Bioavailability of morphine after administration of a new bioadhesive buccal tablet

A new bioadhesive buccal morphine tablet was developed for controlled release delivery of drug and improved bioavailability compared with oral controlled release tablet. In order to characterize the pharmacokinetic properties of this bioadhesive buccal formulation, a bioavailability study was performed in 12 healthy volunteers who received: a 30 mg oral controlled release tablet (A); a 20 mg aqueous solution retained in the mouth for 10 min (B); and the 60 mg bioadhesive buccal tablet placed between the lower gum and lip for 6 h (C). The mean amount of morphine absorbed from the solution was very low, only 2 mg of the 20 mg dose. After administration of forms A and C, plasma levels exhibit typical sustained release concentration–time curves. The mean amount of drug recovered from the residual bioadhesive buccal tablet after 6 h indicated that approximately 50% of the dose was released from the bioadhesive buccal tablet. The relative bioavailability of the buccal tablet (corrected for residual unabsorbed dose) compared with the controlled-release tablet was 98% based on the morphine AUC values. Good correlations between the AUC and the C_max of the bioadhesive tablet for the drug and metabolite plotted versus the amount of morphine absorbed were found. © 1998 John Wiley & Sons, Ltd.     

Comparison of Zafirlukast (Accolate®) Absorption After Oral and Colonic Administration in Humans

Purpose. This study characterized the gastrointestinal (GI) absorptionof zafirlukast after oral and colonic administration in humans. Methods. Five healthy subjects received zafirlukast solution (40 mg)orally and via an oroenteric tube into the colon in a randomized,crossover fashion. Two additional subjects were dosed into the distalileum. Serial blood samples were obtained and plasma concentrationswere quantitated by HPLC. Results. Mean ± SD pharmacokinetic parameters after oral vs. colonicadministration were: AUC of 2076 ± 548 vs. 602 ± 373 ng*h/mL,respectively, and C_max of 697 ± 314 vs. 194 ± 316 ng/mL, respectively.Mean colon:oral AUC and C_max were 0.29 and 0.30, respectively.Median t_max values were 2.0 and 1.35 hr after oral and colonicadministration. First-order absorption rate constants (K_a and K_ac) wereestimated from a two-compartment model with first-order elimination.K_ac:K_a was <0.5 in 4 of the 5 subjects dosed in the colon. Conclusions. Zafirlukast was absorbed at multiple sites in the GI tract.The rate and extent of zafirlukast absorption was less after colonicthan oral administration. Zafirlukast was significantly absorbed in thedistal ileum. This study demonstrated that gamma scintigraphy, digitalradiography, and fluoroscopy can be used to track the movement andconfirm the location of the oroenteric tube in the GI tract.     

Mucoadhesive buccal films containing phospholipid-bile salts-mixed micelles as an effective carrier for Cucurbitacin B delivery

Abstract

Cucurbitacin B (Cu B), a potent anti-cancer agent, suffers with the problems of water-insoluble, gastrointestinal side effects and non-specific toxicity via oral administration and drawbacks in patient’s compliance and acceptance through injections. An integration of nanoscale carriers with mucoadhesive buccal films drug delivery system would resolve these issues effectively with greater therapeutic benefits and clinical significance. Thus, the drug loaded mucoadhesive buccal film was developed and characterized in this study and the carboxymethyl chitosan (CCS) was chosen as a bioadhesive polymer, glycerol was chosen as a plasticizer and phospholipid-bile salts-mixed micelles (PL-BS-MMs) was selected as the nanoscale carriers. The CCS-films containing Cu B loaded PL-SDC-MMs was evaluated for the mechanical properties, mucoadhesion properties, in vitro water-uptake, in vitro release and morphological properties, respectively. The optimal CCS-films containing Cu B loaded PL-SDC-MMs was easily reconstituted in a transparent and clear solution with spherical micelles in the submicron range. The in vivo study revealed a greater and more extended release of Cu B from nanoscale CCS-films compared to that from a conventional CCS films (C-CCS-films) and oral marketed tablet (Hulusupian). The absorption of Cu B from CCS-films containing Cu B loaded PL-SDC-MMs resulted in 2.69-fold increased in bioavailability as compared to conventional tablet formulation and 10.46 times with reference to the C-CCS-films formulation. Thus, this kind of mucoadhesive buccal film might be an alternative safe route for delivery of Cu B with better patient compliance and higher bioavailability for the treatments.     

Development and characterization of Eudragit based mucoadhesive buccal patches of salbutamol sulfate

For systemic drug delivery, the buccal region offers an attractive route of drug administration. Salbutamol sulfate is a short-acting β₂-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease. It’s oral bioavailability is ∼40% due to extensive first pass metabolism. Salbutamol sulfate patches were prepared using Eudragit L-100, HPMC, PVA and Carbopol 934 in various proportions and combinations using PEG-400/PG as plasticizers. Patches were laminated on one side with a water impermeable backing layer for unidirectional drug release. The thickness of medicated patches were ranged between 0.23 ± 0.008 and 0.59 ± 0.007 mm and mass varied between 65.23 ± 3.3 and 117.92 ± 4.2 mg. Patches showed an increase in mass and swelling index with PEG-400 when compared with PG. The surface-pH of patches ranged between 6 and 7. Formulations E7 (7.5 mL Eudragit L-100, 15 mL HPMC K4M, 7.5 mL PVA and 2 mL PEG-400), E12 (7.5 mL Eudragit L-100, 7.5 mL PVA, 15 mL Carbopol and 2 mL PEG-400), F7 (7.5 mL Eudragit L-100, 15 mL HPMC K4M, 7.5 mL PVA and 2 mL PG), and F12 (7.5 mL Eudragit L-100, 7.5 mL PVA, 15 mL Carbopol and 2 mL PG) showed high folding endurance. Residence time of the tested patches ranged between 101 and 110 min. The maximum in vitro release was found to be 99.93% over a period of 120 min for formulation F12. Data of in vitro release from patches were fitted to different kinetic models such as Higuchi and Korsmeyer–Peppas models to explain the release profile. Formulations E7 and F7 were best fitted to the non-Fickian, where as formulations E12 and F12 showed Fickian/anomalous drug release. Stability studies indicated that there was no change in the chemical and physical characteristics during the test period.     

Controlled release effervescent buccal discs of buspirone hydrochloride: in vitro and in vivo evaluation studies

Abstract

In the present study controlled release effervescent buccal discs of buspirone hydrochloride (BS) were designed using HPMC as rate controlling and bioadhesive polymer by direct compression method. Sodium bicarbonate and citric acid were used in varying amounts as effervescence forming agents. Carbon dioxide evolved due to reaction of sodium bicarbonate and citric acid was explored for its potential as buccal permeation enhancer. The designed buccal discs were evaluated for physical characteristics and in vitro drug release studies. Bioadhesive behavior of designed buccal discs was assessed using texture analyzer. In vivo animal studies were performed in rabbits to study bioavailability of BS in the designed buccal discs and to establish permeation enhancement ability of carbon dioxide. It was observed that effervescent buccal discs have faster drug release compared to non-effervescent buccal discs in vitro and effervescent buccal discs demonstrated significant increase in bioavailability of drug when compared to non-effervescent formulation. Hence, effervescent buccal discs can be used as an alternative to improve the drug permeation resulting in better bioavailability. However, the amount of acid and base used for generation of carbon dioxide should be selected with care as this may damage the integrity of bioadhesive dosage form.     

Buccal Absorption of Testosterone and Its Esters Using a Bioadhesive Tablet in Dogs

Purpose. As the oral bioavailability of testosterone is very low because of its high first pass effect, buccal administration might present a viable alternative. In this study a buccal bioadhesive tablet was used in order to sustain the delivery and bypass the liver. Methods. Testosterone and testosterone acetate, propionate, enanthate and decanoate were investigated. The influence of the concentration of testosterone (10–50%) and testosterone esters (30%) on in vitro bioadhesion was investigated. The absolute (IV) and relative (oral) bioavailability of 60 mg testosterone or an equivalent amount of testosterone ester was determined in castrated male dogs. Results. Both the in vitro detachment force and the work of adhesion decreased gradually with an increasing amount of testosterone and for an increasing chain length of the esters, except in the case of testosterone enanthate. The in vivo results revealed that the bioavailability of testosterone was significantly higher (p < 0.05) than that of the esters, which is probably due to the lower solubility of the esters. The mean absolute bioavailability of testosterone from the bioadhesive tablet was 14.1%, while the mean relative bioavailability was 1370%. The buccal administration of testosterone via the bioadhesive tablet allowed the maintenance of the plasma level at above 3 ng/ml for 15 to 24 h. Conclusions. Buccal absorption of testosterone was significantly higher than that of its esters.     

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.     

In Vivo Buccal Delivery of the Peptide Drug Buserelin with Glycodeoxycholate as an Absorption Enhancer in Pigs

Purpose. To study the potential of buccal delivery of the peptide drug in pigs. Methods. Intravenous administration and buccal delivery without and with 10 mM sodium glycodeoxycholate (GDC) as absorption enhancer were investigated as a randomised cross-over study in six pigs. The buccal delivery device consisted of an application chamber with a solution of buserelin and was attached to the buccal mucosa for 4 hours using an adhesive patch. Results. Buccal administration of buserelin resulted in rapidly reached steady state plasma levels. The absolute bioavailability of the peptide after buccal delivery for 4 hours could be increased from 1.0 ± 0.3 to 5.3 ± 1.1% (mean ± S.D.) by co-administration of 10 mM GDC (0.45% w/v)). Conclusions. The results of this study demonstrate that buccal administration with the use of absorption enhancers is a useful approach for the delivery of peptide drugs such as buserelin.     

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.     

Absolute bioavailability of oral immediate and slow release fluphenazine in healthy volunteers

Objective: The present study was conducted with the aim of investigating the absolute bioavailability of fluphenazine in healthy volunteers after administration of immediate and slow release oral formulations. Methods: The oral dose was 12 mg fluphenazine hydrochloride. The intravenous bolus dose was 2.5 mg. Fourteen healthy volunteers of both sexes were enrolled in this randomised, crossover trial. Twelve volunteers completed the trial according to protocol. Results: The concentration maxima after administration of the slow release formulation were approximately half those measured after the immediate release formulation and were recorded later by a factor of 2 (immediate release: C_max = 2.3 ng⋅ml⁻¹, t_max = 2.8 h; slow release: C_max = 1.2 ng⋅ml⁻¹, t_max = 4.6 h). The concentrations measured 10 min after intravenous bolus administration of 2.5 mg fluphenazine hydrochloride were approximately 100 times higher (261 ng⋅ml⁻¹). The geometric means for the absolute bioavailability of fluphenazine were 2.7% for the immediate release formulation and 3.4% for the slow release formulation. The absolute bioavailability of fluphenazine is thus much lower than previously generally accepted. Received: 14 December 1995/Accepted in revised form: 26 March 1996     

Oral absorption of CGS-20625, an insoluble drug,in dogs and man

Oral bioavailability of highly water-insoluble drugs is often quite limited and variable, requiring the development of improved formulations. Animal models are an essential aspect of the design and testing of such formulations designed to improve absorption in man. The present report compares the absorption of CGS-20625, an insoluble drug, in dog and man after oral administration of the drug as a powder, a solid dispersion capsule, and after gastric and duodenal administration in PEG 400 solution. CGS-20625 powder (20 mg) given orally exhibited slow, delayed absorption in both dog and man, with aC _max of 0.26±0.07 μg/ml atT _max of 3 hr in dog, and 0.01±0.004 μg/ml at 2 hr in man. Administration of CGS-20625 in PEG 400 solution improved absorption in dog and man, with aC _max of 1.2±0.10 μg/ml atT _max of 0.25 hr in dog, and aC _max of 0.10±0.04 μg/ml at 0.5 hr in man.T _max after administration of the hard gelatin capsule formulation was 0.9 and 1.0 hr in dog and man, withC _max of 0.89±0.16 and 0.052±0.014 μg/ml, respectively. Absolute bioavailability of CGS-20625 powder in the dog was 0.67±0.21, whereas the bioavailabilities of the powder and the capsule relative to the PEG 400 solution were 0.84 and 1.1, respectively, in dog, and 0.41 and 0.85 respectively, in man. No significant benefits of duodenal administration were observed. Plasma levels were approximately 10-fold greater and oral clearance was approximately 5-fold less in the dog than in man. Furthermore, pharmacokinetic data were less variable and relative bioavailability was greater in dogs than in humans. Physiological factors in the gastrointestinal tract or greater first-pass metabolism in man may account for these species differences. The relative rate and extent of CGS-20625 absorption were similar between dog and man, in the order of powder <capsule<PEG 400 solution. In addition,in vivo absorption rates in both species reflectin vitro dissolution differences between the powder and the capsule. These data strongly support the use of the dog as a model for developing improved formulations of CGS-20625. Further investigation of the dog as a model to evaluate insoluble drug absorption is warranted.     

Bioavailability of tramadol hydrochloride after administration via different routes in rats

Tramadol is a synthetic non‐opiate analgesic drug and effective for many kinds of chronic and acute pain. This study compared the bioavailability of tramadol after different administration routes in rats (oral, buccal and nasal). A simple HPLC analytical approach was used to determine the concentration of tramadol in plasma. The pharmacokinetic behavior and bioavailability of tramadol after administration via different routes in rats were investigated. Nasal and buccal administration of tramadol resulted in a fast increase followed by a rapid decrease in the plasma tramadol concentration. The C_max values following buccal and nasal administration were 6 times and 20 times higher than that of oral administration, respectively, (6827.85 ± 7970.87 ng/ml, 22191.84 ± 5364.86 ng/ml, vs 1127.03 ± 778.34 ng/ml). The relative bioavailabilities of the nasal‐ and buccal‐administered drug when compared with the oral route were 504.8% and 183.4%, respectively, which is much higher than that of oral administration. Nasal and buccal administration increased the bioavailability of tramadol, which may allow for a reduction in the dose of tramadol and a subsequent decrease in both side effects and toxicity. Therefore, this approach provides an effective choice for the delivery of tramadol, an analgesic drug. Copyright © 2014 John Wiley & Sons, Ltd.     

Microparticulated anti-HIV vaginal gel: In vitro-in vivo drug release and vaginal irritation study

The aim of this study was to develop and evaluate a Zidovudine (AZT)-loaded microparticulated bioadhesive vaginal gel (MBVG) in order to obtain a controlled releasing, safe gel delivery system. AZT microparticles (ZMPs) were evaluated for encapsulation efficiency, drug loading, surface morphology and in vitro drug release profiles and drug release mechanism and optimized. The optimized ZMPs were then encompassed in bioadhesive gel using different bioadhesive polymers and evaluated for the drug encapsulation efficiency, drug loading, in vitro and in vivo drug release profiles, drug release mechanism and vaginal irritancy study. From the dissolution data of ZMP4 and MBVG4 showed a zero-order diffusion pattern and Fickian diffusion case I transport mechanism in 24 and 36?h, respectively. On the basis of a pharmacokinetic study of MBVG4 (containing ZMP: Carbopol 1:4), it was found to have better bioavailability, larger AUC and T_max in comparison to an oral pure suspension of AZT.     

A Review of: “Statistics: Concepts and Controversies,Sixth Edition,by D. S. Moore and W. I. Notz (Eds.)”

Contrasts were evaluated for the maximum blood or plasma concentration (C _max) of drugs measured after repeated and single oral administrations. Variances C _max of were calculated and also simulated for a single drug as well as the comparison of two formulations, i.e., for the analysis of investigations of both bioavailability and bioequivalence. The coefficient of variation (C V) of C _max was higher in the steady state than after a single drug administration when the variability of the disposition rate constant (k) was substantially larger than that of the absorption rate constant (k_a )In turn, the CV of C _max was substantially lower following repeated than after single drug administration when the variability of k_a dominated that of k.The latter condition often prevails in practice since the relative variation of absorption rates generally substantially exceeds that of clearance (the latter being proportional to k) The statistical insensitivity is superimposed on the low kinetic sensitivity exhibited by C _maxfollowing repeated drug administrations. Consequently, bioequivalence trials conducted in the steady state generally permit a declaration of equivalence even between drug products that have very different absorption rates     

Evaluation of in vivo behavior of controlled and pulsatile release pastilles using pharmacokinetic and γ-scintigraphic techniques

Objective: To evaluate the in vivo behavior of controlled and pulsatile release pastilles for chronic treatment of asthma and chronic obstructive pulmonary disease (COPD) and for the chronotherapeutic management of nocturnal asthma, respectively.

Research design & methods: The prepared immediate release and controlled release pastilles were subjected to in vivo pharmacokinetic studies in rats. Whereas, pulsatile release formulation was subjected to γ-scintigraphic study in rats to study the gastrointestinal transit of the formulations and its results were correlated with the previous pharmacokinetic data.

Results: The in vivo pharmacokinetic study of controlled release pastille formulation showed significant decrease in C_max with increase in t_max, which indicates that the effect of dosage form would last for longer duration. Thus, the prepared formulation can be useful for the chronic treatment of asthma and COPD. The γ-scintigraphic study and pharmacokinetic data indicated that the pastilles coated with the enteric coat and the additional floating coat were effective in significantly delaying the in vivo drug release (by 4–5 h) required for the chronotherapeutic treatment of nocturnal asthma.

Conclusion: This study opens a new alternative to the conventional tablet or capsule dosage form for the development of both immediate and modified release drug delivery systems.     

Development of bioadhesive buccal tablets for felodipine and pioglitazone in combined dosage form: In vitro,ex vivo,and in vivo characterization

The purpose of the present research was to develop bioadhesive buccal tablets for Felodipine (FDP) and Pioglitazone (PIO), low bioavailability drugs, in a combined dosage form for the management of diabetes and hypertension. Buccal tablets were prepared by direct compression method using bioadhesive polymers hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and carbopol, alone or in combination of two polymers, and were evaluated for physicochemical properties, swelling index, in vitro bioadhesion, in vivo residence time, in vitro drug release, and ex vivo permeation through porcine buccal membrane. Formulation (PF6) showed peak detachment force (3.12 N), work of adhesion (0.72 mJ), swelling index (196%), erosion (10.8%), in vivo residence time of 280?min, in vitro drug release (99.65% and 98.96% in 6?h for FDP and PIO, respectively) with higuchi model release profile and permeated 66.1 and 64.6 % with a flux of 0.118 and 0.331?mg/h/cm² of FDP and PIO through porcine buccal membrane. The bioavailability study for optimized formulation (PF6) in pigs showed 2.05- and 2.13-times statistically significant (p?<?0.05) improvement in bioavailability for FDP and PIO, respectively, after administration of buccal tablets compared to oral suspension. The ex vivo–in vivo correlation was found to have a biphasic pattern and followed type A correlation. The stability of the PF6 was studied and no significant changes were detected in drug content and in vitro release and ex vivo permeation through porcine buccal membrane after 6 months.     

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.     

Effect of HPMC and mannitol on drug release and bioadhesion behavior of buccal discs of buspirone hydrochloride: In-vitro and in-vivo pharmacokinetic studies

Delivery of orally compromised therapeutic drug molecules to the systemic circulation via buccal route has gained a significant interest in recent past. Bioadhesive polymers play a major role in designing such buccal dosage forms, as they help in adhesion of designed delivery system to mucosal membrane and also prolong release of drug from delivery system. In the present study, HPMC (release retarding polymer) and mannitol (diluent and pore former) were used to prepare bioadhesive and controlled release buccal discs of buspirone hydrochloride (BS) by direct compression method. Compatibility of BS with various excipients used during the study was assessed using DSC and FTIR techniques. Effect of mannitol and HPMC on drug release and bioadhesive strength was studied using a 3² factorial design. The drug release rate from delivery system decreased with increasing levels of HPMC in formulations. However, bioadhesive strength of formulations increased with increasing proportion of HPMC in buccal discs. Increased levels of mannitol resulted in faster rate of drug release and rapid in vitro uptake of water due to the formation of channels in the matrix. Pharmacokinetic studies of designed bioadhesive buccal discs in rabbits demonstrated a 10-fold increase in bioavailability in comparison with oral bioavailability of buspirone reported.     

Development and evaluation of buccal films impregnated with selegiline-loaded nanospheres

Poor peroral therapeutic efficiency of selegiline is primarily due to the extensive hepatic metabolism and hence the need for an alternative route of administration. The present study is based on evaluation of a buccal film which is impregnated with selegiline nanospheres to enhance the systemic bioavailability. Selegiline-loaded nanospheres prepared using poly(lactide-co-glycolide) was embedded into buccal films (F₁–F₄) with varying polymer composition [hydroxypropyl methylcellulose and eudragit]. The developed films were evaluated for their physicomechanical properties, hydration, mucoadhesive strength, in vitro drug release and ex vivo permeation in order to identify the ideal system suitable for further development. In vivo studies were carried out on rabbits to assess the comparative pharmacokinetics profile of the selected buccal film with oral solution. Preliminary studies indicated that the prepared films exhibited excellent physical properties, adequate mucoadhesive strength and moderate hydration. In vitro drug release data of the buccal films (F₁, F₂ and F₃) showed distinct profiles. Permeation studies indicated higher steady-state flux from film F₃ (p?<?0.0001) when compared to film F₂. In-vivo results of film (F₃) demonstrated significant increase in absorption (p?<?0.0001), C_max (～1.6-fold), T_max, AUC_0–α (～3-fold, p?<?0.0001) and improved bioavailability, when compared to control. This study concludes that the buccal delivery of selegiline using the developed buccal film (F₃) would be a promising alternative approach for the treatment of Parkinson's disease.     

Effect of Nanonization on Absorption of 301029: Ex Vivo and In Vivo Pharmacokinetic Correlations Determined by Liquid Chromatography/Mass Spectrometry

Purpose. To compare Caco-2 monolayer permeability and in vivo bioavailability of microparticle with nanoparticle 301029, a thiadiazole derivative, and to determine whether nanonization could improve oral bioavailability of the poorly soluble compound. Methods. The mean particle size of 301029 was reduced from 7 m to 280 nm by pearl milling. In the ex vivo assay, both microparticle and nanoparticle 301029 at the same concentration were separately added to apical side and were collected from basolateral side of Caco-2 monolayer. In the bioavailability study, the two particle sizes of 301029 were orally administered to rats, respectively, and blood samples were collected. Nanoparticle 301029 in culture medium and rat serum was detected by a liquid chomatography-mass spectrometer (LC/MS) coupled with atmospheric pressure chemical ionization (APCI). Results. Permeability rate and permeated amounts of nanoparticle 301029 across the Caco-2 monolayer were about four times higher than those of microparticle 301029. In a pharmacokinetic study, nanoparticle 301029 showed T_max about 1 h, whereas the microparticle 301029 showed T_max at 4 h. The C_max and AUC of nanoparticle 301029 were 3- to 4-fold greater than those of microparticle 301029, resulting in a significant increase in oral bioavailability of 301029 as compared with microparticle 301029. The ex vivo permeability and in vivo pharmacokinetic data indicate that nanoparticle formulation improves both absorption rate and absorption extent of the poorly soluble drug. Conclusions. Nanoparticle formulation enhances both Caco-2 monolayer permeability and rat oral bioavailability of the poorly soluble 301029. The result also demonstrates a close correlation between ex vivo Caco-2 permeability model and in vivo gastrointestinal absorption.