Lacidipine encapsulated gastroretentive microspheres prepared by chemical denaturation for Pylorospasm

Abstract

The purpose of this research work was to formulate and systematically evaluate in vitro performance of mucoadhesive microspheres of lacidipine for treatment of pylorospasm. Lacidipine microspheres containing chitosan were prepared by chemical denaturation using glutaraldehyde as a cross-linking agent. The microspheres were evaluated for physical characteristics such as particle size, particle shape and surface morphology by scanning electron microscopy, drug entrapment efficiency and in vitro mucoadhesion. Results of preliminary trials indicated that the polymer concentration, cross-linking agent and stirring speed had a noticeable effect on size and surface morphology. A central composite design was employed to study the effect of independent variables, polymer concentration (X₁), volume of glutaraldehyde (X₂), stirring speed (X₃) and cross-linking time (X₄) on dependent variables, drug entrapment efficiency and percentage mucoadhesion. The entrapment efficiency varied from 14–40.82% depending upon the polymer concentration, volume of cross-linker and stirring speed. All batches of microspheres exhibited good mucoadhesive property (73–83%) in the in vitro wash-off test. It was observed that polymer concentration and glutaraldehyde volume had a more significant effect on the dependent variables. Maximum entrapment (36.53%) and mucoadhesion (81.33%) was predicted at 3.5% chitosan, 3 ml glutaraldehyde, 3000 rpm stirring speed and 75 min cross-linking time under optimized process condition. The selected formulation showed controlled release for more than 6 h. The release followed Higuchi kinetics via a Fickian diffusion.     

Formulation and evaluation of stomach-specific amoxicillin-loaded carbopol-934P mucoadhesive microspheres for anti-Helicobacter pylori therapy

The purpose of this research was to formulate and systemically evaluate in vitro and in vivo performances of mucoadhesive amoxicillin microspheres for the potential use in the treatment of gastric and duodenal ulcers, which were associated with Helicobacter pylori. Amoxicillin mucoadhesive microspheres containing carbopol-934P as mucoadhesive polymer and ethyl cellulose as carrier polymer were prepared by an emulsion-solvent evaporation technique. Results of preliminary trials indicate that quantity of emulsifying agent, time for stirring, drug-to-polymers ratio and speed of rotation affected the characteristics of microspheres. Microspheres were discrete, spherical, free flowing and showed a good percentage of drug entrapment efficiency. An in vitro mucoadhesive test showed that amoxicillin mucoadhesive microspheres adhered more strongly to the gastric mucous layer and could retain in the gastrointestinal tract for an extended period of time. A 3² full factorial design was employed to study the effect of independent variables, drug-to-polymer-to-polymer ratio (amoxicillin-ethyl cellulose-carbopol-934P) (X₁) and stirring speed (X₂) on dependent variables, i.e. percentage mucoadhesion, drug entrapment efficiency, particle size and t₈₀. The best batch exhibited a high drug entrapment efficiency of 56%; mucoadhesion percentage after 1 h was 80% and the particle size was 109 µm. A sustained drug release was obtained for more than 12 h. The drug-to-polymer-to-polymer ratio had a more significant effect on the dependent variables. The morphological characteristics of the mucoadhesive microspheres were studied under a scanning electron microscope. In vitro release test showed that amoxicillin released slightly faster in pH 1.2 hydrochloric acid than in pH 7.8 phosphate buffer. In vivo H. pylori clearance tests were also carried out by administering amoxicillin powder and mucoadhesive microspheres to H. pylori infectious Wistar rats under fed conditions at single dose or multiple dose(s) in oral administration. The results showed that amoxicillin mucoadhesive microspheres had a better clearance effect than amoxicillin powder. In conclusion, the prolonged gastrointestinal residence time and enhanced amoxicillin stability resulting from the mucoadhesive microspheres of amoxicillin might make a contribution to H. pylori complete eradication.     

Stomach specific anti-helicobacter pylori therapy: preparation and evaluation of amoxicillin-loaded chitosan mucoadhesive microspheres

The purpose of this research was to formulate and systematically evaluate in vitro and in vivo performances of mucoadhesive amoxicillin microspheres for the potential use of treating gastric and duodenal ulcers, which were associated with Helicobacter pylori. Amoxicillin mucoadhesive microspheres containing chitosan as mucoadhesive polymer were prepared by simple emulsification phase separation technique using glutaraldehyde as a cross-linking agent. Results of preliminary trials indicate that volume of cross-linking agent, time for cross-linking, polymer-to-drug ratio, and speed of rotation affected characteristics of microspheres. Microspheres were discrete, spherical, free flowing and also showed high percentage drug entrapment efficiency. In vitro mucoadhesive test showed that amoxicillin mucoadhesive microspheres adhered more strongly to gastric mucous layer and could retain in gastrointestinal tract for an extended period of time. A 3(2) full factorial design was employed to study the effect of independent variables, polymer-to-drug ratio (X(1)), and stirring speed (X(2)) on dependent variables i.e. percentage mucoadhesion, t(80), drug entrapment efficiency, particle size and swelling index. The best batch exhibited a high drug entrapment efficiency of 70 % and a swelling index of 1.39; percentage mucoadhesion after 1 h was 79 %. The drug release was also sustained for more than 12 h. The polymer-to-drug ratio had a more significant effect on the dependent variables. The morphological characteristics of the mucoadhesive microspheres were studied using scanning electron microscopy. In vitro release test showed that amoxicillin released slightly faster in pH 1.0 hydrochloric acid than in pH 7.8 phosphate buffer. In vivo H. pylori clearance tests were also carried out by administering amoxicillin mucoadhesive microspheres and powder, to H. pylori infectious Wistar rats under fed conditions at single dose or multiple dose(s) in oral administration. The results showed that amoxicillin mucoadhesive microspheres had a better clearance effect than amoxicillin powder. In conclusion, the prolonged gastrointestinal residence time and enhanced amoxicillin stability resulting from the mucoadhesive microspheres of amoxicillin might make contribution complete eradication of H. pylori.     

Lacidipine encapsulated gastroretentive microspheres prepared by chemical denaturation for pylorospasm

The purpose of this research work was to formulate and systematically evaluate in vitro performance of mucoadhesive microspheres of lacidipine for treatment of pylorospasm. Lacidipine microspheres containing chitosan were prepared by chemical denaturation using glutaraldehyde as a cross-linking agent. The microspheres were evaluated for physical characteristics such as particle size, particle shape and surface morphology by scanning electron microscopy, drug entrapment efficiency and in vitro mucoadhesion. Results of preliminary trials indicated that the polymer concentration, cross-linking agent and stirring speed had a noticeable effect on size and surface morphology. A central composite design was employed to study the effect of independent variables, polymer concentration (X(1)), volume of glutaraldehyde (X(2)), stirring speed (X(3)) and cross-linking time (X(4)) on dependent variables, drug entrapment efficiency and percentage mucoadhesion. The entrapment efficiency varied from 14-40.82% depending upon the polymer concentration, volume of cross-linker and stirring speed. All batches of microspheres exhibited good mucoadhesive property (73-83%) in the in vitro wash-off test. It was observed that polymer concentration and glutaraldehyde volume had a more significant effect on the dependent variables. Maximum entrapment (36.53%) and mucoadhesion (81.33%) was predicted at 3.5% chitosan, 3 ml glutaraldehyde, 3000 rpm stirring speed and 75 min cross-linking time under optimized process condition. The selected formulation showed controlled release for more than 6 h. The release followed Higuchi kinetics via a Fickian diffusion.     

Formulation and evaluation of stomach-specific amoxicillin-loaded carbopol-934P mucoadhesive microspheres for anti-Helicobacter pylori therapy

The purpose of this research was to formulate and systemically evaluate in vitro and in vivo performances of mucoadhesive amoxicillin microspheres for the potential use in the treatment of gastric and duodenal ulcers, which were associated with Helicobacter pylori. Amoxicillin mucoadhesive microspheres containing carbopol-934P as mucoadhesive polymer and ethyl cellulose as carrier polymer were prepared by an emulsion-solvent evaporation technique. Results of preliminary trials indicate that quantity of emulsifying agent, time for stirring, drug-to-polymers ratio and speed of rotation affected the characteristics of microspheres. Microspheres were discrete, spherical, free flowing and showed a good percentage of drug entrapment efficiency. An in vitro mucoadhesive test showed that amoxicillin mucoadhesive microspheres adhered more strongly to the gastric mucous layer and could retain in the gastrointestinal tract for an extended period of time. A 3(2) full factorial design was employed to study the effect of independent variables, drug-to-polymer-to-polymer ratio (amoxicillin-ethyl cellulose-carbopol-934P) (X(1)) and stirring speed (X(2)) on dependent variables, i.e. percentage mucoadhesion, drug entrapment efficiency, particle size and t(80). The best batch exhibited a high drug entrapment efficiency of 56%; mucoadhesion percentage after 1 h was 80% and the particle size was 109 μm. A sustained drug release was obtained for more than 12 h. The drug-to-polymer-to-polymer ratio had a more significant effect on the dependent variables. The morphological characteristics of the mucoadhesive microspheres were studied under a scanning electron microscope. In vitro release test showed that amoxicillin released slightly faster in pH 1.2 hydrochloric acid than in pH 7.8 phosphate buffer. In vivo H. pylori clearance tests were also carried out by administering amoxicillin powder and mucoadhesive microspheres to H. pylori infectious Wistar rats under fed conditions at single dose or multiple dose(s) in oral administration. The results showed that amoxicillin mucoadhesive microspheres had a better clearance effect than amoxicillin powder. In conclusion, the prolonged gastrointestinal residence time and enhanced amoxicillin stability resulting from the mucoadhesive microspheres of amoxicillin might make a contribution to H. pylori complete eradication.     

Design and characterization of chitosan-alginate microspheres for ocular delivery of azelastine

Abstract

The use of mucoadhesive biopolymers is one of the best approaches to prolong the drug residence inside the cul-de-sac, consequently increasing the bioavailability. Thus, the focus of this work was to develop mucoadhesive microspheres to overcome the limitations of ocular drug delivery. The chitosan-sodium alginate microspheres of azelastine hydrochloride were fabricated using modified ionotropic gelation technique. The particle size, zeta potential, entrapment efficiency and drug release kinetics were evaluated and characterized by SEM, FT-IR, DSC, in vitro mucoadhesion and in vivo study. The microspheres had average particle size in the range of 3.55 to 6.70?µm and zeta potential +24.55 to +49.56?mV. The fabricated microspheres possess maximum drug entrapment of 73.05% with 65% mucin binding efficiency and revealed a controlled release over the 8-h period following a non-Fickian diffusion. SEM showed that microspheres were distinct solid with irregular shape. FT-IR and DSC results concluded the drug entrapment into microspheres. In vivo studies on ocular rat model revealed that azelastine microspheres had better efficacy. Chitosan sodium alginate microspheres prepared were in particle size range suitable for ocular purpose. In vitro release and in vivo efficacy studies revealed that the microspheres were effective in prolonging the drug’s presence in cul de sac with improved therapeutic efficacy.     

Bioavailability enhancement of ondansetron after nasal administration of Caesalpinia pulcherrima-based microspheres

Abstract

Context: Natural polymers have attracted a great deal of attention for use as potential carriers in site-specific delivery over past decades. Mucoadhesive microspheres are useful tools for nasal drug delivery.

Objectives: To prepare and evaluate mucoadhesive microspheres as mode for nasal delivery of ondansetron using Caesalpinia pulcherrima galactomannan (CPG).

Materials and methods: Conventional spray-dried CPG nasal microspheres loaded with ondansetron for intranasal drug delivery in order to avoid the first pass metabolism with improved therapeutic efficiency in treatment of nausea and vomiting as an alternative therapy to parenterals. Developed microspheres were evaluated for characteristics like particle size, entrapment efficiency, zeta potential, swelling ability, in-vitro mucoadhesion, in-vitro drug release, DSC, XRD study and histopathological evaluation of tissue. CPG-based ondansetron microspheres were studied in rabbits for screening nasal absorption potential of nasal formulation.

Results: Developed nasal microspheres possess entrapment efficiency of 80–89%, higher mucoadhesion of 72–84% across goat nasal mucosa. In-vivo study showed that microspheres based on mucoadhesive polymer were able to promote quick drug absorption as well as enhanced bioavailability of drug.

Discussion: Histopathological studies evaluated biocompatible and nontoxic nature of CPG in nasal cavity. Developed mucoadhesive microspheres by nasal route showed enhancement of bioavailability as compared to oral route in rabbits.

Conclusion: CPG-based mucoadhesive microspheres can successfully deliver ondansetron intranasally, sustain its effect, avoid first pass effect, an alternative route of administration to injection and thus enhance systemic bioavailability of ondansetron hydrochloride.     

Statistical optimization of controlled release microspheres containing cetirizine hydrochloride as a model for water soluble drugs

Abstract

The purpose was to improve the encapsulation efficiency of cetirizine hydrochloride (CTZ) microspheres as a model for water soluble drugs and control its release by applying response surface methodology. A 3³ Box–Behnken design was used to determine the effect of drug/polymer ratio (X₁), surfactant concentration (X₂) and stirring speed (X₃), on the mean particle size (Y₁), percentage encapsulation efficiency (Y₂) and cumulative percent drug released for 12?h (Y₃). Emulsion solvent evaporation (ESE) technique was applied utilizing Eudragit RS100 as coating polymer and span 80 as surfactant. All formulations were evaluated for micromeritic properties and morphologically characterized by scanning electron microscopy (SEM). The relative bioavailability of the optimized microspheres was compared with CTZ marketed product after oral administration on healthy human volunteers using a double blind, randomized, cross-over design. The results revealed that the mean particle sizes of the microspheres ranged from 62 to 348?µm and the efficiency of entrapment ranged from 36.3% to 70.1%. The optimized CTZ microspheres exhibited a slow and controlled release over 12?h. The pharmacokinetic data of optimized CTZ microspheres showed prolonged t_max, decreased C_max and AUC_0–∞ value of 3309?±?211 ng?h/ml indicating improved relative bioavailability by 169.4% compared with marketed tablets.     

Development of novel sustained release matrix pellets of betahistine dihydrochloride: effect of lipophilic surfactants and co-surfactants

Sustained release matrix pellets of the freely water soluble drug, betahistine dihydrochloride (BH), were prepared using freeze pelletization technique. Different waxes and lipids (cetyl alcohol, beeswax, glyceryl tripalmitate (GTP) and glyceryl tristearate) were evaluated for the preparation of matrix pellets. A D-optimal design was employed for the optimization and to explore the effect of drug loading (X₁), concentration of lipophilic surfactant (X₂), concentration of co-surfactant (X₃) and wax type (X₄) on the release extent of the drug from matrix pellets. The entrapment efficiency (Y₁), pellet diameter (Y₂), and the percentage drug released at given times were selected as dependent variables. Results revealed a significant impact of all independent variables on drug release from the formulated pellets. The lipophilic surfactant significantly increased both the entrapment efficiency and the in vitro drug release and significantly decreased the pellet size. The optimized BH-loaded pellets were composed of 19.95% drug loading, 9.95% Span^® 80 (surfactant), 0.25% Capmul^® (co-surfactant) using glyceryl tripalmitate as a matrix former. The release profiles of the drug from hard gelatin capsule containing optimized pellets equivalent to 32?mg BH was similar to that of target release model for once-daily administration based on similarity factor. It could be concluded that a promising once-daily capsule containing sustained release pellets of BH was successfully designed.     

Formulation,optimization and evaluation of spray-dried mucoadhesive microspheres as intranasal carriers for Valsartan

This investigation deals with the intranasal delivery of Valsartan, encapsulated in HPMC-based spray-dried mucoadhesive microspheres, with an aim to provide rapid absorption and quick onset of action for treating hypertension. A 2³-factorial design has been employed for the assessment of influence of three independent variables, namely inlet temperature, feed-flow rate and drug-polymer ratio on production yield, particle size and in vitro drug diffusion of the prepared microspheres. Microspheres were evaluated for particle size, entrapment efficiency, swelling property, in vitro mucoadhesion, in vitro drug diffusion, ex vivo drug permeation, histopathological examination and stability studies. The results of differential scanning calorimetry, X-ray diffraction and scanning electron microscopy revealed molecular dispersion of Valsartan into microspheres with spherical shape and smooth surface. Optimized formulation indicated good mucoadhesion with no severe sign of damage on nasal mucosa. Results of the non-invasive animal studies in dexamethasone-induced hypertensive rat model suggested the suitability of investigated drug delivery system for intranasal administration.     

QbD-enabled systematic development of gastroretentive multiple-unit microballoons of itopride hydrochloride

Abstract

The objectives of present studies were to develop the systematically optimized multiple-unit gastroretentive microballoons, i.e. hollow microspheres of itopride hydrochloride (ITH) employing quality by design (QbD)-based approach. Initially, the patient-centric QTPP and CQAs were earmarked, and preliminary studies were conducted to screen the suitable polymer, solvent, solvent ratio, pH and temperature conditions. Microspheres were prepared by non-aqueous solvent evaporation method employing Eudragit S-100. Risk assessment studies carried out by constructing Ishikawa cause-effect fish-bone diagram, and techniques like risk estimation matrix (REM) and failure mode effect analysis (FMEA) facilitated the selection of plausible factors affecting the drug product CQAs, i.e. percent yield, entrapment efficiency (EE) and percent buoyancy. A 3³ Box–Behnken design (BBD) was employed for optimizing CMAs and CPPs selected during factor screening studies employing Taguchi design, i.e. drug–polymer ratio (X₁), stirring temperature (X₂) and stirring speed (X₃). The hollow microspheres, as per BBD, were evaluated for EE, particle size and drug release characteristics. The optimum formulation was embarked upon using numerical desirability function yielding excellent floatation characteristics along with adequate drug release control. Drug-excipient compatibility studies employing FT-IR, DSC and powder XRD revealed absence of significant interaction among the formulation excipients. The SEM studies on the optimized formulation showed hollow and spherical nature of the prepared microspheres. In vivo X-ray imaging studies in rabbits confirmed the buoyant nature of the hollow microspheres for 8?h in the upper GI tract. In a nutshell, the current investigations report the successful development of gastroretentive floating microspheres for once-a-day administration of ITH.     

Iron oxide induced enhancement of mucoadhesive potential of Eudragit RLPO: formulation,evaluation and optimization of mucoadhesive drug delivery system

Objectives: The objective of the study was to investigate the effect of iron oxide in the development of mucoadhesive tablets of cinnarizine using Eudragit RLPO polymer. A simplex lattice design was employed for optimizing the drug delivery system.

Methods: Different concentrations of Eudragit RLPO (X₁), iron oxide (X₂) and PVP K 30 (X₃) were taken as independent variables and mucoadhesive strength, t_50%, t_90%, MDT and tablet tensile strength were the selected response variables. Contour and 3D plots were drawn to portray the relationship between independent and response variables. Ex vivo studies were performed for the determination of mucoadhesive strength of formulated tablets employing texture analyzer. ATR-FTR, DSC and zeta potential determination were conducted for drug-excipient and ionic interaction studies.

Results: Friability, hardness and tensile strength of mucoadhesive tablet formulation were found to be 0.42 ± 0.21%, 3.93 ± 1.57 kg/cm² and 0.65 ± 0.26 mN/m², respectively. Mucoadhesive strength was found to be ranging between 5.75 ± 4.41 and 42.85 ± 3.94 g. Value of release exponent (n) was found to be 0.65 ± 0.22, indicating anomalous drug release behavior from the formulations. Numerical optimization using the desirability approach was employed for developing optimized formulation by setting constraints of the dependent and independent variables. The mucoadhesive tablet formulation composition consisting of 8.58% w/w Eudragit RLPO, 7.02% w/w iron oxide and 7.26% w/w PVP K 30 fulfilled maximum requirements of an optimum formulation with better regulation of the selected constraints.

Conclusions: Eudragit RLPO and iron oxide combination showed high level potential for fabricating gastroretentive as well as mucoadhesive drug delivery systems.     

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.     

An Improvement of the Efficacy of Moxifloxacin HCl for the Treatment of Bacterial Keratitis by the Formulation of Ocular Mucoadhesive Microspheres

The aim of this study was to prepare novel ocular mucoadhesive microspheres of Moxifloxacin HCl to increase its residence time on the ocular surface and to enhance its therapeutic efficacy in ocular bacterial keratitis. Microspheres were fabricated with different grades of Methocel and Sodium CMC as polymers. Microspheres were evaluated for their particle size, morphology, encapsulation efficiency, mucoadhesion, antimicrobial efficacy, and in vitro drug release studies. In vivo studies were carried out for the promising formulation on eyes of albino rabbits by inducing bacterial keratitis. A sterile microspheres suspension in light mineral oil was applied to infected eyes twice a day. A marketed conventional eye drop was used as a positive control. Eyes were examined daily for improvement of clinical signs of bacterial keratitis by an ophthalmologist. The average particle size of microspheres was found to be less than 80 μm. Methocel microspheres were found to have a smoother surface than Sodium CMC. Entrapment efficiency was enhanced with an increased polymer concentration and viscosity. The formulation containing Methocel K100M with a drug: polymer ratio of 1:2 exerted longer corneal and conjunctival mucoadhesion time of 8.45±0.15 h and 9.40±0.53 h respectively. In vitro release of Moxifloxacin HCl from microspheres was retarded with increased viscosity and concentration of polymers, and was controlled by diffusion as well as polymer relaxation. All formulations showed comparable antimicrobial activity in comparison with conventional marketed eye drops. The formulation containing Methocel K100M with a drug: polymer ratio of 1:2 was found to be a promising formulation and was used for the in vivo studies. The in vivo studies revealed that microspheres demonstrated significantly lower clinical scores and reduced the total duration of therapy than the marketed Moxifloxacin HCl eye drops. In vitro and in vivo studies showed that ocular mucoadhesive microspheres of Moxifloxacin HCl were found to have an improved efficacy in the treatment of ocular bacterial keratitis in comparison with the marketed formulation.     

Development of Biodegradable Starch Microspheres for Intranasal Delivery

Domperidone microspheres for intranasal administration were prepared by emulsification crosslinking technique. Starch a biodegradable polymer was used in preparation of microspheres using epichlorhydrine as cross-linking agent. The formulation variables were drug concentration and polymer concentration and batch of drug free microsphere was prepared for comparisons. All the formulations were evaluated for particle size, morphological characteristics, percentage drug encapsulation, equilibrium swelling degree, percentage mucoadhesion, bioadhesive strength, and in vitro diffusion study using nasal cell. Spherical microspheres were obtained in all batches with mean diameter in the range of above 22.8 to 102.63 μm. They showed good mucoadhesive property and swelling behaviour. The in vitro release was found in the range of 73.11% to 86.21%. Concentration of both polymer and drug affect in vitro release of drug.     

Chitosan-based mucoadhesive microspheres of clarithromycin as a delivery system for antibiotic to stomach

The objective of the present study was to develop chitosan-based mucoadhesive microspheres of clarithromycin to provide prolonged contact time for drug delivery of antibiotics to treat stomach ulcers. Microspheres based mucoadhesive formulation were extensively evaluated and characterized for in vitro performance followed by investigation of in vivo pharmacokinetics in rats. Microspheres were prepared by emulsification technique using glutaraldehyde as a crosslinking agent. Formulation conditions were optimized for percent drug entrapment and mucoadhesion, by varying different formulation and process parameters like drug to polymer ratio, concentration of crosslinking agent and time of crosslinking. Prepared microspheres were evaluated extensively for particle size, percent drug entrapment, swelling kinetics, in vitro mucoadhesion using rat stomach membrane and in vitro drug release studies. In vitro permeation studies across rat stomach membrane were carried out to determine diffusion parameters and drug retention in the stomach membrane of the formulation and the plain drug. Finally in vivo performance of microsphere formulation in comparison to plain drug was evaluated by pharmacokinetic studies in albino rats. Drug entrapment upto 74% was obtained. Swelling studies indicated that with an increase in cross-linking, the swelling ability decreased. The in vitro drug release and in vitro mucoadhesion studies showed a dependence on the extent of cross-linking and concentration of chitosan. Extent of cross-linking exhibited an inverse relation to drug release rate as well as mucoadhesion, whereas polymer concentration exhibited an inverse correlation with drug release while linear relationship with mucoadhesion (up to 86%). In vitro permeation studies across stomach tissue showed higher accumulation of drug in the stomach tissue with microspheres formulation as compared to that of free drug. This is evident from higher value of K (partition coefficient) and Qm/Csf values for microspheres (68.34 and 106.42X10(3), respectively) as compared to that of free drug (1.86 and 173.00, respectively). These findings when analyzed showed an increase in the bioavailability of clarithromycin from microsphere formulation as compared to plain drug suspension in vivo, with AUC 0-->alpha being 91.7 (microg h/ml)and 24.9 (microg h/ml) respectively. Results of the study demonstrated good mucoadhesion of the microspheres with the stomach mucosa as well as higher accumulation of drug in the stomach membrane. Microspheres also exhibited sustained release of drug. Thus chitosan microspheres appear, technically, promising mucoadhesive drug delivery systems for delivering clarithromycin to treat stomach ulcers.     

Development,optimization and in vitro evaluation of alginate mucoadhesive microspheres of carvedilol for nasal delivery

Abstract

The present research work was aimed at development and optimization of alginate mucoadhesive microspheres of carvedilol for nasal delivery to avoid first pass metabolism and to improve the therapeutic efficacy in the treatment of hypertension and angina pectoris. The microspheres were prepared by a water-in-oil (w/o) emulsification technique. A 2³ factorial design was employed with drug : polymer ratio, calcium chloride concentration and cross-linking time as independent variables while particle size of the microspheres and in vitro mucoadhesion were the dependent variables. Regression analysis was performed to identify the best formulation conditions. Particle size was analysed by dynamic laser light diffraction technique and found to be in the range of 26.36–54.32 µm, which is favourable for intranasal absorption. The shape and surface characteristics were determined by scanning electron microscopy (SEM) which depicted the spherical nature and nearly smooth surfaces of the microspheres. The percentage encapsulation efficiency was found to be in the range between 36.62–56.18. In vitro mucoadhesion was performed by adhesion number using sheep nasal mucosa and was observed in a range from 69.25–85.28. Differential scanning calorimetry and X-ray diffraction results indicated a molecular level dispersion of carvedilol in the microspheres. In vitro release studies in pH 6.2 phosphate buffer indicated non-Fickian or anomalous type of transport for the release of carvedilol from the microspheres.     

星点设计法优化盐酸小檗碱树脂复合胃黏附给药系统的研究

本文以离子交换树脂(IER)作为载体吸附盐酸小檗碱，通过包衣将其制成胃黏附微囊，并以胃黏附微囊的载药量，胃滞留时间和体外释药时间作为评价指标，对处方进行优化。考察不同型号载体与不同浓度、温度和pH值的药物溶液对IER载药量的影响；以卡伯姆934与IER的比例(X₁)、丙烯酸树脂(Eudragit)与IER的比例(X₂)、Eudragit RL与Eudragit RS的比例(X₃)为自变量，以制剂累计释放量85%的时间点(Y₁)、制剂在大鼠胃体外黏附滞留百分比(Y₂)为因变量，通过星点设计—效应面法优化胃黏附包衣处方。优化后载药工艺为在37 ℃、pH 5左右条件下，用IRP88离子交换树脂对1.0 mg·mL^-1盐酸小檗碱溶液载药；优化后的包衣液组成为X₁=0.75、 X₂=0.9、 X₃=0.6，所得制剂单位质量载药量高，可在300 min左右达到累计释放总量的85%，同时在所设计条件范围内胃黏附作用最强。     

Formulation and evaluation of chitosan microspheres of aceclofenac for colon‐targeted drug delivery

The objective of this investigation was to develop novel colon specific drug delivery. Aceclofenac, a NSAID, was successfully encapsulated into chitosan microspheres. Various formulations were prepared by varying the ratio of chitosan, span‐85 and stirring speed and the amount of glutaraldehyde. The SEM study showed that microspheres have smooth surfaces. Microspheres were characterised by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) to confirm the absence of chemical interactions between drug and polymer and to know the formation of microspheres structure. The microspheres were evaluated for particle size, encapsulation efficiency, drug loading capacity, mucoadhesion studies, stability studies, in vitro and in vivo drug release studies. Particle sizes, as measured by the laser light scattering technique, were of an average size in the range 41–80 µm. The swelling index was in the range 0.37–0.82 and the entrapment efficiency range was 51–75% for all the formulations. The optimised batch ACM₁₃ released 83.6% at 8 h and 104% at 24 h in SCF containing rat caecal content. Eudragit coated chitosan microspheres prevented the release of the aceclofenac in the physiological environment of the stomach and small intestine and released 95.9±0.34% in the colon. With regard to release kinetics, the data were best fitted with the Higuchi model and showed zero order release with non‐Fickian diffusion mechanism. The in vivo findings suggest that aceclofenac microspheres exhibit a prolonged effect of aceclofenac in rats and produce a significant anti‐inflammatory effect. The findings of the present study conclusively state that chitosan microspheres are promising for colon targeting of aceclofenac to synchronise with chronobiological symptoms of rheumatoid arthritis. Copyright © 2010 John Wiley & Sons, Ltd.     

Formulation and optimization of alkaline extracted ispaghula husk microparticles of isoniazid – in vitro and in vivo assessment

Microparticles containing isoniazid were prepared by the emulsification internal ionic gelation method using a novel, alkaline extracted ispaghula husk as a wall forming material. A four-factor three-level Box–Behnken design was employed to study the effect of independent variables on dependent variables. Sodium alginate concentration (X₁), alkaline extraction of ispaghula husk (AEISP) concentration (X₂), concentration of cross-linking agents (X₃) and stirring speed (X₄) were four independent variables considered in the preparation of microparticles, while the particle size (Y₁) and entrapment efficiency (Y₂) were dependent variables. Optimized microparticles exhibited 83.43% drug entrapment and 51.53?µm particle size with 97.80% and 96.37% validity, respectively, at the following conditions – sodium alginate (3.55% w/v), alkaline extracted ispaghula husk (3.60% w/v), cross-linker concentration (7.82% w/v) and stirring speed (1200?rpm). The optimized formulation showed controlled drug release for more than 12?h by following Higuchi kinetics via non-Fickian diffusion. The gamma scintigraphy of the optimized formulation in Wistar rats showed that microparticles could be observed in the intestinal lumen after 1?h and were detectable in the intestine up to 12?h, with decreased percentage of radioactivity (t_1/2 of ^99mTc 4–5?h).