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.     

Preparation and in vitro evaluation of slow release ketoprofen microcapsules formulated into tablets and capsules

Abstract

Ketoprofen powder was encapsulated with Eudragit RL/RS polymer solutions in isopropanol-acetone 1:1, using a simple and rapid method. Microcapsules were prepared using Eudragit solutions with different RL/RS ratios. The encapsulation process produces free-flowing microcapsules with good drug content and marked decrease in dissolution rate. The retardation in release profile of ketoprofen from microcapsules was a function of the polymer ratio employed in the encapsulation process. In vitro release of ketoprofen from microcapsules either filled in gelatin capsules or compressed into tablets, using calcium sulphate as diluent, confirmed the efficiency of the encapsulation process for preparing prolonged release medication. A capsule formulation with optimum sustained-release profile was suggested.     

Preparation and in vitro evaluation of polylactic acid-mitomycin C microcapsules

Abstract

An emulsion method was developed for the incorporation of water-soluble mitomycin C into polylactic acid biodegradable microcapsules. With an average particle size of about 95 μm, microcapsules with a desired loading of from 3.65 to 13.80 per cent were prepared. These microcapsules, which contained both crystalline and finely dispersed drug particles, showed a dose-dependent drug release pattern with microcapsules of higher drug loading having a faster release rate than those of lower drug loading. Effective sterilization of the microcapsules for parenteral use was achieved by ⁶⁰Co γ-ray irradiation, which did not affect the microcapsule structure, release rate or drug stability. Mitomycin C showed dose-dependent antiproliferative activity against the growth of the K562 human erythroleukaemia cells. The microencapsulated dosage form of mitomycin C was found to enhance the drug's activity through sustained drug release. In experiments where drug concentrations in the cell medium were reduced according to the drug's biological half-life, the microcapsule systems showed a distinct advantage over the non-capsulated dose for the kinetic inhibition of K562 cell growth.     

Influence of coacervation-inducing agents and cooling rates on the preparation and in vitro release of bleomycin hydrochloride microcapsules

Abstract

Two types of coacervation-inducing agents (EVA, PIB) and three cooling rates (0.01998, 0.03482 and 0.06725d`C/min) affecting the preparation, micromeritic and drug release properties of bleomycin hydrochloride microcapsules were investigated. Particle size distribution of microcapsules induced by EVA significantly depended on the cooling rate, but that induced by PIB was independent of the cooling rate. Higher viscosity of PIB led to a smaller particle size of microcapsules than when EVA was used. The surface topography of the microcapsules for both types of coacervation-inducing agents was obviously different. We found that the release behaviour of bleomycin hydrochloride from the microcapsules also depended on the type of coacervation-inducing agent and the cooling rate. In general, the slower the cooling rate the more prolonged the release of the drug. Higuchi matrix model was followed for bleomycin hydro chloride released from the microcapsules. T₅₀ of both types of microcapsules decreased with the increase of the cooling rate. To simulate the absorption behaviour of the GI tract, the continuous flow dialysis method was modified for drug release from the microcapsules. The data indicate that the diffusion of the dissolution medium and dissolved drug through the ethylcellulose wall of the microcapsules is the rate-limiting step before dialysis. This also implies that the release rate of the drug from dosage form significantly determined the absorption in the GI tract.     

An experimental study of the antitumour effect of bleomycin hydrochloride microcapsules

Abstract

The controlled release behaviour of bleomycin hydrochloride microcapsules was investigated by an in vitro dissolution method and an in vivo antitumour test. Bleomycin hydrochloride microcapsules prepared using the highest cooling rate exhibited sustained release characteristics and its release rate obeyed a nearly zero order release kinetics. Microcapsules containing bleomycin hydrochloride were locally injected into the solid tumour of uterine cervix carcinoma bearing nude mice. Tumour growth was markedly inhibited by treatment using bleomycin hydrochloride microcapsules compared to the control group and the group receiving direct local administration of bleomycin hydrochloride. No significant differences in the changes of body weight after treatment were found between the control group and the treated group. These results suggest that controlled release microcapsules may be applicable as a drug carrier for delivery of antitumour agents in cancer chemotherapy.     

Preparation and characterization of methotrexate-loaded microcapsules

Abstract

Methotrexate (MTX) has toxic effect to healthy tissues. Microencapsulation coats particles with a functional coat to optimize storage stability and to modulate release. In the present study, a new MTX encapsulated microcapsules were synthesized for controlling MTX release. Controlled drug release provides releasing of efficient dose and prevent drug side effect to tissues and also protects MTX from oxygen, pH and other interactions. MTX was encapsulated through biocompatible hyaluronic acid (HA) and sodium alginate (SA) with an encapsulation system to reduce its toxicity and for controlled release. The microcapsules prepared by vibrating nozzle were cross-linked with SA, HA and calcium chloride. Nozzle diameter and MTX concentration were changed according to loaded MTX and encapsulation efficiency were determined using HPLC. For the reliability of the data, validation studies of the HPLC method were performed. The precision of the method was demonstrated using intra- and inter-day assay relative standard deviation (RSD) values which are less than 2% in all instances. For the characterization of microcapsules, particle size, drug loading and in vitro drug release studies were performed. Diameters of MTX-loaded microcapsules were acquired approximately 160, 400 and 800?µm. Surface morphology of encapsulated microcapsules were displayed with light microscope. Eighty-nine percent MTX encapsulation efficiencies were achieved. Encapsulated MTX microcapsules showed controlled release when compared to pure MTX. While powder MTX dissolved completely in 10?min in the dissolution medium, MTX release from encapsulated MTX microcapsules became 40?h in 0.1?M PBS pH 7.4, including NaCl. MTX release from MTX-loaded microcapsules was reached to 79%. Moreover, drug efficiency was examined in vitro cell culture tests. Viability of 5RP7 cells were decreased to 88.5% for 96?h. When MTX was given directly to 5RP7 cells, viability of 5RP7 cells was decreased to 49.7% for 96?h. Flow cytometry studies also showed that, MTX microcapsules induced apoptosis. The goal of this study is to provide controlled release of MTX and to reduce the toxic effect of MTX.     

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.     

Preparation and evaluation of ethylcellulose microcapsules of indomethacin

Indomethacin was microencapsulated with ethylcellulose using a modified spherical agglomeration process, aiming at a sustained release preparation without side effects on the stomach. The surface morphology of the microcapsules was examined using scanning electron microscopy. The microcapsules were porous and spherical, and their porosity increased with increasing the viscosity of ethylcellulose.In vitro dissolution process followed Higuchi’s diffusion model for first 3 hr. Release rate of the drug from microcapsules decreased as the viscosity of ethylcellulose or the weight ratio of indomethacin to ethylcellulose was decreased. The release rate also decreased with increasing the microcapsule size. The microcapsules induced less gastric ulcer in rats than raw drug.     

Preparation and in vitro evaluation of slow release ketoprofen microcapsules formulated into tablets and capsules.

Ketoprofen powder was encapsulated with Eudragit RL/RS polymer solutions in isopropanol-acetone 1:1, using a simple and rapid method. Microcapsules were prepared using Eudragit solutions with different RL/RS ratios. The encapsulation process produces free-flowing microcapsules with good drug content and marked decrease in dissolution rate. The retardation in release profile of ketoprofen from microcapsules was a function of the polymer ratio employed in the encapsulation process. In vitro release of ketoprofen from microcapsules either filled in gelatin capsules or compressed into tablets, using calcium sulphate as diluent, confirmed the efficiency of the encapsulation process for preparing prolonged release medication. A capsule formulation with optimum sustained-release profile was suggested.     

Release kinetics of salbutamol sulphate from wax coated microcapsules and tableted microcapsules.

Microcapsules of salbutamol sulphate were prepared using beeswax and carnauba wax as coating materials. In vitro release kinetics were studied following the zero order, first order and Higuchi equations. Beeswax alone was not effective but beeswax and carnauba wax combinations were suitable in controlling the in vitro release of the drug. Microcapsules were compressed into tablets to get a controlled release oral dosage form. Release from tableted microcapsules was significantly more prolonged than the respective batches of the microcapsules. Best data fit with the highest correlation coefficient for the tableted microcapsules was obtained for first order.     

Preparation of ranitidine hydrochloride microcapsules and its biphasic release kinetics

Abstract

The emulsion–solvent–evaporation technique has been adopted in microencapsulation of ranitidine HCl, an antiulcer drug using coating polymer Eudragit RS-100. The biphasic release kinetics of ranitidine HCl has been evaluated. A matrix mechanism predominates in the early phase of the release of drug from the micro-capsules followed by a first-order release kinetics in the second phase. Drug release from the microcapsules was determined in the light of different kinetic models like zero-order, Higuchi matrix, first-order, and Baker-Lonsdale. These have been characterized by differential rate treatment and correlation coefficient analysis. In vitro dissolution study has been carried out to evaluate diffusion coefficient (D_α) and diffusivity rate constant (k_bl) with the help of the Baker-Lonsdale model for the first phase. Similarly the first-order re-lease rate constant (k₁) and the permeability constant (P_i) for the first-order mechanism during the second phase of release have been evaluated.     

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.     

Influence of the atomization time on the properties of ethylcellulose microcapsules of isoniazid prepared by a fluidized bed

Microcapsules containing isoniazid were produced by the fluidized bed method with ethylcellulose by varying the total atomization time. The kinetics of capsules growth during the preparation was discussed on the basis of the distribution of particle size. The quality of the capsules was evaluated using the particle size characteristics, the total content of ethylcellulose, the particle and wall density, and the time needed for the 50 per cent release of the drug. An increase in the atomization time of the ethylcellulose solution gave rise to an increase in the mean diameter of particles and the ethylcellulose content of capsules; it also produced a more dense product with a prolonged release of the drug. The release of the drug from tabletted microcapsules was further prolonged.     

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.     

Controlled release of vancomycin from biodegradable microcapsules

Poly D,L-lactic acid (PLA) and its copolymers with glycolide PLGA 90:10 and 70:30 were polymerized under various conditions to yield polymers in the molecular weight range 12000-40000 daltons, as determined by gel permeation chromatography. Vancomycin hydrochloride was the hydrophilic drug of choice for the treatment of methicillin resistant Staphyloccoccal infections. It was microencapsulated in the synthesized polymers using water-oil-water (w/o/w) double emulsion and solvent evaporation. The influence of microcapsule preparation medium on product properties was investigated. An increase in polymer-to-drug ratio from 1:1 to 3:1 caused an increase in the encapsulation efficiency (i.e. from 44-97% with PLGA). An increase in the emulsifier (PVA) molecular weight from 14-72 kD caused an increase in encapsulation efficiency and microcapsule size. The in vitro release of vancomycin from microcapsules in phosphate buffer saline (pH 7.4) was found to be dependent on molecular weight and copolymer type. The kinetic behaviour was controlled by both diffusion and degradation. Sterilization with ⁶⁰Co (2.5 Mrad) also affected the degradation rate and release profiles. Degradation of microcapsules could be seen by scanning electron microscopy, by the increase in the release rate from PLA and by the decrease in the T_g values of microcapsules. In vitro bactericidal effects of the microcapsule formulations on S.aureus were determined with a special diffusion cell after the preparations had been sterilized, and were found to have bactericidal effects lasting for 4 days.     

Drug Release from Tablets Containing Cellulose Acetate Phthalate As an Additive or Enteric-Coating Material

A formulation containing cellulose acetate phthalate for preparing enteric-coated granules was developed with the use of granulation and microencapsulation techniques. Drug release from tablets or tabletted microcapsules was measured in a disintegration apparatus and an in vitro variable-pH release simulator of the flow type. The release mechanism for the tablets or tabletted microcapsules was determined with the Higuchi matrix model, a first-order kinetic model, and the Weibull distribution function. Adding acetone directly to the mixture of sulfamethoxazole and cellulose acetate phthalate resulted in enteric-coated granules with more prolonged release than other granulation methods. Microencapsulation of the granules significantly delayed the drug release and enhanced the effectiveness of the enteric coating. Microencapsulated granules show release patterns that are sustained and can be simulated with three different release models, i.e., with square-root time plotting, diffusional first-order plotting, and Weibull distribution plotting. The enteric-coating behavior of the tablets was more clearly demonstrated with the variable-pH release simulator than with a fixed-pH dissolution method.     

Preparation and physical evaluation of microcapsules of hydrophilic drug-cyclodextrin complexes.

An emulsion-solvent evaporation method for preparation of microcapsules containing water-soluble 2-hydroxypropyl-beta-cyclodextrin complex of a lipophilic water-insoluble drug, hydrocortisone, is described. The release of the drug from the microcapsules was determined in simulated gastric fluid. The drug release rate from the microcapsules could be controlled by addition of a plasticizer and it was sustained over extended time. Addition of solubilizing compounds to the dissolution medium did not affect the drug release rate.     

Production of BSA-loaded alginate microcapsules: Influence of spray dryer parameters on the microcapsule characteristics and BSA release

The aim of this study was to optimize the production of BSA-loaded alginate microcapsules by spray drying and to study the release of bovine serum albumin fraction V (BSA) under gastric simulated conditions. Microcapsule yield, BSA release, microcapsule size and size distribution were characterized following the application of different production parameters including inlet air temperature, inlet air pressure and liquid feed rate. The microcapsules were incubated in 0.1?N HCl and BSA release was quantified over time. The yields were higher with the pressure of 3?bar compared to 4?bar and with a feed rate of 0.45 vs. 0.2?ml s^?1. A high feed rate (0.45 vs. 0.2?ml s^?1) allows one to obtain microcapsules with a low BSA release (p?=?0.0327). The increase of the atomizer inlet temperature leads to microcapsules with a higher BSA release (p?=?0.0230). A higher air pressure of 4?bar compared to 3?bar resulted in a lower microcapsule size (2.55 vs. 2.80?µm) and led to a narrower size distribution (0.92 vs. 1.07). In conclusion, the spray dryer parameters influenced the alginate microcapsule characteristics as well as subsequent protein release into a simulated gastric medium.     

Polyacrylate resin microcapsules for taste masking of antibiotics

Abstract

Various microencapsulated dosage forms were prepared to limit the release of an antibiotic in solution for up to 3 days and in the oral cavity following per oral administration. An experimental antibiotic, clarithromycin (TE-031), was used in these studies. The drug was first encapsulated in gelatin followed in some cases by crosslinking with glutaraldehyde. The gelatin microcapsules were then coated with acrylic resins (Eudragit®), whose solubility properties vary according to pH. A non-solvent coacervation technique was used to apply the Eudragit resins. It was found that crosslinking the gelatin retarded release of TE-031 somewhat relative to that from uncrosslinked gelatin microcapsules in a 72 h release experiment conducted at room temperature. Coating the gelatin microcapsules with Eudragit resins L100, S100, or E100 slowed the release of TE-031 further still; less TE-031 was released over 72 h from the Eudragit-coated formulations prepared with crosslinked gelatin compared with formulations prepared with uncrosslinked gelatin. The Eudragit ElOO-coated crosslinked gelatin microcapsule formulation was most effective in preventing release of the TE-031 under simulated conditions of storage in an aqueous solution.     

Oral controlled release formulation of diclofenac sodium by microencapsulation with ethyl cellulose

The aim of this study was to formulate and evaluate microencapsulated controlled release preparations of diclofenac sodium (DFS) using different proportions of ethyl cellulose (EC) as the retardant material to extend the release. The formulated microcapsules were then compressed into tablets to obtain controlled release oral formulations. Phase separation-coacervation technique was employed to prepare microcapsules of DFS using different proportions of EC in cyclohexane. Physical characteristics of microcapsules and their tablets, in vitro release pattern of the designed microcapsules and their tablets prepared from them were studied using USP dissolution apparatus (USP 2000) type 2 (paddle method) in triple distilled water. The prepared microcapsules were white, free flowing and spherical in shape, with the particle size varying from 49.94-52.72 microm. The duration of DFS release from microcapsules was found to be directly proportional to the proportion of EC and, thus, coat thickness. All tablets were of good quality with respect to appearance, drug content uniformity, hardness, weight variation, friability and thickness uniformity. In vitro release study of the tabletted microcapsules in triple distilled water showed a zero order release kinetics and extended release beyond 24 h. A good correlation was obtained between drug release (t(60)) and proportion of EC in the microcapsules. In the case of tabletted microcapsules, very good correlation could be established between t(60), proportion of EC, weight of the tablets and between release rate constant (K) and proportion of EC. All the formulations were highly stable and possessed reproducible release kinetics across the batches.