Development of Level A In Vitro–Vivo Correlation for Electrosprayed Microspheres Containing Leuprolide: Physicochemical, Pharmacokinetic, and Pharmacodynamic Evaluation

This study optimized the preparation of electrosprayed microspheres containing leuprolide and developed an in vitro–in vivo correlation (IVIVC) model that enables mutual prediction between in vitro and in vivo dissolution. The pharmacokinetic (PK) and pharmacodynamic (PD) study of leuprolide was carried out in normal rats after subcutaneous administration of electrosprayed microspheres. The parameters of the IVIVC model were estimated by fitting the PK profile of Lucrin depot® to the release compartment of the IVIVC model, thus the in vivo dissolution was predicted from the in vitro dissolution. From this correlation, the PK profile of leuprolide was predicted from the results of in vivo dissolution. The IVIVC model was validated by estimating percent prediction error (%PE) values. Among prepared microspheres, an optimal formulation was selected using the IVIVC model. The maximum plasma concentration and the area under the plasma concentration–time curve from zero to infinity from the predicted PK profile were 4.01 ng/mL and 52.52 h·ng/mL, respectively, and from the observed PK profile were 4.14 ng/mL and 56.95 h·ng/mL, respectively. The percent prediction error values of all parameters did not exceed 15%, thus the IVIVC model satisfies the validation criteria of the Food and Drug Administration (FDA) guidance. The PK/PD evaluation suggests that the efficacy of OL5 is similar to Lucrin depot®, but the formulation was improved by reducing the initial burst release.

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Developing a new formulation of sodium phenylbutyrate

Archives of Disease in Childhood ◽

10.1136/archdischild-2012-302398 ◽

2012 ◽

Vol 97 (12) ◽

pp. 1081-1085 ◽

Cited By ~ 25

Author(s):

Nathalie Guffon ◽

Yves Kibleur ◽

William Copalu ◽

C Tissen ◽

Joerg Breitkreutz

Keyword(s):

Plasma Concentration ◽

Healthy Adult ◽

Taste Perception ◽

In Vitro Dissolution ◽

Time Curve ◽

New Formulation ◽

Adult Volunteers ◽

Sodium Phenylbutyrate

BackgroundSodium phenylbutyrate (NaPB) is used as a treatment for urea cycle disorders (UCD). However, the available, licensed granule form has an extremely bad taste, which can compromise compliance and metabolic control.ObjectivesA new, taste-masked, coated-granule formulation (Luc 01) under development was characterised for its in vitro taste characteristics, dissolution profiles and bioequivalence compared with the commercial product. Taste, safety and tolerability were also compared in healthy adult volunteers.ResultsThe in vitro taste profile of NaPB indicated a highly salty and bitter tasting molecule, but Luc 01 released NaPB only after a lag time of ∼10 s followed by a slow release over a few minutes. In contrast, the licensed granules released NaPB immediately. The pharmacokinetic study demonstrated the bioequivalence of a single 5 g dose of the two products in 13 healthy adult volunteers. No statistical difference was seen either for maximal plasma concentration (Cmax) or for area under the plasma concentration–time curve (AUC). CI for Cmax and AUC0–inf of NaPB were included in the bioequivalence range of 0.80–1.25. One withdrawal for vomiting and five reports of loss of taste perception (ageusia) were related to the licensed product. Acceptability, bitterness and saltiness assessed immediately after administration indicated a significant preference for Luc 01 (p<0.01), confirming the results of the taste prediction derived from in vitro measurements.ConclusionsIn vitro dissolution, in vitro and in vivo taste profiles support the view that the newly developed granules can be swallowed before release of the bitter active substance, thus avoiding stimulation of taste receptors. Moreover, Luc 01 was shown to be bioequivalent to the licensed product. The availability of a taste-masked form should improve compliance which is critical to the efficacy of NaPB treatment in patients with UCD.

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Soybean Milk Inhibits Absorption and Intestinal Transmembrane Transport of Gegen in Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/7146813 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Xiao Ling ◽

Yuqiang Xiang ◽

Qingfa Tang ◽

Zhen Jin ◽

Feilong Chen ◽

...

Keyword(s):

Plasma Concentration ◽

Ussing Chamber ◽

Transmembrane Transport ◽

Maximum Plasma ◽

Apparent Permeability ◽

Time Curve ◽

Soybean Milk ◽

Rich Food

Puerariae Lobatae Radix, known as Gegen in Chinese, is widely used to treat cardiovascular diseases, diabetes, and many other chronic illnesses. Flavonoids are the main active components in Gegen and are found in high concentrations in soybeans. Few studies, however, have focused on the effects of flavonoid-rich food on the absorption of Gegen. Here, we report an in vivo pharmacokinetic study on rats to explore the effects of soybean milk on the absorption of Gegen and an in vitro Ussing chamber study of puerarin intestinal transmembrane absorption. Area under the plasma concentration-time curve (AUC0–t) and maximum plasma concentration (Cmax) values of puerarin in rats were significantly decreased after drinking soybean milk, when taking Gegen decoction or a Gegen patent medicine (P < 0.01). In the Ussing chamber experiment, cumulative transmission (Qtn) after 2 h and apparent permeability coefficient (Papp) were lower in the puerarin-daidzin and puerarin-soybean milk solution groups than in the puerarin group. Daidzin in soybean milk inhibited the transmembrane transport of puerarin, resulting in decreased bioavailability of puerarin in Gegen. The results of this study strongly suggest that Gegen should not be taken with flavonoid-rich food, particularly soybean products.

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Development of Biodegradable Injectable In situ Forming Implants for Sustained Release of Lornoxicam

Current Drug Delivery ◽

10.2174/1567201815666180927155710 ◽

2018 ◽

Vol 16 (1) ◽

pp. 66-78 ◽

Cited By ~ 2

Author(s):

Ruby Christian ◽

Vaishali Thakkar ◽

Tushar Patel ◽

Mukesh Gohel ◽

Lalji Baldaniya ◽

...

Keyword(s):

Plasma Concentration ◽

Drug Release ◽

Entrapment Efficiency ◽

Burst Release ◽

Maximum Plasma ◽

Sustained Drug Release ◽

Drug Entrapment Efficiency ◽

Ft Ir

Objective: The focus of this study was to develop in situ injectable implants of Lornoxicam which could provide sustained drug release. Methods: Biodegradable in situ injectable implants were prepared by polymer precipitation method using polylactide-co-glycolide (PLGA). An optimized formulation was obtained on the basis of drug entrapment efficiency, gelling behavior and in vitro drug release. The compatibility of the formulation ingredients were tested by Fourier transform infrared (FT-IR) spectroscopy, and differential scanning colorimetry (DSC). SEM study was performed to characterize in vivo behavior of in situ implant. Pharmacokinetic study and in vivo gelling study of the optimized formulation were performed on Sprague-Dawley rats. Stability testing of optimized formulation was also performed. Results: The drug entrapment efficiency increased and burst release decreased with an increase in the polymer concentration. Sustained drug release was obtained up to five days. SEM photomicrographs indicated uniform gel formation. Chemical interaction between the components of the formulation was not observed by FT-IR and DSC study. Pharmacokinetic studies of the optimized formulation revealed that the maximum plasma concentration (Cmax), time to achieve Cmax (Tmax) and area under plasma concentration curve (AUC) were significantly higher than the marketed intramuscular injection of lornoxicam. Stability study of optimized batch showed no change in physical and chemical characteristics. Conclusion: Lornoxicam can be successfully formulated as in situ injectable implant that provides long-term management of inflammatory disorders with improved patient compliance.

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Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

Pharmaceutics ◽

10.3390/pharmaceutics13060782 ◽

2021 ◽

Vol 13 (6) ◽

pp. 782

Author(s):

Ji-Min Kim ◽

Seong-Wook Seo ◽

Dong-Gyun Han ◽

Hwayoung Yun ◽

In-Soo Yoon

Keyword(s):

Plasma Concentration ◽

Liver Microsome ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Systemic Exposure ◽

Concurrent Administration ◽

Time Curve ◽

Mixed Inhibition

Repaglinide (RPG), a rapid-acting meglitinide analog, is an oral hypoglycemic agent for patients with type 2 diabetes mellitus. Quercetin (QCT) is a well-known antioxidant and antidiabetic flavonoid that has been used as an important ingredient in many functional foods and complementary medicines. This study aimed to comprehensively investigate the effects of QCT on the metabolism of RPG and its underlying mechanisms. The mean (range) IC50 of QCT on the microsomal metabolism of RPG was estimated to be 16.7 (13.0–18.6) μM in the rat liver microsome (RLM) and 3.0 (1.53–5.44) μM in the human liver microsome (HLM). The type of inhibition exhibited by QCT on RPG metabolism was determined to be a mixed inhibition with a Ki of 72.0 μM in RLM and 24.2 μM in HLM as obtained through relevant graphical and enzyme inhibition model-based analyses. Furthermore, the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of RPG administered intravenously and orally in rats were significantly increased by 1.83- and 1.88-fold, respectively, after concurrent administration with QCT. As the protein binding and blood distribution of RPG were observed to be unaltered by QCT, it is plausible that the hepatic first-pass and systemic metabolism of RPG could have been inhibited by QCT, resulting in the increased systemic exposure (AUC and Cmax) of RPG. These results suggest that there is a possibility that clinically significant pharmacokinetic interactions between QCT and RPG could occur, depending on the extent and duration of QCT intake from foods and dietary supplements.

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Dissolution Effect of Gastric and Intestinal pH fora BCS class II drug, Pioglitazone: New in vitro Dissolution System to Predict in vivo Dissolution

Journal of Bioequivalence & Bioavailability ◽

10.4172/jbb.1000162 ◽

2013 ◽

Vol 05 (06) ◽

Cited By ~ 17

Author(s):

Yasuhiro Tsume

Keyword(s):

Class Ii ◽

In Vitro Dissolution ◽

Bcs Class Ii ◽

In Vivo Dissolution

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Measurement of in Vitro Dissolution of Aerosol Particles for Comparison to in Vivo Dissolution in the Lower Respiratory Tract after Inhalation

Health Physics ◽

10.1097/00004032-197305000-00004 ◽

1973 ◽

Vol 24 (5) ◽

pp. 497-507 ◽

Cited By ~ 65

Author(s):

G. M. Kanapilly ◽

O. G. Raabe ◽

C. H. T. Goh ◽

R. A. Chimenti

Keyword(s):

Respiratory Tract ◽

Lower Respiratory Tract ◽

Aerosol Particles ◽

In Vitro Dissolution ◽

In Vivo Dissolution

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Application of the Correlation of in Vitro Dissolution Behavior and in Vivo Plasma Concentration Profile (IVIVC) for Soft-Gel Capsules—a Pointless Pursuit?

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.30.2221 ◽

2007 ◽

Vol 30 (11) ◽

pp. 2221-2225 ◽

Cited By ~ 11

Author(s):

Hidekatsu Nishimura ◽

Chiaki Hayashi ◽

Tetsuya Aiba ◽

Ichiro Okamoto ◽

Yuji Miyamoto ◽

...

Keyword(s):

Plasma Concentration ◽

Concentration Profile ◽

In Vitro Dissolution ◽

Dissolution Behavior

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A Pharmacokinetic Evaluation of a Pectin-Based Oral Multiparticulate Matrix Carrier of Carbamazepine

Advances in Pharmacological and Pharmaceutical Sciences ◽

10.1155/2021/5527452 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Seth Kwabena Amponsah ◽

Simon Yeboah ◽

Kennedy Kwami Edem Kukuia ◽

Benoit Banga N’guessan ◽

Ofosua Adi-Dako

Keyword(s):

Citric Acid ◽

Elimination Rate ◽

Pharmacokinetic Profile ◽

Maximum Plasma ◽

Acid Solutions ◽

Time Curve ◽

In Vivo Models ◽

Cocoa Pod Husks

Background. Carbamazepine is a drug used in the treatment of neurological disorders such as epilepsy. However, due to its erratic absorption, oral bioavailability is often poor. There is, therefore, the need to develop alternative formulations for carbamazepine with better pharmacokinetic characteristics. Aim. The aim of this study was to formulate an oral modified-release multiparticulate matrix of carbamazepine from cocoa pod husk (CPH) pectin and evaluate the pharmacokinetic profile of this formulation using in vitro and in vivo models. Methods. CPH pectin was extracted from cocoa pod husks with hot aqueous and citric acid solutions. Oral multiparticulate carbamazepine matrices were formulated from CPH pectin cross-linked with calcium. The formulation was evaluated for carbamazepine content and release profile in vitro. For in vivo pharmacokinetic profile estimation, rats were put into 4 groups of 5 animals each to receive carbamazepine multiparticulate matrix formulations A and B, carbamazepine powder, and Tegretol CR®. Animals in each group received 200 mg/kg of each drug via the oral route. Maximum plasma concentration C max , area under the concentration-time curve (AUC), elimination rate constant K e , and terminal half-life t 1 / 2 of the formulations were estimated by noncompartmental analysis. Results. The pectin extraction from fresh cocoa pod husks using hot aqueous and citric acid solutions gave pectin yields of 9.63% and 11.54%, respectively. The drug content of carbamazepine in CPH pectin formulations A and B was 95% and 96%, respectively. There was controlled and sustained release of carbamazepine for both formulations A and B in vitro. AUC0⟶36 (176.20 ± 7.97 µg.h/mL), C max (8.45 ± 0.71 μg/mL), T max (12 ± 1.28 h), and t 1 / 2 (13.75 ± 3.28 h) of formulation A showed a moderately enhanced and comparable pharmacokinetic profile to Tegretol CR® (AUC0⟶36: 155 ± 7.15 µg.h/mL, C max : 8.24 ± 0.45 μg/mL, T max : 8.0 ± 2.23 h, and t 1 / 2 : 13.51 ± 2.87 h). Conclusion. Findings from the study suggest that formulations of CPH pectin had the potential to control and maintain therapeutic concentrations of carbamazepine in circulation over a period of time in the rat model.

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