Sustained-release dosage form of oxolamine citrate: preparation and release kinetics.

One of the principal uses of microencapsulation for pharmaceuticals has been the preparation of sustained-release dosage forms which have been usually presented in the form of a suspension or gel. However, a non-disintegrating tablet would be a better formulation to obtain sustained-release effect. Microencapsulation has been employed to provide protection of the core material against atmospheric effects, to cover the unpleasant taste and to enhance the stability. A number of drugs have also been encapsulated to reduce gastric and other GI tract irritations, to alter release properties and to change availability. Oxolamine citrate is one of the synthetic derivatives of 3,5-disubstituted 1,2,4-oxodiazole, used particularly for its antitussive activity. The usual dose of the drug is 200 mg given four times a day. Its use was limited by side-effects of nausea and vomiting. In order to prevent the disadvantages caused by taking the drug four times daily, and to reduce the side-effects, a sustained-release dosage form of oxolamine citrate was prepared by the microencapsulation technique and microcapsules thus formed were pressed into tablets. Dissolution tests were done with microcapsules and tablets formed by microcapsules by using the USPXXI paddle method and dissolution kinetics were studied and evaluated.     

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 of microcapsules with self-microemulsifying core by a vibrating nozzle method

Incorporation of drugs in self-microemulsifying systems (SMES) offers several advantages for their delivery, the main one being faster drug dissolution and absorption. Formulation of SMES in solid dosage forms can be difficult and, to date, most SMES are applied in liquid dosage form or soft gelatin capsules. This study has explored the incorporation of SMES in microcapsules, which could then be used for formulation of solid dosage forms. An Inotech IE-50 R encapsulator equipped with a concentric nozzle was used to produce alginate microcapsules with a self-microemulsifying core. Retention of the core phase was improved by optimization of encapsulator parameters and modification of the shell forming phase and hardening solution. The mean encapsulation efficiency of final batches was more than 87%, which resulted in 0.07% drug loading. It was demonstrated that production of microcapsules with a self-microemulsifying core is possible and that the process is stable and reproducible.     

Preparation of microcapsules with self-microemulsifying core by a vibrating nozzle method

Incorporation of drugs in self-microemulsifying systems (SMES) offers several advantages for their delivery, the main one being faster drug dissolution and absorption. Formulation of SMES in solid dosage forms can be difficult and, to date, most SMES are applied in liquid dosage form or soft gelatin capsules. This study has explored the incorporation of SMES in microcapsules, which could then be used for formulation of solid dosage forms. An Inotech IE-50?R encapsulator equipped with a concentric nozzle was used to produce alginate microcapsules with a self-microemulsifying core. Retention of the core phase was improved by optimization of encapsulator parameters and modification of the shell forming phase and hardening solution. The mean encapsulation efficiency of final batches was more than 87%, which resulted in 0.07% drug loading. It was demonstrated that production of microcapsules with a self-microemulsifying core is possible and that the process is stable and reproducible.     

Ethyl cellulose as a potential sustained release coating for oral pharmaceuticals.

This current study was motivated, and designed in an attempt to determine the possible application of the inert, pH-insensitive, ethyl cellulose polymer as a potential sustained-release coating for oral pharmaceuticals. Coating was effected using two relatively recent techniques, namely microencapsulation by phase separation coacervation, induced by temperature change, and drug entrapment by flocculation, induced by nonsolbent addition. Chloramphenicol was used as a model drug. Results of this study revealed the fact that ethyl cellulose proved to be a potential sustained-release coating for oral dosage forms. Moreover, the effect of the coating/core ratio was exhibited both qualitatively and quantitatively. This finding could help in the design of programmed or timed-release drugs. Accordingly, this study could be considered a successful attempt towards the utlization of ethyl cellulose in of the design of sustained-release oral pharmaceuticals.     

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.     

Continuous dissolution rate determination as a function of the pH of the medium.

A method was developed for varying the pH of the medium during dissolution rate studies of timed-release tablets with the aid of compressed, totally soluble, alkaline powder mixtures. Commercial as well as experimental timed-release capsules or tablets were used as models, and dissolution rates were determined at pH 1.1, 2.4, and 7.4. The system can be applied to other pH values or other variations of the dissolution medium (e.g., ionic strength) to: (a) correlate in vitro release rates with bioavailability data, (b) discriminate between alternative formulations during dosage form development, or (c) serve as a selective control procedure for a series of sustanined-release dosage forms.     

A contribution to the evaluation of microcapsules by light microscopy.

Light microscopy has been used for the evaluation of the internal and external structure of dry microcapsules. The method involves surface and penetrative staining with various dyes after which the microcapsules were embedded in suitable optically translucent material. Using this method the core material, its shape and position within the microcapsules either in total or as subunits of the core are clearly distinguishable from the wall material. The surface characteristics of the microcapsules can be observed with either light or fluorescent microscopy after staining with a fluorescent dye. Furthermore, it is a relatively simple and inexpensive method by comparison with the scanning electron microscopy. The natural character of microcapsules, without any artificial structures, has been maintained. It could serve as a routine auxiliary method for complex evaluation or control of the microencapsulation process and its optimization.     

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 Agglomerated Crystals for Direct Tabletting and Microencapsulation by the Spherical Crystallization Technique with a Continuous System

Adhesive and cohesive properties of chlorpromazine hydrochloride (CP) crystals were modified to improve their powder processing, e.g., direct tabletting and microencapsulation, by agglomeration. Moreover, sustained-released gelling microcapsules of CP were devised to prolong the pharmacological effect. The spherical crystallization technique was applied to prepare agglomerates for direct tabletting and microencapsulation to use them as core materials. The ethanolic solution dissolving CP was poured into a stirred cyclohexane, yielding spherically agglomerated crystals. The resultant agglomerates were free-flowing and easily packable spheres with average diameters of 200 to 1000 µm. The agglomerates reserved the high compressibility of the original powder having a small particle size (14 µm). The compression behavior represented by Heckels equation suggested that the agglomerates were disintegrated to individual primary crystals at low compression pressures, and then they were closely repacked and plastically deformed at higher pressures. After agglomeration, microencapsulation was continuously performed in the same batch by a phase separation method. Coacervate droplets produced by pouring cyclohexane into a dichloromethane solution, dissolving poly vinyl acetate as a coating polymer, were added to the crystallization system under stirring, to prepare the microcapsules. By filling the microcapsules in gelatin hard capsules or tabletting them, their drug release rates became retarded compared with the physical mixture treated in the same way, having the same formulation as the microcapsules. This phenomenon was due to the gelation of poly vinyl acetate of the microcapsules in the dissolution medium, whose glass transition temperature is very low. This novel sustained-release dosage form is termed gelled microcapsules.     

Some factors affecting the microencapsulation of pharmaceuticals with cellulose acetate phthalate

Phase diagrams were prepared to indicate the region of microcapsule formation for the following system: cellulose acetate phthalate, light mineral oil, acetone: 95% ethanol solvent, and sorbitan monooleate. The microencapsulation of pharmaceuticals having widely different solubility properties was carried out. Various factors affecting microencapsulation, namely trituration, order and time of addition of the pharmaceutical, core size, and the core to coat ratio, were investigated. The evidence for a mechanism of microencapsulation is also presented. The phase diagrams showed that microcapsules readily formed when the cellulose acetate phthalate concentration was in the 0.93-3.85% range and the polymer solvent concentration was in the 7-16% range. Aggregation of microcapsules was minimized at low solvent concentrations. Pharmaceuticals could be microencapsulated regardless of their solubility in the polymer solvent or hardening liquid. The size of the microencapsulated pharmaceutical increased as the core:coat ratio increased to a maximum of 1.5:1. There is an upper size limit of the pharmaceuticals which can be coated.     

Preparation and evaluation of celecoxib-loaded microcapsules with self-microemulsifying core

The purpose of this study was to prepare alginate microcapsules with a self-microemulsifying system (SMES) containing celecoxib in the core. An Inotech IE-50 R encapsulator equipped with a concentric nozzle was used to prepare the microcapsules. The encapsulated SMES was shown to increase celecoxib solubility over that of the pure drug more than 400-fold. Microcapsules prepared with a high SMES:celecoxib ratio exhibited distinct core vesicles containing liquid SMES. By modifying the SMES and including an additional chitosan coating, drug loading in the range from 12–40% could be achieved with the degree of encapsulation ranging from 60–82%. Alginate microcapsules loaded with SMES and celecoxib showed increased dissolution rate of celecoxib over that of alginate microcapsules loaded with celecoxib or of the celecoxib alone. Compared to the previous report, drug loading capacity was significantly improved, enabling the formulation of dosage forms which are of suitable size for peroral application.     

Phospholipid-based microemulsion formulation of all-trans-retinoic acid for parenteral administration

All-trans-retinoic acid (ATRA) shows anti-cancer activities, especially in patients with acute promyelocytic leukemia. Due to the highly variable bioavailability of ATRA and induction of its own metabolism after oral treatment, development of alternative parenteral dosage form is required. The principal aim of this study was to develop a parenteral formulation of ATRA by overcoming its solubility limitation by utilizing phospholipid-based microemulsion system as a carrier. Microemulsion was prepared with pharmaceutically acceptable ingredients such as soybean oil and phospholipids. The mean particle diameter and polydispersity of ATRA microemulsion could be decreased to be applicable for parenteral administration by modulation of composition of microemulsion. The loading concentration of ATRA in microemulsion increased by increasing the oil contents and also by inclusion of distearoylphosphatidyl-ethanolamine-N-poly(ethyleneglycol) 2000 (DSPE-PEG). Furthermore, loading of ATRA in microemulsion improved the chemical stability of ATRA. The pharmacokinetic profile of ATRA after intravenous injection of microemulsion formulation to rats was similar to that of sodium ATRA. The growth inhibitory effects of ATRA on human cancer HL-60 and MCF-7 cell lines were also similar between free ATRA and microemulsion formulation of ATRA, suggesting that its anti-cancer activity was not impaired by loading in microemulsion. Our study herein demonstrates that phospholipid-based microemulsion may provide an alternative parenteral formulation of ATRA.     

Micromeritic studies on nicardipine hydrochloride microcapsules

In this study, nicardipine hydrochloride (N.HCl) microcapsules were prepared by means of coacervation phase separation technique using ethylcellulose (EC) as a coating material. Micromeritic investigations were carried out on nicardipine hydrochloride, ethylcellulose and nicardipine hydrochloride microcapsules in order to standardize the microcapsule product and to optimize the pilot production of dosage forms prepared with these microcapsules. Microcapsules we prepared had the ratio of 2:1 core:wall and then by sieving, were divided into two groups according to their particle sizes which were > 840 μm and 476–840 μm. The bulk volume and weight, tapping volume and weight, fluidity, angle of repose, weight deviation, particle size distribution, density and porosity of nicardipine hydrochloride, ethylcellulose and nicardipine hydrochloride microcapsules were studied. To determine flowability, Hausner ratio and Consolidation index were also calculated from the results obtained. The findings of the study suggested that the micromeritic properties of the crude materials were significantly changed by the microencapsulation process. In addition, it was shown by scanning electron microscopy, that the changes were due to changes in the physicochemical properties of drug particles.     

Preparation of microcapsules masking the bitter taste of enoxacin by using one continuous process technique of agglomeration and microencapsulation

Abstract

In order to mask the bitter taste of drugs, a novel microencapsulation process combined with the wet spherical agglomeration (WSA) technique was developed by using a modified phase separation method. The spherical agglomerates of enoxacin (ENX) with various additives including disintegrants were successfully produced in the system of acetone-n-hexane-ammonia water or acetone-n-hexane-distilled water by the WSA, using flocculation phenomena of particles in liquid. Resultant agglomerates could be microencapsulated continuously with Eudragit RS utilizing the phase separation method in the same system as agglomeration under stirring. ‘Explosible' microcapsules which were free from the bitter taste could be produced in formulating finer particle size of ENX and 50 per cent of Primojel in core agglomerates, using distilled water as a bridging liquid, and treating with 20 per cent polymer coating level. These microcapsules were bioequivalent to the commercial ENX 100 mg tablets in beagle dogs. One continuous process technique of agglomeration and microencapsulation was useful for the design of ENX powders which masked the bitter taste and controlled the drug release rate.     

Phase diagram studies for microencapsulation of pharmaceuticals using cellulose acetate trimellitate

Phase diagrams were prepared to indicate the region of microcapsule formation for the following system: cellulose acetate trimellitate, light mineral oil, and the solvent mixture (acetone:ethanol), using chloroform as the hardening agent. The effect of sorbitan monoleate, sorbitan monolaurate, and sorbitan trioleate on the region of the phase diagram for the formation of microcapsules was investigated. The results indicate that microcapsules are readily formed when the polymer concentration is in the 0.5-1.5% range and the solvent concentration is in the 5-10% range. Aggregation of microcapsules was minimized by using lower solvent concentration. Low concentrations of sorbitan monooleate in mineral oil (less than or equal to 1%) gave products that had smoother coats and more uniform particle size. Surfactants with low hydrophile:lipophile balance produced larger regions on the phase diagram for microencapsulation compared with a surfactant with higher hydrophile:lipophile balance. A mechanism for microencapsulation is described. Tartrazine microcapsules produced using different concentrations of surfactant were tested for dissolution characteristics in both acidic and neutral conditions. Tartrazine-containing microcapsules prepared by using 3% sorbitan monooleate had the lowest release in acidic conditions. The effect of surfactant and formulation concentration on microcapsule size was studied by analyzing the particle size distribution for both blank and tartrazine-containing microcapsules. The smallest microcapsule size was obtained when the sorbitan monooleate concentration was 3%. It appears that there is an upper limit for the surfactant concentration that could be used to achieve successful microencapsulation.     

Microenvironment-Controlled Encapsulation (MiCE) Process: Effects of PLGA Concentration,Flow Rate,and Collection Method on Microcapsule Size and Morphology

Purpose To evaluate the real-time effects of formulation and instrumental variables on microcapsule formation via natural jet segmentation, a new microencapsulation system termed the microenvironment-controlled encapsulation (MiCE) process was developed. Methods A modified flow cytometer nozzle hydrodynamically focuses an inner drug and outer polymer solution emanating from a coaxial needle assembly into a two-layer compound jet. Poly(lactic-co-glycolic acid) (PLGA) dissolved in a water-miscible organic solvent resulted in formation of reservoir-type microcapsules by interfacial phase separation induced at the boundary between the PLGA solution and aqueous sheath. Results The MiCE process produced microcapsules with mean diameters ranging from 15–25 μm. The resultant microcapsule size distribution and number of drug cores existing within each microcapsule was largely influenced by the PLGA concentration and microcapsule collection method. Higher PLGA concentrations yielded higher mean diameters of single-core microcapsules. Higher drug solution flow rates increased the core size, while higher PLGA solution flow rates increased the PLGA film thickness. Conclusion The MiCE microencapsulation process allows effective monitoring and control of the instrumental parameters affecting microcapsule production. However, the microcapsule collection method in this process needs to be further optimized to obtain microcapsules with desired morphologies, precise membrane thicknesses, high encapsulation efficiencies, and tight size distributions.     

Preparation and evaluation of press-coated aminophylline tablet using crystalline cellulose and polyethylene glycol in the outer shell for timed-release dosage forms

In an attempt to achieve chronopharmacotherapy for asthma, press-coated tablets (250 mg), which contained aminophylline in the core tablet in the form of low-substituted hydroxypropylcellulose (L-HPC) and coated with crystalline cellulose (PH-102) and polyethylene glycol (PEG) at various molecular weights and mixing ratios in the amounts of PH-102 and PEG as the outer shell (press-coating material), were prepared (chronopharmaceutics). Their applicability as timed-release (delayed-release) tablets with a lag time of disintegration and a subsequent rapid drug release phase was investigated. Various types of press-coated tablets were prepared using a tableting machine, and their aminophylline dissolution profiles were evaluated by the JP paddle method. Tablets with the timed-release characteristics could be prepared, and the lag time of disintegration was prolonged as the molecular weight and the amount of PEG, for example PEG 500,000, in the outer shell were increased. The lag time of disintegration could be controlled by the above-mentioned method, however, the pH of the medium had no effect on disintegration of the tablet and dissolution behavior of theophylline. The press-coated tablet (core tablet:aminophylline 50 mg, L-HPC and PEG 6000; outer shell:PH-102:PEG = 8:2 200 mg) with the timed-release characteristics was administered orally to rabbits for an in vivo test. Theophylline was first detected in plasma more than 2 h after administration; thus, this tablet showed a timed-release characteristics in the gastrointestinal tract. The time (tmax) required to reach the maximum plasma theophylline concentration (Cmax) observed after administration of the press-coated tablet was significantly (p < 0.05) delayed compared with that observed after administration of aminophylline solution in the control experiment. However, there was no difference in Cmax and area under the plasma theophylline concentration-time curve (AUC0-->24) between the press-coated tablet and aminophylline solution. These results suggest that the press-coated aminophylline tablet (with the timed-release characteristic) offers a promising forms of theophylline chronotherapy for asthma.     

Eudragit RS and RL (acrylic resins) microcapsules as pH insensitive and sustained release preparations of ketoprofen

Microencapsulation of ketoprofen using Eudragit RS and RL (acrylic resins) was investigated based on the dispersion system of ketoprofen-containing acetone in liquid paraffin. Aluminium tristearate was used as an additive for the preparation of microcapsules. Good reproducibility was observed in the microencapsulation and the resulting microcapsules were uniform, free-flowing particles. The phase diagram of ketoprofen-Eudragit RS or RL-aluminium tristearate indicated that it is only in a very limited region that spherical microcapsules ranging from 250 to 1000 microns in diameter could be prepared. Instrumental analysis using an energy dispersive-type X-ray microanalyser and a scanning electron microscope showed that aluminium tristearate was localized near the surface of the microcapsules. From these results, it was presumed that aluminium tristearate reduces the phase tension between Eudragit microcapsules and liquid paraffin. The dissolution patterns of ketoprofen from Eudragit RS and RL microcapsules were independent of the pH of the dissolution medium, and the dissolution rates were considerably lower than those from ketoprofen powders.     

Reservoir-type microcapsules prepared by the solvent exchange method: effect of formulation parameters on microencapsulation of lysozyme

A new microencapsulation technique based on the solvent exchange method was implemented using an ultrasonic atomizer system to encapsulate a protein drug in mild conditions. The reservoir-type microcapsules encapsulating lysozyme as a model protein were prepared by inducing collisions between the aqueous droplets containing lysozyme and the droplets of organic solvent with dissolved poly(lactic acid-co-glycolic acid) (PLGA). The main focus of the study was to examine formulation variables on the size and the encapsulation efficiency of the formed microcapsules. The formulation variables examined were concentrations of mannose in the aqueous cores, NaCl in the aqueous collection medium, and PLGA in organic solvent. The mean diameter of the microcapsules ranged from 40 microm to 100 microm. Smaller microcapsules showed lower encapsulation efficiencies. The resulting microcapsules released native lysozyme in a sustained manner, and the release rate was dependent on the formulation conditions, such as the concentration and molecular weight of the polymer used. The solvent exchange method does not induce lysozyme aggregation and loss of its biological activity. The solvent exchange method, implemented by the ultrasonic atomizer system, provides an effective tool to prepare reservoir-type microcapsules for delivering proteins.