Skin delivery of resveratrol encapsulated lipidic formulation for melanoma chemoprevention.

Objective: An unmet need for patient friendly products can be achieved with novel, biocompatible lipidic formulations which encapsulate and prolong release of medicaments. The aim of this study was to develop a commercially scalable resveratrol-loaded solid-lipid microparticulate (SLM) topical gel for melanoma chemoprevention. Methods: Preformulation studies were conducted and drug-excipient interactions examined using infra-red spectroscopy and differential scanning calorimetry (DSC). Resveratrol-loaded SLM topical gel was prepared and evaluated by in vitro and in vivo parameters. Results: Spherical microparticles of 2.98 µm average size were obtained and DSC thermograms provide evidence of trans-resveratrol encapsulation. In vitro and ex vivo drug diffusion studies revealed sustained release profiles. Optimised SLM gel provides optimum antioxidant, tyrosinase inhibition, cytotoxicity in B16F10 melanoma cell line and apoptosis efficacy. In vivo studies on C57BL mice exhibit significant tumour reduction. Conclusion: Promising role of trans-resveratrol-loaded SLM topical gel in melanoma chemoprevention is proven.

In Situ Salification in Polar Solvents: a Paradigm for Enabling Drug Delivery of Weakly Ionic Drugs as Amorphous Solid Dispersion.

Solubility challenge for a poorly water-soluble drug gets further intensified when it is weakly ionic because the most common solubility enhancement technique, salt formation, becomes less feasible. Salt screening for such drugs often concludes with either a difficult to crystalize salt or an unstable salt, leading the scientists to explore other solubility enhancement technique like amorphous solid dispersions which is comparatively costlier, time-consuming and may require use of hazardous organic solvents. Present study evaluated in situ salification in polar protic solvents for dissolving poorly water-soluble drug Itraconazole which is weakly ionic and not very amenable to formation of stable inorganic salts. Through systematic selection of solvents, counterions and polymers, an amorphous solid dispersion of drug salt was obtained. In vitro characterizations with polarized light microscopy (PLM), modulated differential scanning calorimetry (mDSC), Fourier transform infrared spectroscopy (FTIR) and X-ray powder diffraction (XRD) confirmed the physical and chemical stability of the amorphous solid dispersion. In vivo pharmacokinetic study showed that the drug salt amorphous solid dispersion achieved 45 times higher plasma exposure compared to crystalline drug. This study provides one of the first data sets for the hypothesis that in situ drug salts can be utilized for manufacturing amorphous solid dispersions of weakly ionic drugs and leverages the solubility advantage of salts and amorphous state.

Lidocaine Transdermal Patch: Pharmacokinetic Modeling and In Vitro-In Vivo Correlation (IVIVC).

The present study aims to develop the correlation between in vitro and in vivo skin permeation of lidocaine in its transdermal patch. In order to minimize the run-to-run variability during in vitro skin permeation studies, release normalized cumulative percent (%Ct n) was calculated. A suitable polynomial mathematical model was used to establish a correlation between time and %Ct n. Percent in vivo absorbed was calculated by using numerical deconvolution (NDC) and non-compartmental analysis (NCA) methods. Pharmacokinetic (PK) parameters such as AUC last and C max were predicted with the established in vitro-in vivo correlation (IVIVC) models. The minimum prediction errors in NDC method for C max were found to be -30.9 and -25.4% for studies I (in vivo study in human volunteers with one batch of Lidoderm patch; internal validation) and II (in vivo study in human volunteers with another batch of Lidoderm patch; external validation), respectively, whereas minimum prediction errors in NCA method were relatively low (3.9 and 0.03% for studies I and II, respectively) compared to those in NDC method. The prediction errors for AUC last were found to be less than 2% for both methods and studies. The established method in this study could be a potential approach for predicting the bioavailability and/or bioequivalence for transdermal drug delivery systems.

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.

Inclusion complex of aprepitant with cyclodextrin: evaluation of physico-chemical and pharmacokinetic properties.

OBJECTIVE: Aprepitant (APR) is a water insoluble drug approved for the treatment of chemotherapy induced nausea and vomiting (CINV) and post-operative nausea and vomiting (PONV). The innovator Emend® is a formulation incorporating drug nanoparticles with good bioavailability (~67%). The objective of the current work was to evaluate the feasibility of formulating a cyclodextrin complex of APR with enhanced solubility/dissolution rate and concomitantly bioavailability. METHODS: The complex was prepared using two approaches: kneading and slurry method. The formulated complex was evaluated using DSC, XRPD and FT-IR studies. RESULTS: DSC, XRPD and FT-IR studies confirmed the interaction of ß-cyclodextrin with APR indicating formation of a true complex wherein the drug was encapsulated in the cyclodextrin cavity (inclusion phenomenon). In addition to inclusion complexation, non inclusion phenomenon viz., interaction among hydroxyl groups of cyclodextrin and APR was also observed. The saturation solubility and dissolution rate of drug complex was higher than that of aprepitant API. The rate (C(max)) and extent of absorption (AUC) of APR from the complex were found to be comparable to that of Emend® (Reference product). CONCLUSION: These studies established that cyclodextrin complexation may provide another viable and cost effective option for enhancing solubility and bioavailability of APR.

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.

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.

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.