Improved Dissolution of Dipyridamole with the Combination of pH-Modifier and Solid Dispersion Technology.

The aim of this study was to develop a pH-independent release formulation of dipyridamole (DP) by the combined use of pH-modifier technology and solid dispersion (SD) technology employing enteric polymer, Eudragit® S100 (Eud). Tartaric acid (TA) was selected as an appropriate pH-modifier in terms of improving the dissolution behavior of DP under neutral conditions. Upon optimization of the ratio of TA to DP, SD of DP with Eud and TA (SD-Eud/DP/TA) was prepared by a freeze-drying method. Scanning electron microscopic images revealed that DP was dispersed in the polymer in SD-Eud/DP/TA, and DP in SD-Eud/DP/TA was in an amorphous state, supported by powder X-ray diffraction and differential scanning calorimetry analyses. The dissolution behavior of SD-Eud/DP/TA was not dependent on the pH of the medium, although SD-Eud/DP exhibited very limited dissolution behavior under neutral conditions. Spectroscopic analysis suggested that there might be inter-molecular interaction among DP, TA and enteric polymer in SD-Eud/DP/TA, possibly leading to the stable pH-independent dissolution behavior of SD-Eud/DP/TA. TA in SD-Eud/DP/TA promoted the degradation of DP, suggesting that improving the stability of DP in SD-Eud/DP/TA might be key for its practical use. From these results, pH-independent dissolution behavior of SD-Eud/DP/TA could be achieved by an enteric polymer-based solid dispersion with a pH-modifier.

Biological behavior of the intramucosal Helicobacter pylori-negative undifferentiated-type early gastric cancer: comparison with Helicobacter pylori-positive early gastric cancer.

BACKGROUND: The differences in the growth morphology, proliferative ability, and background mucosa of the cancer between Helicobacter pylori (HP)-positive (HP+) gastric cancer (GC) and HP-negative (HP-) GC are still unclear. To clarify the differences, we compared the characteristics of the two types of cancer. METHODS: Of the 91 patients with undifferentiated-type early GC who underwent endoscopic treatment at our hospital between August 2005 and April 2011, 23 HP- GC patients (all of whom had signet ring cell carcinoma measuring 20 mm or less in diameter) and 46 HP+ GC patients with signet ring cell carcinoma measuring 20 mm or less in diameter (out of a total of 68 HP+ GC patients) were enrolled in this study. Endoscopic atrophy and background mucosa were classified according to the updated Sydney system. The proliferative capacity of the cancer was assessed by examining the MIB-1 labeling index. RESULTS: With regard to the growth in the mucosal layer, the proportion of patients with cancer confined to the proliferative zone was significantly higher in the HP- GC group. Moderate or severer atrophy, intestinal metaplasia, mononuclear cell infiltration, and neutrophil infiltration according to the updated Sydney system were significantly commoner in the HP+ GC patients. Also, the MIB-1 labeling index was significantly higher in the HP+ GC group. CONCLUSION: HP+ GC appeared to show a higher proliferative capacity, more extensive spread, and more rapid progression, and inflammation associated with HP infection was suggested to be involved in the proliferation of this type of GC.

[Endoscopic therapy for cancer of the esophagogastric junction].

In Japan, the criteria for cancer of the esophagogastric junction (EGJ) are that the center of the lesions are located within 2cm from the EGJ orally and anally. The main histology of these lesions are squamous cell carcinoma and adenocarcinoma. Squamous cell carcinoma of the esophagus is treated following the guidelines published by the Japan Esophageal Society. This paper focuses on EGJ adenocarcinomas, which include cardiac gastric cancer and Barrett's cancer originating from the short-segment Barrett's esophagus. EGJ cancer is resected endoscopically at the termination of the palisade vessels or upper end of the gastric fold. The various types of cancer involving the EGJ are treated following the guidelines published by each medical specialist society in Japan. The main endoscopic treatment is endoscopic submucosal dissection. The EGJ is a narrow space, and therefore lesions are approached from the oral approach or anal approach using a reverse endoscope. Bleeding, perforation, and stenosis are major complications. When two-thirds or more of the wall is resected, stenosis occurs. Endoscopic therapy for cancer originating in the EGJ has not yet been fully established.

Microenvironmental pH-modification to improve dissolution behavior and oral absorption for drugs with pH-dependent solubility.

INTRODUCTION: Drug release and oral absorption of drugs with pH-dependent solubility are influenced by the conditions in the gastrointestinal tract. In some cases, poor oral absorption has been observed for these drugs, causing insufficient drug efficacy. The pH-modification of a formulation could be a promising approach to overcome the poor oral absorption of drugs with pH-dependent solubility. AREAS COVERED: The present review aims to summarize the pH-modifier approach and strategic analyses of microenvironmental pH for formulation design and development. We also provide literature- and patent-based examples of the application of pH-modification technology to solid dosage forms. EXPERT OPINION: For the pH-modification approach, the microenvironmental pH at the diffusion area can be altered by dissolving pH-modifying excipients in the formulation. The modulation of the microenvironmental pH could improve dissolution behavior of drugs with pH-dependent solubility, possibly leading to better oral absorption. According to this concept, the modulated level of microenvironmental pH and its duration can be key factors for improvement in drug dissolution. The measurement of microenvironmental pH and release of pH-modifier would provide theoretical insight for the selection of an appropriate pH-modifier and optimization of the formulation.

New dipyridamole salt with improved dissolution and oral bioavailability under hypochlorhydric conditions.

The aim of this study was to develop new dipyridamole (DP) salts with pH-independent solubility for improving oral bioavailability under hypochlorhydria. Salt screening was carried out using nine counterions by the temperature gradient method. Six DP salts were obtained, and there was marked improvement in dissolution behavior for all DP salts in a neutral medium. Most DP salts were stable under accelerated conditions. On the basis of the dissolution and stability data, DP tosylate (DP/TS) was selected as a promising DP salt. The pharmacokinetics of DP and the promising DP salt were assessed in normal rats and omeprazole-treated rats as a hypochlorhydric model. After oral administration of DP/TS (10 mg-DP/kg) in normal rats, enhanced DP exposures with increased C(max) and AUC0₋3 were observed compared with those with DP by ca. 2.8- and 1.7-fold, respectively. There was ca. 1 h delay of T(max) and ca. 62% reduction of AUC0₋3 for DP in omeprazole-treated rats compared with those for DP in normal rats; however, oral absorption for DP/TS under hypochlorhydria was almost identical to that in normal rats. The newly developed DP/TS might provide better therapeutic efficacy in clinical use for hypochlorhydric patients.

Novel formulations of dipyridamole with microenvironmental pH-modifiers for improved dissolution and bioavailability under hypochlorhydria.

This study was undertaken to develop new dipyridamole (DP) formulations with acidic microenvironmental pH-modifiers for improving dissolution and absorption under hypochlorhydric conditions. Dipyridamole granules (DPG) with ten acidic pH-modifiers were prepared with conventional wet granulation, and their manufacturability, stability and dissolution behavior were characterized. Pharmacokinetic profiling of the optimized DPG with acid was carried out in omeprazole-treated rats as a hypochlorhydric model. On the basis of the manufacturability, stability and dissolution behavior of new DPG formulations, p-toluenesulfonic acid (TS) was found to be a suitable acidic pH-modifier for DPG formulation. Although DPG showed pH-dependent dissolution behavior, DPG with TS exhibited a high rate and extent of dissolution in both acidic and neutral media. After oral administration of DPG (10mg DP/kg) in omeprazole-treated hypochlorhydric rats, there was ca. 40% reduction of the area under the curve of plasma concentration vs. time from zero to 3h (AUC(0-3)) for DPG compared with that in normal rats. However, AUC(0-3) for DPG/TS under hypochlorhydria was almost identical to that of DPG in normal rats. From these findings, the addition of TS as a microenvironmental pH-modifier in DP formulation might be beneficial in expanding the therapeutic potential of DP in hypochlorhydric patients.

Improved dissolution and pharmacokinetic behavior of dipyridamole formulation with microenvironmental pH-modifier under hypochlorhydria.

The present study aimed to develop and characterize new formulations of dipyridamole (DP), a pH-dependent poorly soluble drug, employing an acidic pH-modifier for improving dissolution and absorption under hypochlorhydric condition. Granule formulations of DP (DPG) with and without fumaric acid (FA) were prepared with wet granulation, physicochemical properties of which were characterized focusing on morphology, dissolution and stability. Pharmacokinetic profiling of orally dosed DPG or DPG with 60% loading of FA (DPG/FA60) was carried out in omeprazole-treated rats as a hypochlorhydric model. Although pH-dependent dissolution behavior was observed in DPG, DPG/FA exhibited high rate and extent of dissolution in both acidic and neutral media. Complete supersaturation was achieved with a 2 h testing period in pH6.8 medium, and co-existing fumaric acid had no impact on the chemical/photochemical stability of DP in solid-state. After oral administration of DPG or DPG/FA60 (10 mg-DP/kg), there was ca. 40% reduction of AUC(0-3) for DPG in omeprazole-treated rats as compared to that in normal rats; however, AUC(0-3) for DPG/FA60 under hypochlorhydria was almost identical to that of DPG in normal rats. Given the improved systemic exposure early after oral administration in hypochlorhydric rats, the DPG/FA might provide better clinical outcomes in hypochlorhydric patients.