Application of Box–Behnken Design and Desirability function in the Optimization of Aceclofenac-Loaded Micropsonges for Topical Application

Background: The aim of the present investigation was to develop optimized Aceclofenac-loaded microsponges using Box-Behnken design (BBD) and desirability function. Material and Method: Aceclofenac-loaded microsponges were developed using ethyl cellulose, ethanol and polyvinyl alcohol (PVA). Initially, a trial batch was developed using quasi-emulsion solvent diffusion method, and by optimizing the drug-polymer ratio. A 3-level, 3-factor BBD was used to investigate the effect of PVA, ethanol and stirring speed on particle size and entrapment efficiency (EE). The models used for the optimization were analyzed through ANOVA and diagnostic plots. Finally, the desirability function was used for the selection of optimized formulation composition. Results: A drug-polymer ratio of 1.5:1 was taken as optimized ratio for all the formulations. The developed microsponges were of the spherical shape having size and %EE in the range of 22.54±2.85 µm to 49.08±5.01 µm and 70.57±4.19% to 86.43±2.58 %, respectively. The amounts of PVA, ethanol and stirring speed were noted to have a significant impact on particle size and %EE. Finally, an optimized formulation (size-22.69 and %EE-86.42) was developed with a desirability value of 0.9967. Conclusion: The BBD is a valuable tool for the development of optimized microsponges with desired properties.

Pulsatile Delivery of Fexofenadine Hydrochloride Pulsincap by Box-Behnken Design

Objective: Fexofenadine hydrochloride is a selective peripheral H1-blocker, used for allergy symptoms, such as hay fever and urticaria. Allergic symptoms are aggressive during early morning hours, so a pulsatile delivery system with a lag time of 4-5 hours was formulated and optimized by Box-Behnken design. Materials and Methods: Pulsincap system using formaldehyde-treated capsules and hydrogel plug. Box-Behnken design was applied for optimization in which three independent variables, X1= Drug: polymer ratio, X2 = Polymer: polymer ratio (Ethylcellulose: HPMC E15) and X3 = Plug weight were selected. Three dependent variables R1 = Percent release of drug after 4 hours, R2 = percent release after 10 hours and R3 = Lag time were selected. Results: FTIR and DSC studies confirmed compatibility of drug and excipients. The empty formaldehyde-treated capsules were evaluated for physical appearance, solubility, capsule dimensions and formaldehyde content. Hydrogel plugs, powder blend and pulsincap formulations were evaluated for Physico-chemical parameters and all the parameters were within acceptable limits. Contour plots and Response surface plots indicated that as Drug: Polymer ratio (X1) and Plug weight (X3) increased, Lag time increased but% drug release decreased. As Polymer: Polymer ratio (X2) increased, the lag time was at a moderate level. Predicted vs actual responses showed the correlation of 0.786 for% release in 4hrs, 0.9744 for% release in 10hrs and 0.6281 for lag time. Optimized formulation G1 was suggested by design (with criteria 4.5-6hrs lag time, 10-20% release in 4hrs & 60-70% drug release within 10hrs). The optimised formulation was stable. Conclusion: Pulsincap system of Fexofenadine hydrochloride can be obtained by using retarding polymers like ethyl cellulose, HPMC E15 and formaldehyde cross-linked capsules.

Gelatin-Alginate Coacervates Optimized by DOE to Improve Delivery of bFGF for Wound Healing

Metabolic disorders in diabetic patients are associated with altered protein and lipid metabolism and defects in granulation tissue formation, resulting in non-healing wounds such as diabetic foot ulcers (DFU). Growth factors have essential roles in tissue re-epithelization and angiogenesis during wound healing. In this study, a complex coacervate was evaluated as an enhanced delivery system for fibroblast growth factor (bFGF) to control its release rate and protect it from proteases. Coacervates composed of gelatin Type A (GA) and sodium alginate (SA) were optimized by the Design of Experiments (DOE), with the polymer ratio and the medium’s pH as the independent variables, and turbidity, particle size, polydispersity index, and encapsulation efficiency (EE, %) as the responses. The optimized coacervate protected bFGF from trypsin digestion and showed controlled release compared with bFGF in solution or a physical mixture of GA and SA. It enhanced the viability, migration, and procollagen I C-terminal propeptide synthesis of human dermal fibroblasts in hyperglycemic conditions. In summary, the DOE approach was successfully applied to optimize bFGF GA-SA coacervates as a potential novel therapeutic modality to treat DFU.

Formation development and evaluation of microsphere of sulfasalazine for the treatment inflammatory bowel diseases

Inflammatory bowel disease (IBD) is a chronic relapsing and remitting inflammatory disorder of the small intestine and colon. IBD includes ulcerative colitis (UC) and Crohn’s disease (CD), and it is a main reason for the expansion of colon cancer, referred to as colitis-associated cancer (CAC). Oral colon-targeted microsphere based drug delivery system containing sulfasalazine was prepared, optimized and characterized. The microspheres were effectively prepared by simple emulsification phase-separation technique followed by cross-linking. The formulations were optimized on the basis of drug: polymer ratio, stirring speed, concentration of glutaraldehyde. The prepared microspheres were characterized on the basis of morphology, entrapment efficiency, particle size and in-vitro release. Keywords: Microspheres, Sulfasalazine, Inflammatory bowel disease, Colon-targeted, Chitosan

Preparation of Solid Dispersions of Simvastatin and Soluplus Using a Single-Step Organic Solvent-Free Supercritical Fluid Process for the Drug Solubility and Dissolution Rate Enhancement

The study was designed to investigate the feasibility of supercritical carbon dioxide (scCO2) processing for the preparation of simvastatin (SIM) solid dispersions (SDs) in Soluplus® (SOL) at temperatures below polymer’s glass transition. The SIM content in the SDs experimental design was kept at 10, 20 and 30% to study the effect of the drug–polymer ratio on the successful preparation of SDs. The SIM–SOL formulations, physical mixtures (PMs) and SDs were evaluated using X-ray diffraction (XRD), differential scanning calorimetry (DSC), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), and dissolution studies. The scCO2 processing conditions and drug–polymer ratio were found to influence the physicochemical properties of the drug in formulated SDs. SIM is a highly crystalline drug; however, physicochemical characterisation carried out by SEM, DSC, and XRD demonstrated the presence of SIM in amorphous nature within the SDs. The SIM–SOL SDs showed enhanced drug dissolution rates, with 100% being released within 45 min. Moreover, the drug dissolution from SDs was faster and higher in comparison to PMs. In conclusion, this study shows that SIM–SOL dispersions can be successfully prepared using a solvent-free supercritical fluid process to enhance dissolution rate of the drug.

Design and Evaluation of Novel Sustained-Release Floating Microspheres for Oral Delivery of Ciprofloxacin Hydrochloride

Background: Ciprofloxacin (CIP) is a broad-spectrum antibiotic, used to treat various bacterial infections. Administration of conventional oral dosage forms of CIP is associated with multiple challenges such as short residence time of the drug in the gastrointestinal tract which could reduce bioavailability and effectiveness of the drug. This study aimed to design and develop novel floating microspheres for the sustained release of CIP in the stomach over 24 hours after oral administration, besides evaluating the effect of different variables on the characteristics of developed microspheres. Methods: Microspheres were developed by the solvent-evaporation method utilizing cellulose acetate and polyvinyl alcohol, then characterized for physicochemical properties including bulk density, buoyancy, and entrapment efficacy. The drug-excipient compatibility was evaluated by Fourier-transform infrared spectroscopy and the Scanning electron microscopy was used to observe the morphology of microspheres. The effects of the drug to polymer ratio, polymer concentration, and the pace of stirring through the preparation process, on the size and release rate were also evaluated. Results: Morphology analysis indicated round-shape microspheres with a mean particle size between 66-344 µm. The polydispersity index of prepared formulations was determined to be in the range of 0.129 to 0.230. It was observed that at higher polymer concentrations the drug release rate from microspheres decreased while the mean particle size increased. Increasing the drug to polymer ratio and decreasing the stirring speed increased the mean particle size. All formulations showed more than 70% cumulative drug release in the prolonged period of 24 h while remaining buoyant in the meantime. The formulations followed Higuchi and Korsmeyer-Peppas kinetics and release the drug by diffusion mechanism. Conclusions: Based on the results obtained from in vitro release study besides floating properties the prepared microspheres could be considered suitable for enhanced sustained-release of CIP following the oral administration.

Dissolution profiles of fenbendazole from binary solid dispersions: a mathematical approach

Aim: Understanding a drug dissolution process from solid dispersions (SD) to develop formulations with predictable in vivo performance. Materials & methods: Dissolution data of fenbendazole released from the SDs and the control physical mixtures were analyzed using the Lumped mathematical model to estimate the parameters of pharmaceutical relevance. Results: The fit data obtained by Lumped model showed that all SDs have a unique dissolution profile with an error of ±4.1% and an initial release rate 500-times higher than the pure drug, without incidence of drug/polymer ratio or polymer type. Conclusion: The Lumped model helped to understand that the main factor influencing the fenbendazole release was the type formulation (SD or physical mixture), regardless of the type or amount of polymer used.

Formulation Development and Optimization of Sustained Release Microspheres of Acebrophylline

Objectives: Aim of present work is to prepare and evaluate Sustained release microspheres of Acebrophylline for treatment of Asthma. Experimental work: In present investigation, attempt was made to prepare sustained release microspheres of Acebrophylline with different polymer ratio using Ionic gelation method. Drug- excipient compatibility studies were performed by FTIR. The best suited Microspheres formulation was found on the basis production yield, entrapment efficiency and in vitro release study. Optimized batch of microspheres (B2) was characterized for FTIR, DSC, and SEM analysis. The drug release data of optimized batch was fitted into different release kinetic models. The optimized batch of microspheres (B2) was subjected for the short term stability study at 40 ± 2°C with RH of 75% for a period of 1 month. Results and discussion: There was no interaction found between drug and excipients. Sodium alginate (2%) concentration, Eudragit RS-100 (1:2) ratio gave highest sustainable property and CaCl2 (2.5%) concentration had a good cross linking property. This observation done on the basis of production yield, entrapment efficiency and In vitro release study. The Microspheres prepared from Ionic gelation method had Drug : Eudragit RS100 (1:2), 2 % Sodium alginate and 2.5 % CaCl2 (B2) give 99.2 % drug release over the periods of 12 hr. The drug release from optimized microspheres formulation (B2) follows first order release kinetic. DSC study showed the melting behavior of drug present into microspheres. SEM studies showed that optimized microspheres were spherical and rough surface. Stability study proved that optimized formulation (B2) was stable. Conclusion: Drug: Polymer ratio and Volume of CaCl2 had significant effect on % Entrapment efficiency and Drug release. From the Scanning Electron Microscopy (SEM) study observed that microspheres was spherical and rough surface. Non Fickian diffusion was the mode of drug release from Acebrophylline- loaded microspheres. After stability study no physical changes & almost same drug release was observed in microspheres. Hence, the formulation B2 was stable.