Polyacrylate resin (Eudragit Retard) microcapsules as a controlled release drug delivery system improved non-solvent addition phase separation process

Abstract

Eudragit retard microcapsules were prepared using an improved non-solvent addition phase separation process with tetrahydrofuran as the solvent. The evolution of microcapsule wall formation was studied by direct methodology. Eudragit coacervation was effected by progressive uptake of tetrahydrofuran by the non-solvent cyclohexane in the presence of a protective colloid, polyisobu tylene (PIB). The core materials had a higher affinity for the acrylic that the PIB phase, thus ensuring encapsulation. Microcapsule batch reproducibility depended mainly on the variation in particle size distribution of the recrystallized core material. All batches gave apparent first-order release profiles, confirmed by regression procedures. The release rate was decreased by raising the wall/core ratio, holding constant concentration of either the wall polymer or the core material. Increase in the non-solvent addition rate elevated the release rate, probably due to structural changes in the microcapsule wall. The velocity fell, however, with decrease in particle size of the core material, contrary to expectations. PIB concentration increase elevated the release rate by enhancing wall porosity, shown by scanning electron microscopy.     

Formulation and evaluation of controlled release Eudragit buccal patches

Controlled release buccal patches were fabricated using Eudragit NE40D and studied. Various bioadhesive polymers, namely hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and Carbopol of different grades, were incorporated into the patches, to modify their bioadhesive properties as well as the rate of drug release, using metoprolol tartrate as the model drug. The in-vitro drug release was determined using the USP 23 dissolution test apparatus 5 with slight modification, while the bioadhesive properties were evaluated using texture analyzer equipment with chicken pouch as the model tissue. The incorporation of hydrophilic polymers was found to affect the drug release as well as enhance the bioadhesiveness. Although high viscosity polymers can enhance the bioadhesiveness of the patches, they also tend to cause non-homogeneous distribution of the polymers and drug, resulting in non-predictable drug-release rates. Of the various bioadhesive polymers studied, Cekol 700 appeared to be most satisfactory in terms of modifying the drug release and enhancement of the bioadhesive properties.     

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.     

Microencapsulation using poly(DL-lactic acid). III: Effect of polymer molecular weight on the release kinetics

Poly(DL-lactic acid) [DL-PLA] microcapsules containing phenobarbitone (PB) were prepared using a w/o emulsion-evaporation method. DL-PLA of three different molecular weights, 20,200, 13,300 and 5,200 were used to prepare microcapsules of nominal core: polymer (C:P) ratios of 1 : 2, 1 : 2.5, 1 : 3 and 1 : 4. The release of PB was investigated in aqueous buffer of pH 2, pH 7 and pH 9 at 37 degrees C and found to follow a square root of time dependent release mechanism. The first order and zero order release mechanisms were disproved by the lower correlation coefficient of the release data as compared to that of the t1/2 mechanism. These microcapsules showed an initial burst phase release followed by a lag phase, during which time little PB was released. This lag time was affected by the polymer molecular weight and pH of the buffer. The polymer matrix was hydrated during the lag phase and a steady state release occurred. The steady state release rate per unit specific surface area (Kh2/SSA) was found to increase exponentially with the increase in core loading of the microcapsules. However the extent of normalized release rate reduced linearly with the increase in polymer molecular weight at any particular core loading (e.g. 20 per cent or 30 per cent). Increases in the normalized steady state release rate with an increase in buffer pH could be correlated to PB solubility in the dissolution medium. PB release from these microcapsules was diffusion controlled. However, swelling and erosion also contributed to the release process.     

Eudragit E, L and S (acrylic resins) microcapsules as pH sensitive release preparations of ketoprofen

Microencapsulation of ketoprofen using Eudragit E, L and S (acrylic resins) was investigated. The preparation is based on the dispersion of acetone containing ketoprofen in liquid paraffin. Aluminium tristearate was used as an additive for the preparation of microcapsules. In the preparation of microcapsules, the reproducibility of the Eudragit E microcapsule was better than that of Eudragit L and S microcapsules. The microcapsules obtained were uniform and free-flowing particles. From the phase diagram of ketoprofen-Eudragit E or S-aluminium tristearate, it became clear that the region in which the spherical microcapsules ranging from 250 to 1000 microns in size could be prepared was limited. The dissolution patterns of ketoprofen from Eudragit E, L and S microcapsules were dependent on the pH of the dissolution medium.     

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

Abstract

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

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

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

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

Physicochemical characterization and drug release properties of Eudragit E PO/Eudragit L 100-55 interpolyelectrolyte complexes.

The formation of interpolyelectrolyte complexes (IPEC) between Eudragit E PO (EE) and Eudragit L 100-55 (EL) was investigated, using turbidimetry, apparent viscosity measurements, elementary analysis and MT-DSC. The structure of the synthesized IPEC was investigated using FT-IR spectroscopy. The binding ratio of a unit molecule of EL with EE was found to be approximately 1:1 at pH 5.5. Based on the results of elementary analysis and FT-IR, the binding ratio of each component in the solid complexes was very close to that observed in turbidity and apparent viscosity measurements and indicate that the synthesized products can be considered as IPEC. As a result of electrostatic interaction between the polymer chains, the glass transition temperature of the IPEC increased significantly. Due to the structure of the IPEC, two maxima were observed in the swelling behavior as a function of pH. The release of the model drug ibuprofen (IBF) was significantly retarded from tablets made up of the IPEC as compared with individual copolymers, its physical mixture and Eudragit RL PO (RL), RS PO (RS).     

In vitro evaluation of drug release kinetics from liposomes by fractional dialysis

A new dialysis method was designed with the purpose of studying drug release rate from liposomes. The liposomes were diluted directly in the continuous phase and dialysed against a small volume of buffer. The dialysate was changed at 10 min intervals and the amount of carboxyfluorescein released was calculated from a standard curve. To evaluate the new method, parallel measurements were recorded with the traditional carboxyfluorescein assay, which is based on direct measurements on liposomes containing a self-quenching concentration. The new method is called fractional dialysis, and is shown to have sensitivity similar to that of the carboxyfluorescein assay. In certain cases the fractional dialysis method gives a more accurate release profile. It is suggested that fractional dialysis can be a useful alternative to other techniques for recording the in vitro release characteristics of specific drugs from liposomes or other colloidal carriers.     

The preparation and evaluation of sustained release suppositories containing ketoprofen and Eudragit RL 100 by using factorial design

The preparation of ketoprofen (KP) sustained release (SR) suppositories was designed according to the 3(2) x 2(1) factorial design as three different KP:Eudragit RL 100 ratios (1:0.5, 1:1, 1:2), three particle sizes of prepared granules (250-500, 500-710, and 710-1000 microm) and two different PEG 400:PEG 6000 ratios (40:60, 50:50). The conventional KP suppositories were also prepared by using Witepsol H 15, Massa Estarinum B, Cremao and the mixture of PEG 400:PEG 6000. The dissolution studies of suppositories prepared were carried out according to the USP XXIII basket method in the phosphate buffer (pH = 7.2) at 50 rpm, and it was shown that the dissolution time was sustained up to 8 hours. According to the results of the factorial design, the most important independent variable on t50 and t80 was drug:polymer ratios. The log of partition coefficient of KP was determined as 1.46, showing the high affinity to the oily phase. n exponent and kinetic studies were conducted to explain diffusion mechanism, and it is understood that if the inert KP:Eudragit RL 100 ratio is increased in the particles, the Fickian difusion dominates and the best kinetic turns to Higuchi from the Hixson-Crowell. There is neither crystalline form of KP nor degradation product in the suppositories detected with the differential scanning calorimetry (DSC) studies. In addition to these studies, antiinflammatory activity of SR suppositories also determined that it was significantly extended according to the conventional suppositories.     

Analgesic efficacy of immediate and sustained release paracetamol and plasma concentration of paracetamol. Double blind,placebo-controlled evaluation using painful laser stimulation

Summary The analgesic efficacy of single doses of immediate release paracetamol 500 mg and 1000 mg, sustained release paracetamol 2000 mg, and placebo was evaluated over a 12 h period in 10 healthy volunteers. The efficacy was related to the concurrent plasma concentrations of paracetamol. Experimental pain was induced by brief cutaneous application of argon laser pulses, and the analgesic effect was assessed as change in pricking pain threshold.Both 0.5 g and 1.0 g immediate release paracetamol had an analgesic effect superior to that of placebo from 1 to 5 h after administration. Peak analgesia was reached after 2 h. No difference was found in the analgesic effect of the two dosages. Sustained release paracetamol was not significantly superior to placebo at any time. The plasma concentration of paracetamol had peaked in the 1 h sample after of the immediate release tablet. The peak plasma concentration was reached 3–4 h after 2.0 g sustained release paracetamol.It is not known why the sustained release formulation did not produce any detectable analgesia. It is proposed, that the rate of increase in the plasma concentration of paracetamol might be important in the alleviation of acute (laser-induced) pain.     

Design and evaluation of sustained release microspheres of potassium chloride prepared by Eudragit.

The aim of the present work was to prepare and evaluate the sustained release of potassium chloride formulations. Eudragit RS and/or RL loaded with potassium chloride microspheres were prepared by a solvent evaporation method. The effect of sustained release of Eudragit microspheres was evaluated by an in vitro dissolution test and in vivo oral absorption study, and the results were compared to a commercial product (Slow-K). The results showed that Eudragit microspheres loaded with potassium chloride can be easily prepared and satisfactory results obtained considering the size distribution and shapes of microspheres by incorporating aluminum stearate. The encapsulation efficiency and loading capacity were about 84-90% and 27%, respectively. Moreover, the Eudragit RS (30-45 mesh) and Eudragit RS/RL (20-30 mesh) microspheres showed a similar sustained release effect of commercial product via in vitro dissolution and in vivo oral absorption study.     

Evaluation of the sustained release properties of Eudragit RS, RL and S (acrylic resins) microcapsules containing ketoprofen in beagle dogs

Eudragit RS, RS-RL, RL and S microcapsules containing ketoprofen were prepared by the solvent evaporation process in oil phase. The sustained release effect of these microcapsules and Oruvail, the representative commercial product of ketoprofen, was evaluated by the pH shift dissolution method and in beagle dogs, respectively. The dissolution patterns of ketoprofen from Eudragit RS, RS-RL and RL microcapsules were independent of the pH of the dissolution medium, and its dissolution rate increased with increasing content of ketoprofen in microcapsules. But the dissolution pattern of ketoprofen from Eudragit S microcapsules and Oruvail was found to depend on the pH of the dissolution medium. The rank order of the dissolution rate of ketoprofen from Eudragit RS, RS-RL and RL microcapsules containing 30 and 40 per cent (w/w) ketoprofen was sufficiently clear as to enable prediction of the relative bioavailability of ketoprofen from these microcapsules. In vivo evaluation using beagle dogs, sustained release effects of Eudragit RL and Eudragit S microcapsules containing 30 per cent (w/w) ketoprofen and Eudragit RS-RL microcapsules containing 40 per cent (w/w) ketoprofen were almost the same as or slightly superior to that of Oruvail.     

Preparation and evaluation of Eudragit S 100 microspheres as pH-sensitive release preparations for piroxicam and theophylline using the emulsion-solvent evaporation method

Microencapsulation of the anti-inflammatory drug piroxicam and the anti-asthmatic drug theophylline was investigated as a means of controlling drug release and minimizing or eliminating local side effects. Microspheres of both drugs that are different in the chemical nature and size were successfully encapsulated at a theoretical loading of 25% with the pH sensitive Eudragit S 100 polymer using the emulsion-solvent evaporation method. Solvent composition, stirring rate and the volume of the external phase were adjusted to obtain reproducible, uniform and spherical microspheres. The size distribution of microsphere batches generally ranged from 125-500 microm with geometric means close to 300 microm. Optical light microscopy was used to identify the microsphere shape. Drug loading was determined by completely dissolving the microspheres in an alkaline borate buffer at pH 10. In vitro dissolution studies were carried out on the microspheres at 37 degrees C (+/-0.5 degrees C) at 100 rpm with USP Dissolution Apparatus II using the procedure for enteric-coated products at two successive different pH media (1.2 and 6.5). Both preparations exhibited an initial rapid release in the acidic medium with theophylline showing a larger increase in the amount released during this stage. The drug release was sustained for both preparations at pH 6.5 with theophylline microspheres, showing more extended release. Drug release rate kinetics followed a Higuchi spherical matrix model for both microsphere preparations.     

Modulation of drug release kinetics from hydroxypropyl methyl cellulose matrix tablets using polyvinyl pyrrolidone

Hydrophilic matrix tablets are widely used to extend the release of a broad range of pharmaceutically active materials. The mechanism and kinetics of drug release are dependent on the solubility of the active moiety and the swelling and erosion properties of the polymer, with water soluble compounds released predominantly by diffusion. The swelling and erosion properties of hydroxypropyl methyl cellulose (HPMC), typically lead to a first order release rate for water soluble compounds as opposed to the more desirable zero-order kinetics. In addition, for compounds with differences in regional absorption within the gastrointestinal tract a dosage form with a bi-modal release profile may be required, which is difficult to achieve with a simple dosage form. The following paper presents a simple, cost effective and elegant solution for achieving a range of predictable release profiles from linear to bi-modal for a water soluble drug (caffeine) from HPMC matrices, through the inclusion of polyvinyl pyrrolidone (PVP). Mechanistic studies using gel rheology, excipient dissolution and near-infrared microscopy (NIR) microscopy are presented which show that the modulation of drug release kinetics is mediated through a reduction in HPMC viscosity in the presence of a critical concentration of PVP, which leads to a break-up of the extended release tablet. A validated mathematical model is also presented which allows drug release profiles to be reliably predicted based on the initial HPMC and PVP content in the tablet.     

Erythropoietin encapsulation in chitosan nanoparticles and kinetics of drug release

Recombinant human erythropoietin (rHu-EPO) is a glycoprotein, which is produced commercially from Chinese hamster ovary (CHO) cells. It is used for the therapy of renal anemia and chemotherapy-induced anemia in cancer patients. Recent evidence suggests that rHu-EPO exerts tissue protective effects via multiple mechanisms which include inhibition of apoptosis, promotion of angiogenesis and decreased inflammation. After intravenous (i.v.) injection, the blood concentration of rHu-EPO rapidly decreases due to proteolysis resulting in a relatively short half-life of 8.5 h, which necessitates regular dosing with intervals that do not exceed 7 days. It would be desirable to develop an encapsulated formulation providing controlled release of rHu-EPO to maintain therapeutic concentrations in plasma, and for potential tissue protective applications to maintain high local therapeutic concentrations in tissue while minimizing potential unwanted systemic effects such as polycythemia and platelet activation, both of which can predispose to intravascular thrombosis. Nanoparticle encapsulation of rHu-EPO can also allow for direct injection at sites of injury in specific tissues/organs, again minimizing systemic exposure of the drug. In this paper, we report the production of biopolymer nanoparticles by ionotropic gelation of chitosan with tripolyphosphate (TPP). The nanoparticle size distribution in aqueous solution was determined and rates of rHu-EPO release from chitosan-TPP nanoparticles were measured in PBS at 37°C. It was observed that almost 30% of the encapsulated rHu-EPO was released within the first 48 hours and thereafter a linear release profile was observed for up to 2 weeks. Total drug release over 15 days was 63% of the initial amount.     

Sustained release of drugs from ethylcellulose--polyethylene glycol films and kinetics of drug release.

Cast films composed of different ratios of polyethylene glycol and ethylcellulose containing salicylic acid, caffeine, and tripelennamine as model dispersed drugs were prepared and exhibited sustained release. The drug content of the film declined at an apparent first-order rate initially, whereas the drug quantity released was proportional to the square root of time. Data analysis validated the latter treatment, which is in accordance with the diffusional matrix model, and disproved the validity of the apparent first-order conformity. The release rates were independent of film thickness and proportional to drug concentration in pure ethylcellulose films; in polyethylene glycol--ethylcellulose films, a positive deviation from linearity was observed. The logarithm of the rate constant was proportional to the fraction of polyethylene glycol in the film. Unlike in pure ethylcellulose films, the release rate in mixed films was altered by a change in the external fluid pH.     

In vitro drug liberation and kinetics of sustained release indomethacin suppository

The aim of this study was to formulate sustained release (SR) suppositories containing indomethacin (IND) microspheres. In the first part of the study, IND microspheres were prepared by solvent evaporation method. Ethyl cellulose was used as polymer. Shape and surface characteristics, particle size and size distribution of microspheres were determined. The effect of drug: polymer ratio and stirring rate on microsphere formation, average particle size, drug loading capacity and in vitro IND release were investigated. The highest drug loading capacity was found with 1:1 drug-polymer ratio. Stirring rate caused insignificant effect on drug loading capacity but particle size. Increase in stirring rate resulted in a decrease in particle size. In the second part, SR suppositories were formulated by incorporating IND microspheres having the highest drug loaded. The bases used were PEG mixtures (400:1500:4000) and Witepsol H15. Qualitative controls and IND assay on the suppositories were carried out. The drugs released were evaluated by in vitro dissolution tests. Comparative results of SR suppositories containing IND microspheres with that of conventional ones showed that the former has sustained effect up to 480 min in vitro. Release results were evaluated kinetically and the data was fitted (Bt)(a) kinetics.