Shigeru Itai

Polymorphic Transformation of Antibiotic Clarithromycin Under Acidic Condition

Clarithromycin (CAM) is a 14-membered semisynthetic macrolide antibiotic used to treat the infection of various bacteria including Helicobacter pylori. The polymorphic transformation of CAM form II crystals under acidic conditions is, however, still unclear, and was investigated using X-ray powder diffraction method. Gel of CAM, which was immediately formed by mixing form II crystals with the hydrochloric acid solution, transformed at first to unstable form A crystals and then to form B crystals. Both forms A and B crystals are hydrochloride salts. Analyses using Hancock-Sharp equation revealed that the mechanism of form B formation was three-dimensional growth of nuclei. The rate constant of the transformation indicated that the times for 95% of form A transforming to form B at 37 °C are 0.69, 1.90, and 3.79 h at pH 1.5, 2.5, and 3.4, respectively. These suggest that the transformation from form II to form B via gel and form A could occur on the surface of form II formulation of prolonged gastric residence time, in the case that the pH in stomach stays low.

Impact of active ingredients on the swelling properties of orally disintegrating tablets prepared by microwave treatment

The impact of different active pharmaceutical ingredients (APIs) loading on the properties of orally disintegrating tablets (ODTs) prepared according to our previously reported microwave (MW) treatment process was evaluated using famotidine (FAM), acetaminophen (AAP), and ibuprofen (IBU). None of the APIs interrupted the tablet swelling during the MW treatment and the tablet hardness were improved by more than 20 N. MW treatment, however, led to a significant increase in the disintegration time of the ODTs containing IBU, but it had no impact on that of the ODTs containing FAM or AAP. This increased disintegration time of the ODTs containing IBU was attributed to the relatively low melting point of IBU (Tm=76 °C), with the IBU particles melting during the MW treatment to form agglomerates, which interrupted the penetration of water into the tablets and delayed their disintegration. The effects of the MW treatment on the chemical stability and dissolution properties of ODTs were also evaluated. The results revealed that MW treatment did not promote the degradations of FAM and AAP or delay their release from the ODTs, while dissolution of the ODTs containing IBU delayed by MW treatment. Based on these results, the MW method would be applicable to the preparation of ODTs containing APIs with melting points higher than 110 °C.

Suppressed Release of Clarithromycin from Tablets by Crystalline Phase Transition of Metastable Polymorph Form I

The pharmaceutical properties of clarithromycin (CAM) tablets containing the metastable form I of crystalline CAM were investigated. Although the dissolution rate of form I was higher than that of stable form II, the release of CAM from form I tablet was delayed. Disintegration test and liquid penetration test showed that the disintegration of the tablet delayed because of the slow penetration of an external solution into form I tablet. Investigation by scanning electron microscopy revealed that the surface of form I tablet was covered with fine needle-shaped crystals following an exposure to the external solution. These crystals were identified as form IV crystals by powder X-ray diffraction. The phenomenon that CAM releases from tablet was inhibited by fine crystals spontaneously formed on the tablet surface could be applied to the design of sustained-release formulation systems with high CAM contents by minimizing the amount of functional excipients.

Structural changes of polymer-coated microgranules and excipients on tableting investigated by microtomography using synchrotron X-ray radiation

Multiple-unit tablets consisting of polymer-coated microgranules and excipients have a number of advantageous pharmaceutical properties. Polymer-coated microgranules are known to often lose their functionality because of damage to the polymer coating caused by tableting, and the mechanism of polymer coating damage as well as the structural changes of excipients upon tableting had been investigated but without in-situ visualization and quantitative analysis. To elucidate the mechanism of coating damage, the internal structures of multiple-unit tablets were investigated by X-ray computed microtomography using synchrotron X-rays. Cross sectional images of the tablets with sub-micron spatial resolution clearly revealed that void spaces remained around the compressed excipient particles in the tablets containing an excipient composed of cellulose and lactose (Cellactose(®) 80), whereas much smaller void spaces remained in the tablets containing an excipient made of sorbitol (Parteck(®) SI 150). The relationships between the void spaces and the physical properties of the tablets such as hardness and disintegration were investigated. Damage to the polymer coating in tablets was found mainly where polymer-coated microgranules were in direct contact with each other in both types of tablets, which could be attributed to the difference in hardness of excipient particles and the core of the polymer-coated microgranules.

Clarithromycin highly-loaded gastro-floating fine granules prepared by high-shear melt granulation can enhance the efficacy of Helicobacter pylori eradication.

In an effort to develop a new gastro-retentive drug delivery system (GRDDS) without a large amount of additives, 75% clarithromycin (CAM) loaded fine granules were prepared with three different hydrophobic binders by high-shear melt granulation and their properties were evaluated. Granules containing the higher hydrophobic binder showed sustained drug release and were able to float over 24h. The synchrotron X-ray CT measurement indicated that both the high hydrophobicity of the binder and the void space inside the granules might be involved in their buoyancy. In an in vivo experiment, the floating granules more effectively eradicated Helicobacter pylori than a CAM suspension by remaining in the stomach for a longer period. In short, CAM highly-loaded gastro-floating fine granules can enhance the eradication efficiency of H. pylori compared with CAM alone.

Preparation and Characterization of SN-38-Encapsulated Phytantriol Cubosomes Containing α-Monoglyceride Additives

SN-38 is a potent active metabolite of irinotecan that has been considered as an anticancer candidate. However, the clinical development of this compound has been hampered by its poor aqueous solubility and chemical instability. In this study, we developed SN-38-encapsulated cubosomes to resolve these problems. Six α-monoglyceride additives, comprising monocaprylin, monocaprin, monolaurin, monomyristin, monopalmitin, and monostearin, were used to prepare phytantriol (PHYT) cubosomes by probe sonication. The mean particle size, polydispersity index, and zeta potential values of these systems were around 190-230u2009nm, 0.19-0.25 and -17 to -22u2009mV, respectively. Small-angle X-ray scattering analyses confirmed that the SN-38-encapsulated cubosomes existed in the Pn̄3m space group both with and without the additives. The monoglyceride additives led to around a two-fold increase in the solubility of SN-38 compared with the PHYT cubosome. The drug entrapment efficiency of PHYT cubosomes with additives was greater than 97%. The results of a stability study at 25°C showed no dramatic changes in the particle size or polydispersity index characteristics, with at least 85% of the SN-38 existing in its active lactone form after 10u2009d, demonstrating the high stability of the cubosome nanoparticles. Furthermore, approximately 55% of SN-38 was slowly released from the cubosomes with additives over 96u2009h in vitro under physiological conditions. Taken together, these results show that the SN-38-encapsulated PHYT cubosome particles are promising drug carriers that should be considered for further in vivo experiments, including drug delivery to tumor cells using the enhanced permeability and retention effect.

Structural investigation of spherical hollow excipient Mannit Q by X-ray microtomography

The structure of Mannit Q particles, an excipient made by spray-drying a d-mannitol solution, and Mannit Q tablets were investigated by synchrotron X-ray microtomography. The Mannit Q particles had a spherical shape with a hollow core. The shells of the particles consisted of fine needle-shaped crystals, and columnar crystals were present in the hollows. These structural features suggested the following formation mechanism for the hollow particles:during the spray-drying process, the solvent rapidly evaporated from the droplet surface, resulting in the formation of shells made of fine needle-shaped crystals.Solvent remaining inside the shells then evaporated slowly and larger columnar crystals grew as the hollows formed. Although most of the Mannit Q particles were crushed on tableting, some of the particles retained their hollow structures, probably because the columnar crystals inside the hollows functioned as props. This demonstrated that the tablets with porous void spaces may be readily manufactured using Mannit Q.

Development and evaluation of a tacrolimus cream formulation using a binary solvent system.

We developed an oil/water-type tacrolimus (FK506) cream formulation as an alternative to Protopic ointment for atopic dermatitis treatment. We determined the effects of solvents used in topical preparations on FK506 solubility and stability, and evaluated FK506 transdermal absorption into rat skin from solutions, emulsions, and creams. Screening indicated that diethyl sebacate (DES), isopropyl myristate (IPM), propylene glycol (PG), and oleyl alcohol (OA) were adequate FK506 solvents. When FK506 solutions prepared using these solvents were transdermally administered, AUC0-24 values for DES and IPM were higher than or similar to that for 0.1% Protopic ointment. The AUC0-24 values for PG and OA were low, so these solvents did not enhance absorption. The residual ratios of FK506 in DES and IPM solutions after incubation at 70°C for 9d were 95.6% and 88.6%, respectively, so DES and IPM were chosen for emulsion preparation. When the emulsions were transdermally administered, the IPM emulsion AUC0-24 values increased 4.6-fold; DES emulsions did not show high transdermal absorption, but showed sustained characteristics. A cream formulation prepared by mixture of IPM and DES also showed high absorption and transdermal absorption increased with increasing IPM ratio. We developed an FK506 cream formulation with a controllable transdermal absorption rate by manipulating the IPM:DES ratio.

Effect of gel formation on the dissolution behavior of clarithromycin tablets

Clarithromycin (CAM) is a macrolide antibiotic that is widely used at clinical sites. We found that release of CAM is suppressed when tablets of CAM were exposed to an external solvent containing carboxylate buffers such as citrate. The suppressed release of CAM can be attributed to the formation of gels on the tablet surfaces, which inhibits penetration of the solvent into the tablet and thus disintegration of the tablets. Delayed disintegration of the tablets was also observed for commercial tablets. This suggests that taking CAM and carboxylates at the same time might be avoided. The crystal structure of CAM citrate reveals that molecular chains of CAM are cross-linked by hydrogen bond between citrate groups in the crystal. The crystal structure indicates that cross-linked CAM chains of the three-dimensional mesh structure might also be formed in high concentration CAM solutions in the presence of carboxylates, resulting in gel formation.

Enhancing the Solubility and Oral Bioavailability of Poorly Water-Soluble Drugs Using Monoolein Cubosomes

Monoolein cubosomes containing either spironolactone (SPI) or nifedipine (NI) were prepared using a high-pressure homogenization technique and characterized in terms of their solubility and oral bioavailability. The mean particle size, polydispersity index (PDI), zeta potential, solubility and encapsulation efficiency (EE) values of the SPI- and NI-loaded cubosomes were determined to be 90.4u2009nm, 0.187, -13.4u2009mV, 163u2009µg/mL and 90.2%, and 91.3u2009nm, 0.168, -12.8u2009mV, 189u2009µg/mL and 93.0%, respectively, which were almost identical to those of the blank cubosome. Small-angle X-ray scattering analyses confirmed that the SPI-loaded, NI-loaded and blank cubosomes existed in the cubic space group Im3̄m. The lattice parameters of the SPI- and NI-loaded cubosomes were 147.6 and 151.6u2009Å, respectively, making them almost identical to that of blank cubosome (151.0u2009Å). The in vitro release profiles of the SPI- and NI-loaded cubosomes showed that they released less than 5% of the drugs into various media over 12-48u2009h, indicating that most of the drug remained encapsulated within the cubic phase of their lipid bilayer. Furthermore, the in vivo pharmacokinetic results suggested that these cubosomes led to a considerable increase in the systemic oral bioavailability of the drugs compared with pure dispersions of the same materials. Notably, the stability results indicated that the mean particle size and PDI values of these cubosomes were stable for at least 4 weeks. Taken together, these results demonstrate that monoolein cubosomes represent promising drug carriers for enhancing the solubility and oral bioavailability of poorly water-soluble drugs.