Transdermal delivery system for zidovudine: in vitro, ex vivo and in vivo evaluation

The objective of this study was to prepare a transdermal delivery system (TDS) for zidovudine (AZT) with a combination of menthol and oleic acid as penetration enhancers incorporated in hydroxypropyl methylcellulose, and to evaluate ex vivo as well as in vivo permeation across rat skin. It was found that AZT in gel formulation was stable in both refrigerated as well as accelerated stability conditions for 3 months and further, the gel did not significantly retard the permeability of AZT across the skin in comparison with solution formulation. Ex vivo steady state flux of AZT across rat skin from gel was 2.26 mg cm(-2) h(-1), which is sufficient to achieve therapeutic plasma concentrations. Intravenous pharmacokinetic parameters of AZT in rats were determined and used together with ex vivo flux data to generate theoretical plasma profiles of AZT and compared with plasma concentrations achieved after application of TDS. Further, steady state plasma concentrations of drug following multiple applications of TDS were determined and good correlations between ex vivo and in vivo data were observed. In addition, the combination of penetration enhancers used at 2.5% w/w in this study proved efficient in achieving sufficient enhancement in the transdermal permeability of AZT across rat skin with reduced skin irritation potential when compared with individual penetration enhancers at higher concentrations.     

In vitro and in vivo characterization of a newly developed clonidine transdermal patch for treatment of attention deficit hyperactivity disorder in children

The aim of this study was to characterize a newly developed clonidine transdermal patch, KBD-transdermal therapeutic system (TTS), for the treatment of attention deficit hyperactivity disorder in children. In vitro release, penetration, and in vivo pharmacokinetics in rabbits were investigated. The smaller size of KBD-TTS (2.5 mg/2.5 cm2) showed a similar in vitro penetration to those of Catapres-TTS (2.5 mg/3.5 cm2, a clonidine transdermal patch used for the treatment of hypertension, Alza Corporation, U.S.A.). The transdermal penetration rate of clonidine was mainly controlled by the ethylene vinylacetate membrane used in the patch. The skin layer may be only a minor rate-limiting barrier after the topical skin layer at the dosing site is saturated with penetrating clonidine in the initial phase (0 to 12 h). A sensitive liquid chromatography-mass spectrometry method for the quantification of clonidine in rabbit plasma was developed using solid-phase extraction and gradient elution on LC combined with the selected-ion monitoring (SIM) mode. A single dose of clonidine transdermal patch (KBD-TTS) or Catapres-TTS was transdermally administered to rabbits (n=6 each) and removed after 168 h. The average half-life, Tmax, Cmax and Css values of clonidine in rabbits following administration of KBD-TTS were 19.27+/-4.68 h, 52.56+/-25.77 h, 27.39+/-9.03 ng/ml, and 25.82+/-9.34 ng/ml, similar to those of Catapres-TTS, respectively. The clonidine plasma concentration of KBD-TTS reached a steady state at 24 h through 168 h. The in vitro release rate of the clonidine from KBD-TTS significantly correlated with the in vivo absorption rate (p<0.001).     

Transdermal delivery of flurbiprofen: permeation enhancement, design, pharmacokinetic, and pharmacodynamic studies in albino rats

The enhancing effects of lemon oil on the transdermal penetration of flurbiprofen through rat skin invitro and in vivo was investigated. The maximum flux achieved by Isopropyl alcohol (IPA):Propylene glycol (PG) (70:30% v/v) solvent mixture was further increased by lemon oil. The flux of flurbiprofen through ethylene vinyl acetate microporous membrane was evaluated. The membrane altered the flux of flurbiprofen significantly. The reservoir type of transdermal patch was fabricated using flurbiprofen viscous system, ethylene vinyl acetate membrane, and backing film. Histological investigations were done on rat skin samples treated with solvent systems with or without penetration enhancer for 24 hr. No skin irritation was seen. Lemon oil produced more pronounced change in stratum corneum and the epidermis as compared with the control groups. The pharmacokinetics of flurbiprofen in albino rats following application of a transdermal patch for 24 hr was evaluated. The maximum plasma concentration (C(max)) and AUC(0-alpha) of the patch formulation was 1.7 and 1.6 times, increased respectively as compared with the control patch formulation. Quantity of the drug accumulated in the excised skin to which test patch formulation was applied was more than the one to which control patch formulation was applied. Anti-inflammatory effect in the Carrageenin-induced paw edema in rat was significantly higher than the control patch formulation.     

A novel transdermal patch incorporating isosorbide dinitrate with bisoprolol: in vitro and in vivo characterization

The combination therapy of nitrate and selective beta-adrenoceptor antagonist has shown benefits for treatment of hypertension and heart disease than either drug alone. The objectives of the present study were to define effects on the anti-hypertension activity and pharmacokinetics of a novel transdermal patch incorporating isosorbide dinitrate (ISDN) with bisoprolol (BP). The 3:2 ratio of ISDN to BP (mg/mg) in the transdermal patches exhibited better anti-hypertension effect synergistically with a similar inhibiting heart rates effect to that of BP alone in renovascular hypertensive rats, and was therefore selected as a final formulation. The in vitro transdermal penetration of both ISDN and BP from the patches displayed a zero-order process, and the penetration rate constants were 7.4 microg/(cm(2)h) for ISDN, and 5.9 microg/(cm(2)h) for BP, respectively. After transdermal administration at single dose or multiple doses, the synergistic anti-hypertension effect was confirmed in spontaneously hypertensive rats also. The effect of each patch lasts for 3 days, and increased with the total dose of two drugs (2mg/cm(2), ISDN:BP=3:2, mg/mg), showing a dose dependant manner. After transdermal administration to rabbits, the absolute bioavailabilities were 33.6% for ISDN, and 31.3% for BP, respectively. The maximal concentrations (C(max)) of both drugs were significantly reduced while the areas under the plasma concentration-time curve (AUC), and mean residence times (MRT) were evidently increased and extended, respectively. As a patient-friendly, convenient, and multi-day dosing therapeutic system, the transdermal patches incorporating ISDN and BP could be promising for prevention and treatment of hypertension.     

Pharmacokinetics of Memantine after a Single and Multiple Dose of Oral and Patch Administration in Rats

Memantine is a non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple‐ or single‐dose oral and transdermal administration. Venous blood was collected at preset intervals in single‐ and multiple‐dose studies. Non‐compartmental pharmacokinetics was analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg and 8.21 ± 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half‐life longer after patch administration than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single to multiple dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each dose. Additionally, the memantine patch formulation displayed a smaller interindividual variability and lower accumulation than the oral formulation.     

Transdermal drug delivery using microemulsion and aqueous systems: influence of skin storage conditions on the in vitro permeability of diclofenac from aqueous vehicle systems

The objective of this study was to evaluate the transdermal delivery potential of diclofenac-containing microemulsion system in vivo and in vitro. It was found that the transdermal administration of the microemulsion to rats resulted in 8-fold higher drug plasma levels than those obtained after application of Voltaren Emulgel. After s.c. administration (3.5 mg/kg), the plasma levels of diclofenac reached a peak of 0.94 microg/ml at t=1 h and decreased rapidly to 0.19 microg/ml at t=6 h, while transdermal administration of the drug in microemulsion maintained constant levels of 0.7-0.9 microg/ml for at least 8 h. The transdermal fluxes of diclofenac were measured in vitro using skin excised from different animal species. In three rodent species, penetration fluxes of 53.35+/-8.19 (furry mouse), 31.70+/-3.83 (hairless mouse), 31.66+/-4.45 (rat), and 22.89+/-6.23 microg/cm(2)/h (hairless guinea pig) were obtained following the application of the microemulsion. These fluxes were significantly higher than those obtained by application of the drug in aqueous solution. In contrast to these results, a 'flip-flop' phenomenon was observed when frozen porcine skin (but not fresh skin) was significantly more permeable to diclofenac-in-water than to the drug-in-microemulsion. In fact, the drug penetration from the microemulsion was not affected by the skin storage conditions, but it was increased when an aqueous solution was applied. However, this unusual phenomenon observed in non-freshly used porcine skin places a question mark on its relevancy for in vitro penetration studies involving aqueous vehicle systems.     

In vivo immunomodulatory, cumulative skin irritation, sensitization and effect of d-limonene on permeation of 6-mercaptopurine through transdermal drug delivery

Using skin as a port for systemic drug administration, transdermal drug delivery has expanded greatly over the last two decades. Our aim was to formulate the single layer drug-in-adhesive transdermal patch for 6-mercaptopurine (6-MP). In vitro permeation study was carried out using modified Franz diffusion cell with and without of different concentration of d-limonene in human cadaver skin. In vivo immunomodulatory was carried out in mice, cumulative skin irritation, sensitization and patch adherence study was done in both mice and human subjects. 6-MP flux increased from 43+/-12.2 microg/cm2h (control) to 162.8+/-32.2 microg/cm2h (6% w/v d-limonene) data was significant (p<0.05), with decrease in the lag time to 35+/-9.3 min compared to control of 90 +/-15.3 min. In vivo immunomodulatory effect was shown in the Balb/c mice with 100 mumol/kg/body wt of animal for 5d (one dose/d) of d-limonene. WBC count of 13469 cells/mm peak was observed on 12th day, bone marrow cells of 26.3 x 10(6) cells/femur and alpha-esterase positive cells of 1259+/-328.4 cells/4000 bone marrow cells. Cumulative skin irritation, sensitisation and patch adherence in animals and human subjects showed no skin irritation and sensitization. Patch adhesion was greater than 90.0% respectively in both human subjects and mice. The percentage of human subjects with adhesive residue was significantly less with scores of zero. d-Limonene proved as good chemical enhancer by increasing in the skin permeability with shortened the lag time. It proved that therapeutic amount of 6-MP can be delivered through transdermal drug delivery.     

青藤碱脂质体贴剂的经皮渗透行为研究

目的:研究青藤碱脂质体贴剂的经皮渗透行为.方法:以青藤碱脂质体贴剂与不含脂质体的普通贴剂为模型药物,分别采用离体和在体经皮渗透试验进行比较研究.结果:离体试验结果表明,脂质体贴剂的皮肤药物滞留率为21.20%,普通贴剂为5.38%;在体试验结果表明,青藤碱脂质体贴剂的皮肤药物滞留率为17.44%,普通贴剂为3.97%.结论:青藤碱脂质体能增强皮肤内的贮库效应,并能以零级均衡释放药物,从而更有效地形成对局部病灶组织的靶向.     

RP-HPLC method and its validation for the determination of naloxone from a novel transdermal formulation

The aim of the present work was to develop a simple and reliable liquid chromatographic method for the quantitative determination of naloxone (NLX) in a novel transdermal formulation. Chromatography was carried out by reversed-phase technique on a C-18 column with a mobile phase composed of methanol, acetonitrile and 50 mM phosphate buffer (pH 7) in the proportion of 40:20:40 v/v/v, at a flow rate of 1 ml/min. The UV spectrophotometric determination was performed at 220 nm. This method was found to be specific and accurate with the mean recovery of 98.72% in the range of 2-50 microg/ml, and a run time of 15 min (retention time of NLX 11.3 min). Method was applied for stability testing of novel transdermal formulation developed in our laboratory. Assay content of NLX in the formulation was determined in stability samples and compared with the control samples. Statistical analysis by Student's t-test showed no significant difference between the assay content of NLX in control and test samples at 95% confidence interval. Overall, the proposed method is highly sensitive, precise and accurate and can be used for the reliable quantitation of NLX in developed transdermal formulation with the added advantage of simple procedure.     

Quercetin in w/o microemulsion: In vitro and in vivo skin penetration and efficacy against UVB-induced skin damages evaluated in vivo.

The present study evaluated the potential of a w/o microemulsion as a topical carrier system for delivery of the antioxidant quercetin. Topical and transdermal delivery of quercetin were evaluated in vitro using porcine ear skin mounted on a Franz diffusion cell and in vivo on hairless-skin mice. Skin irritation by topical application of the microemulsion containing quercetin, and the protective effect of the formulation on UVB-induced decrease of endogenous reduced glutathione levels and increase of cutaneous proteinase secretion/activity were also investigated. The w/o microemulsion increased the penetration of quercetin into the stratum corneum and epidermis plus dermis at 3, 6, 9 and 12h post-application in vitro and in vivo at 6h post-application. No transdermal delivery of quercetin occurred. By evaluating established endpoints of skin irritation (erythema formation, epidermis thickening and infiltration of inflammatory cells), the study demonstrated that the daily application of the w/o microemulsion for up to 2 days did not cause skin irritation. W/o microemulsion containing quercetin significantly prevented the UVB irradiation-induced GSH depletion and secretion/activity of metalloproteinases.     

Effect of penetration enhancers on gel formulation of Zidovudine: in vivo and ex vivo studies

To overcome many challenges associated with antiretroviral drug therapy, novel drug delivery systems present an opportunity for formulation scientists to improve the management of patients with HIV/AIDS. The purpose of this study was to prepare a transdermal delivery system for zidovudine using different penetration enhancers incorporated in carbopol 971P gel and to evaluate the same for rheology, percent drug content, drug deposition, in vitro, ex vivo, and in vivo permeation across rat skin. The rheology studies indicated that 1% w/w carbopol gel had a higher linear viscoelastic region, good creep recovery, and desirable viscosity. Among all gel formulations, gel containing cineole and menthol as penetration enhancers attained a steady-state flux of 5.9 mg/cm(2)/h and 5.4 mg/cm(2)/h of zidovudine, respectively, leading to plasma concentration in the therapeutic range. The drug deposition was also found to be highest in the case of gel containing cineole and menthol as penetration enhancers. The results indicated a linear relationship between in vitro flux and in vivo bioavailability of zidovudine transdermal gel.     

Topical skin penetration of diclofenac after single- and multiple-dose application

OBJECTIVE: Transdermal penetration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to be highly variable. The present study was performed to gain insight into the transdermal penetration process of topically applied diclofenac and to test whether transdermal absorption leads to pharmacologically effective concentrations in dermal tissue layers beneath the application site. MATERIAL AND METHOD: Six healthy male volunteers participated in this 2-way crossover study and were assigned to 2 treatment groups. In the first group, diclofenac was applied at a therapeutic dose of 60 mg/100 cm2 3 times daily for 4 days with subsequent occlusion with a plastic foil for 4 hours to enhance transdermal drug absorption. After a 1-week wash-out, diclofenac was applied at a single dose of 300 mg/100 cm2 without occlusion. Diclofenac in both groups was applied on a previously shaven area of the thigh. Transdermal penetration was assessed employing in vivo microdialysis. RESULTS: After multiple-dose administration mean diclofenac concentrations of 0.48 +/- 0.35 ng x ml(-1) were observed in subcutaneous tissue (mean +/- SEM). The mean AUC(subcutis/plasma) ratio of 0.08 +/- 0.02 indicates redistribution of diclofenac from the systemic circulation to the tissue. After single-dose treatment, mean tissue concentrations were 24.26 +/- 46.43 ng x ml(-1) with a mean AUC(subcutis/plasma) ratio of 60.85 +/- 57.59, which suggests direct tissue penetration of diclofenac. CONCLUSIONS: Transdermal penetration of diclofenac after multiple as well as after single application of the present formulation is highly variable. In addition to other factors influencing the transdermal penetration process, dose and mode of administration are important factors determining whether pharmacologically effective local tissue concentrations are attained.     

Formulation and in vitro/in vivo correlation of a drug‐in‐adhesive transdermal patch containing azasetron

The aim of the present study was to develop a transdermal drug delivery system for azasetron and evaluate the correlation between in vitro and in vivo release. The effects of different adhesives, permeation enhancers, and loadings of azasetron used in patches on the penetration of azasetron through rabbit skin were investigated using two‐chamber diffusion cells in vitro. For in vivo studies, azasetron pharmacokinetic parameters in Bama miniature pigs were determined according to a noncompartment model method after topical application of transdermal patches and intravenous administration of azasetron injections. The best permeation profile was obtained with the formulation containing DURO‐TAK 87‐9301 as adhesive, 5% of isopropyl myristate as penetration enhancer, and 5% of azasetron. The optimal patch formulation exhibited sustained release profiles in vivo for 216 h. The in vivo absorption curve in Bama miniature pigs obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve of the azasetron patch. These findings indicated that the developed patch for azasetron is promising for the treatment of delayed chemotherapy‐induced nausea and vomiting, and the in vitro skin permeation experiments could be useful to predict the in vivo performance of transdermal azasetron patches. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4540–4548, 2012     

In-vitro and in-vivo transdermal iontophoretic delivery of tramadol, a centrally acting analgesic

Objectives The feasibility of transdermal delivery of tramadol, a centrally acting analgesic, by anodal iontophoresis using Ag/AgCl electrodes was investigated in vitro and in vivo. Methods To examine the effect of species variation and current strength on skin permeability of tramadol, in‐vitro skin permeation studies were performed using porcine ear skin, guinea‐pig abdominal skin and hairless mouse abdominal skin as the membrane. In an in‐vivo pharmacokinetic study, an iontophoretic patch system was applied to the abdominal skin of conscious guinea pigs with a constant current supply (250 µA/cm²) for 6 h. An intravenous injection group to determine the pharmacokinetic parameters for estimation of the transdermal absorption rate in guinea pigs was also included. Key findings The in‐vitro steady‐state skin permeation flux of tramadol current‐dependently increased without significant differences among the three different skin types. In the in‐vivo pharmacokinetic study, plasma concentrations of tramadol steadily increased and reached steady state (336 ng/ml) 3 h after initiation of current supply, and the in‐vivo steady‐state transdermal absorption rate was 499 µg/cm² per h as calculated by a constrained numeric deconvolution method. Conclusions The present study reveals that anodal iontophoresis provides current‐controlled transdermal delivery of tramadol without significant interspecies differences, and enables the delivery of therapeutic amounts of tramadol.     

Design and evaluation of a novel transdermal patch containing diclofenac and teriflunomide for rheumatoid arthritis therapy

The aim of this study was to design a compound transdermal patch containing diclofenac (DA) and teriflunomide (TEF) for the treatment of rheumatoid arthritis (RA). The various organic amines salts of DA were prepared and their forming was confirmed using DSC and FTIR. The percutaneous permeation of organic amines salt of DA was investigated in vitro using a two-chamber diffusion cell with excised rabbit skin as transdermal barrier. The formulation of the patch was optimized in terms of the concentration of percutaneous permeation enhancer and the loading dose of drugs. The pharmacokinetic behavior of the optimal formulation was studies in rabbits and the anti-inflammatory and analgesic effects of the optimal patch were evaluated with the adjuvant arthritis model in rats and the pain model in mice, respectively. The result showed that skin penetration of diclofenac-triethylamine (DA-TEtA) salt was better than other organic amine salts. Based on previous study of our laboratory, teriflunomide-triethylamine (TEF-TEtA) significantly enhanced the skin permeation of TEF. 10% of azone (AZ) was the best enhancer for the two drugs. The optimal patch formulation was composed of 2% of TEF-TEtA, 6% of DA-TEtA and 10% of AZ. The cumulative permeated amount of DA-TEtA in vitro was comparable with that of the commercial diclofenac-diethylamine (DA-DEtA) patch. The absolute bioavailability of TEF-TEtA was 42%, which could achieve the therapeutic drug levels. In animal study, the optimized compound patch containing DA-TEtA and TEF-TEtA displayed significant anti-inflammatory and analgesic effect, which indicated the potential of the compound patch.     

Pharmacodynamic effects of transdermal bupranolol and timolol in vivo: comparison of microemulsions and matrix patches as vehicle

Transdermal administration of drugs possesses several advantages in therapy, but is limited by generally poor penetration through the skin. The aim of this study was to assess whether in vivo transdermal absorption could be enhanced by using microemulsions (ME) as vehicles. Water uptake from the occluded skin changes the water-free microemulsion base (MEB) into a ME. The increasing content of water decreases the solubility of apolar drugs. This leads to in situ formation of a super-saturated ME that possesses a particularly high absorption rate due to the enhanced diffusion pressure of the drug. A saturated solution of the model drugs bupranolol (B) and timolol (T) in a water-free microemulsion base was applied to an clipped area of the dorsal skin of rabbits with an occlusive patch. Evaluations were made in comparison to matrix patches (M) containing 1.2 mg/cm2 B or 2.0 mg/cm2 T. The beta-blocker dose applied was 2.0 mg/kg body weight throughout the study. The measured parameter of the pharmacodynamic effect was the maximal heart rate (HR) after an i.v. bolus injection of a standard dose of isoproterenol. Observations were made in different intervals over a 10-h time period after application of the patches. The response to isoproterenol was calculated as beta-blocker effect. Faster increasing effects and higher maxima for both drugs was found after application in MEB compared to M. After administration of B and T in MEB the effects were found to be identical, with a maximum (85-90%) after 2 h. Application in M showed B to be less effective (34%, 10h no plateau) than T (74%, 10h). Therefore microemulsions represent an improved vehicle for transdermal administration of test drugs.     

非洛地平-美托洛尔复方经皮给药系统的制备及其兔体内生物利用度

制备了非洛地平-美托洛尔复方经皮给药系统，并研究其药剂学性质及经兔皮肤给药的药代动力学和生物利用度。先建立了同时测定贴剂和经皮渗透液中非洛地平与美托洛尔含量的RP-HPLC方法，以考察贴剂的药物体外稳态透皮速率和经皮渗透机制，并进行质量控制和评价；再以高灵敏度的GC-ECD方法分别测定非洛地平和美托洛尔的血药浓度，研究贴剂经皮给药后在兔体内的药代动力学和生物利用度。结果显示，该给药系统的复方药物体外透皮转运具有零级动力学特征，其含量均匀度检查符合2005版中国药典规定，稳定性好；经皮给药的血药浓度明显较口服平稳，且波动性小，达峰时间推后，持效时间延长，非洛地平与美托洛尔的相对生物利用度分别为275.37%和189.76%。以上结果表明，非洛地平-美托洛尔复方经皮给药系统具有明显缓释特征，可较长时间维持稳定有效的血药浓度。     

Development and evaluation of a monolithic drug-in-adhesive patch for valsartan

The purpose of this study was to investigate the feasibility of a monolithic drug-in-adhesive (DIA) patch as a transdermal therapeutic system for the administration of valsartan (VAL). To improve the penetration of VAL in the patch, several chemical penetration enhancers were investigated by in vitro hairless mouse and Yucatan micro pig (YMP) skin permeation studies. A combination of isopropyl myristate (IPM)/diisooctyl sodium sulfosuccinate (AOT) most strongly enhanced the permeation of VAL. Since the concentration of VAL through the patch in hairless rat (HR) in vivo was correlated with that in HR skin in vitro, VAL that permeated through the skin could effectively pass into the systemic circulation. The plasma concentration-time profile of VAL after the patch was applied in humans was estimated by a convolution technique from the results of the in vitro YMP study, which indicated that the concentration of VAL could be sufficient to produce a pharmacological effect. These results demonstrate that the combination of IPM/AOT may be useful for the development of a practical DIA patch for VAL.     

Formulation,in vitro,and in vivo evaluation of matrix-type transdermal patches containing olanzapine

Transdermal patches of olanzapine were aimed to be prepared to overcome the side effects by oral application. The strategy was formulation of eudragit-based polymeric films to prepare transdermal patches by using nonionic (span-20), anionic (sodium lauryl sulfate), cationic surfactant (benzalkonium chloride), and vegetable oil (olive oil) as permeation enhancers. The patches were subjected to physicochemical, in vitro release and ex vivo permeation studies. On the basis of in vitro release performance, ERL 100:ERS 100 in the ratio of 3:2 was selected for incorporation of permeation enhancers. The permeation studies showed that formulation containing 10% span 20 (OD3) exhibited greatest cumulative amount of drug permeated (19.02?±?0.21?mg) in 72?h, so OD3 was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic, and skin irritation potential. In vivo studies of optimized olanzapine patch in rabbit model revealed prolongation of action with F_rel 116.09% during 72-h study period. Neuroleptic efficacy of transdermal patch was comparable to oral formulation during rotarod and grip test in Wistar albino rats with no skin irritation. Thus, developed formulation of olanzapine is expected to improve the patient compliance, form better dosage regimen, and provide maintenance therapy to psychotic patients.     

Release of naltrexone on buccal mucosa: permeation studies, histological aspects and matrix system design.

Transbuccal drug delivery has got several well-known advantages especially with respect to peroral way. Since a major limitation in buccal drug delivery could be the low permeability of the epithelium, the aptitude of NLX to penetrate the mucosal barrier was assessed. Ex vivo permeation across porcine buccal mucosa 800 microm thick was investigated using Franz type diffusion cells and compared with in vitro data previously obtained by reconstituted human oral epithelium 100 microm thick. Both fluxes (Js) and permeability coefficients (K(p)) are in accordance, using either buffer solution simulating saliva or natural human saliva. Permeation was evaluated also in presence of chemical enhancers or iontophoresis. No significant differences in penetration rate were observed using chemical enhancers; in contrast, Js and K(p) were extensively affected by application of electric fields. Tablets, designed for Naltrexone hydrochloride (NLX) administration on buccal mucosa, were developed and prepared by direct compression of drug loaded (56%) poly-octylcyanocrylate (poly-OCA) matrices. NLX is slowly discharged from buccal tablets following Higuchian kinetic. Histologically, no signs of flogosis ascribable to NLX and/or poly-OCA were observed, while cytoarchitectural changes due to iontophoresis were detected. Buccal tablets containing NLX may represent a potential alternative dosage form in addiction management.