Oral Bioavailability Enhancement of Poorly Soluble Drug by Amorphous Solid Dispersion Using Sucrose Acetate Isobutyrate.

The focus of the present work was to develop amorphous solid dispersion (ASD) formulation of aprepitant (APT) using sucrose acetate isobutyrate (SAIB) excipient, evaluate for physicochemical attributes, stability, and bioavailability, and compared with hydroxypropyl methylcellulose (HPMC) based formulation. Various formulations of APT were prepared by solvent evaporation method and characterized for physiochemical and in-vivo performance attributes such as dissolution, drug phase, stability, and bioavailability. X-ray powder diffraction indicated crystalline drug conversion into amorphous phase. Dissolution varied as a function of drug:SAIB:excipient proportion. The dissolution was more than 80% in the optimized formulation (F10) and comparable to HPMC based formulation (F13). Stability of F10 and F13 formulations stored at 25 C/60% and 40°C/75% RH for three months were comparable. Both ASD formulations (F10 and F13) were bioequivalent as indicated by the pharmacokinetic parameters Cmax and AUC0-∞. Cmax and AUC0-∞ of F10 and F13 formulations were 2.52 ± 0.39, and 2.74 ± 0.32 µg/ml, and 26.59 ± 0.39, and 24.79 ± 6.02 µg/ml.h, respectively. Furthermore, the bioavailability of ASD formulation was more than twofold of the formulation containing crystalline phase of the drug. In conclusion, stability and oral bioavailability of SAIB based ASD formulation is comparable to HPMC-based formulation of poorly soluble drugs.

Coating characterization by hyperspectroscopy and predictive dissolution models of tablets coated with blends of cellulose acetate and cellulose acetate phthalate.

The objective of current research was to develop the models of dissolution prediction of tablets coated with cellulose acetate (CA 320S or CA 398-10) and cellulose acetate phthalate (C-A-P) blends. Independent variables selected were coating percent (X1) and percent of CA 320S or CA 398-10 (X2) in the blend. Dependent variables selected were dissolution in 1 (Y1), 8 (Y2), and 24 h (Y3). Diclofenac sodium core tablets were coated with blend of either CA 320S and C-A-P or CA 398-10 and C-A-P at approximately 5, 7.5, and 10% weight gain. CA 320S and CA 398-10 content in the corresponding blends varied from 33.3-66.7% and 25.0-50.0% relative to C-A-P, respectively. Dissolution was performed in phosphate buffer 6.8 using USP apparatus 2. Coated tablets were also characterized for surface morphology and coating uniformity by near infrared hyperspectroscopy. Y1, Y2, and Y3 were statistically (p < 0.05) affected by X2 in CA 320S/C-A-P and CA 398-10/C-A-P blends coated tablets. On the other hand, X1 had statistically significant (p < 0.05) effect only on the Y3 in CA 320S/C-A-P while Y1 was statistically (p < 0.05) affected by X2 in CA 398-10/C-A-P. Analysis of variance also indicated statistically significant (p < 0.05) effect of the studied variables on the dependent variables for both the blends. The models were verified by independent experiment. Model predicted and empirical values of Y1, Y2, and Y3 were close with maximum residual of 7.0%. In conclusion, dissolution can be modulated by varying composition of blend, polymer type, and coating weight.

Liposome Formation Using a Coaxial Turbulent Jet in Co-Flow.

PURPOSE: Liposomes are robust drug delivery systems that have been developed into FDA-approved drug products for several pharmaceutical indications. Direct control in producing liposomes of a particular particle size and particle size distribution is extremely important since liposome size may impact cellular uptake and biodistribution. METHODS: A device consisting of an injection-port was fabricated to form a coaxial turbulent jet in co-flow that produces liposomes via the ethanol injection method. By altering the injection-port dimensions and flow rates, a fluid flow profile (i.e., flow velocity ratio vs. Reynolds number) was plotted and associated with the polydispersity index of liposomes. RESULTS: Certain flow conditions produced unilamellar, monodispersed liposomes and the mean particle size was controllable from 25 up to >465 nm. The mean liposome size is highly dependent on the Reynolds number of the mixed ethanol/aqueous phase and independent of the flow velocity ratio. CONCLUSIONS: The significance of this work is that the Reynolds number is predictive of the liposome particle size, independent of the injection-port dimensions. In addition, a new model describing liposome formation is outlined. The significance of the model is that it relates fluid dynamic properties and lipid-molecule physical properties to the final liposome size.

An index for evaluating difficulty of Chewing Index for chewable tablets.

Chewing difficulty index, a potential measure of difficulty in chewing the chewable tablets, has been described herein as the product of tablet thickness and tablet hardness measured under the diametral loading. The proposed index was evaluated by measuring the dimensions and mechanical strength of commercial and in-house prepared chewable tablets. Data collected on tablets with different thickness but same hardness or tensile strength suggests that the proposed index provides a good assessment of the force needed to chew the chewable tablets. Influence of brief exposure to salivary fluid during chewing on the mechanical strength of the chewable tablets was also evaluated. Thirty seconds exposure to the simulated salivary fluid was also found to significantly reduce (p < 0.05) the hardness and the chewing difficulty index of a number of evaluated chewable tablet drug products.

Development and optimization of taste-masked orally disintegrating tablets (ODTs) of clindamycin hydrochloride.

The purpose of this research was to develop an orally disintegrating tablet (ODT) dosage form containing taste-masked beads of clindamycin HCl. Several formulation strategies were evaluated and a taste-masked ODT of clindamycin HCl was prepared without the use of a waxy cushioning agent. Clindamycin HCl (ca. 46% w/w) was coated onto microcrystalline cellulose beads (Cellets® 200) followed by the addition of a taste-masking layer of amino methacrylate copolymer, NF (Eudragit EPO® (EPO)) coating suspension. The efficiency of both the drug coating process and the taste-masking polymer coating process, as well as the taste masking ODTs was determined using potency and drug release analysis. Magnesium stearate was found to be advantageous over talc in improving the efficiency of the EPO coating suspension. A response surface methodology using a Box-Behnken design for the tablets revealed compression force and levels of both disintegrant and talc to be the main factors influencing the ODT properties. Blending of talc to the EPO-coated beads was found to be the most critical factor in ensuring that ODTs disintegrate within 30 s. The optimized ODTs formulation also showed negligible (<0.5%) drug release in 1 min using phosphate buffer, pH 6.8 (which is analogous to the residence time and pH in the oral cavity). By carefully adjusting the levels of coating polymers, the amounts of disintegrant and talc, as well as the compression force, robust ODTs can be obtained to improve pediatric and geriatric patient compliance for clindamycin oral dosage forms.

Formulation and transport properties of tenofovir loaded liposomes through Caco-2 cell model.

The aim was to investigate the potential of proliposomes to improve the permeability of tenofovir, anti-HIV, for oral delivery. Tenofovir was incorporated into phosphatidylcholine proliposomes and their absorption was determined in Caco-2 cell cultures grown on Transwell inserts using aqueous drug solutions as reference. Five batches of proliposomes were prepared with different stearylamine levels and characterized in terms of vesicular morphology, drug encapsulation efficiency (EEF), drug leakage, vesicular sizing and surface charges. Cytotoxicity of the reconstituted liposomes was evaluated by the MTT assay. The obtained results showed that increasing the incorporated percentage of stearylamine led to an increase in drug encapsulation, a slower drug leakage and larger liposomes formed. Compared to the drug solutions at corresponding concentrations, the proposed formulations showed a positive relationship (R²= 0.9756) for the influence of increasing the stearylamine percentage on reduction of mitochondrial activity. Regarding the drug permeability, enhancements of apparent permeability by 16.5- and 5.2-folds were observed for proliposomes formulations with 5% and 15% stearylamine, respectively. A good correlation was observed between the Caco-2 and dialysis models that might indicate passive diffusion as well as paracellular transport as suggested mechanisms for drug absorption. Cationic proliposomes offered a potential formulation to improve the permeation of tenofovir.

Pyrimethamine 3D printlets for pediatric toxoplasmosis: design, pharmacokinetics, and anti-toxoplasma activity.

OBJECTIVES: The focus of the present research is to develop printlet formulations of pyrimethamine (PMT). METHODS: Printlets formulation of PMT were developed by screening design by varying laser scanning speed, Kollidon® VA 64, polyvinylpyrrolidone, and disintegrant. RESULTS: Laser scanning speed, Kollidon® VA, and disintegrant had statistically significant effect on hardness, disintegration time, and/or dissolution (p < 0.05). Dissolution was almost 100% in 30 min. X-ray powder diffraction indicated partial amorphous transformation of the crystalline drug. Pharmacokinetic and anti-toxoplasma activity profiles of the printlets and compressed tablets were superimposable with no statistical difference (p > 0.05). CONCLUSION: Clinical performance of the printlets would be similar to the compressed tablets.

NIR spectroscopy applications in the development of a compacted multiparticulate system for modified release.

The purpose of this study was to utilize near-infrared spectroscopy and chemical imaging to characterize extrusion-spheronized drug beads, lipid-based placebo beads, and modified release tablets prepared from blends of these beads. The tablet drug load (10.5-19.5 mg) of theophylline (2.25 mg increments) and cimetidine (3 mg increments) could easily be differentiated using univariate analyses. To evaluate other tablet attributes (i.e., compression force, crushing force, content uniformity), multivariate analyses were used. Partial least squares (PLS) models were used for prediction and principal component analysis (PCA) was used for classification. The PLS prediction models (R (2) >0.98) for content uniformity of uncoated compacted theophylline and cimetidine beads produced the most robust models. Content uniformity data for tablets with drug content ranging between 10.5 and 19.5 mg showed standard error of calibration (SEC), standard error of cross-validation, and standard error of prediction (SEP) values as 0.31, 0.43, and 0.37 mg, and 0.47, 0.59, and 0.49 mg, for theophylline and cimetidine, respectively, with SEP/SEC ratios less than 1.3. PCA could detect blend segregation during tableting for preparations using different ratios of uncoated cimetidine beads to placebo beads (20:80, 50:50, and 80:20). Using NIR chemical imaging, the 80:20 formulations showed the most pronounced blend segregation during the tableting process. Furthermore, imaging was capable of quantitating the cimetidine bead content among the different blend ratios. Segregation testing (ASTM D6940-04 method) indicated that blends of coated cimetidine beads and placebo beads (50:50 ratio) also tended to segregate.

Complexation between risperidone and amberlite resin by various methods of preparation and binding study.

PURPOSE: The purpose of this work was to investigate the effect of preparation methods and the drug-to-resin ratio on complex formation between risperidone and amberlite resin. METHODS: The existence of such resin complex may provide taste-masking properties to the dosage forms. It is important to determine when and how the complex forms. Therefore, in this study, the complexes of risperidone and amberlite resin were prepared by granulation, solution, and freeze-drying methods at various drug-to-resin ratios. The physical mixtures of drug-resin were used to compare the results of complexes prepared by granulation, solution, and freeze drying. The complexes were evaluated by various methods of characterization including differential scanning calorimetry, X-ray diffraction, spectroscopy (near infrared, Fourier transform infrared, and Raman), drug release, and binding studies. RESULTS: Complexation between risperidone and amberlite was investigated for various preparation methods. It was found that complexation occurred at lower amounts of amberlite resin (drug-to-resin ratios of 1:1 and 1:2) when solution form of drug was contacted with the resin as in the case of solution and freeze-drying techniques compared with granulation (drug-to-resin ratios of 1:4 and 1:6). Characterization studies such as differential scanning calorimetry, X-ray diffraction, spectroscopic techniques, and drug release studies differentiated complexes from the physical mixtures. Binding studies between them revealed that the binding was linear with solubility of the drug limiting the adsorption capacity. CONCLUSIONS: Results of the study highlighted the importance of the preparation methodologies to formulate complexes. When the drug and the resin were simply mixed physically, no complexation occurred. Thus, a careful evaluation of manufacturing procedure would indicate the nature and extent of complexation.

Complexation of risperidone with a taste-masking resin: novel application of near infra-red and chemical imaging to evaluate complexes.

The purpose of the study was to investigate the complexation between a weakly basic drug (risperidone) and an ion exchange resin (amberlite IRP-64) used as a taste-masking agent via two preparation methods: physical mixture and solvent evaporation. Both methods were prepared in different drug-to-resin ratios by weight (1:1, 1:2, 1:4, 1:6). Physicochemical characterizations were performed using differential scanning calorimetry, x-ray diffraction, infra-red spectroscopy, Raman spectroscopy, near infra-red spectroscopy, chemical imaging and drug release studies. These physicochemical techniques revealed that risperidone formed complex with the resin via the solvent evaporation method where enhanced dissolution occurred but not with the physical mixtures.

Blend of cellulose ester and enteric polymers for delayed and enteric coating of core tablets of hydrophilic and hydrophobic drugs.

The focus of this work was to explore feasibility of using blends of cellulose esters (CA 320S, CA 3980-10 or CAB 171-15) and enteric polymers (C-A-P, Eudragit® L100 or HPMCP HP-55) for delayed and enteric coating of tablets containing either diclofenac sodium (DFS, high dose) or prednisone (PDS, low dose) drug. The core tablets of DFS or PDS were coated with polymer blends to achieve approximate weight gain of 5% and 10%. The coated tablets were characterized for dissolution (0.1 N HCl and phosphate buffer pH 6.8) and surface morphology. The surface morphology of CA 398-10 or CAB 171-15 based polymer blends was rough and fibrous. Less than 0.5% drug was dissolved in 120 min from 5% w/w coated tablets in acid-phase dissolution testing. The dissolution in phosphate buffer pH 6.8 medium varied from 16.2 ±â€¯0.2 to 98 ±â€¯2.1%, and 30.1 ±â€¯0.5% to 101.7 ±â€¯3.4% in 120 min from DFS and PDS coated tablets, respectively. Dissolution was less in CA 320S based blends compared to CA 398-10 or CAB 171-15 blends in phosphate buffer medium. Furthermore, there were no significant differences observed in dissolution profiles of coated tablets of DFS or PDS. This can be explained by dose of the drugs. Additionally, dissolution was higher in tablets coated with enteric polymer alone compared with the blends. In conclusion, core tablets can be coated with cellulose ester and enteric polymers blend to impart both delayed and enteric release feature to the tablets containing hydrophilic or hydrophobic drug.

Optimization and in vivo evaluation of an oral dual controlled-release tablet dosage form of insulin and duck ovomucoid.

The objectives of the present study were to (1) optimize the release rate of insulin from compressed microparticulates and (2) compare the in vivo hypoglycemic effect of optimized insulin microparticulates with compressed enzyme inhibitor (duck ovomucoid) and without inhibitor. A 3-factor, 15-run Box Behnken design was used to construct polynomial models correlating the dependent and independent variables. Independent processing variables were rate of addition of the alcoholic Eudragit L100 dispersion, volume of the antisolvent, and compression pressure. Responses were cumulative percent of insulin released from 1-6 hours. Insulin and ovomucoid release was simultaneously analyzed by high-performance liquid chromatography. They demonstrated variable release rates, which were optimized to the Higuchi's square root of time model to release the insulin and the inhibitor over 6 hours. The relationship between dissolution profiles and process parameters were demonstrated by contour and response surface plots. In vivo hypoglycemic effect was evaluated in rabbits in a 3-way crossover design. Cocompressed microparticulates of insulin and duck ovomucoid displayed a 3.2-fold greater hypoglycemic effect when compared with a similar preparation without ovomucoid. This study demonstrated the potential benefits of dosage forms with dual controlled-release mechanisms for both the protein and enzyme inhibitor.

Process analytical technology (PAT): effects of instrumental and compositional variables on terahertz spectral data quality to characterize pharmaceutical materials and tablets.

The aim of this study was to use terahertz spectroscopy to characterize pharmaceutical materials and tablets, and to understand the effects of measuring conditions and compositional variability on the data quality. Tests were performed on five formulation components (theophylline, lactose, starch, Avicel, magnesium stearate) and a series of tablets composed of various concentrations of theophylline and excipients. Transmission spectra of polyethylene (PE) disks derived from each of the samples were analyzed. Three factors (component loading, component chemistry, and disk drying time) were screened as critical factors associated with the magnitude and location of THz absorbance peaks. Applying the standard sample spectra divided by PE reference spectra ratio method revealed that, to a large extent, PE was responsible for the disk drying time dependence. Direct spectral feature analysis along with mass-transfer analysis of the disk drying process revealed THz absorption peak maxima of lactose (255 cm(-1)) and water (54 and 210 cm(-1)) which is also supported by literature values for the peak maxima assignment for water. Particle scattering due to specimen and PE was found to be also partially responsible for the observed spectral intensities. The importance of THz spectroscopy was demonstrated for characterization of pharmaceutical materials and tablet.

Quality by design: understanding the formulation variables of a cyclosporine A self-nanoemulsified drug delivery systems by Box-Behnken design and desirability function.

Quality by design (QBD) refers to the achievement of certain predictable quality with desired and predetermined specifications. A very useful component of the QBD is the understanding of factors and their interaction effects by a desired set of experiments. The present project deals with a case study to understand the effect of formulation variables of nanoemulsified particles of a model drug, cyclosporine A (CyA). A three-factor, three-level design of experiment (DOE) with response surface methodology (RSM) was run to evaluate the main and interaction effect of several independent formulation variables that included amounts of Emulphor El-620 (X(1)), Capmul MCM-C8 (X(2)) and 20% (w/w) CyA in sweet orange oil (X(3)). The dependent variables included nanodroplets size (Y(1)), nanoemulsions turbidity (Y(2)), amounts released after 5 and 10min (Y(3), Y(4)), emulsification rate (Y(5)) and lag time (Y(6)). A desirability function was used to minimize lag time and to maximize the other dependent variables. A mathematical relationship, Y(5)=9.09-0.37X(1)+0.37X(2)-0.45X(3)+0.732X(1)X(2)-0.62X(1)X(3)+0.3X(2)X(3)+0.02X(1)(2)-0.28X(2)(2)+0.471X(3)(2) (r(2)=0.92), was obtained to explain the effect of all factors and their colinearities on the emulsification rate. The optimized nanodroplets were predicted to yield Y(1), Y(2), Y(3), Y(4), Y(5) and Y(6) values of 42.1nm, 50.6NTU, 56.7, 107.2, 9.3%/min and 3.5min, respectively, when X(1), X(2), and X(3) values were 36.4, 70 and 10mg, respectively. A new batch was prepared with these levels of the independent variables to yield Y(1)-Y(6) values that were remarkably close to the predicted values. In conclusion, this investigation demonstrated the potential of QBD in understanding the effect of the formulation variables on the quality of CyA self-nanoemulsified formulations.

Effects of excipients and curing process on the abuse deterrent properties of directly compressed tablets.

The objective of the present investigation was to understand the effects of excipients and curing process on the abuse deterrent properties (ADP) of Polyox™ based directly compressible abuse deterrent tablet formulations (ADFs). The excipients investigated were lactose (monohydrate or anhydrous), microcrystalline cellulose and hydroxypropyl methylcellulose. The ADPs studied were tablet crush resistance or hardness, particle size distribution following mechanical manipulation, drug extraction in water and alcohol, syringeability and injectability. Other non-ADPs such as surface morphology and tablet dissolution were also studied. It was found that presence of 50% or more of water soluble or swellable excipient in the ADF tablets significantly affected the tablet hardness, particle size distribution following mechanical manipulation and drug extraction while small amount (5%) of excipients had either minimal or no effect on ADPs of these tablets. Addition of high molecular weight HPMC (K 100M) affected syringeability and injectability of ADF. Curing process was found to affect ADPs (hardness, particle size distribution, drug extraction and syringeability and injectability) when compared with uncured tablet. In conclusion, addition of large amount of excipients, especially water soluble ones in Polyox™ based ADF tablets increase the risk of abuse by various routes of administration.

Formulation of anastrozole microparticles as biodegradable anticancer drug carriers.

The purpose of this study was to develop poly(d,l-lactic-co-glycolic acid) (PLGA)-based anastrozole microparticles for treatment of breast cancer. An emulsion/extraction method was used to prepare anastrozole sustained-release PLGA-based biodegradable microspheres. Gas chromatography with mass spectroscopy detection was used for the quantitation of the drug throughout the studies. Microparticles were formulated and characterized in terms of encapsulation efficiency, particle size distribution, surface morphology, and drug release profile. Preparative variables such as concentrations of stabilizer, drug-polymer ratio, polymer viscosity, stirring rate, and ratio of internal to external phases were found to be important factors for the preparation of anastrozole-loaded PLGA microparticles. Fourier transform infrared with attenuated total reflectance (FTIR-ATR) analysis and differential scanning calorimetry (DSC) were employed to determine any interactions between drug and polymer. An attempt was made to fit the data to various dissolution kinetics models for multiparticulate systems, including the zero order, first order, square root of time kinetics, and biphasic models. The FTIR-ATR studies revealed no chemical interaction between the drug and the polymer. DSC results indicated that the anastrozole trapped in the microspheres existed in an amorphous or disordered-crystalline status in the polymer matrix. The highest correlation coefficients were obtained for the Higuchi model, suggesting a diffusion mechanism for the drug release. The results demonstrated that anastrozole microparticles with PLGA could be an alternative delivery method for the long-term treatment of breast cancer.

Impact of formulation and process variables on solid-state stability of theophylline in controlled release formulations.

Understanding the impact of pharmaceutical processing, formulation excipients and their interactions on the solid-state transitions of pharmaceutical solids during use and in storage is critical in ensuring consistent product performance. This study reports the effect of polymer viscosity, diluent type, granulation and granulating fluid (water and isopropanol) on the pseudopolymorphic transition of theophylline anhydrous (THA) in controlled release formulations as well as the implications of this transition on critical quality attributes of the tablets. Accordingly, 12 formulations were prepared using a full factorial screening design and monitored over a 3 month period at 40 °C and 75%. Physicochemical characterization revealed a drastic drop in tablet hardness accompanied by a very significant increase in moisture content and swelling of all formulations. Spectroscopic analysis (ssNMR, Raman, NIR and PXRD) indicated conversion of THA to theophylline monohydrate (TMO) in all formulations prepared by aqueous wet granulation in as early as two weeks. Although all freshly prepared formulations contained THA, the hydration-dehydration process induced during aqueous wet granulation hastened the pseudopolymorphic conversion of theophylline during storage through a cascade of events. On the other hand, no solid state transformation was observed in directly compressed formulations and formulations in which isopropanol was employed as a granulating fluid even after the twelve weeks study period. The transition of THA to TMO resulted in a decrease in dissolution while an increase in dissolution was observed in directly compressed and IPA granulated formulation. Consequently, the impact of pseudopolymorphic transition of theophylline on dissolution in controlled release formulations may be the net result of two opposing factors: swelling and softening of the tablets which tend to favor an increase in drug dissolution and hydration of theophylline which decreases the drug dissolution.

Assessing impact of formulation and process variables on in-vitro performance of directly compressed abuse deterrent formulations.

Prescription drug products abuse/misuse is epidemic in United States. Opioids drug forms major portion of prescription drug product abuse. Abuse deterrence formulation (ADF) is one of the many approaches taken by sponsors to tackle this problem. It involves formulating opioids into dosage forms that will be difficult to abuse/misuse. Current investigation focused on evaluating the abuse deterrent properties (ADP) of ADF manufactured by direct compression method. Effect of process and formulation variables on ADP was investigated by statistical design of experiment (fractional factorial design). Independent factors studied were molecular weight of polyethylene oxide (Polyox™), curing time, temperature and method, and antioxidant type. Sotalol hydrochloride was selected as a model drug. ADP investigated were hardness/crush resistance, syringeability and injectability, physical manipulation (reduction into powder) and drug extraction in water and alcohol. Hardness and syringeability are evaluated by newly developed quantitative procedure. Other properties were also investigated such as morphology, crystallinity, assay and dissolution. The hardness and drug extraction was significantly (p<0.05) affected by curing temperature. Formulations could be powdered in 3 min irrespective of their hardness. Syringeability and injectability were intrinsic properties of the polymer used in the formulation, and were not affected by the investigated factors. Crystallinity of the polymer and drug changed, and was dependent upon curing temperature and time. The dissolution and assay were independent of formulation and process parameters studied. In conclusion, the study indicated some advantages of ADF product compared to non-ADF prepared by direct compression. However, the ADF should not be viewed as abuse proof product rather as incrementally improved product.

Targeting to macrophages: role of physicochemical properties of particulate carriers--liposomes and microspheres--on the phagocytosis by macrophages.

Heterogeneous functions of macrophages in human immune systems have renewed interest in targeting of drugs to these cells. Various carrier systems have emerged to deliver drugs to macrophages, albeit the efficacy, reliability and selectivity of these carriers are still in question. To date, the most extensively studied carriers are liposomes and microspheres. Various physicochemical properties of these carriers can alter their efficacy and specificity to a great extent. These properties include hydrophilicity, surface charge, composition, concentration, and presence of various ligands. In this review, a comprehensive evaluation of the literature has been carried out in order to show the role of these parameters in the design of carriers for targeting of drugs to macrophages.

Optimization and characterization of controlled release multi-particulate beads formulated with a customized cellulose acetate butyrate dispersion.

The objectives of the present investigation were: (1) to model the effect of process and formulation variables viz., coating weight gain, duration of curing, and plasticizer concentration on in-vitro release profile of verapamil HCl from multi-particulate beads formulated with a novel aqueous-based pseudolatex dispersion; (2) to optimize the formulation by response surface methodology (RSM) and artificial neural network (ANN); and (3) to characterize the optimized product by thermal and X-ray analyses. Inert beads (Nupareil) were loaded with verapamil HCl and subsequently coated with a custom designed aqueous-based pseudolatex dispersion of cellulose acetate butyrate (CAB). Experiments were designed and data was collected according to a three factor, three level face centered central composite design. Data was analyzed for modeling and optimizing the release profile using both RSM and ANN. Model fitted the data and explained 90% of variability in response in the case of RSM and at least 70% in the case of ANN. Release profile was optimized for a zero-order model. Optimized formulations were prepared according to the factor combinations dictated by RSM and ANN. In each case, the observed drug release data of the optimized formulations was close to the predicted release pattern. However, the modeling and optimization abilities of RSM as evaluated by the R-squared values, were found to be higher than that of ANN. X-ray and drug content analysis suggested the absence of any degradation of verapamil HCl and excipients incorporated in the formulation.