Preparation and Bioavailability Assessment of SMEDDS Containing Valsartan

A self-microemulsifying drug delivery system (SMEDDS) has been developed to enhance diffusion rate and oral bioavailability of valsartan. The solubility of valsartan was checked in different oils, surfactants, and cosurfactants and ternary phase diagrams were constructed to evaluate the microemulsion domain. The valsartan SMEDDS was prepared using Capmul MCM (oil), Tween 80 (surfactant), and polyethylene glycol 400 (cosurfactant). The particle size distribution, zeta potential, and polydispersity index were determined and were found to be 12.3 nm, −0.746, and 0.138, respectively. Diffusion rate of valsartan was measured by in vitro dialysis bag method using phosphate buffer pH 6.8 as diffusion media. Developed high-performance liquid chromatography method was used to determine drug content in diffusion media. Oral bioavailability of valsartan SMEDDS was checked by using rabbit model. Results of diffusion rate and oral bioavailability of valsartan SMEDDS were compared with those of pure drug solution and of marketed formulation. Diffusion of valsartan SMEDDS showed maximum drug release when compared to pure drug solution and marketed formulation. The area under curve and time showed significant improvement as the values obtained were 607 ng h/mL and 1 h for SMEDDS in comparison to 445.36 and 1.36 h for market formulation suggesting significant increase (p < 0.01) in oral bioavailability of valsartan SMEDDS.     

Spray-dried mucoadhesive microspheres: Preparation and transport through nasal cell monolayer

The purpose of this research was to prepare spray-dried mucoadhesive microspheres for nasal delivery. Microspheres composed of hydroxypropyl methylcellulose (H), chitosan (CS), carbopol 934P (CP) and various combinations of these mucoadhesive polymers, and maltodextrin (M), colloidal silicon dioxide (A), and propylene glycol (P) as filler and shaper, were prepared by spray-drying technique. Using propranolol HCl as a model drug, microspheres were prepared at loadings exceedings 80% and yields between 24% and 74%. Bulky, free flowing microspheres that had median particle size between 15 and 23 μm were obtained. Their zeta potential was according to the charge of polymer. Adhesion time of mucoadhesive microspheres on isolated pig intestine was ranked, CS>CP: H>CP>H, while the rank order of swelling was CP>CS>H. Increasing the amount of CP in CP∶H formulations increased the percentage of swelling. Infrared (IR) spectra showed no interaction between excipients used except CS with acetic acid. The release of drug from CP and CP∶H microspheres was slower than the release from H and CS microspheres, correlated to their viscosity and swelling. Long lag time from the CP microspheres could be shortened when combined with H. The permeation of drug through nasal cell monolayer corresponded to their release profiles. These microspheres affected the integrity of tight junctions, relative to their swelling and charge of polymer. Cell viability was not affected except from CS microspheres, but recovery could be obtained. In conclusion, spray-dried microspheres of H, CS, CP, and CP∶H could be prepared to deliver drug through nasal cell monolayer via the opening of tight junction without cell damaging. Published: February 10, 2006     

Cellulose-Based Matrix Microspheres of Prednisolone Inclusion Complex: Preparation and Characterization

The purpose of the present investigation was to encapsulate pure prednisolone (PRD) and PRD–hydroxypropyl-β-cyclodextrin (HPβCD) complex in cellulose-based matrix microspheres. The system simultaneously exploits complexation technique to enhance the solubility of low-solubility drug (pure PRD) and subsequent modulation of drug release from microspheres (MIC) at a predetermined time. The microspheres of various compositions were prepared by an oil-in-oil emulsion–solvent evaporation method. The effect of complexation and presence of cellulose polymers on entrapment efficiency, particle size, and drug release had been investigated. The solid-state characterization was performed by Fourier transform infrared spectroscopy, thermogravimetry, differential scanning calorimetry, and powder X-ray diffractometry. The morphology of MIC was examined by scanning electron microscopy. The in vitro drug release profiles from these microspheres showed the desired biphasic release behavior. After enhancing the solubility of prednisolone by inclusion into HPβCD, the drug release was easily modified in the microsphere formulation. It was also demonstrated that the CDs in these microspheres were able to modulate several properties such as morphology, drug loading, and release properties. The release kinetics of prednisolone from microspheres followed quasi-Fickian and first-order release mechanisms. In addition to this, the f ₂-metric technique was used to check the equivalency of dissolution profiles of the optimized formulation before and after stability studies, and it was found to be similar. A good outcome, matrix microspheres (coded as MIC5) containing PRD–HPβCD complex, showed sustained release of drug (95.81%) over a period of 24 h.     

Development,Optimization, and Anti-diabetic Activity of Gliclazide-Loaded Alginate–Methyl Cellulose Mucoadhesive Microcapsules

The purpose of this work was to develop and optimize gliclazide-loaded alginate–methyl cellulose mucoadhesive microcapsules by ionotropic gelation using central composite design. The effect of formulation parameters like polymer blend ratio and cross-linker (CaCl₂) concentration on properties of gliclazide-loaded alginate–methyl cellulose microcapsules like drug encapsulation efficiency and drug release were optimized. The optimized microcapsules were subjected to swelling, mucoadhesive, and in vivo studies. The observed responses coincided well with the predicted values from the optimization technique. The optimized microcapsules showed high drug encapsulation efficiency (83.57 ± 2.59% to 85.52 ± 3.07%) with low T _50% (time for 50% drug release, 5.68 ± 0.09 to 5.83 ± 0.11 h). The in vitro drug release pattern from optimized microcapsules was found to be controlled-release pattern (zero order) with case II transport release mechanism. Particle sizes of these optimized microcapsules were 0.767 ± 0.085 to 0.937 ± 0.086 mm. These microcapsules also exhibited good mucoadhesive properties. The in vivo studies on alloxan-induced diabetic rats indicated the significant hypoglycemic effect that was observed 12 h after oral administration of optimized mucoadhesive microcapsules. The developed and optimized alginate–methyl cellulose microcapsules are suitable for prolonged systemic absorption of gliclazide to maintain lower blood glucose level and improved patient compliance.     

Development of Budesonide Microparticles Using Spray-Drying Technology for Pulmonary Administration: Design, Characterization, In Vitro Evaluation, and In Vivo Efficacy Study

The purpose of this research was to generate, characterize, and investigate the in vivo efficacy of budesonide (BUD) microparticles prepared by spray-drying technology with a potential application as carriers for pulmonary administration with sustained-release profile and improved respirable fraction. Microspheres and porous particles of chitosan (drug/chitosan, 1:2) were prepared by spray drying using optimized process parameters and were characterized for different physicochemical parameters. Mass median aerodynamic diameter and geometric standard deviation for conventional, microspheres, and porous particles formulations were 2.75, 4.60, and 4.30 μm and 2.56, 1.75, and 2.54, respectively. Pharmacokinetic study was performed in rats by intratracheal administration of either placebo or developed dry powder inhalation (DPI) formulation. Pharmacokinetic parameters were calculated (Ka, Ke, T _max, C _max, AUC, and Vd) and these results indicated that developed formulations extended half life compared to conventional formulation with onefold to fourfold improved local and systemic bioavailability. Estimates of relative bioavailability suggested that developed formulations have excellent lung deposition characteristics with extended T _1/2 from 9.4 to 14 h compared to conventional formulation. Anti-inflammatory activity of BUD and developed formulations was compared and found to be similar. Cytotoxicity was determined in A549 alveolar epithelial cell line and found to be not toxic. In vivo pulmonary deposition of developed conventional formulation was studied using gamma scintigraphy and results indicated potential in vitro–in vivo correlation in performance of conventional BUD DPI formulation. From the DPI formulation prepared with porous particles, the concentration of BUD increased fourfold in the lungs, indicating pulmonary targeting potential of developed formulations.     

Evaluation of mucoadhesive hydrogels loaded with diclofenac sodium-chitosan microspheres for rectal administration

Considering the advantageous for the rectal administration of non-steroidal anti-inflammatory drugs, the objective of this study was to formulate and evaluate rectal mucoadhesive hydrogels loaded with diclofenac-sodium chitosan (DFS-CS) microspheres. Hydroxypropyl methylcellulose (HPMC; 5%, 6%, and 7% w/w) and Carbopol 934 (1% w/w) hydrogels containing DFS-CS microspheres equivalent to 1% w/w active drug were prepared. The physicochemical characterization revealed that all hydrogels had a suitable pH for rectal application (6.5–7.4). The consistency of HPMC hydrogels showed direct proportionality to the concentration of the gelling agent, while carbopol 934 gel showed its difficulty for rectal administration. Farrow’s constant for all hydrogels were greater than one indicating pseudoplastic flow. In vitro drug release from the mucoadhesive hydrogel formulations showed a controlled drug release pattern, reaching 34.6–39.7% after 6 h. The kinetic analysis of the release data revealed that zero-order was the prominent release mechanism. The mucoadhesion time of 7% w/w HPMC hydrogel was 330 min, allowing the loaded microspheres to be attached to the surface of rectal mucosa. Histopathological examination demonstrated the lowest irritant response to the hydrogel loaded with DFS-CS microspheres in response to other forms of the drug.     

Design and <Emphasis Type="Italic">In Vitro</Emphasis> Performance Evaluation of Purified Microparticles of Pravastatin Sodium for Intestinal Delivery

The purpose of research was to develop a mucoadhesive multiparticulate sustained drug delivery system of pravastatin sodium, a highly water-soluble and poorly bioavailable drug, unstable at gastric pH. Mucoadhesive microparticles were formulated using eudragit S100 and ethyl cellulose as mucoadhesive polymers. End-step modification of w/o/o double emulsion solvent diffusion method was attempted to improve the purity of the product, that can affect the dose calculations of sustained release formulations and hence bioavailability. Microparticles formed were discrete, free flowing, and exhibited good mucoadhesive properties. DSC and DRS showed stable character of drug in microparticles and absence of drug polymer interaction. The drug to polymer ratio and surfactant concentration had significant effect on mean particle size, drug release, and entrapment efficiency. Microparticles made with drug: eudragit S100 ratio of 1:3 (F6) exhibited maximum entrapment efficiency of 72.7% and ex vivo mucoadhesion time of 4.15 h. In vitro permeation studies on goat intestinal mucosa demonstrated a flux rate (1,243 μg/cm²/h) that was 169 times higher than the flux of pure drug. The gastric instability problem was overcome by formulating the optimized microparticles as enteric-coated capsules that provided a sustained delivery of the highly water-soluble drug for 12 h beyond the gastric region. The release mechanism was identified as fickian diffusion (n = 0.4137) for the optimized formulation F6. Conclusively, a drug delivery system was successfully developed that showed delayed and sustained release up to 12 h and could be potentially useful to overcome poor bioavailability problems associated with pravastatin sodium.     

Studies on Formulation Development of Mucoadhesive Sustained Release Itraconazole Tablet Using Response Surface Methodology

The purpose of this research was to prepare and evaluate sustained release mucoadhesive tablets of Itraconazole. It is practically insoluble in aqueous fluids hence its solid dispersion with Eudragit E100 was prepared by spray drying. This was formulated in matrix of hydrophilic mucoadhesive polymers Carbopol 934P (CP) and Methocel K4M (HPMC). The formulation was optimized using a 3² factorial design. Amounts of CP and HPMC were taken as formulation variables for optimizing response variables i.e. mucoadhesion and dissolution parameters. The optimized mucoadhesive formulation was orally administered to albino rabbits, and blood samples collected were used to determine pharmacokinetic parameters. The solid dispersion markedly enhanced the dissolution rate of itraconazole. The bioadhesive strength of formulation was found to vary linearly with increasing amount of both polymers. Formulations exhibited drug release fitting Peppas model with value of n ranging from 0.61 to 1.18. Optimum combination of polymers was arrived at which provided adequate bioadhesive strength and fairly regulated release profile. The experimental and predicted results for optimum formulations were found to be in close agreement. The formulation showed C _max 1898 ± 75.23 ng/ml, t _max of the formulation was 2 h and AUC was observed to be 28604.9 ng h/ml     

Design and Development of Gliclazide Mucoadhesive Microcapsules: In Vitro and In Vivo Evaluation

In this study an attempt was made to prepare mucoadhesive microcapsules of gliclazide using various mucoadhesive polymers designed for oral controlled release. Gliclazide microcapsules were prepared using sodium alginate and mucoadhesive polymer such as sodium carboxymethyl cellulose (sodium CMC), carbopol 934P or hydroxy propylmethyl cellulose (HPMC) by orifice-ionic gelation method. The microcapsules were evaluated for surface morphology and particle shape by scanning electron microscope. Microcapsules were also evaluated for their microencapsulation efficiency, in vitro wash-off mucoadhesion test, in vitro drug release and in vivo study. The microcapsules were discrete, spherical and free flowing. The microencapsulation efficiency was in the range of 65–80% and microcapsules exhibited good mucoadhesive property in the in vitro wash off test. The percentage of microcapsules adhering to tissue at pH 7.4 after 6 h varied from 12–32%, whereas the percentage of microcapsules adhering to tissue at pH 1.2 after 6 h varied from 35–68%. The drug release was also found to be slow and extended for more than 16 h. In vivo testing of the mucoadhesive microcapsules in diabetic albino rats demonstrated significant antidiabetic effect of gliclazide. The hypoglycemic effect obtained by mucoadhesive microcapsules was for more than 16 h whereas gliclazide produced an antidiabetic effect for only 10 h suggesting that mucoadhesive microcapsules are a valuable system for the long term delivery of gliclazide.     

Rice germ oil as multifunctional excipient in preparation of self-microemulsifying drug delivery system (SMEDDS) of tacrolimus

Surmounting the constraints of limited solubilization efficiency and prime requisite of antioxidant for conventional lipid formulations, the research work explores an edge over formulation utilizing potential applicability of rice germ oil (RGO) as a multifunctional excipient. Self-microemulsifying drug delivery system (SMEDDS) of tacrolimus (TAC) was formulated with RGO, an indigenous source of gamma-oryzanol. Being the same biological source, RGO and rice bran oil (RBO) were compared and it was found that RGO have more solubilization potential for TAC (2.2-fold) as well as higher antioxidant activity (8.06-fold) than the RBO. TAC-SMEDDS was prepared using RGO/Capmul PG8 (2:3) as an oil phase, Cremophore EL as a surfactant, and Transcutol P as a cosurfactant. The approximate particle size of TAC-SMEDDS was found to be 38 nm by dynamic light scattering and 12 nm by small angle neutron scattering. The in vitro dissolution studies showed complete and rapid drug release in 30 min compared to a plain drug (<5%) and marketed capsule (<50%). AUC and C _max were found to be 45.05 ± 15.64 ng h/ml and 3.91 ± 1.2 ng/ml for TAC-SMEDDS, 12.59 ± 5.54 ng h/ml and 0.48 ± 0.12 ng/ml for plain TAC, and 30.23 ± 10.34 ng h/ml and 2.31 ± 0.68 ng/ml for marketed formulation, respectively. The improved pharmacokinetic profile of TAC-SMEDDS is correlating to the dissolution results. Thus, gamma-oryzanol-enriched RGO acts as a potential multifunctional excipient for lipid formulations.     

Development and Characterization of Enteric-Coated Immediate-Release Pellets of Aceclofenac by Extrusion/Spheronization Technique Using κ-Carrageenan as a Pelletizing Agent

In the present study, an attempt was made to prepare immediate-release enteric-coated pellets of aceclofenac, a poorly soluble nonsteroidal anti-inflammatory drug that has a gastrointestinal intolerance as its serious side effect. Formulation of enteric-coated pellets with improved solubility of aceclofenac could address both of these problems. To achieve these goals, pellets were prepared by extrusion–spheronization method using pelletizing agents that can contribute to the faster disintegration and thereby improve the solubility of the drug. Different disintegrants like β-cyclodextrin, kollidon CL, Ac-Di-Sol, and sodium starch glycolate were tried in order to further improve disintegration time. The pellets were characterized for drug content, particle size distribution, flow properties, infrared spectroscopy, surface morphology, disintegration rate, and dissolution profile. The formulations, which showed best disintegration and dissolution profiles, were coated with Eudragit L100-55, an enteric-coated polymer which does not dissolve at gastric pH but dissolves at intestinal pH, releasing the drug immediately in the dissolution medium. The optimized enteric-coated formulation containing 20% κ-carrageenan, lactose, and sodium starch glycolate as a disintegrant did inhibit the release of the drug for 2 h in 0.1 N HCl, whereas 87% of the drug was released within 45 min. The improvement was substantial when it was compared with solubility of pure drug under the same conditions. Thus, dissolution profiles suggested that combination of κ-carrageenan and sodium starch glycolate resulted into fast-disintegrating, immediate-release pellets, overcoming the bioavailability problem of the poorly soluble drug, aceclofenac, and enteric coating of these pellets avoids the exposure of aceclofenac to ulcer-prone areas of the gastrointestinal tract.     

Eudragit-coated pectin microspheres of 5-fluorouracil for colon targeting

An objective of the present investigation was to prepare and evaluate Eudragit-coated pectin microspheres for colon targeting of 5-fluorouracil (FU). Pectin microspheres were prepared by emulsion dehydration method using different ratios of FU and pectin (1:3 to 1:6), stirring speeds (500–2000 rpm) and emulsifier concentrations (0.75%–1.5% wt/vol). The yield of preparation and the encapsulation efficiencies were high for all pectin microspheres. Microspheres prepared by using drug:polymer ratio 1:4, stirring speed 1000 rpm, and 1.25% wt/vol concentration of emulsifying agent were selected as an optimized formulation. Eudragit-coating of pectin microspheres was performed by oil-in-oil solvent evaporation method using coat: core ratio (5:1). Pectin microspheres and Eudragit-coated pectin microspheres were evaluated for surface morphology, particle size and size distribution, swellability, percentage drug entrapment, and in vitro drug release in simulated gastrointestinal fluids (SGF). The in vitro drug release study of optimized formulation was also performed in simulated colonic fluid in the presence of 2% rat cecal content. Organ distribution study in albino rats was performed to establish the targeting potential of optimized formulation in the colon. The release profile of FU from Eudragit-coated pectin microspheres was pH dependent. In acidic medium, the release rate was much slower; however, the drug was released quickly at pH 7.4. It is concluded from the present investigation that Eudragit-coated pectin microspheres are promising controlled release carriers for colon-targeted delivery of FU. Published: February 16, 2007     

Mucoadhesive vaginal tablets as veterinary delivery system for the controlled release of an antimicrobial drug,acriflavine

The aim of the study was the development of mucoadhesive vaginal tablets designed for the local controlled release of acriflavine, an antimicrobial drug used as a model. The tablets were prepared using drug-loaded chitosan microspheres and additional excipients (methylcellulose, sodium alginate, sodium carboxymethylcellulose, or Carbopol 974). The microspheres were prepared by a spray-drying method, using the drug to polymer weight ratios 1:1 and 1:2 and were characterized in terms of morphology, encapsulation efficiency, and in vitro release behavior, as MIC (Minimum Inhibitory Concentration), MBC (Minimum Bacterial Concentration), and killing time (KT). The tablets were prepared by direct compression, characterized by in vitro drug release and in vitro mucoadhesive tests. The microparticles have sizes of 4 to 12 microm; the mean encapsulation yields are about 90%. Acriflavine, encapsulated into the polymer, maintains its antibacterial activity; killing time of the encapsulated drug is similar to that of the free drug. In vitro release profiles of tablets show differences depending on the excipient used. In particular Carbopol 974, which is highly cross-linked, is able to determine a drug-controlled release from the matrix tablets for more than 8 hours. The in vitro adhesion tests, carried out on the same formulation, show a good adhesive behavior. The formulation containing microspheres with drug to polymer weight ratios of 1:1 and Carbopol 974 is characterized by the best release behavior and shows good mucoadhesive properties. These preliminary data indicate that this formulation can be proposed as a mucoadhesive vaginal delivery system for the controlled release of acriflavine.     

Improved Bioavailability of Poorly Water-Soluble Drug Curcumin in Cellulose Acetate Solid Dispersion

Curcumin (Cur), one of the most widely used natural active constituents with a great variety of beneficial biological and pharmacological activities, is a practically water-insoluble substance with a short biologic half-life. The aim of this study was to develop a sustained-release solid dispersion by employing water-insoluble carrier cellulose acetate for solubility enhancement, release control, and oral bioavailability improvement of Cur. Solid dispersions were characterized by solubility, in vitro drug release, Fourier transform infrared spectroscopy, X-ray diffractometry, and differential scanning calorimetry studies. The in vivo performance was assessed by a pharmacokinetic study. Solid-state characterization techniques revealed the amorphous nature of Cur in solid dispersions. Solubility/dissolution of Cur was enhanced in the formulations in comparison with pure drug. Sustained-release profiles of Cur from the solid dispersions were ideally controlled in vitro up to 12 h. The optimized formulation provided an improved pharmacokinetic parameter (C _max = 187.03 ng/ml, t _max = 1.95 h) in rats as compared with pure drug (C _max = 87.06 ng/ml, t _max = 0.66 h). The information from this study suggests that the developed solid dispersions successfully enhanced the solubility and sustained release of poorly water-soluble drug Cur, thus improving its oral bioavailability effectively.     

Enhanced Oral Bioavailability of Griseofulvin via Niosomes

The aim of the present report was to develop nonionic surfactant vesicles (niosomes) to improve poor and variable oral bioavailability of griseofulvin. Niosomes were prepared by using different nonionic surfactants span 20, span 40, and span 60. The lipid mixture consisted of surfactant, cholesterol, and dicetyl phosphate in the molar ratio of 125:25:1.5, 100:50:1.5, and 75:75:1.5, respectively. The niosomal formulations were prepared by thin film method and ether injection method. The influence of different formulation variables such as surfactant type, surfactant concentration, and cholesterol concentration was optimized for size distribution and entrapment efficiency for both methods. Result indicated that the niosomes prepared by thin film method with span 60 provided higher entrapment efficiency. The niosomal formulation exhibited significantly retarded in vitro release as compared with free drug. The in vivo study revealed that the niosomal dispersion significantly improved the oral bioavailability of griseofulvin in albino rats after a single oral dose. The maximum concentration (C _max) achieved in case of niosomal formulation was approximately double (2.98 μg/ml) as compared to free drug (1.54 μg/ml). Plasma drug profile also suggested that the developed niosomal system also has the potential of maintaining therapeutic level of griseofulvin for a longer period of time as compared to free griseofulvin. The niosomal formulation showed significant increase in area under the curve_0-24 (AUC; 41.56 μg/ml h) as compared to free griseofulvin (22.36 μg/ml h) reflecting sustained release characteristics. In conclusion, the niosomal formulation could be one of the promising delivery system for griseofulvin with improved oral bioavailability and prolonged drug release profiles.     

Controlled Release of Oral Tetrahydrocurcumin from a Novel Self-Emulsifying Floating Drug Delivery System (SEFDDS)

The objectives of this study were to develop and evaluate a novel self-emulsifying floating drug delivery system (SEFDDS) that resulted in improved solubility, dissolution, and controlled release of the poorly water-soluble tetrahydrocurcumin (THC). The formulations of liquid self-emulsifying drug delivery system (SEDDS; mixtures of Labrasol, Cremophor EL, Capryol 90, Labrafac PG) were optimized by solubility assay and pseudo-ternary phase diagram analysis. The liquid SEDDS was mixed with adsorbent (silicon dioxide), glyceryl behenate, pregelatinized starch, sodium starch glycolate, and microcrystalline cellulose and transformed into pellets by the extrusion/spheronization technique. The resulting pellets with 22% liquid SEDDS had a uniform size and good self-emulsification property. The microemulsions in aqueous media of different self-emulsifying floating pellet formulations were in a particle size range of 25.9–32.5 nm. Use of different weight proportions of glyceryl behenate and sodium starch glycolate in pellet formulations had different effects on the floating abilities and in vitro drug release. The optimum formulation (F2) had a floating efficiency of 93% at 6 h and provided a controlled release of THC over an 8-h period. The release rate and extent of release of THC liquid SEDDS (80% within 2 h) and self-emulsifying floating pellet formulation (80% within 8 h) were significantly higher than that of unformulated THC (only 30% within 8 h). The pellet formulation was stable under intermediate and accelerated storage conditions for up to 6 months. Controlled release from this novel SEFDDS can be a useful alternative for the strategic development of oral solid lipid-based formulations.     

Investigation on Processing Variables for the Preparation of Fluconazole-Loaded Ethyl Cellulose Microspheres by Modified Multiple Emulsion Technique

Fluconazole-loaded ethyl cellulose microspheres were prepared by alginate facilitated (water-in-oil)-in-water emulsion technology and the effects of various processing variables on the properties of microspheres were investigated. Scanning electron microscopy revealed spherical nature and smooth surface morphology of the microspheres except those prepared at higher concentration of emulsifiers and higher stirring speeds. The size of microspheres varied between 228 and 592 μm, and as high as 80% drug entrapment efficiency was obtained depending upon the processing variables. When compared up to 2 h, the drug release in pH 1.2 HCl solution was slower than in pH 7.4 phosphate buffer saline solution. However, this trend was reversed at high shear conditions. The microspheres provided extended drug release in alkaline dissolution medium and the drug release was found to be controlled by Fickian-diffusion mechanism. However, the mechanism shifted to anomalous diffusion at high shear rates and emulsifier concentrations. The aging of microspheres did not influence the drug release kinetics. However, the physical interaction between drug and excipients affected the drug dissolution behaviors. X-ray diffractometry (X-RD) and differential scanning calorimetry (DSC) analysis revealed amorphous nature of drug in the microspheres. Fourier transform infrared (FTIR) spectroscopy indicated stable character of fluconazole in the microspheres. The stability testing data also supported the stable nature of fluconazole in the microspheres. The fluconazole extracted from 80% drug-loaded formulation showed good in vitro antifungal activity against Candida albicans. Thus, proper control of the processing variables involved in this modified multiple emulsion technology could allow effective incorporation of slightly water soluble drugs into ethyl cellulose microspheres without affecting drug stability.     

Development and Evaluation of Buccoadhesive Controlled Release Tablets of Lercanidipine

The purpose of this research was to develop and evaluate buccal mucoadhesive controlled release tablets of lercanidipine hydrochloride using polyethylene oxide and different viscosity grades of hydroxypropyl methylcellulose individually and in combination. Effect of polymer type, proportion and combination was studied on the drug release rate, release mechanism and mucoadhesive strength of the prepared formulations. Buccal mucoadhesive tablets were made by direct compression and were characterized for content uniformity, weight variation, friability, surface pH, thickness and mechanism of release. In order to estimate the relative enhancement in bioavailability one optimized formulation was evaluated in rabbits. Further, placebo tablets were also evaluated for acceptability in human subjects. Results indicated acceptable physical characteristics of designed tablets with good content uniformity and minimum weight variation. Drug release and mucoadhesive strength were found to depend upon polymer type, proportion and viscosity. The formulations prepared using poly ethylene oxide gave maximum mucoadhesion. The release mechanism of most formulations was found to be of anomalous non-Fickian type. In vivo studies of selected formulation in rabbits demonstrated significant enhancement in bioavailability of lercanidipine hydrochloride relative to orally administered drug. Moreover, in human acceptability studies of placebo formulations, the designed tablets adhered well to the buccal mucosa for more than 4 h without causing any discomfort. It may be concluded that the designed buccoadhesive controlled release tablets have the potential to overcome the disadvantage of poor and erratic oral bioavailability associated with the presently marketed formulations of lercanidipine hydrochloride.     

Glyceryl Monooleate/Poloxamer 407 Cubic Nanoparticles as Oral Drug Delivery Systems: I. In Vitro Evaluation and Enhanced Oral Bioavailability of the Poorly Water-Soluble Drug Simvastatin

Glyceryl monooleate (GMO)/poloxamer 407 cubic nanoparticles were investigated as potential oral drug delivery systems to enhance the bioavailability of the water-insoluble model drug simvastatin. The simvastatin-loaded cubic nanoparticles were prepared through fragmentation of the GMO/poloxamer 407 bulk cubic-phase gel using high-pressure homogenization. The internal structure of the cubic nanoparticles was identified by cryo-transmission electron microscopy. The mean diameter of the cubic nanoparticles varied within the range of 100–150 nm, and both GMO/poloxamer 407 ratio and theoretical drug loading had no significant effect on particle size and distribution. Almost complete entrapment with efficiency over 98% was achieved due to the high affinity of simvastatin to the hydrophobic regions of the cubic phase. Release of simvastatin from the cubic nanoparticles was limited both in 0.1 M hydrochloride solution containing 0.2% sodium lauryl sulfate and fasted-state simulated intestinal fluid with a total release of <3.0% at 10 h. Pharmacokinetic profiles in beagle dogs showed sustained plasma levels of simvastatin for cubic nanoparticles over 12 h. The relative oral bioavailability of simvastatin cubic nanoparticles calculated on the basis of area under the curve was 241% compared to simvastatin crystal powder. The enhancement of simvastatin bioavailability was possibly attributable to facilitated absorption by lipids in the formulation rather than improved release.     

Intracellular Delivery of Nanoparticles of an Antiasthmatic Drug

The aim of the investigation was to prepare and characterize wheat germ agglutinin(WGA)-conjugated poly(d,l-lactic-co-glycolic) acid nanoparticles encapsulating mometasone furoate (MF) as a model drug and assess changes in its fate in terms of cellular interactions. MF loaded nanoparticles were prepared using emulsion–solvent evaporation technique. WGA-conjugation was done by carbodiimide coupling method. The nanoparticles were characterized for size, zeta potential, entrapment efficiency and in-vitro drug release. The intracellular uptake of nanoparticles, drug cellular levels, and anti-proliferative activity studies of wheat germ agglutinin-conjugated and unconjugated nanoparticles were assessed on alveolar epithelial (A549) cells to establish cellular interactions. Prepared nanoparticles were spherical with 10–15 μg/mg of WGA conjugated on nanoparticles. The size of nanoparticles increased after conjugation and drug entrapment and zeta potential reduced from 78 ± 5.5% to 60 ± 2.5% and −15.3 ± 1.9 to −2.59 ± 2.1 mV respectively after conjugation. From the cellular drug concentration–time plot, AUC was found to be 0.4745, 0.6791 and 1.24 for MF, MF-nanoparticles and wheat germ agglutinin-MF-nanoparticles respectively. The in-vitro antiproliferative activity was improved and prolonged significantly after wheat germ agglutinin-conjugation. The results conclusively demonstrate improved availability and efficacy of antiasthmatic drug in alveolar epithelial cell lines. Hence, a drug once formulated as mucoadhesive nanoparticles and incorporated in dry powder inhaler formulation may be used for targeting any segment of lungs for more improved therapeutic response in other lung disorders as well.