In vitro and in vivo evaluation of a hydrogel-based prototype transdermal patch system of alfuzosin hydrochloride

The first-line therapy for moderate to severe benign prostatic hyperplasia is the oral therapy by alfuzosin hydrochloride. Unfortunately, the oral therapy of alfuzosin is associated with several route-specific systemic side-effects. The current study was aimed to develop a prototype transdermal patch system for alfuzosin using a hydrogel polymer and optimize the drug delivery through the skin for systemic therapy. The prospective of different chemical enhancers (polyethylene glycol (PEG 400), isopropyl myristate, propylene glycol, menthol and L-methionine; 5% w/v) and iontophoresis (0.3?mA/cm²) in the alfuzosin delivery across the full thickness rat skin was assessed in vitro. In vivo iontophoretic studies were carried out using selected patch system (PEG 400) for a period of 6?h in Sprague-Dawley rats. Passive permeation studies indicated that the incorporation of chemical agents have moderate effect (~?4- to 7-fold) on the alfuzosin skin permeability and reduced the lag time. Combined approach of iontophoresis with chemical enhancers significantly augmented the drug transport (~ 43- to 72-fold). In vivo pharmacokinetic parameters revealed that the iontophoresis (transdermal patch with PEG 400) significantly enhanced the C_max (~ 3-fold) and AUC_0-α (~ 4-fold), when compared to control. The current study concludes that the application of iontophoresis (0.3?mA/cm²) using the newly developed agaorse-based prototype patch with PEG 400 could be utilized for the successful delivery of alfuzosin by transdermal route.     

特立氟胺经皮吸收贴剂的处方筛选和体内外相关性评价

目的制备特立氟胺经皮吸收贴剂,评价其体内外经皮透过行为。方法有机溶媒挥散法制备特立氟胺压敏胶分散型贴剂;采用水平双室扩散池,以离体兔皮为通透屏障,单因素考察法筛选贴剂系统中的压敏胶、载药量及促透剂;以家兔为实验动物,考察特立氟胺经皮吸收贴剂及注射液在体内的药动学行为,用HPLC法测定血药浓度,Win Nonlin软件求算药物动力学参数并进行体内外相关性评价。结果特立氟胺贴剂最优处方为DURO-TAK1压敏胶,质量分数为10%的氮酮和2.75%的特立氟胺。体内结果表明血药浓度在(12.92±3.95)h达到峰值,达峰质量浓度为(5.44±1.36)mg·L-1,MRT(mean retention time,MRT)达(16.30±3.70)h,血药浓度可长时间维持;体内外相关系数为0.9822。结论所制备的特立氟胺贴剂体内药物浓度平缓,体内外相关性良好。     

In vitro and In vivo characterization of the transdermal delivery of sertraline hydrochloride Films

Background and the purpose of the study

Sertraline hydrochloride is a selective serotonin reuptake inhibitor principally used in the treatment of major depressive disorder. To maintain the therapeutic plasma drug concentration of the drug for prolonged period, the transdermal drug delivery has been chosen as an alternative route of drug delivery. The pharmacokinetic properties of sertraline hydrochloride make it suitable for transdermal delivery. The purpose of the study was to investigate the effect of polymers and penetration enhancers on the transdermal delivery of the drug in order to improve its therapeutic efficacy.

Methods

In the preparation of films, Eudragit RL 100, Eudragit RS 100, hydroxy propyl methyl cellulose (HPMC) and ethyl cellulose were used as polymers. The films were characterized for thickness, tensile strength, drug content, moisture uptake, moisture content, water vapor transmission rate and drug release. The films exhibiting higher rates of drug release were subjected to study the effect of oleic acid and propylene glycol as penetration enhancers on skin permeation of sertraline hydrochloride. In vivo and skin irritation studies were performed for the optimized film.

Results

Films containing Eudragit RL 100, Eudragit RL 100 and HPMC showed the highest drug release of 94.34% and 96.90% respectively in a period of 42 hrs. The release data fitted into kinetic equations, yielded zero-order and fickian mechanism of drug release. There was a two-fold increase in skin permeation of sertraline hydrochloride in the presence of penetration enhancers in the film. The physical evaluation indicated the formation of smooth, flexible and translucent films. No skin irritation occurred on rabbit skin and the infrared studies showed the compatibility of the drug with the formulation excipients. The in vivo study revealed a constant plasma concentration of drug for long periods and the films containing penetration enhancers had achieved adequate plasma levels of the drug.

Conclusions

The obtained results indicated the feasibility for transdermal delivery of sertraline hydrochloride using eudragit RL 100 and HPMC.     

茶碱透皮贴片的制备及其体外渗透性研究

目的:制备茶碱透皮贴片,并考察其体外经皮渗透性。方法:以丙烯酸酯压敏胶为骨架材料,月桂氮酮和丙二醇为促渗剂,用离体人皮和Franz扩散池作为体外经皮释药模型,研究茶碱贴片体外渗透性。结果:茶碱贴片中的药物经皮渗透符合零级动力学,4%月桂氮酮和20%丙二醇有较好的促进渗透作用,其增渗倍数分别为不含促渗剂的茶碱对照贴片的2.30和2.04倍。结论:茶碱贴片体外经皮渗透作用较好。     

In vitro and in vivo evaluation of ranitidine hydrochloride ethyl cellulose floating microparticles

The real issue in the development of oral controlled release dosage forms is not just to prolong the delivery of drugs but also to prolong the presence of dosage forms in the stomach in order to improve the bioavailability of drugs with a 'narrow absorption window'. In the present study, an anti-ulcer drug, ranitidine hydrochloride, is delivered through a gastroretentive ethyl cellulose-based microparticulate system capable of floating on simulated gastric fluid for > 12 h. Preparation of microparticles is done by solvent evaporation technique with modification by using an ethanol co-solvent system. The formulated microspheres were free flowing with good packability and encapsulation efficiencies were up to 96%. Scanning electron microscopy confirmed porous, spherical particles in the size range 300-750 microm. Microspheres showed excellent buoyancy and a biphasic controlled release pattern with 12h. In vivo bioavailability studies performed on rabbits and T(max), C(max), AUC were calculated and confirmed significant improvement in bioavailability. The data obtained thus suggests that a microparticulate floating delivery system can be successfully designed to give controlled drug delivery, improved oral bioavailability and many other desirable characteristics.     

In vitro and in vivo evaluation of ranitidine hydrochloride ethyl cellulose floating microparticles

The real issue in the development of oral controlled release dosage forms is not just to prolong the delivery of drugs but also to prolong the presence of dosage forms in the stomach in order to improve the bioavailability of drugs with a ‘narrow absorption window’. In the present study, an anti-ulcer drug, ranitidine hydrochloride, is delivered through a gastroretentive ethyl cellulose-based microparticulate system capable of floating on simulated gastric fluid for?>?12 h. Preparation of microparticles is done by solvent evaporation technique with modification by using an ethanol co-solvent system. The formulated microspheres were free flowing with good packability and encapsulation efficiencies were up to 96%. Scanning electron microscopy confirmed porous, spherical particles in the size range 300–750 µm. Microspheres showed excellent buoyancy and a biphasic controlled release pattern with 12 h. In vivo bioavailability studies performed on rabbits and T_max, C_max, AUC were calculated and confirmed significant improvement in bioavailability. The data obtained thus suggests that a microparticulate floating delivery system can be successfully designed to give controlled drug delivery, improved oral bioavailability and many other desirable characteristics.     

In vitro and in vivo evaluation of the transdermal iontophoretic delivery of sumatriptan succinate.

The objective was to evaluate the transdermal delivery of the 5-HT(1B/1D) agonist, sumatriptan from an iontophoretic patch system, in vivo. Initial in vitro experiments were conducted to optimize formulation parameters prior to iontophoretic delivery in Yorkshire swine. It was found in vitro that increasing drug load in the patch from 9.7 to 39 mg had no statistically significant effect on cumulative delivery (cf. 305.6+/-172.4 vs. 389.4+/-80.4 microg cm(-2), respectively). However, for a given drug load (39 mg) increasing formulation pH from pH 4.7 to 6.8 significantly increased the cumulative amount of sumatriptan delivered across the skin (389.4+/-80.4 vs. 652.4+/-94.2 microg cm(-2)). A biphasic current profile comprising intensities of 1.8 mA from t=0 to t=180 min and 0.8 mA from t=181 min to t=360 min was used for the in vivo experiments. Drug levels in the blood were 13.7+/-4.5 and 53.6+/-10.2 ng ml(-1) at the 30 and 60 min time-points, rising to 90-100 ng ml(-1) during the 90-180 min time-period. The in vivo results show that the pharmacokinetics following transdermal iontophoretic delivery are comparable to those after oral, nasal or rectal administration, but do not match those upon subcutaneous injection.     

Nortriptyline hydrochloride skin absorption: Development of a transdermal patch

The influence of propylen glycol (PG), ethanol, and oleic acid (OA) on nortriptyline hydrochloride (NTH) penetration through human epidermis was studied in vitro at two different pH values (5.5 and 7.4). The influence of lactic acid and polysorbate 80 was studied for a pH of 5.5. Permeation studies through Heat Separated Epidermis, as well as the enhancing effect of the different vehicles, showed a pH dependency. A pH value of 5.5 in the donor solution decreases significantly the permeability coefficient (Kp) with respect to a pH value of 7.4 (0.011+/-0.004 x 10(-6) versus 0.36+/-0.04 x 10(-6)cm/s). The vehicles showed an increasing enhancement effect in the order: polysorbate 80>ethanol/PG/OA>PG>ethanol>ethanol/lactic acid>lactic acid at pH 5.5 while they reduced the permeation of NTH at pH 7.4. Considering the results obtained at pH 5.5, the maximum enhancement ratios were found for polysorbate 80 and the combination ethanol/PG/OA (10.72 and 3.90). Both vehicles were selected for designing a NTH transdermal delivery system (NTH-TDS) using (hydroxypropyl)methyl-cellulose as polymer. The NTH-TDS based on the combination of ethanol/PG/OA showed an enhancement ratio with respect to control of 2.09 and the addition of polysorbate 80 to the matrix, of 5.82.     

In vitro and in vivo evaluation of ranitidine hydrochloride loaded hollow microspheres in rabbits

The objective of this investigation was to develop the hollow microspheres as a new dosage form of floating drug delivery systems with prolonged stomach retention time. Hollow microspheres containing ranitidine hydrochloride (RH) were prepared by a novel solvent diffusion-evaporation method using ethyl cellulose (EC) dissolved in a mixture of ethanol and ether (6:1.0, v/v). The yield and drug loading amount of hollow microspheres were 83.21±0.28% and 20.71±0.32%, respectively. The in vitro release profiles showed that the drug release rate decreased with increasing viscosity of EC and the diameter of hollow microspheres, while increased with the increase of RH/EC weight ratio. Hollow microspheres could prolong drug release time (approximately 24 h) and float over the simulate gastric fluid for more than 24 h. Pharmacokinetic analysis showed that the bioavailability from RH-hollow microspheres alone was about 3.0-times that of common RH gelatin capsules, and it was about 2.8-times that of the solid microspheres. These results demonstrated that RH hollow microspheres were capable of sustained delivery of the drug for longer period with increased bioavailability.     

In vitro and in vivo evaluation of targeting efficiency of Adriamycin hydrochloride magnetic microspheres

The objective of this study was to prepare magnetic microspheres as a targeting drug delivery system and to specifically evaluate its targeting efficiency. The magnetic microspheres were prepared by emulsion cross-linking techniques. Targeting efficiency was specifically investigated by experiments of biodistribution on rats and histological study. Adriamycin hydrochloride (ADR)-loaded magnetic microspheres were successfully prepared with the mean diameter of 3.853 μm (± 1.484 μm), and had its speciality of superparamagnetism. The results of the targeting efficiency study showed that application of the external magnetic field significantly increased the ADR concentration from 40.28 μg/ml to 100.70 μg/ml at 10?min, 36.99 μg/ml to 91.16 μg/ml at 60?min, and 13.71 μg/ml to 28.30 μg/ml at 180?min in liver as the targeting tissue. The relative uptake efficiencies in liver by injection treatment of ADR magnetic microspheres with external magnetic field were 3.87, 5.59, and 3.34 at 10?min, 60?min, and 180?min after administration, respectively. In conclusion, distinguished targeting efficiency was displayed, which indicated that the magnetic microspheres could be applied as a novel targeting drug delivery system.     

In vitro and in vivo evaluation of targeting efficiency of Adriamycin hydrochloride magnetic microspheres

The objective of this study was to prepare magnetic microspheres as a targeting drug delivery system and to specifically evaluate its targeting efficiency. The magnetic microspheres were prepared by emulsion cross-linking techniques. Targeting efficiency was specifically investigated by experiments of biodistribution on rats and histological study. Adriamycin hydrochloride (ADR)-loaded magnetic microspheres were successfully prepared with the mean diameter of 3.853 μm (± 1.484 μm), and had its speciality of superparamagnetism. The results of the targeting efficiency study showed that application of the external magnetic field significantly increased the ADR concentration from 40.28 μg/ml to 100.70 μg/ml at 10?min, 36.99 μg/ml to 91.16 μg/ml at 60?min, and 13.71 μg/ml to 28.30 μg/ml at 180?min in liver as the targeting tissue. The relative uptake efficiencies in liver by injection treatment of ADR magnetic microspheres with external magnetic field were 3.87, 5.59, and 3.34 at 10?min, 60?min, and 180?min after administration, respectively. In conclusion, distinguished targeting efficiency was displayed, which indicated that the magnetic microspheres could be applied as a novel targeting drug delivery system.     

In vitro evaluation of a hydroxypropyl cellulose gel system for transdermal delivery of timolol

In this work, the development of a gel reservoir for a timolol (TM) transdermal iontophoretic delivery system is investigated. TM gel is prepared using hydroxypropyl cellulose (HPC) and the permeability of TM from the gel through an artificial membrane (Polyflux) and pig stratum corneum (SC) is studied. For a constant TM donor concentration, the TM transport across the Polyflux membrane alone decreases when the concentration of the gel increases due to increase of the gel viscosity. For constant gel concentration, however, the TM permeation across the membrane increases when the TM donor concentration increases. In addition, no effect of the electrical current (iontophoresis, current density 0.5 mA cm-2) on the TM permeation is found. For the combination of the Polyflux membrane with pig SC, the TM transport is much lower than for the membrane alone and the SC fully controls the TM delivery. In this case, the application of electrical current enhances the TM delivery 13-15 times in comparison to passive (no current) transport. According to our estimation, the daily TM dose (10-60 mg) can be delivered by an iontophoretic patch with Polyflux membrane area of 6-36 cm2 containing 20% (w/w) HPC gel and 15 mg cm-3 of TM.     

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).     

In vivo evaluation of limonene-based transdermal therapeutic system of nicorandil in healthy human volunteers

Hydroxypropyl methylcellulose (HPMC) gel drug reservoir system prepared with 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene was effective in promoting the in vitro transdermal delivery of nicorandil. The objective of the present study was to fabricate and evaluate a limonene-based transdermal therapeutic system (TTS) for its ability to provide the desired steady-state plasma concentration of nicorandil in human volunteers. The in vitro permeation of nicorandil from a limonene-based HPMC gel drug reservoir was studied across excised rat skin (control), EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite to account for their effect on the desired flux of nicorandil. The flux of nicorandil from the limonene-based HMPC drug reservoir across EVA2825 membrane decreased to 215.8 +/- 9.7 microg/cm(2).h when compared to that obtained from control, indicating that EVA2825 was effective as a rate-controlling membrane. The further decrease in nicorandil flux across adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite showed that the adhesive coat and skin also controlled the in vitro transdermal delivery. The limonene-based drug reservoir was sandwiched between adhesive-coated EVA2825-release liner composite and a backing membrane. The resultant sandwich was heat-sealed as circle-shaped patch (20 cm(2)), trimmed and subjected to in vivo evaluation in human volunteers against immediate-release tablets of nicorandil (reference formulation). The fabricated limonene-based TTS of nicorandil provided a steady-state plasma concentration of 21.3 ng/ml up to 24 h in healthy human volunteers. It was concluded that the limonene-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations and improved bioavailability.     

In vitro and in vivo transdermal studies of atenolol using iontophoresis

Matrix formulations of Eudragit E 100: NE 40D polymers (100:0, 70:30, 60:40, 50:50% w/w) with 20% w/w of triacetine and 5% w/w of atenolol were prepared by film casting method with different solvents (methanol, 2-propanol and acetone). In vitro release of atenolol from the films were studied by vertical Franz diffusion cells in HEPES buffer (pH 7.4) for 78 h. Direct currents of 0.1 and 0.5 mA/cm2 were applied for 6 h to the formulations with Ag/AgCl electrodes. Also, transdermal application for the Eudragit E 100: NE 40 D (70:30% w/w) formulation was compared by iontophoresis or oleic acid (2.5% w/v) with control group on Wistar rats. As a result, the in vitro release rate of atenolol from films were increased with iontophoresis by increasing the current density (from 0.240 to 0.424 mg/cm2 for 70:3% w/w formulation) and also increased with the amount of Eudragit NE 40D (from 0.646 to 1.30 mg/cm2 at the end of 78 h). It is obtained from the in vivo studies that oleic acid provided a higher plasma and skin concentration (0.825 mg/mL and 12.5 mg/cm2, respectively) than iontophoresis treatment (0.399 mg/mL and 1.81 mg/cm2, respectively) due to the different mechanisms. However, the results showed that iontophoresis is a good alternative for enhancing the transdermal delivery of atenolol.     

盐酸尼卡地平贴剂的大鼠离体皮肤渗透研究

目的 :研制盐酸尼卡地平贴剂 ,考察其释药影响因素。方法 :采用正交试验法 ,对盐酸尼卡地平贴剂进行大鼠离体皮肤体外渗透实验 ,考察其最优处方。结果 :盐酸尼卡地平贴剂中药物的渗透可用Higuchi方程来表达。最佳处方中盐酸尼卡地的浓度为 15mg·g-1,氮酮的浓度 4 0mg·g-1,丁酮的浓度为 75mg·g-1。结论 :氮酮和丁酮可以提高盐酸尼卡地平的皮肤渗透性。     

Rufloxacin体内和体外抗菌活性研究

检测了ｒｕｆｌｏｘａｃｉｎ（ＲＦＬＸ）对１０４０株致病菌的ＭＩＣ，其总的ＭＩＣ５０为２ｍｇ／Ｌ，低于该药在体内可能达到的峰浓度（Ｃｍａｘ）。与诺氟沙星比较其体外抗菌活性与之相近或略低。体内药效研究显示ＲＦＬＸ对金葡球菌、伤寒沙门氏菌、大肠埃希氏菌和不动杆菌等引起的小鼠感染有明显的治疗效果，其疗效与氧氟沙星和洛美沙星相近或略优。建议建立体内药效指数ＥＤ５０／ＭＩＣ，以比较ＭＩＣ不同时不同药物的体内疗效。     

盐酸阿夫唑嗪分散片在健康人体的生物等效性及安全性评价

目的：研究中国健康受试者单次口服盐酸阿夫唑嗪分散片和片剂的药代动力学行为并评价2种药物间的生物等效性。方法随机交叉,单次试验设计。24名健康男性受试者口服受试和参比药物各5 mg,测定给药前和给药后24 h内的血药浓度,用DAS软件计算药代动力学参数。结果24名健康受试者口服受试药物和参比药物后,血浆中阿夫唑嗪的主要药代动力学参数如下,t1/2分别为（4.7±1.7）,（5.5±1.6）h,cmax分别为（23.1±7.0）,（24.3±8.7）ng· mL-1, AUC0-t分别为（127.0±34.0）,（136.8±41.9）ng· h· mL-1;受试药物的相对生物利用度（98.6±32.1）％。结论阿夫唑嗪2种药物间体内生物作用等效。     

In vivo wound healing performance of drug loaded electrospun composite nanofibers transdermal patch

Acute injuries or wound is required the fast delivery of drug to control infections without any side effect. In this direction in the present investigation, antibiotic ciprofloxacin loaded hydrophilic biodegradable poly vinyl alcohol (PVA) and sodium alginate (NaAlg) electrospun composite nanofiber based transdermal patch was developed for local delivery of antibiotic drug. The antibiotic drug ciprofloxacin was loaded in it by active loading. The drug entrapped in the composite nanofibers was confirmed by the scanning electron microscopy and swelling behavior. The in vivo studies were carried on male rabbits by using the drug loaded and unloaded composite nanofibers transdermal patch and marketed one. It is observed that, in vitro activity provides a sustained and controlled release pattern of the drug from transdermal patch. The mechanism of drug release was also studied using different models. The nanofiber transdermal patch follows the Higuchi and Korsmeyer–Peppas model for drug release. The in vivo studies demonstrate that, wound healing takes place in less time as compared drug unloaded patch. Hydroxyproline produced in wound bed with time shows that it content is maximum in case drug loaded PAV-NaAlg patch. This demonstrates that wound healing rate is higher in case drug loaded PVA-NaAlg transdermal patch.