Evaluation of Pazopanib Phase Behavior Following pH-Induced Supersaturation.

Salts of weakly basic active pharmaceutical ingredients are widely used to improve aqueous solubility and/or dissolution rate. However, these compounds are prone to precipitation due to the lower solubility of the un-ionized species at the higher pH in the intestinal region, and this can result in poor and/or variable absorption. The goal of this study was to investigate the degree of supersaturation achieved following dissolution of different amounts of pazopanib hydrochloride at low pH, followed by rapid pH increase. Using pH solubility profiles, phase boundaries were defined for crystalline and amorphous free base forms. The resultant phase diagram was used to rationalize the observed supersaturation and phase behavior of pazopanib following pH adjustment. In the presence of a crystallization inhibitor, hydroxypropylmethyl cellulose (HPMC), the degree of supersaturation was found to be very high, approximately 600-fold, at pH 6.5. At a dose equivalent to the clinical dose, the maximum free drug concentration observed at pH 6.5 was dictated by the amorphous solubility. Solutions that exceeded the amorphous solubility upon pH increase were found to undergo glass-liquid phase separations (GLPS) with the formation of amorphous colloidal drug-rich particles. Microscopic observations confirmed that HPMC delayed the appearance of pazopanib free base crystals. The phase behavior upon pH change is thus well predicted by the phase diagram, after taking into consideration the initial dose, the extent of supersaturation generated upon pH change, and the presence or absence of a crystallization inhibitor.

Appropriate selection of an aggregation inhibitor of fine particles used for inhalation prepared by emulsion solvent diffusion.

CONTEXT: Dry powder inhaler (DPI) formulations have been developed to deliver large amounts of drugs to the lungs. OBJECTIVE: Fine particles of a poorly water-soluble drug, the model drug ONO-2921, were prepared by the emulsion solvent diffusion (ESD) method for use in a DPI. METHODS: The effects of additives on the fine particle formation of ONO-2921 were estimated when droplets of an ethanolic drug solution were dispersed into aqueous media containing various additives. Subsequently, the suspensions were freeze-dried to create powdered samples to estimate the inhalation properties using a twin impinger and an Andersen cascade impactor. RESULTS: This simple ESD method produced submicron-sized ONO-2921 particles (approximately 600 nm) in combination with suitable additives. In addition, the freeze-dried powder produced using additives exhibited superior in vitro inhalation properties. Among these methods, the freeze-dried powder produced with 0.50% weight/volume one type of polyvinyl alcohol (PVA-205) displayed the most efficient features in the fine particle fraction (FPF). These results could be explained by the stabilization of the ONO-2921 suspension by PVA-205, indicating that PVA-205 acts as an aggregation inhibitor of fine particles. CONCLUSIONS: The ESD method, in combination with appropriate types and amounts of additives, may be useful for preparing a DPI suitable for delivering drugs directly to the lungs without the assistance of carrier particles.

Development of a gastric retentive system as a sustained-release formulation of pranlukast hydrate and its subsequent in vivo verification in human studies.

Pranlukast hydrate was demonstrated in a human site-of-absorption study to have extremely poor absorption properties in the lower gastrointestinal tract. The ratios of AUC0-24 in the distal small bowel and colon compared to stomach delivery were approximately 1/7 and 1/70, respectively. As a consequence, a gastroretentive double-layered tablet formulation (gastric swelling system; GSS), consisting of a swelling layer and a drug release layer, was developed for once-daily dosing. To study the gastric retention of the optimized GSS, an in vivo gamma scintigraphic study was carried out in nine healthy volunteers. The transit profiles demonstrated that the GSS was retained in the stomach for more than 10h. The plasma profile was prolonged, especially following administration after an evening meal. The human data validated the design concept and suggest that GSS could be a promising approach for the development of sustained-release formulation for drugs with a limited absorption window in the upper small bowel.

Effects of food intake on the mucoadhesive and gastroretentive properties of submicron-sized chitosan-coated liposomes.

The gastrointestinal transition of mucoadhesive drug carriers may be affected by food intake, since food changes the physiological conditions of the gastrointestinal tract, and the food content itself is a physical obstruction for the drug carriers. Here we investigated the effects of food intake on the gastrointestinal transition and mucoadhesive function of submicron-sized chitosan-coated liposomes (ssCS-Lip). The stomach and small intestine were removed after oral administration of ssCS-Lip and non-coated liposomes (ssLip) containing fluorescent dye to fasted or fed rats, and retentive properties were quantitatively confirmed by measuring the amount of dye in each part of the gastrointestinal tract. Both types of liposome were retained in the stomach at approx. 40% in the fed rats at 1 h after oral administration, whereas transitions in the intestine were reduced compared to the fasted rats. However, the transition of ssCS-Lip in intestine was prolonged compared to ssLip even, in the fed state. The mucoadhesive behavior of ssCS-Lip was evaluated by confocal laser scanning microscopy. The ssCS-Lip tended to penetrate into the mucosal part of the intestine, and in addition, ssCS-Lip was detected in the basolateral side in both conditions, and therefore the mucopenetrative function was confirmed in the fed condition. Based on these results, we confirmed that ssCS-Lip shows a predominant gastrointestinal transition and mucopenetration, even after food intake.

Effectiveness of submicronized chitosan-coated liposomes in oral absorption of indomethacin.

The plasma profile of indomethacin (IMC) after oral administration of IMC-loaded submicronized chitosan-coated liposomes (ssCS-Lip) was evaluated to reveal the effectiveness of the mucoadhesive function for improving the absorption of this poorly absorbable drug. The stomach and small intestine were removed from rats after 1, 2, and 4 hours of oral administration of submicron-sized liposomes (ssLip) or ssCS-Lip containing fluorescent dye, and the retentive properties were confirmed by measuring the amount of dye in each part of the gastrointestinal (GI) tract. Results showed that ssCS-Lip tended to be better retained in the upper part of the GI tract, compared with ssLip, at 1, 2, and 4 hours after administration, and was significantly better retained in the small intestine at 4 hours. The plasma profile and bioavailability of IMC after oral administration of both types of liposomes were improved, compared with oral administration of IMC solution. The maximum residence time of ssCS-Lip was significantly longer than those of ssLip. The extended plasma profile of ssCS-Lip was attributed to its prolonged retention in the upper region of the GI tract, and its delayed migration to the lower part of the intestine, the neutral pH of which is more soluble for IMC, an acidic drug. Therefore, the chitosan-coated ssLip, with its higher retention in the GI tract, is a promising drug carrier for the oral administration of poorly absorbed compounds.

Prostaglandin E2 receptor type 2-selective agonist prevents the degeneration of articular cartilage in rabbit knees with traumatic instability.

INTRODUCTION: Osteoarthritis (OA) is a common cause of disability in older adults. We have previously reported that an agonist for subtypes EP2 of the prostaglandin E2 receptor (an EP2 agonist) promotes the regeneration of chondral and osteochondral defects. The purpose of the current study is to analyze the effect of this agonist on articular cartilage in a model of traumatic degeneration. METHODS: The model of traumatic degeneration was established through transection of the anterior cruciate ligament and partial resection of the medial meniscus of the rabbits. Rabbits were divided into 5 groups; G-S (sham operation), G-C (no further treatment), G-0, G-80, and G-400 (single intra-articular administration of gelatin hydrogel containing 0, 80, and 400 µg of the specific EP2 agonist, ONO-8815Ly, respectively). Degeneration of the articular cartilage was evaluated at 2 or 12 weeks after the operation. RESULTS: ONO-8815Ly prevented cartilage degeneration at 2 weeks, which was associated with the inhibition of matrix metalloproteinase-13 (MMP-13) expression. The effect of ONO-8815Ly failed to last, and no effects were observed at 12 weeks after the operation. CONCLUSIONS: Stimulation of prostaglandin E2 (PGE2) via EP2 prevents degeneration of the articular cartilage during the early stages. With a system to deliver it long term, the EP2 agonist could be a new therapeutic tool for OA.

[Absorption of calcitonin in oral and pulmonary administration with polymer-coated liposomes].

We have developed polymer-coated liposomes for effective and non-invasive delivery of peptide drugs. Polymer-coated liposomes, which are liposomal particles coated with functional polymers, were designed in order to have suitable functions required for drug delivery. So far, we have reported prolonged retention in the gastro-intestinal tract owing to the mucoadhesive properties of the polymer-coated liposomes. This review shows outline of effectiveness of polymer-coated liposomes in absorption of calcitonin after oral administration. The main factors for absorption enhancing of calcitonin are mucoadhesion and penetration of polymer-coated liposomes into the mucus layer. Application of polymer-coated liposomes in pulmonal drug delivery and novel strategies for designing mucoadhesive particulate systems are also described.

Novel mucoadhesion tests for polymers and polymer-coated particles to design optimal mucoadhesive drug delivery systems.

To design an effective particulate drug delivery system having mucoadhesive function, several mucoadhesion tests for polymers and the resultant particulate systems were developed. Mucin particle method is a simple mucoadhesion test for polymers, in which the commercial mucin particles are used. By measuring the change in particle size or zeta potential of the mucin particle in a certain concentration of polymer solution, we could estimate the extent of their mucoadhesive property. BIACORE method is also a novel mucoadhesion test for polymers. On passing through the mucin suspension on the polymer-immobilized chip of BIACORE instrument, the interaction was quantitatively evaluated with the change in its response diagram. By using these mucoadhesion tests, we detected a strong mucoadhesive property of several types of chitosan and Carbopol. Evaluation of mucoadhesive property of polymer-coated particulate systems was demonstrated with the particle counting method developed by us. To detect the mucoadhesive phenomena in the intestinal tract, we observed the rat intestine with the confocal laser scanning microscope (CLSM) after oral administration of the particulate systems. The resultant photographs clearly showed a longer retention of submicron-sized chitosan-coated liposomes (ssCS-Lip) in the intestinal tract than other liposomal particles tested such as non-coated liposomes and chitosan-coated multilamellar one. These observations explained well the superiority of the ssCS-Lip as drug carrier in oral administration of calcitonin in rats than other liposomal particles.

Effectiveness of submicron-sized, chitosan-coated liposomes in oral administration of peptide drugs.

The mucoadhesive behavior of chitosan-coated liposomes in the intestinal tract of the rat was examined to elucidate their particle size effects on the absorption of an entrapped drug, calcitonin. The intestine was removed from rats after oral administration of liposomes containing a fluorescent dye, and its various parts were observed with confocal laser scanning microscopy. Penetration of submicron-sized liposomes (ssLip) or chitosan-coated ssLip (ssCS-Lip) into the mucosa was observed, while such behavior was not observed for the multilamellar liposomes, even when coated with chitosan (CS-Lip). The retentive property of ssCS-Lip was confirmed by measuring the amount of dye in each part of the intestine. The pharmacologic effects of calcitonin-loaded liposomes of different particle size were measured after oral administration in rats. The pharmacologic effect of oral administration of ssLip coated with chitosan was detected up to 120 h after administration. The extensive pharmacologic effect of ssCS-Lip was attributed to their prolonged retention in the intestinal mucosa, partly owing to their penetrative property into the intestinal mucosa. The chitosan-coated ssLip, with their higher retentive property in the intestinal tract, are much more effective than ssLip and CS-Lip in improving the enteral absorption of peptide drugs.