Buccal delivery of thiocolchicoside: in vitro and in vivo permeation studies

Thiocolchicoside, a muscle-relaxant agent, is administered by the oral, intra-muscular and topical route. After oral administration the extent of bioavailability compared with intra-muscular administration is low, due to a first pass effect. In this paper, the delivery of thiocolchicoside through oral mucosa is studied to improve the bioavailability. Thiocolchicoside in vitro permeation through porcine oral mucosa and in vivo buccal transport in humans were investigated. Two dosage forms, a bioadhesive disc and a fast dissolving disc for buccal and sublingual administration of thiocolchicoside, respectively, were designed. The in vitro permeation of thiocolchicoside through porcine buccal mucosa from these dosage forms was evaluated and compared with in vivo absorption. Results from in vitro studies demonstrated that thiocolchicoside is quite permeable across porcine buccal mucosa and that permeation enhancers, such as sodium taurocholate and sodium taurodeoxycholate, were not able to increase its flux. The in vivo thiocolchicoside absorption experiments, in which the drug loss from oral cavity was measured, indicated that both formulations could be useful for therapeutic application. The fast dissolving (sublingual) form resulted in a quick uptake of 0.5 mg of thiocolchicoside within 15 min whereas with the adhesive buccal form the same dose can be absorbed over an extended period of time.     

Enantioselective skin permeation of ibuprofen enantiomers: mechanistic insights from ATR-FTIR and CLSM studies based on synthetic enantiomers as naphthalimide fluorescent probes

Objective: The aim of this study was to investigate the mechanisms of different skin permeability of ibuprofen racemate and enantiomers.

Methods: The percutaneous permeation of ibuprofen racemate and enantiomers through rabbit normal skin and damaged skin (without stratum corneum [SC]) was investigated in vitro using side-by-side diffusion cells. With the melting temperature-membrane transport model, the flux ratio of enantiomer/racemate was calculated from their thermodynamic properties obtained by differential scanning calorimetry. Attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) study was performed to evaluate the interaction between the enantiomers and the SC. New fluorescent probes were designed and utilized in confocal laser scanning microscopy (CLSM) study for visualization of the enantioselective permeation of the enantiomers through the intact rabbit skin.

Result: The flux of (S)-ibuprofen through normal skin was significantly higher than that of (RS)-ibuprofen and (R)-ibuprofen (p < 0.05), whereas in damaged skin, there was no significant difference (p > 0.05). The predicted flux ratio of (S)-ibuprofen/(RS)-ibuprofen (2.50) was in close agreement with the experimentally determined ratio (2.48). These results were supported by ATR-FTIR and CLSM studies that indicated that a chiral environment of the skin led to the enantioselective permeation of enantiomers.

Conclusions: The chiral nature of the SC and the different physicochemical properties of the enantiomers should be taken into account in the assessment of different skin permeability of the racemate and enantiomers. The synthetic fluorescent probes used in this study could visualize the enantioselective permeation of the chiral compounds across the skin.     

Behavioral and neurochemical studies on the anticonflict actions of buspirone

A series of behavioral and neurochemical studies were performed in order to determine if buspirone (or an active metabolite of this compound) could perturb a component of the γ-aminobutyric (GABA)-benzodiazepine receptor-chloride ionophore complex. In confirmation of previous findings, buspirone was shown to have anticonflict actions in both the rat and monkey. However, in these tests, buspirone was not as efficacious as benzodiazepines in producing an anticonflict action. The benzodiazepine receptor antagonists CGS 8216 and Ro 15–1788 did not reverse the anticonflict actions of buspirone. Small but statistically significant increases in the binding of [³H]diazepam to brain were observed in vivo after doses of buspirone which are active in the “thirsty rat conflict” test. However, a similar change was not observed in the ex vivo binding of [³H]flunitrazepam. These observations suggest that a metabolite of buspirone may perturb some component of the GABA-benzodiazepine receptor-chloride ionophore complex in an indirect fashion. Further work is necessary to determine whether a causal relationship exists between the changes in [³H]diazepam binding observed in vivo and the anticonflict actions of buspirone.     

Mechanistic studies on transcorneal permeation of fluorometholone

The mechanism of corneal fluorometholone penetration was studied using albino rabbits, and the apparent rate and extent of steroid accumulation in the various cell layers of the cornea and aqueous humor were determined for normal and abraded eyes. The results are compared and contrasted to the mechanism previously reported for pilocarpine. Fluorometholone readily penetrates the intact corneal epithelium and accumulates in the hydrophilic stromal layers of the cornea. The kinetic profile is similar to that of pilocarpine and is largely a result of the pre-corneal dynamic processes. Pharmacokinetic parameters for each tissue were determined to establish an overall mechanism for corneal permeation of the steroid.     

Mechanistic studies on transcorneal permeation of pilocarpine.

The mechanism of corneal pilocarpine penetration was studied in the albino rabbit using radiochemical techniques. The apparent rate and extent of pilocarpine accumulation in the aqueous humor and the various cell layers of the cornea were determined for both intact and abraded eyes. For the first time, drug levels were monitored in the epithelium and stroma-endothelium of the intact cornea using a tissue-scraping technique. In addition, a new postinstillation rinsing method was devised to evaluate the rate of corneal uptake. The results demonstrate a dual role for the corneal epithelium, both as a barrier to drug penetration and as a reservoir for drug in the intact cornea. The transcorneal pilocarpine flux is slower than the data appear to indicate, and previous overestimates of the apparent absorption rate constant are due to parallel elimination processes occurring at the absorption site. Pharmacokinetic parameters were determined for each tissue to generate an overall mechanism for corneal permeation.     

Transdermal delivery of naloxone: ex vivo permeation studies

The purpose of this investigation was to study the feasibility of transdermal drug delivery of the potent opioid antagonist naloxone. The pharmacokinetic profile of naloxone makes it a suitable candidate for transdermal delivery. Ex vivo permeation of naloxone through excised rat skin was studied using a diffusion cell. Radiochemical assay of drug concentration and the use of rat as an animal model were adopted in this study. Naloxone possesses characteristics favorable to percutaneous absorption: i.e. a low molecular weight (327.37), water solubility and a good lipid-water partition coefficient of 12.94+/-1.29 at pH 7.4. The flux (microg/cm2/h) values varied from 6.59+/-0.72 in control to 27. 18+/-4.26 in dimethyl formamide. The affinity of naloxone to skin in the presence of propylene glycol was decreased by 6.2 times compared to the control. Fourier transform infrared spectroscopy was used to study the effect of various sorption promoters on intercellular lipid pathways in skin. A change in lipid fluidization corresponding to broadening for both C-H symmetric (near 2850 cm-1) and C-H asymmetric (near 2920 cm-1) stretching was observed. An attempt was made to correlate the molecular weight of sorption promoters with skin affinity values of naloxone.Copyright     

The solubility-permeability interplay: mechanistic modeling and predictive application of the impact of micellar solubilization on intestinal permeation

Surfactants are routinely employed to increase the apparent aqueous solubility of poorly soluble drugs. Yet the impact of micellar solubilization on the intestinal membrane permeability of a lipophilic drug is often overlooked and poorly understood. In this work, the interplay between the apparent solubility increase and intestinal membrane permeability decrease that exists when surfactants are used as drug solubility enhancers is described. A quasi-equilibrium mechanistic mass transport analysis was developed and employed to describe the effect of micellar solubilization by sodium taurocholate (STC) and sodium lauryl sulfate (SLS) on the intestinal membrane permeability of the lipophilic drug progesterone. The model considers the effects of micellar solubilization on both the membrane permeability (P(m)) and the unstirred water layer (UWL) permeability (P(aq)), to predict the overall effective permeability (P(eff)) dependence on surfactant concentration (C(S)). The analysis reveals that (1) the effective UWL thickness (h(aq)) quickly decreases with increasing C(S) above the critical micelle concentration (CMC), such that P(aq) markedly increases with increasing C(S); (2) the free fraction of drug available for membrane permeation decreases with increasing C(S) above CMC, such that P(m) decreases with increasing C(S); and (3) P(aq) increases and P(m) decreases with increasing C(S) above CMC, consequently the UWL is effectively shorted out and the overall P(eff) tends toward membrane control with increasing C(S). The model enabled excellent quantitative prediction of the progesterone P(eff) as a function of C(S) in the rat jejunal perfusion model. This work demonstrates that a trade-off exists between micellar apparent solubility increase and permeability decrease that must be taken into account to strike the optimal solubility-permeability balance. The model presented in this work offers the formulation scientist a simple method for a priori prediction of this interplay, in order to maximize the overall oral absorption.     

Intranasal mucoadhesive buspirone formulation: in vitro characterization and nasal clearance studies

Oral administration is unsuitable for drugs prone to extensive first-pass metabolism, like buspirone. Thus, in the present study an attempt has been made to develop a mucoadhesive intranasal formulation improving permeation characteristics of buspirone HCl. Nasal formulations containing different concentrations of chitosan HCl and hydroxypropyl-beta-cyclodextrins (HP-beta-CD) were prepared and compared with control buspirone HCl solution regarding permeability, in vitro duration of mucoadhesion, in vivo nasal clearance in rats and in vitro cytotoxicity on cell culture. Nearly two fold increase in buspirone permeation was observed with 1% chitosan HCl and a 3.5 fold increase with 1% chitosan HCI and 5% HP-beta-CD. Nasal clearance studies showed retention of 50% radioactivity up to about 3.5 h for formulation F7 containing 1% chitosan HCI compared to 1.5 h for control buspirone solution (F1). Results conclusively demonstrated enhancement in permeation with no cytotoxicity. Thus formulations can be used to improve bioavailability of buspirone HCl.     

水溶性月桂氮(艹/卓)酮对达克罗宁粘膜促渗作用的药效学研究

目的 :考察月桂氮艹卓 酮的粘膜促渗作用。方法 :以达克罗宁为模型药 ,用青蛙和蚯蚓试验法分别研究了月桂氮艹卓 酮对达克罗宁麻醉效果的影响。结果 :与不含月桂氮艹卓 酮的样品比较 ,体积分数为 1 %的月桂氮艹卓 酮能显著促进达克罗宁的粘膜渗透作用 (P <0 .0 1 ) ,短麻缩醉的潜伏期 ;用 0 .5%的月桂氮艹卓 酮作促渗剂 ,可使达克罗宁的麻醉作用效价强度提高 3倍。结论 :考察了月桂氮 艹卓 酮对达克罗宁粘膜促渗作用的影响 ,其结果为进一步研究月桂氮艹卓 酮在透皮给药系统方面的应用提供了有益的参考     

水溶性月桂氮酮对达克罗宁粘膜促渗作用的药效学研究

目的：考察月桂氮Ｚｕｏ酮的粘膜中渗作用,方法：以达克罗宁为模型药,用青蛙和蚯蚓试验法分别研究了月桂氮Ｚｕｏ酮对达克罗麻醉效果的影响。结果：与不含月桂氮Ｚｕｏ酮的样品比较,体积分数为１％的月桂氮Ｚｕｏ酮能显著促进达克罗宁的粘膜渗透作用（Ｐ〈０．０１）。短麻缩醉的潜伏期,用０．５％的月桂氮Ｚｕｏ酮作促渗剂,可使达罗宁的麻醉作用效价强度提高３倍,结论：考察了月桂氮Ｚｕｏ酮对达克罗粘膜促渗作用的影响,其结     

Buccal transport of flecainide and sotalol: effect of a bile salt and ionization state

Patients with infrequent attacks of supraventricular arrhythmia may benefit from self administration of antiarrhythmic drugs on an 'as required' basis. The oral cavity is easily accessible and the potential for rapid absorption exists. The effects of ionization state and sodium glycocholate on the ex vivo transport of sotalol and flecainide across porcine buccal mucosa were studied. The permeated amounts at 3 h (Q) and fluxes (J) of sotalol in an aqueous solution at pH 7.4 and 9.0 were similar. At pH 7.4, in contrast to pH 9.0, the addition of 1.0% (w/v) sodium glycocholate decreased Q and J four and five fold. Flecainide base in propylene glycol resulted in a nine and 12 fold higher Q and J as compared with an aqueous solution of flecainide acetate at pH 5.8. The presence of sodium glycocholate reduced the transport rate of the flecainide base. However, Q and J were increased 110 and 75 fold by adding 1.0% (w/v) sodium glycocholate to a solution of flecainide acetate at pH 5.8. Sodium glycocholate seems to be an effective penetration enhancer for the buccal absorption of the more polar ionized form of flecainide in an aqueous solution. Sodium glycocholate does not seem to improve the transport of sotalol.     

Oral delivery of insulin with the eligen technology: mechanistic studies

The development of oral insulin using the eligen technology represents a significant advance in insulin administration which is expected to improve the quality of life of diabetic patients. As clinical studies progress, a great deal of interest has focused on the process by which this technology enables insulin absorption from the intestinal lumen into the bloodstream. The eligen technology employs low molecular weight compounds (termed drug delivery agents or carriers) which interact weakly and non-covalently with insulin, increasing its lipophilicity and thereby its ability to cross the gastrointestinal epithelium. In this study we investigated the mechanism of insulin absorption across caco-2 cell monolayers with one of these drug delivery agents, N-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC). Our results show that SNAC increases insulin permeability approximately ten fold across cell monolayers and does so without affecting mannitol permeability or disrupting cell membranes. Confocal microscopy and immunocytochemistry revealed that insulin is transported transcellularly without detectable alteration of the tight junctions between adjacent cells. SNAC also appears to play some role in protecting insulin from proteolytic degradation, potentially allowing for more intact insulin to be available at the site of absorption.     

Brain targeting studies on buspirone hydrochloride after intranasal administration of mucoadhesive formulation in rats

Objectives The purpose of this study was to find out whether nasal application of buspirone could increase its bioavailability and directly transport the drug from nose to brain. Methods A nasal formulation (Bus‐chitosan) was prepared by dissolving 15.5 mg buspirone hydrochloride, 1% w/v chitosan hydrochloride and 5% w/v hydroxypropyl β‐cyclodextrin (HP‐β‐CD) in 5 ml of 0.5% sodium chloride solution. The formulation was nasally administered to rats and the plasma and brain concentration compared with that for buspirone hydrochloride solution after intravenous and intranasal (Bus‐plain) administration. The brain drug uptake was also confirmed by gamma scintigraphic study. Key findings The nasal Bus‐chitosan formulation improved the absolute bioavailability to 61% and the plasma concentration peaked at 30 min whereas the peak for nasal Bus‐plain formulation was 60 min. The AUC_0‐480 in brain after nasal administration of Bus‐chitosan formulation was 2.5 times that obtained by intravenous administration (711 ± 252 ng/g vs 282 ± 110 ng/g); this was also considerably higher than that obtained with the intranasal Bus‐plain formulation (354 ± 80 ng/g). The high percentage of direct drug transport to the brain (75.77%) and high drug targeting index (>1) confirmed the direct nose to brain transport of buspirone following nasal administration of Bus‐chitosan formulation. Conclusions These results conclusively demonstrate increased access of buspirone to the blood and brain from intranasal solution formulated with chitosan and HP‐β‐CD.     

Lipid-based delivery systems and intestinal lymphatic drug transport: a mechanistic update

After oral administration, the majority of drug molecules are absorbed across the small intestine and enter the systemic circulation via the portal vein and the liver. For some highly lipophilic drugs (typically log P>5, lipid solubility>50 mg/g), however, association with lymph lipoproteins in the enterocyte leads to transport to the systemic circulation via the intestinal lymph. The attendant delivery benefits associated with lymphatic drug transport include a reduction in first-pass metabolism and lymphatic exposure to drug concentrations orders of magnitude higher than that attained in systemic blood. In the current review we briefly describe the mechanisms by which drug molecules access the lymph and the formulation strategies that may be utilised to enhance lymphatic drug transport. Specific focus is directed toward recent advances in understanding regarding the impact of lipid source (both endogenous and exogenous) and intracellular lipid trafficking pathways on lymphatic drug transport and enterocyte-based first-pass metabolism.     

In vitro permeation studies of triamcinolone acetonide mouthwashes

The effects of vehicle composition, contact time of mouthwash and cosolvent on permeation of triamcinolone acetonide (TA) were investigated in vitro using hamster cheek pouch mucosa and synthetic membranes. Mouthwashes containing 0.1% TA with and without the mucoadhesive carboxyvinyl polymer were formulated. Aqueous suspensions and Orabase were used as control formulations. The contact time of mouthwash was varied from 1 to 5 min. Ethanol was used as a cosolvent in various binary-water mixtures. TA was delivered to a significantly lesser extent to mucosal tissue by the mouthwash than by the aqueous suspension (P<0.001), but to a higher extent than by the Orabase formulation (P<0.001). No effects of contact time or the mucoadhesive polymer were observed on amount of TA accumulated in the mucosal membrane. These observations have suggested that the use of carboxyvinyl polymer and a high content of ethanol are not appropriate as vehicles for local drug delivery but are suitable for transmucosal drug carriers.     

Drug silica nanocomposite: preparation,characterization and skin permeation studies

The aim of this work was to evaluate silica nanocomposites as topical drug delivery systems for the model drug, caffeine. Preparation, characterization, and skin permeation properties of caffeine-silica nanocomposites are described. Caffeine was loaded into the nanocomposites by grinding the drug with mesoporous silica in a ball mill up to 10?h and the efficiency of the process was studied by XRPD. Formulations were characterized by several methods that include FTIR, XRPD, SEM and TEM. The successful loading of caffeine was demonstrated by XRPD and FTIR. Morphology was studied by SEM that showed particle size reduction while TEM demonstrated formation of both core-shell and multilayered caffeine-silica structures. Solid-state NMR spectra excluded chemical interactions between caffeine and silica matrix, thus confirming that no solid state reactions occurred during the grinding process. Influence of drug inclusion in silica nanocomposite on the in vitro caffeine diffusion into and through the skin was investigated in comparison with a caffeine gel formulation (reference), using newborn pig skin and vertical Franz diffusion cells. Results from the in vitro skin permeation experiments showed that inclusion into the nanocomposite reduced and delayed caffeine permeation from the silica nanocomposite in comparison with the reference, independently from the amount of the tested formulation.     

Stereoselective skin permeation of organic nitrates: application of partitioning and porous transport theories

The effect of the stereochemistry of organic nitrates on rat skin permeability was investigated. Skin permeabilities significantly differed between dinitrates and mononitrates, and also among their diastereomers. The maximum flux and permeability coefficient of dinitrate diastereomers from water were dependent on the solubility in octanol and the octanol/water partition coefficient, respectively. On the other hand, the key parameters determining the maximum flux and permeability coefficient of mononitrate isomers were the aqueous solubility and diffusivity. These results suggest that dinitrate diastereomers permeate across skin via the lipid domain of the stratum corneum according to a partitioning mechanism, and that skin permeation of mononitrate isomers occurs via an aqueous domain by a porous mechanism. Factors raising stereoselectivity in skin permeation of organic nitrates were closely related with stereostructure, especially the functional groups at the exo position, of diastereomers. The interaction between the functional groups and surrounding molecules thus causes the differences in physicochemical properties and skin permeability of stereoisomers.     

Retinol potentiates acetaminophen-induced hepatotoxicity in the mouse: mechanistic studies.

This study was designed to elucidate the mechanism of retinol's potentiation of acetaminophen-induced hepatotoxicity. To accomplish this, the major bioactivation and detoxification pathways for acetaminophen were investigated following retinol (75 mg/kg/day, 4 days), acetaminophen (400 mg/kg), and retinol + acetaminophen treatment. Hepatic microsomes were used to determine the catalytic activity and polypeptide levels of cytochrome P450 enzymes involved in the murine metabolism of acetaminophen. Results showed that the catalytic activity and polypeptide levels of CYP1A2, CYP2E1, and CYP3A were unchanged in the treatment groups compared to vehicle and untreated controls. In combination, retinol + acetaminophen caused a significantly greater depletion of GSH compared to corn oil + acetaminophen (0.36 +/- 0.11 vs 0.89 +/- 0.19 micromol/g, respectively, p < 0.05). This greater GSH depletion correlated with a higher degree of hepatic injury in the retinol + acetaminophen-treated animals but is probably not the cause of the potentiated injury since the results showed that retinol treatment itself did not alter hepatic glutathione (3.34 +/- 0.43 vs 3.44 +/- 0.46 micromol/g for retinol vs vehicle, respectively). However, hepatic UDPGA stores were decreased in the retinol-treated group compared to untreated and corn oil controls (54.6 +/- 10.6 vs 200.6 +/- 17.6 nmol/g for retinol and untreated control, respectively, p < 0.001). This demonstrates that there is significantly less hepatic UDPGA available for conjugation following retinol administration. The results suggest that decreased hepatic UDPGA is likely the cause of retinol's potentiation of acetaminophen-induced hepatic injury.     

Skin delivery of oestradiol from deformable and traditional liposomes: mechanistic studies

Deformable vesicles and traditional liposomes were compared as delivery systems for oestradiol to elucidate possible mechanisms of drug delivery through human skin. Accordingly, epidermal permeation of oestradiol from optimized deformable vesicles and traditional liposome formulations was studied under low dose non-occluded conditions. Five mechanisms were investigated. A free drug mechanism compared low-dose permeation through skin with drug release determined after separation of the free drug. Penetration enhancement was researched by studying skin pretreatment with empty vesicles. Improved drug uptake by skin was monitored by dipping stratum corneum into different formulations for 10 min and determining drug uptake. The possibility that intact vesicles permeate through the epidermis was tested by comparing permeation from 136-nm vesicles with that from >500-nm vesicles, assuming that penetration depends on vesicle size. The possibility that different entrapment efficiencies in alternative formulations could be responsible for the difference in delivery was also evaluated. Lipid vesicles improved the skin delivery of oestradiol compared with delivery from an aqueous control. Maximum flux (Jmax) was increased 14- to 17-fold by use of deformable vesicles and 8.2- to 9.8-fold by use of traditional liposomes. Deformable vesicles were thus superior to traditional liposomes. Drug release was negligible over the period during which skin flux was maximum. Pretreatment with empty vesicles resulted in an enhancement ratio of 4.3 for pure phosphatidylcholine (PC) vesicles but the enhancement ratio ranged from only 0.8 to 2.4 for other formulations. Vesicles increased drug uptake into the stratum corneum 23- to 29-fold. Relative flux values obtained from small and large vesicles were similar. No correlation was found between entrapment efficiency and skin delivery. The results showed no evidence of a free drug mechanism, but revealed a possible penetration-enhancing effect for pure PC vesicles, although this was not the only mechanism operating. The positive uptake suggested that lipid vesicles increased drug partitioning into the skin. The data provided no evidence for in-vitro liposome penetration through skin as distinct from vesicle penetration into the stratum corneum.