Protective microencapsulation of ß-lapachone using porous glass membrane technique based on experimental optimisation.

Even though ß-lapachone is a novel drug with pharmacological activity, it has limitations including instability under light conditions. The main purpose of the study was to enhance the stability of ß-lapachone using the microencapsulation method. The Shirasu porous glass membrane was used to achieve uniform-sized microcapsules. The prepared microcapsules were evaluated to investigate how process parameters affect the encapsulation efficiency, photostability and particle size distribution. The experimental design was conducted to obtain optimal formulations. In addition, an operating space was drawn to identify the safer range of control factors. All control factors showed significant effects on the encapsulation efficiency and photostability. For example, when a large amount of polymers was used, encapsulation efficiency and photostability were improved. However, as the amount of polymers increased, large and polydisperse microcapsules were produced. The robust design method provided information to characterise significant factors, thereby allowing effective control of photostability and size of microcapsules.

A robust experimental design method to optimize formulations of retinol solid lipid nanoparticles.

A robust experimental design method was developed using a response surface methodology and models to facilitate the development process of retinol solid lipid nanoparticles (SLNs). The SLNs were evaluated to determine how different parameters including lipid and surfactant affect size and encapsulation efficiency. This was conducted using factorial analysis and a robust design (RD) method was used to achieve optimal formulations. Two models were developed based on the RD principle and both mean and variance of the response characteristics were estimated functionally using the least squares method. They proved useful in formulation studies aiming to develop optimum by allowing a systematic and reliable design method. A model for maximizing the overall desirability represented by the geometric mean of all objectives was found to provide a better solution. The newly designed method provides useful information to characterize significant factors and obtain optimum formulations, thereby allowing a systematic and reliable design method.

A new experimental design method to optimize formulations focusing on a lubricant for hydrophilic matrix tablets.

A robust experimental design method was developed with the well-established response surface methodology and time series modeling to facilitate the formulation development process with magnesium stearate incorporated into hydrophilic matrix tablets. Two directional analyses and a time-oriented model were utilized to optimize the experimental responses. Evaluations of tablet gelation and drug release were conducted with two factors x1 and x2: one was a formulation factor (the amount of magnesium stearate) and the other was a processing factor (mixing time), respectively. Moreover, different batch sizes (100 and 500 tablet batches) were also evaluated to investigate an effect of batch size. The selected input control factors were arranged in a mixture simplex lattice design with 13 experimental runs. The obtained optimal settings of magnesium stearate for gelation were 0.46 g, 2.76 min (mixing time) for a 100 tablet batch and 1.54 g, 6.51 min for a 500 tablet batch. The optimal settings for drug release were 0.33 g, 7.99 min for a 100 tablet batch and 1.54 g, 6.51 min for a 500 tablet batch. The exact ratio and mixing time of magnesium stearate could be formulated according to the resulting hydrophilic matrix tablet properties. The newly designed experimental method provided very useful information for characterizing significant factors and hence to obtain optimum formulations allowing for a systematic and reliable experimental design method.

Robust optimization for the simultaneous enhancement of nitric oxide inhibition and reduction of hepatotoxicity from green tea catechins.

To provide a platform for evaluating significant interactions contributing to the enhanced physiological efficacy and reduced hepatotoxicity, we used a robust design to determine the optimal combination of six major green tea catechins, epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), epicatechin (EC), gallocatechin, and catechin. Based on the mixture design, 28 experiments were performed to inhibit nitric oxide (NO) in RAW 264.7 cells and hepatotoxicity in Chang liver cells. Significant candidates, EGCG, EC, gallocatechin and catechin, were selected after optimization. The combination showing simultaneous enhancement of NO inhibition and reduction of hepatotoxicity was EGCG and gallocatechin at a ratio of 0.65 to 0.35 by surface response methodology and desirability function, through which their co-treatment was validated. Here, we describe a platform for simultaneously determining the optimized combination of natural components exerting enhanced efficacy and reduced toxicity.

Basal buffer systems for a newly glycosylated recombinant human interferon-ß with biophysical stability and DoE approaches.

The purpose of this study was to develop a basal buffer system for a biobetter version of recombinant human interferon-ß 1a (rhIFN-ß 1a), termed R27T, to optimize its biophysical stability. The protein was pre-screened in solution as a function of pH (2-11) using differential scanning calorimetry (DSC) and dynamic light scattering (DLS). According to the result, its experimental pI and optimal pH range were 5.8 and 3.6-4.4, respectively. Design of experiment (DoE) approach was developed as a practical tool to aid formulation studies as a function of pH (2.9-5.7), buffer (phosphate, acetate, citrate, and histidine), and buffer concentration (20 mM and 50 mM). This method employed a weight-based procedure to interpret complex data sets and to investigate critical key factors representing protein stability. The factors used were Tm, enthalpy, and relative helix contents which were obtained by DSC and Fourier Transform Infrared spectroscopy (FT-IR). Although the weights changed by three responses, objective functions from a set of experimental designs based on four buffers were highest in 20 mM acetate buffer at pH 3.6 among all 19 scenarios tested. Size exclusion chromatography (SEC) was adopted to investigate accelerated storage stability in order to optimize the pH value with susceptible stability since the low pH was not patient-compliant. Interestingly, relative helix contents and storage stability (monomer remaining) increased with pH and was the highest at pH 4.0. On the other hand, relative helix contents and thermodynamic stability decreased at pH 4.2 and 4.4, suggesting protein aggregation issues. Therefore, the optimized basal buffer system for the novel biobetter was proposed to be 20 mM acetate buffer at pH 3.8±0.2.

A novel experimental design method to optimize hydrophilic matrix formulations with drug release profiles and mechanical properties.

To investigate the effects of hydrophilic polymers on the matrix system, an experimental design method was developed to integrate response surface methodology and the time series modeling. Moreover, the relationships among polymers on the matrix system were studied with the evaluation of physical properties including water uptake, mass loss, diffusion, and gelling index. A mixture simplex lattice design was proposed while considering eight input control factors: Polyethylene glycol 6000 (x1 ), polyethylene oxide (PEO) N-10 (x2 ), PEO 301 (x3 ), PEO coagulant (x4 ), PEO 303 (x5 ), hydroxypropyl methylcellulose (HPMC) 100SR (x6 ), HPMC 4000SR (x7 ), and HPMC 10(5) SR (x8 ). With the modeling, optimal formulations were obtained depending on the four types of targets. The optimal formulations showed the four significant factors (x1 , x2 , x3 , and x8 ) and other four input factors (x4 , x5 , x6 , and x7 ) were not significant based on drug release profiles. Moreover, the optimization results were analyzed with estimated values, targets values, absolute biases, and relative biases based on observed times for the drug release rates with four different targets. The result showed that optimal solutions and target values had consistent patterns with small biases. On the basis of the physical properties of the optimal solutions, the type and ratio of the hydrophilic polymer and the relationships between polymers significantly influenced the physical properties of the system and drug release. This experimental design method is very useful in formulating a matrix system with optimal drug release. Moreover, it can distinctly confirm the relationships between excipients and the effects on the system with extensive and intensive evaluations.

Time-oriented experimental design method to optimize hydrophilic matrix formulations with gelation kinetics and drug release profiles.

A new experimental design methodology was developed by integrating the response surface methodology and the time series modeling. The major purposes were to identify significant factors in determining swelling and release rate from matrix tablets and their relative factor levels for optimizing the experimental responses. Properties of tablet swelling and drug release were assessed with ten factors and two default factors, a hydrophilic model drug (terazosin) and magnesium stearate, and compared with target values. The selected input control factors were arranged in a mixture simplex lattice design with 21 experimental runs. The obtained optimal settings for gelation were PEO, LH-11, Syloid, and Pharmacoat with weight ratios of 215.33 (88.50%), 5.68 (2.33%), 19.27 (7.92%), and 3.04 (1.25%), respectively. The optimal settings for drug release were PEO and citric acid with weight ratios of 191.99 (78.91%) and 51.32 (21.09%), respectively. Based on the results of matrix swelling and drug release, the optimal solutions, target values, and validation experiment results over time were similar and showed consistent patterns with very small biases. The experimental design methodology could be a very promising experimental design method to obtain maximum information with limited time and resources. It could also be very useful in formulation studies by providing a systematic and reliable screening method to characterize significant factors in the sustained release matrix tablet.

A pharma-robust design method to investigate the effect of PEG and PEO on matrix tablets.

Even though polyethyleneoxide (PEO)-polyethyleneglycol (PEG) blends have been used widely for sustained release matrix tablets, evaluations of the effects of PEG or PEO on the matrix properties have been limited. In order to evaluate gelling behavior and drug release profiles of PEG, various contents of the polymers were investigated through a robust experimental design method. When exposed to an aqueous environment, the PEO-PEG matrix hydrated slowly and swelled, causing a thick gel layer to form on the surface, the thickness of which increased significantly depending on the PEG contents. Since polyacrylate plates were used for the study, the matrix was not completely hydrated and gelled even after 5h. However, the results could be applied to the time-oriented responses RD (robust design) models to obtain optimal settings and responses for the observed times. The optimal settings of PEO and PEG were 94.26 and 140.04 mg, respectively (PEG rate of 148.57%). Moreover, as the amount of PEG increased, the release rate also increased. When the formulation contained more than 150% of PEG, most of the drug loaded in the tablet was released in about 12 h. When the amount of PEG was less than 100%, the drug release rate was sustained significantly. Based on the RD optimization model for drug release, the optimal settings were PEG and PEO of 124.3 and 110 mg, respectively (PEG rate of 88.50%). Therefore, PEG rate of about 90-150% is suggested for matrix tablet formulations, and the exact ratio could be formulated according to the resulting tablet's properties.