Parshotam Madan

Evaluation of polyoxyethylene homopolymers for buccal bioadhesive drug delivery device formulations

Our objective was to evaluate the application of polyoxyethylene homopolymers in buccal bioadhesive drug (BBD) delivery device formulations. The bioadhesive strength of four different molecular weight (MW) polyoxyethylene polymers was measured by Instronâ tensile tester using glass plate and bovine sublingual tissue as substrate surfaces. Several BBD device formulations containing polyoxyethylene polymer (MW 7,000,000) were prepared by direct compression and compression molding processes. The prepared BBD devices were evaluated for their elasticity, in vitro adhesion and drug release characteristics. The in vivo bioadhesion characteristics of a placebo compression molded device were examined in 3 adult healthy male beagle dogs. The bioadhesive strength of polyoxyethylene polymers appeared to be directly related to their molecular weights. When bovine sublingual mucosa or a glass plate was used as model mucosal substrate surface, the rank order of bioadhesive strength of different molecular weight polyoxyethylene polymers was similar. The bioadhesive strength of devices prepared by the compression molding process was greater than those prepared by direct compression, but the kinetics of drug release were independent of the process used for the preparation of the devices. The drug release and the bioadhesive strength of the similarly prepared device formulations appeared to be dependent on the drug:polymer ratios. The elasticity of the BBD devices prepared by compression molding was improved by the inclusion of polyisobutylene polymer in the formulations. When adhered to the oral cavity of the dogs, the compression molded placebo BBD device exhibited adhesion for at least 4 hours and appeared to show no signs of local irritation. In conclusion, BBD devices containing polyoxyethylene polymer (MW 7,000,000) can be prepared by direct compression or compression molding process in order to provide controlled drug release to the oral cavity while maintaining appropriate bioadhesive characteristics.

Microencapsulation I. Phase Separation or Coacervation

AbstractPhase separation or coacervation is one of the oldest and perhaps the most widely used method of microencapsulation. This paper discusses phase separation or coacervation as a technique of preparing microcapsules. The basic differences between simple and complex coacervation are described and the various factors which influence simple and complex coacervation are discussed. Schematic ternary phase diagrams involved in the phase separation or coacervation processes are included and the basic schemes describing the process of microencapsulation are outlined.

Preparation, in vitro evaluation and statistical optimization of carvedilol-loaded solid lipid nanoparticles for lymphatic absorption via oral administration

Abstract Carvedilol-loaded solid lipid nanoparticles (SLNs) were prepared using solubility parameter (δ) to select the lipid, and hot homogenization to fabricate SLNs. The effect of concentration of Compritol 888 ATO (COMP) and Poloxamer 188 (P-188) on the particle size of blank SLNs was studied using the design of experiments. Further narrow concentration range of COMP and P-188 was selected and carvedilol-loaded SLNs were prepared to obtain an optimized formulation which was lyophilized (L-SLNs), transformed into enteric compression-coated tablet and evaluated for drug release, X-ray diffraction and cellular uptake mechanism. COMP was chosen as lipid due to its least value of Δδ with carvedilol. The optimized formulation (7.5% COMP, 5.0% P-188 and 1.11% carvedilol) had 161 nm particle size and 94.8% entrapment efficiency. The enteric-coated carvedilol-loaded SLNs tablet protected carvedilol from acidic environment and similar prolonged release profiles were obtained from L-SLNs, core tablet and enteric-coated tablet. Absence of crystalline carvedilol XRD peak indicated the presence of amorphous carvedilol in SLNs. Higher carvedilol uptake from SLNs compared to drug solution in the Caco-2 cell line exhibited a potential prolonged drug release. Moreover, upon cellular uptake, SLNs could then enter the lymphatic system which will avoid first pass metabolism and hence higher oral bioavailability.

In Vitro-In Vivo Evaluation of a Controlled Release Buccal Bioadhesive Device for Oral Drug Delivery

AbstractPurpose. To investigate the use of buccal bioadhesive device in targeting controlled drug delivery to the gastrointestinal tract. Methods. A three-leg crossover study was designed to evaluate the application of buccal bioadhesive device for providing controlled drug delivery to the gastrointestinal tract of a model drug cyanocobalamin in four healthy adult male beagle dogs. Results. In vitro dissolution studies using deionized water as the medium indicated that 100% of the drug was released within 15 min from a immediate release oral capsule formulation, whereas 90% of the drug was released within a period of 18 hrs from a buccal bioadhesive device formulation. Drug release from the buccal bioadhesive devices appeared to follow Higuchis square root of time dependent model. The terminal half-life of the drug following I.V. administration in four dogs was found to be 16.4 ± 2.4 hrs. Following immediate release oral capsule administration of the drug Cmax, tmax and bioavailability were 2333 ± 1469 ng/L, 2.5± 1.0 hrs and 14.1 ± 7.9%, respectively. Following buccal bioadhesive device administration of the drug Cmax, tmax and bioavailability were 4154 ± 1096 ng/L, 11 ± 1.2 hrs and 35.8 ± 4.1%, respectively. Significantly higher bioavailability of the drug was observed with the buccal bioadhesive device administration when compared to the immediate release oral capsule. Conclusions. The buccal bioadhesive device appears to improve the oral bioavailability of cyanocobalamin by providing controlled delivery of the drug to the gastrointestinal tract.

Formulation and Evaluation of Albuterol Metered Dose Inhalers Containing Tetrafluoroethane (P134a), a Non-CFC Propellant

This study was undertaken to evaluate tetrafluoroethane (P134a) as a possible chlorofluorocarbon (CFC) replacement for albuterol metered dose inhaler (MDI) formulations. Preformulation studies using three conventional (oleic acid, sorbitan trioleate, lecithin) and a nonconventional (oleyl alcohol) surfactant indicated that P134a is a poor solvent for these surfactants. A slight improvement in the solubility of oleic acid and oleyl alcohol was observed by the addition of low concentrations of a nonconventional cosolvent diethyl ether (< or = 0.5% w/w). Formulation screening of the prepared albuterol formulations indicated that suspensions containing oleyl alcohol and diethyl ether had a slower rate of separation. Product performance of four albuterol formulations containing oleyl alcohol, diethyl ether, and P134a was evaluated and compared to a leading commercial formulation containing CFC propellants (Ventolin). Ventolin showed excellent agreement between the emitted dose and the expected dose but only a reasonable agreement was observed with one of the better P134a-containing formulations. P134a formulations showed higher internal pressure in comparison to the CFC formulation. The concentrations of the surfactant, drug, and cosolvent appeared to have a significant impact on the uniformity of the emitted dose. Determination of particle size using the time-of-flight and the laser diffraction analyzer revealed that P134a formulations had equal or smaller particle size than the formulation containing CFC. However, the CFC formulation showed a higher respirable fraction than the P134a formulation when measured by the two inertial impaction methods. The observed particle size distribution of the formulation appeared to depend on the measuring method used.

Transdermal delivery of diclofenac using water-in-oil microemulsion: formulation and mechanistic approach of drug skin permeation

Abstract The objective of the present investigation was to enhance skin permeation of diclofenac using water-in-oil microemulsion and to elucidate its skin permeation mechanism. The w/o microemulsion formulations were selected based on constructed pseudoternary phase diagrams depending on water solubilization capacity and thermodynamic stability. These formulations were also subjected to physical characterization based on droplet size, viscosity, pH and conductivity. Permeation of diclofenac across rat skin using side-by-side permeation cells from selected w/o microemulsion formulations were evaluated and compared with control formulations. The selected w/o microemulsion formulations were thermodynamically stable, and incorporation of diclofenac sodium into microemulsion did not affect the phase behavior of system. All microemulsion formulations had very low viscosity (11–17 cps) and droplet size range of 30–160 nm. Microemulsion formulations exhibited statistically significant increase in diclofenac permeation compared to oily solution, aqueous solution and oil–Smix solution. Higher skin permeation of diclofenac was observed with low Smix concentration and smaller droplet size. Increase in diclofenac loading in aqueous phase decreased the partition of diclofenac. Diclofenac from the oil phase of microemulsion could directly partition into skin, while diclofenac from the aqueous droplets was carried through skin by carrier effect.

Quality by design approach for formulation, evaluation and statistical optimization of diclofenac-loaded ethosomes via transdermal route

Abstract The objective of this study was to fabricate and understand ethosomal formulations of diclofenac (DF) for enhanced anti-inflammatory activity using quality by design approach. DF-loaded ethosomal formulations were prepared using 4 × 5 full-factorial design with phosphatidylcholine:cholesterol (PC:CH) ratios ranging between 50:50 and 90:10, and ethanol concentration ranging between 0% and 30% as formulation variables. These formulations were characterized in terms of physicochemical properties and skin permeation kinetics. The interaction of formulation variables had a significant effect on both physicochemical properties and permeation kinetics. The results of multivariate regression analysis illustrated that vesicle size and elasticity of ethosomes were the dominating physicochemical properties affecting skin permeation, and could be suitably controlled by manipulation of formulation variables to optimize the formulation and enhance the skin permeation of DF-loaded ethosomes. The optimized formulation had ethanol concentration of 22.9% and PC:CH ratio of 88.4:11.6, with vesicle size of 144 ± 5 nm, zeta potential of −23.0 ± 3.76 mV, elasticity of 2.48 ± 0.75 and entrapment efficiency of 71 ± 4%. Permeation flux for the optimized formulation was 12.9 ± 1.0 µg/h cm2, which was significantly higher than the drug-loaded conventional liposome, ethanolic or aqueous solution. The in vivo study indicated that optimized ethosomal hydrogel exhibited enhanced anti-inflammatory activity compared with liposomal and plain drug hydrogel formulations.

Statistical optimization of insulin-loaded Pluronic F-127 gels for buccal delivery of basal insulin.

The principle of statistical optimization was employed to fabricate insulin-loaded Pluronic F-127 (PF-127) gel formulations having the potential for buccal delivery of basal insulin. A two-level resolution III fractional factorial design was applied to simultaneously evaluate five independent formulation variables: PF-127 concentration, insulin concentration, sodium sulfate concentration, hydroxypropylmethyl cellulose (HPMC) concentration, and presence of sodium glycocholate. The amount of insulin released and permeated from gels as well as gelation time and mucoadhesion force of gels were measured and used as dependent response variables for formulation optimization. Optimization of a gel formulation was achieved by applying constrained optimization via regression analysis. In vitro permeation flux of insulin from the optimized formulation through procine buccal mucosa was 93.17 (±0.058, n = 3) μg/cm2. Plasma insulin levels following buccal administration of the optimized formulation at 10, 25 and 50 IU/kg to healthy rats were found to be dose dependent and basal insulin levels were maintained at least for 8 h. Furthermore, continuous hypoglycemia for at least 8 h was observed with 89%, 51% and 25% of blood glucose reduction, respectively, for these three doses. The results of this investigation conclude the feasibility of development of optimized buccal insulin-loaded Pluronic F-127 gels for basal insulin delivery.

Compatibility Evaluation of Metered-Dose Inhaler Valve Elastomers with Tetrafluoroethane (P134a), a Non-CFC Propellant

Compatibility of propellants, excipients, and solvents with the components of the valve greatly influences performance of metered-dose inhalers (MDIs). Ozone-friendly hydrofluoroalkane propellant 134a has potential for use as a chlorofluorocarbon (CFC) replacement. No suitable replacement for propellant 11 and 114 has yet been found and the problems arising from this may be overcome by use of ethanol as a solvent. In this study, compatibility of MDI valve elastomers Dowty Nitrile 0117, White Buna, and Type 674 (B) with P134a placebo formulations having different concentrations of ethanol was investigated. The results indicate that formulations containing no ethanol adversely affected the functioning of the valves. Higher concentrations of ethanol improved valve performance, but showed increased leakage. Physical characteristics of the valve elastomers evaluated by determining swelling caused after exposure to the P134a placebo formulations exhibited increased swelling with increasing concentrations of ethanol in the formulation.

Microencapsulation II. Interfacial Reactions

AbstractIn recent years a number of papers and patents describing the use of interfacial reactions as a means of microencapsulation have been reported in the literature. This paper discusses the technique of microencapsulation by interfacial reactions and the effect of variables which may influence the integrity of the microcapsules. Variations of the basic interfacial polymerization techniques are described with special reference to interfacial polycondensation, the formation of polymer material by induced catalyzation, vapor deposition technique, and in-situ polymerization. Examples of some processes used and/or the types of reacting species are also included.