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Controlled release and comparative pharmacokinetics of bethanechol- loaded oral dosage forms

  • 정형모 (아주대학교 일반대학원)

초록/요약

Betanechol chloride (BTC) was synthesized in 1935 by Major at the suggestion of Simonart(Finkbeiner, 1985), and is still used today as a treatment for patients with urinary difficulties. BTC is orally administered in 10–25 mg doses three to four times daily. This frequency of administration can be inconvenient to patients, reducing adherence. To improve patient compliance, there is a strong need to develop advanced BTC dosage formulations that are more patient-friendly. To achieve these goals, BTCloaded controlled-release formulations are needed. This study aimed to investigate the release-modulating mechanism and compare in vivo pharmacokinetics of four different BTC-loaded oral dosage forms to reduce dosing frequency: gastro-retentive tablet (GRT), controlledrelease tablet (CRT), bilayer tablet (BLT), and tablet-in-tablet (TIT). The highly water-soluble BTC was selected as the model drug. The release profiles of the four BTC-loaded dosage forms varied according to system design and formulation composition. The optimized GRT F-5 showed rapid buoyancy within 15 s and floated for 12 h, while continuously releasing the drug. CRT showed Fickian diffusion release, whereas BLT and TIT exhibited distinct immediate and sustained release profiles. In the 30-min dissolution tests, the GRT F-5, BLT, and TIT released 18.2, 27.5, and 32.2% of the drug, respectively. However, CRT F-7 coated with ethyl cellulose did not release the drug. According to instrumental analysis using Field Emission Scanning Electron Microscopy and FT-IR spectroscopy, the hydrogen bond formation of BTC with polymers, such as hydroxypropyl methylcellulose and polyethylene oxide as release-modulating agents and loosening of the polymer structure was crucial as the water influx increased. In pharmacokinetic studies in beagle dogs, the area under the plasma concentration-time curve (AUC) by dose for 48 h for GRT, CRT, BLT, and TIT were 90.2%, 108.6%, 83.8%, and 76.4%, respectively, compared with that of the reference drug (Mytonin® tablet, immediate release, four times a day). Notably, the plasma maximum concentration and area under the curve (AUC)0-12 h of GRT F-5 and Mytonin®tablet for the first 12-h period were much higher compared with that of other BTC-loaded CRT, BLT, and TIT. BTC was absorbed throughout the gastrointestinal tract but preferentially absorbed in the stomach and upper gastrointestinal site. However, GRT F-5 can be more appropriate for better patient compliance in the rapid onset time of efficacy and more prolonged duration time for patients with bladder dysfunction to reduce the dosing frequency of the Mytonin®tablet.

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목차

1. Introduction 1
2. Materials and Methods 13
2.1. Materials 13
2.2. Solubility studies 14
2.3. BTC-excipient compatibility studies 14
2.4. Preparation of BTC-loaded tablet formulations 17
2.5. In vitro buoyancy studies 22
2.6. Swelling and erosion studies by gravimetric analysis of GRTs and CRTs tablet 22
2.7. In vitro dissolution studies 24
2.8. Release kinetics and mechanism of BTC-loaded tablets and CRTs tablets 24
2.9. Water penetration 26
2.10. Field emission scanning electron microscopy (FE-SEM) 26
2.11. HPLC analysis 27
2.12. Fourier transform-infrared (FT-IR) spectroscopy analysis 27
2.13. In vivo pharmacokinetic studies 28
2.13.1. Animals 28
2.13.2. Experimental design 28
2.13.3. UPLC – MS/MS analysis 31
2.13.4. Statistical analysis 32
3. Results and Discussion 33
3.1. Solubility studies 33
3.2. BTC-excipient compatibility studies 36
3.3. In vitro buoyancy studies 38
3.4. Swelling and erosion studies by gravimetric analysis of GRTs and CRTs tablet 41
3.5. In vitro dissolution studies 50
3.6. Drug release kinetic modeling 55
3.7. Release-modulating mechanism – Relationship between dissolution, matrix, erosion, and water uptake 60
3.8. Field Emission Scanning Electron Microscopy (FE-SEM) 65
3.9. Fourier-transform infrared (FT-IR) spectroscopy analysis 67
3.10. In vivo pharmacokinetic studies in beagle dogs 71
4. Conclusions 82
5. Graphical abstract 84
6. References 85

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