Ahmed Elshafeey

Lacidipine (LCD) is a potent antihypertensive agent. Fatty-based nanovesicles (FNVs) were designed to improve LCD low solubility and bioavailability. LCD-FNVs were formulated according to different proportions of cetyl alcohol, cremophor®RH40, and oleic acid adopting Box-Behnken Design. The optimized LCD-FNVs, composed of cetyl alcohol 48.4 mg, cremophor®RH40 120 mg, and oleic acid 40 mg, showed minimum vesicle size (124.8 nm), maximum entrapment efficiency % (91.04 %) and zeta potential (-36.3 mV). The optimized FNVs were then used to formulate the lyophilized orally fast-disintegrating sponge (LY-OFDS). The LY-OFDS had a very short disintegration time (58 sec), remarkably high % drug release (100 % after 15 mins), and increased the drug transbuccal permeation by over 9.5-fold compared to the drug suspension. In-vivo evaluation of antihypertensive activity in rats showed that the LY-OFDS reduced blood pressure immediately after 5 min and reached normal blood pressure 4.5-fold faster than the marketed oral tablets. In the In-vivo pharmacokinetic study in rabbits, the LY-OFDS showed 4.7-fold higher bioavailability compared with the marketed oral tablet. In conclusion, the LY-OFDS loaded with LCD-FNVs is a safe, and non-invasive approach that can deliver LCD effectively to the blood circulation via the buccal mucosa giving superior immediate capabilities of lowering high blood pressure and increasing the drug bioavailability. © 2024 Elsevier B.V.

{Acute otitis media (AOM) is an infection that occurs in the middle ear and may cause complications and affect quality of life. The study focused on the preparation of niflumic acid (NA) loaded novasomes for the efficient treatment of AOM through trans-tympanic drug delivery. NA loaded novasomes were formulated using Span 60 with oleic acid or lauric acid as a free fatty acid (FFA). Novasomes were prepared via ethanol injection technique using D-optimal design to evaluate the influence of 3 independent variables on the novasomes’ characteristics which are: entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP), and identify the best formula for additional investigations. The best formula determined was (N6) which contains 50 mg Span 60 and 50 mg oleic acid used as FFA. N6 exhibited EE% = 92.96 ± 0.37 %

The aim of this study was to formulate and optimize by statistical means mucoadhesive and biodegradable sponge-like inserts loaded with voriconazole (VCZ) which increases the contact time of the drug with the eye and sustain its release from the formula in a controlled manner. This avoids the pulsed effect reported for the drug suspension and results in reducing the number of drug instillations in the eye with the result of enhancing the patient compliance. Also, the sponge like nature of the insert reduces the foreign body sensation caused by other ocular solid dosage forms. They were prepared using casting/freeze-drying technique using five polymers namely high molecular weight chitosan (CH), sodium alginate (AL), sodium carboxy methyl cellulose (CMC), gellan gum (GG) and xanthan gum (XG). The prepared inserts were subjected to evaluations of their visual appearance, weight variation, drug content, surface pH, in-vitro release (percent drug released after 1h (Q1 (%)), mean dissolution time (MDT) and dissolution efficiency (DE)) in addition to kinetic analysis of the release data, water uptake, mucoadhesion and rheology of the forming plain polymer solution at the maximum rate of shear. The independent variables of the D-optimal factorial design were the polymer type and concentration while Q1 (%), MDT, DE, % water uptake after 15 minutes and rheology at the maximum rate of shear were chosen as dependant variables. The performed optimization process using design expert software showed an optimum formula consisting of 2 % GG. It showed slow release behavior compared to the drug suspension. FTIR and DSC studies showed that there is no interaction between VCZ and GG. The optimum formula has good in-vitro mucoadhesive properties and pH in the safe ocular range. Moreover, it showed promising in-vivo results of rapid hydration and gelling in addition to good mucoadhesive behavior when instilled in the eye, high ocular safety and biocompatibility, sustained antifungal activity in comparison to the drug suspension and finally biodegradation. So, it may be taken into consideration as an outstanding carrier for the ocular delivery of VCZ. © 2023

Carvedilol (CV), a β-blocker essential for treating cardiovascular diseases, faces bioavailability challenges due to poor water solubility and first-pass metabolism. This study developed and optimized chitosan (CS)-coated niosomes loaded with CV (CS/CV-NS) for intranasal (IN) delivery, aiming to enhance systemic bioavailability. Utilizing a Quality-by-Design (QbD) approach, the study investigated the effects of formulation variables, such as surfactant type, surfactant-to-cholesterol (CHOL) ratio, and CS concentration, on CS/CV-NS properties. The focus was to optimize specific characteristics including particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and mucin binding efficiency (MBE%). The optimal formulation (Opt CS/CV-NS), achieved with a surfactant: CHOL ratio of 0.918 and a CS concentration of 0.062 g/100 mL, using Span 60 as the surfactant, exhibited a PS of 305 nm, PDI of 0.36, ZP of + 33 mV, EE% of 63 %, and MBE% of 57 %. Opt CS/CV-NS was characterized for its morphological and physicochemical properties, evaluated for stability under different storage conditions, and assessed for in vitro drug release profile. Opt CS/CV-NS demonstrated a 1.7-fold and 4.8-fold increase in in vitro CV release after 24 h, compared to uncoated CV-loaded niosomes (Opt CV-NS) and free CV, respectively. In vivo pharmacokinetic (PK) study, using a rat model, demonstrated that Opt CS/CV-NS achieved faster Tmax and higher Cmax compared to free CV suspension indicating enhanced absorption rate. Additionally, Opt CV-NS showed a 1.68-fold higher bioavailability compared to the control. These results underscore the potential of niosomal formulations in enhancing IN delivery of CV, offering an effective strategy for improving drug bioavailability and therapeutic efficacy. © 2024 Elsevier B.V.

Bilosomes are innovative vesicular carriers containing bile salt with a non-ionic surfactant. Being highly flexible, bilosomes can squeeze themselves through the skin carrying the drug to the action site and improving its skin penetration. The objective of this research was to encapsulate niflumic acid (NA), a non-steroidal anti-inflammatory drug into Brij® integrated bilosomes (BIBs) for effective treatment of osteoarthritis through transdermal delivery. BIBs were formulated using 100 mg of Span 20 with different amounts of sodium cholate (NaC), sodium taurocholate (NaTC), or sodium glycocholate (NaGC) as bile salt, with the addition of 5 mg of Brij-93 or Brij-35. BIBs were prepared utilizing ethanol injection method with the application of (31 × 22) complete factorial design using Design-Expert® software. The optimal BIBs formulation determined was (B5) which contains 5 mg of NaTC used as bile salt and 5 mg of Brij-93. B5 exhibited entrapment efficiency% = 95.21 ± 0.00%, particle size = 373.05 ± 0.07 nm, polydispersity index = 0.27 ± 0.01, and zeta potential = –32.00 ± 0.00 mV. It also had a high elasticity with a spherical shape. B5 gel displayed a sustained release profile with a significantly 2.3 folds’ higher drug permeation percent across rat skin than that permeated from NA gel. Moreover, in vivo anti-osteoarthritic and histopathological studies assured the efficacy and safety of B5 gel and its superiority over NA gel. Generally, the outcomes confirmed the great efficacy of NA loaded BIBs for the topical treatment of osteoarthritis. © 2023 Elsevier B.V.

The current medical practice in treating Hepatocellular carcinoma (HCC) using Drug Eluting Transarterial chemoembolization (DEB-TACE) technique is limited only to hydrophilic ionizable drugs, that can be attached ionically to the oppositely charged beads. This limitation has forced physicians to subscribe the more hydrophobic, first treatment option drugs, like sorafenib systemically via the oral route, thus flooding the patient system with a very powerful, non-specific, multiple-receptor tyrosine kinase inhibitor that is associated with notorious side effects. In this paper, a new modality is introduced, where highly charged, drug loaded liposomes are added to oppositely charged DEBs in a manner causing them to “explode” and the drug is eventually attached to the beads in the lipid patches covering their surfaces; therefore we call them “Explosomes”. After fully describing the preparation process and in vitro characterization, this manuscript delves into an in vivo pharmacokinetic study over 50 New Zealand rabbits, where explosomal loading is challenged vs oral as well as current practice of emulsifying sorafenib in lipiodol. Over 14 days of follow up, and compared to other groups, explosomal loading of SRF on embolic beads proved to cause a slower release pattern with longer Tmax, lower Cmax and less washout to general circulation in healthy animals. This treatment modality opens a new untapped door for local sustained delivery of hydrophobic drugs in catheterized organs. © 2023 Elsevier B.V.

The consumption of non-steroidal anti-inflammatory drugs (NSAIDs) have increased lately around the world, as they are considered essential and popular drugs for effective reduction of pain and inflammation. They have analgesic, antipyretic, and anti-inflammatory activities; also, it was reported recently that they protect against various critical disorders like heart attacks and cancer. However, oral use of NSAIDs may cause several pulmonary, gastrointestinal, hepatic, cardiovascular, cerebral, and renal complications. Therefore, topical NSAIDs were recommended as a substitute to oral NSAIDs for the treatment of inflammation and pain. Still, the skin permeation of NSAIDs is considered a challenge, as the skin have an effective barrier function. Therefore, this review investigates various advanced vesicular nanocarriers and their applications through the skin, to augment the topical delivery of NSAIDs through stratum corneum over the conventional systems, enhance their effectiveness, and reduce the unwanted side effects. These innovative systems can manage bioavailability, solubility, stability, safety, and efficacy issues present in conventional systems. © 2023, The Author(s).

Etilefrine hydrochloride (ET) is a water-soluble drug that is used to treat hypotension, but it has a bitter taste and low bioavailability due to undergoing the first-pass effect. Thus, this study aimed to develop and evaluate oral medicated jelly (OMJ) containing ET that could offer an easily taken palatable dosage form with higher bioavailability. OMJ is a novel palatable drug delivery system that can easily be taken by pediatric and geriatric patients, as well as those with dysphagia. Moreover, OMJs offer rapid disintegration in saliva and rapid drug absorption through the buccal mucosa, avoiding the first-pass effect and increasing the drug bioavailability. Natural polymers such as pectin, guar gum, xanthan gum, tragacanth gum, and sodium alginate were used as jellifying agents, with the addition of calcium chloride as a crosslinking agent, to prepare OMJs using the heat and congealing method. The prepared OMJs were investigated by testing their viscosity, in vitro release, and texture analysis of firmness, consistency, stickiness, cohesiveness, springiness, gumminess, and chewiness using a texture analyzer. A full factorial design (21 × 51) was utilized to select the optimized OMJ. The optimized OMJ (J2), containing 4 % pectin, had a 7563 ± 55 cps viscosity, 8.32 ± 0.21 N firmness, 5.72 ± 0.18 µJ consistency, 1.30 ± 0.04 mJ stickiness, and 96.02 ± 3.74 % ET dissolved after 10 min. ET release was significantly increased (greater than4-fold) from the optimized OMJ compared with the market tablet. Moreover, the obtained results clarified the stability and the acceptable palatability of the optimized OMJ. The clinical investigation on healthy human volunteers revealed that the optimized OMJ (J2) had significantly higher Cmax (1.7 folds) when compared with the market tablet with a relative bioavailability of 154.55 %. Therefore, OMJs can be considered as promising, palatable, and easily swallowed dosage form that could enhance the bioavailability of drugs undergoing the first-pass effect.

Background: Favipiravir is an antiviral drug that was recently approved for the management of COVID-19 infection. Aim: This work aimed to develop a new method, using sugaring-out induced homogeneous liquid-liquid microextraction followed by HPLC/UV for the determination of favipiravir in human plasma. Materials & methods: The optimum extraction conditions were attained using 500 μl of tetrahydrofuran as an extractant and 1400 mg of fructose as a phase-separating agent. Results: The developed method was validated according to the US FDA bioanalytical guidelines and was found linear in the range of 25-80,000 ng/ml with a correlation coefficient of 0.999. Conclusion: These results showed that the developed method was simple, easy, valid and adequately sensitive for determination of favipiravir in plasma for bioequivalence studies. © 2022 Newlands Press.

Favipiravir is a potential antiviral medication that has been recently licensed for Covid-19 treatment. In this work, a gadolinium-based magnetic ionic liquid was prepared and used as an extractant in dispersive liquid–liquid microextraction (DLLME) of favipiravir in human plasma. The high enriching ability of DLLME allowed the determination of favipiravir in real samples using HPLC/UV with sufficient sensitivity. The effects of several variables on extraction efficiency were investigated, including type of extractant, amount of extractant, type of disperser and disperser volume. The maximum enrichment was attained using 50 mg of the Gd-magnetic ionic liquid (MIL) and 150 μl of tetrahydrofuran. The Gd-based MIL could form a supramolecular assembly in the presence of tetrahydrofuran, which enhanced the extraction efficiency of favipiravir. The developed method was validated according to US Food and Drug Administration bioanalytical method validation guidelines. The coefficient of determination was 0.9999, for a linear concentration range of 25 to 1.0 × 105 ng/ml. The percentage recovery (accuracy) varied from 99.83 to 104.2%, with RSD values (precision) ranging from 4.07 to 11.84%. The total extraction time was about 12 min and the HPLC analysis time was 5 min. The method was simple, selective and sensitive for the determination of favipiravir in real human plasma. © 2022 John Wiley & Sons, Ltd.

Introduction: Ledipasvir is an effective direct acting antiviral agent used in the treatment of hepatitis C virus. The high price of ledipasvir was a reason for its limited provision to wide population of HCV patients. Objectives: Our objective is the formulation of liver targeted drug delivery system that can increase the amount of ledipasvir delivered to liver and prolong its liver residence in an attempt to reduce its recommended dose and its costing in the treatment of HCV. Methods: Different ledipasvir-loaded spanlastic formulations were prepared using the ethanol injection method and evaluated with respect to the particle size, zeta potential, polydispersity index, and entrapment efficiency %. Using Design-Expert ® software, the optimum spanlastics formulation was selected; then, it was coated by synthesized galactosylated chitosan. A pharmacokinetic study was carried out to evaluate the ability of the prepared galactosylated chitosan-coated spanlastics formulation to enhance ledipasvir liver bioavailability when it was administrated via the oral route. Results: The pharmacokinetic study revealed that the optimized galactosylated chitosan–coated spanlastics exhibited significantly higher liver peak concentration (Cmax) and area under liver concentration versus time curve (AUC0–72 h) and significant prolongation in the liver terminal half life (t½) and mean residence time (MRT) compared to the free ledipasvir dispersion with values of 6270 ng/g, 61,706.3 ng.h/g, 15.85 h, and 24.66 h, respectively. Conclusions: Enhanced liver bioavailability of ledipasvir has been accomplished using the developed galactosylated chitosan–coated spanlastics which can be a base for probable reduction in the required dose of ledipasvir in HCV treatment. Graphical abstract: [Figure not available: see fulltext.] © 2021, Controlled Release Society.

Ocular infections are classified into superficial keratitis, conjunctivitis or deep infections such as corneal abscesses and blepharitis. Herein, we focused on the development of formulation approaches that could prolong the residence time of gemifloxacin (GM) and enhance its corneal penetration to facilitate GM effects both superficially and at the deep tissues. Ionic gelation method was used to prepare eight forms of GM nanoparticles (NPs) formulated from chitosan polymer using sodium tripolyphosphate (TPP)-induced precipitation method. Differential scanning colorimetry (DSC) and X-ray diffraction (XRD) demonstrated the interaction between the chitosan and GM. Particle size, entrapment efficiency and cumulative in vitro release were used to select the optimal formula using Design Expert® software. The mean diameter of the selected NPs was 158. 4 nm. The average entrapment efficiency and cumulative release exhibited by the formulated NPs were 46.6% and 74.9%, respectively. Pharmacokinetics studies carried out on rabbits revealed that the ocularly-administered NPs significantly increased the loaded GM concentration in the tear and aqueous humour samples that suggested enhancement of precorneal retention and transcorneal permeation, respectively. Furthermore, ocular pharmacodynamic studies conducted on rabbits following ocular infection with Staphylococcus aureus or Pseudomonas aeruginosa showed that the administered NPs augmented the antibacterial activity of the delivered GM. This was demonstrated via the histopathological examination of the dissected corneas that showed preserved histological features and reduced bacterial keratitis on using the GM NPs rather than GM solution. Moreover, the GM NPs-treated corneas showed lower viable bacterial counts than the GM solution-treated corneas. Accordingly, our study illustrated the capability of the chitosan NPs to promote the antibacterial activity of GM against eye infections via ocular administration. © 2021 American Pharmacists Association

The current study aimed to load terconazole (TCZ), an antifungal agent with low permeability characteristics, into highly deformable bilosomes (HBs) for augmenting its topical delivery. HBs contain edge activator in addition to the constituents of traditional bilosomes (Span 60, cholesterol, and bile salts). More elasticity is provided to the membrane of vesicles by the existence of edge activator and is expected to increase the topical permeation of TCZ. HBs were formulated using ethanol injection technique based on 2⁴ complete factorial design to inspect the impact of various formulation variables (bile salt type and amount, edge activator type, and sonication time) on HBs characteristics (entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP)). The optimum formula (HB14) was decided based on Design-Expert^® software and was utilized for further explorations. HB14 exhibited EE% = 84.25 ± 0.49%, PS = 400.10 ± 1.69 nm, PDI = 0.23 ± 0.01, and ZP = - 56.20 ± 0.00 mV. HB14 showed spherical vesicles with higher deformability index (9.94 ± 1.91 g) compared to traditional bilosomal formula (3.49 ± 0.49 g). Furthermore, HB14 showed superior inhibition of Candida albicans growth relative to TCZ suspension using XTT (2,3-bis(2-methyloxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) reduction assay. Moreover, in vivo skin deposition studies revealed superior TCZ deposition inside the skin from HB14 compared to traditional bilosomal formula and TCZ suspension. Moreover, histopathological examination in rats assured the safety of HB14 for topical use. Concisely, the obtained outcomes confirmed the pronounced efficacy of HBs for topical delivery of TCZ.

This study aimed to formulate and statistically optimize cubosomal formulations loaded with voriconazole to enhance and control its ocular bioavailability. The independent variables of the employed central composite face-centered design were the percentages of monoolein and Pluronic F127. Particle size, zeta potential, drug content, entrapment efficiency and drug release parameters were adopted as dependent responses. The conducted factorial analysis resulted in an optimum formulation composed of 15% monoolein and 1.2% Pluronic F127. The optimum cubosomal formulation showed well-dispersed vesicles with a particle size of 160 nm and a relatively high drug loading (0.81%). Then, it was coated with chitosan to further enhance its precorneal residence time. The chitosan-coated formulation showed high mucoadhesive properties, in addition to being safe and biocompatible. Moreover, it showed higher Cmax, Tmax, AUC(0-8), AUC(0-∞), MRT, T1/2 and HVDt50%Cmax when compared to voriconazole suspension. It showed also higher concentration in the vitreous humor when compared to the drug suspension which indicates deeper penetration into the ocular tissue. Finally, the chitosan-coated optimum cubosomal formulation could be considered an efficient ocular nanocarrier for voriconazole.

Ledipasvir is a novel antiviral agent used in the treatment of hepatitis C. We aim in our study to increase its delivery to hepatocytes and prolong its retention within liver. Several formulae of ledipasvir loaded liposomes were prepared and the best formula regarding particle size, zeta potential, polydispersity index and entrapment efficiency was selected. On the other hand, galactosylated chitosan was synthesized in a chemical reaction. Then the best liposomes formula was coated with the galactosylated chitosan. Having galactose residues on their surface, the coated liposomes can bind to the asialoglycoprotein receptors on the targeted hepatocytes enhancing ledipasvir uptake into them. The galactosylated chitosan coated liposomes had particle size of 218.2 nm ± 7.21, zeta potential of 27.15 mV ± 1.76, polydispersity index of 0.278 ± 0.055 and entrapment efficiency % of 54.63% ± 0.05 respectively. The pharmacokinetic study revealed a significant increase in the liver peak concentration (Cmax) and the area under liver concentration versus time curve AUC(0–72 h) and significant prolongation in the liver terminal half life (t½) and mean residence time (MRT) in comparison to the oral dispersion of ledipasvir with values of 11,400 ng/g, 88,855 ng∗h/g, 32.00 h and 18.11 h respectively.

Ledipasvir is an effective direct acting antiviral agent used in the treatment of hepatitis C virus. The high price of ledipasvir was a reason for its limited provision to wide population of HCV patients.

Paroxetine (PX) is the most potent serotonin reuptake inhibitor utilized in depression and anxiety treatment. It has drawbacks, such as having a very bitter taste, low water solubility, and undergoing extensive first pass metabolism, leading to poor oral bioavailability (<50%). This work aimed to develop and optimize palatable oral fast-dissolving films (OFDFs) loaded with a paroxetine nanosuspension. A PX nanosuspension was prepared to increase the PX solubility and permeability via the buccal mucosa. The OFDFs could increase PX bioavailability due to their rapid dissolution in saliva, without needing water, and the rapid absorption of the loaded drug through the buccal mucosa, thus decreasing the PX metabolism in the liver. OFDFs also offer better convenience to patients with mental illness, as well as pediatric, elderly, and developmentally disabled patients. The PX nanosuspension was characterized by particle size, poly dispersity index, and zeta potential. Twelve OFDFs were formulated using a solvent casting technique. A 22 × 31 full factorial design was applied to choose the optimized OFDF, utilizing Design-Expert® software (Stat-Ease Inc., Minneapolis, MN, USA). The optimized OFDF (F1) had a 3.89 ± 0.19 Mpa tensile strength, 53.08 ± 1.28% elongation%, 8.12 ± 0.13 MPa Young’s modulus, 17.09 ± 1.30 s disintegration time, and 96.02 ± 3.46% PX dissolved after 10 min. This optimized OFDF was subjected to in vitro dissolution, ex vivo permeation, stability, and palatability studies. The permeation study, using chicken buccal pouch, revealed increased drug permeation from the optimized OFDF; with a more than three-fold increase in permeation over the pure drug. The relative bioavailability of the optimized OFDF in comparison with the market tablet was estimated clinically in healthy human volunteers and was found to be 178.43%. These findings confirmed the success of the OFDFs loaded with PX nanosuspension for increasing PX bioavailability.

{Purpose: The aim of this study was to encapsulate clotrimazole (CLT), an antifungal drug with poor water solubility characteristics, into spanlastics (SPs) to provide a controlled ocular delivery of the drug. Methods: Span 60 was used in the formulation of SPs with Tween 80, Pluronic F127, or Kolliphor RH40 as an edge activator (EA). The presence of EA offers more elasticity to the membrane of the vesicles which is expected to increase the corneal permeation of CLT. SPs were prepared using ethanol injection method applying 32 complete factorial design to study the effect of formulation variables (ratio of Span 60: EA (w/w) and type of EA) on SPs characteristics (encapsulation efficiency percent (EE%), average vesicle size (VS), polydis-persity index (PDI) and zeta potential (ZP)). Design-Expert software was used to determine the optimum formulation for further investigations. Results: The optimum formulation determined was S1, which contains 20 mg of Tween 80 used as an EA and 80 mg of Span 60. S1 exhibited EE% = 66.54 ± 7.57%

Pluronic-based nanostructured gels were developed and optimized to increase the permeability of vinpocetine through the skin and the mucous layer of the nasal cavity. A modified thin-film hydration technique was utilized to prepare the nanostructured gel formulae containing different concentrations of Pluronic F127, Pluronic F68 and oleic acid. The formed nanodispersions were tested for their pH, particle size, zeta potential, polydispersity index, entrapment efficiency and gelation temperature. Box-Behnken statistical design was used to choose the optimized nasal and transdermal nanostructured gel formulae utilizing Design-Expert® software. The nasal optimized formula consisted of 2.4% oleic acid, 23.46% total surfactants and 27.13% Pluronic F68, had a gelation temperature of 35 °C which could be suitable to form in situ gel upon application into the nasal cavity. On the other hand, the transdermal optimized formula, composed of 1.77% oleic acid, 22.46% total surfactants and 11.54% Pluronic F68, formed gel at room temperature that could be suitable to be applied onto the skin. The optimized gel formulae were investigated for their in vitro drug release, rheology, morphology, histopathology and ex vivo permeation. The extent of drug permeated from the optimized formula through both nasal and skin membranes was significantly increased by 3.39 and 4.7 folds when compared to the drug suspension. Finally, the obtained findings ensured the creditable impact of the nanostructured gels as promising nanocarriers for enhancing transmucosal and transdermal vinpocetine permeation.

The objective of this work was to design a diclofenac epolamine (DE) flash tablets (FTs) intended to dissolve in the mouth saliva, thereby improving the DE bioavailability and reducing its first-pass liver metabolism. Design-Expert software was used to build a 31.22 full factorial design (12 runs). FTs were fabricated using lyophilization process. The dissolution response was selected to pick the optimized run. The results indicate that the optimized run (R1) showed the fastest drug dissolution (total dissolution in 12 min). The predicted run (Rp) showed a desirability of about 0.93. Differential scanning calorimetry(DSC) analysis results showed a decrease in the drug melting point of the R1 formulation. Fourier–transform infrared spectroscopy (FTIR) showed the compatibility of the drug with other components of formulation, X-ray powder diffraction (XRPD) analysis showed the evolution of the drug physical state from a crystalline to an amorphous form and scanning electron microscopy(SEM) divugled the disappearance of drug crystals in gelatin strands. The results of the pharmacokinetic study performed in 6 human volunteers evidenced an increase in the maximum DE concentration in plasma and, consequently, an increased bioavailability of the FT formulation as compared with a reference formulation(Fr). Concisely, the developed FTs (R1) showed promising results which could be able to enhance oral bioavailability, reduce the therapeutic dose of the drug, and abate of the complications accompanied with conventional dosage forms.

Statins are mainly used for the treatment of hyperlipidemia, but recently, their anticancer role was extremely investigated. The goal of this study was to statistically optimize novel elastic nanovesicles containing rosuvastatin calcium to improve its transdermal permeability, bioavailability, and anticancer effect. The elastic nanovesicles were composed of Tween® 80, cetyl alcohol, and clove oil. The nanodispersions were investigated for their entrapment efficiency, particle size, zeta potential, polydispersity index, and elasticity. The optimized elastic nanovesicular dispersion is composed of 20% cetyl alcohol, 53.47% Tween 80, and 26.53% clove oil. Carboxy methylcellulose was utilized to convert the optimized elastic nanovesicular dispersion into elastic nanovesicular gels. Both the optimized dispersion and the optimized gel (containing 2% w/v carboxymethylcellulose) were subjected to in vitro release study, scanning and transmission electron microscopy, histopathological evaluation, and ex vivo permeation. The cell viability assay of the optimized gel on MCF-7 and Hela cell lines showed significant antiproliferative and potent cytotoxic effects when compared to the drug gel. Moreover, the optimized gel accomplished a significant increase in rosuvastatin bioavailability upon comparison with the drug gel. The optimized gel could be considered as a promising nanocarrier for statins transdermal delivery to increase their systemic bioavailability and anticancer effect.