Exploring clinically relevant dissolution specifications for oral solid dosage forms of weak acid drugs using an in silico modeling and simulation approach.

The aim of this study was to explore clinically relevant dissolution specifications for weak acid drugs using an in silico drug absorption model. Loxoprofen sodium and ibuprofen were used as model drugs in this study. An in silico drug absorption model was developed using Stella Professional software and the prediction model accurately represented the plasma concentration profiles of the model drugs following oral administration.

Morphological Analysis of Spherical Adsorptive Carbon Granules Using Three-Dimensional X-Ray Micro-computed Tomography.

The purpose of this study was to clarify applicability of three-dimensional X-ray micro-computed tomography (3D X-ray micro-CT) to elucidate interior morphology of spherical adsorptive carbon fine granules. Scanning of small single spherical granule hold on the rotating sample stage provided the structural information without particular preparation (e.g.

Investigation of factors affecting in vitro doxorubicin release from PEGylated liposomal doxorubicin for the development of in vitro release testing conditions.

Establishing appropriate drug release testing methods of liposomal products for assuring quality and performance requires the determination of factors affecting in vitro drug release. In this study, we investigated the effects of test conditions (human plasma lot, pH/salt concentration in the test media, dilution factor, temperature, ultrasound irradiation, etc.), and liposomal preparation conditions (pH/concentration of ammonium sulfate solution), on doxorubicin (DXR) release from PEGylated liposomal DXR.

Effects of formulation and process factors on the crystal structure of freeze-dried Myo-inositol.

The objective of this study was to elucidate effects of formulation and process variables on the physical forms of freeze-dried myo-inositol. Physical properties of myo-inositol in frozen solutions, freeze-dried solids, and cooled heat-melt solids were characterized by powder X-ray diffraction (PXRD), thermal analysis (differential scanning calorimetry [DSC] and thermogravimetric), and simultaneous PXRD-DSC analysis. Cooling of heat-melt myo-inositol produced two forms of metastable anhydrate crystals that change to stable form (melting point 225 °C-228 °C) with transition exotherms at around 123 °C and 181 °C, respectively.

Studying the morphology of lyophilized protein solids using X-ray micro-CT: effect of post-freeze annealing and controlled nucleation.

The objective of this study was to determine how different techniques used during the freezing step of lyophilization affect morphology of the dried protein solids. Aqueous solutions containing recombinant human albumin, trehalose, and sodium phosphate buffer were dried after their freezing by shelf-ramp cooling, immersion in liquid nitrogen, or controlled ice nucleation. Some shelf-frozen solutions were heat treated (annealed) before the vacuum drying.

Biorelevant in vitro performance testing of orally administered dosage forms-workshop report.

Biorelevant in vitro performance testing of orally administered dosage forms has become an important tool for the assessment of drug product in vivo behavior. An in vitro performance test which mimics the intraluminal performance of an oral dosage form is termed biorelevant. Biorelevant tests have been utilized to decrease the number of in vivo studies required during the drug development process and to mitigate the risk related to in vivo bioequivalence studies.

Thermotropic phase behavior of hydrogenated soybean phosphatidylcholine-cholesterol binary liposome membrane.

By combination of differential scanning calorimetry (DSC) and fluorescence spectroscopy of 6-propionyl-2-(dimethylamino)naphthalene (Prodan), we elucidated the thermotropic phase behavior of hydrogenated soybean phosphatidylcholine (HSPC)-cholesterol binary liposome membrane which has similar lipid composition to Doxil®, the widely used liposome product in treatment of various tumors. We found that the characteristic points at cholesterol mole fraction (Xch)=0.023 and 0.

Impact of heat treatment on miscibility of proteins and disaccharides in frozen solutions.

The purpose of this study was to elucidate the effect of heat treatment (annealing) on the miscibility of concentrated protein and disaccharide mixtures in the freezing segment of lyophilization. Frozen solutions containing a protein (e.g.

Simultaneous determination of polyethylene glycol-conjugated liposome components by using reversed-phase high-performance liquid chromatography with UV and evaporative light scattering detection.

Liposomes incorporating polyethylene glycol (PEG)-conjugated lipids (PEGylated liposomes) have attracted attention as drug delivery carriers because they show good in vivo stability. The lipid component of PEGylated liposomal formulations needs to be quantified for quality control. In this study, a simple reversed-phase high-performance liquid chromatography (HPLC) method with an evaporative light-scattering detector (ELSD) was established for simultaneous determination of hydrogenated soy phosphatidylcholine, cholesterol, PEG-conjugated lipid, and hydrolysis products of phospholipid in PEGylated liposomal formulations.

[Trends in the quality evaluation of generic products and bioequivalence guidelines].

Recent activities on the generic products such as the revision of bioequivalence guidelines, the accomplish of the reevaluation of the oral dosage forms approved before 1995, and the action program for promoting comfortable use of generics issued by MHLW in 2007, were summarized in this review. The bioequivalence guidelines established in 1997 were revised in 2012 based on the discussion in a dissolution working group (WG). The WG were consists of the members from pharmaceutical companies, academia and regulators belonging to MHLW, PMDA and NIHS.

Polyethylene glycol prevents in vitro aggregation of slightly negatively-charged liposomes induced by heparin in the presence of bivalent ions.

Liposomes are of great interest as drug delivery vehicles, and studies have focused on understanding how the physical and chemical characteristics of liposomes can be modified to improve their in vivo behavior. In a previous study, we found that the slightly negatively-charged liposomes aggregate only in the culture medium of human umbilical vein endothelial cells, whereas the liposomes modified with polyethylene glycol (PEG) (PEGylated) did not aggregate. In the present study, we investigated the underlying mechanism of this phenomenon.

Component crystallization and physical collapse during freeze-drying of L-arginine-citric acid mixtures.

Component crystallization and physical collapse during freeze-drying of aqueous solutions containing protein-stabilizing L-arginine and citric acid mixtures were studied. Freeze-drying microscopy (FDM) and thermal analysis of the solute-mixture frozen solutions showed collapse onset at temperatures (T(c)) approximately 10°C higher than their T(g)'s (glass transition temperatures of the maximally freeze-concentrated solute phase). Experimental freeze-drying of these solutions at a low chamber pressure showed the occurrence of physical collapse at shelf temperatures close to or slightly higher than the T(c).

Alterations in the detergent-induced membrane permeability and solubilization of saturated phosphatidylcholine/cholesterol liposomes: effects of poly(ethylene glycol)-conjugated lipid.

We have investigated the effects of two bile salts, chenodeoxycholate (CDC) and ursodeoxycholate (UDC), and a widely used detergent, Triton X-100 (T(X-100)), on normal and poly(ethylene glycol)-modified liposomes (PEGylated liposomes). We tested various lipid compositions, including hydrogenated soybean phosphatidylcholine/cholesterol/PEG-conjugated lipid (HSPC/PEG-lipid). Alterations in permeability were determined by the rate of drug release from the liposomes and solubilization was assessed by measuring the particle size of liposomes.

Comparison of particle size and dispersion state among commercial cyclosporine formulations and their effects on pharmacokinetics in rats.

Generic versions of Neoral, a microemulsion capsule formulation of cyclosporine, have been approved worldwide. However, there are concerns about the quality and efficacy of the generics due to the formulation specificity and differences in inactive ingredients among products. In this study, we measured the physicochemical properties of both the innovator and the generic formulations, and compared their bioavailability in rats.

Impact of heat treatment on the physical properties of noncrystalline multisolute systems concentrated in frozen aqueous solutions.

The purpose of this study was to elucidate the effect of heat treatment on the miscibility of multiple concentrated solutes that mimic biopharmaceutical formulations in frozen solutions. The first heating thermal analysis of frozen solutions containing either a low-molecular-weight saccharide (e.g.

FIP/AAPS joint workshop report: dissolution/in vitro release testing of novel/special dosage forms.

In 2003, the FIP Dissolution Working group published a position paper on dissolution/drug release testing for special/novel dosage forms that represented the scientific opinions of many experts in the field at that time (1). The position paper has supported activities, programs, and decisions in the scientific, technical, and regulatory community. Due to the rapid evolution of new practices and techniques for testing, the FIP Special Interest Group (SIG) on Dissolution/Drug Release decided to revise the previous paper and added proposals for further harmonization of release testing practices for different pharmaceutical dosage forms.

Genetic variations of orosomucoid genes associated with serum alpha-1-acid glycoprotein level and the pharmacokinetics of paclitaxel in Japanese cancer patients.

Alpha-1-acid glycoprotein (AGP) encoded by orosomucoid genes (ORM1 and ORM2) is an acute-phase response protein and functions as a drug-binding protein that affects pharmacokinetics (PK)/pharmacodynamics of binding drugs. To explore the effects of genetic variations of ORMs and a role of AGP on paclitaxel (PTX) therapy, we analyzed the duplication and genetic variations/haplotypes of ORMs in 165 Japanese cancer patients and then investigated their associations with serum AGP levels and the PK parameters of PTX. No effects of ORM duplications on serum AGP levels at baseline or PK of PTX were observed, but close associations of ORM1 -559T > A with the increases of AGP levels and area under the curve (AUC) of PTX metabolites were detected.

Stabilization of liposomes in frozen solutions through control of osmotic flow and internal solution freezing by trehalose.

The purpose of this study was to elucidate the effect of trehalose distribution across the membrane on the freeze-related physical changes of liposome suspensions and their functional stability upon freeze-thawing. Cooling thermal analysis of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine liposome suspensions showed exotherm peaks of bulk (-15 °C to -25 °C) and intraliposomal (approx. -45 °C) solution freezing initiated by heterogeneous and homogeneous ice nucleation, respectively.

Freeze-drying of proteins with glass-forming oligosaccharide-derived sugar alcohols.

Physical properties and protein-stabilizing effects of sugar alcohols in frozen aqueous solutions and freeze-dried solids were studied. Various frozen sugar alcohol solutions showed a glass transition of the maximally freeze-concentrated phase at temperatures (T(g)'s) that depended largely on the solute molecular weights. Some oligosaccharide-derived sugar alcohols (e.

Stabilization of protein structure in freeze-dried amorphous organic acid buffer salts.

The purpose of this study was to elucidate the physical properties and protein-stabilizing effects of some pH-adjusting excipients (carboxylic acids and their sodium salts) in frozen solutions and in freeze-dried solids. Thermal and powder X-ray diffraction (XRD) analysis indicated a high propensity of sodium citrates to form glass-state amorphous solids upon freeze-drying. Some salts (e.

FIP position paper on qualification of paddle and basket dissolution apparatus.

The qualification process for ensuring that a paddle or basket apparatus is suitable for its intended use is a highly debated and controversial topic. Different instrument qualification and suitability methods have been proposed by the pharmacopeias and regulatory bodies. In an effort to internationally harmonize dissolution apparatus suitability requirements, the International Pharmaceutical Federation's (FIP) Dissolution/Drug Release Special Interest Group (SIG) reviewed current instrument suitability requirements listed in the US, European, and Japanese pharmacopeias and the International Conference on Harmonization (ICH) Topic Q4B on harmonization of pharmacopoeial methods, in its Annex 7, Dissolution Test General.

Pharmaceutical quality evaluation of lipid emulsions containing PGE1: alteration in the number of large particles in infusion solutions.

There are two generics of a parenteral lipid emulsion of prostaglandin E1 (PGE(1)) (Lipo-PGE(1)) in addition to two innovators. It was reported the change from innovator to generic in clinical practice caused the slowing of drip rate and formation of aggregates in the infusion line. Thus, we investigated the difference of pharmaceutical quality in these Lipo-PGE(1) formulations.

Near-infrared analysis of hydrogen-bonding in glass- and rubber-state amorphous saccharide solids.

Near-infrared (NIR) spectroscopic analysis of noncrystalline polyols and saccharides (e.g., glycerol, sorbitol, maltitol, glucose, sucrose, maltose) was performed at different temperatures (30-80 degrees C) to elucidate the effect of glass transition on molecular interaction.

Freeze-drying of proteins in glass solids formed by basic amino acids and dicarboxylic acids.

The purpose of this study was to produce and characterize glass-state amorphous solids containing amino acids and organic acids that protect co-lyophilized proteins. Thermal analysis of frozen solutions containing a basic amino acid (e.g.

Glass-state amorphous salt solids formed by freeze-drying of amines and hydroxy carboxylic acids: effect of hydrogen-bonding and electrostatic interactions.

We studied effect of molecular interactions on the physical properties of binary freeze-dried solids and frozen aqueous solutions using model chemicals containing various functional groups (amino, carboxyl, hydroxyl). Thermal analysis of frozen solutions containing alkyl diamines and hydroxy di- or tricarboxylic acids showed thermal transitions (T(g)': glass transition of maximally freeze-concentrated phase) at temperatures higher than those of the individual solutes. A binary frozen solution containing 80 mM 1,3-diamino-2-hydroxypropane (single-solute T(g)'<-60 degrees C) and 120 mM citric acid (single-solute T(g)': -55.