Hiroyasu Kokubo

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.

Dry coating: an innovative enteric coating method using a cellulose derivative.

A novel enteric coating method was developed. This method involves direct feeding of coating polymer powder and simultaneous spraying of plasticizing agent, without either organic solvent or water, using a centrifugal granulator, fluidized bed, or tablet-coating machine. For film formation, a curing step was then necessary; this involved spraying a small amount (3-8% of core weight) of water or hydroxypropyl methylcellulose solution, followed by heating. Hydroxypropyl methylcellulose acetate succinate was used as the enteric coating polymer, and a combination of triethyl citrate and acetylated monoglyceride was used for plasticization. The coated beads and tablets were evaluated for gastric resistance, intestinal disintegration, and stability, in comparison with beads and tablets from a conventional aqueous coating with the same enteric polymer. The new method required a higher coating amount for gastric resistance compared with the conventional coating, but the processing time was dramatically reduced. The results show that this dry coating method is applicable to the preparation of enteric-coated beads and tablets using commercially available lab-scale apparatus.

Study of standard tablet formulation based on fluidized-bed granulation

In this study, acetaminophen, ascorbic acid, and ethenzamide were selected as model drugs for tableting granules. Agitation and fluidized-bed granulation were carried out at three drug contents of 30, 50, and 70%. Compared with agitation granulation, granules made by fluidized-bed granulation showed superior compressibility with wide formulation allowance for drug type and amount. Fluidized-bed granulation resulted in less granule hardness and greater plastic deformability. The granules had considerable compactness and for tablets containing 70% ethenzamide, prolonged disintegration and dissolution times were noted. These are typical features of granules produced by fluidized-bed granulation.

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.

Critical Design Features of Phenyl Carboxylate-Containing Polymer Microbicides

ABSTRACT Recent studies of cellulose-based polymers substituted with carboxylic acids like cellulose acetate phthalate (CAP) have demonstrated the utility of using carboxylic acid groups instead of the more common sulfate or sulfonate moieties. However, the pKa of the free carboxylic acid group is very important and needs careful selection. In a polymer like CAP the pKa is approximately 5.28. This means that under the low pH conditions found in the vaginal lumen, CAP would be only minimally soluble and the carboxylic acid would not be fully dissociated. These issues can be overcome by substitution of the cellulose backbone with a moiety whose free carboxylic acid group(s) has a lower pKa. Hydroxypropyl methylcellulose trimellitate (HPMCT) is structurally similar to CAP; however, its free carboxylic acids have pKas of 3.84 and 5.2. HPMCT, therefore, remains soluble and molecularly dispersed at a much lower pH than CAP. In this study, we measured the difference in solubility and dissociation between CAP and HPMCT and the effect these parameters might have on antiviral efficacy. Further experiments revealed that the degree of acid substitution of the cellulose backbone can significantly impact the overall efficacy of the polymer, thereby demonstrating the need to optimize any prospective polymer microbicide with respect to pH considerations and the degree of acid substitution. In addition, we have found HPMCT to be a potent inhibitor of CXCR4, CCR5, and dual tropic strains of human immunodeficiency virus in peripheral blood mononuclear cells. Therefore, the data presented herein strongly support further evaluation of an optimized HPMCT variant as a candidate microbicide.

Granulation of Acetaminophen by a Rotating Fluidized-Bed Granulator

The purpose of this research was to evaluate the use of a rotating fluidized-bed granulator to produce acetaminophen granules with sufficient binding force between particles and good plasticity in tablets. Ethenzamide and ascorbic acid were used to compare the relationship between granulation and the sample wetness. It was revealed that a blade rotation rate of 300 rpm, inlet air flow rate of 42 m3/hr, and spraying pressure of 1.5 kg/cm3 produced tablets with the best properties. The granule and tablet properties of ethenzamide and ascorbic acid were compared to those of acetaminophen. These compounds showed different wetting behaviors with water and different compression behaviors. With an increase in medicament content, tablet hardness increased except for the ascorbic acid formulation. Capping and sticking were observed in acetaminophen and in ascorbic acid, respectively, and acetaminophen and ethenzamide showed prolonged disintegration time.

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.