Drug Permeability Coefficient Research Articles

Formulation and Evaluation of Mixed Micelles Containing Quercetin for Inhibiting Intestinal Metabolism of Atorvastatin

Atorvastatin is a poorly bioavailable drug due to fast-pass metabolism. The objective of the study was to prepare quercetin-containing mixed micelles for inhibiting intestinal metabolism of Atorvastatin. Mixed micelles of atorvastatin were prepared using the film hydration method and optimized the formulations were based on different ratios of poloxamer 188 and SDC. The drug permeation and permeability coefficients of mixed micelles were calculated from ex vivo study using goat intestine. To the optimized formulation (F7), quercetin was added to improve the permeability of Atorvastatin. The vesicle size, % entrapment efficiency, and % in vitro drug release of optimized formulation (F7) were found 273.11 nm, 91.34 % and 72.14 %, respectively. The ex vivo results of Atorvastatin with quercetin (25 mg) showed two times more permeation (flux = 2.69 µg/cm2h) and Atorvastatin mixed micelles with quercetin (25 mg) showed three times (flux = 4.33 µg/cm2h ) compared to Atorvastatin without quercetin (flux = 1.34 µg/cm2h). The improvement of Atorvastatin permeation in the form of mixed micelles may be due to the blockage of the p glycoprotein efflux pump in the presence of quercetin. Histopathology study indicated that the formulation changed the microenvironment of tissue when using mixed micelles compared to no significant changes that occurred during control tissue. Based on the obtained results, we can conclude that the mixed micelles containing Atorvastatin enhanced the permeability effect in the presence of quercetin compared to the plain formulation without quercetin.

Utilization of Human iPS Cells for Evaluation of Drug Disposition and Mucosal Damages in the Small Intestine

The expression of multiple drug transporters and drug-metabolizing enzymes in the small intestine entails a detailed evaluation of the intestinal drug absorption in light of the contribution of these pharmacokinetic-related molecules. The intestinal mucosal damage and barrier disruption caused by diseases and xenobiotics influences health. Therefore, developing models to evaluate drug disposition and mucosal damage in humans is essential. We generated intestinal models from human induced pluripotent stem (iPS) cells and evaluated the availability of the models. The human iPS cell-derived intestinal epithelial cells demonstrated enhanced cellular uptake and multiple efflux transporters. The CYP3A4/5 activity of the human iPS cell-derived intestinal epithelial cells was comparable to that of the human primary enterocytes. Moreover, the correlation between the fraction absorbed (Fa) and apparent permeability coefficient (Papp) of drugs in human iPS cell-derived intestinal epithelial cells was better than in Caco-2 cells, except for the CYP3A4 substrates. Furthermore, we established a method for the differentiation of intestinal organoids from human iPS cells. The budding-like intestinal organoids consisted of various intestinal cells. The organoids demonstrated intestinal mucosal damage caused by tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β), the main factors of inflammatory bowel diseases. Furthermore, when the organoids were dissociated and seeded on cell culture inserts, transepithelial electrical resistant values-an index of barrier function-increased gradually. These results demonstrate that human iPS cell-derived intestinal epithelial cells and intestinal organoids could be applied to evaluate intestinal drug disposition and mucosal damage.

Construction of a novel blood brain barrier-glioma microfluidic chip model: Applications in the evaluation of permeability and anti-glioma activity of traditional Chinese medicine components

Since most anti-glioma drug candidates hardly permeate through the blood-brain barrier (BBB), preclinical models that can integrate the complexity of the tumor microenvironment and the structure and function of the BBB is urgently needed for the treatment of glioma. Herein, we constructed an in vitro BBB-glioma microfluidic chip model lined by primary human brain microvascular endothelial cells, pericytes, astrocytes and glioma cells, which could recapitulate the high level of barrier function of the in vivo human BBB and glioma microenvironment. The BBB unit in BBB-glioma microfluidic chip (BBB–U251 chip) displayed selective permeability to fluorescein isothiocyanate isomer-dextran (FITC-dextran) with different molecular weights and three model drugs with different permeability behavior across BBB, which indicated that this glioma model included a functional barrier. Six potential anti-glioma components in traditional Chinese medicine (TCM) were delivered into the blood channel and the permeated amount was quantified by high-performance liquid chromatography combined with ultraviolet (HPLC-UV). The permeated drugs then directly acted on 3D cultured glioma cells (U251) to evaluate the drug efficacy. The results of permeability coefficients of drugs showed that the data were closer to the in vivo data of traditional Transwell model. The effect of the drugs on U251 cells in the BBB-U251 chip was significantly lower due to the existence of BBB. Drug responses on glioma demonstrated the necessity to take BBB into account during the development of anti-glioma new drugs. Therefore, this 3D glioma microfluidic models integrating the BBB functionality can be a useful platform for screening the anticancer drug for brain tumors.

Papain-cyclodextrin complexes as an intestinal permeation enhancer: Permeability and in vitro safety evaluation

Oral drug delivery is the main route for drugs administration. However, some drugs have poor permeability across the intestinal barrier. Papain has been widely used in pharmaceutical applications due to its debridement properties and the ability to promote skin permeation of drugs. It is known that papain complexation with cyclodextrins improves its biological stability. In this paper, the ability of the native papain-cyclodextrin complexes is shown be an oral permeation enhancer to furosemide, using a Caco-2 monolayer system to evaluate drug permeability and apparent permeability coefficient. Analysis of the in vitro cytotoxicity over CHO–K1, Hep G2 and Caco-2 cell lines and genotoxicity over CHO–K1 and Hep G2 cell lines were also performed. Papain-cyclodextrins complexes did not show any cytotoxicity above 31 μg/mL. No significant genotoxic damage was observed. Papain and cyclodextrin complexes induced almost 2.5-fold increase in furosemide permeation compared to controls, and maintenance of the paracellular integrity of the Caco-2 cells monolayer was confirmed. The papain complexes may be safely applied in pharmaceutical formulations, not only as a therapeutic agent but also as a strategic pharmaceutical adjuvant, promoting permeation of low oral permeability drugs.

Formulation and Evaluation of Benazepril Hydrochloride Transdermal Films for Controlled Drug Release

The current research deals with formulation and evaluation of Benazepril hydrochloride transdermal films, by varying ratios of polymers Eudragit RL100, Eudragit RS100 by film casting technique. Preformulation studies were conducted to check the solubility, melting point and partition coefficient. The eleven formulations were analyzed for physicochemical parameters and drug dissolution potential of transdermal films. All the formulations are transparent with minimum weight variation and uniform thickness. The drug content uniformity of all the formulations vary between 96.84 ± 3.7% to 96.98 ± 1.6% indicate uniform drug distribution. The low water vapour transmission values indicate good water vapour permeation. The folding endurance is between 246 ± 4.60 to 315 ± 4.13 indicates that the transdermal films can withstand rupture. In vitro drug dissolution study indicates maximum amount of drug 96.8% (F2) released in 24 h when compared with marketed formulation 84.81%. The release order follows Fickian diffusion. The formulation F2 was optimized based on drug flux, permeability coefficient and enhancement ratio.

Resveratrol-loaded nanoemulsion gel system to ameliorate UV-induced oxidative skin damage: from in vitro to in vivo investigation of antioxidant activity enhancement.

In the present study resveratrol nanoemulsion gel was developed and optimized with the aim of enhancing the permeability and antioxidant activity against ultraviolet (UV)-induced oxidative skin damage. Droplet size, polydispersity index, drug permeation flux, permeability coefficient and drug deposition in skin of resveratrol-loaded nanoemulsion were found to be 65.00 ± 5.00nm, 0.171 ± 0.082, 144.50μg/cm2/h, 2.90 × 10-2cm/h and 45.65 ± 4.76%, respectively, whereas drug permeation flux, permeability coefficient and drug deposition in skin from nanoemulsion gel were found to be 107.70μg/cm2/h, 2.06 × 10-2cm/h and 62.65 ± 4.98%, respectively. Confocal studies depicted deeper penetration of resveratrol from nanoemulsion gel. Differential scanning calorimetry and Fourier-transform infrared spectrophotometer studies confirmed that nanoemulsion gel enhanced fluidization of stratum corneum lipids and conformational disruption of lipid bilayer, thereby enhancing skin permeation of resveratrol. Histopathology study of skin revealed that resveratrol-loaded nanoemulsion gel inhibited UV-induced spongosis, edema and epidermal hyperplasia response. Levels of glutathione, superoxide dismutase, catalase and protein carbonyl in the skin of UV-irradiated rats were significantly (p < 0.01) improved in the skin of animals treated with nanoemulsion gel. Experimental results suggested that nanoemulsion gel could be explored as a promising carrier for topical delivery of resveratrol for prevention of UV-induced oxidative skin damage owing to its enhanced permeability and retention effect.

Smart Bandage Based on Molecularly Imprinted Polymers (MIPs) for Diclofenac Controlled Release.

The aim of the present study was the development of a “smart bandage” for the topical administration of diclofenac, in the treatment of localized painful and inflammatory conditions, incorporating Molecularly Imprinted Polymers (MIPs) for the controlled release of this anti-inflammatory drug. For this purpose, MIP spherical particles were synthesized by precipitation polymerization, loaded with the therapeutic agent and incorporated into the bandage surface. Batch adsorption binding studies were performed to investigate the adsorption isotherms and kinetics and the selective recognition abilities of the synthesized MIP. In vitro diffusion studies were also carried out using Franz cells and the obtained results were reported as percentage of the diffused dose, cumulative amount of diffused drug, steady-state drug flux and permeability coefficient. Moreover, the biocompatibility of the developed device was evaluated using the EPISKIN™ model. The Scatchard analysis indicated that the prepared MIP is characterized by the presence of specific binding sites for diclofenac, which are not present in the corresponding non-imprinted polymer, and the obtained results confirmed both the ability of the prepared bandage to prolong the drug release and the absence of skin irritation reactions. Therefore, these results support the potential application of the developed “smart bandage” as topical device for diclofenac sustained release.

Influence of different formulation variables on the performance of transdermal drug delivery system containing tizanidine hydrochloride: in vitro and ex vivo evaluations

The present study was aimed at preparation of transdermal patches of tizanidine HCl, evaluation of the effect of polymers on in vitro release pattern of the drug, and the effect of permeation enhancers on the penetration of the drug through the rabbit skin. Various proportions of hydrophilic (HPMC) and hydrophobic (Eudragit L-100) polymers were used with PEG 400 as film-forming agent, and Span 20 or DMSO as permeation enhancer. The formulations were assessed for physicochemical characteristics and in vitro drug release studies using USP paddle over disc method in phosphate buffered saline (pH 7.4) at 32.0±1°C. On the basis of in vitro studies and physicochemical evaluations, S03-A and S04-A were selected at Eudragit : HPMC ratios of 8 : 2 and 7 : 3, respectively, for further ex vivo analysis. The effects of different concentrations of Span 20 and DMSO were evaluated on excised rabbit skin using Franz diffusion cell. Cumulative drug permeation, flux, permeability coefficient, target flux, and enhancement ratio were calculated and compared with the control formulations. Kinetic models and Tukey’s multiple comparison test were applied to evaluate the drug release patterns. Formulation SB03- PE containing Eudragit L-100:HPMC (7:3) with Span 20 (15% w/w) produced the highest enhancement in drug permeation, and followed zero order kinetic model with super case-II drug release mechanism.

Optimization of nutraceutical coenzyme Q10 nanoemulsion with improved skin permeability and anti-wrinkle efficiency

Coenzyme Q10 (CoQ10) is an insoluble, poorly permeable antioxidant with great biological value which acts as anti-aging and anti-wrinkle agent. To improve its permeability through topical application, the current study aimed at formulating oil/water (o/w) nanoemulsion (NE) as an efficient vehicle for delivering (CoQ10) through the skin barriers. The solubility of (CoQ10) was tested for various oils, surfactants (S), and co-surfactants (CoS). The NE region was determined by constructing pseudoternary phase diagrams. NE formulae containing 1, 2, and 3% w/w drug have been subjected to thermodynamic stability test. The formulae that passed thermodynamic stability tests were characterized by physical properties as pH, viscosity, refractive index, droplet size, zeta-potential, TEM, electroconductivity, in vitro release, and ex vivo permeation. The formula ‘F2’ containing 10% w/w isopropyl myristate (oil phase), 60% w/w of Tween 80: Transcutol HP mixture (S/CoSmix) at ratio 2:1, 30% w/w water and 2% w/w drug was evaluated for its anti-wrinkle efficiency using an animal model. The ‘F2’ formula showed 11.76 ± 1.1 nm droplet size, 1.4260 ± 0.0016 refractive index, 0.228 PDI, −14.7 ± 1.23 mv zeta potential, 7.06 ± 0.051 pH, 199.05 ± 0.35 cp viscosity, and the highest percentage of drug release in the selected dissolution media. About 47.21% of the drug was released in phosphate buffer 7.4 containing 5% w/v Labrasol and 5% w/v isopropyl alcohol through 24 h. It also showed the highest drug flux (Jss = 3.164 µg/cm2/h), enhancement ratio (Er = 8.32), and permeability coefficient (Kp = 22.14 × 10−4 cm2/h). CoQ10 NE reduced the skin wrinkles and gave the skin smooth appearance. Our investigation suggests the potential use of NE as a vehicle for enhancing solubility and permeability of CoQ10 and thus improving its anti-wrinkle efficiency.

NANOEMULSION GEL OF NUTRACEUTICAL CO-ENZYME Q10 AS AN ALTERNATIVE TO CONVENTIONAL TOPICAL DELIVERY SYSTEM TO ENHANCE SKIN PERMEABILITY AND ANTI-WRINKLE EFFICIENCY

Objective: The object of our investigation was to develop and characterize nanoemulsion gel (NEG) as transdermal delivery systems for the poorly water soluble drug, Co-enzyme Q10 (CoQ10), to improve its solubility and skin permeability and thus improving its anti-wrinkle efficiency.Methods: An optimized nanoemulsion (NE) formula was chosen according to its particle size and stability and converted into nanoemulsion gel using different gelling agents, including; carbopol 934 (1%), xanthan gum (2%) and sodium carboxymethyl cellulose(NaCMC) (2%). Drug loaded nanoemulsion gels were characterized for particle size, zeta potential, viscosity and rheological behavior, conductivity, spreadability, drug content and permeation studies using Franz diffusion cell.Results: NEG containing 10% w/v isopropyl myristate (IPM) as oil, 60% w/v tween 80 and transcutol HP as surfactant/co-surfactant mixture (S/CoS), 30%w/v water, 2%w/v drug, and 1% w/v carbopol 934 as gelling gent was concluded as an optimized NEG formula. It exhibited pH, viscosity, drug content, particle size, zeta potential, polydispersity index(PDI) and spreadability, as 5.4±0.011, 27588±2034.34 cps,101.51±0.93%,120.5±1.19 nm,-29.8±1.46, 0.273 and 6.16±0.28 cm, respectively. Also, it showed significantly higher cumulative amount of drug permeated through dialysis membrane (281.71±0.97μg/cm2) and through rat skin (20.73±2.5 μg/cm2) than the other formulae and marketed formulation (P&lt;0.001). In addition, its permeability parameters like drug flux (Jss), enhancement ratio (Er) and permeability coefficient (Kp) exhibited the highest values; 12.79µg/cm2/h, 95.92×10-4 cm2/h and 57.35, respectively for in vitro permeation study and 0.968µg/cm2/h, 7.26×10-4 cm2/h and 1.183, respectively for ex-vivo permeation study.Further histopathological evaluation test showed that CoQ10 NEG has a good anti-wrinkle efficacy compared to the conventional topical dosage form.Conclusion: These results judged NEG to be a promising alternative carrier for topical delivery of CoQ10 to enhance its solubility, skin permeability and thus anti-wrinkle efficiency.

Combining amino amide salts in mucoadhesive films enhances needle-free buccal anesthesia in adults

Needle-phobia is usually a great concern in dentistry, and the replacement of painful injections by patient-friendly needle-free topical formulations would bring several advantages in dental practice worldwide. In this pursuit, the effects of combining prilocaine hydrochloride (PCL) and lidocaine hydrochloride (LCL) in different proportions in mucoadhesive films on their in vitro permeation and retention through porcine esophageal mucosa was studied. Complementarily, the permeation and retention of isolated LCL was investigated. The in vitro model used for evaluating buccal anesthetic penetration and retention in buccal epithelium was validated. In addition, the feasibility of a novel in vivo model to evaluate the painful sensation due to puncture “needle-shaped” gum jaw of adults at shallow and deep levels was demonstrated. The in vivo clinical survey revealed the efficiency of the films, which had onset of anesthesia at 5min, peak of anesthetic effect within 15 and 25min and anesthesia duration of 50min after being placed in maxillary sites. The in vitro drug flux, permeability coefficient and retention in the epithelium significantly correlated with in vivo onset, peak and extent of shallow and deep anesthetic effect. At shallow level, the permeation of LCL has shown to be closely related to the onset of anesthesia, while the penetration of PCL has a significant impact in the peak of anesthetic effect. Concerning the deep level, the penetration of PCL is required to attain the onset of anesthetic effect. The total amount of drug retained in the epithelium showed to modulate the extent of both shallow and deep anesthesia. Thus, the combination of LCL and PCL in mucoadhesive films may offer dentists and their patients a safe improvement for pain management during dental procedures.

Effect of ablative laser on in vitro transungual delivery

Topical therapy of nail psoriasis using methotrexate has not been realized due to the high molecular weight and low permeability of the compound. In this study, we used a 2940nm fractional ablative laser to disrupt the nail barrier to enhance the in vitro transungual delivery of methotrexate. Bovine hoof membrane―an in vitro model of the human nail―was treated by the laser at different energy levels and pore densities. A successful microporation was characterized by mechanical properties, scanning electron microscopy, Fourier transform infrared spectrophotometer, dye binding, histology, pore uniformity, confocal laser microscopy, nail integrity measurement, and permeation studies. No significant difference in the pore dimension was found in different treatment groups (p>0.05). Increases in pore depth corresponded with increases in the laser energy. Laser ablation was found to affect the mechanical properties of the hoof membrane. In in vitro permeation studies, laser ablation resulted in a significant increase in the drug cumulative delivery, flux, and permeability coefficient as compared to the untreated group (n=3, p<0.05). A change in the laser energy and pore density was found to alter the drug permeability. Thus, transungual methotrexate delivery was enhanced by the fractional laser ablation.

Novel inulin-based mucoadhesive micelles loaded with corticosteroids as potential transcorneal permeation enhancers

In this work a new copolymer of inulin (INU) derivatized with ethylendiamine (EDA) and retinoic acid (RA), named INU-EDA-RA, was synthetized, characterized and employed to produce micelles as carriers for topical administration of corticosteroids for the potential treatment of diseases of posterior eye segment. Spectroscopic analysis confirmed a molar derivatization degree of 11.30 and 4.30% in EDA and RA, respectively. INU-EDA-RA micelles are capable of strong mucoadhesive interactions which result time-independent and stable over time but concentration depending. Moreover micelles are able to encapsulate efficiently from 3 to 13% (w/w) of lipophilic drugs, as dexamethasone, triamcinolone and triamcinolone acetonide. Drug loaded micelles are stable for three months when stored as freeze-dried powders and able to release high amount of drug when compared to drug dissolution profiles from suspensions. Moreover, drug loaded micelles are compatible with different ocular cell lines that are also able to internalize fluorescent micelles. Finally, drug loaded micelles enhance drug fluxes and permeability coefficients across corneal epithelial cells, thus reducing drug loss due to retention inside the cells.

Modification of gellan gum films by halloysite: physicochemical evaluation and drug permeation properties

The aim of this study was to determine the potential of gellan gum (GG) and halloysite (HS) dispersions at different mixing ratios and to investigate the potential of GG-HS dispersions in film formation. To this end, the dispersions and films were characterized. The dispersions formed films with large particles ranging from 3 to 4 μm in size, with a zeta potential of ∼−35 mV. The GG-HS films were fabricated using a solvent-casting technique, which generated films with a white opaque appearance and rough surface. The GG-HS films were formed via hydrogen bonding and electrostatic interactions at the inner cavity and outer surface, as confirmed by ATR-FTIR spectroscopy and X-ray diffractometry. The %water uptake and erosion of the GG-HS film decreased with increasing HS content, whereas both puncture strength and elongation were increased in the GG-HS ratios of 1:0.4 and 1:1.2. Moreover, addition of HS into the GG films could possibly decrease drug permeability coefficient when using higher HS ratio in acidic and neutral media. These results suggested that HS modifies the characteristics of the GG used to coat modified-release tablets.

Membrane Rigidity Determined by Atomic Force Microscopy Is a Parameter of the Permeability of Liposomal Membranes to the Hydrophilic Compound Calcein.

We determined the permeability coefficient of a model hydrophilic drug, calcein, encapsulated within saturated lipid-based nano-sized liposomes of various lipid profiles. We demonstrated that the addition of cholesterol to liposomes containing saturated lipids increased the permeability of the liposomal membrane to calcein via a decrease in the membrane bending modulus, as determined by means of atomic force microscopy. We found an inverse correlation between the membrane bending modulus of saturated lipid-based nano-sized liposomes and the permeability coefficient of encapsulated calcein, demonstrating that bending modulus, as determined by means of atomic force microscopy, is a quantitative parameter describing the permeability of liposomal membranes to calcein.

Evaluation of the artificial membrane permeability of drugs by digital simulation

A digital simulation method has been developed for evaluating the membrane permeability of drugs in the parallel artificial membrane permeation assay (PAMPA). The simulation results have shown that the permeability coefficient (log Ppampa) of drugs is linearly increased with increasing their distribution coefficient (log KD,M) to the lipid membrane, i.e., the hydrophobicity of the drug molecules. However, log Ppampa shows signs of leveling off for highly hydrophobic drugs. Such a dependence of log Ppampa is in harmony with the reported experimental data, and has been well explained in terms of the change in the rate-determining step from the diffusion in the membrane to that in the unstirred water layer (UWL) on both sides of the membrane. Additionally, the effects of several factors, including lag time, diffusion coefficient, pH, and pKa, on the permeability coefficient have been well simulated. It has thus been suggested that the proposed method should be promising for in silico evaluation of the membrane permeability of drugs.

Mathematical modeling for local trans-round window membrane drug transport in the inner ear

The structure and composition of the round window membrane (RWM) make it a particularly effective pathway for drug delivery to the inner ear. Therefore, predicting the efficiency of RWM transport would provide useful information for enhancing local application. In the present study, a mathematical model was established to achieve this goal. A series of drugs with different physicochemical properties were introduced in the inner ear cavity of guinea pigs via RWM by intratympanic application. The perilymphatic drug concentration (C) data were used to calculate the permeability coefficient (Kp) of different drugs diffusing through the RWM. The experimental data were fitted using the Matlab software to set up the numerical model based on Fick’s diffusion law and the single-compartment model following extravascular administration, which facilitated the prediction of the permeation profiles of different drugs while trans-RWM. In summary, this mathematical model is a contribution toward developing potentially useful RWM administration simulating tools.

Toxicity Study of a Self-nanoemulsifying Drug Delivery System Containing N-methyl pyrrolidone.

Recently within the lipid based formulation category, Self-nanoemulsifying drug delivery system (SNEDDS) has received considerable attention in the enhancement of bioavailability of poorly water-soluble drugs. Self-emulsifying formulation should have good solvent properties to allow appropriate solubility of the drug in the formulation. Drug incorporated in the formulation should also be readily dissolved as clear and monophasic liquid at ambient temperature when introduced to aqueous phase. N-methyl pyrrolidone (NMP) is one of the main pharmaceutical cosolvents and is a solubilizing excipient used in parenteral and oral medications. Marketed Leuprolide acetate (Sanofi-aventis, Quebec, Canada) is formulated as a solution composed of 55-66% NMP and 34-45% poly(DL-lactide-co-glycolide). Self-emulsifying oral formulation of fenofibrate containing NMP as solubilizer has been patented. Based on these reports we successfully developed SNEDDS formulation using NMP as cosolvent and found ~ 4 fold improvement in apparent permeability coefficient of model drug. To ensure the safety of the developed SNEDDS formulation, in the present study we further investigated its toxicity studies in mice and evaluated for various parameter. From the results it can be concluded that oral administration of SNEDDS formulation containing NMP did not exhibit significant toxicity in mice and further detail toxicity study is required so as to ensure the safety of this system in oral drug delivery.

Dynamic, nonsink method for the simultaneous determination of drug permeability and binding coefficients in liposomes.

Drug release from liposomal formulations is governed by a complex interplay of kinetic (i.e., drug permeability) and thermodynamic factors (i.e., drug partitioning to the bilayer surface). Release studies under sink conditions that attempt to mimic physiological conditions are insufficient to decipher these separate contributions. The present study explores release studies performed under nonsink conditions coupled with appropriate mathematical models to describe both the release kinetics and the conditions in which equilibrium is established. Liposomal release profiles for a model anticancer agent, topotecan, under nonsink conditions provided values for both the first-order rate constant for drug release and the bilayer/water partition coefficient. These findings were validated by conducting release studies under sink conditions via dynamic dialysis at the same temperature and buffer pH. A nearly identical rate constant for drug release could be obtained from dynamic dialysis data when appropriate volume corrections were applied and a mechanism-based mathematical model was employed to account for lipid bilayer binding and dialysis membrane transport. The usefulness of the nonsink method combined with mathematical modeling was further explored by demonstrating the effects of topotecan dimerization and bilayer surface charge potential on the bilayer/water partition coefficient at varying suspension concentrations of lipid and drug.

FABRICATION, DEVELOPMENT AND CHARACTERIZATION OF CARVEDILOL TRANSDERMAL PATCHES: AN EMPIRICAL STUDY

Carvedilol is a nonselective beta-adrenergic blocking agent and is employed for the treatment of hypertension. Carvedilol is subjected to considerable first-pass metabolism when it is administered orally. Transdermal preparation of carvedilol was prepared to achieve a sustained effect and to reduce the dose size &amp; dosing frequency as compared to multiple oral dosing and also developed to minimize first pass metabolism. Various polymers such as Ethyl cellulose, PVP K-30, HPMC K15M and Carbopol 934 were selected on the basis of their adhering property and nature of non toxicity, to develop transdermal film of carvedilol. The patches fabricated by EC and Carbopol (F-5 and F-6) were showed very good folding endurance compared to patches containing PVP K-30 and HPMC K15M. Based on physicochemical and in-vitro permeation studies, F-3 and F-5 were chosen as the best formulations. Among these two patches, F-5 film was found to have maximum in vitro permeation, maximum steady state flux and maximum permeability coefficient of drug. Key words: Transdermal patch, Carvedilol, ethylcellulose, PVP K-30, HPMC K15M and Carbopol 934