Formulation Optimization and <Emphasis Type="Italic">Ex Vivo</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Celecoxib Microemulsion-Based Gel for Transdermal Delivery

Celecoxib (CXB) is a poorly aqueous solubility sulfonamide non-steroidal anti-inflammatory drug (NSAID). Hence, the formulation of CXB was selected for solubilization and bioavailability. To find out suitable formulation for microemulsion, the solubility of CXB in triacetin (oil phase), Tween 80 (surfactant), and Transcutol-P (co-surfactant) was screened respectively and optimized by using orthogonal experimental design. The Km value and concentration of oil, S_mix, and water were confirmed by pseudo-ternary phase diagram studies and central composite design. One percent carbopol 934 was added to form CXB microemulsion-based gel. The final formulation was evaluated for its appearance, pH, viscosity, stability, drug content determination, globule size, and zeta potential. Its ex vivo drug permeation and the in vivo pharmacokinetic was investigated. Further research was performed to ensure the safety and validity by skin irritation study and in vivo anti-inflammatory activity study. Ex vivo permeation study in mice was designed to compare permeation and transdermal ability between microemulsion formulation and conventional gel. The results revealed that optimized microemulsion-based gel gained higher permeation based on smaller globule size and high drug loading of microemulsion. Transdermal ability was also greatly improved. Bioavailability was compared to market Celebrex® by the in vivo pharmacokinetic study in rabbits. The results indicated that CXB microemulsion-based gel had better bioavailability than Celebrex®.     

<Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Assessment of Docetaxel Formulation Developed for Esophageal Stents

Esophageal cancer (EC) mostly affects the elderly population and is frequently diagnosed at an advanced stage. Self-expanding metal stents (SEMS) are the most popular mode of palliation, but they are associated with reocclusion caused by tumor growth. To overcome this problem, docetaxel (DTX)-loaded polyurethane formulations were prepared for stent application. The films were evaluated against the cancer cell lines, OE-19 and OE-21, and normal esophageal cell line Het-1A. The DTX and the formulations were evaluated in vitro for the cytotoxicity and in vivo in nude mice. It was found that DTX and the formulations have a weak activity against the EC cell lines and an even weaker activity against Het-1A cell line. Preliminary in vivo studies showed skin toxicity in nude mice necessitating modification of the formulation. Reevaluation in a mouse xenograft model resulted in toxicity at high dose formulations while the low dose formulation exhibited modest advantage over commercial IV formulation; however, there was no significant difference between the commercial IV and blank formulation. DTX combination with an anti-cancer agent having complementary mode of action and non-overlapping toxicity could yield better outcome in future.     

<Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">Ex Vivo</Emphasis> Evaluation of Novel Curcumin-Loaded Excipient for Buccal Delivery

This study aimed to develop a mucoadhesive polymeric excipient comprising curcumin for buccal delivery. Curcumin encompasses broad range of benefits such as antioxidant, anti-inflammatory, and chemotherapeutic activity. Hyaluronic acid (HA) as polymeric excipient was modified by immobilization of thiol bearing ligands. L-Cysteine (SH) ethyl ester was covalently attached via amide bond formation between cysteine and the carboxylic moiety of hyaluronic acid. Succeeded synthesis was proved by H-NMR and IR spectra. The obtained thiolated polymer hyaluronic acid ethyl ester (HA-SH) was evaluated in terms of stability, safety, mucoadhesiveness, drug release, and permeation-enhancing properties. HA-SH showed 2.75-fold higher swelling capacity over time in comparison to unmodified polymer. Furthermore, mucoadhesion increased 3.4-fold in case of HA-SH and drug release was increased 1.6-fold versus HA control, respectively. Curcumin-loaded HA-SH exhibits a 4.4-fold higher permeation compared with respective HA. Taking these outcomes in consideration, novel curcumin-loaded excipient, namely thiolated hyaluronic acid ethyl ester appears as promising tool for pharyngeal diseases.     

Self-Assembling Raloxifene Loaded Mixed Micelles: Formulation Optimization, <Emphasis Type="Italic">In Vitro</Emphasis> Cytotoxicity and <Emphasis Type="Italic">In Vivo</Emphasis> Pharmacokinetics

Raloxifene (RLX) has been strongly recommended for postmenopausal women at high risk of invasive breast cancer and for prevention of osteoporosis. However, low aqueous solubility and reduced bioavailability hinder its clinical application. The objective of this study was to explore the potential of RLX loaded mixed micelles (RLX-MM) using Pluronic F68 and Gelucire 44/14 for enhanced bioavailability and improved anticancer activity on human breast cancer cell line (MCF-7). RLX-MM were prepared by solvent evaporation method and optimized using 3² factorial design. The average size, entrapment efficiency and zeta potential of the optimized formulation were found to be 190?±?3.3 nm, 79?±?1.3%, 13?±?0.8 mV, respectively. In vitro study demonstrated 74.68% drug release from RLX-MM in comparison to 42.49% drug release from RLX dispersion. According to the in vitro cytotoxicity assay, GI₅₀ values on MCF-7 breast cancer cell line for RLX-MM and free RLX were found to be 22.5 and 94.71 μg/mL, respectively. Significant improvement (P?<?0.05) in the anticancer activity on MCF-7 cell line was observed in RLX-MM over RLX pure drug. Additionally, oral bioavailability of RLX-MM was improved by 1.5-fold over free RLX when administered in female Wistar rats. Incorporation of RLX in the hydrophobic core and improved solubility of the drug due to hydrophilic shell attributed to the enhanced cytotoxicity and bioavailability of RLX-MM. This research establishes the potential of RLX loaded mixed micelles of Pluronic F68 and Gelucire 44/14 for improved bioavailability and anticancer activity on MCF-7 cell line.     

Preparation and <Emphasis Type="Italic">In Vitro</Emphasis>/<Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Microparticle Formulations Containing Meloxicam

In this study, we have formulated chitosan-coated sodium alginate microparticles containing meloxicam (MLX) and aimed to investigate the correlation between in vitro release and in vivo absorbed percentages of meloxicam. The microparticle formulations were prepared by orifice ionic gelation method with two different sodium alginate concentrations, as 1% and 2% (w/v), in order to provide different release rates. Additionally, an oral solution containing 15 mg of meloxicam was administered as the reference solution for evaluation of in vitro/in vivo correlation (ivivc). Following in vitro characterization, plasma levels of MLX and pharmacokinetic parameters [elimination half-life (t _1/2), maximum plasma concentration (C _max), time for C _max (t _max)] after oral administration to New Zealand rabbits were determined. Area under plasma concentration–time curve (AUC_0–∞) was calculated by using trapezoidal method. A linear regression was investigated between released% (in vitro) and absorbed% (in vivo) with a model-independent deconvolution approach. As a result, increase in sodium alginate content lengthened in vitro release time and in vivo t _max value. In addition, for ivivc, linear regression equations with r ² values of 0.8563 and 0.9402 were obtained for microparticles containing 1% and 2% (w/v) sodium alginate, respectively. Lower prediction error for 2% sodium alginate formulations (7.419 ± 4.068) compared to 1% sodium alginate formulations (9.458 ± 5.106) indicated a more precise ivivc for 2% sodium alginate formulation.     

Development and <Emphasis Type="Italic">In Vitro</Emphasis>/<Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Etodolac Controlled Porosity Osmotic Pump Tablets

The aim of the current work was the design and evaluation of etodolac controlled porosity osmotic pump (CPOP) tablets exhibiting zero-order release kinetics. Variables influencing the design of (1) core tablets viz., (a) osmogent type (sodium chloride, potassium chloride, mannitol, and fructose) and (b) drug/osmogent ratio (1:0.25, 1:0.50, and 1:0.75), and (2) CPOP tablets viz., (a) coating solution composition, (b) weight gain percentage (1–5%, w/w), and (c) pore former concentration (5%, 10%, and 20%, v/v), were investigated. Statistical analysis and kinetic modeling of drug release data were estimated. Fructose-containing core tablets showed significantly (P < 0.05) more retarded drug release rates. An inverse correlation was observed between drug/fructose ratio and drug release rate. Coating of the optimum core tablets (F4) with a mixture of cellulose acetate solution (3%, w/v), diethyl phthalate, and polyethylene glycol 400 (85:10:5, v/v, respectively) till a 4% w/w weight gain enabled zero-order sustained drug delivery over 24 h. Scanning electron microscopy micrographs of coating membrane confirmed pore formation upon contact with dissolution medium. When compared to the commercial immediate-release Napilac® capsules, the optimum CPOP tablets (F4–34) provided enhanced bioavailability and extended duration of effective etodolac plasma concentration with minimum expected potential for side effects in healthy volunteers.KEY WORDS: cellulose acetate, controlled porosity osmotic pump, etodolac, osmogent, zero order     

Nanovesicular Formulation of Brimonidine Tartrate for the Management of Glaucoma: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation

In this study, nanovesicles were developed for brimonidine tartrate by film hydration technique and dispersed in viscous carbopol solution for ocular delivery. Scanning electron microscopy revealed spherical shape of the vesicles. As high as 32.27% drug entrapment efficiency was achieved depending upon the surfactant/cholesterol molar ratio (7:4 to 7:8). The vesicles were in the size range of 298.0–587.9 nm. Release study showed a biphasic drug-release pattern for the lyophilized vesicular formulation in buffered saline solution, i.e., initial burst release followed by gradual release over the period of 8 h. On contrary, the isolated vesicles reduced the burst effect in 3 h by two to three times and the drug release was comparatively slower at the intermediate ratio in both cases. With variation in cholesterol content, the drug release followed either first order or Higuchi’s kinetics. Physically the lyophilized vesicular formulations were more stable at refrigerated temperature. DSC and X-RD analyses indicated loss of drug crystallinity in the vesicles. FTIR spectroscopy did not reveal any interaction between drug and excipients. The lyophilized formulation showed better ocular hypotensive activity than marketed drops on albino rabbits and in vivo efficacy was sustained up to 7.5 h. Furthermore, the formulation was found to be non-irritant to the rabbit eye. Hence, the lyophilized vesicles, when dispersed in viscous carbopol solution, had the potential in reducing dosing frequency and could improve patient compliance.     

Formulation and <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Lipid-Based Terbutaline Sulphate Bi-layer Tablets for Once-Daily Administration

The objective of this study was to prepare and evaluate terbutaline sulphate (TBS) bi-layer tablets for once-daily administration. The bi-layer tablets consisted of an immediate-release layer and a sustained-release layer containing 5 and 10 mg TBS, respectively. The sustained-release layer was developed by using Compritol®888 ATO, Precirol® ATO 5, stearic acid, and tristearin, separately, as slowly eroding lipid matrices. A full 4?×?2² factorial design was employed for optimization of the sustained-release layer and to explore the effect of lipid type (X ₁), drug–lipid ratio (X ₂), and filler type (X ₃) on the percentage drug released at 8, 12, and 24 h (Y ₁, Y ₂, and Y ₃) as dependent variables. Sixteen TBS sustained-release matrices (F1–F16) were prepared by melt solid dispersion method. None of the prepared matrices achieved the targeted release profile. However, F2 that showed a relatively promising drug release was subjected to trial and error optimization for the filler composition to develop two optimized matrices (F17 and F18). F18 which consisted of drug–Compritol®888 ATO at ratio (1:6 w/w) and Avicel PH 101/dibasic calcium phosphate mixture of 2:1 (w/w) was selected as sustained-release layer. TBS bi-layer tablets were evaluated for their physical properties, in vitro drug release, effect of storage on drug content, and in vivo performance in rabbits. The bi-layer tablets showed acceptable physical properties and release characteristics. In vivo absorption in rabbits revealed initial high TBS plasma levels followed by sustained levels over 24 h compared to immediate-release tablets.     

Development of Molecularly Imprinted Olanzapine Nano-particles: <Emphasis Type="Italic">In Vitro</Emphasis> Characterization and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation

Molecularly imprinted nano-particles (MINPs) selective for olanzapine were prepared using methacrylic acid (MA) as monomer, ethylene glycol dimethacrylate (EGDMA) as a cross-linker, and 2,2-azobis (2-isobutyronitrile) (AIBN) as the initiator in 36 different ratios. The reaction runs with considerable fine powder formation were selected for further binding and selectivity studies. The MINP with the best selectivity (MINP-32) was chosen for further structural characterization by Fourier transform infrared spectroscopy (FT-IR), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM), adsorption-desorption isotherm for specific surface area, volume and average pore diameter determination. All characterization methods confirmed the successful formation of MINP. The optimum conditions for maximum template loading on the MINP-32 were found by experimental design using response surface methodology (RSM) and choosing absorbent amount, pH, and time as the main factors. MINPs with maximum template loading also indicated significant selectivity between template and its analog (clozapine). The release profile demonstrated a maximum release of about 95% after 288 h for MINP-32 in comparison with about 94% after 120 h for non-MINP-32. The same slow release of drug from MINP-32 was also observed during animal study of the plasma level of template, 20–28 μg/ml versus 5–10 μg/ml. The MINP-32 of this study represents a desirable ability to keep the memory of the template with significant selectivity and good capability to control the release of template in vitro and in vivo and hence could be a promising drug delivery system.     

Development of a Prolonged-Release Pramipexole Transdermal Patch: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation

The current study aimed to develop a prolonged-release pramipexole (PPX) transdermal patch for the treatment of Parkinson’s disease. Permeation parameters of PPX were investigated using human cadaver skin. Pramipexole patches were prepared using DURO-TAK^® pressure-sensitive-adhesive (PSA) and evaluated for drug stability, drug loading, in vitro drug release, and in vitro permeation through mouse skin. The results indicated that blends of DURO-TAK^® 87-2852 and DURO-TAK^® 87-2510 were suitable for creating a prolonged-release PPX patch due to their advantages in drug release, drug loading, and stability. The final formulation consisted of 87-2852/87-2510 (70:30), 10% PG, and 15% PPX and showed a cumulative permeation amount of 1497.19?±?102.90 μg/cm² with a continuous flux over 6.0 μg/(cm²·h) across human cadaver skin for 7 days. In vivo studies in rats indicated that PPX patch produced a significantly longer (p?<?0.001) half-life (t _1/2, 75.16?±?17.37 h) and mean residence time (MRT, 135.89?±?24.12 h) relative to oral tablets (Sifrol^®) and had a relative bioavailability of 51.64?±?21.32%. Therefore, this study demonstrated the feasibility of developing a prolonged-release PPX patch, which proposed the potential to serve as an alternate to conventional oral tablets and may therefore improve patient compliance.     

<Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">Ex Vivo</Emphasis> Evaluations of Lipid Anti-Cancer Nanoformulations: Insights and Assessment of Bioavailability Enhancement

Lipid-based nanoformulations have been extensively investigated for improving oral efficacy of plethora of drugs. Chemotherapeutic agents remain a preferred option for effective management of cancer; however, most chemotherapeutic agents suffer from limitation of poor oral bioavailability that is associated with their physicochemical properties. Drug delivery via lipid-based nanosystems possesses strong rational and potential for improving oral bioavailability of such anti-cancer molecules through various mechanisms, viz. improving their gut solubilisation owing to micellization, improving mucosal permeation, improving lymphatic uptake, inhibiting intestinal metabolism and/or inhibiting P-glycoprotein efflux of molecules in the gastrointestinal tract. Various in vitro characterization techniques have been reported in literature that aid in getting insights into mechanisms of lipid-based nanodevices in improving oral efficacy of anti-cancer drugs. The review focuses on different characterization techniques that can be employed for evaluation of lipid-based nanosystems and their role in effective anti-cancer drug delivery.     

<Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Proniosomes Containing Celecoxib for Oral Administration

The objectives of this research were to prepare celecoxib proniosomes and evaluate the influence of proniosomal formulation on the oral bioavailability of the drug in human volunteers. A new proniosomal delivery system for a poorly water-soluble drug such as celecoxib was developed and subjected to in vitro and in vivo studies. Proniosomes were prepared by sequential spraying method, which consisted of cholesterol, span 60, and dicetyl phosphate in a molar ratio of 1:1: 0.1, respectively. The average entrapment percent of celecoxib proniosome-derived niosomes was about 95%. The prepared proniosomes showed marked enhancement in the dissolution of celecoxib as compared to pure drug powder. The bioavailability of 200 mg single dose of both celecoxib proniosomal formulation and a conventional marketed celecoxib capsule was studied in human volunteers. The obtained results show that the proniosomal formulation significantly improved the extent of celecoxib absorption than conventional capsule. The mean relative bioavailability of the proniosomal formulation to the conventional capsule was 172.06 ± 0.14%. The mean T _max for celecoxib was prolonged when given as proniosomal capsule. There was no significant difference between the values of K _el and t _1/2 for both celecoxib preparations. In conclusion, the proniosomal oral delivery system of celecoxib with improved bioavailability was established.     

<Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Hydroxyzine Hydrochloride Microsponges for Topical Delivery

Hydroxyzine HCl is used in oral formulations for the treatment of urticaria and atopic dermatitis. Dizziness, blurred vision, and anticholinergic responses, represent the most common side effects. It has been shown that controlled release of the drug from a delivery system to the skin could reduce the side effects while reducing percutaneous absorption. Therefore, the aim of the present study was to produce an effective drug-loaded dosage form that is able to control the release of hydroxyzine hydrochloride into the skin. The Microsponge Delivery System is a unique technology for the controlled release of topical agents, and it consists of porous polymeric microspheres, typically 10–50 μm in diameter, loaded with active agents. Eudragit RS-100 microsponges of the drug were prepared by the oil in an oil emulsion solvent diffusion method using acetone as dispersing solvent and liquid paraffin as the continuous medium. Magnesium stearate was added to the dispersed phase to prevent flocculation of Eudragit RS-100 microsponges. Pore inducers such as sucrose and pregelatinized starch were used to enhance the rate of drug release. Microsponges of nearly 98% encapsulation efficiency and 60–70% porosity were produced. The pharmacodynamic effect of the chosen preparation was tested on the shaved back of histamine-sensitized rabbits. Histopathological studies were driven for the detection of the healing of inflamed tissues.     

Comparative Pharmaceutical Evaluation of Candesartan and Candesartan Cilexetil: Physicochemical Properties, <Emphasis Type="Italic">In Vitro</Emphasis> Dissolution and <Emphasis Type="Italic">Ex Vivo In Vivo</Emphasis> Studies

The aim of the present work is to answer the question is it possible to replace the ester prodrug candesartan cilexetil (CC) by its active metabolite candesartan (C) to bypass the in vivo variable effect of esterase enzymes. A comparative physicochemical evaluation was conducted through solubility, dissolution, and stability studies; additionally, ex vivo permeation and in vivo studies were assessed. C demonstrated higher solubility over CC at alkaline pH. Moreover, dissolution testing using the pharmacopeial method showed better release profile of C even in the absence of surfactant in the testing medium. Both drugs demonstrated a slight degradation in acidic pH after short-term stability. Instead, shifting to alkaline pH of 6.5 and 7.4 showed superiority of C solution stability compared to CC solution. The ex vivo permeation results demonstrated that the parent compound C has a significant (P < 0.05) enhanced permeation compared to its prodrug from CC, that agreed with in vivo results in which C suspension reached significantly (P < 0.05) higher C _max of 1.39 ± 0.59 μg/mL at T _max of 0.66 ± 0.11 h, while CC suspension reached C _max of 0.47 ± 0.22 μg/mL at T _max of 2.00 ± 0.27 h, a lag period of 40 min is needed prior to detection of any absorbed CC in plasma. Those findings are not in agreement with the previously reported rationale on the prodrug formation owing to the poor permeability of the parent compound, suggesting the possibility of marketing the parent drug candesartan for clinical use similarly to azilsartan and its prodrug.     

Ocular Cubosome Drug Delivery System for Timolol Maleate: Preparation,Characterization, Cytotoxicity, <Emphasis Type="Italic">Ex Vivo</Emphasis>, and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation

Glaucoma is an ocular disease featuring increased intraocular pressure (IOP) and its primary treatment strategy is to lower IOP by medication. Current ocular drug delivery in treating glaucoma is confronting a variety of challenges, such as low corneal permeability and bioavailability due to the unique anatomical structure of the human eye. To tackle these challenges, a cubosome drug delivery system for glaucoma treatment was constructed for timolol maleate (TM) in this study. The TM cubosomes (liquid crystalline nanoparticles) were prepared using glycerol monooleate and poloxamer 407 via high-pressure homogenization. These constructed nanoparticles appeared spherical using transmission electron microscopy and had an average particle size of 142 nm, zeta potential of ?6.27 mV, and over 85% encapsulation efficiency. Moreover, using polarized light microscopy and small-angle X-ray scattering (SAXS), it was shown that the TM cubosomes have cubic liquid crystalline D-type (Pn3m) structure, which provides good physicochemical stability and high encapsulation efficiency. Ex vivo corneal permeability experiments showed that the total amount of TM cubosomes penetrated was higher than the commercially available eye drops. In addition, in vivo studies revealed that TM cubosomes reduced the IOP in rabbits from 27.8～39.7 to 21.4～32.6 mmHg after 1-week administration and had a longer retention time and better lower-IOP effect than the commercial TM eye drops. Furthermore, neither cytotoxicity nor histological impairment in the rabbit corneas was observed. This study suggests that cubosomes are capable of increasing the corneal permeability and bioavailability of TM and have great potential for ocular disease treatment.     

Etoposide-Loaded Poly(Lactic-co-Glycolic Acid) Intravitreal Implants: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation

Etoposide-loaded poly(lactic-co-glycolic acid) implants were developed for intravitreal application. Implants were prepared by a solvent-casting method and characterized in terms of content uniformity, morphology, drug-polymer interaction, stability, and sterility. In vitro drug release was investigated and the implant degradation was monitored by the percent of mass loss. Implants were inserted into the vitreous cavity of rabbits’ eye and the in vivo etoposide release profile was determined. Clinical examination and the Hen Egg Test-Chorioallantoic Membrane (HET-CAM) method were performed to evaluate the implant tolerance. The original chemical structure of the etoposide was preserved after incorporation in the polymeric matrix, which the drug was dispersed uniformly. In vitro, implants promoted sustained release of the drug and approximately 57% of the etoposide was released in 50 days. In vivo, devices released approximately 63% of the loaded drug in 42 days. Ophthalmic examination and HET-CAM assay revealed no evidence of toxic effects of implants. These results tend to show that etoposide-loaded implants could be potentially useful as an intraocular etoposide delivery system in the future.     

Preparation and <Emphasis Type="Italic">In Vitro</Emphasis>/<Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Puerarin Solid Self-Microemulsifying Drug Delivery System by Spherical Crystallization Technique

The aim of this work was to establish a method for preparing stable and controllable solid self-microemulsifying drug delivery system (S-SMEDDS) by spherical crystallization technique, which was explored for promoting the dissolution, oral bioavailability, and process efficiency. Solubility test, preparation of liquid self-microemulsifying drug delivery system (L-SMEDDS), and the obtained ternary phase diagrams test have been performed to screen and optimize the composition of LSMEDDS. The optimized formulation was used to prepare puerarin solid self-microemulsifying drug delivery system (Pue-SSMEDDS) by spherical crystallization technique. Droplet size and morphological analysis of the optimal Pue-SSMEDDS were determined to evaluate the final formulation. And the Pue-SSMEDDS was also assessed by flowability study, angle of repose, Carr’s index, and flow velocity. Furthermore, the vitro dissolution and pharmacokinetic profile in vivo were analyzed. The study in vitro showed the Pue-SSMEDDS could disperse in the dispersion medium within 60 s and was spherical with the particle size of 19.66 nm and zeta potential of ?28.3 mV. It could keep stable at low temperature and seal condition for 3 months. In vivo pharmacokinetic experiments of rats, the mean plasma concentration of self-microemulsion group was much higher than that of conventional tablets and could play a long-lasting efficacy, while there was no significant difference between the LSMEDDS and S-SMEDDS. The results suggested the potential of S-SMEDDS could improve the oral bioavailability of poorly water-soluble drug, such as puerarin.     

Biodegradable Ocular Inserts for Sustained Delivery of Brimonidine Tartarate: Preparation and <Emphasis Type="Italic">In Vitro</Emphasis>/<Emphasis Type="Italic">In Vivo</Emphasis> Evaluation

The bioavailability of therapeutic agents from eye drops is usually limited due to corneal barrier functions and effective eye protective mechanisms. Therefore, the current study aims to enhance ocular bioavailability of brimonidine, a potent antiglaucoma drug, through the preparation of ocular inserts. Solvent casting technique was employed to prepare the inserts using polyvinylpyrrolidone K-90 (PVP K-90) as film-forming polymer blended with different viscosity grades of bioadhesive polymers namely hydroxypropyl methycellulose, carbopol, sodium alginate, and chitosan. The prepared ocular inserts were evaluated for various physicochemical parameters, swelling behavior, and in vitro release patterns. Sodium alginate-based ocular inserts revealed the most sustainment in drug release (99% at 6 h), so it was selected for further modifications via coating it, on one side or dual sides, using hydrophobic film composed of either ethylcellulose or Eudragit RSPO. The obtained in vitro release results for the modified ocular inserts revealed that ethylcellulose is superior to Eudragit RSPO in terms of brimonidine release sustainment effect. Ocular inserts composed of 7% PVP K-90, 1.5% low molecular weight sodium alginate with or without ethylcellulose coat were able to sustain the in vitro release of brimonidine. Their therapeutic efficacy regarding intraocular pressure (IOP) lowering effect when inserted in albino rabbits eyes showed superior sustainment effect compared with that of brimonidine solution. Furthermore, due to both the mucoadhesive property and the drug sustainment effect, the one-side-coated ocular insert showed more IOP lowering effect compared with that of its non-coated or dual-side-coated counterpart.     

Enhancement of the Oral Bioavailability of Felodipine Employing 8-Arm-Poly(Ethylene Glycol): <Emphasis Type="Italic">In Vivo</Emphasis>, <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Silico</Emphasis> Evaluation

Poor oral bioavailability is the single most important challenge in drug delivery. Prominent among the factors responsible for this is metabolic activity of the intestinal and hepatic cytochrome P450 (CYP450) enzymes. In preliminary studies, it was demonstrated that 8-arm-PEG was able to inhibit the felodipine metabolism. Therefore, this report investigated the oral bioavailability-enhancing property of 8-arm-PEG employing detailed in vitro, in vivo, and in silico evaluations. The in vitro metabolism of felodipine by cytochrome P450 3A4-expressed human liver microsomes (HLM) was optimized yielding a typical Michaelis–Menten plot through the application of Enzyme Kinetic Module software from where the enzyme kinetic parameters were determined. In vitro investigation of 8-arm-poly(ethylene glycol) against CYP3A4-catalyzed felodipine metabolism employing human liver microsomes compared closely with naringenin, a typical grapefruit flavonoid, yielding IC₅₀ values of 7.22 and 121.97 μM, respectively. The investigated potential of 8-arm-poly(ethylene glycol) in oral drug delivery yielded satisfactory in vitro drug release results. The in vivo studies of the effects of 8-arm-poly(ethylene glycol) on the oral bioavailability of felodipine as performed in the Large White pig model showed a >100% increase in plasma felodipine levels compared to controls, with no apparent effect on systemic felodipine clearance. The outcome of this research presents a novel CYP3A4 inhibitor, 8-arm-poly(ethylene glycol) for oral bioavailability enhancement.     

Liposomes as a Novel Ocular Delivery System for Brinzolamide: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Studies

The objective of this study was to investigate the potential of liposomes as an ophthalmic delivery system for brinzolamide (Brz) to enhance the local glaucomatous therapeutic effect. The liposomes of Brz (Brz-LPs) were produced by the thin-film dispersion method with a particle size of 84.33?±?2.02 nm and an entrapment efficiency of 98.32?±?1.61%. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) analysis proved that Brz was successfully entrapped into Brz-LPs. Brz-LPs displayed a biphasic release pattern in vitro with burst release initially and sustained release afterwards. The corneal permeability was measured using modified Franz-type diffusion cells, and Brz-LPs showed 6.2-fold increase in the apparent permeability coefficient when compared with the commercial available formulation (B rz-Sus). Moreover, Brz-LPs (1 mg/mL Brz) showed a more sustained and effective intraocular pressure reduction (5–10 mmHg) than Brz-Sus (10 mg/mL Brz) in white New Zealand rabbits. Therefore, Brz-LPs were a hopeful formulation of Brz for glaucoma treatment and worthy of further investigation.