Formulation and evaluation of gelatin micropellets of aceclofenac: effect of process variables on encapsulation efficiency, particle size and drug release

In the present study aceclofenac-gelatin micropellets were prepared by the cross linking technique using gluteraldehyde as cross linking agent and characterized by X-ray diffractometry, differential scanning calorimetry and scanning electron microscopy. The effect of drug: polymer ratio, temperature of oil phase, amount of gluteraldehyde and stirring time was studied with respect to entrapment efficiency, micropellet size and drug release characteristics. Spherical micropellets having an entrapment efficiency of 57% to 97% were obtained. Differential scanning calorimetric analysis confirmed the absence of any drug-polymer interaction. The micromeritic studies of micropellets show improved flow property. The entrapment efficiency, micropellet size and drug release profile was altered significantly by changing various processing parameters.     

Novel micropelletization technique: highly improved dissolution, wettability and micromeritic behavior of domperidone

The aim of the investigation is to improve the dissolution, wettability, and micromeritic behavior of domperidone, a dopamine antagonist, used in the treatment of nausea and vomiting. Micropelletization technique, a possible approach for ensuring maximum dissolution with enhanced wettability, and uniform pellet size almost spherical so as to achieve the smooth gastric transit of drug have been estimated. Micropellets were prepared utilizing solvent diffusion technique and all the process parameters such as solvent-non-solvent ratio, stirring speed, temperature, and effect of aggregating agent on the micropellets formulation have been optimized. The addition of an aggregating agent (10%v/v of isopropyl alcohol) improved the uniform micropellets formation and the method was reproducible. The micromeritic properties such as size distribution, surface property (using Scalar-USB digital photomicroscope), packability, and flowability of the formulated micropellets were characterized. Fourier transform infrared spectroscopy (FTIR) and Differential scanning calorimetric (DSC) analysis were performed to explain the results. Formulated micropellets showed clear and highly improved in vivo dissolution behavior, probably due to high wettability. The micropelletized drug was stable at room temperature, 25 degrees C/60% relative humidity (RH), and 45 degrees C/70% RH, after 12 weeks.     

Study of processing parameters influencing the properties of diltiazem hydrochloride microspheres

Diltiazem hydrochloride-ethylcellulose microspheres were prepared by the water-in-oil emulsion-solvent evaporation technique. Small and spherical microspheres having a mean microsphere diameter in the range of 40-300 microm and entrapment efficiency of approximately 60-90% were obtained. Scanning electron micrographs of drug-loaded microspheres showed the presence of uniformly distributed small pores and absence of drug crystals on their surface, indicating simultaneous precipitation of drug and the polymer from the solvent during solvent evaporation. Differential scanning calorimetric analysis confirmed the absence of any drug-polymer interaction. The in vitro release profile could be altered significantly by changing various processing parameters to give a controlled release of drug from the microspheres. The stability studies of the drug-loaded microspheres showed that the drug was stable at storage temperatures, 5-55 degreesC, for 12 weeks.     

Study of processing parameters influencing the properties of Diltiazem hydrochloride microspheres

Diltiazem hydrochloride-ethylcellulose microspheres were prepared by the water-in-oil emulsion-solvent evaporation technique. Small and spherical microspheres having a mean microsphere diameter in the range of 40-300 µm and entrapment efficiency of ~60-90% were obtained. Scanning electron micrographs of drug-loaded microspheres showed the presence of uniformly distributed small pores and absence of drug crystals on their surface, indicating simultaneous precipitation of drug and the polymer from the solvent during solvent evaporation. Differential scanning calorimetric analysis confirmed the absence of any drug-polymer interaction. The in vitro release profile could be altered significantly by changing various processing parameters to give a controlled release of drug from the microspheres. The stability studies of the drug-loaded microspheres showed that the drug was stable at storage temperatures, 5-55°C, for 12 weeks.     

A new approach for preparing a controlled release ketoprofen tablets by using beeswax

Solid lipid ketoprofen micropellets (SLKM) at different drug/beeswax ratios [(1:1) and (1:2)] were prepared by emulsion congealing technique and then compressed into tablets. Ketoprofen in solid state was incorporated into the melted beeswax at 90 degrees C and the mixture was emulsified in the hot aqueous Tween 80 solution by stirring at a constant rate. The SLKM were obtained by cooling the coarse emulsion down to room temperature and filtering. Drug entrapment efficiency and particle size analysis by laser diffractometry (LD) were determined, and existence of a drug-lipid interaction was investigated by differential scanning calorimetry (DSC) on the SLKM, before being compressed into the tablets by direct compression method. Finally, in vitro release studies were performed and the release kinetics of the waxy tablets were calculated. A commercial ketoprofen retard tablet (reference: Profenid Retard 200 mg) was also examined to compare the release properties. While the data obtained from DSC were indicating absence of drug-lipid interaction in the SLKM, it was determined that 28.62% (+/-2.08), 38.60% (+/-1.91) and 47.00% (+/-1.82) of ketoprofen was released from the tablets containing (1:2) and (1:1) SLKM and Profenid Retard 200 mg in pH 7.4 phosphate buffer solution after 8 h, respectively.     

Evaluation of furosemide-loaded alginate microspheres prepared by ionotropic external gelation technique

Alginate microspheres containing furosemide were prepared by the ionotropic external gelation technique using Ca2+, Al3+ and Ba2+ ions. The incorporation efficiency of the prepared microspheres ranged between 65% and 93%. The effect of sodium alginate concentration, cross-linking ions and drying conditions was evaluated with respect to entrapment efficiency, particle size, surface characteristics and in vitro release behavior. Infrared spectroscopic study confirmed the drug-polymer compatibility. Differential scanning calorimetric analysis revealed that the drug was molecularly dispersed in the alginate microsphere matrices. Scanning electron microscopic study of microspheres showed the rough surface due to higher concentration of drug molecules dispersed at molecular level in the alginate matrices. The mean particle size and entrapment efficiency were found to be varied by changing various formulation parameters. The in vitro release profile could be altered significantly by changing various formulation parameters to give a sustained release of drug from the microspheres. The kinetic modeling of the release data indicate that furosemide release from the alginate microspheres follow anomalous transport mechanism after an initial lag period when the drug release mechanism was found to be Fickian diffusion controlled.     

Design and Evaluation of Niacin Microspheres

Present study aims to prepare and evaluate niacin microspheres. Niacin-ethyl cellulose microspheres were prepared by water-in-oil-in-oil double emulsion solvent diffusion method. Spherical, free flowing microspheres having an entrapment efficiency of 72% were obtained. The effect of polymer-drug ratio, surfactant concentration for secondary emulsion process and stirring speed of emulsification process were evaluated with respect to entrapment efficiency, in vitro drug release behavior and particle size. FT-IR and DSC analyses confirmed the absence of drug-polymer interaction. The in vitro release profile could be altered significantly by changing various processing and formulation parameters to give a controlled release of drug from the microspheres. The percentage yield was 85%, particle size range was 405 to 560 μm. The drug release was controlled for 10 h. The in vitro release profiles from optimized formulations were applied on various kinetic models. The best fit with the highest correlation coefficient was observed in Higuchi model, indicating diffusion controlled principle. The in vitro release profiles of optimized formulation was studied and compared with commercially available niacin extended release formulation.     

Evaluation of zidovudine encapsulated ethylcellulose microspheres prepared by water-in-oil-in-oil (w/o/o) double emulsion solvent diffusion technique

The preparation of zidovudine-loaded ethylcellulose microspheres by w/o/o double emulsion solvent diffusion method with high entrapment capacity and sustained release is described. A mixed solvent system (MSS) consisting of acetonitrile and dichloromethane in a 1:1 ratio and light liquid paraffin was selected as primary and secondary oil phases, respectively. Span 80 was used as the secondary surfactant for stabilizing the external oil phase. Spherical free flowing microspheres were obtained. The prepared microspheres were characterized by entrapment efficiency, in vitro release behavior, differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The drug-loaded microspheres showed 32 - 55% entrapment capacity. The in vitro release profile could be altered significantly by changing various processing and formulation parameters to give sustained release of drug from the microspheres. The DSC thermograms confirmed the absence of any drug-polymer interaction. SEM studies showed that the microspheres were spherical and porous in nature. The in vitro release profiles from microspheres of different polymer-drug ratios were best fitted to Higuchi model with high correlation coefficient and the n value obtained from Korsmeyer-Peppas model was ranged between 0.23 - 0.54. The drug release was found to be diffusion controlled mechanism.     

Design and in Vitro Evaluation of Dapsone-Loaded Micropellets of Ethyl Cellulose

A controlled-release dosage form was manufactured by dispersing ethyl cellulose sol in acetone into a medium of mineral oil. Dapsone was used as the model drug. The powdered drug was dispersed in the ethyl cellulose sol, and the formulation variables affecting the production of the discrete and spherical micropellets and their size distribution were investigated. The percentage of SPAN 80 in the formulation affected the yield and physical properties of the micropellets. The in vitro drug release followed first-order diffusion-controlled dissolution. More than 85% of the drug was released over 5 hr for all formulation batches, with delayed release over the drug dissolution profile.     

Optimization of Spray-Dried and -Congealed Lipid Micropellets and Characterization of Their Surface Morphology by Scanning Electron Microscopy

Lipid micropellets prepared from glycerides and phospholipids may be a physiological drug carrier system for improving the intestinal absorption of lipophilic drugs. They can be prepared by spray-drying and spray-congealing processes. In this study, formulation and optimization parameters of spray-dried and -congealed lipid pellets in the micro- and nanometer size were investigated. The rapid evaporation of solvents from the droplets, which in turn causes a rapid solidification, influenced the crystalline structures of spray-dried glycerides. Moreover, solvents, the chain length, and the type of lipids and drugs used in the formulations of spray-dried micropellets affected the surface morphology of the micropellets. In contrast to the variations of the surface structure of spray-dried micropellets, formulated spray-congealed micropellets possessed smooth surface properties. The surface morphology and microstructure of both types of micropellets were characterized by SEM.     

Mechanism of in vitro release kinetics of flurbiprofen loaded ethylcellulose micropellets

Flurbiprofen loaded ethylcellulose micropellets with different drug loading were prepared by a quasi-emulsion solvent diffusion technique. Encapsulation parameters of micropellets such as actual drug loading, drug encapsulation efficiency (DEE) and loss of coating polymer (LCP) were determined. Actual drug loading was increased with the increased initial drug loading whereas encapsulation efficiency decreased with the increase of actual drug loading. In vitro drug release profiles of these micropellets were evaluated in distilled water (DW) and also in phosphate buffer solution (PBS) to indicate pH dependency release rates. All the batches of micropellets released about 35-59% in DW and 89-97% in PBS during the period of 8 h and the burst effect of about 50-75% in the first 1.5 h was seen only in PBS. The mechanism of release kinetics was evaluated by fitting the release data to the zero order, first order, Higuchi, Baker-Lonsdale and Peppas equations and also to the differential forms of zero order, first order and Higuchi model. Adequate fitting of release data was found with first order, Higuchi and Peppas models and hence these models were selected for F-test statistics for ascertaining the mechanism of drug release. Higuchi model of drug release in DW and PBS of all the formulations was ruled out due to its significantly different F-value with other models. Thus, mechanism of release of flurbiprofen from ethylcellulose micropellets may be explained by the diffusional exponent model of Peppas et al. as ascertained by F-test statistics rather than the same, based on some other diffusional models even though they have shown good correlation.     

Preparation and In Vitro Characterization of Mucoadhesive Hydroxypropyl Guar Microspheres Containing Amlodipine Besylate for Nasal Administration

Amlodipine besylate microspheres for intranasal administration were prepared with an aim to avoid first-pass metabolism, to achieve controlled blood level profiles and to improve therapeutic efficacy. Hydroxypropyl Guar, a biodegradable polymer, was used in the preparation of microspheres by employing water in oil emulsification solvent evaporation technique. The formulation variables were drug concentration, emulsifier concentration, temperature, agitation speed and polymer concentration. All the formulations were evaluated for particle size, particle shape and surface morphology by scanning electron microscopy, percentage yield, drug entrapment efficiency, in vitro mucoadhesion test, degree of swelling and in vitro drug diffusion through sheep nasal mucosa. The microspheres obtained were free flowing, spherical and the particles ranged in size from 13.4±2.38 μm to 43.4±1.92 μm very much suitable for nasal delivery. Increasing polymer concentration resulted in increased drug entrapment efficiency and increased particle size. Amlodipine besylate was entrapped into the microspheres with an efficiency of 67.2±1.18 % to 81.8±0.64 %. The prepared microspheres showed good mucoadhesion properties, swellability and sustained the release of the drug over a period of 8 h. The data obtained were analysed by fitment into various kinetic models; it was observed that the drug release was matrix diffusion controlled and the release mechanism was found to be non-Fickian. Stability studies were carried out on selected formulations at 5±3°, 25±2°/60±5% RH and 40±2°/75±5% RH for 90 days. The drug content was observed to be within permissible limits and there were no significant deviations in the in vitro mucoadhesion and in vitro drug diffusion characteristics.     

Influence of processing and curing conditions on beads coated with an aqueous dispersion of cellulose acetate phthalate.

The influence of fluidized-bed processing conditions, as well as curing parameters with and without humidity, on drug release from beads coated with cellulose acetate phthalate (CAP) aqueous dispersion was investigated. Theophylline beads prepared by extrusion-spheronization were coated with diethyl phthalate (DEP)-plasticized CAP dispersion (Aquacoat CPD) using a Strea-1 fluidized-bed coater. The parameters investigated were plasticizer level, outlet temperature, spray rate during coating application and fluidizing air velocities using a half-factorial design. The processing temperature during coating applications was identified as a critical factor among the variables investigated. The release rate significantly decreased when the beads were coated at 36 degrees C compared to those coated at 48 degrees C (P<0.01). Higher coating efficiencies and better coalescence of films were obtained at the lower coating temperature. Above the minimum film-formation temperature (MFFT), drug release in acid decreased as the coating temperature was decreased. Curing at 60 degrees C significantly reduced the drug release for beads coated at 32 degrees C, but had no significant effect on drug release for beads coated at temperatures above 36 degrees C. Curing at 50 degrees C in an atmosphere containing 75% RH (relative humidity), irreversibly converted poor film formation into better coalescence, and increased the mechanical toughness of films. Subsequent removal of the moisture absorbed from beads did not significantly alter the enteric profiles obtained through heat-humidity curing. The extent of coalescence via heat-humidity curing was dependent on the curing temperature, % humidity, curing time and coating temperature. The results demonstrated the importance of the selection of coating temperature for CAP-coated beads and the role of moisture on CAP film formation. Curing with humidity was found to be more effective than without.     

Preparation and in vitro release behaviour of 5-fluorouracil-loaded microspheres based on poly (L-lactide) and its carbonate copolymers

A modified oil-in-oil (o/o) emulsion solvent evaporation technique was adopted to prepare 5-fluorouracil (5-Fu)-loaded poly (L-lactide) (PLLA) or its carbonate copolymer microspheres. The disperse phase was a drug:polymer solution using a solvent mixture of N,N-dimethylformamide (DMF) and acetonitrile and the continuous phase was liquid paraffin containing 1-10% (w/v) Span 80(R). The effects of preparative parameters, such as the composition of the inner oil phase, drug:polymer ratio, polymer concentration and agitation rate, on 5-Fu entrapment efficiency and microsphere characteristics were investigated. By introducing 25% (v/v) DMF into the inner oil phase, microspheres with high drug entrapment efficiency and an ameliorated burst effect were achieved. Using this modified method, microspheres with various particle sizes could be produced with a high 5-Fu entrapment efficiency (about 80%). In vitro drug release tests showed a burst release of 5-Fu from PLLA microspheres, followed by a sustained release over 50 days. In the case of poly (L-lactide-co-1,3-trimethylene carbonate) (PLTMC) and poly (L-lactide-co-2,2-dimethyl-1,3-trimethylene carbonate) (PLDTMC), the drug release could be continued for over 60 days.     

双氯芬酸钠缓释微丸在兔体内的药动学

目的：测定双氯芬酸钠缓释微丸（DS－SRMP）在家兔体内药动学及相对生物利用度。方法：用紫外分光光度法测定家兔体内的血药浓度，研究DS－SRMP的吸收动力学及生物利用度。结果：DS－SRMP在体内0－8h的吸收速度符合表观零级动力学过程，其Ka^0＝12．14％/h。结论：体内药动学研究表明，DS－SRMP缓释效果明显，给药后血药浓度较为平缓，持续作用时间长，可减少给药次数。该缓释制剂相对于其普通片剂具有释药稳定，生物利用度高，安全有效等制剂学意义。     

Effect of Formulation and Processing Variables on the Characteristics of Tolmetin Microspheres Prepared by Double Emulsion Solvent Diffusion Method

The aim of this study was to evaluate microencapsulated controlled release preparations of tolmetin sodium using ethylcellulose as a retardant material. Microspheres were prepared by using water-in-oil-in-oil (W/O₁/O₂) double-emulsion solvent diffusion method, using different ratios of ethylcellulose to tolmetin sodium. Span 80 was used as the droplet stabilizer and n-hexane was added to harden the microspheres. The prepared microspheres were characterized for their micromeritic properties, drug content, loading efficiency, production yield, and particle size. Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray powder diffractometry and scanning electron microscopy were used to characterize microparticles. The in vitro release studies were performed in pH 1.2 and 7.4. The prepared microspheres were spherical in shape. The drug-loaded microspheres showed near to the theoretical of entrapment and release was extended up to 24. The X-ray diffractogram and differential scanning thermographs showed amorphous state of the drug in the microspheres. It was shown that the drug: polymer ratio, stirring rate, volume of dispersing medium and surfactant influenced the drug loading, particle size and drug release behavior of the formed microparticles. The results showed that, generally, an increase in the ratio of drug: polymer (0.5:1) resulted in a reduction in the release rate of the drug which may be attributed to the hydrophobic nature of the polymer. The in vitro release profile could be modified by changing various processing and formulation parameters to give a controlled release of drug from the microparticules. The release of tolmetin was influenced by the drug to polymer ratio and particle size and was found to be diffusion and erosion controlled. The best-fit release kinetic was achieved with Peppas model.     

酮咯酸氨丁三醇海藻酸钠-壳聚糖微囊的制备

以微囊的载药量和包封率为指标,采用均匀设计,结合非线性规划法优化酮咯酸氨丁三醇海藻酸钠-壳聚糖微囊的制备工艺.结果表明,按优化条件制得的微囊包封率90%,载药量44%,在水中的释药行为符合Higuchi方程.     

Development and characterization of spray-dried porous nanoaggregates for pulmonary delivery of anti-tubercular drugs

Tuberculosis, MTB or tubercle bacillus (TB) is a lethal, infectious disease mainly caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. In this study, guar gum-based porous nanoaggregates were formulated by precipitation technique with two frontline antitubercular drugs, i.e. isoniazid and rifampicin. The formulations were optimized on the basis of various evaluation parameters such as morphology, density, entrapment efficiency and in vitro drug release. The optimized formulations were administered by inhalable route to Wistar rats for the evaluation of drugs in different organs (lungs, liver and kidneys). High drug encapsulation efficiency was achieved in guar gum porous nanoaggregates, ranging from 50% to 60%. A single pulmonary dose resulted in therapeutic drug concentrations of 30%–50% in the lungs and in other organs (less than 5%) for 24?h. From this study, we can conclude that delivering drugs through pulmonary route is advantageous for local action in lungs. Furthermore, the formulation showed sustained drug release pattern, which could be beneficial for reducing the drug dose or frequency of dosing, thus helpful in improving patient compliance.     

Effect of processing temperature on Eudragit RS PO microsphere characteristics in the solvent evaporation process

Eudragit RS PO microspheres containing stavudine as a model drug were prepared by the solvent evaporation method using acetone liquid paraffin system. The influence of processing temperature: 10, 30 and 40 degrees C on various parameters like particle shape, size distribution, drug loading, drug polymer interaction and release kinetic were studied. It was found that at lower temperature (10 degrees C) small particles of irregular size, rough and wrinkled surface were formed, whereas higher temperature gradually increases the particle size as well as improves the shape and smoothness of microspheres. It was found that temperature had no effect on encapsulation efficiency and drug polymer compatibility. Drug release rate from microspheres were found to be a function of mean particle size distribution.     

Water vapor sorption of hot-melt extruded hydroxypropyl cellulose films: effect on physico-mechanical properties, release characteristics, and stability

Hot-melt extrusion technology was used to prepare thin polymer films containing hydroxypropyl cellulose and clotrimazole (CT). Films containing hydroxypropyl celluloses of different molecular weight and the drug were investigated for moisture-sorption, mechanical properties, and release characteristics. Stability of the films was also studied at 25 degrees C/60% relative humidity (RH) and 40 degrees C/75% RH for up to 3 months. To study the moisture-sorption of the hot-melt extruded films, a rapid dynamic vapor sorption technique was used. Mechanical properties were evaluated using the Texture Analyzer. The molecular weight of the polymer had a significant effect on the mechanical and release characteristics of the films but did not influence the equilibrium moisture content in the films stored at RHs ranging from 0 to 90%. However, the time to reach equilibrium was longer for the higher molecular weight polymers. The drug release rate was dependent on the rate of erosion, which in turn depended on the molecular weight of the polymer. The films were stable at 25 degrees C/60% RH for up to 3 months with no significant degradation or recrystallization of CT. However, recrystallization of the drug was observed within the films stored in accelerated stability conditions at the end of 3 months in which only 92.9% (+/-1.9) CT remained.