Mucoadhesive bilayer buccal tablet of carvedilol-loaded chitosan microspheres: in vitro, pharmacokinetic and pharmacodynamic investigations

A multiple-unit system comprising mucoadhesive bilayer buccal tablets of carvedilol-loaded chitosan microspheres (CMs) was developed to improve bioavailability and therapeutic efficacy of carvedilol. Drug-loaded CMs were prepared by spray drying, evaluated for powder and particle characteristics, and optimized batch of CMs was compressed into bilayer buccal tablets using Carbopol. Tablets were evaluated for physicochemical parameters, in vitro drug release, in vivo pharmacokinetic and pharmacodynamic studies. Optimized formulation, CMT1 (CMT, chitosan microsphere tablet) showed maximum mucoadhesive force (50?±?1.84?dyne/cm2), exhibited 73.08?±?3.05% drug release and demonstrated zero-order kinetics with non-Fickian release mechanism. Pharmacokinetic studies in rabbits showed significantly higher C(max) (71.26?±?6.45?ng/mL), AUC(0-10) (AUC, area under the curve 390.75?±?5.23?ng/mL/h) and AUC(0-∞) (664.72?ng/mL/h) than carvedilol oral tablet. Pharmacodynamic studies confirmed reduction in mean arterial pressure, heart rate, body weight and triglyceride on administration of bilayer buccal tablet compared to oral carvedilol tablet. Multiple-unit system exhibited enhanced bioavailability and sustained release of carvedilol, indicating its improved therapeutic potential for the treatment of hypertension.     

Novel tablet formulation of amorphous candesartan cilexetil solid dispersions involving P-gp inhibition for optimal drug delivery: in vitro and in vivo evaluation

Objective: The aim of this study was to develop a novel tablet formulation of amorphous candesartan cilexetil (CAN) solid dispersion involving effective P-gp inhibition for optimal drug delivery by direct compression (DC) method.

Methods: To accomplish DC, formulation blends were evaluated for micromeritic properties. The Carr index, Hausner ratio, flow rate and cotangent of the angle α were determined. The tablets with and without naringin prepared by DC technique were evaluated for average weight, hardness, disintegration time and friability assessments. The drug release profiles were determined to study the dissolution kinetics. In vivo pharmacokinetic studies were conducted in rabbits. Accelerated stability studies were performed for tablets at 40?±?2?°C/75% RH?±?5% for 6 months.

Results: FTIR studies confirmed no discoloration, liquefaction and physical interaction between naringin and drug. The results indicated that tablets prepared from naringin presented a dramatic release (82%) in 30?min with a similarity factor (76.18), which is most likely due to the amorphous nature of drug and the higher micromeritic properties of blends. Our findings noticed 1.7-fold increase in oral bioavailability of tablet prepared from naringin with mean C_max and AUC_0–12?h values as 35.81?±?0.13?μg/mL and 0.14?±?0.09?μg h/mL, respectively. The tablets with and without naringin prepared by DC technique were physically and chemically stable under accelerated stability conditions upon storage for 6 months.

Conclusion: These results are attractive for further development of an oral tablet formulation of CAN through P-gp inhibition using naringin, a natural flavonoid as a pharmaceutical excipient.     

Buccal films of prednisolone with enhanced bioavailability

Abstract

The conventional formulation of prednisolone is considered to be low in efficacy, primarily on account of their failure in providing and maintaining effective therapeutic drug levels. This study aims to focus on development of a mucoadhesive buccal delivery system with a twofold objective of offering a rapid as well as a prolonged delivery of prednisolone coupled with enhanced therapeutic efficacy. Buccoadhesive films of prednisolone were prepared by solvent-casting method using hydroxyl propyl methyl cellulose (K100), Carbopol 940 and/or Eudragit® NE 40?D. Placebo films possessing the most desirable physicomechanical properties were selected for drug loading. The effect of polymer and its content on film properties, i.e. mucoadhesive strength, swelling and hydration, in vitro drug release was studied. Based on these studies, film F7D was selected for ex vivo permeation across porcine cheek mucosa. The steady state flux of prednisolone across the buccal mucosa was found to be 105.33?±?32.07?µg/cm²/h. A comparative pharmacokinetic study of prepared film (F7D) and oral suspension of prednisolone was conducted. In vivo data of buccal film show greater bioavailability (AUC_0–α: 24.26?±?4.06?µg.h/ml versus 10.65?±?2.15?µg.h/ml) and higher C_max (2.70?±?0.38?µg/ml versus 2.29?±?0.32?µg/ml) value when compared to oral suspension. The data observed from this study highlight the feasibility of the buccal route as a viable option for delivery of prednisolone.     

Controlled porosity osmotic pump system for the delivery of diclofenac sodium: in-vitro and in-vivo evaluation

Abstract

The objective of this study was to develop controlled porosity osmotic pump (CPOP) tablets of diclofenac sodium (DS). The influence of different cores (polymers and osmogens) and coats (thickness and porosigen content) on DS release were studied. Results revealed that decreasing HPMC viscosity grade from 4000cp (K4M) to 15cp (E15) increased DS release. While increasing the tablet coat thickness decreased DS release. The presence of osmogen increased DS release in the following rank: mannitol?>?lactose?>?avicel. There was a direct relationship between increasing PEG-400 in the coating solution and the amount of drug released in all formulations studied, except in one condition. A comparative bioavailability study using a selected CPOP formulation (T) versus the innovator product (R) revealed that CPOP tablet maintained a less fluctuated DS plasma concentration for up to 24?h with a detected mean C_max of 836.8?±?142.4 and 445.0?±?81.0?ng/mL for R and T, respectively. There were no statistically significant differences between R and T, concerning AUC_0?24 and AUC_0?∞. Moreover, the appearance of the multi-peak phenomenon, which is frequently observed with DS absorption, was found in only 25% of volunteers in case of T versus 75% in case of R.     

Effect of poloxamer 188 on lymphatic uptake of carvedilol-loaded solid lipid nanoparticles for bioavailability enhancement

The present work aimed to investigate the effect of different concentrations of poloxamer 188, a surfactant, on lymphatic uptake of carvedilol-loaded solid lipid nanoparticles (SLNs) for oral bioavailability enhancement. Microemulsion technique was employed to prepare the SLN formulations having varying concentrations of poloxamer 188, which were subsequently subjected to various in vitro and in vivo evaluations to study their release pattern. On increasing the percentage concentration of poloxamer 188, the bioavailability decreased from 4.91- to 2.84-fold after intraduodenal administration in the male Wister rat. It could be attributed to the increase in particle size as well as reduction in hydrophobicity of SLNs. As indicated by pharmacokinetic data, the AUC_(0–t) of all three (SLN) formulations (6.27?±?0.24 μgh/mL with FZ-1, 4.13?± 0.11 μgh/mL with FZ-2, and 3.63?±?0.10 μgh/mL with FZ-3) were significantly higher (p?<?0.05) than that of carvedilol suspension (1.27?±?0.23 μgh/mL). These findings augur well with the possibility of enhancement of the oral bioavailability of drug, via the lymphatic system bypassing hepatic first pass metabolism.     

In vitro and in vivo evaluation of locust bean gum and chitosan combination as a carrier for buccal drug delivery

The object of the study was to evaluate locust bean gum and chitosan in ratios of 2:3; 3:2 and 4:1 (F1, F2 and F3) as a mucoadhesive component in buccal tablets and to compare the bioavailability of a propranolol hydrochloride buccal tablet with the oral tablet in healthy human volunteers. Propranolol hydrochloride buccal tablets containing various weight ratios of locust bean gum and chitosan were prepared and coated with 5% w/v ethyl cellulose on one face, and oral tablets containing 10 mg propranolol hydrochloride alone were formulated using a direct compression technique. The strength of mucoadhesion of the tablets was quantified based on the tensile force required to break the adhesive bond between a model membrane (porcine buccal mucosa) and the test polymer. The forces of detachment for the mucoadhesive buccal tablets were 14.61 +/- 0.14, 13.21 +/- 0.13 and 11.71 +/- 0.12. An in vitro study was carried out in pH 6.8 phosphate buffer and the cumulative percentage release of propranolol measured at 10 min intervals for 600 min was found to be 98.31 +/- 0.10, 92.24 +/- 0.41 and 90.18 +/- 0.76 respectively. A bioavailability study was conducted with the prepared formulation in 16 healthy human volunteers to determine the plasma concentration of propranolol at 0, 1, 2, 3, 4, 6, 8, 10 and 12 h. The bioavailability (AUC(0-t*) ng x h/ml) of the buccal propranolol hydrochloride tablets (F1, F2 and F3) and oral tablet (F4) was found to be 2244.18 +/- 210, 3580.69 +/- 460, 3889.19 +/- 290 and 1732 +/- 96 ng x hr/ml respectively. The study indicates that locust bean gum and chitosan in a weight ratio of 2:3 (F1) not only releases the drug unidirectionally from the dosage form, but also gives buccal tablets which are sufficiently mucoadhesive for clinical applications.     

Gastroretentive mucoadhesive tablet of lafutidine for controlled release and enhanced bioavailability

Abstract

Lafutidine a newly developed histamine H2-receptor antagonist having biological half-life of 1.92?±?0.94?h due to its selective absorption from upper part of gastrointestinal tract the development of mucoadhesive sustained release drug delivery system is recommended in order to enhance the bioavailability. A mucoadhesive tablets was developed using the natural polymer, sodium alginate, xanthan gum and karaya gum. Mucoadhesion is a complex phenomenon which involves wetting, adsorption and interpenetration of polymer chains. The prepared tablets of various formulations were evaluated for a total mucoadhesion time, buoyancy lag time and percentage drug released. The formulation with xanthan gum showed better results. Thus, it may be useful for prolonged drug release in stomach to improve the bioavailability and reduced dosing frequency. Non-fickians release transport was confirmed as the drug release mechanism from the optimized formulation by Korsmeyer–Peppas. The optimized formulation (B3) showed a mucoadhesive strength >35?g. In vivo study was performed using rabbits by X-ray imaging technique. Radiological evidences suggest that, a formulated tablet was well adhered for >10?h in rabbit’s stomach. Optimized lafutidine mucoadhesive tablets showed no significant change in physical appearance, drug content, mucoadhesive properties and in vitro dissolution pattern after storage at 40?°C temperature 75?±?5% relative humidity for 3 months.     

Determination of dihydromyricetin in rat plasma by LC-MS/MS and its application to a pharmacokinetic study

Context: The pharmacokinetics properties of dihydromyricetin (DHM) are still unknown.

Objective: This study investigates the pharmacokinetic characteristics of DHM using a sensitive and reliable LC-MS/MS method.

Materials and methods: A rapid and sensitive LC-MS/MS method was developed for the determination of DHM in male Sprague–Dawley rat plasma. Twelve rats were equally randomized into two groups, including the intravenous group (2?mg/kg) and the oral group (20?mg/kg). Blood samples (250?μL) were collected at designated time points and analyzed using this method. The pharmacokinetic parameters were calculated using DAS 3.0 pharmacokinetic software.

Results: The calibration curve was linear within the range of 0.5–200?ng/mL (r?>?0.998) with the lower limit of quantification at 0.5?ng/mL. After the intravenous injection, DHM reached a maximum concentration of 165.67?±?16.35?ng/mL, and t_1/2 was 2.05?±?0.52?h. However, DHM was not readily absorbed and reached C_max 21.63?±?3.62?ng/mL at approximately 2.67?h following the oral administration of DHM, and t_1/2 was 3.70?±?0.99?h. The MRT for the intravenous group and the oral group were 2.62?±?0.36 and 5.98?±?0.58?h, respectively. The AUC_(0-t) for the intravenous group and the oral group were 410.73?±?78.12 and 164.97?±?41.76?ng·L/mL, respectively, so the absolute bioavailability of DHM was 4.02% which was poor.

Discussion and conclusion: The results indicated that the bioavailability was poor. Further work needs to be conducted to investigate the reason for poor bioavailability and improve this situation.     

Metabolite profile analysis and pharmacokinetic study of emodin,baicalin and geniposide in rats

1. Emodin, baicalin and geniposide are the major bioactive components in Da-Huang, Huang-Qin and Zhi-Zi which are herbal medicines widely used in Asian nations.

2. The metabolism of the three compounds was found to undergo hydroxylation, decarboxylation, dehydration, methylation, hydrolysis, hydrogenation, dihydrogenation, sulfation, glucosidation and/or glucuronidation. A total of 63 metabolites were detected in urine, plasma and bile of rats given a mixture of the three compounds.

3. Pharmacokinetic properties of the three compounds were determined in rats given the extracts of Da-Huang, Huang-Qin and Zhi-Zi. The pharmacokinetic parameters for emodin, baicalin and geniposide were found to be 0.13?±?0.11, 0.25?±?0.12 and 0.40?±?0.09?h (T_max); 21?±?9, 1515?±?254 and 482?±?50?ng/mL (C_max); 8.6?±?5.5, 18.3?±?2.8 and 22.1?±?17.2?h (t_1/2); 29?±?20, 16886?±?3734 and 2936?±?551?ng/mL?h (AUC_(0–t)); and 37?±?20, 22624?±?6295 and 3582?±?820?ng/mL?h (AUC_(0–∞)).

4. The metabolism and pharmacokinetic studies facilitate appropriate employment of Da-Huang, Huang-Qin and Zhi-Zi in clinic.     

Preparation and pharmacokinetics evaluation of oral self-emulsifying system for poorly water-soluble drug Lornoxicam

Abstract

The present work was performed aiming to develop a new solid self-emulsifying system (SMEDDS) for poorly water-soluble drug Lornoxicam and evaluate the bioavailability in Wister rats by oral gavage. Liquid SMEDDS of Lornoxicam was formulated with Labrafil M 1944 CS as oil phase, Kolliphor HS 15 as a surfactant and Transcutol HP as a cosurfactant after screening various vehicles. The microemulsion system selected from the phase diagram and optimized by central composite design (CCD) response surface method was transformed into solid-SMEDDS (S-SMEDDS) by lyophilization using sucrose as cryoprotectant. The formulations were further characterized by the particle size, poly dispersity index (PDI), self-emulsifying time, zeta potential, transmission electron microscope (TEM), differential scanning calorimeter (DSC), in vitro drug release and in vivo pharmacokinetics. Results of DSC studies confirmed that the drug was incorporated in the S-SMEDDS. The in vitro drug release from Lornoxicam SMEDDS was found to be greatly higher in comparison with that from the commercial tablets. It was indicated that SMEDDS might be effective in reducing the effect of pH variability of Lornoxicam and improving the release performance of Lornoxicam. HPLC system was applied to study the concentration of Lornoxicam in the plasma of the Wister rats after oral administration of Lornoxicam SMEDDS and Lornoxicam commercial tablets. The pharmacokinetics parameters of the rats were C_max 1065.91?±?224.90 and 1855.22?±?748.25?ngmL^?1, T_max were 2.5?±?0.4?h and 1.8?±?0.5?h, and AUC_0～t were 5316.35?±?323.62 and 7758.07?±?241.57?ngmL^?1?h, respectively. Calculated by AUC_0～∞, the relative bioavailability of Lornoxicam S-SMEDDS was 151.69?±?15.32%. It suggested that this S-SMEDDS could be used as a successful oral solid dosage form to improve the solubility and bioavailability of poorly water-soluble drug Lornoxicam as well.     

Formulation and evaluation of mucoadhesive buccal films impregnated with carvedilol nanosuspension: a potential approach for delivery of drugs having high first-pass metabolism

Abstract

Context: Mucoadhesive buccal films containing three layers (mucoadhesive layer, nanosuspension containing layer and backing membrane) were incorporated with carvedilol nanosuspension.

Objective: Formulation and evaluation of nanosuspension incorporated mucoadhesive buccal films of carvedilol for bioavailability enhancement by avoiding first-pass metabolism.

Methods: Carvedilol-loaded nanosuspension was prepared by a precipitation–ultrasonication method with varying concentrations of the polymer. The formulation was analyzed for size, size distribution, surface charge and morphology. Optimized nanosuspension was incorporated into drug gel layer which was sandwiched between a mucoadhesive layer and a backing layer to form tri-layered buccal films. They were evaluated for their physical, mechanical and bioadhesive parameters followed by in vitro and in vivo studies.

Results and discussion: Nanosuspension showed a negative zeta potential (?17.21?mV) with a diameter of around 495 nm and a polydispersity index of 0.203. Nanosuspension incorporated drug gel layer (62.4% drug loading) was optimized to contain 3% HPMC and 50?mg Carbopol 934P. The mucoadhesive layer and the backing layer were optimized to contain 3% HPMC and 1% ethyl cellulose, respectively. In vitro drug release was 69% and 62.4% in 9?h across synthetic membrane and porcine buccal mucosa, respectively. In vivo studies conducted in rabbit model showed 916% increase in the relative bioavailability in comparison to marketed oral tablet formulation. The C_max and T_max of the prepared formulation increased due to increased surface area of drug and also by-passing hepatic metabolism.

Conclusion: The drug delivery system has been designed as a novel platform for potential buccal delivery of drugs having high first-pass metabolism.     

Pharmacokinetic study of methylnaltrexone after single and multiple subcutaneous administrations in healthy Chinese subjects

1. Pharmacokinetics of methylnaltrexone (MNTX) were evaluated after subcutaneous administrations (s.c.) in healthy Chinese subjects.

2. In a cross-over single dose study, 12 subjects were given 0.075, 0.15, and 0.3?mg/kg of MNTX bromide injection. In a multiple doses study, another 12 subjects subcutaneously received 0.15?mg/kg of MNTX bromide injection every 48?h, in total five administrations. The concentrations of MNTX in plasma were quantified by LC–MS/MS.

3. After single s.c. administrations of 0.075, 0.15, and 0.3?mg/kg of MNTX bromide, C_max values of MNTX were 93.5?±?28.6, 191?±?37, and 364?±?54?ng/mL, respectively, and AUC_0–∞ were 88.8?±?8.8, 181?±?16, and 357?±?34?ng?h/mL, respectively. The t_1/2 of MNTX was about 7.7?h. After multiple doses administration, the C_max, C_av, AUC_ss, and MRT_0–∞ values were 191?±?50, 3.79?±?0.40?ng/mL, 182?±?19?ng?h/mL, and 3.56?±?1.17?h, respectively.

4. Methylnaltrexone bromide displayed dose-proportional pharmacokinetics in the dose range of 0.075–0.3?mg/kg. After multiple doses administration, t_1/2 was slightly prolonged, with the cumulative factor of 1.02. This study provides a pharmacokinetic reference after a single dose and multiple doses of MNTX bromide in Chinese subjects.     

Development of mucoadhesive floating hollow beads of acyclovir with gastroretentive properties

Abstract

This study aimed at improving the oral bioavailability of acyclovir (ACV) through incorporating it into gastroretentive dosage form based on floating hollow chitosan beads. Hollow chitosan beads were prepared using a solvent free, ionotropic gelation method. The effect of formulation parameters, including chitosan molecular weight and drug concentration, on bead characteristics was studied. The drug containing formulations had yields >70.5?±?0.31%. The entrapment efficiencies for the medium molecular weight chitosan formulations (56.29?±?0.94%–62.75?±?0.86%) was greater than the high molecular weight chitosan formulation (29.21?±?0.89%). The density of all formulations was below that of gastric fluid, the greatest density observed was 0.60?±?0.01?g?cm^?3. Unsurprisingly, the formulations were immediate bouyant to different degrees in both pH 1.2 and pH 6.8 media. In addition, the chitosan beads were all seen to swell in pH 1.2 media and demonstrated mucoadhesive properties. A sustained release profile was observed from the chitosan beads, the developed formulations released drug at slower rates than a marketed ACV oral tablet. The developed system has the dual advantages of being gastroretentive, to increase oral bioavailability and releasing drug in a controlled manner, to reduce the required frequency of administration thereby promoting patient adherence.     

Buccal Transmucosal Delivery of Calcitonin in Rabbits Using Thin-Film Composites

Purpose. Salmon Calcitonin (sCT) is used to treat hypercalcemia resulting from Paget's disease and osteoporosis. sCT is available either in a sterile injectable form or nasal spray. Alternative and more cost-effective dosage forms for the delivery of calcitonin are needed. We sought to deliver sCT transmucosally using a previously reported mucoadhesive bilayer thin-film composite (TFC) via the buccal route. Methods. Forty micrograms of salmon calcitonin (200-IU) was loaded on preformed TFCs. In vitro release of sCT from TFCs was monitored in phosphate-buffered saline (10 mM, pH 7.4) at 37°C. Female New Zealand White rabbits (n = 6) were dosed with 40 g of sCT either by injection via the ear vein or by applying sCT-loaded TFCs directly on the buccal pouch. Blood was collected at various times, and the plasma sCT and calcium concentrations were quantified. WinNonlin® was used to determine the relevant pharmacokinetic parameters. Results. In vitro, over 80% of sCT was released from the TFCs within 240 min. Super Case-II transport was indicated as the primary release mechanism. Rabbits injected intravenously had C _max, Cls, Vss, and AUC_0-inf values of 75.1 ± 6.5 ng/mL, 20.7 ± 3.3 mL/min, 637 ± 141 mL, and 1925 ± 237 ng*min/mL, respectively. Rabbits dosed via the buccal route had C _max, Cls, and AUC_{0-400 min} values of 4.6 ± 1.6 ng/mL, 22.0 ± 5.9 mL/min, and 842.9 ± 209.7 ng*min/mL, respectively. The relative bioavailability for rabbits treated with the TFCs was 43.8 ± 10.9% with a CV of 24.9%. The reductions in plasma calcium levels after administration of sCT by both the intravenous and buccal route were comparable. Conclusions. The TFCs effectively delivered therapeutically efficacious amounts of sCT across the buccal mucosa in rabbits.     

Formulation,evaluation and pharmacokinetics of colon targeted pulsatile system of flurbiprofen

Objective: The intent of the present investigation is to develop colon targeted compression coated flurbiprofen pulsatile release tablets that retard the drug release in the upper gastro intestinal system but progressively release in the colon.

Materials and methods: Flurbiprofen core tablets were prepared by direct compression method and were compression coated with hydroxypropyl methylcellulose and Eudragit S100. The formulation is optimized based on the in vitro drug release study and further evaluated by X-ray imaging and pharmacokinetic studies in healthy humans for colonic delivery.

Results and discussions: The optimized formulation showed negligible drug release (7.26?±?0.05%) in the initial lag period followed by progressive release (99.27?±?0.46%) for 24?h. The X-ray imaging study in human volunteers showed that the tablets reached the colon without disintegrating in the upper gastrointestinal tract. The C_max of colon targeted tablets was 10792.62?ng/mL at T_max 10?h where as in case of immediate release tablets the C_max was 15684.79?ng/mL at T_max 3?h signifies the ability of compression coated tablets to target the colon.

Conclusion: Development of pulsatile release compression coated tablets using combination of time dependent and pH sensitive approaches was suitable to target the flurbiprofen to colon.     

Calendar

The objective of the present study was to develop a colon targeted system of meloxicam for potential application in the prophylaxis of colorectal cancer. Efficacy of selective cyclooxygenase–2 inhibitors has been proven in colorectal cancer. Meloxicam is a selective cyclooxygenase–2 inhibitor with pH-dependent solubility. To achieve pH-independent drug release of meloxicam, pH modifying agents (buffering agents) were used. Meloxicam tablets containing polyethylene oxide were dually coated with ethyl cellulose containing hydrophilic material, polyethylene glycol as an inner coating layer and methyl acrylate, methyl methacrylate, and methacrylic acid copolymer (Eudragit^® FS 30D) as outer coating layer for colon targeting. Optimized tablet formulations demonstrated good potential to deliver the drug to the colon by successfully exhibiting a lag time of 5?h during in vitro drug release study. An in vivo evaluation study conducted to ascertain pharmacokinetic parameters in rabbits revealed that the onset of drug absorption from the coated tablets (T_{lag time}?=?4.67?±?0.58?h) was significantly delayed compared to that from the uncoated tablets. The AUC_0→t and AUC_0→∞ for coated tablets were lower than of uncoated tablets, although the difference was not significant (p?>?0.01). The roentgenography study revealed that the tablet remained intact, until it reached the colon (5?h), which demonstrates that the system can efficiently deliver the drug to the colon. This study demonstrated that a meloxicam-loaded colon targeted system exhibited promising targeting and hence may be used for prophylaxis of colorectal cancer.     

Ocular ciprofloxacin hydrochloride mucoadhesive chitosan-coated liposomes

The aim of this work is to improve the ocular bioavailability of ciprofloxacin hydrochloride (CPX) through the preparation of ocular mucoadhesive chitosan (CS)-coated liposomes. Liposomes were prepared by the thin film hydration technique, using different molar ratios of L-α-phosphatidylcholine (PC), cholesterol (CH), stearylamine (SA) and dicetyl phosphate (DP). CS was used to coat the optimal liposomal formulae. The prepared formulae were characterized regarding encapsulation efficiency (%EE), particle size, physical morphology and in vitro drug release. The in vivo characterization of the prepared formulae was performed through evaluating the level of CPX in the external eye tissue of nine albino rabbits. Results showed an alteration in release rate and %EE of CPX from liposomal formulae upon varying the molar ratios of the lipid bilayer composition. The optimal liposomal formulae F1 (10:0, PC:CH), F12 (10:0:0.5, PC:CH:SA) and F15 (10:0:1, PC:CH:DP), showed % EE of 38.5?±?2.10, 39.65?±?1.85 and 30.05?±?0.75 and % in vitro release after 8 hours (Q_8h) of 78.15?±?2.4, 54.07?±?2.3 and 62.14?±?2.9, respectively. In vitro drug release and in vivo results confirmed that CS-coated liposomal formulae have exhibited a higher retention of CPX. Consequently, CS-coated liposomes could be a promising approach to increase the ocular bioavailability of CPX.     

Effects of Danshen tablets on pharmacokinetics of atorvastatin calcium in rats and its potential mechanism

Context: Danshen tablets (DST), an effective traditional Chinese multi-herbal formula, are often combined with atorvastatin calcium (AC) for treating coronary heart disease in the clinic.

Objective: This study investigated the effects of DST on the pharmacokinetics of AC and the potential mechanism.

Materials and methods: The pharmacokinetics of AC (1?mg/kg) with or without pretreatment of DST (100?mg/kg) were investigated using LC-MS/MS. The effects of DST (50?μg/mL) on the metabolic stability of AC were also investigated using rat liver microsome incubation systems.

Results: The results indicated that C_max (23.87?±?4.27 vs. 38.94?±?5.32?ng/mL), AUC_(0–t) (41.01?±?11.32 vs. 77.28?±?12.92?ng h/mL), and t_1/2 (1.91?±?0.18 vs. 2.74?±?0.23?h) decreased significantly (p?t_1/2) of AC was also decreased (25.7?±?5.2 vs. 42.5?±?6.1) with the pretreatment of DST.

Discussion and conclusions: This study indicated that the main components in DST could accelerate the metabolism of AC in rat liver microsomes and change the pharmacokinetic behaviors of AC. So these results showed that the herb-drug interaction between DST and AC might occur when they were co-administered. Therefore, the clinical dose of AC should be adjusted when DST and AC are co-administered.     

Determination of cepharanthine in rat plasma by LC–MS/MS and its application to a pharmacokinetic study

Context: Cepharanthine (CPA) has been reported to possess a wide range of pharmacological activities.

Objective: This study investigates the pharmacokinetic characteristics after oral or intravenous administration of CPA by using a sensitive and rapid LC–MS/MS method.

Materials and methods: A sensitive and rapid LC–MS/MS method was developed for the determination of CPA in Sprague–Dawley rat plasma. Twelve rats were equally randomized into two groups, including the intravenous group (1?mg/kg) and the oral group (10?mg/kg). Blood samples (250?μL) were collected at designated time points and determined using this method. The pharmacokinetic parameters were calculated.

Results: The calibration curve was linear within the range of 0.1–200?ng/mL (r?=?0.999) with the lower limit of quantification at 0.1?ng/mL. After 1?mg/kg intravenous injection, the concentration of CPA reached a maximum of 153.17?±?16.18?ng/mL and the t_1/2 was 6.76?±?1.21?h. After oral administration of 10?mg/kg of CPA, CPA was not readily absorbed and reached C_max 46.89?±?5.25?ng/mL at approximately 2.67?h. The t_1/2 was 11.02?±?1.32?h. The absolute bioavailability of CPA by oral route was 5.65?±?0.35%, and the bioavailability was poor.

Discussion and conclusions: The results indicate that the bioavailability of CPA was poor in rats, and further research should be conducted to investigate the reason for its poor bioavailability and address this problem.     

Iron oxide induced enhancement of mucoadhesive potential of Eudragit RLPO: formulation,evaluation and optimization of mucoadhesive drug delivery system

Objectives: The objective of the study was to investigate the effect of iron oxide in the development of mucoadhesive tablets of cinnarizine using Eudragit RLPO polymer. A simplex lattice design was employed for optimizing the drug delivery system.

Methods: Different concentrations of Eudragit RLPO (X₁), iron oxide (X₂) and PVP K 30 (X₃) were taken as independent variables and mucoadhesive strength, t_50%, t_90%, MDT and tablet tensile strength were the selected response variables. Contour and 3D plots were drawn to portray the relationship between independent and response variables. Ex vivo studies were performed for the determination of mucoadhesive strength of formulated tablets employing texture analyzer. ATR-FTR, DSC and zeta potential determination were conducted for drug-excipient and ionic interaction studies.

Results: Friability, hardness and tensile strength of mucoadhesive tablet formulation were found to be 0.42 ± 0.21%, 3.93 ± 1.57 kg/cm² and 0.65 ± 0.26 mN/m², respectively. Mucoadhesive strength was found to be ranging between 5.75 ± 4.41 and 42.85 ± 3.94 g. Value of release exponent (n) was found to be 0.65 ± 0.22, indicating anomalous drug release behavior from the formulations. Numerical optimization using the desirability approach was employed for developing optimized formulation by setting constraints of the dependent and independent variables. The mucoadhesive tablet formulation composition consisting of 8.58% w/w Eudragit RLPO, 7.02% w/w iron oxide and 7.26% w/w PVP K 30 fulfilled maximum requirements of an optimum formulation with better regulation of the selected constraints.

Conclusions: Eudragit RLPO and iron oxide combination showed high level potential for fabricating gastroretentive as well as mucoadhesive drug delivery systems.