Development, Optimization and Absorption Mechanism of DHP107, Oral Paclitaxel Formulation for Single-Agent Anticancer Therapy

Lee, In-Hyun; Hong, Joo-Heon; Jang, Yura; Park, Yeong Taek; Chung, Heesun

doi:10.5772/33827

Cited by 3 publications

(8 citation statements)

References 37 publications

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“…Recovery of paclitaxel absorption in the second dose after food intake The absorption of paclitaxel after a single oral dose of DHP107 differed according to the food intake of the mice, as shown above. Although the increase in the AUC was only approximately 20% when the mice were fed compared with when they were fasted, we repeatedly observed this difference [1] . Moreover, the T max value in the fed group was 1 h, whereas that in the fasted group was 2 h, thus indicating that food in the gastrointestinal tract influenced drug absorption.…”

Section: Differential Scanning Calorimetry Of Dhp107 and F109mentioning

confidence: 62%

“…DHP107 is an oily formulation that melts completely at approximately 30 °C (Figure 1), undergoes an exothermic transition at approximately -20 °C, and remains as a single solid phase up to 0 °C. As the temperature increases from 0 °C to 30 °C, tricaprylin begins to melt at 4 °C, followed by monoolein at 12 °C; monoolein and tricaprylin then becomes immiscible in the temperature range from 4 to 30 °C [1] . However, after melting above 30 °C, DHP107 forms a single liquid phase without phase separation.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the antitumoral effects of orally administered DHP107 (50 mg/kg) are comparable to those of intravenously injected Taxol ® (10 mg/kg) in mice inoculated with lung, breast, and ovarian cancer cell lines [1,2,20] .…”

Section: Introductionmentioning

confidence: 90%

“…DHP107 is a single-agent oral paclitaxel formulation prepared as a semi-solid wax that melts at approximately 30 °C and is composed of monoolein, tricaprylin, polysorbate 80, and 1% (w/v) paclitaxel [1,2] . DHP107 is an oily liquid at body temperature that can be administered as an oral solution.…”

Section: Introductionmentioning

confidence: 99%

“…DHP107 is an oily liquid at body temperature that can be administered as an oral solution. We have previously designed DHP107 to be mucoadhesive in the gastrointestinal tract to facilitate adhesion to mucosal cells in the stomach and upper intestine [1][2][3][4][5][6][7] . Paclitaxel is one of the most widely used drugs used for the treatment of various cancers, such as breast, lung, and ovarian cancers [8] .…”

Section: Introductionmentioning

confidence: 99%

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Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase

et al. 2016

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Paclitaxel is a most widely used anticancer drug with low oral bioavailability, thus it is currently administered via intravenous infusion. DHP107 is a lipid-based paclitaxel formulation that can be administered as an oral solution. In this study, we investigated the mechanism of paclitaxel absorption after oral administration of DHP107 in mice and rats by changing the dosing interval, and evaluated the influence of bile excretion. DHP107 was orally administered to mice at various dosing intervals (2, 4, 8, 12, 24 h) to examine how residual DHP107 affected paclitaxel absorption during subsequent administration. Studies with small-angle X-ray diffraction (SAXS) and cryo-transmission electron microscopy (cryo-TEM) showed that DHP107 formed a lipidic sponge phase after hydration. The AUC values after the second dose were smaller than those after the first dose, which was correlated to the induction of expression of P-gp and CYP in the livers and small intestines from 2 h to 7 d after the first dose. The smaller AUC value observed after the second dose was also attributed to the intestinal adhesion of residual formulation. The adhered DHP107 may have been removed by ingested food, thus resulting in a higher AUC. In ex vivo and in vivo mucoadhesion studies, the formulation adhered to the villi for up to 24 h, and the amount of DHP107 that adhered was approximately half that of monoolein. The paclitaxel absorption after administration of DHP107 was not affected by bile in the cholecystectomy mice. The dosing interval and food intake affect the oral absorption of paclitaxel from DHP107, which forms a mucoadhesive sponge phase after hydration. Bile excretion does not affect the absorption of paclitaxel from DHP107 in vivo.

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Section: Differential Scanning Calorimetry Of Dhp107 and F109mentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase

et al. 2016

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The battle of “nano” paclitaxel

Sofias

Dunne

Storm

et al. 2017

Advanced Drug Delivery Reviews

297

223

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DHP23002 as a next generation oral paclitaxel formulation for pancreatic cancer therapy

et al. 2019

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ObjectiveThis study aimed to develop a new oral paclitaxel formulation (DHP23002) and to evaluate its absorption and antitumor effects in a pancreatic tumor mouse model.MethodsTo investigate the oral absorption of DHP23002, a newly developed lipid-based orally active paclitaxel formulation, a pharmacokinetic study of DHP23002, was conducted in mice (62.5 and 125 mg/kg). Moreover, to evaluate the antitumor effect of DHP23002 in pancreatic cancer treatment, the drug was administered to female athymic nude mice at 0 (vehicle), 25, 62.5, and 125 mg/kg on alternate days; the efficacy of the agent was compared with the efficacy of intravenous Taxol® injections at 10 mg/kg once per week. After 3 weeks of administration, tumor growth in mice belonging to each group was further monitored for 4 weeks after discontinuing medication. Moreover, to examine paclitaxel (DHP23002) accumulation in the tumor tissue, the amount of paclitaxel in tumor/blood was quantified using liquid chromatography with quadruple-TOF mass spectrometry.ResultsIn the mouse pharmacokinetic study, oral Taxol® showed a negligible absorption, whereas DHP23002 showed a high absorption rate dependent on dosage, with a bioavailability of approximately 40% at a dose of 62.5 mg/kg. In efficacy-related studies, DHP23002 administration at a dose of 25, 62.5, or 125 mg/kg on alternate days for 3 weeks showed a superior tumor inhibitory effect of 80%, 92%, and 97% in a xenograft mouse model, respectively, after 7 weeks. Paclitaxel accumulation in tumors persisted for >24 h in mice, when orally administered once at doses of 25, 62.5, and 125 mg/kg DHP23002.ConclusionOral chemotherapy with DHP23002 showed excellent absorption in animals owing to a strong antitumor activity in a pancreatic cancer mouse model. This demonstrates that paclitaxel is largely distributed and persists for a prolonged period at the tumor site owing to oral DHP23002 administration.

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Development, Optimization and Absorption Mechanism of DHP107, Oral Paclitaxel Formulation for Single-Agent Anticancer Therapy

Cited by 3 publications

References 37 publications

Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase

Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase

The battle of “nano” paclitaxel

DHP23002 as a next generation oral paclitaxel formulation for pancreatic cancer therapy

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