Chikako Yomota

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 in vitro testing, the FIP Special Interest Group (SIG) on Dissolution/Drug Release decided to revise the previous paper and added proposals for further harmonization of in vitro release testing practices for different pharmaceutical dosage forms. This article represents the current updates to the previously published paper. This revision has been aligned to coincide with the USP taxonomy including route of administration, intended site of drug release, and dosage form. The revised paper includes information from current literature, expert discussions, and presentations from recent workshops (2,3). The authors acknowledge and expect further updates to be made as additional progress is made in the relevant areas. Thus, comments and additional contributions are welcome and may be considered for the next revision of the position paper.

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.g., maltitol, lactitol, maltotriitol) formed glass-state amorphous cake-structure freeze-dried solids. Microscopic observation of frozen maltitol and lactitol solutions under vacuum (FDM) indicated onset of physical collapse at temperatures (T(c)) several degrees higher than their T(g)s. Freeze-drying of pentitols (e.g., xylitol) and hexitols (e.g., sorbitol, mannitol) resulted in collapsed or crystallized solids. The glass-forming sugar alcohols prevented activity loss of a model protein (LDH: lactate dehydrogenase) during freeze-drying and subsequent storage at 50 degrees C. They also protected bovine serum albumin (BSA) from lyophilization-induced secondary structure perturbation. The glass-forming sugar alcohols showed lower susceptibility to Maillard reaction with co-lyophilized L-lysine compared to reducing and non-reducing disaccharides during storage at elevated temperature. Application of the oligosaccharide-derived sugar alcohols as alternative stabilizers in lyophilized protein formulations was discussed.

Recyclable characteristics of hyaluronate-polyhydroxyethyl acrylate blend hydrogel for controlled releases.

Hyaluronate-hydroxyethyl acrylate blend hydrogels which have a wide range of composition and characteristics were investigated. Glycidyl methacrylate derivatized hyaluronate (GMA-HA) were synthesized by coupling GMA to hyaluronate (HA) in the presence of a photoinduced initiator for polymerization. By copolymerizing radically GMA-HA and hydroxyethyl acrylate (HEA) under various compositions (weight ratios of HEA and GMA-HA: 1-20), GMA-HA hydrogels could be prepared in wide ranges of characteristics. These HA-PHEA gels possessed the feature that the dried ones recovered completely to the original swelling states on repeated runs, i.e. recyclable gels. The water contents of these hydrogels in equilibrium swellings in water (W(w)) were 0.99-0.86, and their viscoelastic properties were measured by a creep. The spontaneous elastic moduli were 1.05x10(5)-1.94x10(5) N m(-2), and they were mechanically tough. Their effective charge densities were estimated from the partition coefficients of sodium benzoate (NaBA) and decreased from -0.033 to -0.044 mol dm(-3) with increasing contents of HEA. Release of NaBA was studied, and the diffusion coefficients were found to be from 6.95x10(-10) to 0.12x10(-10) m(2) s(-1) with increasing the ratio of HEA. Their diffusion coefficients were found to be much less than the values estimated from the lattice model.

Separation of B-3 monodesamidoinsulin from human insulin by high-performance liquid chromatography under alkaline conditions

The separation of human insulin (HI) and related compounds such as A-21 monodesamido HI (A-21DHI) and B-3 monodesamido HI (B-3DHI) was investigated using reversed-phase HPLC and capillary zone electrophoresis (CZE). In the case of HPLC under the usual acidic conditions, whereas A-21DHI was separately eluted, B-3DHI was included in the HI peak. Then it was found that by applying a novel ODS column resistant to alkaline conditions, a good separation of B-3DHI from HI could be achieved using an alkaline eluent, and two peaks corresponding to B-3DHI were eluted in front of the HI peak.

Discrimination limit for purity test of human insulin by capillary electrophoresis

Because of the inevitable noise in instrumental analysis, a purity test can overlook an illegitimate drug that contains an undesired substance in a higher amount than the prescribed limit. The lowest (average) amount of undesired substance which leads to the right results of the purity test with 95% probability is referred to here as 95% discrimination limit. This paper presents a method for predicting the discrimination limit for the purity test of human insulin in capillary electrophoresis (CE). The theory and experiments show that if the legitimate limit of a degradation product (desamido insulin) is 3.0% of the total amount of the insulin formulation, the 95% discrimination limit in the CE system used in this study is 3.24% desamido insulin. Since the statistical aspects of the purity test are provided by the interpretation of the baseline fluctuation in the instrument, the usual strategy to repeat the instrumental analysis on the same samples is unnecessary in the present study.

Quantitative nuclear magnetic resonance spectroscopic determination of the oxyethylene group content of polysorbates

Guidelines for the oxyethylene group (EO) content of polysorbates are set by the Food and Agriculture Organization/World Health Organization Joint Expert Committee on Food Additives. However, the classical titration method for EO determination is difficult and time-consuming. Here, we show that quantitative 1H-nuclear magnetic resonance spectroscopy can determine the EO contents of polysorbates rapidly and simply. The EO signals were identified through comparisons with sorbitan monolaurate and poly(ethylene glycol) distearate. Potassium hydrogen phthalate was used as an internal standard. The EO contents were estimated from the ratio of the signal intensities of EO to the internal standard. Two nuclear magnetic resonance systems were used to validate the proposed method. The EO content of commercial polysorbates 20, 60, 65, and 80 was determined to be within the recommended limits using this technique. Our approach thus represents an additional or alternative method of determining the EO contents of polysorbates.

IC/ICP-MSによるパン中臭素酸カリウムの特異的分析法

A sensitive method for detecting bromate in bread by ion chromatography with inductively-coupled plasma mass spectrometry (IC/ICP-MS) was developed. Bromate was extracted from bread with water. The clean-up procedure included a 0.2 micron filter, a C18 cartridge for defatting, a silver cartridge to remove halogen anions, a centrifugal ultrafiltration unit to remove proteins, and a cation-exchange cartridge to remove silver ions. A 500 microL sample solution was applied to IC/ICP-MS. The detection limit and the quantitation limit of bromate in the solution were 0.3 ng/mL and 1.0 ng/mL, expressed as HBrO3, respectively, which corresponded to 2 ng/g and 5 ng/g, respectively, in bread. Recovery of bromate was about 90%, and the CV was about 2%. Based on the detection limit in solution and recovery from bread, the detection limit of bromate in bread was estimated to be 2 ng/g.

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. The extent of the intraliposomal solution freezing exotherm depended on liposome size, lipid composition, cosolutes, and thermal history, suggesting that osmotic dehydration occurred due to the increasing difference in solute concentrations across the membrane. A freeze-thawing study of carboxyfluorescein-encapsulated liposomes suggested that controlling the osmotic properties to avoid the freeze-induced intraliposomal solution loss either by rapid cooling of suspensions containing trehalose in both sides of the membrane (retention of the intraliposomal supercooled solution) or by cooling of suspensions containing trehalose in the extraliposomal media prior to freezing (e.g., osmotic shrinkage) led to higher retention of the water-soluble marker. Evaluation and control of the osmotically mediated freezing behavior by optimizing the formulation and process factors should be relevant to the cryopreservation and freeze-drying of liposomes.

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. This report reviews the ability of current in vitro performance tests to predict in vivo performance and generate successful in vitro and in vivo correlations for oral dosage forms. It also summarizes efforts to improve the predictability of biorelevant tests. The report is based on the presentations at the 2013 workshop, Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms, in Washington, DC, sponsored by the FIP Dissolution/Drug Release Focus Group in partnership with the American Association of Pharmaceutical Scientists (AAPS) and a symposium at the AAPS 2012 Annual meeting on the same topic.

Development and release characterization of hyaluronan–doxycycline gels based on metal coordination

A simple mixing with hyaluronan (HA), doxycycline (DC) and divalent metal cation in an aqueous solution enabled a thermoreversible water-soluble gel to form. For the cross-linking, two kinds of interactions were supposed. One was an electrostatic interaction between a positively charged group in DC and a negatively charged carboxyl function of HA, and the other was a chelation at the phenolic diketone moiety in DC. Since the gel was formed physically, the critical polymer concentration for gelation was present, and it was about 0.05% for HA with a molecular weight of 1.6x10(6). The hydrogel would be formed holding water in the HA entanglement network when DCs on HA chains made coordinate bonds through metal chelation. By changing the mixing ratio, two types of gels with different characteristics in drug release could be prepared. One was a gel with zero-order release prepared by mixing the same amount of HA and DC in equivalent. The other was a gel indicating Fickian diffusion-type release by mixing more DC than HA. Further, by controlling the absolute concentration of HA and DC, or the molecular weight of HA, some gels with desired release profiles could be prepared.