Topical Delivery of Carvedilol Loaded Nano-Transfersomes for Skin Cancer Chemoprevention.

The ß-blocker carvedilol has been shown to prevent skin carcinogenesis in vitro and in vivo. Since systemic absorption of the ß-blocker may cause cardiovascular disturbance, we developed a carvedilol loaded transfersome for skin-targeted delivery. Transfersomes were prepared using phospholipids and surfactants at various ratios and characterized. One formulation (F18) selected for further analysis was composed of carvedilol, soy phosphatidylcholine, and Tween-80 at a ratio of 1:3:0.5, which had a particle size of 115.6 ± 8.7 nm, a zeta potential of 11.34 ± 0.67 mV, and an encapsulation efficiency of 93.7 ± 5.1%. F18 inhibited EGF-induced neoplastic transformation of mouse epidermal JB6 P+ cells at non-toxic concentrations, while only high concentrations induced cytotoxicity in JB6 P+ and human keratinocytes HaCaT. Compared to the free drug, F18 released through the dialysis membrane and permeated through the porcine ear skin at a slower rate, but similarly depositing the drug in the epidermis and dermis of the skin. Consistently, surface application of F18 on reconstructed full-thickness human skin showed slower drug permeation, while it suppressed ultraviolet-induced DNA damage, inflammatory gene expression, and apoptosis. These data indicate that transfersome is a promising topical delivery system of carvedilol for preventing ultraviolet-induced skin damage and carcinogenesis.

Comparative evaluation of proliposomes and self micro-emulsifying drug delivery system for improved oral bioavailability of nisoldipine.

The objective of this study was to develop proliposomal formulation and self micro-emulsifying drug delivery system (SMEDDS) for a poorly bioavailable drug, nisoldipine and to compare their in vivo pharmacokinetics. Proliposomes were prepared by thin film hydration method using different lipids such as Soy phosphatidylcholine (SPC), Hydrogenated Soy phosphatidylcholine (HSPC), Dimyristoylphosphatidylcholine (DMPC) and Dimyristoyl phosphatidylglycerol sodium (DMPG), Distearyl phosphatidylcholine (DSPC), and Cholesterol in various ratios. SMEDDS formulations were prepared using varying concentrations of Capmul MCM, Labrasol, Cremophor EL and Tween 80. Both proliposomes and SMEDDS were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug release was carried out in purified water using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague-Dawley rats. Among the different formulations, proliposomes with drug:DMPC:cholesterol in the ratio of 1:2:0.5 and SMEDDS with Capmul MCM (13.04% w/w), Labrasol (36.96% w/w), Cremophor EL (34.78% w/w) and Tween 80 (15.22% w/w) demonstrated the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes and SMEDDS compared to pure nisoldipine in purified water after 1h. Nisoldipine permeability across PAMPA and everted rat intestinal perfusion models was significantly higher with proliposomes and SMEDDS. Following single oral administration of proliposomes and SMEDDS, a relative bioavailability of 301.11% and 239.87% respectively, was achieved compared to pure nisoldipine suspension.

Improved delivery of poorly soluble compounds using nanoparticle technology: a review.

Although a large number of new drug molecules with varied therapeutic potentials have been discovered in the recent decade, yet most of them are still in developmental process. This can be attributed to the limited aqueous solubility which governs the bioavailability of such drug molecules. Hence, there is a requisite for a technology-based product (formulation) in order to overcome such issues without compromising on the therapeutic response. The purpose of this review is to provide an insight to the formulation of drug nanoparticles for enhancing solubility and dissolution velocity with concomitant enhancement in bioavailability. In the recent decade, nanonization has evolved from a concept to reality owing to its versatile applications, especially in the development of drugs having poor solubility. In this review, a relatively simple and scalable approach for the manufacture of drug nanoparticles and latest characterization techniques utilized to evaluate the drug nanoparticles are discussed. The drug nanoparticulate approach described herein provides a general applicability of the platform technology in designing a formulation for drugs associated with poor aqueous solubility.

Design, Characterization, and In Vivo Pharmacokinetics of Tacrolimus Proliposomes.

The objective of this study was to develop proliposomal formulation for a poorly bioavailable drug, tacrolimus. Proliposomes were prepared by thin film hydration method using different lipids such as hydrogenated soy phosphatidylcholine (HEPC), soy phosphatidylcholine (SPC), distearyl phosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), and dimyristoylphosphatidylglycerol sodium (DMPG) and cholesterol in various ratios. Proliposomes were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability, and in vivo pharmacokinetics. In vitro drug release was carried out in purified water using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague-Dawley (SD) rats. Among the different formulations, proliposomes with drug/DSPC/cholesterol in the ratio of 1:2:0.5 demonstrated the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes compared to pure tacrolimus in purified water after 1 h. Tacrolimus permeability across PAMPA and everted rat intestinal perfusion models was significantly higher with proliposomes. The optimized formulation of proliposomes indicated a significant improvement in the rate and absorption of tacrolimus. Following a single oral administration, a relative bioavailability of 193.33% was achieved compared to pure tacrolimus suspension.

Pharmacokinetic Evaluation of Improved Oral Bioavailability of Valsartan: Proliposomes Versus Self-Nanoemulsifying Drug Delivery System.

The objective of this study was to develop proliposomes and self-nanoemulsifying drug delivery system (SNEDDS) for a poorly bioavailable drug, valsartan, and to compare their in vivo pharmacokinetics. Proliposomes were prepared by thin-film hydration method using different lipids such as soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), distearyl phosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), and dimyristoyl phosphatidylglycerol sodium (DMPG) and cholesterol in various ratios. SNEDDS formulations were prepared using varying concentrations of capmul MCM, labrafil M 2125, and Tween 80. Both proliposomes and SNEDDS were evaluated for particle size, zeta potential, in vitro drug release, in vitro permeability, and in vivo pharmacokinetics. In vitro drug release was carried out in purified water and 0.1 N HCl using USP type II dissolution apparatus. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA) and everted rat intestinal permeation techniques. Among the formulations, the proliposomes with drug/DMPG/cholesterol in the ratio of 1:1:0.5 and SNEDDS with capmul MCM (16.0% w/w), labrafil M 2125 (64.0% w/w), and Tween 80 (18.0% w/w) showed the desired particle size and zeta potential. Enhanced drug release was observed with proliposomes and SNEDDS as compared to pure valsartan. Valsartan permeability across PAMPA and everted rat intestinal permeation models was significantly higher with proliposomes and SNEDDS. Following single oral administration of proliposomes and SNEDDS, a relative bioavailability of 202.36 and 196.87%, respectively, was achieved compared to pure valsartan suspension. The study results indicated that both proliposomes and SNEDDS formulations are comparable in improving the oral bioavailability of valsartan.

Insoluble drug delivery strategies: review of recent advances and business prospects.

The emerging trends in the combinatorial chemistry and drug design have led to the development of drug candidates with greater lipophilicity, high molecular weight and poor water solubility. Majority of the failures in new drug development have been attributed to poor water solubility of the drug. Issues associated with poor solubility can lead to low bioavailability resulting in suboptimal drug delivery. About 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble. With the advent of various insoluble drug delivery technologies, the challenge to formulate poorly water soluble drugs could be achieved. Numerous drugs associated with poor solubility and low bioavailabilities have been formulated into successful drug products. Several marketed drugs were reformulated to improve efficacy, safety and patient compliance. In order to gain marketing exclusivity and patent protection for such products, revitalization of poorly soluble drugs using insoluble drug delivery technologies have been successfully adopted by many pharmaceutical companies. This review covers the recent advances in the field of insoluble drug delivery and business prospects.

Improved oral bioavailability of valsartan using proliposomes: design, characterization and in vivo pharmacokinetics.

The objective of our investigational work was to develop a proliposomal formulation to improve the oral bioavailability of valsartan. Proliposomes were formulated by thin film hydration technique using different ratios of phospholipids:drug:cholesterol. The prepared proliposomes were evaluated for vesicle size, encapsulation efficiency, morphological properties, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug-release studies were performed in simulated gastric fluid (pH 1.2) and purified water using dialysis bag method. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA), Caco-2 monolayer and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague Dawley (SD) rats. Among the proliposomal formulations, F-V was found to have the highest encapsulation efficiency of 95.6 ± 2.9% with a vesicle size of 364.1 ± 14.9 nm. The in vitro dissolution studies indicated an improved drug release from proliposomal formulation, F-V in comparison to pure drug suspension in both, purified water and pH 1.2 dissolution media after 12 h. Permeability across PAMPA, Caco-2 cell and everted rat intestinal perfusion studies were higher with F-V formulation as compared to pure drug. Following single oral administration of F-V formulation, a relative bioavailability of 202.36% was achieved as compared to pure valsartan.

Proliposomes for oral delivery: progress and challenges.

Proliposomes are phospholipid based drug delivery systems that are finding important applications in the field of pharmaceutics. Proliposomes have been extensively studied as a potential carrier for oral delivery of drugs with poor bioavailability, but the mechanism of absorption and cellular uptake pathways has not yet been clearly understood. An in-depth insight into the physical and biological behavior of proliposomes is necessary for designing an effective delivery system for enhancing the availability of drug at the intended site. Reformulation of sub optimal drugs using proliposomes has given an opportunity to improve the therapeutic indices of various drugs predominantly by altering their uptake mechanism. This work reviews the proliposomal drug delivery field, summarizes the success of proliposomes for the oral delivery of drugs with poor bioavailability; indicating the key issues to be addressed to affirm that proliposomes can effectively work as a drug carrier in clinical settings with a clear understanding of its behavior in biological environment, as they are now an established platform technology with considerable clinical acceptance.

Media milling process optimization for manufacture of drug nanoparticles using design of experiments (DOE).

Design of experiments (DOE), a component of Quality by Design (QbD), is systematic and simultaneous evaluation of process variables to develop a product with predetermined quality attributes. This article presents a case study to understand the effects of process variables in a bead milling process used for manufacture of drug nanoparticles. Experiments were designed and results were computed according to a 3-factor, 3-level face-centered central composite design (CCD). The factors investigated were motor speed, pump speed and bead volume. Responses analyzed for evaluating these effects and interactions were milling time, particle size and process yield. Process validation batches were executed using the optimum process conditions obtained from software Design-Expert® to evaluate both the repeatability and reproducibility of bead milling technique. Milling time was optimized to <5 h to obtain the desired particle size (d90 < 400 nm). The desirability function used to optimize the response variables and observed responses were in agreement with experimental values. These results demonstrated the reliability of selected model for manufacture of drug nanoparticles with predictable quality attributes. The optimization of bead milling process variables by applying DOE resulted in considerable decrease in milling time to achieve the desired particle size. The study indicates the applicability of DOE approach to optimize critical process parameters in the manufacture of drug nanoparticles.

Drug product development and pharmacological evaluation of a sparingly soluble novel camptothecin analog for peroral administration.

This work focused on the developmental aspects, pharmacokinetic evaluation, and pharmacological assessment of a drug inclusion complex for a novel camptothecin analog (CA) and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD). Camptothecins analog belong to topoisomerase-I inhibitor class of compounds with proven anti-tumor activity but exhibit poor solubility. To enhance solubility a drug inclusion complex with cyclodextrin was developed using a spray-drying process. The powder complex characterized using DSC, XRPD, FT-IR, and ¹H NMR techniques confirmed interaction of cyclodextrin with the CA indicating formation of a true complex wherein the drug is encapsulated in the cyclodextrin cavity. The saturation solubility and dissolution kinetics of drug complex evaluated in a discriminating medium showed significantly higher solubility and faster dissolution as compared to a physical mixture or powder blend comprising of drug and cyclodextrin. Pharmacokinetic (PK) studies in Wistar rats indicated a significant increase in the rate and extent of absorption for the drug complex as compared to a nanoparticulate dispersion that was used as the positive control. Pharmacological activity following peroral administration of drug complex in athymic nude mice with implanted tumors revealed that the tumor inhibition activity was equivalent to commercially available intravenous (IV) formulation with comparable safety profile. These studies demonstrated for the first instance feasibility of developing a safe and efficacious peroral formulation for a sparingly soluble camptothecin analog that may provide another viable, patient compliant, and cost effective option for the treatment of solid tumors.

Development and pharmacological evaluation of a PEG based nanoparticulate camptothecin analog for oral administration.

The aim of this study was to formulate polyethylene glycol (PEG) based nanoparticulate camptothecin analog for oral administration and to evaluate its pharmacological activity. Camptothecin analog (CA) belongs to topoisomerase-I inhibitor class of compounds with proven antitumor activity but exhibits poor solubility. To enhance solubility and oral bioavailability, a PEG based nanoparticulate formulation was developed using a high pressure homogenization technique. The saturation solubility and dissolution characteristics of the nanoparticulate formulation were investigated and compared with as-is drug formulation to ascertain the impact of particle size on drug dissolution in physiologically relevant dissolution media. Systemic exposure of nanoparticulate formulation were evaluated in Wistar rats for increase in the rate and extent of drug absorption. The antitumor activity of nanoparticulate formulation was evaluated on human tumor xenografts (NCI-H460 cell lines) grown in athymic nude mice and compared with a positive control, Irinotecan Hydrochloride administered intravenously. The saturation solubility and dissolution rate of the nanoparticulate formulation were significantly higher as compared to as-is drug formulation. Pharmacokinetic (PK) studies in Wistar rats indicated significant increase in the rate and extent of absorption for the nanoparticulate formulation. Pharmacological activity of nanoparticles in athymic nude mice with implanted tumors revealed that the tumor inhibition activity was equivalent to Irinotecan Hydrochloride intravenous formulation with comparable safety profile at lower doses. These studies demonstrated the feasibility of developing a safe and efficacious oral formulation for a sparingly soluble camptothecin analog that may provide a viable, patient compliant and, cost effective option for the treatment of solid tumors.

Solid self-microemulsifying formulation for candesartan cilexetil.

Sparingly, water-soluble drugs such as candesartan cilexetil offer challenges in developing a drug product with adequate bioavailability. The objective of the present study was to develop and characterize self-microemulsifying drug delivery system (SMEDDS) of candesartan cilexetil for filling into hard gelatin capsules. Solubility of candesartan cilexetil was evaluated in various nonaqueous careers that included oils, surfactants, and cosurfactants. Pseudoternary phase diagrams were constructed to identify the self-microemulsification region. Four self-microemulsifying formulations were prepared using mixtures of oils, surfactants, and cosurfactants in various proportions. The self-microemulsification properties, droplet size, and zeta potential of these formulations were studied upon dilution with water. The optimized liquid SMEDDS formulation was converted into free flowing powder by adsorbing onto a solid carrier for encapsulation. The dissolution characteristics of solid intermediates of SMEDDS filled into hard gelatin capsules was investigated and compared with liquid formulation and commercial formulation to ascertain the impact on self-emulsifying properties following conversion. The results indicated that solid intermediates showed comparable rate and extent of drug dissolution in a discriminating dissolution medium as liquid SMEDDS indicating that the self-emulsifying properties of SMEDDS were unaffected following conversion. Also, the rate and extent of drug dissolution for solid intermediates was significantly higher than commercial tablet formulation. The results from this study demonstrate the potential use of SMEDDS as a means of improving solubility, dissolution, and concomitantly the bioavailability.

Spray-drying process optimization for manufacture of drug-cyclodextrin complex powder using design of experiments.

BACKGROUND: Design of experiments (DOE), a component of Quality by Design, is systematic and simultaneous evaluation of variables (process or formulation) to develop a product with predetermined quality attributes. This study presents a case study to understand the effects of process variables in a spray-drying process used in the manufacture of drug-cyclodextrin complex for a drug that is prone to chemical instability at elevated temperature conditions encountered during processing. METHODS: Experiments were designed, and data were collected according to a three-factor, three-level face-centered central composite design. The factors investigated were inlet temperature, spray rate, and batch size. Responses analyzed for computing the interaction effects were drug content, impurities, moisture content, and process yield. The spray-drying process conditions were optimized using DOE to maximize production yields while minimizing moisture content and drug-related impurities. Process validation batches were executed using the optimum process conditions obtained from software Design-Expert((R)) to evaluate both the repeatability and reproducibility of spray-drying technique. RESULTS: Optimization of process variables using DOE resulted in a significant improvement of process yields, above 90% and moisture content below 6% (w/w). The impurities were controlled within acceptable limits. The desirability function used to optimize the response variables and observed responses were in agreement with experimental values. These results demonstrated the reliability of selected model for manufacture of powder complex with predictable quality attributes. CONCLUSION: The study indicates the general applicability of DOE approach to optimize critical process parameters in the manufacture of drug product with desired quality attributes.

Development and characterization of solid oral dosage form incorporating candesartan nanoparticles.

Sparingly water-soluble drugs such as candesartan cilexetil offer challenges in developing a drug product with adequate bioavailability. The objective of the present study was to develop a tablet dosage form of candesartan cilexetil incorporating drug nanoparticles to increase its saturation solubility and dissolution rate for enhancing bioavailability while reducing variability in systemic exposure. The bioavailability of candesartan cilexetil is dissolution limited following oral administration. To enhance bioavailability and overcome variability in systemic exposure, a nanoparticle formulation of candesartan cilexetil was developed. Candesartan cilexetil nanoparticles were prepared using a wet bead milling technique. The milled nanosuspension was converted into solid intermediate using a spray drying process. The nanosuspensions were characterized for particle size before and after spray drying. The spray dried nanoparticles were blended with excipients for tableting. The saturation solubility and dissolution characteristics of the nanoparticle formulation were investigated and compared with commercial candesartan cilexetil formulation. The drug nanoparticles were evaluated for solid-state transitions before and after milling. This study demonstrated that tablet formulation incorporating drug nanoparticles showed significantly faster rate of drug dissolution in a discriminating dissolution medium as compared to commercially available tablet formulation. Systemic exposure studies in rats indicated a significant increase in the rate and extent of drug absorption.