Preparation and in vitro/in vivo evaluation of metformin hydrochloride rectal dosage forms for treatment of patients with type II diabetes

Background: Metformin hydrochloride (MtHCL) is an oral antidiabetic drug and has many other therapeutic benefits. It has poor bioavailability, narrow absorption window and extensive liver metabolism. Moreover, children and elders face difficulty to swallow the commercial oral tablets.

Objectives: Preparation, in vitro/in vivo evaluation of MtHCL suppositories for rectal administration to solve some of these problems.

Methods: Suppository fatty bases (Witepsol^®, Suppocire^® and Massa^®; different grades) and PEG bases 1000, 4000 and 6000 (different ratios), were used to prepare rectal suppository formulations each containing 500?mg drug. These were characterized for manufacturing defects, and pharmacotechnical performance and formulations showing superior results were subjected to bioavailability testing in human volunteers compared with the commercial oral tablet (Ref) applying LC–MS/MS developed analytical technique.

Results: The preparation method produced suppositories with satisfactory characteristics and free of manufacturing defects. The fatty bases were superior compared with PEG bases regarding the physical characteristics. Three formulations were chosen for bioavailability testing and the results showed comparable bioavailability compared to the Ref.

Conclusions: The fatty bases showed superior characteristics compared with the PEG bases. MtHCL formulated in selected fatty bases could be a potential alternative to the commercial oral tablets particularly for pediatric and geriatric patients.     

In situ lyophilisation of nifedipine directly in hard gelatine capsules

Hydrophobic drugs present a challenge due to: (i) adhesion and agglomeration; hence the choice of the suitable processing technique to have the drugs into orally administered dosage forms is critical. (ii) Poor dissolution and poor aqueous solubility; hence poor bioavailability. A novel method which is in situ lyophilisation directly in hard gelatin capsule shells was used in this research to enhance the dissolution of nifedipine (a model hydrophobic drug) in the presence of co-povidone, Pluronic^®F-127 and inulin as enhancement excipients (to the best of our knowledge those excipients have not been previously used with nifedipine in lyophilised forms).

Solutions of nifedipine and excipients in a range of concentrations (0.5, 1, 5 and 10%w/v) were prepared using a co-solvent system of tert- butyl alcohol/water mixture. These solutions were filled directly into bodies of size 000 hard gelatin capsule shells and freeze dried. Pure drug and all formulations were characterised by solubility, wetting studies and in vitro dissolution. Also, conformational integrity and thermal characteristics of nifedipine formulations were investigated using FT-IR spectroscopy and differential scanning calorimetry (DSC), respectively. The in situ lyophilisation of nifedipine with excipients, looks a promising method not only to improve the hydrophobic drug dissolution but also to be cost effective.     

The formulation of a nasal nanoemulsion zaleplon in situ gel for the treatment of insomnia

Background: Zaleplon is a drug used for the treatment of insomnia and is available in tablet form; however, it has two major problems. First, the drug undergoes extensive first pass metabolism, resulting in only 30% bioavailability, and second, the drug has a poor aqueous solubility, which delays the onset of action.

Objective: The objective of this study is to utilise nanotechnology to formulate zaleplon into a nasal in situ nanoemulsion gel (NEG) to provide a solution for the previously mentioned problems.

Methods: The solubility of zaleplon in various oils, surfactants and co-surfactants was estimated. Pseudo-ternary phase diagrams were developed and various nanoemulsion (NE) formulations were prepared; these formulations were subjected to visual characterisation, thermodynamic stability study and droplet size and conductivity measurements. Carbopol 934 was used as an in situ gelling agent. The gel strength, pH, gelation time, in vitro release and ex vivo nasal permeation were determined. The pharmacokinetic study of the NEG was carried out in rabbits.

Results: Stable NEs were successfully developed with a droplet size range of 35 to 73 nm. A NEG composed of 15% Miglyol, 30% Labrasol and 10% PEG 200 successfully provided the maximum in vitro and ex vivo permeation and enhanced the bioavailability in the rabbits by eightfold, when compared with the marketed tablets.

Conclusion: The nasal NEG is a promising novel formula for zaleplon that has higher nasal tissue permeability and enhanced systemic bioavailability.     

Preclinical efficacy and safety assessment of nano-oxaliplatin oral formulation prepared by novel Fat Employing Supercritical Nano System,the FESNS®

Background: It is expected that oral cancer drug will provide ease of administration with decreased unwanted events to the patients. The purpose of this study is to prepare oral formulation of nano-oxaliplatin and examine the anticancer efficacy and safety. Nano-oxaliplatin was prepared utilizing our proprietary technology, the Fat Employing Supercritical Nano System (FESNS^®).

Result: It showed regular nanoparticles with a mean diameter of around 212?nm. When nano-oxaliplatin was orally administered in rats, the relative bioavailability of nano-oxaliplatin oral formulations was about 25–31% compared to the Eloxatin^® administered intravenously (i.v.). For antitumor activity in xenograft model, nano-oxaliplatin oral formulation (20?mg/kg, once daily) presented superior inhibition of tumor growth against Eloxatin^® (5?mg/kg, i.v. once a week). In single-dose toxicity, dead animals were observed at or above 1000?mg/kg (LD₅₀: 888.38?mg/kg for male; 725.43?mg/kg for female rats). In repeated dose toxicity, there were hematological changes observed in rats, which is a common finding in the class of cancer drugs. It was thought that the expected dose level that has cytotoxic effect without death would be 30?mg/kg in rats, which is double the dose level of Eloxatin^®.

Conclusion: Nano-oxaliplatin oral formulation changed the pharmacokinetic behavior of crude oxaliplatin, thus increasing oral bioavailability as well as its anticancer activity. In addition, single and repeated dose toxicity studies indicated that oral nano-oxaliplatin is superior in toxicity at the pharmacologically active doses compared to Eloxatin^® in rats. Nano-oxaliplatin oral formulation has potential as a novel anticancer therapy.     

Chemoprevention of skin cancer using low HLB surfactant nanoemulsion of 5-fluorouracil: a preliminary study

Abstract

Oral delivery of 5-fluorouracil (5-FU) is difficult due to its serious adverse effects and extremely low bioavailability. Therefore, the aim of present investigation was to develop and evaluate low HLB surfactant nanoemulsion of 5-FU for topical chemoprevention of skin cancer. Low HLB surfactant nanoemulsions were prepared by oil phase titration method. Thermodynamically stable nanoemulsions were characterized in terms of droplet size distribution, zeta potential, viscosity and refractive index. Selected formulations and control were subjected to in vitro skin permeation studies through rat skin using Franz diffusion cells. Optimized formulation F9 was subjected to stability and in vitro cytotoxic studies on melanoma cell lines. Enhancement ratio was found to be 22.33 in formulation F9 compared with control and other formulations. The values of steady state flux and permeability coefficient for formulation F9 were found to be 206.40?±?14.56?µg?cm^?2?h^?1 and 2.064?×?10^?2?±?0.050?×?10^?2?cm?h^?1, respectively. Optimized formulation F9 was found to be physical stable. In vitro cytotoxicity studies on SK-MEL-5 cancer cells indicated that 5-FU in optimized nanoemulsion is much more efficacious than free 5-FU. From these results, it can be concluded that the developed nanoemulsion might be a promising vehicle for chemoprevention of skin cancer.     

Rapid pain relief using transdermal film forming polymeric solution of ketorolac

Context: Ketorolac is one of the most potent nonsteroidal anti-inflammatory drugs and is an attractive alternative to opioids for pain management.

Objective: Development and evaluation of transdermal ketorolac film forming polymeric solution.

Materials and methods: Eudragits^® RLPO, RSPO and E100 as well as polyvinyl pyrrolidone K30 dissolved in ethanol were used as film forming solutions. In vitro experiments were conducted to optimize formulation parameters. Different permeation enhancers were monitored for potentiality of enhancing drug permeation across excised pigskin.

Results: The use of 10% oleic acid, Lauroglycol^® 90 or Azone^® with 5% Eudragit^® RSPO, showed the highest enhancement effect on ketorolac skin permeation and showed faster analgesic effect compared to the ketorolac tablet. The formula comprising 5% Eudragit^® RSPO and 10% Lauroglycol^® 90 showed the greatest pharmacodynamic effect and thus was subjected to pharmacokinetic studies. The pharmacodynamic and pharmacokinetic results didn’t run paralleled to each other, as the ketorolac tablets showed higher plasma concentrations compared to the selected ketorolac transdermal formulation. This might be due to the induction of analgesia by the available ethanol in the transdermal preparation.

Conclusion: Optimized transdermal ketorolac formulation showed marked ability to ensure fast and augmented analgesic effect that is an essential request in pain management.     

Omega 3 fatty acid-enriched nanoemulsion of thiocolchicoside for transdermal delivery: formulation,characterization and absorption studies

Abstract

Thiocolchicoside (TCC) is an effective therapeutic agent against the orthopaedic, traumatic and rheumatologic disorders but it suffer from the drawback of poor bioavailability due to extensive first pass metabolism and low permeability via the oral route. The aim of the present study was to evaluate the potential of nanoemulsion (NE) for bioavailability enhancement of TCC through the transdermal route. The NEs were developed using Linseed: sefsol in 1:1 ratio as the oil phase, span 80, Transcutol P and distilled water as surfactant, co-surfactant and aqueous phase. Furthermore, selected formulations were subjected to physical stability and consequently evaluated for in vitro permeation using porcine skin. The optimized formulation had small average globule diameter of 117?nm with polydispersity index of 0.285. The globules were spherical in shape as observed by transmission electron microscopy. The in vitro skin permeation profile of optimized NE was compared with aqueous solution of TCC. Significant increase in permeability parameters were observed in NEs formulation (p?<?0.05) as compared to aqueous solution of TCC. The steady-state flux (J_ss) and permeability coefficient (K_p) for optimized NE formulation (C1) were found to be 30.63?±?4.18?µg/cm²/h and 15.21?×?10^?3?±?2.81cm²/h, respectively. The results of enhanced permeation through transdermal route suggest that water-in-oil NEs which are compatible with the lipophilic sebum environment of the hair follicle facilitate the transport of TCC, and such transport might be predominantly transfollicular in nature. Overall, these results suggested that water-in-oil NEs are good carriers for transdermal delivery of TCC.     

A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting risperidone

Introduction: This systematic review of therapeutic drug monitoring (TDM) identifies three long-acting injectable (LAI) risperidone formulations.

Areas covered: Limited data is available on two formulations (RBP-7000 and in Situ Microparticle), but 20 TDM articles on the microsphere formulation were found. Risperidone TDM includes the serum concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, used for calculating: 1) the risperidone/9-hydroxyrisperidone (R/9-OH-R) ratio (a measure of CYP2D6; values >1 are indicative of a CYP2D6 poor metabolizer) and 2) the total risperidone concentration-to-dose (C/D) ratio (a measure of risperidone clearance with a normal value around 7 in oral risperidone). The weighted mean R/9-OH-R ratio was 0.48 (approximately twice that of oral risperidone TDM) in a combined analysis from 329 patients in 6 risperidone LAI studies without major confounders. The total C/D ratios from 297 patients in 6 risperidone LAI studies ranged from 7.4 to 9.7 ng/ml/mg/day with a weighted mean of 8.8 ng/ml/mg/day.

Expert commentary: Clinicians using TDM for risperidone LAI microsphere formulation need to: 1) consider steady state to be reached ≥ 6 weeks after the first injection, 2) pay attention to a) co-medications with inducers/inhibitors, b) severe inflammations/infections, and c) hepatic/renal impairment, and 3) use Castberg’s recommendation to calculate risperidone dosing.     

Comparison of traditional and novel tableting excipients: Physical and compaction properties

Context: Novel tableting excipients are continuously developed and advertised with superior flow and compaction characteristics.

Objective: The objective of this study was to compare two traditionally used and two novel tableting excipients with regard to their physical and tableting properties as well as their magnesium stearate sensitivity. Avicel^® PH102 (microcrystalline cellulose) was compared to the novel co-processed excipient Prosolv^® SMCC90 (silicified microcrystalline cellulose), whereas Anhydrous Emcompress^® (anhydrous dicalcium phosphate) was compared to the novel spherically granulated excipient Fujicalin^® (anhydrous dicalcium phosphate).

Materials and methods: True density, particle size, specific surface area (SSA), flowability, tabletability, and magnesium stearate sensitivity of the excipients was determined.

Results and discussion: Due to the silification process (Prosolv^®) and the unique manufacturing process (Fujicalin^®), the novel excipients showed a comparably larger SSA. Hardest tablets by far could be obtained with Prosolv^®, followed by Avicel^® and Fujicalin^®. Avicel^® and Prosolv^® were sensitive to magnesium stearate, whereas Fujicalin^® and Emcompress^® did not show lubricant sensitivity. This confirms the plastic deformation behavior of microcrystalline cellulose and the brittle fracture of anhydrous dicalcium phosphate.

Conclusion: Compared to the traditional excipients the investigated novel tableting excipients were advantageous with regard to their SSA and their tableting properties.     

Ethosomes-based topical delivery system of antihistaminic drug for treatment of skin allergies

Abstract

Cetirizine is indicated for the treatment of allergic conditions such as insect bites and stings, atopic and contact dermatitis, eczema, urticaria. This investigation deals with development of a novel ethosome-based topical formulation of cetirizine dihydrochloride for effective delivery. The optimised formulation consisting of drug, phospholipon 90 G? and ethanol was characterised for drug content, entrapment efficiency, pH, vesicular size, spreadability and rheological behaviour. The ex vivo permeation studies through mice skin showed highest permeation flux (16.300?±?0.300?µg/h/cm²) and skin retention (20.686?±?0.517?µg/cm²) for cetirizine-loaded ethosomal vesicles as compared to conventional formulations. The in vivo pharmacodynamic evaluation of optimised formulation was assessed against oxazolone-induced atopic dermatitis (AD) in mice. The parameters evaluated were reduction in scratching score, erythema score, skin hyperplasia and dermal eosinophil count. Our results suggest that ethosomes are effective carriers for dermal delivery of antihistaminic drug, cetirizine, for the treatment of AD.     

Fabrication and evaluation of lipid nanoparticulates for ocular delivery of a COX-2 inhibitor

Context: The unique physiological limitations of the eye have been assigned as reason of low bioavailability by conventional drug delivery systems. There is need of such drug carriers, which ensure improved bioavailability as well as patient compliance upon instillation into the eye.

Objective: The present investigation deals with development of solid lipid nanoparticles (SLNs) containing celecoxib (CXB) for treatment of ophthalmic inflammations.

Materials and methods: The SLNs were formulated by melt-emulsion sonication and low temperature-solidification process and evaluated for particle size, surface morphology, physicochemical properties, percentage drug incorporation efficiency, in vitro drug release, in vitro trans-corneal permeation, in vivo efficacy in ocular inflammation, stability study and gamma scintigraphy study to assess the residence of solid lipid nanoparticles over ocular surfaces.

Results: The SLNs were spherical and the optimized formulation had particle size of 198.77?±?7.5?nm, which is quite suitable for ocular applications. The maximum entrapment efficiency of 92.46?±?0.07% was achieved for formulation SLN 20. The permeation across the cornea was also significantly better than aqueous suspension (8.21?±?0.67 versus 4.61?±?0.71) at p?<?0.05.

Discussion and conclusion: The SLN formulations demonstrated improved performance of entrapped CXB while mitigating the key parameters of ocular inflammation in rabbits. The particulate formulations have exhibited prolonged retention over ocular surfaces as evident from results of gamma scintigraphy using ^99mTc labeled SLNs.     

Selecting oral bioavailability enhancing formulations during drug discovery and development

Introduction: The role of chemical structure, lipophilicity, physico-chemical, absorption, distribution, metabolism, excretion, toxicity (ADMET) and biopharmaceutical properties of compounds including bioavailability are critical in drug discovery and drug dosage forms design.

Areas covered: The authors discuss a number of parameters including computational approaches used for selected chemical structures with biological activity for lead optimization and chemogenomics and preclinical studies for ADMET process development of ligand properties. The authors also look at a number of other parameters including: early drug product formulations with method selection based on the biopharmaceutical classification system (BCS); in vitro–in vivo correlation (IVIVC) and different formulation strategies to enhance solubility; dissolution rate and permeability; bioavailability evaluation and quality by design as an opportunity to develop ‘safe space' regions, where bioavailability is unaffected by pharmaceutical variations.

Expert opinion: The biopharmaceutical requirements for absorption are solubility and permeability. Both are influenced by lipophilicity, but in the opposite way. The genomic methodology, coupled with combinatorial chemistry, high-throughput screening, structure-based design and in silico ADMET would yield parameters as a starting point for the biopharmaceutical properties determination in further preclinical and clinical studies. Consecutive stages in drug discovery and development are irreplaceable, but pharmacokinetics is the critical step. Selection of drug formulations based on the BCS, IVIVC are the principal aspects to enhance the solubility and dissolution rate, while a rationale management of pharmaceutical and technological factors will enhance the bioavailability.     

Fabrication of Eudragit polymeric nanoparticles using ultrasonic nebulization method for enhanced oral absorption of megestrol acetate

Abstract

Megestrol acetate (MGA) is used as a progestagen to treat advanced cancers in the breast or uterus and anorexia-cachexia syndrome in cancer patients. Due to its low solubility (BCS class II), MGA bioavailability needs to be enhanced for efficacy and safety. We developed MGA-encapsulated Eudragit^® L100 (EUD) nanoparticles (MGA-EUD (1:1) and MGA-EUD (2:1)) using an ultrasonic nebulization method. MGA-EUD (1:1) and MGA-EUD (2:1) consisted of MGA and EUD at the mass ratios of 1:1 and 2:1. Their physicochemical properties, i.e. particle size, loading efficiency, morphology, and crystallinity were determined. Dissolution tests were performed using USP method II. For pharmacokinetics, they were orally administered at 50?mg/kg to mice. Microcrystalline MGA suspension (MGA-MC, Megace^®, BMS) was used as control. MGA-EUD (1:1) and MGA-EUD (2:1) had a smooth and spherical shape of 0.70 and 1.05?µm in diameter with loading efficiencies of 93 and 95% showing amorphous states of MGA. They significantly enhanced the dissolution potential of MGA. Oral bioavailability of MGA-EUD (1:1) and MGA-EUD (2:1) increased 2.0- and 1.7-fold compared to that of MGA-MC. It suggests that ultrasonic nebulization method for the fabrication of polymeric nanoparticles is a promising approach to improve the bioavailability of poorly soluble drugs.     

Optimized self-nanoemulsifying drug delivery system of atazanavir with enhanced oral bioavailability: in vitro/in vivo characterization

Background: Atazanavir (ATV) is a HIV protease inhibitor. Due to its intense lipophilicity, the oral delivery of ATV encounters several problems such as poor aqueous solubility, pH-dependent dissolution and rapid first-pass metabolism in liver by CYP3A5, which result in low and erratic bioavailability.

Objective: The current study aimed to develop self-nanoemulsifying drug delivery systems (SNEDDS) using long-chain triglycerides of ATV in an attempt to circumvent such obstacles.

Methods: Equilibrium solubility studies indicated the choice of Maisine 35-1 as lipid, and of Transcutol P and Span 20 as surfactants, for formulating the SNEDDS. Ternary phase diagrams were constructed to select the areas of nanoemulsions, and the amounts of lipid (X₁) and surfactant (X₂) as the critical factor variables. The SNEDDS were optimized (OPT) using 3² central composite design and the OPT formulation located using overlay plot. The pharmacokinetics and in situ single-pass intestinal perfusion studies of OPT formulation were investigated in Wistar rats.

Results: OPT formulation indicated marked improvement in drug release profile vis-à-vis pure drug. Cloud point determination and accelerated stability studies ascertained the stability of OPT formulation. Augmentation in the values of K_a (1.96-fold) and AUC (2.57-fold) indicated significant enhancement in the rate and extent of bioavailability by the OPT formulation compared to pure drug. Successful establishment of in vitro/in vivo correlation Level A substantiated the judicious choice of the in vitro dissolution milieu for simulating the in vivo conditions.

Conclusion: The studies, therefore, indicate the successful formulation development of SNEDDS with distinctly improved bioavailability of ATV.     

冷冻干燥法制备甲苯磺酸拉帕替尼固体分散体及其大鼠药动学评价

目的用冷冻干燥技术制备甲苯磺酸拉帕替尼固体分散体,以提高其生物利用度。方法以PVPS630和soluplus^■为载体,采用冷冻干燥法制备甲苯磺酸拉帕替尼固体分散体,通过SEM、DSC、XRPD等手段对固体分散体进行表征,通过表观溶解度、溶出度和大鼠体内药动学测定,评价固体分散体的增溶效果和生物利用度的改善情况。结果在相同药载比的条件下,PVPS630组的溶出度和表观溶解度均优于soluplus^■组。DSC、XRPD、SEM等表征结果显示,PVPS630为载体的固体分散体中,原料均以非晶态存在,而以soluplus^■为载体时,只有药载比为1∶3条件下,原料才呈现非晶态特征。大鼠药动学测定结果表明,固体分散体(甲苯磺酸拉帕替尼-PVPS630为1∶3)较上市药品AUC提高23.64%。结论载体PVPS630与甲苯磺酸拉帕替尼的相容性更理想;固体分散技术有助于本品提高生物利用度。     

Microemulsions for oral administration and their therapeutic applications

Introduction: The microemulsion concept was introduced in 1943 by Hoar and Schulman. Self-microemulsifying drug delivery systems (S(M)EDDS) are much more recent and can be described as isotropic solutions of oils and surfactants that form oil-in-water O/W microemulsions when they are poured into an aqueous medium. When they are presented as soft capsules for oral delivery, S(M)EDDS have the ability to considerably improve the intestinal absorption of agents that are incorporated into the S(M)EDDS. Forty percent of newly discovered drug candidates have little or no water solubility and therefore have low and/or variable bioavailability profiles. Many of these drugs are good candidates for formulation into S(M)EDDS.

Areas covered: This paper describes the preparation and assessment of these formulations and their current applications. The characterisation of this type of formulation has improved, and in vitro models (Caco-2 cell cultures, Ussing chambers, the everted sac technique, etc.) can be used for screening different formulations. It describes also marketed formulations (i.e., cyclosporin and saquinavir S(M)EDDS) and some other formulations.

Expert opinion: Actual applications of S(M)EDDS remain rare. The first drug marketed as a S(M)EDDS was cyclosporin, and it had significantly improved bioavailability compared with the conventional solution. In the last decade, several S(M)EDDS loaded with antiviral drugs (e.g., ritonavir, saquinavir) were tested for treatment of HIV infection, but the relative improvement in clinical benefit was not significant. The S(M)EDDS formulation of Norvir® (soft capsules) has been withdrawn in some countries.     

Statistical modeling,optimization and characterization of solid self-nanoemulsifying drug delivery system of lopinavir using design of experiment

Objective: Lopinavir (LPV), an antiretroviral protease inhibitor shows poor bioavailability because of poor aqueous solubility and extensive hepatic first-pass metabolism. The aim of the present work was to investigate the potential of the solid self-nanoemulsifying drug delivery system (S-SNEDDS) in improving dissolution rate and oral bioavailability of LPV.

Materials and methods: Liquid SNEDDS (L-SNEDDS) of LPV were prepared using Capmul MCM C8, Cremophor RH 40 and propylene glycol and their amounts were optimized by Scheffe’s mixture design. L-SNEDDS formulations were evaluated for different physicochemical and in vitro drug release parameters. S-SNEDDS were prepared by adsorbing L-SNEDDS on Neusilin US2 and characterized for solid-state properties. In vivo bioavailability of S-SNEDDS, marketed Lopinavir?+?Ritonavir (LPV/RTV) formulation and pure LPV was studied in Wistar rats. Stability study of S-SNEDDS was performed as per ICH guidelines.

Results and discussion: Optimized L-SNEDDS obtained by Scheffe design had drug loading 160?±?1.15?mg, globule size 32.9?±?1.45?nm and drug release?>95% within 15?min. Solid state studies suggested the transformation of the crystalline drug to amorphous drug. The size and zeta potential of globules obtained on dilution S-SNEDDS remained similar to L-SNEEDS. In vivo bioavailability study revealed that S-SNEDDS has 2.97 and 1.54-folds higher bioavailability than pure LPV and LPV/RTV formulation, respectively. The optimized S-SNEDDS was found to be stable and had a shelf life of 2.85 years.

Conclusion: The significant increase in drug dissolution and bioavailability by prepared SNEDDS suggest that the developed S-SNEDDS is a useful solid platform for improving oral bioavailability of poorly soluble LPV.     

Fabrication and evaluation of Eudragit® polymeric films for transdermal delivery of piroxicam

The aims of this work were to develop and characterize the prolonged release piroxicam transdermal patch as a prototype to substitute oral formulations, to reduce side effects and improve patient compliance. The patches were composed of film formers (Eudragit^®) as a matrix backbone, with PVC as a backing membrane and PEG200 used as a plasticizer. Results from X-ray diffraction patterns and Fourier transform-infrared spectroscopy indicated that loading piroxicam into films changed the drug crystallinity from needle to an amorphous or dissolved form. Piroxicam films were prepared using Eudragit^® RL100 and Eudragit^® RS100 as film formers at various ratios from 1:0 to 1:3. Films prepared solely by Eudragit^® RL100 showed the toughest and softest film, while other formulations containing Eudragit^® RS100 were hard and brittle. Drug release kinetic data from the films fitted with the Higuchi model, and the piroxicam release mechanism was diffusion controlled. Among all formulation tested, Eudragit^® RL100 films showed the highest drug release rate and the highest drug permeation flux across human epidermal membrane. Increasing drug loading led to an increase in drug release rate. Eudragit^® can be used as a film former for the fabrication of piroxicam films.     

Cow ghee fortified ocular topical microemulsion; in vitro,ex vivo,and in vivo evaluation

Abstract

Aim: Utility of cow ghee (CG) as permeation enhancer in development of topical ocular microemulsion (ME) for delivery of fluocinolone acetonide (FA) to posterior eye.

Methods: For ME preparation, oil, surfactant and cosurfactant were screened based on solubility of FA. Pseudoternary phase diagrams were constructed to determine their ratios. The developed MEs were characterised for their physicochemical properties like size, polydispersity index, zeta potential, and stability etc. They were evaluated for ex vivo permeation and irritation. In vivo pharmacokinetic studies were performed on Sprague dawley rats.

Results: Lauroglycol as oil, labrasol as surfactant and Transcutol as cosurfactant were selected. The optimised ratio of oil:surfactant:cosurfactant:water was 4:23:23:50. The developed FA loaded ME fortified with CG was characterised. Ex vivo study revealed higher permeation and non-irritancy. In vivo pharmacokinetic study showed retention of CG fortified ME in posterior rat eye.

Conclusion: Present investigation established CG as permeation enhancer for ocular topical formulation.     

Enhanced ocular bioavailability of fluconazole from niosomal gels and microemulsions: formulation,optimization, and in vitro–in vivo evaluation

Fungal keratitis may cause vision loss if it is not treated. Methods other than ocular delivery exhibited several limitations. No previous studies investigated and compared ocular bioavailability of fluconazole (FLZ) from niosomal gels and microemulsions. Niosomal gels of FLZ (0.3% w/w) based on Span^® 60 and cholesterol (CH) using 1% w/w carbopol^® 934 (CP) were evaluated. FLZ microemulsions (0.3% w/v) containing isopropyl myristate (IPM, as oil phase) and a 3:1 mixture of Tween^® 80 (as surfactant) and polyethylene glycol 400 (PEG 400, as cosurfactant) were characterized. Optimized formulations were compared for their ocular bioavailability in rabbit’s. Nanoscopic niosomes (63.67–117.13?nm) and microemulsions (57.05–59.93?nm) showed respective negative zeta potential ranges of ?45.37 to ?61.40 and ?20.50 to ?31.90?mV and sustained release up to 12?h. Entrapment efficiency (EE%) of niosomes ranged from 56.48% to 70.67%. Niosomal gels were more sustainable than niosomes and microemulsions. The most stable niosomal gel based on Span^® 60 and CH at a molar ratio of 5:5 and microemulsion containing 45% w/w IPM and 40% w/w of 3:1 Tween^® 80-PEG 400 mixture significantly (p?<?0.0001) enhanced FLZ ocular bioavailability compared with its solution. Niosomal gel showed higher bioavailability than microemulsion by ≈2-fold.