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1.  Formulation and Evaluation of Gelatin Micropellets of Aceclofenac: Effect of Process Variables on Encapsulation Efficiency, Particle Size and Drug Release 
In the present study aceclofenac-gelatin micropellets were prepared by the cross linking technique using gluteraldehyde as cross linking agent and characterized by X-ray diffractometry, differential scanning calorimetry and scanning electron microscopy. The effect of drug: polymer ratio, temperature of oil phase, amount of gluteraldehyde and stirring time was studied with respect to entrapment efficiency, micropellet size and drug release characteristics. Spherical micropellets having an entrapment efficiency of 57% to 97% were obtained. Differential scanning calorimetric analysis confirmed the absence of any drug-polymer interaction. The micromeritic studies of micropellets show improved flow property. The entrapment efficiency, micropellet size and drug release profile was altered significantly by changing various processing parameters.
doi:10.4103/0250-474X.49126
PMCID: PMC3040878  PMID: 21369445
Aceclofenac; micropellets; gelatin; cross linking; process variables
2.  The Interplay between Chondrocyte Redifferentiation Pellet Size and Oxygen Concentration 
PLoS ONE  2013;8(3):e58865.
Chondrocytes dedifferentiate during ex vivo expansion on 2-dimensional surfaces. Aggregation of the expanded cells into 3-dimensional pellets, in the presence of induction factors, facilitates their redifferentiation and restoration of the chondrogenic phenotype. Typically 1×105–5×105 chondrocytes are aggregated, resulting in “macro” pellets having diameters ranging from 1–2 mm. These macropellets are commonly used to study redifferentiation, and recently macropellets of autologous chondrocytes have been implanted directly into articular cartilage defects to facilitate their repair. However, diffusion of metabolites over the 1–2 mm pellet length-scales is inefficient, resulting in radial tissue heterogeneity. Herein we demonstrate that the aggregation of 2×105 human chondrocytes into micropellets of 166 cells each, rather than into larger single macropellets, enhances chondrogenic redifferentiation. In this study, we describe the development of a cost effective fabrication strategy to manufacture a microwell surface for the large-scale production of micropellets. The thousands of micropellets were manufactured using the microwell platform, which is an array of 360×360 µm microwells cast into polydimethylsiloxane (PDMS), that has been surface modified with an electrostatic multilayer of hyaluronic acid and chitosan to enhance micropellet formation. Such surface modification was essential to prevent chondrocyte spreading on the PDMS. Sulfated glycosaminoglycan (sGAG) production and collagen II gene expression in chondrocyte micropellets increased significantly relative to macropellet controls, and redifferentiation was enhanced in both macro and micropellets with the provision of a hypoxic atmosphere (2% O2). Once micropellet formation had been optimized, we demonstrated that micropellets could be assembled into larger cartilage tissues. Our results indicate that micropellet amalgamation efficiency is inversely related to the time cultured as discreet microtissues. In summary, we describe a micropellet production platform that represents an efficient tool for studying chondrocyte redifferentiation and demonstrate that the micropellets could be assembled into larger tissues, potentially useful in cartilage defect repair.
doi:10.1371/journal.pone.0058865
PMCID: PMC3598946  PMID: 23554943
3.  Furosemide-loaded Alginate Microspheres Prepared by Ionic Cross-linking Technique: Morphology and Release Characteristics 
Furosemide-loaded alginate microspheres were prepared by the ionic cross-linking technique using CaCl2, Al2(SO4)3 and BaCl2. The process induced the formation of microspheres with the incorporation efficiency of 65% to 93%. The effect of sodium alginate concentration, cross-linking agents and drying conditions was evaluated with respect to entrapment efficiency, particle size, surface characteristics and in vitro release behaviors. Infrared spectroscopic study confirmed the absence of any drug-polymer interaction. Differential scanning calorimetric analysis revealed that the drug was molecularly dispersed in the alginate microspheres matrices showing rough surface, which was confirmed by scanning electron microscopy study. The mean particle size and entrapment efficiency were found to be varied by changing various formulation parameters. The in vitro release profile could be altered significantly by changing various formulation parameters to give a sustained release of drug from the microspheres. The kinetic modeling of the release data indicate that furosemide release from the alginate microspheres follow anomalous transport mechanism after an initial lag period when the drug release mechanism was found to be fickian diffusion controlled.
doi:10.4103/0250-474X.40336
PMCID: PMC2852066  PMID: 20390085
Sodium alginate; microspheres; furosemide; ionic cross-linking technique; anomalous transport mechanism; fickian diffusion controlled
4.  Formulation and Mathematical Optimization of Controlled Release Calcium Alginate Micro Pellets of Frusemide 
BioMed Research International  2013;2013:819674.
Objective. Frusemide loaded calcium alginate micropellets, an oral microparticulate delivery system, was statistically optimized exhibiting prolonged therapeutic action minimizing its adverse effects. Methods. Ionotropic Gelation technique was adopted employing 32 Factorial designs and keeping the entire process free from organic solvents. Physicochemical and the release characteristics of the prepared formulations were studied, keeping variations only in sodium alginate (primary polymer) and Acrycoat E30D (copolymer) dispersion. Result. Sodium alginate was predominant over Acrycoat E30D in all batches. Nonadditives or interaction was observed to be insignificant. Multiple regressions produced second-order polynomial equation, and the predictive results obtained were validated with high degree of correlation. The in vivo study applauded that optimized calcium alginate micropellets of frusemide can produce a much greater diuretic effect over an extended period of 24 hours. Conclusion. This study reveals that the potential of a single dose of the mathematically optimized micro pellets of frusemide formulation is sufficient in the management of peripheral edema and ascites in congestive heart failure and as well in the treatment of chronic hypertension, leading to better patient compliance, and can be produced with minimum experimentation and time, proving far more cost-effective formulation than the conventional methods of formulating dosage forms.
doi:10.1155/2013/819674
PMCID: PMC3736541  PMID: 23971046
5.  Effect of Formulation and Processing Variables on the Characteristics of Tolmetin Microspheres Prepared by Double Emulsion Solvent Diffusion Method 
The aim of this study was to evaluate microencapsulated controlled release preparations of tolmetin sodium using ethylcellulose as a retardant material. Microspheres were prepared by using water-in-oil-in-oil (W/O1/O2) double-emulsion solvent diffusion method, using different ratios of ethylcellulose to tolmetin sodium. Span 80 was used as the droplet stabilizer and n-hexane was added to harden the microspheres. The prepared microspheres were characterized for their micromeritic properties, drug content, loading efficiency, production yield, and particle size. Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray powder diffractometry and scanning electron microscopy were used to characterize microparticles. The in vitro release studies were performed in pH 1.2 and 7.4. The prepared microspheres were spherical in shape. The drug-loaded microspheres showed near to the theoretical of entrapment and release was extended up to 24. The X-ray diffractogram and differential scanning thermographs showed amorphous state of the drug in the microspheres. It was shown that the drug: polymer ratio, stirring rate, volume of dispersing medium and surfactant influenced the drug loading, particle size and drug release behavior of the formed microparticles. The results showed that, generally, an increase in the ratio of drug: polymer (0.5:1) resulted in a reduction in the release rate of the drug which may be attributed to the hydrophobic nature of the polymer. The in vitro release profile could be modified by changing various processing and formulation parameters to give a controlled release of drug from the microparticules. The release of tolmetin was influenced by the drug to polymer ratio and particle size and was found to be diffusion and erosion controlled. The best-fit release kinetic was achieved with Peppas model.
doi:10.4103/0250-474X.62251
PMCID: PMC2883230  PMID: 20582193
Controlled release; double-emulsion; ethylcellulose; microspheres; tolmetin sodium
6.  Preparation and evaluation of sustained release microballoons of propranolol 
Background and the purpose of the study
The purpose of the present investigation was to characterize, optimize and evaluate microballoons of Propranolol hydrochloride and to increase its boioavailability by increasing the retention time of the drug in the gastrointestinal tract.
Methods
Propranolol hydrochloride-loaded microballoons were prepared by the non-aqueous O/O emulsion solvent diffusion evaporation method using Eudragit RSPO as polymer. It was found that preparation temperature determined the formation of cavity inside the microballoon and this in turn determined the buoyancy. Microballoons were subjected to particle size determination, micromeritic properties, buoyancy, entrapment efficiency, drug loading, in vitro drug release and IR study. The correlation between the buoyancy, bulk density and porosity of microballoons were elucidated. The release rate was determined in simulated gastric fluid (SGF) of pH 1.2 at 37±0.5°C.
Results
The microballoons presented spherical and smooth morphologies (SEM) and were porous due to presence of hollow cavity. Microballoons remained buoyant for >12 hrs for the optimized formulation. The formulation demonstrated favorable in vitro floating and release characteristics. The encapsulation efficiency was high. In vitro dissolution kinetics followed the Higuchi model. The drug release from microballoons was mainly controlled by diffusion and showed a biphasic pattern with an initial burst release, followed by sustained release for 12 hrs. The amount of the drug which released up to 12 hrs was 82.05±0.64%. Statistical analysis (ANOVA) showed significant difference (p<0.05) in the cumulative amount of drug released after 30 min, and up to 12 hrs from optimized formulations.
Conclusion
The designed system for propanolol would possibly be advantageous in terms of increased bioavailability and patient compliance.
PMCID: PMC3232109  PMID: 22615657
Floating drug delivery system; O/O emulsion Solvent diffusion/evaporation method; Eudragit RS PO; Buoyancy
7.  Encapsulation of Naproxen in Lipid-Based Matrix Microspheres: Characterization and Release Kinetics 
The objective of this study was to microencapsulate the anti-inflammatory drug (naproxen) to provide controlled release and minimizing or eliminating local side effect by avoiding the drug release in the upper gastrointestinal track. Naproxen was microencapsulated with lipid-like carnauba wax, hydrogenated castor oil using modified melt dispersion (modified congealable disperse phase encapsulation) technique. Effect of various formulation and process variables such as drug-lipid ratio, concentration of modifier, concentration of dispersant, stirring speed, stirring time, temperature of external phase, on evaluatory parameters such as size, entrapment efficiency, and in vitro release of naproxen were studied. The microspheres were characterized for particle size, scanning electron microscopy (SEM), FT-IR spectroscopy, drug entrapment efficiency, in vitro release studies, for in vitro release kinetics. The shape of microspheres was found to be spherical by SEM. The drug entrapment efficiency of various batches of microspheres was found to be ranging from 60 to 90 %w/w. In vitro drug release studies were carried out up to 24 h in pH 7.4 phosphate buffer showing 50-65% drug release. In vitro drug release from all the batches showed better fitting with the Korsmeyer-Peppas model, indicating the possible mechanism of drug release to be by diffusion and erosion of the lipid matrix.
doi:10.4103/0975-1483.80293
PMCID: PMC3122038  PMID: 21731354
Carnauba wax; hydrogenated castor oil; lipid microspheres; modified melt dispersion technique; naproxen; release kinetics
8.  Physicomechanical Properties of Naproxen-Loaded Microparticles Prepared from Eudragit L100 
AAPS PharmSciTech  2009;10(1):120-128.
Microparticles of naproxen with Eudragit L100 and Aerosil were prepared by the emulsion solvent diffusion method in order to avoid local gastrointestinal irritation, one of the major side effects of nonsteroidal anti-inflammatory drugs after oral ingestion. The process of preparation involved the use of ethanol as good solvent, dichloromethane as a bridging liquid, water as poor solvent, Aerosil as anti-adhesion agent, and sodium dodecyl sulfate to aid in the dispersion of the drug and excipients into the poor solvent. The obtained microparticles were evaluated for micromeritic properties, yield, encapsulation efficiency, drug physical state, and drug release properties. The influence of formulation factors and preparation condition (polymer/naproxen ratio, Aerosil/polymer ratio, and the initial difference of temperature between the solvent and nonsolvent) on the properties of the microparticles were also examined. The resultant microparticles were finely spherical and uniform with high incorporation efficiency (>79%) and yield (>71%). The incorporation efficiency was enhanced with increasing the ratio of excipients to drug and the initial difference of temperature between the solvent and nonsolvent. The mean diameter of the microparticles was influenced by all of the manufacturing parameters. Studies carried out to characterize the micromeritic properties of formulations, such as flowability and packability, showed that microparticles were suitable for further pharmaceutical manipulation (e.g., capsule filling). Drug release studies of the microparticles confirmed the gastroresistance, and mathematical studies showed that the drug released followed a Hixon and Crowell kinetic. These microparticles represent a simple method for the preparation of drug-loaded enteric microparticles with desired micromeritic properties and gastroresistance release.
doi:10.1208/s12249-009-9186-5
PMCID: PMC2663676  PMID: 19184624
emulsion solvent diffusion method; Eudragit L100; naproxen
9.  ULTRASTRUCTURAL BASES FOR METABOLICALLY LINKED MECHANICAL ACTIVITY IN MITOCHONDRIA  
The Journal of Cell Biology  1966;30(2):269-297.
By means of a new "quick-sampling" method, micropellets of mouse liver mitochondria were rapidly prepared for electron microscopy during the recording of steady state metabolism. Reversible ultrastructural changes were found to accompany change in metabolic steady states. The most dramatic reversible ultrastructural change occurs when ADP is added to systems in which only phosphate acceptor is deficient, i.e., during the State IV to State III transition as defined by Chance and Williams. After 15 min in State IV, mitochondria display an "orthodox" ultrastructural appearance as is usually observed after fixation within intact tissue. On transition to State III, a dramatic change in the manner of folding of the inner membrane takes place. In addition, the electron opacity of the matrix increases as the volume of the matrix decreases, but total mitochondrial volume does not appear to change during this transition. This conformation is called "condensed." Isolated mitochondria were found to oscillate between the orthodox and condensed conformations during reversible transitions between State III and State IV. Various significant ultrastructural changes in mitochondria also occur during transitions in other functional states, e.g., when substrate or substrate and acceptor is made limiting. Internal structural flexibility is discussed with respect to structural and functional integrity of isolated mitochondria. Reversible changes in the manner of folding of the inner membrane and in the manner of packing of small granules in the matrix as respiration is activated by ADP represent an ultrastructural basis for metabolically linked mechanical activity in tightly coupled mitochondria.
PMCID: PMC2107001  PMID: 5968972
10.  Preparation and characterization of albumin nanoparticles encapsulating curcumin intended for the treatment of breast cancer 
Introduction:
For the real-time clinical utilization of curcumin (an ayurvedic natural product) to treat breast cancer, its dissolution, rate limited solubility, poor tissue absorption, and extensive in vivo metabolism that leads to its poor systemic bioavailability should be overcome. A polymer-based nanoparticle formulation using bovine serum albumin can increase its aqueous solubility and can achieve protected, sustained, and targeted therapy in breast cancer.
Materials and Methods:
Desolvation technique was optimized for the preparation of albumin nanoparticles. Particle size, drug release, encapsulation efficiency, drug polymer interaction were the in vitro properties that were determined. Cell culture studies, in vivo pharmacokinetics in rats were used for biological characterization of the formulation.
Results:
The formulations were successfully prepared using 1:1, 1:2, 1:3, 1:4 drug: polymer ratios and the percent entrapment was found to be 74.76%, 91.01%, 85.36%, 86.42%, respectively, and particle size determined by zetasizer was found to be 225.1, 223.5, 226.3, 228.7 nm, respectively, and in vitro release was sustained for at least one month with drug release of 75.74%, 65.97%, 64.42%, 54%, respectively. The dissolution rate and aqueous solubility of curcumin was enhanced with this formulation. Fourier transform infrared spectroscopy (FTIR) studies demonstrated that the drug was not changed in the formulation during the fabrication process. The proliferation assays in MDA-MB-231 tumor cell lines indicated more effectiveness of the formulation compared to its solution form. In rats, albumin nanoparticles sustained drug release, demonstrated more bioavailability, improved pharmacokinetic properties, and enhanced tissue targetability of the drug.
Conclusions:
An effective curcumin-albumin nanoparticle formulation was successfully developed using a desolvation technique.
doi:10.4103/2230-973X.82432
PMCID: PMC3465130  PMID: 23071931
Albumin nanoparticles; breast cancer; curcumin; solubility; sustained release
11.  Preparation and Characterization of Salbutamol Sulphate Loaded Ethyl Cellulose Microspheres using Water-in-Oil-Oil Emulsion Technique 
The aim of this study was to formulate and evaluate microencapsulated controlled release preparations of a highly water/soluble drug, salbutamol sulphate by (water in oil) in oil emulsion technique using ethyl cellulose as the retardant material. Various processing and formulation parameters such as drug/polymer ratio, stirring speed, volume of processing medium were optimized to maximize the entrapment. The release of salbutamol sulphate from ethyl cellulose microsphere was compared and possible release mechanism proposed. Microspheres were prepared by water in oil emulsion technique using acetonitrile/dichloromethane (1:1 ratio) solvent system. Span 80 was used as the dispersing agent and n-hexane was added to harden the microspheres. The prepared microspheres were characterized for their micromeritic properties and drug loading, as well as compatibility by infrared spectroscopy, differential scanning calorimetry (DSC), X-ray powder diffractometry and scanning electron microscopy (SEM). The in-vitro release studies were carried out in phosphate buffer at pH 7.4. The prepared microspheres were white, free flowing and spherical in shape. The drug-loaded microspheres showed 55.7 - 76.6 % of entrapment and release was extended up to 10 h. Various processing and formulation parameters such as drug/polymer ratio, stirring speed, volume of processing medium, etc. significantly affect the drug release from the microspheres. The best/fit release kinetics was achieved with Higuchi plot followed by zero order and first order. The release of salbutamol sulphate was influenced by altering the drug to polymer ratio and the drug release was found to be diffusion controlled.
PMCID: PMC3862055  PMID: 24363714
Salbutamol sulphate; Ethyl cellulose; Emulsion solvent evaporation method; Microspheres; Higuchi model
12.  Novel sulpiride-loaded solid lipid nanoparticles with enhanced intestinal permeability 
Background
Solid lipid nanoparticles (SLN), novel drug delivery carriers, can be utilized in enhancing both intestinal permeability and dissolution of poorly absorbed drugs. The aim of this work was to enhance the intestinal permeability of sulpiride by loading into SLN.
Methods
A unique ultrasonic melt-emulsification method with minimum stress conditions was used for the preparation of SLN. The mixture of the drug and the melted lipids was simply dispersed in an aqueous solution of a surfactant at a temperature that was 10°C higher than the melting points of the lipids using probe sonication, and was then simultaneously dispersed in cold water. Several formulation parameters were optimized, including the drug-to-lipid ratio, and the types of lipids and surfactants used. The produced SLN were evaluated for their particle size and shape, surface charge, entrapment efficiency, crystallinity of the drug and lipids, and the drug release profile. The rat everted sac intestine model was utilized to evaluate the change in intestinal permeability of sulpiride by loading into SLN.
Results
The method adopted allowed successful preparation of SLN with a monodispersed particle size of 147.8–298.8 nm. Both scanning electron microscopic and atomic force microscopic images showed uniform spherical particles and confirmed the sizes determined by the light scattering technique. Combination of triglycerides with stearic acid resulted in a marked increase in zeta potential, entrapment efficiency, and drug loading; however, the particle size was increased. The type of surfactant used was critical for particle size, charge, drug loading, and entrapment efficiency. Generally, the in vitro release profile demonstrated by all formulations showed the common biphasic mode with a varying degree of burst release. The everted sac model showed markedly enhanced sulpiride permeability in the case of the SLN-loaded formulation. The in situ results showed a very good correlation with the in vitro release data.
Conclusion
Incorporation of sulpiride into SLN results in enhanced intestinal permeability of sulpiride, that may in turn increase overall oral absorption of the drug. The superior attributes of the prepared SLN, specifically the high particle size uniformity and drug loading capacity, is considered novel, especially given the simplicity and modest nature of the sonication method used.
doi:10.2147/IJN.S54413
PMCID: PMC3872145  PMID: 24379671
ultrasonic melt-emulsification; everted sacs; atomic force microscopy; Dynasan®; stearic acid
13.  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.
doi:10.4103/0250-474X.100233
PMCID: PMC3480744  PMID: 23112393
Amlodipine besylate; degree of swelling; drug entrapment efficiency; in vitro mucoadhesion studies; mucoadhesive microspheres; nasal drug delivery; water in oil emulsification solvent evaporation technique
14.  Investigation of Formulation Variables and Excipient Interaction on the Production of Niosomes 
AAPS PharmSciTech  2012;13(3):826-835.
The aim of this study was to investigate the effects of formulation and process variables on the properties of niosomes formed from Span 40 as nonionic surfactant. A variety of formulations encapsulating Paclitaxel, a hydrophobic model drug, were prepared using different dicetyl phosphate (DCP) and Span 40-cholesterol (1:1) amounts. Formulations were optimized by multiple regression analysis to evaluate the changes on niosome characteristics such as entrapment efficiency, particle size, polydispersity index, zeta potential and in vitro drug release. Multiple regression analysis revealed that as Span 40-cholesterol amounts in the formulations were increased, zeta potential and percent of drug released at 24th hour were decreased. Besides, DCP was found to be effective on increasing niosome size. As a process variable, the effect of sonication was observed and findings revealed an irreversible size reduction on Span 40 niosomes after probe sonication. Monodisperse small sized (133 ± 6.01 nm) Span 40 niosomes entrapping 98.2% of Paclitaxel with a weight percentage of 3.64% were successfully prepared. The drug–excipient interactions in niosomes were observed by differential scanning calorimetry and X-ray powder diffraction analysis. Both techniques suggest the conversion of PCTs’ crystal structure to amorphous form. The thermal analyses demonstrate the high interaction between drug and surfactant that explains high entrapment efficiency. After 3-month storage, niosomes preserved their stability in terms of drug amount and particle size. Overall, this study showed that Span 40 niosomes with desired properties can be prepared by changing the content and production variables.
doi:10.1208/s12249-012-9805-4
PMCID: PMC3429677  PMID: 22644706
drug delivery systems; drug release; multiple regression; niosomes; paclitaxel
15.  Hesperidin Gastroresistant Microparticles by Spray-Drying: Preparation, Characterization, and Dissolution Profiles 
AAPS PharmSciTech  2009;10(2):391-401.
Gastroresistant microparticles for oral administration of hesperidin (Hd) were produced by spray-drying using cellulose acetate phthalate (CAP) as enteric polymer in different polymer/Hd weight ratio (1:1, 3:1, and 5:1), and a series of enhancers of the dissolution rate, such as sodium carboxymethylcellulose crosslinked (CMC), sodium dodecylbenzene sulfonate (SDBS), or Tween85. The raw materials and the microparticles were investigated by differential-scanning calorimetry, X-ray diffraction, infrared spectroscopy and imaged using scanning electron and fluorescence microscopy. In vitro dissolution tests were conducted using a pH-change method to investigate the influence of formulative parameters on the dissolution/release properties of the drug. CAP/Hd microparticles showed a good gastro-resistance but incomplete drug dissolution in the simulated intestinal fluid (SIF). The presence of the enhancers in the formulation produced well-formed microparticles with different size and morphology, containing the drug well coated by the polymer. All the enhancers were able to increase the dissolution rate of Hd in the simulated intestinal environment without altering CAP ability to protect Hd in the acidic fluid. The spray-drying technique and process conditions selected were effective in microencapsulating and stabilizing the flavonoid giving satisfactory encapsulation efficiency, product yield, and microparticles morphology, and a complete drug release in the intestine.
doi:10.1208/s12249-009-9219-0
PMCID: PMC2690782  PMID: 19381835
enhancers of the dissolution rate; gastroresistant spray-dried microparticles; hesperidin; morphological and physicochemical characterization
16.  Albumin Microspheres as an Ocular Delivery System for Pilocarpine Nitrate 
Pilocarpine nitrate loaded egg albumin microspheres were prepared by thermal denaturation process in the size range of 1-12 μm. A series of batches were prepared to study factors, which may affect the size and entrapment efficiency of drug in microspheres and optimized the process. Drug loaded microspheres so obtained were evaluated for their size, entrapment efficiency, release rate and biological response. Electron photomicrographs were taken (8000X) to study the morphological characteristics of microspheres. The entrapment and encapsulation of pilocarpine after process optimization was found to be 82.63% and 62.5% respectively. In vitro dissolution rate studies revealed that the release of drug from the microspheres followed spherical matrix mechanism. Biological response of microspheric suspension was measured by reduction in intraocular pressure in albino rabbit eyes and compared with marketed eye drops. Various pharmacokinetic parameters viz. onset of action, duration of action, Tmax and AUC were studied. A measurable difference was found in the mean miotic response, duration and AUC of pilocarpine nitrate microspheric suspension.
doi:10.4103/0250-474X.41454
PMCID: PMC2792486  PMID: 20046711
Egg albumin; microspheres; pilocarpine nitrate; intraoccular pressure
17.  Intrinsic radiosensitivity of human pancreatic tumour cells and the radiosensitising potency of the nitric oxide donor sodium nitroprusside. 
British Journal of Cancer  1996;74(11):1734-1742.
A panel of eight human pancreatic tumour cell lines displayed high intrinsic radioresistance, with mean inactivation doses between 2.4 and 6.5 Gy, similar to those reported for melanoma and glioblastoma. The radiosensitising potency of sodium nitroprusside, a bioreductive nitric oxide donor, was assessed in a model of metabolism-induced hypoxia in a cell micropellet. Sodium nitroprusside at 0.1 mM revealed a radiosensitising effect with an overall enhancement ratio of 1.9 compared with 2.5 for oxygen. Radiosensitising activity correlated with the enhancement of single-strand DNA breakage caused by radiation. In suspensions with cell densities of between 3% and 30% (v/v), the half-life of sodium nitroprusside decreased from 31 to 3.2 min, suggesting a value of around 1 min for micropellets. Despite this variation, the radiosensitising activity was similar in micropellets and in diluted cell suspensions. S-nitroso-L-glutathione was found to possess radiosensitising activity, consistent with a possible role of natural thiols in the storing of radiobiologically active nitric oxide adducts derived from sodium nitroprusside. As measured by a nitric oxide-specific microsensor, activation of sodium nitroprusside occurred by bioreduction, whereas S-nitroso-L-glutathione showed substantial spontaneous decomposition. Both agents appear to exert radiosensitising action through nitric oxide as its scavenging by carboxy phenyltetramethylimidazolineoxyl N-oxide (carboxy-PTI0) and oxyhaemoglobin resulted in attenuated radiosensitisation. Sodium nitroprusside was at least 10-fold more potent than etanidazole, a 2-nitroimidazole used as a reference. Our data suggest that sodium nitroprusside, a drug currently used for the treatment of hypertension, is a potential tumour radioresponse modifier.
PMCID: PMC2077206  PMID: 8956786
18.  Mechanistic Evaluation of the Effect of Sintering on Compritol® 888 ATO Matrices 
AAPS PharmSciTech  2009;10(2):355-360.
The present research studied the effect of sintering technique in the development of a controlled release formulation for ketorolac tromethamine. The method consisted of mixing drug and wax powder (Compritol® 888 ATO) along with lactose as diluent and talc as lubricant followed by direct compression at room temperature. The compressed fluffy matrices were kept at 80°C for 1, 2, and 3 h for sintering. The sintered tablets were characterized by their physical parameters and in vitro dissolution profile. The sintering time markedly affected the drug release properties of Compritol® 888 ATO matrices. It is notable that the release rate of ketorolac tromethamine from matrices was inversely related to the time of sintering. This may be due to the increase in the extent and firmness of sintering which further compacts the mass so that drug release is affected. Contact angle measurement and scanning electron microscopy analysis indicated that heat treatment caused the wax to melt and redistribute. This redistributed wax formed a network-like structure in which the drug along with lactose is entrapped. This particular formed matrix is responsible for retarding the drug release. Fourier transform infrared spectroscopy results did not show any drug–wax interaction due to sintering. Differential scanning calorimetric and powder X-ray diffraction studies ruled out the occurrence of solid solution and polymorphic changes of the drug. Drug release from the wax tablets with or without sintering was best described by the Higuchi equation.
doi:10.1208/s12249-009-9211-8
PMCID: PMC2690774  PMID: 19333763
controlled release; scanning electron microscopy (SEM); sintering; wax
19.  Preparation and in vitro/in vivo characterization of curcumin microspheres intended to treat colon cancer 
Objective:
The objective of the present investigation was to prepare colon targeted curcumin microspheres using Eudragit S100 and evaluate the same for in vitro/in vivo properties.
Materials and Methods:
A “O/O solvent evaporation” technique was used in the preparation of microspheres. The influence of various process variables including stirring speed, drug:polymer ratio and percentage of emulsifier on the fabrication were investigated and the formulation was optimized. Prepared microspheres were evaluated for in vitro and in vivo properties. Surface morphology, particle size, percentage drug entrapment, percentage yield, drug polymer interaction, in vitro drug release in simulated gastrointestinal transit conditions and stability were the in vitro parameters investigated. Using an optimized formulation, drug release into the systemic circulation and organ distribution were investigated as in vivo parameters. In vivo parameters were estimated in male albino rats.
Results:
Curcumin microspheres of Eudragit S100 were successfully prepared using o/o solvent evaporation method. Microspheres prepared using 1:2 drug:polymer ratio, with a stirring speed of 1000 rpm, and using 1.0% w/v concentration of emulsifying agent was selected as an optimized formulation. The release studies with optimized formulation demonstrated that aqueous solubility of curcumin was enhanced by 8 times with the formulation. FTIR studies demonstrated no change in drug characteristics upon microsphere fabrication. The enhancement in solubility is thus due to the increase in the surface area of the drug substance and not due to a change of drug to a different physical state. This was further confirmed by scanning electron microsphere pictures. Drug release followed Korsmeyer and Peppas release model. Accelerated stability studies indicated that the drug is stable in the formulation for a period of atleast 14 weeks at room temperature. In vivo studies demonstrated a sustained drug release into the systemic circulation after oral administration of the formulation. Further, colon target was affectively achieved using the optimized formulation. Eudragit microspheres delivered most of their drug load (79.0%) to the colon, whereas with plain drug suspension only 28.0% of the total dose reached the target site.
Conclusion:
This study successfully developed curcumin microspheres that can be used effectively in the treatment of the colon cancer.
doi:10.4103/0975-7406.94825
PMCID: PMC3341721  PMID: 22557928
Colon targeting; curcumin; eudragit S100; microspheres; pH sensitive
20.  Cellulose-Based Matrix Microspheres of Prednisolone Inclusion Complex: Preparation and Characterization 
AAPS PharmSciTech  2011;12(1):388-400.
The purpose of the present investigation was to encapsulate pure prednisolone (PRD) and PRD–hydroxypropyl-β-cyclodextrin (HPβCD) complex in cellulose-based matrix microspheres. The system simultaneously exploits complexation technique to enhance the solubility of low-solubility drug (pure PRD) and subsequent modulation of drug release from microspheres (MIC) at a predetermined time. The microspheres of various compositions were prepared by an oil-in-oil emulsion–solvent evaporation method. The effect of complexation and presence of cellulose polymers on entrapment efficiency, particle size, and drug release had been investigated. The solid-state characterization was performed by Fourier transform infrared spectroscopy, thermogravimetry, differential scanning calorimetry, and powder X-ray diffractometry. The morphology of MIC was examined by scanning electron microscopy. The in vitro drug release profiles from these microspheres showed the desired biphasic release behavior. After enhancing the solubility of prednisolone by inclusion into HPβCD, the drug release was easily modified in the microsphere formulation. It was also demonstrated that the CDs in these microspheres were able to modulate several properties such as morphology, drug loading, and release properties. The release kinetics of prednisolone from microspheres followed quasi-Fickian and first-order release mechanisms. In addition to this, the f2-metric technique was used to check the equivalency of dissolution profiles of the optimized formulation before and after stability studies, and it was found to be similar. A good outcome, matrix microspheres (coded as MIC5) containing PRD–HPβCD complex, showed sustained release of drug (95.81%) over a period of 24 h.
doi:10.1208/s12249-011-9602-5
PMCID: PMC3066336  PMID: 21359603
drug release; ethylcelluose; hydroxypropyl-β-cyclodextrin; hydroxypropyl methyl cellulose; prednisolone; solubility
21.  Formulation, optimization and evaluation of sustained release microsphere of ketoprofen 
Journal of Pharmacy & Bioallied Sciences  2012;4(Suppl 1):S101-S103.
The objective of this study is to formulate ketoprofen loaded microspheres of Acrycoat S100 by an o/w emulsion solvent evaporation method. It potently inhibits the enzyme cyclooxygenase resulting in prostaglandin synthesis inhibition. Ketoprofen causes an irritation in the gastrointestinal mucous membrane and possesses a bitter taste and aftertaste. The half-life in plasma is about 1-2hrs. This makes ketoprofen a very good candidate for the formulation of controlled release dosage forms. Ketoprofen microspheres help to protect the gastric mucous membrane from drug irritation and to mask its taste. The prepared microspheres were evaluated for micromeritic properties, particle size, effect of surfactant concentration, percentage yield, incorporation efficiency, drug polymer compatibility (IR and DSC study), scanning electron microscopy and in vitro drug release. The microspheres produced exhibited good encapsulation efficiencies and micromeritic properties. Encapsulation efficiency of microsphere is around 78%. The mean diameters of microspheres were found in required micrometer range. The results of optimized formulations showed a narrow size distribution and smooth surface. The DSC and the FTIR analysis showed the absence of any potent incompatibility between the drug and the polymer. In-vitro release showed 86.4% drug release after 12 hours. Results of present study suggest that Acrycoat S100 loaded microsphere of ketoprofen can be successfully designed to develop sustained drug delivery system. The solvent evaporation method is a suitable technique for the preparation of Acrycoat S100 microspheres for controlling the release of Ketoprofen for a prolonged duration.
doi:10.4103/0975-7406.94156
PMCID: PMC3467827  PMID: 23066178
Ketoprofen; Acrycoat S100; solvent evaporation method
22.  Biodegradable Chitosan-Based Ambroxol Hydrochloride Microspheres: Effect of Cross-Linking Agents 
The objective of this study was to investigate the influence of type of cross-linking method used on the properties of ambroxol hydrochloride microspheres such as encapsulation efficiency, particle size, and drug release. Microspheres were prepared by solvent evaporation technique using chitosan as a matrix-forming agent and cross-linked using formaldehyde and heat treatment. Morphological and physicochemical properties of microspheres were then investigated by scanning electron microscopy (SEM), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FTIR) spectroscopy. The cross-linking of chitosan takes place at the free amino group because of formation of imine bond as evidenced by FTIR. The DSC, XRD, and FTIR analysis showed that chitosan microspheres cross linked by heating were superior in properties and performance as compared to the microspheres cross-linked using formaldehyde. SEM results revealed that heat-treated microspheres were spherical, discrete having smooth, and porous structure. The particle size and encapsulation efficiencies of the prepared chitosan microspheres ranged between 10.83–24.11 μm and 39.73μ80.56%, respectively. The drug release was extended up to 12 h, and the kinetics of the drug release was obeying Higuchi kinetic proving diffusion-controlled drug release.
doi:10.4103/0975-1483.76414
PMCID: PMC3094564  PMID: 21607049
Ambroxol hydrochloride; chitosan microspheres; cross-linking agents
23.  Multiparticulate System for Colon Targeted Delivery of Ondansetron 
Targeted delivery of drugs to colon has the potential for local treatment of a variety of colonic diseases. The main objective of the study was to develop a multiparticulate system containing chitosan microspheres for the colon targeted delivery of ondansetron for the treatment of irritable bowel syndrome. This work combines pH-dependent solubility of eudragit S-100 polymers and microbial degradability of chitosan polymers. Chitosan microspheres containing ondansetron were prepared by emulsion cross linking method. The effect of process variables like chitosan concentration, drug-polymer ratio, emulsifier concentration and stirring speed were studied on particle size and entrapment efficiency of chitosan microspheres. In vitro drug release studies in simulated gastro intestinal fluids showed a burst drug release pattern in the initial hour necessitating microencapsulation around the chitosan microspheres. The optimized formulation was then subjected to microencapsulation with eudragit S-100 by solvent evaporation technique. The effect of different coat/core ratio on particle size, drug entrapment efficiency and in vitro drug release were studied. Formulation which contain 1:10 core/coat ratio released lesser amount of drug in the upper gastro intestinal conditions and so selected as best formulation and then subjected to in vitro drug release studies in presence of rat ceacal contents to assess biodegradability of chitosan microspheres in colon. In order to study the drug release mechanism in vitro drug release data was fitted into various kinetic models. Analysis of regression values suggested that the possible drug release mechanism was Peppas model.
doi:10.4103/0250-474X.62237
PMCID: PMC2883228  PMID: 20582191
Chitosan microspheres; colon targeted drug delivery; multiparticulate systems; ondansetron
24.  Theophylline-Ethylcellulose Microparticles: Screening of the Process and Formulation Variables for Preparation of Sustained Release Particles 
Objective(s)
The aim of this study was to formulate and evaluate microencapsulated controlled release preparations of theophylline using ethylcellulose as the retardant material with high entrapment efficiency.
Materials and Methods
Microspheres were prepared by water-in-oil-in-oil (W/O1/O2) emulsion-solvent diffusion (ESD). A mixed solvent system consisting of acetonitrile and dichloromethane in a 1:1 ratio and light liquid paraffin were chosen as primary and secondary oil phases, respectively. In the current study formulations with different drug/polymer ratios were prepared and characterized by drug loading, loading efficiency, scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier Transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC).
Results
The best drug to polymer ratio was 0.5:1 (F2 formulation). F2 Formulation showed 29.53% of entrapment, loading efficiency of 88.59%, and mean particle size of 757.01 µm. SEM studies showed that the microspheres were spherical. FTIR, SEM, XRD and DSC showed that drug in the microspheres was stable and revealed crystallinity form.
Conclusion
The results showed that, generally, an increase in the ratio of drug to polymer resulted in a reduction in the release rate of the drug which may be attributed to the hydrophobic nature of the polymer. The release of theophylline was found to be diffusion controlled and was influenced by the drug to polymer ratio, loading efficiency, and particle size. The in vitro release profile could be modified by changing various processing and formulation parameters (as stirring rate, the volume of dispersing medium, and non-solvent concentration) to give a controlled release of drug from the microparticules.
PMCID: PMC3586866  PMID: 23492721
Emulsion Solvent Diffusion (ESD); Ethylcellulose; Release; Theophylline.
25.  Long-term release of clodronate from biodegradable microspheres 
AAPS PharmSciTech  2001;2(3):6-14.
This paper describes the formulation of a biodegradable microparticulate drug delivery system containing clodronate, a bisphosphonate intended for the treatment of bone diseases. Microspheres were prepared with several poly(D,L-lactide-co-glycolide) (PLGA) copolymers of various molecular weights and molar compositions and 1 poly(D,L-lactide) (PDLLA) homopolymer by a water-in-oil-in-water (w/o/w) double emulsion solvent evaporation procedure. Critical process parameters and formulation variables (ie, addition of stabilizing agents) were evaluated for their effect on drug encapsulation efficiency and clodronate release rate from microparticles Well-formed clodronate-loaded microspheres were obtained for all polymers by selecting suitable process parameters (inner water/oil volume ratio 1∶16, temperature-raising rate in the solvent evaporation step 1°C/min, 2% wt/vol NaCl in the external aqueous phase). Good yields were obtained in all batches of clodronate microspheres (above 60%); drug encapsulation efficiencies ranged between 49% and 75% depending on the polymer used. Clodronate release from all copolymer microspheres was completed in about 48 hours, while those from PDLLA microspheres required about 20 days. The change of microsphere composition by adding a surfactant such as Span 20 or a viscosing agent such as carboxymethylcellulose extended the long-term release up to 3 months. Clodronate was successfully entrapped in PLGA and PDLLA microspheres, and drug release could be modulated from 48 hours up to 3 months by suitable selection of polymer, composition, additives, and manufacturing conditions.
doi:10.1208/pt020310
PMCID: PMC2750575  PMID: 14727869
PLGA microspheres; solvent evaporation method; long-term release; Clodronate

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