Effect of Various Polymers Concentrations on Physicochemical Properties of Floating Microspheres

Floating microspheres have emerged as a potential candidate for gastroretentive drug delivery system. For developing a desired intragastric floatation system employing these microspheres, it is necessary to select an appropriate balance between buoyancy and drug releasing rate. These properties mainly depend on the polymers used in the formulation of the microspheres. Hence it is necessory to study the effect of these polymer concentrations on the various physicochemical properties of the microspheres. Floating microspheres were prepared by emulsion solvent evaporation technique utilising different polymers such as ethyl cellulose, Eudragit^® RS and Eudragit^® RL by dissolving them in a mixture of dichloromethane and methanol. Release modifiers studied were hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose E50 LV and Eudragit^® EPO. Prepared microspheres were analysed for particle size, surface morphology, entrapment efficiency, buoyancy, differential scanning calorimetry and in-vitro drug release. Ethyl cellulose and Eudragit^® EPO resulted microspheres with high percentage yield, excellent spherical shape but had very less buoyancies with a high cumulative drug release. Ethyl cellulose microspheres prepared using hydroxypropyl methylcellulose K4M showed more sustained drug release and high buoyancies than that of the microspheres formulated with the hydroxypropyl methylcellulose E50 LV. Amongst these hydroxypropyl methylcellulose E50 LV showed good balance between buoyancy and the drug release.     

Eudragit? Microparticles for the Release of Budesonide: A Comparative Study

This study compares the behaviour of budesonide-containing microparticles made of Eudragit^®RS or Eudragit^®RS/Eudragit^®RL 70:30 (w/w) prepared either by solvent evaporation or spray-drying technique. The loading efficiency of budesonide within microparticles was about 72% for microparticles prepared by solvent evaporation and around 78% for spray-dried microparticles. Thermal analyses were assessed to collect information about the structural stability of budesonide within the polymeric microspheres. The in vitro release was performed using simulating gastric (fasted state simulated gastric fluid) and intestinal (fasted state simulated intestinal fluid) fluids as the receiving solutions. After 3 h the drug release from Eudragit^®RS/Eudragit^®RL microparticles was about 6-fold higher than that obtained in the case of monopolymer microparticles. Using fasted state simulated intestinal fluid the drug was released between 4 and 30% in both types of preparations. Eudragit^®RS microparticles showed a better protection of the drug from gastric acidity than those of Eudragit^®RS/Eudragit^®RL allowing us to propose Eudragit^®RS microparticles as a hypothetical system of colon specific controlled delivery.     

Fabrication and evaluation of Eudragit® polymeric films for transdermal delivery of piroxicam

The aims of this work were to develop and characterize the prolonged release piroxicam transdermal patch as a prototype to substitute oral formulations, to reduce side effects and improve patient compliance. The patches were composed of film formers (Eudragit^®) as a matrix backbone, with PVC as a backing membrane and PEG200 used as a plasticizer. Results from X-ray diffraction patterns and Fourier transform-infrared spectroscopy indicated that loading piroxicam into films changed the drug crystallinity from needle to an amorphous or dissolved form. Piroxicam films were prepared using Eudragit^® RL100 and Eudragit^® RS100 as film formers at various ratios from 1:0 to 1:3. Films prepared solely by Eudragit^® RL100 showed the toughest and softest film, while other formulations containing Eudragit^® RS100 were hard and brittle. Drug release kinetic data from the films fitted with the Higuchi model, and the piroxicam release mechanism was diffusion controlled. Among all formulation tested, Eudragit^® RL100 films showed the highest drug release rate and the highest drug permeation flux across human epidermal membrane. Increasing drug loading led to an increase in drug release rate. Eudragit^® can be used as a film former for the fabrication of piroxicam films.     

Preparation of Coated Valproic Acid and Sodium Valproate Sustained-release Matrix Tablets

The aim of this research was to investigate the technique for preparation of coated valproic acid and sodium valproate sustained-release matrix tablets. Different diluents were tested and selected as the effective absorbent for oily valproic acid. Effect of the amount of absorbent and hydroxypropylmethylcellulose on drug release from valproic acid-sodium valproate matrix tablets prepared with wet granulation technique was evaluated in pH change system. Colloidal silicon dioxide effectively adsorbed liquid valproic acid during wet granulation and granule preparation. The amounts of colloidal silicon dioxide and hydroxypropylmethylcellulose employed in tablet formulations affected drug release from the tablets. The drug release was prominently sustained for over 12 h using hydroxypropylmethylcellulose-based hydrophilic matrix system. The mechanism of drug release through the matrix polymer was a diffusion control. The drug release profile of the developed matrix tablet was similar to Depakine Chrono^®, providing the values of similarity factor (f2) and difference factor (f1) of 85.56 and 2.37, respectively. Eudragit^® L 30 D-55 was used as effective subcoating material for core matrix tablets before over coating with hydroxypropylmethylcellulose film with organic base solvent. Drug release profile of coated matrix tablet was almost similar to that of Depakine Chrono^®.     

瑞舒伐他汀钙肠溶缓释微球的制备及影响因素考察

目的采用O/O型乳化溶剂挥发法制备瑞舒伐他汀钙肠溶缓释微球,评价各因素对微球性质的影响。方法以微球的粒径、收率、包封率和释放度作为微球的质量评价指标,研究Eudragit类型、乙基纤维素黏度、两种囊材的质量比、搅拌速度、理论载药量和乳化剂用量对微球性质的影响。结果 Eudragit L100-55制得的微球在酸中突释严重,Eudragit L100能很好地抑制药物在酸中的释放;乙基纤维素(20 cp)制得的微球能在pH值6.8的磷酸盐缓冲液中持续释药10 h;Eudragit L100和乙基纤维素(20 cp)的质量比为70∶30时能得到理想的释放曲线;搅拌速度为600 r.min-1、理论载药量为10%和乳化剂Span 80的质量占液体石蜡质量的2%时能得到较好的微球。结论联合应用pH敏感型材料Eudragit L100和缓释材料乙基纤维素,应用乳化溶剂挥发法可以制备瑞舒伐他汀钙肠溶缓释微球。     

In vitro and in vivo evaluation of ranitidine hydrochloride loaded hollow microspheres in rabbits

The objective of this investigation was to develop the hollow microspheres as a new dosage form of floating drug delivery systems with prolonged stomach retention time. Hollow microspheres containing ranitidine hydrochloride (RH) were prepared by a novel solvent diffusion-evaporation method using ethyl cellulose (EC) dissolved in a mixture of ethanol and ether (6:1.0, v/v). The yield and drug loading amount of hollow microspheres were 83.21±0.28% and 20.71±0.32%, respectively. The in vitro release profiles showed that the drug release rate decreased with increasing viscosity of EC and the diameter of hollow microspheres, while increased with the increase of RH/EC weight ratio. Hollow microspheres could prolong drug release time (approximately 24 h) and float over the simulate gastric fluid for more than 24 h. Pharmacokinetic analysis showed that the bioavailability from RH-hollow microspheres alone was about 3.0-times that of common RH gelatin capsules, and it was about 2.8-times that of the solid microspheres. These results demonstrated that RH hollow microspheres were capable of sustained delivery of the drug for longer period with increased bioavailability.     

Floating microspheres of carvedilol as gastro retentive drug delivery system: 32 full factorial design and in vitro evaluation

Abstract

Context: Designing a sustained release system for Carvedilol to increase its residence time in the stomach.

Objective: Preparation of floating microsphere by the emulsion solvent diffusion method, studying the effect of various process parameters and optimize the formulation using full factorial design.

Methods: Different microsphere formulations were prepared by varying the ratio ethanol:dichloromethane (1:0 to 1:1.5), ethyl cellulose:hydroxypropyl methyl cellulose and stirring speed (800–1600?rpm). The effect of these variables on particle size, encapsulation parameters, surface topography, in vitro floatability and drug release were evaluated.

Results: 3² full factorial design was used for the optimization of the formulation. Drug entrapment efficiency, particle size and in vitro drug release were dependent on concentration of ethyl cellulose and stirring speed. Microspheres remained buoyant for more than 10?h and showed sustained release of the drug.

Conclusion: Floating microspheres of Carvedilol with good floating ability and sustained release were developed.     

Formulation and evaluation of ethyl cellulose microspheres prepared by the multiple emulsion technique

The aim of this study was to formulate and evaluate microencapsulated controlled release preparations of metformin hydrochloride using ethyl cellulose as the retardant material with high entrapment efficiency and extended release. Microspheres were prepared by the double emulsion solvent diffusion method. A mixed solvent system consisting of acetonitrile and dichloromethane in 1:1 ratio and light liquid paraffin were chosen as the primary and secondary oil phases, respectively. Span 80 was used as the surfactant for stabilizing the secondary oil phase. The prepared microspheres were characterized by drug loading, optical microscopy and scanning electron microscopy (SEM). The in vitro release studies were performed in a series of buffer solutions with variable pH. The drug loaded microspheres showed 55-85% of entrapment and the release was extended for up to 12 h. SEM studies revealed that the microspheres were spherical and porous in nature. Data obtained from in vitro release studies were fitted to various kinetic models and high correlation was obtained with the Higuchi model. The drug release was found to be diffusion controlled. Oral administration of the microspheres to the albino mice provided decreased plasma glucose for more than 10 h.     

Novel microparticle drug delivery systems based on chitosan and Eudragit®RSPM to enhance diltiazem hydrochloride release property

The aim of this study was to enhance the release properties of diltiazem hydrochloride (diltiazem HCl) by using microparticle system. For this reason, microparticle drug delivery systems based on chitosan and Eudragit^®RSPM were developed. The microparticles were prepared by using double-emulsion solvent extraction method and the mean sizes of microparticles were less than 120?µm. The in vitro drug release from microparticles was studied in simulated gastric (pH 1.2) and intestinal media (pH 7.4) than the results were evaluated by kinetically. In vitro diltiazem HCl release from microparticles showed good zero order kinetic. For the microparticles with chitosan, the release of diltiazem HCl at pH 1.2 could be effectively sustained, while the release of diltiazem HCl increased at pH 7.4 when compared to Eudragit^®RSPM microparticles. The highest release percent obtained was 1:1 ratio of drug: polymer at pH 1.2 and 7.4. All results clearly suggest that the release properties of diltiazem HCl were improved by using microparticle systems especially which contain chitosan.     

Chitosan and chondroitin microspheres for oral-administration controlled release of metoclopramide.

This study investigated the usefulness of chitosan and chondroitin sulphate microspheres for controlled release of metoclopramide hydrochloride in oral administration. Microspheres were prepared by spray drying of aqueous polymer dispersions containing the drug and different amounts of formaldehyde as cross-linker. Drug release kinetics were investigated in vitro in media of different pH. Chondroitin sulphate microspheres scarcely retarded drug release, regardless of cross-linker concentration and medium pH, and were thus not further characterized. Chitosan microspheres prepared with more than 15% formaldehyde (w/w with respect to polymer) showed good control release (more than 8 h), and release rates were little affected by medium pH. Release from chitosan microspheres prepared with 20% formaldehyde was independent of pH, suggesting that this may be the most appropriate formulation. The size distribution of the chitosan microparticles was clearly bimodal, with the smaller-diameter subpopulation corresponding to microsphere fragments and other particles. Electron microscopy showed the chitosan microspheres to be almost-spherical, though with shallow invaginations. The kinetics of drug release from chitosan microspheres were best fitted by models originally developed for systems in which release rate is largely governed by rate of diffusion through the matrix.     

The effect of polymer properties on direct compression and drug release from water-insoluble controlled release matrix tablets

The objective of this study was to identify and evaluate key polymer properties affecting direct compression and drug release from water-insoluble matrices. Commonly used polymers, such as Kollidon^® SR, Eudragit^® RS and ethyl cellulose, were characterized, formulated into tablets and compared with regard to their properties in dry and wet state. A similar site percolation threshold of 65% v/v was found for all polymers in dry state. Key parameters influencing polymer compactibility were the surface properties and the glass transition temperature (T_g), affecting polymer elasticity and particle size-dependent binding. The important properties observed in dry state also governed matrix characteristics and therefore drug release in wet state. A low T_g (Kollidon^® SR < Eudragit^® RS) decreased the percolation threshold, particle size effect and tortuosity, but increased permeability and sensitivity to heat/humidity treatment. Hence, lower permeability and higher stability are benefits of a high-T_g polymer (ethyl cellulose). However, release retardation was observed in the same order as matrix integrity (Eudragit^® RS < ethyl cellulose < Kollidon^® SR), as the high permeability was counteracted by PVP in case of Kollidon^® SR. Therefore, the T_g and composition of a polymer need to be considered in polymer design and formulation of controlled-release matrix systems.     

Formulation, and Evaluation of Pentoxifylline-Loaded Poly(��-caprolactone) Microspheres

Pentoxifylline-loaded poly(ε-caprolactone) microspheres were prepared by solvent evaporation technique with different drug to carrier ratio F1 (1:3), F2 (1:4), F3 (1:5) and F4 (1:6). The microspheres were characterized for particle size, scanning electron microscopy, FT-IR study, percentage yield, drug entrapment, stability studies and for in vitro release kinetics. The shape of microspheres was found to be spherical by SEM. The size of microspheres was found to be ranging 59.3±6.3μm to 86.22±4.23 μm. Among the four drug to carrier ratio, F3 (1:5) showed maximum percentage yield of 83.34±2.46% and F2 (1:4) showed highest drug entrapment of 76.92±3.24% w/w. It was found that there was no interaction between drug and polymer by FT-IR study. No appreciable difference was observed in the extent of degradation of product during 60 d in the microspheres, which were stored at various temperatures. In the in vitro release study formulation F2 (1:4) showed 90.34% drug release at 15 h and found to be sustained. The release followed Higuchi kinetics indicating diffusion controlled drug release.     

Bumadizone calcium dihydrate microspheres compressed tablets for colon targeting: formulation,optimization and in vivo evaluation in rabbits

Abstract

The objective of this study was the development of a colon-targeted microspheres which were compressed into tablets containing the non-steroidal anti-inflammatory bumadizone calcium dihydrate. A 3² full factorial design was adopted for the evaluation of the prepared microspheres. The effect of two independent variables namely polymer type (Eudragit RS100, ethyl cellulose and cellulose acetate butyrate), and drug: polymer ratio (1:1, 9:1 and 18:1) was studied on the entrapment efficiency and in vitro drug release for 12?h. Colon targeting aims to minimize the release of the drug off target area (pH 1.2 and 6.8) and to maximize the release of the drug in target area (pH 7.4). Candidate formulae were compressed into core tablets and colon targeting was achieved using the enzyme-dependent polymer (pectin) as coat in three different concentrations 50, 75 and 90%. Candidate formula F15 (microspheres prepared using BDZ:CAB in a ratio of 18:1 and compressed into tablets using 50% pectin and 50% Avicel in the coat) was able to adequately modulate drug release avoiding drug release in the gastric ambient, and reaching the colonic targeting where 99.7% release was achieved within 12?h following zero-order model. In vivo studies showed that F15 achieved significant decrease in myeloperoxidase activity and inflammation with delayed T_max (4?h) and lower C_max (2700?ng/ml) when compared to marketed product.     

Formulation and bioequivalence of two valsartan tablets after a single oral administration

The aim of this study is to assess the quality of Valzan^® tablet (160 mg, valsartan immediate release test formulation) by comparing its pharmacokinetic parameters with Diovan^® tablet (160 mg, valsartan reference formulation). Valzan^® tablets were prepared according to a dry granulation method (roll compaction). To assess the bioequivalence of Valzan^® tablets a randomized, two-way, crossover, bioequivalence study was performed in 24 healthy male volunteers. The selected volunteers were divided into two groups of 12 subjects. One group was treated with the reference formulation (Diovan^®) and the other one with the generic Valzan^®, with a cross-over after the drug washout period of 14 days. Blood samples were collected at fixed time intervals and valsartan concentrations were determined by a validated HPLC assay method. The pharmacokinetic parameters AUC_0–48, AUC_0–∞, C_max, T_max, K_e and T_1/2 were determined for both the tablets and were compared statistically to evaluate the bioequivalence between the two brands of valsartan, using the statistical model recommended by the FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals (CI) fell within the acceptable range for bioequivalence. Based on this statistical evaluation it was concluded that the test tablets (Valzan^®) is well formulated, since it exhibits pharmacokinetic profile comparable to the reference brand Diovan^®.     

In-vitro and in-vivo evaluation of repaglinide loaded floating microspheres prepared from different viscosity grades of HPMC polymer

During the study repaglinide encapsulated floating microspheres were formulated and characterized for enhancing residence time of drug in git and thereby increasing its bioavailability. Floating microspheres of ethylcellulose (EC) and hydroxypropyl methyl cellulose (HPMC) (5 and 100 cps) were prepared by emulsion solvent diffusion technique. During process optimization various parameters were studied such as: drug: polymer ratio, polymer ratio, concentration of emulsifier and stirring speed. Selected optimized formulations were studied for SEM, entrapment, floating behavior, drug release and kinetics. In-vivo floating ability (X-ray) study and in-vivo antidiabetic activity were performed on alloxan induced diabetic rats. Microspheres prepared with different viscosity grade HPMC were spherical shaped with smooth surface. Size of microspheres was in the range of 181.1–248 μm. Good entrapment and buoyancy were observed for 12 h. X-ray image showed that optimized formulation remained buoyant for more than 6 h. Optimized formulation treated group shows significant (p < 0.01) reduction in blood glucose level as compared to pure drug treated group. Repaglinide loaded floating microspheres expected to give new choice for safe, economical and increased bioavailable formulation for effective management of NIDDM.Abbreviations: EC, ethylcellulose; HPMC, hydroxypropyl methylcellulose; SEM, scanning electron microscopy; GRT, gastric residence time; ATP, adenosine tri phosphate; PVA, polyvinyl alcohol; PEG, polyethylene glycerol; UV, uv–visible     

Cellulose acetate/chitosan multimicrospheres preparation and ranitidine hydrochloride release in vitro

A noval cellulose acetate/chitosan multimicrospheres (CACM) was prepared by the method of w/o/w emulsion. The concentration of cellulose acetate (CA) and the ratio of CA/chitosan (CS) had influence on the CACM size, and appearance. Ranitidine hydrochloride loading, and releasing efficiency in vitro were investigated. The optimal condition for preparation of the microspheres was CA concentration at 2% and the ratio of CA/CS at 3/1. The microspheres size was 200-350 μm. The appearance of microspheres was spherical, porous, and nonaggregated. The highest loading efficiency was 21%. The ranitidine release from the CACM was 40% during 48 hr in buffers.     

Effects of the permeability characteristics of different polymethacrylates on the pharmaceutical characteristics of verapamil hyhdrochloride-loaded microspheres

Microspheres containing verapamil hydrochloride (VRP) were prepared with various polymethacrylates, with different permeability characteristics (Eudragit RS 100, Eudragit RL 100, Eudragit L 100 and Eudragit L 100-55) and also with mixtures of these polymers in a 1:1 ratio using the solvent evaporation method. The aim was to investigate the effects of the permeability of the polymers on drug release rates and the characteristics of the microspheres. To achieve these aims, yield, incorporation efficiency, particle size and the distribution of microspheres were determined, and the influence of the inner phase viscosities prepared with different polymer and polymer mixtures on particle size and the distribution of microspheres were evaluated. Surface morphologies of microspheres were observed by scanning electron microscope. Drug release rates from microspheres were determined by the half-change method using a flow-through cell. The results indicate that microspheres with different surface morphologies and statistically different yields and incorporation efficiencies could be prepared and their particle size and distribution variances resulted from the viscosity of the inner phase. Dissolution profiles showed that the drug release rate could be modified depending on the permeability characteristics of polymethacrylates.     

Effects of the permeability characteristics of different polymethacrylates on the pharmaceutical characteristics of verapamil hyhdrochloride-loaded microspheres

Microspheres containing verapamil hydrochloride (VRP) were prepared with various polymethacrylates, with different permeability characteristics (Eudragit RS 100, Eudragit RL 100, Eudragit L 100 and Eudragit L 100-55) and also with mixtures of these polymers in a 1:1 ratio using the solvent evaporation method. The aim was to investigate the effects of the permeability of the polymers on drug release rates and the characteristics of the microspheres. To achieve these aims, yield, incorporation efficiency, particle size and the distribution of microspheres were determined, and the influence of the inner phase viscosities prepared with different polymer and polymer mixtures on particle size and the distribution of microspheres were evaluated. Surface morphologies of microspheres were observed by scanning electron microscope. Drug release rates from microspheres were determined by the half-change method using a flow-through cell. The results indicate that microspheres with different surface morphologies and statistically different yields and incorporation efficiencies could be prepared and their particle size and distribution xariances resulted from the viscosity of the inner phase. Dissolution profiles showed that the drug release rate could be modified depending on the permeability characteristics of polymethacrylates.     

Microspheres with pH modulated release: design and characterization of formulation variables for colonic delivery

The aim of this study was to design and develop microspheres of indomethacin with pH and transit time dependent release properties for achieving targeted delivery to the colon. Microspheres containing varying proportions of ethyl cellulose and Eudragit (L100 or S100) either alone or in combination were prepared using an oil-in-oil emulsion-based solvent evaporation technique. System comprising of acetone (internal phase) and liquid paraffin (external phase) in the ratio of 1 : 1 and 1 : 9 yielded microspheres with good physical properties (spherical and discrete), high drug loading (70-80%) and entrapment efficiency (70-85%). The lag time in the initial release depended on the proportion of pH-sensitive polymer Eudragit, while the duration of indomethacin release from microspheres was found to be directly proportional to proportion of the total polymer. Thus, a pH- and time-modulated sigmoidal release pattern could be observed in optimized formulations with less than 10% drug release in 4-6 h followed by controlled release extending up to 14-16 h.     

Formulation and Evaluation of Pharmaceutically Equivalent Parenteral Depot Suspension of Methyl Prednisolone Acetate

The aim of the present study was to formulate and evaluate pharmaceutically equivalent injectable aqueous suspension for parenteral depot of methyl prednisolone acetate. Various aqueous suspensions were prepared by rapid stirring and colloid milling method. The prepared aqueous suspensions were subjected to particle size determination, sedimentation study, in vitro release studies (pH dependent dissolution study), and stability studies. The optimized formulation consisted of 4% w/w of methyl prednisolone acetate, 2.91% w/w of PEG-3350, 0.19% w/v of injection grade Tween-80, 0.68% w/w of monobasic sodium phosphate, 0.15% w/w of di-basic sodium phosphate, 0.91% w/v of benzyl alcohol, 0.32% w/w sodium meta bisulphate. The f₂ value was calculated for innovator (DepoMedrol^®, Batch No. MPH-0254) and optimized formulation at pH 6.8 and pH 7.4 phosphate buffers. The f₂ values of 62.94 and 54.37 were obtained at pH 6.8 and pH 7.4 phosphate buffers respectively. The particle size ranged 23-27 μm at D value of 0.9 for both test and innovator product.