Yohko Akiyama

In Vitro and in Vivo Evaluation of Mucoadhesive Microspheres Prepared for the Gastrointestinal Tract Using Polyglycerol Esters of Fatty Acids and a Poly(acrylic acid) Derivative

Two types of polyglycerol ester of fatty acid (PGEF)-based microspheres were prepared: Carbopol 934P (CP)-coated microspheres (CPC-microspheres) and CP-dispersion microspheres (CPD-microspheres). Comparative studies on mucoadhesion were done with these microspheres and PGEF-based microspheres without CP (PGEF-microspheres). In an in vitro adhesion test, the CPD-microspheres adhered strongly to mucosa prepared from rat stomach and small intestine because each CP particle in the CPD-microsphere was hydrated and swelled with part of it remaining within the microsphere and part extending to the surface serving to anchor the microsphere to the mucus layer. The gastrointestinal transit patterns after administration of the CPD-microspheres and PGEF-microspheres to fasted rats were fitted to a model in which the microspheres are emptied from the stomach monoexponentially with a lag time and then transit through the small intestine at zero-order. Parameters obtained by curve fitting confirmed that the gastrointestinal transit time of the CPD-microspheres was prolonged compared with that of the PGEF-microspheres. MRT in the gastrointestinal tract was also prolonged after administration of the CPD-microspheres compared with that following the administration of the PGEF-microspheres.

Evaluation of oral mucoadhesive microspheres in man on the basis of the pharmacokinetics of furosemide and riboflavin, compounds with limited gastrointestinal absorption sites

When sustained‐release adhesive and non‐adhesive microspheres which release the same drugs at similar rates are administered orally, drug absorption after administration of adhesive microspheres should, if the gastrointestinal residence of adhesive microspheres is prolonged as a result of mucoadhesion, be higher than that after administration of non‐adhesive microspheres. The gastrointestinal transit of oral adhesive microspheres in man has been evaluated pharmacokinetically using furosemide and riboflavin, compounds with limited absorption sites in the upper small intestine.

Novel oral controlled-release microspheres using polyglycerol esters of fatty acids

Abstract A novel oral controlled-release drug delivery system which consists of microspheres of 75–500 μm in diameter has been designed and developed. A drug is dispersed in a spherical micromatrix of poly-glycerol esters of fatty acids (PGEFs). The microspheres were prepared by a spray-chilling method using a rotating disc and had a narrow particle size distribution. A required size could easily be obtained by altering the spray conditions. In the in vitro dissolution tests, drug release was found to be affected by the size of the microspheres and the drug content in the microspheres. However, release of the drug could be regulated by selecting an appropriate hydrophile-lipophile balance value of PGEF. PGEF-based micromatrix system could provide stable controlled release, i.e., the surface morphology and the release profiles did not change during a long storage period at 40°C while the surface morphology and the release profiles changed after only one-day storage at 40°C when hydrogenated cotton seed oil (HSCS) was used as the matrix base.

Novel peroral dosage forms with protease inhibitory activities. II. Design of fast dissolving poly(acrylate) and controlled drug-releasing capsule formulations with trypsin inhibiting properties

The purpose of this study was to develop a dosage form for peroral peptide drug delivery which is able to increase the stability of the model substrate N-α-benzoyl-l-arginine ethyl ester (BAEE) against degradation by trypsin. Different capsule formulations, containing carbomer (C934P) and its neutralized freeze-dried modification (FNaC934P), were investigated in a specially designed dissolution test apparatus. The capsules were placed in a dissolution medium with 10 IU trypsin/ml. Carbomer was found to be more efficient in inhibiting trypsin activity than FNaC934P. The recovery of the substrate BAEE was highly dependent on both the swelling velocity of the polymers and the pre-incubation time of trypsin with the poly(acrylates) in the incubation medium. Pre-incubation for at least 20 min in carbomer or FNaC934P dispersions was required to achieve sufficient trypsin inhibition. From all the formulations investigated, a two-phase capsule preparation consisting of a rapid swelling FNaC934P part as the first phase and microparticles of polyglycerol esters of fatty acids containing carbomer particles and the peptide model drug BAEE as the second phase, had the most profound effect on trypsin activity inhibition.

Anti-hypertensive effect of oral controlled-release microspheres containing an ACE inhibitor (Delapril hydrochloride) in rats

Abstract— An oral controlled‐release drug delivery system based on microspheres of polyglycerol esters of fatty acids (PGEFs), was applied to an anti‐hypertensive, delapril hydrochloride. The in‐vitro release profile was controlled by selecting a PGEF with an appropriate hydrophilic‐lipophilic balance value for the matrix. The microspheres from which 80% of the drug was released in 6 h were orally administered to rats. The plasma concentration of the active metabolite was sustained after administration of the microspheres in comparison with administration of a solution. The in‐vivo release profile was in good agreement with the in‐vitro release profile. When the microspheres were administered, the pharmacological effect of delapril hydrochloride on the angiotensin I‐induced pressor response was also sustained showing consistency with the plasma concentration‐time curve.

Novel peroral dosage forms with protease inhibitory activities. I. Design of capsules with fast gel-forming and fast drug-releasing properties

Capsules, containing the poly(acrylic acid) derivative Carbopol® 934P (C934P) with the aim of inhibiting intestinal proteolytic activities after swelling with water into a hydrated state, were designed. Erythrosin was used as a hydrophillic model drug to characterize the release properties of the dosage forms. Capsule formulations which rapidly disintegrated and released the drug quickly, were prepared because both rapid disintegration and rapid swelling of C934P and simultaneous drug release are prerequisites for the enzyme inactivating properties of the system. The capsules containing freeze-dried, neutralized C934P (FNaC934P) disintegrated quicker than the capsules containing C934P. Capsules which contained poly(glycerol ester of fatty acid) microparticles with FNaC934P released erythrosin quicker than capsules containing mixtures of FNaC934P, erythrosin and a disintegrant.