J. R. Nixon

Biodegradable poly(lactic acid) and poly(lactide-co-glycolide) microcapsules: problems associated with preparative techniques and release properties

Poly(lactic acid) [PLA] and its co-polymers with glycolic acid [PLCG] have been known to be biodegradable and histocompatible for the past 20 years. Their physico-chemical and biological properties have been found suitable, in many instances, for sustaining drug release in vivo for days or months. Several dosage forms for parenteral administration have been investigated using these polymers and a microencapsulation technique is chosen frequently for its unique properties. There are a limited number of published papers concerning preparation and characterization of PLA or PLCG microcapsules, possibly because of commercial unavailability and difficulties in the synthesis of reproducible batches of these polymers. However, microcapsules can be made using different traditional and non-traditional techniques containing core materials ranging from biological proteins to synthetic drugs. An attempt is made here to review problems associated with the different microencapsulation techniques using PLA or PLCG. In vivo and in vitro drug release from these microcapsules is also reviewed.

Microencapsulation using Poly(L-Lactic Acid) I: Microcapsule Properties Affected by the Preparative Technique

Microcapsules were prepared using a poly (L-lactic acid) (L = PLA), mol. wt. 43,200, by an emulsification and solvent evaporation technique. Phenobarbitone (PB) was used as a reference drug, (core to polymer ratio, 1:1). Both the o/w and w/o emulsion system were investigated in order to study microcapsule properties affected by the preparative technique. In the o/w system, dichloromethane (DCM) was used to dissolve L = PLA and PB and the resulting solution was dispersed in 1 per cent aqueous gelatin solution. Subsequent evaporation of the DCM resulted in the formation of microcapsules. PB was found to be poorly encapsulated within microcapsules from this o/w system. PB content in the microcapsules was found to improve using PB saturated aqueous gelatin solution as the continuum. In the w/o system, acetonitrile (AN) was used as a solvent for L-PLA and PB and light liquid paraffin (LLP), containing 2 per cent w/w Span 40, as the continuous phase. PB loading in the microcapsules was found to be very high from this w/o system. Microcapsules from the o/w system were very small compared to microcapsules obtained from the w/o system. The morphology of the microcapsules and the surface properties were found to be affected distinctly by the two techniques. Microcapsules from the o/w system showed a smooth and less porous surface, whereas a highly porous surface containing embedded PB crystals was found in the microcapsules from the w/o system.

Microencapsulation using poly(l-lactic Acid) iv: Release properties of microcapsules containing phenobarbitone

Microcapsules containing phenobarbitone were prepared from poly(L-lactic acid), using a water/oil emulsification and evaporation process. Polymers of three different molecular weights were used. Particle size was found to increase with an increase in core loading and polymer molecular weight. Release studies were carried out at buffer pHs of 2 and 9 at 37 degrees C. The release mechanism was found to follow a square root of time relationship. Almost 90 per cent of the phenobarbitone was released within 2 h. The release rate was not a direct relationship with the phenobarbitone content of the microcapsules because of the differing size and surface area of the microcapsules. However, normalized release rates (release rate/specific surface area) were found to increase linearly with the increase in phenobarbitone content. First order release plots of the data were not found consistent with the core loading. The release at a buffer pH of 9 was very rapid and with some microcapsules was faster than solution of the uncoated crystalline phenobarbitone. At pH 2 release was also very rapid, due to the presence of large pores in the microcapsules of high molecular weight polymers. Release from the microcapsules prepared from low molecular weight polymer was slower than those from high molecular weight polymers. Microcapsules from the low molecular weight polymer were found to swell in the dissolution medium and finally disintegrated into smaller fragments.

Microencapsulation using poly(DL-lactic acid) III: Effect of polymer molecular weight on the release kinetics

Poly(DL-lactic acid) [DL-PLA] microcapsules containing phenobarbitone (PB) were prepared using a w/o emulsion-evaporation method. DL-PLA of three different molecular weights, 20,200, 13,300 and 5,200 were used to prepare microcapsules of nominal core: polymer (C:P) ratios of 1 : 2, 1 : 2.5, 1 : 3 and 1 : 4. The release of PB was investigated in aqueous buffer of pH 2, pH 7 and pH 9 at 37 degrees C and found to follow a square root of time dependent release mechanism. The first order and zero order release mechanisms were disproved by the lower correlation coefficient of the release data as compared to that of the t1/2 mechanism. These microcapsules showed an initial burst phase release followed by a lag phase, during which time little PB was released. This lag time was affected by the polymer molecular weight and pH of the buffer. The polymer matrix was hydrated during the lag phase and a steady state release occurred. The steady state release rate per unit specific surface area (Kh2/SSA) was found to increase exponentially with the increase in core loading of the microcapsules. However the extent of normalized release rate reduced linearly with the increase in polymer molecular weight at any particular core loading (e.g. 20 per cent or 30 per cent). Increases in the normalized steady state release rate with an increase in buffer pH could be correlated to PB solubility in the dissolution medium. PB release from these microcapsules was diffusion controlled. However, swelling and erosion also contributed to the release process.

Microencapsulation using poly(DL-lactic acid) IV : effect of storage on the microcapsule characteristics

Poly (DL-lactic acid) [DL-PLA] microcapsules containing phenobarbitone were prepared using a W/O emulsion method. Microcapsules of nominal C : P ratio, 1 : 2 and 1 : 3 using three different molecular weight polymers, 20,500, 13,300 and 5,200 were investigated to study the effect of storage conditions on the microcapsule properties. All microcapsules were stored under desiccated condition at temperatures of 4 degrees, 20 degrees and 37 degrees C for six months. Storage temperatures of 4 degrees and 20 degrees C did not cause appreciable changes in the release rate after storage. Microcapsules stored at 37 degrees C showed an annealing effect, causing shrinkage of microcapsules, and lowering of the release rate after storage for six months. The microcapsules prepared from low molecular weight DL-PLA fused completely whilst stored at 37 degrees C and the other two high molecular DL-PLA also showed some aggregation. There were insignificant variations in the mean microcapsule diameter during storage. The phenobarbitone content of the microcapsules was also unchanged.

Specific surface area measurement of ethyl cellulose-walled microcapsules containing theophylline

The choice of microencapsulation system was limited by drug solubility and the possibility of its thermal decomposition at elevated temperatures. On the basis of the solubility study the toluene-petroleum ether system was found to be suitable. An accurate determination of specific surface area was obtained by gas adsorption. By use of the BET equation, the monolayer capacity of the microcapsules could be calculated. The results showed variations due to microcapsule size, petroleum ether fraction used in the preparation and the core to wall ratio. Dissolution from the microcapsules appeared to depend on a number of factors including the wall thickness, the amount of core material enclosed and the surface area available for diffusion.

Preparation of microencapsulated liposomes, II. Systems containing nylon-gelatin and nylon-gelatin-acacia walling material

Liposome suspension was encapsulated and isolated in nylon-gelatin and nylon-gelatin-acacia walled microcapsules. The resulting liposomal microcapsules could be stored in the dry state as a free-flowing powder. Liposomes remained intact after the microencapsulation, and encapsulation efficiency was greater than 90 per cent. The release of drug from microcapsules was retarded in the presence of drug-loaded liposomes.

The effect of surfactants on the microencapsulation and release of phenobarbitone from gelatin-acacia complex coacervate microcapsules

The effects of sodium lauryl sulphate (SLS), cetrimide and polysorbate 20 surfactants at concentrations below, at and above their critical micelle concentration (CMC) on the microencapsulation and release of phenobarbitone have been described. Bimodal particle size distributions were produced both in the absence and presence of each of the three surfactants. The presence of surfactant had little or no effect on the particle size distribution at any given stirring speed. A large variation was noted in the amount of phenobarbitone microencapsulated dependent upon the type of surfactant and its concentration. The amount of phenobarbitone encapsulated decreased with increasing concentration of polysorbate 20 and with SLS. Cetrimide (0.025 per cent w/v) enhanced encapsulation with 2 per cent w/w colloids but higher concentrations at the CMC and above decreased encapsulation. The results are explained in terms of decreased interfacial tension by the surfactant and by steric and electrostatic effects caused by surfactant adsorption onto the coacervate droplets and phenobarbitone particles.