In vitro-in vivo evaluation of a controlled release buccal bioadhesive device for oral drug delivery.

PURPOSE: 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 Higuchi's 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, t(max) 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.

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 Instron 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.

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.

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.

Nylon microcapsules. II. Effect of selected variables on theophylline release.

The effect of selected variables on the release characteristics of theophylline microcapsules prepared with 1,6-hexamethylene diamine and sebacoyl chloride via interfacial polycondensation has been investigated. The nature of the microcapsules and the release characteristics of theophylline from the microcapsules were affected by the type of organic phase, particle size, stirring speed, and rate of addition of sebacoyl chloride during the preparation of microcapsules. The aggregation of the final product was generally less at the lower speeds of stirring. Decreasing the rate of addition of sebacoyl chloride increased the aggregation of the final product as well as the release of theophylline. Decreasing the particle size of the microcapsules increased the release of theophylline from the microcapsules.

Clofibrate microcapsules II: Effect of wall thickness on release characteristics.

The effect of wall thickness on the release characteristics of clofibrate from microcapsules prepared in gelatin-sodium sulfate was investigated. The wall thickness, calculated by recovering the wall material from the microcapsules and using the relationship between two concentric spheres, was related to the surface area of the droplets being encapsulated. Thinner walled microcapsules gave faster release and showed greater deviation from zero-order kinetics but followed the square root of time plots. Microcapsules having thicker walls approximated zero-order release but deviated from the square root of time plots. A theoretical model was developed to explain the release characteristics of the microcapsules. A linear correlation was found between the thickness and the in vitro t50% release time.

New method of preparing gelatin microcapsules of soluble pharmaceuticals.

A new method of preparing gelatin microcapsules of soluble pharmaceuticals is described. Spherical droplets of a gelatin dispersion prepared in the drug solution were produced by the capillary method, and the droplets were congealed rapidly to yield discrete units in the form of a free-flowing powder. The microcapsules obtained were spherical in shape and showed no tendency to form agglomerates. Hardening of the microcapsules resulted in a significant reduction of the release rate without altering the reproducibility. The results indicated that the process of microencapsulation described is simple, reproducible, economical, and amenable to industrial application.

Effect of intensity of agitation on disintegration time of tablets.

The effect of the intensity of agitation on the disintegration time of tablets was studied. Preliminary results obtained using tablets fabricated under controlled conditions and selected commercial tablets revealed that the intensity of agitation produced in the test apparatus was not reproducible with fixed geometry for successive runs when the settings were maintained constant. The disintegration times increased at a lower intensity of agitation. The intertablet range values obtained were rather large at the start and increased with a corresponding decrease in the intensity of agitation. The results showed that the measurement of disintegration times with the existing apparatus may not serve as a guide to the pharmaceutical formulator in the preparation of optimal dosage forms of drugs for clinical trial and may not ensure lot-to-lot uniformity of the pharmaceutical product.

Clofibrate microcapsules: preparation and release rat studies.

Microencapsulation of clofibrate and dissolution characteristics of clofibrate microcapsules were investigated. Spherical droplets of clofibrate, prepared by a capillary jet method, were encapsulated in gelatin by simpel coacervation, using sodium sulfate as the coacervating agent. The microcapsules, which were hardened up to 8 hr with formaldehyde, were recovered as discrete, free-flowing particles. Dissolution of clofibrate from the microcapsules was not adequately described by either square root of time or Langenbucher kinetics but followed predominantly zero-order release patterns at all hardening times. A linear correlation was found between the hardening times and the t50% release time.