulative investigations on preformed inclusion complexes of the poorly water-soluble, lipid-lowering agent gemfibrozil and naturally occurring cyclodextrins (CDs). Phase solubility studies showed a linear AL- type diagram with alpha, beta, and y cyclodextrins, indicating the formation of inclusion complexes in a 1:1 molar ratio with all the three CDs. beta-CD-gemfibrozil complex having a maximum stability constant of 148.88 M(-1) was selected for preparation of preformed inclusion complex by kneading, co-precipitation, co-evaporation, and freeze-drying and compared with the physical mixture. The kneaded product was subjected to microwave-drying, with this mode of drying studied as an alternative method for preparation of the complex. The prepared complexes were assessed by equilibrium solubility analysis and intrinsic dissolution rate studies. Further characterization was done by differential scanning calorimetry, X-ray powder diffractometry, Fourier transform infrared spectroscopy, and scanning electron microscopy. The freeze-dried product was identified as the inclusion complex having the maximum intrinsic dissolution rate and hence was assessed for changes in permeability characteristics. pH partition studies and partial in vivo permeability studies showed no changes in the permeability of the freeze-dried product when compared to the pure drug.

Abstract: The purpose of this study was to develop a dosage form that was easy to administer and provides rapid release of the drug roxithromycin, using modified polysaccharides as rapidly disintegrating excipients. Modified polysaccharides co grinded treated agar (C-TAG) and co grinded treated guar gum (C-TGG) were prepared by subjecting pure polysaccharides namely agar and guar gum respectively to sequential processes of wetting, drying and co grinding with mannitol (1:1). The modified polysaccharides were characterized by Scanning Electron Microscopy and Diffuse Reflectance Spectroscopy and evaluated for particle size distribution, derived properties, swelling index and biodegradability. Optimization studies based on 2(2) factorial designs, with friability and disintegration time as response parameters were used to formulate orodispersible tablets of roxithromycin and evaluated for wetting time, water absorption ratio and in vitro drug release at salivary pH 6.4 and physiological pH 7.4. Results indicated that lower levels of modified polysaccharides namely C-TAG in F(3) and C-TGG in F(7) and higher levels of microcrystalline cellulose, exhibited least disintegration times without friability concerns. In vitro release of optimized formulations F(3) and F(7,) both at salivary pH and physiological pH was found to be more than 90% within 30 min as compared to 27.82% at the same time point of conventional formulation. Stability studies carried out as per ICH Q1A guidelines suggested the formulations to be stable for a period of 6 months. Thus the approach of using modified polysaccharides as fast disintegrating excipient can be used to formulate a stable orodispersible formulation.

Abstract: The objective of investigation was to prepare nanoemulsion containing risperidone (RSP) to accomplish the delivery of drug to the brain via nose. Risperidone nanoemulsion (RNE) and mucoadhesive nanoemulsion (RMNE) were characterized for drug content, pH, percentage transmittance, globule size and zeta potential. Biodistribution of RNE, RMNE, and risperidone solution (RS) in the brain and blood of Swiss albino rats following intranasal (i.n.) and intravenous (i.v.) administration was examined using optimized technetium labeled ((99m)Tc-labeled) RSP formulations. Gamma scintigraphy imaging of rat brain following i.v. and i.n. administrations were performed to ascertain the localization of drug in brain. The brain/blood uptake ratio of 0.617, 0.754, 0.948, and 0.054 for RS (i.n.), RNE (i.n.), RMNE (i.n.), and RNE (i.v.), respectively, at 0.5h are indicative of direct nose to brain transport bypassing the blood-brain barrier. Higher drug transport efficiency (DTE%) and direct nose to brain drug transport (direct transport percentage, DTP%) for mucoadhesive nanoemulsions indicated more effective and best brain targeting of RSP amongst the prepared nanoemulsions. Studies conclusively demonstrated rapid and larger extent of transport of RSP by RMNE (i.n.) when compared to RS (i.n.), RNE (i.n.) and RNE (i.v.) into the rat brain.

Abstract: Risperidone nanoemulsion (NE) and mucoadhesive NE formulations were successfully prepared by the spontaneous emulsification method (titration method) using Capmul MCM as the oily phase on the basis of solubility studies. The NE formulation containing 8% oil, 44% S(mix), 48% (wt/wt) aqueous phase that displayed an optical transparency of 99.82%, globule size of 15.5 +/- 2.12 nm, and polydispersity of 0.172 +/- 0.02 was selected for the incorporation of mucoadhesive components. The mucoadhesive formulation that contained 0.5% by weight of chitosan displayed highest diffusion coefficient that followed Higuchi model was free from nasal ciliotoxicity and stable for 3 months.

Abstract: The objective of this study was to optimize floating microballoons of famotidine by the emulsion solvent diffusion technique using central composite design. Formulations F1-F15 were prepared using three independent variables (pH of medium, drug: Eudragit S100 ratio and ethanol : dichloromethane ratio) and evaluated for dependent variables (shape, percentage buoyancy, and encapsulation). The optimized formulation F9 was fractionated and a polymer combination of (Eudragit S100 : Eudragit L100-55, 9.5:0.5) resulted in microballoons that exhibited zero order release (94.73%) with 84.20% buoyancy at the end of the eighth hour when studied in the mesh-designed modified USP type II apparatus.

Abstract: The objective of the present study was to optimize olanzapine nanoemulsion (ONE), for nose-to-brain delivery. The nanoemulsions and olanzapine mucoadhesive nanoemulsions (OMNEs) were prepared using water titration method and characterized for technical and electrokinetic properties. Biodistribution of nanoemulsions and olanzapine solution (OS) in the brain and blood of rats following intranasal (intranasal) and intravenous (intravenous) administrations were examined using optimized technetium-labeled ((99m)Tc-labeled) olanzapine formulations. The brain/blood uptake ratios of 0.45, 0.88, 0.80, and 0.04 of OS (intranasal), ONE (intranasal), OMNE (intranasal), ONE (intravenous), respectively, at 0.5 h are indicative of direct nose-to-brain transport (DTP). Higher % drug targeting efficiency (%DTE) and %DTP for mucoadhesive nanoemulsions indicated effective brain targeting of olanzapine among the prepared nanoemulsions. Gamma scintigraphy imaging of the rat brain conclusively demonstrated rapid and larger extent of transport of olanzapine by OMNE (intranasal), when compared with OS (intranasal), ONE (intranasal), and ONE (intravenous), into the rat brain.

Abstract: A phase-transited, nondisintegrating, controlled release, asymmetric membrane capsular system for poorly water-soluble model drug flurbiprofen was developed and evaluated both in vitro and in vivo for osmotic and controlled release of the drug. Asymmetric membrane capsules (AMCs) were prepared using fabricated glass mold pins through wet phase inversion process. Effect of varying osmotic pressure of the dissolution medium on drug release was studied. Membrane characterization by scanning electron microscopy showed an outer dense region with less pores and an inner porous region for the prepared asymmetric membrane. In vitro release studies for all the prepared formulations were carried out (n = 6). Statistical test was applied for in vitro drug release at p > .05. Predicted in vivo concentration from in vitro release data closely matched the minimum effective concentration (in vivo) level achieved by the drug from its release through phase-transited AMC in rabbits for the first hour. The drug release was found to be independent of the pH but dependent on the osmotic pressure of the dissolution medium. In vivo pharmacokinetic studies showed level A correlation (R(2) > .99) with 42.84% relative bioavailability compared to immediate release tablet of flurbiprofen. Excellent correlation achieved suggested that the in vivo performance of the AMCs could be accurately predicted from their in vitro release profile.

Abstract: A gastro retentive controlled release system of loratadine was formulated to increase the residence time in stomach and to modulate the release behaviour of the drug. Oil entrapped floating microbeads prepared by the emulsion gelation method were optimized by 23 factorial design and a polymer ratio of 2.5:1.5 (pectin/sodium alginate) by mass, 15% (m/V) of oil (mineral oil or castor oil) and 0.45 mol L(-1) calcium chloride solution as the optimized processing conditions for the desired buoyancy and physical stability. In vitro drug release in the fed state conditions demonstrated sustained release of loratadine for 8 h, which best fitted the Peppas model with n<0.45. The ethyl cellulose coating on microbeads optimized by 22 factorial design resulted in a controlled release formulation of loratadine that provided zero-order release for 8 h.

Abstract: A non-disintegrating, in situ-formed, asymmetric membrane, polymeric capsular system, offering improved osmotic effect, was used to deliver poorly water-soluble drug in a controlled manner. The poorly water-soluble drug ketoprofen was selected as a model drug to demonstrate how controlled release characteristics can be manipulated by design of in situ-formed polymeric capsule with an asymmetric membrane and core formulations. In situ-formed, asymmetric membrane capsule was made by dry method via precipitation of asymmetric membrane on the walls of hard gelatin capsule. Resulting asymmetric membrane composed of a dense outer region with fewer pores and a lighter inner porous region. The present study evaluates the influence of variables based on two-factor composite design, namely, ethylcellulose and osmogen (sodium chloride), apart from studying effect of varying osmotic pressures of dissolution medium and level of pore-former concentration (glycerol) on drug release. Statistical significance was tested at P < 0.05. Results showed the best formulation (F-5) to closely corresponded to extra design checkpoint formulation by a similarity (f2) value of 95.41 and capsules made with 15% w/v EC, 50 mg sodium chloride, 8% w/v glycerol and 30 mg citric acid (F-11), to achieve therapeutic concentration within first hour of dissolution not observed with any other formulations used in the study. Drug release followed Fickinan diffusion and was independent of pH but dependent on the osmotic pressure of the dissolution medium.

Abstract: An inclusion complex of hydroxypropyl beta-cyclodextrin (HPbetaCD), an amorphous, highly water soluble derivative and aceclofenac (AC), was prepared by the kneading method. The complex was further characterized by differential scanning calorimetry (DSC), X-ray powder diffractometry (XRD), fourier-transform infra red spectroscopy (FT-IR), scanning electron microscopy (SEM) and in vitro dissolution studies. The dissolution of AC from the inclusion complex studied by the dispersed powder technique showed significant dissolution enhancement in case of the kneaded product (KN) compared to pure AC. The complex possessed good compressibility and the tablets so compressed displayed good dissolution profile. The dissolution data were characterized by different model independent parameters such as dissolution efficiency (DE), difference factor (f1) and similarity factor (f2).

Abstract: The aim of this study is to prepare and characterize binary systems of aceclofenac (AC) with hydroxypropyl beta-cyclodextrin (HPbetaCD) in equimolar ratio. Solid binary systems of aceclofenac with HPbetaCD were prepared using cogrinding, kneading, and coevaporating methods, and a physical mixture was prepared for comparison. The binary systems were characterized by differential scanning calorimetry, thermogravimetric analysis, mass spectroscopy, 1H nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy, and in vitro dissolution studies. 1H NMR studies showed that AC partially fits into the HPbetaCD torus cavity with a preferential inclusion of the phenyl ring of the drug. All the binary systems showed superior dissolution and lower dose:solubility ratio (D:S ratio) as compared to pure AC, but the kneaded product exhibited the best dissolution, with complete drug release within 10 min and a D:S ratio of 5 mL. Hence, it was suggested that complexation of aceclofenac with HPbetaCD may be used as an approach to change the drug from Biopharmaceutics Classification System BCS Class II to BCS Class I without changing its intrinsic permeability.