methylcellulose and tocophersolan

The goal of this study was to demonstrate that MK-0364 solid dispersions can be developed as a means to increase the solubility and bioavailability of a poorly water-soluble drug, MK-0364. The potential solid dispersions would enable an oral solid dosage form as a monotherapy or combination product of MK-0364. Preliminary screening included sample preparation via a solvent casting method, physical characterization, and in vitro dissolution testing. Lead formulations were subsequently manufactured using hot melt extrusion (HME) and spray-drying (SD). All HME (without polyvinyl pyrrolidone) and SD formulations exhibit characteristics of a single phase glass including an amorphous halo when analyzed with X-ray powder diffraction (XRPD), a single glass transition temperature (Tg) measured with differential scanning calorimetry (DSC), and supersaturation when dissolved in dissolution media. The oral absorption of MK-0364 from selected HME and SD formulations in monkeys results in marginally greater exposure with a consistently longer Tmax relative to a liquid filled capsule reference. Based on the processability, physical characterization, in vitro dissolution, and animal pharmacokinetic results, copovidone- and hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based solid dispersion formulations are viable product concepts. The physical stability of both the solid dispersion formulations was also evaluated for 54 weeks under different conditions. The copovidone-based solid dispersion requires protection from moisture.

Topics: Amides; Animals; Cannabinoid Receptor Agonists; Excipients; Hexoses; Macaca mulatta; Methylcellulose; Polyethylene Glycols; Polysorbates; Pyridines; Pyrrolidines; Solubility; Surface-Active Agents; Vinyl Compounds; Vitamin E; Water

Wet media milling by top down method has proved to be an effective method to prepare nanosuspension of poorly soluble drugs/APIs. Few or no attempts have been made so far to understand the feasibility of nanosuspension formulation in terms of the mechanism of stabilization as a function of drug properties. The objective of this study was to understand the effect of drug substance and stabilizer properties to form a successful nanosuspension product. From this study, logP and enthalpy were concluded to have a direct correlation on the feasibility of formation of a stable nanosuspension. The most likely candidate for media milling was a drug substance with a high enthalpy and hydrophobicity which can be stabilized either electrostatically or sterically. The least likely candidate will be one that is hydrophilic and having a very low enthalpy value. Also the choice of an ideal stabilizer/surfactant was found to be influenced by the degree of hydrophobicity of the drug itself. Finally the morphology of the starting drug was found to significantly affect the milling time required to produce submicron particles.

Topics: 1-Octanol; Dioctyl Sulfosuccinic Acid; Drug Compounding; Drug Stability; Hypromellose Derivatives; Methylcellulose; Molecular Weight; Nanoparticles; Naproxen; Pharmaceutical Preparations; Poloxamer; Polyethylene Glycols; Sodium Dodecyl Sulfate; Solubility; Surface-Active Agents; Suspensions; Transition Temperature; Vitamin E; Water

The purpose of this study was to develop supersaturatable formulations for the enhanced solubility and oral absorption of sirolimus. Supersaturatable formulations of hydrophilic polymers and/or surfactants were screened by formulation screening, which is based on solvent casting. The solid dispersion particles in the optimized formulations were prepared by spray drying. The particles were characterized in vitro and in vivo. The most effective supersaturatable formulation found in the formulation screening process was hydroxypropylmethyl cellulose (HPMC)-D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), followed by HPMC-Sucroester. In addition, the supersaturated state generated from HPMC-TPGS and HPMC-Sucroester 15 particles prepared by spray drying significantly improved the oral absorption of sirolimus in rats. Based on the pharmacokinetic parameters and supporting in vitro supersaturated dissolution data, the enhanced supersaturation properties of sirolimus led to enhanced in vivo oral absorption. In addition, the experimental results from the formulation screening used in our study could be useful for enhancing the bioavailability of sirolimus in preformulation and formulation studies.

Topics: Absorption; Administration, Oral; Animals; Biological Availability; Drug Compounding; Excipients; Hypromellose Derivatives; Immunosuppressive Agents; Male; Methylcellulose; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Sirolimus; Sucrose; Vitamin E

In transdermal drug delivery systems (TDDS), it is a challenge to achieve stable and prolonged high permeation rates across skin, because the concentration of the drug dissolved in the matrix has to be high in order to maintain zero order release kinetics of the drug. In case of poorly soluble drugs, due to thermodynamic challenges, there is a high tendency for the drug to nucleate immediately after formulating or even during storage. The present study focuses on the efficiency of vitamin E TPGS/HPMC supersaturated solution and other solubilizer/polymer systems to improve the solubility of the drug and inhibit crystal growth in the transdermal formulation. Effect of several solubilizers, for example, Pluronic F-127, vitamin E TPGS and co-solvent, for example, propylene glycol (PG) were studied on the supersaturated systems of ibuprofen as model drug. Various stabilizers such as hydroxylpropyl methylcellulose (HPMC 3 cps) and polyvinylpyrrolidone (PVP K-30) were examined to evaluate their crystal inhibitory effects. Different analytical tools were used in this study to detect the growth of crystals in the systems. Vitamin E TPGS and HPMC 3 cps formulation produced the highest permeation rate of the drug as compared to other systems. In addition, the onset of crystallization time was shown to be longer with this formulation as compared to other solubilizer/polymer combinations.

Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chromatography, High Pressure Liquid; Crystallization; Drug Stability; Hypromellose Derivatives; Ibuprofen; In Vitro Techniques; Membranes, Artificial; Methylcellulose; Particle Size; Permeability; Poloxamer; Polyethylene Glycols; Povidone; Propylene Glycol; Skin; Skin Absorption; Solubility; Solvents; Swine; Vitamin E

In transdermal drug delivery systems (TDDS), it is a challenge to achieve stable and prolonged high permeation rates across the skin since the concentrations of the drug dissolved in the matrix have to be high in order to maintain zero order release kinetics. Several attempts have been reported to improve the permeability of poorly soluble drug compounds using supersaturated systems, however, due to thermodynamic challenges, there was a high tendency for the drug to nucleate immediately after formulating or even during storage. The present study focuses on the efficiency of drug crystals at the submicron/nano range in presence of different solubilizers to improve the permeation rate. Effect of several solubilizers, e.g. Pluronic F-127, Vitamin E TPGS, propylene glycol were studied on the submicron suspension systems of ibuprofen as a model drug. Various stabilizers such as hydroxylpropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were examined to evaluate their crystal inhibitory effects on particle growth of the drug compound at submicron range. The overall permeation enhancement process through the skin seems to be influenced by the presence of solubilizers and also the presence of submicron drug crystal. The most promising stable formulation was developed with Vitamin E TPGS+HPMC submicron suspension, which produced higher permeation rate compared to other vehicles.

Topics: Administration, Cutaneous; Crystallization; Drug Carriers; Drug Compounding; Drug Delivery Systems; Drug Stability; Drug Storage; Excipients; Hypromellose Derivatives; Ibuprofen; Methylcellulose; Particle Size; Permeability; Poloxamer; Polyethylene Glycols; Povidone; Skin Absorption; Solubility; Thermodynamics; Vitamin E

The purpose of this study was to develop a nanosuspension of a poorly soluble drug by nanomilling process using wet media milling to achieve superior in vitro dissolution and high in vivo exposure in pharmacokinetic studies. A promising nanosuspension was developed with Vitamin E TPGS based formulation with particle size in the nano range. Although the formulation showed significant improvement during in vitro dissolution and in vivo plasma level, probably due to the strong hydrophobic interaction between Vitamin TPGS and the drug molecule, crystal growth was observed during stability studies. A systematic study was done with different combinations of solubilizer/stabilizer system in order to obtain a more stable nanosuspension. Hydroxypropyl methylcellulose (HPMC 3 cps) was found to stabilize the nanosuspension by better surface coverage due to stronger interaction with the drug as compared to other stabilizers used in this study.

Topics: Animals; Benzodiazepinones; Biological Availability; Crystallization; Dogs; Drug Carriers; Drug Stability; Excipients; Hydrophobic and Hydrophilic Interactions; Hypromellose Derivatives; Male; Methylcellulose; Nanoparticles; Particle Size; Phenylurea Compounds; Polyethylene Glycols; Solubility; Suspensions; Vitamin E

Biocompatible microparticles prepared by lyophilization were developed for intranasal protein delivery. To test for the feasibility of this formulation, stability of the incorporated protein and enhancement of in vitro permeation across the nasal epithelium were evaluated. Lyophilization was processed with hydroxypropylmethylcellulose (HPMC) or water soluble chitosan (WCS) as biocompatible polymers, hydroxypropyl-β-cyclodextrin (HP-β-CD) and d-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) as permeation enhancers, sugars as cryoprotectants and lysozyme as the model protein. As a result, microparticles ranging from 6 to 12μm were developed where the maintenance of the protein conformation was verified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism and fluorescence intensity detection. Moreover, in vitro bioassay showed that the lysozyme activity was preserved during the preparation process while exhibiting less cytotoxicity in primary human nasal epithelial (HNE) cells. Results of the in vitro release study revealed slower release rate in these microparticles compared to that of the lysozyme itself. On the other hand, the in vitro permeation study exhibited a 9-fold increase in absorption of lysozyme when prepared in lyophilized microparticles with HPMC, HP-β-CD and TPGS 1000 (F4-2). These microparticles could serve as efficient intranasal delivery systems for therapeutic proteins.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Absorption; Administration, Intranasal; beta-Cyclodextrins; Chitosan; Freeze Drying; Humans; Hypromellose Derivatives; Methylcellulose; Muramidase; Nasal Mucosa; Particle Size; Polyethylene Glycols; Powders; Primary Cell Culture; Protein Stability; Succinates; Vitamin E

Solid dispersion formulations made up of d-alpha-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000) and polyvinyl pyrrolidone co-vinyl acetate 64 (PVPVA 64) or hydroxy propyl methyl cellulose 2910 (HPMC 2910) were developed in order to improve the dissolution of UC 781. UC 781 dissolution rate was markedly improved as compared to the physical mixtures and the pure drug, attaining maximum drug releases of up to 100% after only 5 min in the case of TPGS 1000-UC 781-PVPVA 64 solid dispersions and 30 min in TPGS 1000-UC 781-HPMC 2910. The increased UC 781 dissolution rate could be maintained when formulating UC 781 in PVPVA 64 tablets. The latter disintegrated in only 4 min, reaching drug releases of up to 90% (w/w). In addition, as opposed to the corresponding solid dispersions, no decrease in drug release occurred upon dissolution of PVPVA 64 tablets when the pH was increased to 6.8. Contrary to the PVPVA 64 tablet formulations, HPMC 2910 tablets showed a slow dissolution process due to the gelling nature of the polymer. The drug was slowly released as HPMC 2910 dissolved in the medium, however also in this case 90% (w/w) of the drug was dissolved after 4 h. Both polymers formed compatible blends in combination with the drug. Thermal analysis of the ternary mixtures revealed eutectic behavior exhibiting an extremely fine dispersion of the drug in the carrier. This was confirmed by the fact that no drug crystals could be detected using X-ray diffraction (XRD). As opposed to the physical mixtures, PVPVA 64 and HPMC 2910 solid dispersions did not contain any isolated polymer-rich phases, hence showed improved homogeneity. Amorphous TPGS 1000 clusters occurred in PVPVA 64 and HPMC 2910 formulations upon addition of at least 10% (w/w) UC 781, showing extremely low glass transition temperatures depending of the thermal history of the samples.

Topics: Anilides; Anti-HIV Agents; Chemistry, Pharmaceutical; Drug Carriers; Drug Compounding; Furans; Hypromellose Derivatives; Kinetics; Methylcellulose; Models, Chemical; Polyethylene Glycols; Povidone; Pyrrolidines; Solubility; Tablets; Technology, Pharmaceutical; Thermodynamics; Thioamides; Transition Temperature; Vinyl Compounds; Vitamin E