Controlled delivery of ropinirole hydrochloride through skin using modulated iontophoresis and microneedles

Abstract

The objective of this study was to investigate the effect of modulated current application using iontophoresis- and microneedle-mediated delivery on transdermal permeation of ropinirole hydrochloride. AdminPatch® microneedles and microchannels formed by them were characterized by scanning electron microscopy, dye staining and confocal microscopy. In vitro permeation studies were carried out using Franz diffusion cells, and skin extraction was used to quantify drug in underlying skin. Effect of microneedle pore density and ions in donor formulation was studied. Active enhancement techniques, continuous iontophoresis (74.13?±?2.20?µg/cm²) and microneedles (66.97?±?10.39?µg/cm²), significantly increased the permeation of drug with respect to passive delivery (8.25?±?2.41?µg/cm²). Modulated iontophoresis could control the amount of drug delivered at a given time point with the highest flux being 5.12?±?1.70?µg/cm²/h (5–7?h) and 5.99?±?0.81?µg/cm²/h (20–22?h). Combination of modulated iontophoresis and microneedles (46.50?±?6.46?µg/cm²) showed significantly higher delivery of ropinirole hydrochloride compared to modulated iontophoresis alone (84.91?±?9.21?µg/cm²). Modulated iontophoresis can help in maintaining precise control over ropinirole hydrochloride delivery for dose titration in Parkinson’s disease therapy and deliver therapeutic amounts over a suitable patch area and time.     

Enhanced transbuccal salmon calcitonin (sCT) delivery: Effect of chemical enhancers and electrical assistance on in vitro sCT buccal permeation

This study investigates the combined effect of absorption enhancers and electrical assistance on transbuccal salmon calcitonin (sCT) delivery, using fresh swine buccal tissue. We placed 200 IU (40 μg/mL) of each sCT formulation—containing various concentrations of ethanol, N-acetyl-l-cysteine (NAC), and sodium deoxyglycocholate (SDGC)—onto the donor part of a Franz diffusion cell. Then, 0.5 mA/cm² of fixed anodal current was applied alone or combined with chemical enhancers. The amount of permeated sCT was analyzed using an ELISA kit, and biophysical changes of the buccal mucosa were investigated using FT-IR spectroscopy, and hematoxylin–eosin staining methods were used to evaluate histological alteration of the buccal tissues. The flux (J_s) of sCT increased with the addition of absorption enhancer groups, but it was significantly enhanced by the application of anodal iontophoresis (ITP). FT-IR study revealed that all groups caused an increase in lipid fluidity but only the groups containing SDGC showed statistically significant difference. Although the histological data of SDGC groups showed a possibility for tissue damage, the present enhancing methods appear to be safe. In conclusion, the combination of absorption enhancers and electrical assistance is a potential strategy for the enhancement of transbuccal sCT delivery.     

盐酸丁卡因凝胶剂经皮渗透作用

目的：制备盐酸丁卡因凝胶剂，并考察不同透皮促进剂对其透皮吸收的影响。方法：配制含不同透皮促进剂的盐酸丁卡因凝胶剂，采用简单扩散小室和紫外分光光度法测定药物透皮吸收量。结果：加1%月桂氮Zhuo酮，加1%，3%，5%薄荷脑或加两者混合透皮促进剂，将药物碱化均可显著增加盐酸丁卡因凝胶剂的透皮吸收量，其累积释药量与时间呈线性关系。结论：单独使用1%月桂氮Zhuo酮对盐酸丁卡因凝胶透皮吸收作用不明显，3%，5%薄荷脑或加1%月桂氮Zhuo酮两者混合透皮保进剂对盐酸丁卡因凝胶透皮吸收作用明显，1%月桂氮Zhuo酮 3%薄荷脑对盐酸丁卡因凝胶透皮吸收作用最明显。     

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.     

Solid lipid nanoparticles as a drug delivery system for the treatment of neurodegenerative diseases

ABSTRACT

Introduction: The failure of many molecules as CNS bioactive compounds is due to many restrictions: poor water solubility, intestinal absorption, in vivo stability, bioavailability, therapeutic effectiveness, side effects, plasma fluctuations, and difficulty crossing physiological barriers, like the brain blood barrier (BBB), to deliver the drug directly to the site of action.

Area covered: Nanotechnology-based approaches with the employment of liposomes, micelles, dendrimers, and solid lipid nanoparticles (SLN) as drug delivery systems, are used to overcome the above reported limitations. Here, we focus on the delivery of drugs based on SLN formulation to treat neurodegenerative diseases. Notably, SLN have the ability to protect drugs from chemical and enzymatic degradation, direct the active compound towards the target site with a substantial reduction of toxicity for the adjacent tissues, and pass physiological barriers increasing bioavailability without resorting to high dosage forms.

Expert opinion: We believe that SLN could represent a suitable tool to pass the BBB and permit drugs to reach damaged areas of the CNS in patients affected by neurodegenerative pathologies, such as Alzheimer’s and Parkinson’s diseases.     

Preparation and solid-state characterization of bupivacaine hydrochloride cyclodextrin complexes aimed for buccal delivery

Binary products of bupivacaine hydrochloride (BVP HCl), an amide type local anesthetic, with parent β-cyclodextrin (β-CD) and its soluble β-cyclodextrin-epichlorohydrin polymer (EPI-β-CD) were prepared and evaluated as a first phase in the development of a novel mucoadhesive formulation aimed for buccal delivery of this drug. The solid products were obtained by physical mixing, ball milling in high-energy mills, co-evaporation and lyophilisation, in order to rationally select the most effective preparation technique. The solid products obtained were carefully characterised by differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier transform infrared spectroscopy (FTIR) and environmental scanning electron microscopy (ESEM). The impact of the preparation techniques on the physicochemical properties of plain drug was also studied. Results of solid-state analysis revealed more intense interactions of BVP HCl with EPI-β-CD than with native β-CD, accompanied by stronger reduction of drug crystallinity in the samples, probably favoured by the amorphous nature of the polymeric carrier. While summarising the results of DSC and XRPD analyses, it seems that ball milling of drug/cyclodextrin binary mixtures was particularly efficient in inducing solid-state interaction between the components and it can be considered as the method of choice for preparation of complexes of BVP HCl with β-CD and EPI-β-CD. In vitro dissolution properties in artificial saliva of ball-milled BVP HCl and corresponding CD complexes were investigated by simulating the conditions present at the surface of the buccal mucosa. The obtained results confirmed that complexation of BVP HCl with β-CD and EPI-β-CD is a suitable tool for properly tailoring the dissolution properties of the drug and it can be favourably exploited for the development of an effective buccal drug delivery system.     

渗透促进剂对葛根素角膜透过性的影响

目的研究葛根素(puerarin)的角膜透过性,为其处方设计提供理论基础。方法采用体外扩散实验以林格溶液为扩散介质考察在多种渗透促进剂条件下PUE的离体兔眼角膜透过性。结果10 g.L-1吐温80和5 g.L-1乙二胺四乙酸二钠(EDTA)分别使PUE的表观渗透系数增加到1.69和2.10倍,与对照组呈现显著性差异(P<0.01),而20 g.L-1羟丙基-β-环糊精(HP-β-CD)与1 g.L-1月桂氮卓酮(azone)未能显著增大PUE的表观渗透系数(P>0.05);5 g.L-1乙二胺四乙酸二钠(EDTA-2Na),10 g.L-1吐温80能显著缩短PUE透过角膜的滞后时间(P<0.01);而20 g.L-1羟丙基-β-环糊精(HP-β-CD)与1 g.L-1月桂氮卓酮(azone)未能显著缩短PUE的滞后时间(P>0.05);所有渗透促进剂对眼组织均没有显著刺激性。结论5 g.L-1的EDTA-2Na能够显著增加PUE的表观渗透系数并能显著缩短其角膜透过时间,且对角膜无明显刺激性。     

Challenges and trends in apomorphine drug delivery systems for the treatment of Parkinson's disease

 Parkinson’s disease (PD) is a chronic debilitating disease affecting approximately 1% of the population over the age of 60. The severity of PD is correlated to the degree of dopaminergic neuronal loss. Apomorphine has a similar chemical structure as the neurotransmitter dopamine and has been used for the treatment of advanced PD patients. In PD patients, apomorphine is normally administered subcutaneously with frequent injections because of the compound’s extensive hepatic first-pass metabolism. There is, hence, a large unmet need for alternative administrative routes for apomorphine to improve patient compliance. The present review focuses on the research and development of alternative delivery of apomorphine, aiming to highlight the potential of non-invasive apomorphine therapy in PD, such as sublingual delivery and transdermal delivery     

透皮吸收促进剂在经皮给药系统中的质控和评价方法

透皮吸收制剂是国际上第三代药物制剂的研究重点领域。透皮吸收促进剂在处方中的合理应用和质量控制及其评价方法日益重要。通过对透皮促进机理、协同作用等的探讨,介绍透皮吸收促进剂的选用原则,并对透皮给药制剂和局部用药局部起效的皮肤外用制剂处方中使用的要求加以讨论,介绍了现有的评价方法和基本的技术要求。     

Transdermal delivery of venlafaxine hydrochloride: the effects of enhancers on permeation across pig ear skin

Venlafaxine representing a new class of antidepressants is a potent serotonin/ norepinephrine reuptake inhibitor. Transdermal delivery of venlafaxine hydrochloride (VHCl) may result in proper patient compliance by reducing the incidence of the undesirable GI problems generally associated with its plural oral dosing. The present study is an attempt to investigate the improvement of the transdermal flux of the hydrophilic VHCl by certain permeation enhancers viz. glycerin, urea, propylene glycol and mixture of propylene glycol and ethanol across pig ear skin. The cumulative drug release was the highest from the formulation F5 consisting of the mixture of propylene glycol and ethanol in sodium alginate gel with a load of 25% w/w VHCl with 96% permeation enhancement. The steady state flux observed with F5 was 0.203 mg cm(-2) hr and an area of 15.27 cm(2) would suffice to arrive at a required therapeutic concentration of VHCl in the blood.     

Recent trends in the transdermal delivery of therapeutic agents used for the management of neurodegenerative diseases

With the increasing proportion of the global geriatric population, it becomes obvious that neurodegenerative diseases will become more widespread. From an epidemiological standpoint, it is necessary to develop new therapeutic agents for the management of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and other neurodegenerative disorders. An important approach in this regard involves the use of the transdermal route. With transdermal drug delivery systems (TDDS), it is possible to modulate the pharmacokinetic profiles of these medications and improve patient compliance. Transdermal drug delivery has also been shown to be useful for drugs with short half-life and low or unpredictable bioavailability. In this review, several transdermal drug delivery enhancement technologies are being discussed in relation to the delivery of medications used for the management of neurodegenerative disorders.     

Effect of permeation enhancers on transdermal delivery of fluoxetine: In vitro and in vivo evaluation

The aim of this study was to investigate the feasibility of transdermal fluoxetine (FX) delivery. The effects of chemical forms (base or salt) and permeation enhancers on in vitro skin permeation of FX were assessed using hairless mouse, rat and human cadaver skin. The optimized formulations from the in vitro studies were then evaluated in an in vivo pharmacokinetic study in rats. The in vitro skin permeation studies suggested that the FX base (FXB) and isopropyl myristate (IPM)–limonene mixture could be suitable for transdermal delivery of FX. The permeation parameters of FX through human cadaver skin were well correlated with that through hairless mouse and rat skin, suggesting that these animal models can be used for predicting the permeability of FX through human skin. After transdermal administration of FX with IPM or the IPM–limonene mixture to rats, the mean steady-state plasma concentration (C_ss) was 66.20 or 77.55 ng/mL, respectively, which was maintained over 36 h and had a good correlation with the predicted C_ss from the in vitro data. These in vitro and in vivo data demonstrated that permeation enhancers could be a potential strategy for transdermal delivery of FX.     

Transdermal delivery of highly lipophilic drugs: in vitro fluxes of antiestrogens,permeation enhancers,and solvents from liquid formulations

Purpose. Highly lipophilic basic drugs, the antiestrogens AE 1 (log P = 5.82) and AE 2 (log P = 7.8) shall be delivered transdermally. Methods. Transdermal permeation of drugs, enhancers, and solvents from various fluid formulations were characterized by in-vitro permeation studies through excised skin of hairless mice. Furthermore, differential scanning calorimetry (DSC) measurements of skin lipid phase transition temperatures were conducted. Results. Transdermal flux of highly lipophilic drugs was extraordinarily enhanced by the unique permeation enhancer combination propylene glycol-lauric acid (9 + 1): steady-state fluxes of AE 1 and AE 2 were as high as 5.8 g·cm^–2·h^–1 and 3.2 g·cm^–2·h^–1, respectively. This dual enhancer formulation also resulted in a marked increase in the transdermal fluxes of the enhancers. Furthermore, skin lipid phase transition temperatures were significantly reduced by treatment with this formulation. Conclusion. Transdermal delivery of highly lipophilic drugs can be realized by using the permeation enhancer combination propylene glycol-lauric acid. The extraordinary permeation enhancement for highly lipophilic drugs by this formulation is due to mutual permeation enhancement of these two enhancers and their synergistic lipid-fluidising activity in the stratum corneum.     

Drug in adhesive type transdermal matrix systems of ondansetron hydrochloride: optimization of permeation pattern using response surface methodology

The present investigation aims at development of pressure sensitive adhesive (PSA) based drug in adhesive type transdermal systems of ondansetron hydrochloride with higher permeation flux. The effect of mixture of two chemical permeation enhancers (oleic acid and lauric acid diethanolamide); and drug loading dose on the ex vivo human cadaver skin permeation from the transdermal patches has been investigated using a d-optimal combined mixture design. Incorporation of chemical permeation enhancers significantly improved the permeability parameters and it was also found that blend of permeation enhancers is more effective than either permeation enhancer. Criterion of desirability was employed to numerically optimize the transdermal system. Optimized formulation was achieved with 67.5% lauric acid diethanolamide, 32.5% oleic acid and 10% drug loading in an acrylate based PSA matrix. Optimized formulation was found to be nonirritating and safe for dermatological application.     

混合促进剂在经皮给药中的应用研究进展

研究表明混合促进剂对药物具有良好的促透效果,克服了使用单个化学促进剂的不足,随着对其促透机制和处方高通量筛选方法的进一步研究,混合促进剂在经皮给药系统中将有更好的发展前景。本文依据近年来国内外相关文献,从药物在皮肤的转运、化学促进剂及混合促进剂对药物的促透机制、处方筛选和实践应用等方面对混合促进剂在经皮给药系统中的应用研究进展进行了综述。     

Brain targeted delivery of mucoadhesive thermosensitive nasal gel of selegiline hydrochloride for treatment of Parkinson's disease

Selegiline hydrochloride (SL), is an anti-Parkinson’s agent, has low-oral bioavailability due to its high first pass metabolism and scarce oral absorption. In the present study, SL mucoadhesive nasal thermosensitive gel (SNT-gel) was prepared to enhance the bioavailability and subsequently, its concentration in the brain. The SNT-gel was prepared using Poloxamer 407-Chitosan combination and optimised formulation was further evaluated for physicochemical parameters. The comparative pharmacodynamic studies including behavioural studies, biochemical testing and histopathology of the brain was carried out in rats for SNT-gel, SL-nasal solution and SL Marketed Tablets. The optimised SNT-gel formulation (SNT-V) revealed sol-gel transition at 33–34°C. In-vitro diffusion study of SNT-V showed 102.37?±?2.1% diffusion at 12?h which reduced to 89.64?±?1.2% in Ex-vivo diffusion. Comparative results of behavioural studies indicated an improved score of photoactometer and reduced motor deficit (catalepsy score) in SNT-gel treatment group as compared with other groups. Similarly, a significant increase in brain dopamine, reduction in monoamine oxidase B level, increase in catalase activity and level of reduced glutathione upon treatment with SNT-gel indicated its effectiveness which was also supported by histopathology results. Therefore, nasal thermosensitive gel holds better potential for brain targeting in Parkinson’s disease over the conventional nasal or oral formulations.     

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.     

Enhanced<Emphasis Type="Italic">ex vivo</Emphasis> buccal transport of propranolol: Evaluation of phospholipids as permeation enhancers

The aim of the present study was to evaluate the effects of two phospholipid permeation enhancers, lysophosphatidylcholine (LPC) and didecanoylphosphatidylcholine (DDPC), along with a fusidic acid derivative, sodium taurodihydrofusidate (STDHF) and ethanol (EtOH) on the buccal transport of propranolol hydrochloride (PPL) using an ex vivo buccal diffusion model. The permeation rate of [3H]PPL as measured by steady-state fluxes increased with increasing EtOH concentration. A significant flux enhancement (P<0.05) was achieved by EtOH at 20 and 30 %v/v concentrations. At a 0.5 %w/v permeation enhancer concentration, the buccal permeation of [3H]PPL was significantly enhanced by all the enhancers studied (i.e., LPC, DDPC and STDHF) compared to the control (phosphate-buffered saline pH 7.4, PBS). LPC and DDPC displayed a greater degree of permeation enhancement compared with STDHF and EtOH-PBS mixtures with an enhancement ratio of 3.2 and 2.9 for LPC and DDPC, respectively compared with 2.0 and 1.5 for STDHF and EtOH:PBS 30:70 %v/v mixture, respectively. There was no significant difference between LPC and DDPC for the flux values and apparent permeability coefficients of [3H]PPL. These results suggest that phospholipids are suitable as permeation enhancers for the buccal delivery of drugs.     

Oleodendrimers: A novel class of multicephalous heterolipids as chemical penetration enhancers for transdermal drug delivery

This paper reports synthesis and evaluation of Janus type generation G-1 and G-2 dendrimers. The dendrimers have been constructed by linking two building blocks, dendrons and oleic acid, through ester and amide bonds and were well characterized by Fourier-transform infrared (FT-IR), ¹H NMR, ¹³C NMR and electrospray ionization mass spectrometry (ESI-MS). The dendrimers have been evaluated for in vitro cytotoxicity using sulforhodamine B assay (SRB assay) and in vivo skin irritation potential. The ester linked dendrimers did not exhibit any cytotoxicity even up to 80 μg/ml while G-1 and G-2 generations dendrimers with amide linkage exhibited toxicity above 70 μg/ml and 21 μg/ml, respectively, none of the dendrimers showed any skin irritation. All the dendrimers, tested for their skin permeation enhancement potential using diclofenac sodium (DS) as a model drug at a concentration of 1% in gels, showed significant increase in steady-state flux (ER_flux) of the drug as compared to control (without enhancer), and oleic acid. Amongst the dendrimers, the ester linked G-1 and G-2 dendrimers showed highest ER_flux, 3.33 ± 0.31 and 3.39 ± 0.21, respectively.