Fumie Tanno

Evaluation of Hypromellose Acetate Succinate (HPMCAS) as a Carrier in Solid Dispersions

The utility of hypromellose acetate succinate (HPMCAS), a cellulosic enteric coating agent, as a carrier in a solid dispersion of nifedipine (NP) was evaluated in comparison with other polymers, including hypromellose (HPMC), hypromellose phthalate (HPMCP), methacrylic acid ethyl acrylate copolymer (MAEA), and povidone (PVP). An X‐ray diffraction study showed that the minimum amount of HPMCAS required to make the drug completely amorphous was the same as that of other cellulosic polymers, and less than that in dispersions using non‐cellulosic polymers. Hypromellose acetate succinate showed the highest drug dissolution level from its solid dispersion in a dissolution study using a buffer of pH 6.8. This characteristic was unchanged after a storage test at high temperature and high humidity. The inhibitory effect of HPMCAS on recrystallization of NP from a supersaturated solution was the greatest among all the polymers examined. Further, the drug release pattern could be modulated by altering the ratio of succinoyl and acetyl moieties in the polymer chain. Our results indicate that HPMCAS is an attractive candidate for use as a carrier in solid dispersions.

Stability assessment of hypromellose acetate succinate (HPMCAS) NF for application in hot melt extrusion (HME)

HPMCAS is a widely used polymer in the pharmaceutical industry as an excipient. In this work, the physicochemical stability of HPMCAS was investigated for hot melt extrusion (HME) application. The reduction in zero rate viscosity (η0) of the polymer with the increase in temperature was determined using rheological evaluation prior to HME processing. The energy of activation for AS-MF determined by fitting Arrhenius model to the temperature dependent reduction in η0 was found to be slightly lower than that for the other grades of HPMCAS. Glassy yellowish HMEs were obtained using Haake Mini-Lab MicroCompounder operated at 160, 180, and 200°C and 100, 200, and 300 rpm for all the grades at each temperature. Various physicochemical properties of HPMCAS such as glass transition temperature, semi-crystalline nature, solid state functional group properties, moisture content, and solution viscosity were not significantly affected by the HME processing. The most significant change was the release of acetic and succinic acid with the increase in HME temperature and speed. The free acid content release due to HME was directly proportional to the speed at lower operating temperatures. AS-LF was found to be the most stable with the lowest increase in total free acid content even at higher HME temperature and speed. Although the dissolution time was not affected due to HME for AS-LF and AS-MF grades, it was notably increased for AS-HF, perhaps due to significant reduction of succinoyl content. In conclusion, the HME processing conditions for solid dispersions of HPMCAS should be based on the acceptance levels of free acid for the drug and the drug product.

Antimicrobial TMSAH-Added Wood-Inorganic Composites Prepared by the Sol-Gel Process

To add stable antimicrobial properties to woods, an amphoteric sterilant, 3-(trimethoxysilyl))propyl (carboxymethyl) decylmethyl ammonium hydroxide inner salt (TMSAH) was applied to the sol-gel process, as SiO 2 wood-inorganic composites were prepared. The obtained TMSAH-added SiO 2 composites could reveal the high antimicrobial activities against a fungal attack by brown-rot fungi, but their activities against white-rot fungi were somewhat less. This result would be, therefore, due to the amphoteric nature of the TMSAH sterilant, which was stable under acidic conditions. However, the addition of property-enhancer, 2-haptadecanuorooctylethyltrimethoxysilane (HFOETMOS) to the above reaction system could provide HFOETMOS-(TMSAH-SiO 2 composites with water-repellency and its water-repellent property has improved antimicrobial activities in the composites, against both brown-rot and white-rot fungi.

Site-specific drug delivery to the middle-to-lower region of the small intestine reduces food-drug interactions that are responsible for low drug absorption in the fed state.

Food-drug interactions may reduce the bioavailability of drugs taken after meals (negative food effects). We designed enteric-coated tablets that start to disintegrate when they reach the middle-to-lower region of the small intestine, and examined whether they could reduce negative food effects in dogs. Tablets containing trientine as a model drug were coated with hypromellose acetate succinate (HPMCAS) with various values of succinoyl group content. The time lag of drug dissolution from these enteric-coated tablets in simulated intestinal fluid of pH 6.8 increased as the succinoyl group content was decreased. The AUC of trientine after oral administration of its aqueous solution to fed dogs was one-eighth of that in fasted dogs. The low drug absorption in fed dogs was improved when trientine was administered as enteric-coated tablets. The average ratio of AUC in the fed state to that in the fasted state increased with decreasing succinoyl group content of HPMCAS. Negative food effects completely disappeared after oral administration of tablets coated with HPMCAS having a succinoyl group content of 6.2% or less, which probably disintegrated in the middle-to-lower small intestine. Our results indicated that food-drug interactions were avoided by separating the main absorption site of drugs from that of food components.

Correlation between in vitro dissolution profiles from enteric-coated dosage forms and in vivo absorption in rats for high-solubility and high-permeability model drugs.

We examined the in vitro dissolution-in vivo absorption correlation (IVIVC) for enteric-coated granules containing theophylline, antipyrine or acetaminophen as model drugs with high solubility and high permeability. More than 85% of each drug was released from granules coated with hypromellose acetate succinate (HPMCAS) (AS-LG grade, which dissolves at pH above 5.5) at a mean dissolution rate of more than 5 %/min after a lag time of less than 4 min in simulated intestinal fluid of pH 6.8. The lag time and the dissolution rate were significantly extended and reduced, respectively, when AS-LG was replaced with AS-HG (a grade of HPMCAS that dissolves at pH above 6.8). Enteric-coated granules were administered intraduodenally to anesthetized rats. Statistical significances of differences of in vitro lag time between AS-LG- and AS-HG-coated granules were consistent with those in vivo, for all drugs. Significant differences in dissolution rates between granules also corresponded to those in absorption rates calculated using a deconvolution method, and both parameters had comparable absolute values, except in the case of antipyrine-containing granules with relatively fast dissolution rates. Thus, a good IVIVC was generally obtained; however, the exception suggests the importance of developing a dissolution test that fully reflects the in vivo situation.

Properties and Applications of Hypromellose Acetate Succinate (HPMCAS) for Solubility Enhancement Using Melt Extrusion

The development of bioavailable solid dispersions requires the use of secondary materials for stabilizing the amorphous dispersion while also enhancing dissolution and solubility of the new chemical entity. With the increased use of amorphous dispersions, hypromellose acetate succinate (HPMCAS) has emerged as a commonly used excipient for formulation design. This unique material, originally designed to enhance thermoplastic properties of cellulosics, can be used to enhance the solubility of many poorly soluble amorphous products. This chapter details the properties of HPMCAS that make it a beneficial material for use in solid dispersion formulation, with a specific focus on relevant properties for melt extrusion.