Solid dispersion systems for enhanced dissolution of poorly water-soluble candesartan cilexetil: In vitro evaluation and simulated pharmacokinetics studies.

BACKGROUND: Candesartan cilexetil (CC) is a selective angiotensin II receptor antagonist widely used to treat hypertension. CC is a substrate of P-glycoprotein (P-gp), causing its efflux to the intestinal lumen. It is also practically insoluble in water and has low oral bioavailability (14%). Thus, the current study aims to improve the in vitro dissolution of CC by developing solid dispersion systems (SDSs) and corroborating the in vitro results using a simulated pharmacokinetics study. METHODS: The SDSs were prepared using polyvinyl pyrrolidone (PVP) as a water-soluble polymer, Eudragit E100 (EE100) as a pH-dependent soluble carrier, and a combination of these two polymers. The saturation solubility and the dissolution rate studies of the prepared systems in three dissolution media were performed. The optimized system SE-EE5 was selected for further investigations, including DSC, XRD, FTIR, FESEM, DLS, TSEM, IVIVC convolution study, and stability studies. RESULTS: The solubility of CC significantly increased by a factor of 27,037.344 when formulated as a solid dispersion matrix using EE100 at a ratio of 1:5 (w/w) drug to polymer (SE-EE5 SD), compared to the solubility of the pure drug. The mechanism of solubility and dissolution rate enhancement of CC by the optimized SDS was found to be via the conversion of the crystalline CC into the amorphous form as well as nanoparticles formation upon dissolution at a pH below 5. The instrumental analysis tests showed good compatibility between CC and EE100 and there was no chemical interaction between the drug and the polymer. Moreover, the stability tests confirmed that the optimized system was stable after three months of storage at 25°C. CONCLUSION: The utilization of the solid dispersion technique employing EE 100 polymer as a matrix demonstrates significant success in enhancing the solubility, dissolution, and subsequently, the bioavailability of water-insoluble drugs like CC.

Pomegranate extract-loaded sphingosomes for the treatment of cancer: Phytochemical investigations, formulation, and antitumor activity evaluation.

AIM: Formulation of Pomegranate Extracts (PE)-loaded sphingosomes as an antitumor therapy for the intravenous and passive targeted delivery to various tumor types, especially that of the breast, colon, and uterus; to increase the therapeutic activity and decrease the adverse effects profile. METHODS: The pericarp and seeds' juice of Punica granatum were each extracted using D.W. and ethanol. Phytochemical investigation of all extracts was carried out including total phenolics, flavonoids, and anthocyanins contents, the antioxidant activity, as well as HPLC analysis of phenolics and flavonoids. The antitumor potential of all extracts was also tested utilizing three cell lines: MCF-7, HeLa, and HCT116. The candidate extract was chosen for the formulation phase and was entrapped into the sphingosomes using the thin-film hydration method and employing three different PE: lipids weight ratios. The synthesized formulations were characterized for their size, morphological features, zeta potential, entrapment efficiency, and in vitro drug release and kinetics modeling studies. The optimized formula was further analyzed by FTIR spectroscopy and electron microscopy. The antitumor activity of F2 was also investigated using the same cancer cell lines compared to the plant extract. RESULTS: The highest phenolics, flavonoids, and anthocyanins contents were observed in the ethanolic pericarps extract (EPE), followed by the ethanolic seeds extract (ESE). Consequently, EPE showed a higher antitumor activity hence it was selected for the formulation phase. PE-loaded sphingosomes formula (F2) was selected for having the highest EE% (71.64%), and a sustained release profile with the highest in vitro release (42.5±9.44%). By employing the DDSolver, the Weibull model was found the most suitable to describe the PE release kinetics compared to other models. The release mechanism was found to follow Fickian diffusion. Simulated pharmacokinetic parameters have portrayed F2 as the candidate formula, with the highest AUC (536.095) and slowest MDT (0.642 h). In addition, F2 exhibited a significant (p>0.05) stronger and prolonged anticancer effect against MCF-7, HeLa, and HCT116 cell lines at all concentrations tested compared to the free extract. CONCLUSION: The results proved that sphingosomes are an effective delivery system, improving pharmacological efficacy and reducing serious side effects of anticancer medications and natural products.

Development of Clindamycin Loaded Oral Microsponges (Clindasponges) for Antimicrobial Enhancement: In Vitro Characterization and Simulated in Vivo Studies.

Clindamycin phosphate (CLP) is a broad-spectrum antibiotic that is used widely for different types of infections. It has a short half-life and hence it should be taken every six hours to ensure adequate antibiotic blood concentration. On the other hand, microsponges are extremely porous polymeric microspheres, offering the prolonged controlled release of the drug. The present study aims to develop and evaluate innovative CLP-loaded microsponges (named Clindasponges) to prolong and control the drug release and enhance its antimicrobial activity, consequently improving patient compliance. The clindasponges were fabricated successfully by quasi-emulsion solvent diffusion technique using Eudragit S100 (ES100) and ethyl cellulose (EC) as carriers at various drug-polymer ratios. Several variables were optimized for the preparation technique including the type of solvent, stirring time, and stirring speed. The clindasponges were then characterized in terms of particle size, production yield, encapsulation efficiency, scanning electron microscopy, Fourier Transform Infrared Spectroscopy analysis, in vitro drug release with kinetic modeling, and antimicrobial activity study. Moreover, in vivo, pharmacokinetics parameters of CLP from the candidate formula were simulated based on the convolution method and in vitro-in vivo correlation (IVIVC-Level A) was built up successfully. Uniform spherical microsponges with 82.3 µm mean particle size with a porous spongy structure were evident. ES2 batch exhibited the highest production yield and encapsulation efficiency (53.75 and 74.57%, respectively) and it was able to exhaust 94% of the drug at the end of 8 h of the dissolution test. The release profile data of ES2 was best fitted to Hopfenberg kinetic model. ES2 was significantly (p < 0.05) effective against Staphylococcus aureus and Escherichia coli compared to the control. Also, ES2 displayed a twofold increase in the simulated area under the curve (AUC) compared to the reference marketed product.

An Overview of Microparticulate Drug Delivery System and its Extensive Therapeutic Applications in Diabetes.

Microparticulate drug delivery system (MDDS) has attained much consideration in the modern era due to its effectiveness in overcoming traditional treatment problems. Microparticles (MPs) are spherical particles of a diameter ranging from 10 µm to 1000 µm. MPs can encapsulate both water-soluble and insoluble compounds. MDDS proved their efficacy in improving drugs bioavailability, stability, targeting, and controlling their release patterns. MPs also offer comfort, easy administration, and improvement in patient compliance by reducing drugs toxicity and dosage frequency. This review elucidates the fabrication techniques, drug release, and therapeutic application of MDDS. Further details concerning the therapeutic applications of antidiabetic drugs-loaded MPs were also reviewed, including controlling drugs release by gastroretention, improving drugs dissolution, reducing side effects, localizing drugs to the site of disease, improving insulin stability, natural products loaded with MPs, sustained drug release, mucosal delivery, and administration routes. Additionally, the current situation and future prospects in developing MPs loaded with antidiabetic drugs were discussed.

Optimizing and Evaluating the Transdermal Permeation of Hydrocortisone Transfersomes Formulation Based on Digital Analysis of the In Vitro Drug Release and Ex Vivo Studies.

BACKGROUND: Transfersomes can be used to enhance transdermal drug delivery due to their flexibility and ability to incorporate various molecules. For example, hydrocortisone (HC), a corticosteroid, is taken by different routes and serves as immunosuppressive, anticancer, and antiallergenic; however, it is poorly absorbed by the skin. OBJECTIVE: Therefore, the current study suggested HC-loaded transfersomes as an alternative route of administration for reaching deeper skin layers or systemic circulation, to reduce the side effects of HC and improve its bioavailability. METHODS: HC transfersomes were prepared by the thin-film hydration method and characterized for their vesicular size, zeta potential, drug entrapment efficiency, elasticity, FTIR spectroscopy, in vitro drug release, ex vivo permeation, and irritancy in rabbits. The optimized formulation, F15 (containing HC 20 mg, egg phosphatidylcholine (EPC) 400 mg, and 75 mg of Span 80), was chosen because it showed the highest (p< 0.05) EE% (60.4±0.80) and optimized sustained in vitro drug release (Q8 = 87.9±0.6%). RESULTS: Extensive analysis of the drug release data from all formulas was performed using the DDSolver software which quantitatively confirmed the successful formulation. The Weibull equation was the best model to fit the release data compared to others, and the release mechanism was Fickian diffusion. CONCLUSION: The simulated pharmacokinetic parameters showed that F15 had the highest AUC, MDT, and DE. Furthermore, F15 significantly enhanced HC permeation by 12-folds compared to the control through the excised rat's skin. The skin irritancy test has proven F15 safety and skin compatibility.

DDSolver Software Application for Quantitative Analysis of In vitro Drug Release Behavior of the Gastroretentive Floating Tablets Combined with Radiological Study in Rabbits.

BACKGROUND: Gastroretentive drug delivery systems (GRDDSs) are designed to release the drug in the stomach over a prolonged time; thus, they can reduce drug dosing frequency and dose size and improve patient compliance. GRDDSs are also highly effective in enhancing the bioavailability of the drug that exhibits window absorption in specific segments of the gastrointestinal (GI) tract. Famotidine (FMT), an H2 receptor antagonist, is an example of these drugs. FMT is a slightly watersoluble drug but well soluble in an acidic medium. This research aims to formulate FMT gastroretentive floating tablets (FMT-GRFTs) to improve the bioavailability and therapeutic activity of the drug and increase patients' adherence to treatment. In addition, the in vitro release behavior of the prepared FMT-GRFTs was quantitatively analyzed using the DDSolver software to assist in selecting the successful formulation that was then evaluated in vivo. METHODS: The direct compression technique prepared numerous tablet formulations and was subjected to the pre-and post-compression evaluation. Data of FMT dissolution in the simulated gastric medium was analyzed by various kinetic models built in the DDSolver program. In addition, the simulated pharmacokinetics (AUC, MDT, and MRT), R2 adjusted, AIC, MSC, correlation of the residuals, and similarity factor (f2) were also generated. RESULTS: The results revealed that FMT release from the candidate formula (FH3) fitted to the first-order kinetic model, with a high value of R2 adjusted and MSC and a low AIC. The release behavior exhibited the Fickian diffusion mechanism. The similarity factor showed no significant difference (p < 0.05) of the test sample compared to the reference product. Nevertheless, the simulated pharmacokinetic parameter, AUC, proved a two-fold enhancement in FMT bioavailability, with a significant increment in the MDT and MRT compared with the reference product.The FT-IR spectroscopy analysis indicated the absence of drug-excipients/polymer interaction.The in vivo X-ray studies on rabbits confirmed that the floating tablets showed nearly eight hours of gastric residence. CONCLUSION: DDSolver software was helpful in deciding the optimized formulation of FMT floating tablets. The radiological examination in rabbits for gastric retention was consistent with the release data analysis in vitro.

Employment of Alginate Floating In Situ Gel for Controlled Delivery of Celecoxib: Solubilization and Formulation Studies.

Celecoxib (CXB) is a COX-2-selective nonsteroidal anti-inflammatory drug used to control pain and various inflammatory conditions. CXB has limited oral bioavailability and a slow dissociation rate due to its poor water solubility. In order to enhance the oral bioavailability of CXB and reduce the frequency of administration, the present study was aimed at enhancing the aqueous solubility of CXB by a cosolvency technique and then at formulating and evaluating a CXB in situ floating gelling system for sustained oral delivery. Three cosolvents, namely, PEG 600, propylene glycol, and glycerin, at different concentrations, were used to solubilize CXB. Particle size analysis was performed to confirm the solubility of CXB in the solutions. The floating in situ gel formulations were then prepared by the incorporation of the CXB solution into sodium alginate solutions (0.25, 0.5, and 1% w/v). Formulations, in sol form, were then in vitro characterized for their physical appearance, pH, and rheological behaviors, while formulations in gel form were evaluated for their floating behavior and in vitro drug release studies. FTIR spectroscopy was performed to examine drug-polymer interaction. The selected formula was evaluated biologically for its anti-inflammatory and analgesic activities. Results revealed that the less-polar solvent PEG 600 at 80% v/v had the highest solubilization potential, and it was used to optimize the in situ gel formulation. The candidate formula (F3) was found to have the highest sodium alginate concentration (1% w/v) and showed the optimum sustained release profile with the Higuchi model release kinetics. The results from the FTIR spectroscopy analysis showed noticeable drug-polymer molecular interaction. Moreover, F3 exhibited a significantly higher percentage of paw edema inhibition at 8 h compared with the reference drug (p < 0.05). Also, it showed a sustained duration of analgesia that persisted for the entire experimental time.

Optimized Mucoadhesive Coated Niosomes as a Sustained Oral Delivery System of Famotidine.

The objective of this study is to develop an oral formulation of famotidine niosomes coated with a mucoadhesive polymer, chitosan. Famotidine (FMT) has low oral bioavailability of 40-45% and short half-life between 2.5 to 4 h. Famotidine is classified as class IV in BCS because of its low aqueous solubility (0.1% w/v) and low permeability. Thus, FMT was loaded to the bioadhesive coated niosomes to improve its solubility, enhance its oral bioavailability, and sustain FMT release pattern. Different formulations were prepared by thin-film hydration method and characterized in terms of entrapment efficiency, morphological features, vesicle size, and zeta potential. In vitro release and ex vivo permeability of famotidine from the formulations were evaluated. The optimized formula was coated with chitosan and its mucoadhesion and stability in bile salt was tested. The optimized formula showed a high entrapment efficiency of 74%, as well sustained the in vitro release of FMT in the simulated gastric medium and enhanced its permeation through an excised goat's intestinal membrane by 1.4 fold in comparison to FMT control suspension. The mucoadhesive coated formula exhibited a significantly higher (p < 0.05) mucoadhesive efficiency and more stability in the bile salt as compared to the uncoated formula. Therefore, it could be considered as an efficient delivery system to maintain the prolonged release of FMT and improve its oral bioavailability.