Ibuprofen-loaded ethylcellulose microspheres: Release studies and analysis of the matrix structure through the Higuchi model

Abstract

The following work deals with ibuprofen-loaded ethylcellulose microspheres. The drug exists either in a state of molecular dispersion or in crystalline form, depending on the encapsulation ratio. The in vitro release profiles have been studied and the Higuchi model applied to the experimental results. With an appropriate treatment of the results, it has been shown that the surface crystals responsible for the observed burst effect are really encapsulated by the polymer. The calculation of the tortuosity factor clearly shows that the release kinetics are controlled by the hydrophobicity of ethylcellulse and the geometry of the porous volume resulting from the dissolution of ibuprofen crystals. It thus appears that crystals are probably differently distributed in the matrix depending on the microsphere size.     

Ibuprofen-loaded ethylcellulose/polystyrene microspheres: an approach to get prolonged drug release with reduced burst effect and low ethylcellulose content

The aim of this study was to develop ethylcellulose microspheres for prolonged drug delivery with reduced burst effect. Ethylcellulose microspheres loaded with ibuprofen were prepared with and without polystyrene, which was used to retard drug release from ethylcellulose microspheres. Ibuprofen-loaded ethylcellulose microspheres with a polystyrene content of 0-25% were prepared by the solvent evaporation technique and characterized by drug loading, infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy. The in vitro release studies were performed to study the influence of polystyrene on ibuprofen release from ethylcellulose microspheres. The microspheres showed 28-46% of drug loading and 80-92% of entrapment, depending on polymer/drug ratio. The infrared spectrum and thermogram showed stable character of ibuprofen in the microspheres and revealed an absence of drug polymer interaction. The prepared microspheres were spherical in shape and had a size range of 0.1-4 microm. Ethylcellulose/polystyrene microspheres showed prolonged drug release and less burst effect when compared to microspheres prepared with ethylcellulose alone. Microspheres prepared with an ethylcellulose/polystyrene ratio of 80:20 gave a required release pattern for oral drug delivery. The presence of polystyrene above this ratio gave release over 24 h. To find out the mechanism of drug release from ethylcellulose/polystyrene microspheres, the data obtained from in vitro release were fitted in various kinetic models. High correlation was obtained in Higuchi and Korsmeyer-Peppas models. The drug release from ethylcellulose/polystyrene microspheres was found to be diffusion controlled.     

Ibuprofen-loaded ethylcellulose/polystyrene microspheres: An approach to get prolonged drug release with reduced burst effect and low ethylcellulose content

The aim of this study was to develop ethylcellulose microspheres for prolonged drug delivery with reduced burst effect. Ethylcellulose microspheres loaded with ibuprofen were prepared with and without polystyrene, which was used to retard drug release from ethylcellulose microspheres. Ibuprofen-loaded ethylcellulose microspheres with a polystyrene content of 0–25% were prepared by the solvent evaporation technique and characterized by drug loading, infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy. The in vitro release studies were performed to study the influence of polystyrene on ibuprofen release from ethylcellulose microspheres. The microspheres showed 28–46% of drug loading and 80–92% of entrapment, depending on polymer/drug ratio. The infrared spectrum and thermogram showed stable character of ibuprofen in the microspheres and revealed an absence of drug polymer interaction. The prepared microspheres were spherical in shape and had a size range of 0.1–4μm. Ethylcellulose/polystyrene micro-spheres showed prolonged drug release and less burst effect when compared to microspheres prepared with ethylcellulose alone. Microspheres prepared with an ethylcellulose/polystyrene ratio of 80:20 gave a required release pattern for oral drug delivery. The presence of polystyrene above this ratio gave release over 24 h. To find out the mechanism of drug release from ethylcellulose/polystyrene microspheres, the data obtained from in vitro release were fitted in various kinetic models. High correlation was obtained in Higuchi and Korsmeyer-Peppas models. The drug release from ethylcellulose/polystyrene microspheres was found to be diffusion controlled.     

Novel Film Modifiers to Alter the Physical Properties of Composite Ethylcellulose Films

No HeadingPurpose. Polyvinylpyrrolidone (PVP), molecular-composite PVP, and Plasdone S-630 copolyvidonum are potential polymeric film modifiers for achieving improved drug release. The aim of this study was to investigate how these polymeric additives would affect the physicomechanical properties of composite ethylcellulose films.Methods. The miscibility of these polymeric additives with ethylcellulose was determined from the differential scanning calorimetry (DSC) thermograms of various polymer blends formed from organic solvents. It was found that ethylcellulose (EC) was miscible with the polymeric additives up to a concentration of 50%. Ten percent to 30% w/w polymeric additives were then added to aqueous ethylcellulose dispersion to form composite films. The morphology, film transparency, dynamic mechanical analysis (DMA) thermograms, and mechanical properties of the composite ethylcellulose films were studied. In addition, puncture strength and % elongation of the dry and wet films were also compared from indentation test.Results. Significant reduction and change in film transparency and morphology was obtained for EC films blended with PVP of higher molecular weight (MW). The composite EC films also showed higher T_g, greater elastic modulus, tensile and puncture strength depending on the concentration and type of additives present.Conclusions. The interaction between ethylcellulose and the polymeric additives is dependent on the MW and concentration of additives. The composite films offer new opportunities for the use of ethylcellulose as modified release coatings for dosage forms.     

Modification of ketoprofen bead structure produced by the spherical crystallization technique with a two-solvent system

Poorly-compressible crystals of ketoprofen were agglomerated by the spherical crystallization technique with a two-solvent system (acetone/demineralized water). In order to study a possible modification of particle texture, spherical crystals were formulated with low concentrations of additives. The results showed that the procedure was possible with ethylcellulose, cross-linked PVP and cross-linked CMC, all at a concentration of 1%. However, no spherical beads could be obtained with the water-soluble compounds tested (PVP and Eudragit L100-55®), Eudragit RS100® and colloidal silica. These formulation trials have indicated two main factors with their possible influences: the polymer solubility and viscosity in the solvent/non-solvent system leading to two kinds of nucleation and changes in mass transfer and drug/polymer interactions leading to the formation of reversible complexes or irreversible complexes and possibility of drug release modifications. Moreover, formulations with the methacrylic acid derivatives were found to be incompatible with the operating conditions, in terms of temperatures changes, stirring or residence time. Furthermore, an optimization of the formulation with ethylcellulose yielded a controlled release form with 1% of the polymer, whereas the addition of very low concentrations increased the drug release.     

Preparation and evaluation of sustained release microspheres of potassium chloride prepared with ethylcellulose

The water-insoluble polymer ethylcellulose is used as a retardant to prepare the sustained release of potassium chloride microspheres by drying in a liquid process. The effect of sustained release of potassium from ethylcellulose microspheres was evaluated by the in vitro dissolution test, and was compared to a commercial product (Slow-K). The results showed that ethylcellulose microspheres loaded with potassium chloride could be easily prepared and satisfactory results could be obtained considering size distribution and shapes of microspheres by incorporating aluminum stearate. The encapsulation efficiency and loading capacity were about 84-93 and 36%, respectively. However, the potassium/ethylcellulose 2/2 (30-45 mesh) microspheres showed the similar sustained release effect of commercial product.     

Effect of viscosity and concentration of wall former, emulsifier and pore-inducer on the properties of amoxicillin microcapsules prepared by emulsion solvent evaporation

This study reports the laboratory optimization for the preparation of sustained release amoxicillin (AMX) ethylcellulose microcapsules by an emulsion solvent evaporation process by adjusting the viscosity and concentration of ethylcellulose, ratio of amoxicillin to ethylcellulose, and concentration of emulsifier and pore inducer. When ethylcellulose with a viscosity of 45 mPa.s was used, almost no material stuck to the inside wall of the beaker and uniform microcapsules were prepared. The average diameter of microcapsules increased and yield and release rate decreased as the concentration of ethylcellulose increased from 1% to 8%. The release of amoxicillin from microcapsules was influenced by the ratio of the weight of drug to that of ethylcellulose and ratios of 2:1 and 4:1 were most suited for optimum amoxicillin release. The average diameter of microcapsules decreased and the release rate increased as the concentration of the emulsifier increased from 1.5% to 6.0%, however, the size distribution became significantly wider with the increase in the concentration of sorbitan monooleate. Addition of small amounts of a water-soluble agent sucrose improved the release of active ingredient from the microcapsule matrix without influencing the morphology and particulate properties of the microcapsules.     

Evaluation of the Properties of Ethylcellulose-Cellulose Triacetate Microcapsules Containing Theophylline Prepared by Different Microencapsulation Techniques

Abstract

Using cellulose triacetate as an added complementary coating material in preparing sustained-release ethylcellulose-cellulose triacetate microcapsules of theophylline, three microencapsulation techniques were investigated. Ethylcellulose-cellulose triacetate composite microcapsules, ethylcellulose-cellulose triacetate dual-walled microcapsules and ethylcellulose microcapsules containing cellulose triacetate matrices were prepared using the non-solvent addition phase separation method. The effects of cellulose triacetate on the release of theophylline from the different ethylcellulose-cellulose triacetate microcapsules were obtained from dissolution studies. The results showed that the release rates of ethylcellulose-cellulose triacetate microcapsules were slower than those obtained from the ethylcellulose microcapsules prepared with similar core to wall ratios. The ethylcellulose microcapsules containing cellulose triacetate matrices had longer release half-times and smaller surface areas than the other capsule preparation. The release patterns of theophylline from the different ethylcellulose-cellulose triacetate microcapsules fitted first-order kinetics. Scanning electron micrographs showed that the surfaces of various ethylcellulose-cellulose triacetate microcapsules were different from those of theophylline, cellulose triacetate matrices of cellulose triacetate microcapsules, and that the surface morphology of ethylcellulose-cellulose triacetate microcapsules was affected by the preparative method.     

Improved drug delivery to the lower intestinal tract with tablets compression-coated with enteric/nonenteric polymer powder blends

The objective of this study was to develop pH-erosion-controlled compression-coated tablets for potential colonic drug delivery with improved gastric resistance and pulsatile release based on compression-coatings of powder blends of the enteric polymer Eudragit® L100-55 and the extended release polymer ethylcellulose. Tablet cores containing model drugs of varying solubilities (acetaminophen, carbamazepine and chlorpheniramine maleate) were compression-coated with different ratios of Eudragit® L100-55:ethylcellulose 10cP FP at different compression forces and tablet core:compression-coat ratios. The compression-coated tablets were characterized by drug release, media uptake, erosion behaviour and wettability. All drugs were released in a pulsatile fashion in higher pH-media after a lag time, which was controlled by the erosion properties of the Eudragit L:ethylcellulose compression-coating. The addition of ethylcellulose avoided premature drug release in lower pH-media and significantly increased the lag time in higher pH-media because of a reduction in wettability, media uptake and erosion of the compression-coatings. Importantly, ethylcellulose also reduced the pH-dependency of the erosion process between pH 5.5 and 7.4. The lag time could also be increased by increasing the compression force and decreasing the core:compression-coat ratio. In conclusion, tablets compression-coated with blends of Eudragit L and ethylcellulose resulted in excellent release properties for potential targeting to the lower intestinal tract with no release in lower pH-media and rapid release after a controllable lag time in higher pH-media.     

制备条件对丝裂霉素微囊载药量及释放度的影响

目的:筛选制备高载药量和释放性能良好的丝裂霉素微囊的条件。方法:以溶剂非溶剂法制备了丝裂霉素微囊,用高效液相色谱法和紫外分光光度法测定丝裂霉素微囊载药量及释放度。结果:随着囊材用量减少,载药量升高,释放显现突释效应;随着吐温-80用量的增加,释放度逐渐加快,直至无规律释药;随着搅拌速度的加快,载药量先增加后减少,释放度增大。结论:以正己烷、环己烷为溶剂,最佳制备工艺条件是:0.8%的乙基纤维素,4%的吐温-80,100 r.min-1的搅拌速度。     

Use of fine particle ethylcellulose as the diluent in the production of pellets by extrusion-spheronization

The effect of small ethylcellulose particle size on the manufacture and properties of pellets produced by extrusion-spheronization was investigated. A factorial design revealed the effects of microcrystalline cellulose (MCC), polyethylene oxide (PEO), water, and spheronization speed and time on pellet properties. Response surface modeling allowed optimization of the responses with expansion to a central composite design. Pellet yield, size, shape, friability and drug release profile were studied, along with surface and interior morphology. Pellets were spherical irrespective of the formulation and process variables and exhibited physical and mechanical characteristics appropriate for further processing. Yield in the 12/20 mesh cut was lower with FPEC than observed with coarse particle ethylcellulose (CPEC), but FPEC-containing pellets were more rugged and the PEO to obtain optimal pellets was lower for FPEC compared to CPEC. Immediate release products were obtained and ethylcellulose particle size was of no consequence to drug release. Observed responses for the optimized product agreed with predicted values, demonstrating the success of the optimization procedure. These results suggest that FPEC is a good diluent for extrusion-spheronization.     

Evaluation of the drug release patterns and long term stability of aqueous and organic coated pellets by using blends of enteric and gastrointestinal insoluble polymers

The major aim of this study was to identify an efficient tool to adjust drug release patterns from aqueous and organic ethylcellulose (a gastrointestinal insoluble polymer) coated pellets and to evaluate the long term stability of the film coatings. Drug release was monitored during open and closed storage at 25 °C/60% RH (ambient conditions) and 40 °C/75% RH (stress conditions) for up to 24 months. Release of vatalanib succinate, a poorly soluble drug that demonstrates pH-dependent solubility, from pure ethylcellulose coated pellets was slow irrespectively of the type of coating and release medium. By addition of the enteric polymer methacrylic acid/ethyl acrylate copolymer (applied as aqueous Kollicoat MAE 30 DP dispersion or organic solution of Kollicoat MAE 100 P) to ethylcellulose broad ranges of drug release patterns could be achieved. For aqueous film coatings the addition of Kollicoat MAE 30 DP to ethylcellulose dispersions resulted in unaltered drug release kinetics during closed storage at ambient and stress conditions. The storage stabilizing effect of the added enteric polymer might be explained by the more hydrophilic nature of Kollicoat MAE 30 DP compared to ethylcellulose trapping water during film formation and improving polymer particle coalescence. However, during open storage of aqueous coated ethylcellulose:Kollicoat MAE 30 DP pellets at stress conditions drug release decreased due to further gradual polymer particle coalescence. In contrast, drug release rates from organic coated ethylcellulose:Kollicoat MAE 100 P pellets stored at ambient and stress conditions did not change which could be explained by differences in the film formation process. This clearly indicates that the presented concept of the addition of methacrylic acid/ethyl acrylate copolymer to ethylcellulose film coatings in combination with an organic coating process is able to achieve broad ranges of drug release patterns and to overcome storage instability.     

Studies on drug release from pectin/ethylcellulose film-coated tablets: a potential colonic delivery system

Combinations of pectin and ethylcellulose, when applied as a film coat, have potential value as a colonic delivery system. Aqueous dispersions of pectin and ethylcellulose were used to film coat paracetamol tablet cores. Drug release mechanisms were assessed using flow through dissolution testing in the presence and absence of enzymes. Drug release from the coated systems was complex and depended on the nature and characteristics of the mixed film as well as the composition of the dissolution medium. Drug release profiles were compatible with a mechanism involving the formation of channels in the film caused by pectin dissolution. Channel formation was in most cases accelerated by the presence of pectinolytic enzymes showing that the pectin in the mixed film was susceptible to enzymic attack. Pectin, ethylcellulose combinations may have value as film coating preparations for colonic delivery. Formulation effects and mechanisms of drug release have been identified as a basis for further studies.     

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.     

Ibuprofen-loaded ethylcellulose microspheres: analysis of the matrix structure by thermal analysis.

The determination of the drug dispersion state in microspheres prepared by the solvent evaporation method is essential to foresee the stability of the particles and the drug release behavior. The present work deals with ibuprofen-loaded ethylcellulose microspheres, that are characterized by a lower drug melting point than the polymer glass transition temperature. Although annealing experiments were not possible, the study has evidenced the presence of a metastable molecular dispersion for intermediate loadings, coexisting with a solid solution and a crystalline dispersion of the drug in the polymer matrix. In addition, differential scanning calorimetry helped to distinguish between surface and inner ibuprofen crystals, which interact differently with the polymer matrix and therefore have different melting points.     

结肠定位释药瓜尔胶/乙基纤维素包衣小丸

体外研究瓜尔胶/乙基纤维素混合包衣小丸的结肠靶向性。以5-氟尿嘧啶为模型药， 采用流化包衣技术以瓜尔胶/乙基纤维素混合物的水/醇混悬液对载药小丸进行喷液包衣。瓜尔胶/乙基纤维素混合包衣小丸的释药行为取决于包衣处方中瓜尔胶与乙基纤维素的比例和包衣厚度。分别以混合包衣液中瓜尔胶与乙基纤维素的比例及包衣增重为自变量， 以T₅和T₉₀（药物释放5%和90%所需要的时间）为效应， 进行3×4析因设计/效应面优化， 筛选较优处方。结果表明随着乙基纤维素在衣层中所占比例的增大及包衣厚度的增加， 药物释放时滞增加。当瓜尔胶与乙基纤维素的比例在0.2~0.7， 并且包衣增重在250%~500%时， T_5%为5.1～7.8 h， T_90%为9.8～16.3 h。并且在释药时滞之后， 进入模拟结肠微菌群酶解作用的释放环境中(pH 6.5)药物释放速度加快， T_90%缩短到9.0～14.5 h。由此可以看出适当的瓜尔胶/乙基纤维素混合衣层既可以保护药物顺利通过上消化道而不释放， 达到结肠后药物开始释放， 并且可在结肠微菌群的酶解作用下加速药物的释放， 实现结肠定位释药的目的。     

Assessment of bioavailability of experimental single-unit sustained release tablets of verapamil hydrochloride using the stable isotope technique

A stable isotope technique has been used to assess the bioavailability of sustained release verapamil products. The test formulations were tablets with a core containing 90 mg of verapamil hydrochloride coated with ethylcellulose film, the permeability of which was controlled using different amounts of hydroxypropyl methylcellulose. A product containing ethylcellulose 75% hydroxypropyl methylcellulose 25% w/w gave a single-unit sustained release tablet of verapamil hydrochloride that allowed a dose interval of 24 h. There was no loss in bioavailability, even though verapamil had extensive first-pass metabolism.     

Formulation parameters affecting the preparation and properties of microencapsulated ion-exchange resins containing theophylline

A method of microencapsulating theophylline ion-exchange resins with ethylcellulose was developed to produce smooth and uniform coats which were predominantly mononucleated. This was achieved by controlling the amount of ethylcellulose and the particle size, and through the use of a protective colloid, polyisobutylene. The rate of release of theophylline was influenced by the ion-exchange resin crosslinking, the amount of ethylcellulose, and the smoothness of the coat. Mesh size and polyisobutylene did not appear to affect the rate in a regular manner. It was found that the release rate from coated resins with low crosslinking followed a logarithmic plot, indicating membrane-controlled release, whereas coated resins with high crosslinking fitted a t1/2 plot, suggesting particle diffusion control.     

The effect of hydrophilic and lipophilic polymers and fillers on the release rate of atenolol from HPMC matrices

The objective of this study is to investigate the effect of various polymers, and fillers, and their concentrations on the release rate of atenolol from polymeric matrices. Four polymers namely hydroxypropylmethylcellulose (HPMC), Eudragit RSPO, ethylcellulose (EC) and sodium carboxymethylcellulose (NaCMC) were used. The dissolution profiles showed that an increase in the concentration of HPMC and EC resulted in a reduction in the release rate of atenolol. The results indicate that it is difficult to obtain a zero-order release from the matrices containing either HPMC or EC. It is also observed that the amount of HPMC played a dominant role, affecting the drug release in binary mixtures of Eudragit-HPMC. Generally, the presence of NaCMC caused an increase in the release rate of atenolol from HPMC matrices. To determine the effect of fillers on the release rate of atenolol from HPMC matrices, lactose (a soluble filler) and dicalcium phosphate (an insoluble filler) were used. The results showed that an increase in the concentration of fillers resulted in an increase in the release rate of the drug from matrices and hydrophilicity or hydrophobicity of fillers had no significant effect on the release profile. In order to determine the mode of release, the data were analysed based on the equation Q = K (t - l)(m). Values of m were in the range of 0.32-0.99 indicating that release was controlled by both diffusion and erosion, depending on the type of polymer and concentration.     

Encapsulated microcapsules

A microencapsulation procedure has been developed which allows an oil slurry of microcapsules to be filled into soft gelatin capsules. Ethylcellulose solutions in ethyl acetate can be desolvated by the addition of light liquid paraffin so that an ethylcellulose coat is deposited on a core material such as aspirin. Approximately 1% of the aspirin is imperfectly encapsulated. The use of light liquid paraffin enables the slurry to be filled directly into soft gelatin capsules without the usual filtering, drying, and redispersion steps.Different release characteristics can be devised by varying the ratio of ethylcellulose to drug. In vitro release into a simulated gastric juice shows that essentially first-order kinetics exist for periods up to 12 hours.