Journal of Pharmaceutical Investigation

3(2) factorial design and response surface methodology in the fabrication of matrix transdermal films of aceclofenac (ACL) was utilized in this study to investigate the effects of polymers (hydrophilic and hydrophobic) and penetration enhancer (PE) on ex vivo and in vivo drug performance. FTIR and DSC showed no interaction of drug with polymers. The physicochemical characterization showed uniformity among the formulations. Results from the permeation study suggested the effect of polyvinyl pyrrolidone (PVP K-30) and PE, on increasing concentration of PVP K-30 with respect to ethyl cellulose as well as increased concentration of PE resulted in enhanced permeation through the matrix. Significant effect of PE on the lipid and protein framework of the skin was also observed which is responsible for increased permeation. From response surface curve and contour plots, an optimized formulation was selected and evaluated for their ex vivo permeation, skin irritation, in vivo efficacy and stability studies. The optimized formulation showed Higuchi controlled diffusion and was found to be non-irritant and efficacious in reducing carrageenan induced paw edema in rats over a prolonged duration of time as compared to oral delivery. Thus, results indicated that the prepared transdermal system can be a promising non-oral approach to deliver effective amount of ACL to treat various inflammatory conditions.

Digestive enzyme supplements are used in various fields, including prescription drugs, over-the-counter drugs, and enzyme foods, but few comprehensively organized data are available. In addition, the classification of products containing digestive enzymes differs by country, and except for the treatment of pancreatic insufficiency (PEI), clinical data are lacking. This review summarizes current knowledge about digestive enzymes used in pharmaceuticals and foods. Products containing digestive enzymes are divided into prescription drugs for PEI treatment, over-the-counter medicines for dyspepsia, and food enzymes, and the related diseases, prevalence, and market sizes are examined. In addition, the characteristics of enzyme raw materials listed in the Pharmacopoeia and Food Enzyme Database and the characteristics of commercially available products are reviewed. The market for digestive enzymes is growing rapidly, and its boundaries are becoming unclear. More accurate verification of the efficacy of enzyme products is required, and the selection of enzyme raw materials and design of formulations that consider the pH in the digestive tract are needed.

This study aimed to use machine learning to predict the quality of a drug product prepared through continuous manufacturing. A design of experiment (DoE) was employed to identify the relationship between process parameters in continuous twin screw granulation and intermediate and drug product quality. Subsequently, unsupervised and supervised machine learning were applied to develop a dissolution prediction model. Hierarchical clustering analysis (HCA) was conducted to evaluate the similarity between the datasets generated by the DoE. In addition, supervised learning, such as partial least squares (PLS) regression with variable importance in projection (VIP), was conducted, and a prediction model was developed using an artificial neural network (ANN) as a machine learning model. Moreover, principal component analysis (PCA), which is an unsupervised learning method, was used to preprocess the ANN model to reduce the number of features. HCA divided the data set obtained by DoE into three clusters, and it was confirmed that the L/S ratio significantly affected granule and tablet properties. The ANN, PLS-VIP(0.8)-ANN, PLS-VIP(1.0)-ANN, and PCA-ANN models were developed and statistically compared. The PLS-VIP(0.8)-ANN accurately predicted the dissolution profile with a high coefficient of determination and low mean absolute deviation, root mean square error, and sum of squared errors. This paper describes the application of various machine learning algorithms to predict drug product quality as a control strategy of continuous manufacturing.

A selective and simple HPLC method was developed for ibuprofen (IBF) and pamabrom (PAMB) from in bulk and drug product using the same conditions, which was operated on a reverse phase (C18 column) with water (60 %) and acetonitrile (40 %.) solutions at a flow rate of 1.0 mL/min. IBF was detected at 2.6 min and PAMB at 8.0 min, respectively at 254 nm. The correlation coefficient (R 2 ) for IBF was 0.9999 and that of PAMB was 0.9998 in 125–2000 and 63–100 μg/mL, respectively. Intraday precision showed less than 1.0 % RSD. This method was validated in an aspect of linearity, precision, accuracy, limit of detection and limit of quantitation. This method was suggested to analysis the fixed dose combination tablet of IBF and PAMB.

Dexamethasone palmitate (DXPL) is a lipophilic derivative of dexamethasone (DXM) used to overcome the low drug-loading capacity and immediate release characteristics of DXM from nanoparticles. In this study, we investigated the potential of DXPL-loaded solid lipid nanoparticles (DXPL-SLNs) to increase drug encapsulation efficiency, prolong drug release, and alleviate skin inflammation. DXPL-SLNs were prepared using the nano-emulsion template technique with trilaurin as a lipid matrix and Tween 20, Span 20, and Brij 58 as a surfactant mixture. The physicochemical properties of DXPL-SLNs were examined in terms of particle size, polydispersity index, zeta potential, encapsulation efficiency, loading capacity, morphology, and crystalline behavior. The in vitro release profile of DXM from the DXPL-SLNs incubated in mouse plasma was assessed using a plasma conversion assay. In vivo anti-inflammatory effects of topically applied DXPL-SLNs were evaluated in mice with 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced ear edema. The optimized DXPL-SLNs (DXPL/trilaurin/Tween 20/Span 20/Brij 58:4/2/2/0.2/4, w/w ratio, respectively) displayed a mean particle size of 182.8 ± 2.7 nm with a very high drug loading capacity of 30.4%. DXPL-SLNs showed substantially prolonged drug release in mouse plasma compared to DXPL solution. Furthermore, DXPL-SLNs showed enhanced anti-inflammatory effects by efficiently reducing TPA-induced ear edema. These findings suggest that DXPL-SLNs have great potential as anti-inflammatory therapeutics against acute skin inflammation.

During the last 5 years, there has been a marked rise in publications regarding exosomes. Exosomes find potential applications as diagnostic biomarkers, therapeutics, drug delivery vehicles, and functional cosmetics and several exosome-based therapies are under clinical trials. Exosomes are nanosized vesicles that contain cell-derived lipid membranes, nucleic acids, and proteins, and are released from the cells of origin, circulate in eukaryotic fluids, and are taken up by recipient cells. The originating cell can be engineered to express specific genes, which enhance immunity, cross-presentation of antigens, or cell targeting by exosomes. Various methods using centrifugation, size-exclusion chromatography, filtration, precipitation, affinity, and microfluidics have been assessed for the isolation and purification of exosomes from biological samples. In addition, exosomes have advantages as drug delivery systems, with biocompatibility, preservation of cargo drugs during circulation in physiological fluids, uptake into the target cells, and drug release after endosomal escape. In this review, we discuss the various aspects of pharmaceutical investigation into exosomes with special focus on engineering, production, characterization, biological activities, applications of exosomes as drug delivery systems, and regulations for evaluation of exosome products.

The objective of this study was to develop and evaluate the microemulsion (ME) and mucoadhesive microemulsion (MME) for intranasal delivery of Asenapine maleate (APM) for the treatment of schizophrenia. APM loaded ME (AME1 to AME5) and MME (AMME) were prepared by spontaneous microemulsification method and evaluated for drug content, globule size and polydispersity index, % transmittance, zeta potential, pH, viscosity, conductivity, drug content, refractive index, ex vivo diffusion study using sheep nasal mucosa, nasal ciliotoxicity study and Fourier transform infrared spectroscopy study. The AME4 (5 mg/mL of APM) containing 11% Capmul MCM, 38% Smix (Tween80: Propylene glycol (1:1)) and 51% (v/v) water that displayed optical transparency of 99.77%, globule size of 79.50 nm, polydispersity index (PDI) of 0.356 were selected for preparation of MME. The highest diffusion coefficient (P < 0.05) was found for AMME (2.61 × 10−5 ± 0.016 × 10−5 cm2/min) and followed higuchi model. The nasal ciliotoxicity study showed no damage to nasal mucosa and thus the formulation components were considered biocompatible. IR spectra showed no interaction between APM and ME components. Optimized AME and AMME formulations were found to be stable for the period of 6 months. Looking at the results of physicochemical properties and ex vivo studies, it can be concluded that formulated AMME can deliver the APM directly to the brain which has potential of increasing the bioavailability of APM which may alleviate side effects by decreasing the dose and frequency of administration.

The objective of this study was to design a fixed-dose combination (FDC) tablet with minimal interaction of valsartan, amlodipine, rosuvastatin and ezetimibe to improve medication compliance in patients with hypertension and dyslipidemia and to evaluate its feasibility for development through in vitro dissolution test and pharmacokinetic assessment in humans. The formulation was designed as a bilayer FDC tablet to minimize the interaction of the four drugs based on the results of drug‒drug interaction evaluations in which the drugs were mixed and exposed at 50 °C for 4 weeks. The FDC tablet was then evaluated against the reference listed drug (RLD) products, Exforge® tablet 10/160 mg and Rosuzet® tablet 10/20 mg, through in vitro dissolution studies and in vivo pharmacokinetic studies in humans. The in vitro release profiles of valsartan, rosuvastatin and ezetimibe were similar to those of the RLD products. Although the Cmax of ezetimibe in the FDC tablet was slightly higher, there were no significant differences in the area under the plasma drug concentration–time curve (AUC). There were also no notable discrepancies in the Cmax and AUC of the other three drugs. Furthermore, the absence of statistically significant variations in the frequency of adverse events and the lack of serious adverse reactions indicate a comparable safety profile between the FDC and RLD tablets. The feasibility of bilayer FDC tablet formulation to improve medication compliance in patients with hypertension and dyslipidemia was demonstrated.

In order to compare the effects of a solid carrier on the formulation of a solid self-microemulsifying drug delivery system (s-SMEDDS), a liquid SMEDDS was prepared with simvastatin. The SMEDDS was optimized using polyoxyl 35 castor oil [Kolliphor® EL] as a surfactant (S), diethylene glycol monoethylether [Transcutol® P] as a co-surfactant (C), and prophyleneglycol monocaprylate [Capryol 90] as the oil phase (O). The microemulsion area at the surfactant to co-surfactant ratio (1:1) was evaluated, and the SMEDDS at an S and C/O ratio of 7:3 was selected. Four types of adsorbents with high specific areas were used: Aerosil® 200, Sylysia® 350, Neusilin® US2, Neusilin® UFL2. SEM, DSC, and PXRD results revealed rough-surfaced particles that represent the amorphous state of s-SMEDDS. The optimized formulation with Neusilin® UFL2 markedly improved drug release. The present study concluded that s-SMEDDS was effectively formulated via adsorption with solid carriers.