D-optimal mixture design for optimization of topical dapsone niosomes: in vitro characterization and in vivo activity against Cutibacterium acnes.

This study aimed to illustrate the use of D-optimal mixture design (DOMD) for optimization of an enhancer containing Dapsone niosomal formula for acne topical treatment. Mixture components (MixCs) studied were: Span 20, Cholesterol, and Cremophor RH. Different responses were measured. Optimized formula (OF) was selected to minimize particle size and maximize absolute zeta potential and entrapment efficiency. Optimized formula gel (OF-gel) was prepared and characterized. OF-gel in vivo skin penetration using confocal laser scanning microscopy and activity against Cutibacterium acnes in acne mouse model were studied. Based on DOMD results analysis, adequate models were derived. Piepel and contour plots were plotted accordingly to explain how alteration in MixCs L-pseudo values affected studied responses and regions for different responses' values. The OF had suitable predicted responses which were in good correlation with the actually measured ones. The OF-gel showed suitable characterization and in vivo skin penetration up to the dermis layer. In vivo acne mouse-model showed that OF-gel-treated group (OF-gel-T-gp) had significantly better recovery (healing) criteria than untreated (UT-gp) and Aknemycin®-treated (A-T-gp) groups. This was evident in significantly higher reduction of inflammation percent observed in OF-gel-T-gp than both UT-gp and A-T-gp. Better healing in OF-gel-T-gp compared with other groups was also verified by histopathological examination. Moreover, OF-gel-T-gp and A-T-gp bacterial loads were non-significantly different from each other but significantly lower than UT-gp. Thus, DOMD was an adequate statistical tool for optimization of an appropriate enhancer containing Dapsone niosomal formula that proved to be promising for topical treatment of acne.

Formulation, characterization, optimization, and in-vivo performance of febuxostat self-nano-emulsifying system loaded sublingual films.

Febuxostat (FXS) is a potent antigout drug with poor water solubility and relative high first-pass effect leading to moderate oral bioavailability (<49%). This study aimed to increase FXS solubility and bioavailability by optimizing sublingual fast-dissolving films (SFs) containing a selected FXS self-nano-emulsifying system (s-SNES) previously prepared by our team. The s-SNES was loaded into SFs by solvent casting technique. A full factorial design (32) was applied to study the effects of polymer and plasticizer types on mechanical characteristics and the dissolution profile of FXS from the SFs. Numerical optimization was performed to select the SF having highest desirability according to predetermined characteristics. The optimized SF (O-SF) contained 1 g of s-SNES, polyvinylpyrrolidone K30 (6%w/v), polyethylene glycol 300 (20%w/w of polymer wt.), and Avicel PH101 (0.5%w/v). O-SF showed good permeation of FXS through sheep sublingual tissue. Storage of O-SF for three months showed no significant change in the FXS dissolution profile. In-vivo performance of O-SF in rabbits was compared to that of oral marketed tablets (Staturic® 80 mg). A cross-over design was applied and pharmacokinetic parameters were calculated after ensuring absence of sequence effect. Statistical analysis revealed better performance for O-SF with significantly higher Cmax, AUC0-24, AUC0-∞, apparent t1/2 together with lower tmax, and apparent kel than marketed tablets. Relative bioavailability of O-SF compared to the marketed tablet was found to be 240.6%. This confirms the achievement of the study aims of improving dissolution rate and bioavailability of FXS using a patient-wise convenient formula.

Enhancement of Transdermal Delivery of Haloperidol via Spanlastic Dispersions: Entrapment Efficiency vs. Particle Size.

Haloperidol (Hal) is a well-known typical antipsychotic. Hepatic first pass metabolism leads to its limited oral bioavailability. This study aimed at enhancing transdermal delivery of Hal via spanlastic formulae. Hal-loaded spanlastics of Span®60 and an edge activator (EA) were successfully prepared by ethanol injection method according to a 31.41 full factorial design. In this design, independent variables were X1, EA type, and X2, Span®60 to EA ratio. Y1, percentage entrapment efficiency (EE%); Y2, particle size (PS); Y3, deformability index (DI); and Y4, percentage drug released after 4h (Q4h), were chosen as dependent variables. The Fourier-transform infrared spectral analysis showed no considerable chemical interaction between Hal and the used excipients. Both factors affected significantly all the responses except DI. Desirability of each prepared formula was calculated based on maximizing EE% and Q4h and minimizing PS. Formula F6, with X1, Tween®80, and X2, 8:2, had the highest desirability value followed by F7, with X1, Tween®80, and X2, 6:4, and both were chosen as selected formulae (SF) for further investigation. F6 (having more entrapped Hal), F7 (of smaller PS), and Hal solution in propylene glycol were subjected to ex vivo permeation test through newborn rat skin. Both formulae showed marked enhancement in drug permeation compared with drug solution. The significantly higher Q36h and J36h of F7 from F6 may indicate that the smaller particle size aided more than higher entrapment in achieving a higher permeation for Hal of 3.5±0.2µg/cm2.h. These results are promising for further investigation of this formula.

Resolution V fractional factorial design for screening of factors affecting weakly basic drugs liposomal systems.

This study aims to investigate factors affecting weakly basic drugs liposomal systems. Resolution V fractional factorial design (2V5-1) is used as an example of screening designs that would better be used as a wise step before proceeding with detailed factors effects or optimization studies. Five factors probable to affect liposomal systems of weakly basic drugs were investigated using Amisulpride as a model drug. Factors studied were; A: Preparation technique B: Phosphatidyl choline (PhC) amount (mg) C: Cholesterol: PhC molar ratio, D: Hydration volume (ml) and E: Sonication type. Levels investigated were; Ammonium sulphate-pH gradient technique or Transmembrane zinc chelation-pH gradient technique, 200 or 400 mg, 0 or 0.5, 10 or 20 ml and bath or probe sonication for A, B, C, D and E respectively. Responses measured were Particle size (PS) (nm), Zeta potential (ZP) (mV) and Entrapment efficiency percent (EE%). Ion selective electrode was used as a novel method for measuring unentrapped drug concentration and calculating entrapment efficiency without the need for liposomal separation. Factors mainly affecting the studied responses were Cholesterol: PhC ratio and hydration volume for PS, preparation technique for ZP and preparation technique and hydration volume for EE%. The applied 2V5-1 design enabled the use of only 16 trial combinations for screening the influence of five factors on weakly basic drugs liposomal systems. This clarifies the value of the use of screening experiments before extensive investigation of certain factors in detailed optimization studies.

Enhanced transdermal delivery of ondansetron using nanovesicular systems: Fabrication, characterization, optimization and ex-vivo permeation study-Box-Cox transformation practical example.

This study aimed to formulate suitable nanovesicles (NVs) for transdermal delivery of Ondansetron. It also illustrated a practical example for the importance of Box-Cox transformation. A 23 full factorial design was used to enable testing transfersomes, ethosomes, and transethosomes of Ondansetron simultaneously. The independent variables (IVs) studied were sodium taurocholate amount, ethanol volume in hydration medium and sonication time. The studied dependent variables (DVs) were: particle size (PS), zeta potential (ZP) and entrapment efficiency (EE). Polynomial equations were used to study the influence of IVs on each DV. Numerical multiple response optimization was applied to select an optimized formula (OF) with the goals of minimizing PS and maximizing ZP absolute value and EE. Box-Cox transformation was adopted to enable modeling PS raised to the power of 1.2 with an excellent prediction R2 of 1.000. ZP and EE were adequately represented directly with prediction R2 of 0.9549 and 0.9892 respectively. Response surface plots helped in explaining the influence of IVs on each DV. Two-sided 95% prediction interval test and percent deviation of actual values from predicted ones proved the validity of the elucidated models. The OF was a transfersomal formula with desirability of 0.866 and showed promising results in ex-vivo permeation study.

Tri-block co-polymer nanocarriers for enhancement of oral delivery of felodipine: preparation, in vitro characterization and ex vivo permeation.

This study aimed to prepare, optimize and characterize novel felodipine-loaded polymeric nanomicelles, using a pluronic mixture of F127 and P123. Thin-film hydration method was adopted for the preparation of different polymeric nanomicelles (T1-T12) according to a 41.31 full factorial design. Factors studied were: Pluronic®:drug ratio (P:D ratio) (10, 20, 30 and 40 w/w) and percent of hydrophilic polymer (F127%) (33.33%, 50% and 66.67% w/w). Optimization criteria were to maximize transmittance percent (T%) and entrapment efficiency percent (EE%) and to minimize particle size (PS) and polydispersity index (PDI). The optimized formulation was further characterized by DSC, FTIR and 1H NMR studies. It was also subjected to stability testing and ex vivo permeation using rabbit intestines. Spherical nanomicelles of particle size ranging from 26.18 to 87.54 nm were successfully obtained. The optimized formulation was found to be the already prepared formulation T12 (P:D ratio of 40 and 66.67% F127) with suitable T% and EE% of 95.12% and 91.75%, respectively. DSC, FTIR and 1H NMR studies revealed felodipine (FLD) incorporation within T12 nanomicelles. T12 enhanced the ex vivo intestinal permeation of FLD when compared to a drug suspension and showed good stability. Therefore, pluronic nanomicelles could be promising for improved oral delivery of FLD.

Penetration enhancer-containing spanlastics (PECSs) for transdermal delivery of haloperidol: in vitro characterization, ex vivo permeation and in vivo biodistribution studies.

Haloperidol (Hal) is one of the widely used antipsychotic drugs. When orally administered, it suffers from low bioavailability due to hepatic first pass metabolism. This study aimed at developing Hal-loaded penetration enhancer-containing spanlastics (PECSs) to increase transdermal permeation of Hal with sustained release. PECSs were successfully prepared using ethanol injection method showing reasonable values of percentage entrapment efficiency, particle size, polydispersity index and zeta potential. The statistical analysis of the ex vivo permeation parameters led to the choice of F1L - made of Span® 60 and Tween® 80 at the weight ratio of 4:1 along with 1% w/v Labrasol® - as the selected formula (SF). SF was formulated into a hydrogel by using 2.5% w/v of HPMC K4M. The hydrogel exhibited good in vitro characteristics. Also, it retained its physical and chemical stability for one month in the refrigerator. The radiolabeling of SF showed a maximum yield by mixing of 100 µl of diluted formula with 50 µl saline having 200 MBq of 99mTc and containing 13.6 mg of reducing agent (NaBH4) and volume completed to 300 µl by saline at pH 10 for 10 min as reaction time. The biodistribution study showed that the transdermal 99mTc-SF hydrogel exhibited a more sustained release pattern and longer circulation duration with pulsatile behavior in the blood and higher brain levels than the oral 99mTc-SF dispersion. So, transdermal hydrogel of SF may be considered a promising sustained release formula for Hal maintenance therapy with reduced dose size and less frequent administration than oral formula.

Combined mixture-process variable approach: a suitable statistical tool for nanovesicular systems optimization.

OBJECTIVES: This study aims to illustrate the applicability of combined mixture-process variable (MPV) design and modeling for optimization of nanovesicular systems. METHODS: The D-optimal experimental plan studied the influence of three mixture components (MCs) and two process variables (PVs) on lercanidipine transfersomes. The MCs were phosphatidylcholine (A), sodium glycocholate (B) and lercanidipine hydrochloride (C), while the PVs were glycerol amount in the hydration mixture (D) and sonication time (E). The studied responses were Y1: particle size, Y2: zeta potential and Y3: entrapment efficiency percent (EE%). Polynomial equations were used to study the influence of MCs and PVs on each response. Response surface methodology and multiple response optimization were applied to optimize the formulation with the goals of minimizing Y1 and maximizing Y2 and Y3. RESULTS: The obtained polynomial models had prediction R(2) values of 0.645, 0.947 and 0.795 for Y1, Y2 and Y3, respectively. Contour, Piepel's response trace, perturbation, and interaction plots were drawn for responses representation. The optimized formulation, A: 265 mg, B: 10 mg, C: 40 mg, D: zero g and E: 120 s, had desirability of 0.9526. The actual response values for the optimized formulation were within the two-sided 95% prediction intervals and were close to the predicted values with maximum percent deviation of 6.2%. CONCLUSIONS: This indicates the validity of combined MPV design and modeling for optimization of transfersomal formulations as an example of nanovesicular systems.

Feasibility of optimizing trimetazidine dihydrochloride release from controlled porosity osmotic pump tablets of directly compressed cores.

The aim of this study was to develop and optimize Trimetazidine dihydrochloride (TM) controlled porosity osmotic pump (CPOP) tablets of directly compressed cores. A 2(3) full factorial design was used to study the influence of three factors namely: PEG400 (10% and 25% based on coating polymer weight), coating level (10% and 20% of tablet core weight) and hole diameter (0 "no hole" and 1 mm). Other variables such as tablet cores, coating mixture of ethylcellulose (4%) and dibutylphthalate (2%) in 95% ethanol and pan coating conditions were kept constant. The responses studied (Yi ) were cumulative percentage released after 2 h (Q%2h), 6 h (Q%6h), 12 h (Q%12h) and regression coefficient of release data fitted to zero order equation (RSQzero), for Y 1, Y 2, Y 3, and Y 4, respectively. Polynomial equations were used to study the influence of different factors on each response individually. Response surface methodology and multiple response optimization were used to search for an optimized formula. Response variables for the optimized formula were restricted to 10% â©½ Y 1 â©½ 20%, 40% â©½ Y 2 â©½ 60%, 80% â©½ Y 3 â©½ 100%, and Y 4 > 0.9. The statistical analysis of the results revealed that PEG400 had positive effects on Q%2h, Q%6h and Q%12h, hole diameter had positive effects on all responses and coating level had positive effect on Q%6h, Q%12h and negative effect on RSQzero. Full three factor interaction (3FI) equations were used for representation of all responses except Q%2h which was represented by reduced (3FI) equation. Upon exploring the experimental space, no formula in the tested range could satisfy the required constraints. Thus, direct compression of TM cores was not suitable for formation of CPOP tablets. Preliminary trials of CPOP tablets with wet granulated cores were promising with an intact membrane for 12 h and high RSQzero. Further improvement of these formulations to optimize TM release will be done in further studies.