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(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) I: Effect of preparative variables on the microcapsule characteristics and release kinetics

Abstract

Poly(DL-lactic acid) (DL-PLA, molecular weight 20 500) microcapsules containing phenobarbitone (PB) as a reference core were prepared using a water/oil (W/O) emulsion system. Surface morphology, particle size and ‘encapsulation efficiency’ of the microcapsules prepared using different preparative variables have been investigated. Buffer pH 9 was used as a dissolution medium to determine the affect of preparative variables on the release rate from these microcapsules.

With an increase in temperature of evaporation the microcapsule surface became increasingly irregular and porous, due to deposition of phenobarbitone crystals near the vicinity of the microcapsule surface leading to rapid release of the core. The normalized release rate was found to increase exponentially with an increase in the temperature of evaporation. Microcapsule morphology was also severely affected due to differences in polymer concentration in the disperse phase solvent. With the increase in polymer concentration, the microcapsule surface was found to be increasingly irregular and non-continuous, due to rapid precipitation of the polymer. Increased polymer concentrations also increased mean microcapsule diameter. The release rate increased with the increase in polymer concentration due to surface defects and did not exhibit a straight line correlation. When core loading was very high (e.g. C:P, 2:1 and 1:1), crystals of phenobarbitone appeared at the surface and these caused a very rapid burst effect. However, microcapsules containing a lower phenobarbitone content were found to follow t^1/2 dependent release. The encapsulation efficiency was not seriously affected due to variations in temperature of preparation and polymer concentration. However, with the decrease in initial core loading the encapsulation efficiency of microcapsules was found to be reduced.     

Microencapsulation using poly(DL-lactic acid). I: Effect of preparative variables on the microcapsule characteristics and release kinetics

Poly(DL-lactic acid) (DL-PLA, molecular weight 20,500) microcapsules containing phenobarbitone (PB) as a reference core were prepared using a water/oil (W/O) emulsion system. Surface morphology, particle size and 'encapsulation efficiency' of the microcapsules prepared using different preparative variables have been investigated. Buffer pH 9 was used as a dissolution medium to determine the affect of preparative variables on the release rate from these microcapsules. With an increase in temperature of evaporation the microcapsule surface became increasingly irregular and porous, due to deposition of phenobarbitone crystals near the vicinity of the microcapsule surface leading to rapid release of the core. The normalized release rate was found to increase exponentially with an increase in the temperature of evaporation. Microcapsule morphology was also severely affected due to differences in polymer concentration in the disperse phase solvent. With the increase in polymer concentration, the microcapsule surface was found to be increasingly irregular and non-continuous, due to rapid precipitation of the polymer. Increased polymer concentrations also increased mean microcapsule diameter. The release rate increased with the increase in polymer concentration due to surface defects and did not exhibit a straight line correlation. When core loading was very high (e.g. C:P, 2:1 and 1:1), crystals of phenobarbitone appeared at the surface and these caused a very rapid burst effect. However, microcapsules containing a lower phenobarbitone content were found to follow t1/2 dependent release. The encapsulation efficiency was not seriously affected due to variations in temperature of preparation and polymer concentration. However, with the decrease in initial core loading the encapsulation efficiency of microcapsules was found to be reduced.     

Suspensions of prolonged-release diclofenac-Eudragit and ion-exchange resin microcapsules: II. Improved dissolution stability

PURPOSE: The stability of prolonged release 100 microm -size ion-exchange resin (IER) diclofenac microcapsules (prepared by the Wurster process) and coated with Eudragit RS30D was evaluated using dissolution analysis. METHODS: The IER microcapsules were suspended in 0.1% methylcellulose and stored at 23 and 37 degrees C and the dissolution study conducted over a 6-month period. The surface morphology of the microcapsules was examined using scanning electron microscopy (SEM). RESULTS: The dissolution of the suspensions stored at 23 degrees C on day 1 or 7 and was similar to that of day 30 with slightly faster dissolution on day 60. In contrast, release from suspensions stored at 37 degrees C decreased with storage. The decrease in dissolution with increased temperature was possibly due to the polymer relaxation (micromelting) that was enough to seal the drug within the matrix, resulting in slow dissolution. SEM of the suspended microcapsules correlated with the dissolution data, i.e. the surfaces of microcapsule stored at 37 degrees C showed decreased roughness or smoothening and closing of pores with time and, hence, retardation of drug release, compared with samples stored at 23 degrees C. The dissolution kinetics (shown by the linearity of Bt vs. time profiles) indicated that release mechanism was diffusion. CONCLUSIONS: The suspensions of diclofenac IER microcapsules were stable up to 30 days at ambient temperature, which makes the formulation potentially useful as reconstitutable product.     

Suspensions of prolonged-release diclofenac-Eudragit® and ion-exchange resin microcapsules: II. Improved dissolution stability

Purpose:?The stability of prolonged release 100?µm -size ion-exchange resin (IER) diclofenac microcapsules (prepared by the Wurster process) and coated with Eudragit® RS30D was evaluated using dissolution analysis.

Methods:?The IER microcapsules were suspended in 0.1% methylcellulose and stored at 23 and 37°C and the dissolution study conducted over a 6-month period. The surface morphology of the microcapsules was examined using scanning electron microscopy (SEM).

Results:?The dissolution of the suspensions stored at 23°C on day 1 or 7 and was similar to that of day 30 with slightly faster dissolution on day 60. In contrast, release from suspensions stored at 37°C decreased with storage. The decrease in dissolution with increased temperature was possibly due to the polymer relaxation (micromelting) that was enough to seal the drug within the matrix, resulting in slow dissolution. SEM of the suspended microcapsules correlated with the dissolution data, i.e. the surfaces of microcapsule stored at 37°C showed decreased roughness or smoothening and closing of pores with time and, hence, retardation of drug release, compared with samples stored at 23°C. The dissolution kinetics (shown by the linearity of Bt vs. time profiles) indicated that release mechanism was diffusion.

Conclusions:?The suspensions of diclofenac IER microcapsules were stable up to 30 days at ambient temperature, which makes the formulation potentially useful as reconstitutable product.     

Taste masking of diclofenac sodium using microencapsulation.

This study addresses how to mask the undesirable taste of diclofenac sodium (DS) without interfering with an adequate rate of drug release. DS microcapsules were successfully prepared using a system of ethylcellulose (EC)-toluene-petroleum ether. The system was optimized by the construction of the phase diagram and determination of the amount of EC precipitated under different solvent:non-solvent ratios to determine the most appropriate conditions for preparing good microcapsules. Microcrystalline cellulose (Avicel) and lactose were mixed with DS powder and converted into spherical cores by the wet agglomeration technique which facilitated coacervation and formation of thin and uniform microcapsule walls. Diethylphthalate (DEP) and Polyethyleneglycol 600 (PEG) in different concentrations (20 or 40% w/w) were used as plasticizers to impart better elasticity to the microcapsules. The microcapsules were evaluated for DS released against crushed commercial DS enteric coated tablet (Voltaren). The prepared microcapsules were taste evaluated by a taste panel of 10 volunteers. The results revealed that the optimum solvent:non-solvent ratio required for microcapsule formation was 1:2. Microcapsules containing PEG 20% or DEP 40% showed a faster rate of DS release compared to that obtained from other microcapsules and crushed commercial enteric coated tablets (Voltaren). The palatability and the taste of DS were significantly improved by microencapsulation. The extent of taste masking was influenced by the microcapsule core:wall ratio, the presence of additives within the core, the type and concentration of plasticizer and initial core size.     

Investigation of alternative compounds to poly(E-MA) as a polymeric surfactant for preparation of microcapsules by phase separation method

Various water-soluble polymers were used to examine an alternative emulsifier for poly(ethylene-alt-maleic anhydride), used in the preparation of crosslinked polyurea microcapsules. Microcapsules were successfully prepared by using the water-soluble polymers with large molecular weight alternating copolymers, namely poly(olefin-maleic anhydride), poly(olefin-maleic acid), and poly(acrylic acid). On the other hand, no microcapsule resulted from olefin-maleic acid with small molecular weight alternating copolymers. From these results, the following guidelines were obtained for the selection of polymeric surfactants suitable for crosslinked polyurea microcapsule. A polymeric surfactant must have maleic acid or a carboxyl group in order to form a crosslinked polyurea microcapsule membrane. Furthermore, to form a stronger capsule membrane it is desirable to have a maleic anhydride group. It is also important for membrane formation that the polymeric surfactant has a suitable molecular weight.     

Investigation of alternative compounds to poly(E-MA) as a polymeric surfactant for preparation of microcapsules by phase separation method

Various water-soluble polymers were used to examine an alternative emulsifier for poly(ethylene-alt-maleic anhydride), used in the preparation of crosslinked polyurea microcapsules. Microcapsules were successfully prepared by using the water-soluble polymers with large molecular weight alternating copolymers, namely poly(olefin-maleic anhydride), poly(olefin-maleic acid), and poly(acrylic acid). On the other hand, no microcapsule resulted from olefin-maleic acid with small molecular weight alternating copolymers. From these results, the following guidelines were obtained for the selection of polymeric surfactants suitable for crosslinked polyurea microcapsule. A polymeric surfactant must have maleic acid or a carboxyl group in order to form a crosslinked polyurea microcapsule membrane. Furthermore, to form a stronger capsule membrane it is desirable to have a maleic anhydride group. It is also important for membrane formation that the polymeric surfactant has a suitable molecular weight.     

Effect of storage temperature on the stability of the liquid polyvalent antivenom produced in Costa Rica

The effect of storage temperature on the stability of the liquid polyvalent (crotaline) antivenom produced at the Instituto Clodomiro Picado, Costa Rica, was studied during a twelve-month period. The following parameters were evaluated: neutralizing potency against lethal activity of Bothrops asper venom; protein and phenol concentrations; pH; turbidity; safety; and sterility. Analyses were performed each month on different samples of a batch, stored at 4, 23, 30 and 37 degrees C. No significant (P greater than 0.1) variations occurred in potency, protein and phenol concentrations, pH, sterility or safety, at any of the storage temperatures during the study period. However, visual inspection revealed a moderate increase in turbidity of the samples stored at 23, 30 and 37 degrees C, at nine, four and three months, respectively. Culture of samples excluded the possibility of microbial contamination of the product leading to turbidity. Chromatographic and electrophoretic analyses demonstrated that turbidity was caused by the formation of heterogeneous protein aggregates of high molecular weight. Present results support the conclusion that, although storage temperature (up to 37 degrees C for twelve months) does not alter antivenom potency, it significantly influences the formation of protein aggregates. This phenomenon can be prevented by recommending the storage of antivenom at refrigeration temperature.     

Sustained release bioadhesive effervescent ketoconazole microcapsules tabletted for vaginal delivery

Microcapsules of ketoconazole with 1:1 and 1:2 core-wall ratios were prepared by means of the phase separation technique using sodium carboxymethylcellulose as a coating material. The microcapsules were mixed with effervescent granules and were tabletted. Dissolution studies of microcapsules, tabletted microcapsules and commercial ovules were carried out with a new basket method (horizontal rotating basket). A good sustained action was obtained with tablets. Micromeritic investigations were carried out on microcapsules in order to standardize the microcapsule product and to optimize the pilot production of the dosage forms prepared with these microcapsules. Bulk volume and weight, tapping volume and weight, fluidity, angle of repose, weight deviation, relative deviation, particle size distribution, density and porosity values of the microcapsules were determined. In addition, to evaluate whether some kind of glidant will be needed during tabletting of microcapsules, the Hausner ratio o and consolidaton index were also calculated and it may be concluded that microcapsules do not need any glidant.     

Sustained release bioadhesive effervescent ketoconazole microcapsules tabletted for vaginal delivery

Microcapsules of ketoconazole with 1:1 and 1:2 core-wall ratios were prepared by means of the phase separation technique using sodium carboxymethylcellulose as a coating material. The microcapsules were mixed with effervescent granules and were tabletted. Dissolution studies of microcapsules, tabletted microcapsules and commercial ovules were carried out with a new basket method (horizontal rotating basket). A good sustained action was obtained with tablets. Micromeritic investigations were carried out on microcapsules in order to standardize the microcapsule product and to optimize the pilot production of the dosage forms prepared with these microcapsules. Bulk volume and weight, tapping volume and weight, fluidity, angle of repose, weight deviation, relative deviation, particle size distribution, density and porosity values of the microcapsules were determined. In addition, to evaluate whether some kind of glidant will be needed during tabletting of microcapsules, the Hausner ratio and consolidation index were also calculated and it may be concluded that microcapsules do not need any glidant.     

Biodegradable cross-linked starch/protein microcapsules containing proteinase inhibitor for oral protein administration.

The objective of this study is to demonstrate the feasibility of microcapsules containing a protein and a proteinase inhibitor in order to allow the oral administration of proteic or peptidic drug. Starch/bovine serum albumin mixed-walled microcapsules were prepared using interfacial cross-linking with terephthaloyl chloride. The microcapsules were loaded with native or amino-protected aprotinin by incorporating protease inhibitors in the aqueous phase during the cross-linking process. Microcapsules can be degraded in the presence of alpha-amylase. The influence of the formulation parameters on the in vitro release of the inhibitor activity and the protein was studied. The protective effect of microcapsules with aprotinin for bovine serum albumin was revealed in vitro. The presence of the native bovine serum albumin was demonstrated after incubation of the microcapsules with aprotinin in a mixture of alpha-amylase (5.4 U/ml) and trypsin (900 spectrophotometric BAEE units/ml) for 3 h at 37 degrees C, whereas the protein was completely degraded in the release medium of the microcapsules without aprotinin.     

Microencapsulation of beta-galactosidase with Eudragit L-100

Microcapsules containing beta-galactosidase (lactase) were prepared by solvent evaporation using the pH sensitive polymer, Eudragit L-100. Formulations were prepared using various polymer-enzyme ratios with total solids content of the internal phase using sucrose stearate as a droplet stabilizer. Particle size distributions were invariant to relative proportion of ingredients but were dependent on stirring conditions. Although sucrose stearate had no effect on particle size distribution, release rate or encapsulation efficiency, its presence at a minimum 2% level was necessary to ensure intact microcapsules. Encapsulation efficiencies were higher for formulations prepared with 15% compared to 10% total solid content. DSC results revealed an interaction between encapsulated Eudragit L-100-enzyme-sucrose stearate vs their physical mixtures. The enzyme activities of the freshly prepared product vs those stored under stressed condition (40 degrees C and 75% RH) were 68 and 40% of their pre-processing activity, respectively. In vitro dissolution showed no enzyme release at 1 h in acidic media but 80% of the lactase was released from the microcapsules over 2.5 h in pH 6.8 media, thus establishing the feasibility of lactase microencapsulation to retard enzyme release in an acidic environment and ensuring release at intestinal pH.     

Stability and Release Kinetics of an Advanced Gliclazide-Cholic Acid Formulation: The Use of Artificial-Cell Microencapsulation in Slow Release Targeted Oral Delivery of Antidiabetics

Introduction

In previous studies carried out in our laboratory, a bile acid (BA) formulation exerted a hypoglycaemic effect in a rat model of type-1 diabetes (T1D). When the antidiabetic drug gliclazide (G) was added to the bile acid, it augmented the hypoglycaemic effect. In a recent study, we designed a new formulation of gliclazide-cholic acid (G-CA), with good structural properties, excipient compatibility and exhibits pseudoplastic-thixotropic characteristics. The aim of this study is to test the slow release and pH-controlled properties of this new formulation. The aim is also to examine the effect of CA on G release kinetics at various pH values and different temperatures.

Method

Microencapsulation was carried out using our Buchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G-SA (control) and G-CA-SA (test) at a constant ratio (1:3:30), respectively. Microcapsules were examined for efficiency, size, release kinetics, stability and swelling studies at pH 1.5, pH 3, pH 7.4 and pH 7.8 and temperatures of 20 and 30 °C.

Results

The new formulation is further optimised by the addition of CA. CA reduced microcapsule swelling of the microcapsules at pH 7.8 and pH 3 at 30 °C and pH 3 at 20 °C, and, even though microcapsule size remains similar after CA addition, percent G release was enhanced at high pH values (pH 7.4 and pH 7.8, p?<?0.01).

Conclusion

The new formulation exhibits colon-targeted delivery and the addition of CA prolonged G release suggesting its suitability for the sustained and targeted delivery of G and CA to the lower intestine.     

Stability of microencapsulated B. lactis (BI 01) and L. acidophilus (LAC 4) by complex coacervation followed by spray drying

Microcapsules containing Bifidobacterium lactis (BI 01) and Lactobacillus acidophilus (LAC 4) were produced by complex coacervation using a casein/pectin complex as the wall material, followed by spray drying. The aim of this study was to evaluate the resistance of these microorganisms when submitted to the spray drying process, a shelf-life of 120 days at 7-37 degrees C and the in vitro tolerance after being submitted to acid pH (pH 1.0 and 3.0) solutions besides morphology of microcapsules. Microencapsulated microorganisms were shown to be more resistant to acid conditions than free ones. Microencapsulated L. acidophilus maintained its viability for a longer storage period at both temperatures. The microcapsules presented a spherical shape with no fissures. The process used and the wall material were efficient in protecting the microorganisms under study against the spray drying process and simulated gastric juice; however, microencapsulated B. lactis lost its viability before the end of the storage time.     

Formulation and release of dihydralazine sulphate from tabletted microcapsules

One of the principal uses suggested for the microencapsulation of pharmaceuticals has been the preparation of the sustained release dosage form. The finished microcapsules have usually been presented in the form of suspensions or gels, but in order to obtain greater sustained release effect a non-disintegrating tablet would be a better formulation. Dihydralazine sulphate (Nepresol) is a dihydralazine-1,4-phthalazine derivative and used as an antihypertensive drug. This work was planned to prepare sustained action preparations of dihydralazine sulphate by microencapsulation and by tabletted microcapsules. Microcapsules were prepared from the microcapsule fractions using biconvex punches with 0.81 cm diameter fitted into a single punch by hand compressor. Avicel PH 101 and lactose were used as disintegrating materials in tablets having 2 kg hardness. Dissolution from both suspended microcapsules and the tablets was studied using the USP XX basket method. A study of in vitro release for both the free and tabletted microcapsules showed basically the same pattern but the time for the release was extended in the case of the tabletted preparations. Dissolution of dihydralazine sulphate was found to be governed by the core: wall ratio, microcapsule size, and the amount and kind of disintegrating agents. Dissolution kinetics were studied and evaluated.     

The prolongation of the in vitro dissolution of a soluble drug (phenethicillin potassium) by microencapsulation with ethyl cellulose

Microcapsules of phenethicillin potassium as a model water-soluble drug, coated with ethyl cellulose, have been prepared (core: wall ratios 1:1, 1:2 and 1:3) in which the taste has been masked, the odour almost eliminated and the release retarded. Sieve analysis showed that with decreasing core: wall ratios there was a trend towards increasing amounts of larger sized microcapsules. At constant core: wall ratios in vitro release of drug was generally greatest from the larger microcapsules. This result correlated with the surface areas of the microcapsules which became less as the asymmetry of the microcapsules diminished with decrease in microcapsule size. There was a linear relation between the amount of ethyl cellulose and the time for 60% release of drug, and the release pattern was analogous to that from insoluble porous matrices. Scanning electron micrographs showed the microcapsules to be irregularly shaped with circular surface pores, and they did not alter in shape or size during dissolution. Tableting of 1:1 core: wall ratio microcapsules significantly further retarded the dissolution.     

Preparation and in vitro evaluation of salbutamol sulphate microcapsules.

Microcapsules of salbutamol sulphate were prepared using cellulose acetate phthalate as a coating material and by the coacervation phase separation (solvent evaporation) technique for obtaining sustained action. Prepared microcapsules were evaluated for their drug content, physical properties, release characteristics and stability. The effect of coat to core ratio on release pattern was studied and it was found that microcapsules prepared with coat to core ratio 2:1 were able to retard the release of drug for 12 hours. No significant change was observed in drug content and release pattern even after storage.     

Optimization and characterization of chitosan-coated alginate microcapsules containing albumin

In order to obtain small microcapsules with high protein encapsulation efficiency and extended release characteristics various processing factors were studied. Bovine serum albumin-loaded alginate microcapsules were prepared by an emulsion method and further incubated in chitosan. Many process factors were tested including the concentration and molecular weight of alginate, the concentration and pH of chitosan, and surfactants, etc. Microcapsules were achieved with diameters less than 2 microm, high encapsulation efficiency (> 80%) and high loading rate (> 10% w/w). The results also showed that the initial BSA amount of 20%-30% loaded alginate microcapsules coated with 0.2%-0.5% chitosan solutions at pH 4 by the two-stage procedure present the best sustained releasing characteristics.