吡罗昔康两种给药途径的血药浓度与局部浓度比较

探讨和比较了吡罗昔康以口服和透皮两种途径给药后的血药浓度与局部浓度。将小鼠随机分组,分别给予口服混悬剂0.072mg·ml^-1或透皮凝胶剂1mg·g^-1(或2mg·g^-1)。以HPLC法测定小鼠的血药浓度(C_s)和局部浓度(C₁)。结果表明,透皮给药以血药浓度计算凝胶剂的相对生物利用度仅为口服混悬剂的10%。但是透皮给药的C₁/C_s=0.13,远远大于口服给药的C₁/C_s(0.01)。透皮给药后,局部药物浓度—时间曲线下面积为15.85μg·h^-1·ml^-1,远远高于口服给药相应值(1.93μg·h-1·ml^-1)。揭示单纯以血药浓度作为局部作用透皮制剂的生物利用度评价标准是不全面的,应同时考察作用部位的药物浓度。     

缓释植入剂局部给药治疗系统的药动学模型

目的:创建缓释植入剂局部给药治疗系统的药动学模型.方法:分析体内过程,建立微分方程并特别关注其中局部靶位的数学表达,进而对药物在血循环中及局部吸收部位的分布作理论比较.结果:缓释植入剂局部给药治疗系统的药动学二室模型为:Cc(t)=A1e -Krt A2e -Kat A3e-at A4e-βt,吸收部位与血循环中药物分布的比值为:ACc/ACa≈(Va/V)·(Ka/Ke).结论:该模型立意严谨,有一定的理论意义和实用价值.     

克林霉素局部给药与口服给药药物代谢动力学比较研究

目的探讨通过不同途径使用克林霉素药物代谢动力学的临床研究。方法选取20例年龄在25~35岁的健康女性志愿者,首先给志愿者采用克林霉素100 mg阴首给药;1个月后给予此20例志愿者口服克林霉素100 mg,给药后,分别使用液/质联用法,对患者给药后24 h内的血药浓度进行监测,时间间隔为1次/h。结果通过阴道给药的t1/2半衰期为：（15.2±2.5）h;通过口服给药的克林霉素给药的t1/2半衰期为：（3.6±0.6）h;通过阴道给药的血药浓度的情况：给药后1 h的血药浓度：0.54 ng/ml;6 h的血药浓度：15.43 ng/ml;12 h的血药浓度：253.2 ng/ml;通过口服给药的血药浓度的情况：给药后1小时的血药浓度：1.3 ng/ml;6小时的血药浓度：21.4 ng/ml;12小时的血药浓度：256.2 ng/ml;结论克林霉素通过局部给药,药物能够较长时间的停留在药物作用的表面,发挥局部治疗的作用。     

局部给药长效缓释的药代模型初探

目的创建局部给药长效缓释治疗系统的药代动力学模型。方法分析体内过程,建立微分方程并特别关注其中局部靶位的数学表达,进而对药物在血循环中及局部吸收位的分布作理论比较。结果缓释植入剂局部给药治疗系统的药代动力学二室模型为:Cc(t)=A1e-K rt A2e-Kat A3e-αt A4e-βt,吸收位与血循环中药物分布的比值为:ACc/ACa≈(Va/V)(Ka/Ke)。结论该模型立意严谨,有一定的理论意义和实用价值。     

吡罗昔康贴片在中国健康志愿者的药代动力学

目的研究吡罗昔康贴片在中国健康志愿者的药代动力学。方法按平行设计方法,健康受试者33例,随机分为3组,分别单次贴吡罗昔康贴片48,96和144mg后,用高效液相色谱法测定血液中吡罗昔康浓度,用DAS软件进行数据处理,计算药代动力学参数。结果在给药72h后,各剂量组吡罗昔康吸收总量分别为(3.74±1.66),(7.47±2.49),(10.57±4.03)mg;主要药代动力学参数Cmax分别为(34.57±8.01),(57.89±13.84),(90.99±20.77)ng·mL-1;AUC0-∞分别为(4.06±0.71),(6.88±2.35),(9.95±2.81)μg·h·mL-1;tmax分别为(48.64±16.35),(46.91±15.37),(50.27±14.91)h;t1/2分别为(57.74±23.27),(58.63±16.73),(58.91±20.23)h;3组药代动力学参数经方差分析差异无统计学意义。结论在48~144mg内,吡罗昔康贴片具有线性动力学特征,和口服吡罗昔康相比,吡罗昔康贴片具备经皮给药系统的特征。     

利培酮慢性给药对条件性线索激发大鼠海洛因觅药行为的影响

目的：观察不同剂量的利培酮慢性给药对大鼠条件性线索激发的复吸行为的影响。方法：大鼠建立海洛因自身给药行为后，动物分四组进行环境消退7d，消退期间分别给予不同剂量的药物慢性处理。第8d给予药物处理后进行2h条件性线索激发测定；测定结束后立即取脑组织，运用WESTERN-BLOT测定NAc和VTA脑区p-CREB表达水平。结果：不同浓度利培酮（0．01mg／kg、0．03mg／kg和0．1mg／kg）慢性给药处理后，     

局部药代动力学的药物浓度时空方程初探

目的 建立局部植入给药的药物浓度时空方程。方法 将局部药物浓度时空方程构建为空间分布函数和时间分布函数(药物浓度经时方程)的积函数。并以加权平均及多元分析的数学手段予以证明及推导。结果 四维时空的局部植入给药的药物浓度时空方程的通式为：C(t，X，Y，Z)＝F(X，Y，Z)．C(t)，F(X，Y，Z)＝B0 B1X B2Y B3Z B4r3 B5r2 B6r,C(t)＝A1e^-Ket A2e^-Ket A3c^-Ket.。两维变量的简化的药物浓度时空方程为：C(t,ρ)＝F(ρ)．C(t)F(ρ)＝D0 D1ρ D2ρ2 D3ρ3，C(t)同上。结论 推导基本合理，并在初步的动物试验探索中得以验证。理论有较好科研价值，有助于揭示局部给药的药代动力学规律。     

[^3H]洛非西定在大鼠体内的药动学

目的 研究[^3H]洛非西定在大鼠体内不同给药途径的药代动力学。方法 TLC法分离原型药物，液闪法洲定血浆中药物放射性强度，用3P87程序计算药动学参数。结果 大鼠iv[^3H]OF其时-量曲线符合开放3室模型。T1/2为0．031-0．042h,T1/2(a)为0．352-0．398h,T1/2(B)为10．982-11．763h。大鼠po[^3H]LOF,其时-量曲线符合开放2室模型。T1/2(Ka)为1．037-1．102h T1/2(a)为2．113-2．325h,T1/2(B)为11.805-10．465h,Tmax为2.448-2.196h,F为53％55％。AUC和Cmax与剂量呈线性关系。结论 药物在大鼠体内呈一级动力学过程。     

微透析法研究罗通定经皮给药在大鼠体内不同部位的浓度分布

目的研究罗通定经皮给药后,药物在大鼠脑、皮下、血管3个部位微透析液和尾静脉血浆的浓度变化。方法采用微透析技术取样,HPLC测定不同时间点大鼠脑、皮下、血管的微透析液的药物浓度以及尾静脉血浆的药物浓度,DAS2．0药动学软件计算药动学参数。结果罗通定20cm^2经皮给药后,在大鼠体内消除缓慢,脑、皮下、血管和血浆AUC0→10h分别为（387．19±162．81）、（245．97±74．60）、（211．41±65．19）和（1677．05±598．83）min·mg·L^-1。体内药物含量血浆中最高,脑微透析次之,血管微透析最低,经皮给药后的AUC脑／AUC血浆、AUC皮下／AUC血浆、AUC血管／AUC血浆分别为（23．45±6．51）％、（15．66±5．03）％和（13．87±5．84）％。结论微透析法能很好地应用于罗通定经皮给药后大鼠不同部位的浓度研究,反映脑、皮下和血管之间的关系。     

基于直肠给药系统的研究和最新进展

口服给药形式简单方便,是常规药物治疗的首选途径,然而对于禁食或其他原因不能口服的药物及服药依从性差的患者,直肠给药是一种安全的替代给药方式.直肠黏膜内血管丰富,给药可发挥局部或全身治疗作用,避免肝脏首过效应,防止胃酸及酶对药物的破坏作用,减少胃的刺激.但由于缺乏经证实的药代动力学研究和对给药器械依赖大,以及给药部位特殊...     

Pharmacokinetic and local tissue disposition studies of naproxen following topical and systemic administration in dogs and rats

The pharmacokinetic profiles of naproxen in blood and synovial fluid (SF) following topical and i.v. bolus administration in dogs, and the local tissue disposition of the drug following topical and oral administration in rats, were investigated to assess the feasibility of topical delivery of naproxen for local and systemic effects. The naproxen gel in poloxamer 407 (PF-127) was applied on the stifle joint of dogs, and serum and synovial fluid samples were collected. For local tissue disposition studies, the naproxen gel was applied on the dorsal skin in rats, and blood, skin, and muscle samples were taken at 3, 6, and 12 h postdose after removing the residual gel from the skin. Steady state serum concentrations occurred at ∼20 h after topical doses and lasted for the next ∼30 h in dogs. Similar SF–serum concentration ratios of naproxen were found between i.v. (0·61±0·16) and topical (0·55±0·14) routes of administration. Following the i.v. dose, the half-life of naproxen in SF (∼60 h) was significantly longer than that in serum (∼40 h). The bioavailability of naproxen in the topical gel was ∼2% of the applied dose in dogs. A large accumulation of drug in the epidermis, dermis, and muscle tissue beneath the gel application site was found in rats. Isopropyl myristate (IPM) significantly increased the systemic absorption as well as the concentrations of naproxen in the underlying dermis and muscle tissues, but exerted little effect on the disposition of naproxen in the epidermis. © 1997 John Wiley & Sons, Ltd.     

Local Enhanced Topical Delivery (LETD) of Drugs: Does It Truly Exist?

There is considerable uncertainty over whether and to what extent topically applied drugs can be delivered directly to anatomical sites beneath the skin, without prior entry into the systemic blood circulation. The in vivo studies reported in this work were designed to assess whether local enhanced topical delivery (LETD) can be achieved with piroxicam, a nonsteroidal antiinflammatory drug. Equivalent doses of tritium-labeled drug were administered by the i.v. or topical routes to male rats. The topical plasma profile reveals a maximum concentration (Cp_max) at 12 hr, compared to a typical, multiexponential decline in plasma concentration after i.v. dosing. All four muscles from the topically dosed shoulder exhibit two distinct peaks, the first at 4 hr and a later one at 12 hr (which coincides with the topical Cp_max). The contralateral muscles from the non-dosed shoulder, in contrast, produce only a single peak at 12 hr after topical dosing. After the i.v. administration of piroxicam, the concentration-time profiles for each muscle closely parallel that seen for the i.v. plasma. Tissue-to-plasma ratios (T/P) show that the topical nondosed and the i.v. muscles are nearly constant over the entire time course of this study, indicating a pseudo-equilibrium between the plasma and those muscles. However, the early T/P ratios for the topically dosed muscles are markedly elevated and gradually decline to a constant value only after 12 hr, indicating that a similar pseudo-equilibrium is not established in this case. Thus, these results strongly imply that the topical administration of a drug can lead to LETD for tissues subjacent to the skin. Further, based on the elevated T/P ratios, these local enhanced drug levels cannot be solely attributed to entry from the systemic blood and suggest summarily that the cutaneous microvasculature is simply not an infinite sink for removal of all topically applied drugs.     

吡罗昔康普朗尼克磷脂有机凝胶的体外评价和局部组织分布

目的制备普朗尼克磷脂有机凝胶,以吡罗昔康为模型药物,评价其体外性能并考察其局部组织分布特征。方法应用椎-板模型流变仪测定普朗尼克磷脂有机凝胶的流变学参数,Franz扩散池法测试其体外释放和经皮通透性,考察大鼠局部给药的局部组织分布。结果普朗尼克磷脂有机凝胶具有典型的凝胶的流变学特征;48 h体外累积释放率和经皮通透率分别为(81.56±3.09)%和(3.80±1.59)%;皮肤和肌肉的药时曲线具有双峰特征,给药侧的组织药物浓度高于血药浓度和对侧相同组织的浓度,原因在于药物的直接通透和系统再分布。结论普朗尼克磷脂有机凝胶适用于皮肤局部给药的载体。     

Topical Penetration of Piroxicam Is Dependent on the Distribution of the Local Cutaneous Vasculature

The mechanism of the topical delivery of piroxicam, a nonsteroidal antiinflammatory drug, has been controversial as to whether systemic absorption is required for topical efficacy. This study, using in vivo pigs treated with topical ³H-piroxicam gel, was designed to assess the role of systemic absorption on its delivery to deep tissues. Further, the role of the structure of the cutaneous vasculature (e.g., direct cutaneous or musculocutaneous) was studied. Finally, piroxicam delivery was measured using in vitro diffusion cells with pig skin obtained from the same sites to determine inherent permeability independent of vascular anatomy. These studies showed that penetration of the radiolabel occurred in subcutaneous and muscle tissue only under the dosed sites and not at the remote sites, ruling out systemic absorption as a prerequisite for local delivery. Tissue penetration in vivo was enhanced at the musculocutaneous compared to the direct cutaneous sites. In contrast, in vitro flux was identical in skin harvested from the two vascular sites, suggesting that the vasculature plays a pivotal role in deep tissue penetration of piroxicam. In conclusion, local delivery of topical drugs occurs independent of systemic absorption and the nature of the cutaneous vasculature at different sites must be taken into consideration for optimal delivery.     

Inclusion complex of piroxicam with beta-cyclodextrin and incorporation in hexadecyltrimethylammonium bromide based microemulsion.

The interaction of piroxicam with beta-cyclodextrin (beta-CD), hexadecyltrimethylammonium bromide-based microemulsion (ME), and ME in the presence of beta-CD aimed at the optimization of topical drug delivery was studied. UV-VIS absorption spectra at pH 5.5 were obtained with and without beta-CD and ME. The stability constant (K) values for the piroxicam/beta-CD complex in the pH range 4.5-6.0 varied from 87 to 29 M-1. The cationic microemulsion was characterized by pseudo-ternary phase diagram. The association constant (Ks) of piroxicam/ME was determined using the framework of the pseudophase model. The value of Ks obtained for piroxicam at pH 5.5 was 132 M-1. At the same pH, the value of Ks for the incorporation of piroxicam/beta-CD complex in the ME was 150 M-1. Copyright     

Novel piroxicam-loaded nanospheres generated by the electrospraying technique: physicochemical characterisation and oral bioavailability evaluation

To determine if a novel electrospraying technique could be applied to an oral drug delivery system for improving the solubility and oral bioavailability of poorly water-soluble piroxicam; the nanospheres were generated with drug and polyvinylpyrrolidone (PVP) using electrospraying technique; and their physicochemical properties, solubility, release and pharmacokinetics were evaluated in comparison with piroxicam powder. All nanospheres had significantly increased drug solubility and dissolution rates in comparison with the drug powder. In particular, the nanosphere composed of piroxicam and PVP at a weight ratio of 2:8 gave about 600-fold higher solubility, 15-fold higher release rate and 3-fold higher AUC in comparison to piroxicam powder, leading to significantly enhanced oral bioavailability in rats, due to the mingled effect of nanonisation along with transformation to the amorphous state. Thus, this electrospraying technique can be utilised to produce a novel oral nanosphere delivery system with enhanced solubility and oral bioavailability for poorly water-soluble piroxicam.     

Fast-dissolving mucoadhesive microparticulate delivery system containing piroxicam.

We have studied the feasibility of preparing fast-dissolving mucoadhesive microparticulate delivery systems containing amorphous piroxicam to improve drug residence time on sublingual mucosa and drug dissolution rate. Two new mucoadhesive carriers, Eudragit L100 (EuLNa) and Eudragit S100 (EuSNa) sodium salts, both characterized by a fast intrinsic dissolution rate, have been selected. Microparticles containing piroxicam and EuLNa (series 1) or EuSNa (series 2) in ratios from 15/85 to 85/15% (m/m) were prepared by spray drying. The morphology and physical state of the microparticles and the effect of the microparticle composition on the piroxicam release and mucoadhesion were investigated. Piroxicam loaded into the microparticles was found to be in the amorphous form at all drug/copolymer ratios. This feature was ascribed to the presence of an H-bond between the NH of piroxicam and a CO of the copolymers. The formation of solid solutions improved the dissolution rate and the apparent drug solubility. The mucoadhesive properties were affected by the drug/copolymer ratio and in series 2 the microparticles containing more than 50% (m/m) of piroxicam did not show mucoadhesive properties. The delivery system made of piroxicam and EuLNa in the ratio 70/30% (m/m) appears to be the most promising because it contains the lowest amount of polymer able to confer mucoadhesive properties and increase apparent drug solubility.     

Analysis of skin disposition of flurbiprofen after topical application using dual agar gel discs-inserted rats

Most of the drug fraction penetrating the skin after topical application is taken up by the cutaneous blood flow, although the rest directly migrates into deeper tissues such as the subcutis and muscle. A new in situ experimental hairless rat model was designed to distinguish these fractions of topically applied drugs. Flurbiprofen, a non-steroidal anti-inflammatory drug, was selected as the model drug. In this model, two agar gel discs were subcutaneously inserted into the abdominal region of hairless rats as a drug receptor, and a topical formulation containing the drug was placed above either side of the gel disc. Plasma and agar levels of flurbiprofen were followed every 2 h over 10 h. The migration fraction of the drug into the systemic circulation and that directly to subcutaneous tissues were calculated to be 99.8% and 0.2% against the total amount which penetrated the skin, and the drug ratios into agar gel from the systemic circulation and not from the systemic circulation (i.e. directly migrated from the formulation) were 16.0% and 84.0%, respectively, at 10 h. This in situ drug disposition profile in skin was similar to the in vivo profile calculated from the in vivo muscle amount of flurbiprofen using muscle clearance. These results clearly suggest that the present in situ experimental model is a valuable tool for easy analysis of the skin disposition of topically applied drugs.     

Preclinical characterisation of NSAIDs in ultradeformable carriers or conventional topical gels

We compared in vivo transport and biodistribution of ketoprofen applied on the skin in ultradeformable carriers (Diractin) or a conventional topical gel (Gabrilen) with oral drug (Oruvail); for reference we used in vitro study data. The drug from Gabrilen diffuses into body with low bioavailability (<10%) and limited regio-selectivity (AUC(deep muscle/plasma) approximately 45/0.8 (t=0-8h), reaching maximum concentration in subcutaneous tissues and plasma at similar time (t(max) approximately 3-4h). The apparent drug elimination half-life is then similar to oral ketoprofen (t1/2,a) approximately 2 h). In contrast, Diractin containing ultradeformable carriers (Transfersome vesicles) delivers the drug more efficiently (>50%) and more directly into peripheral muscles (AUC(deep muscle/plasma) approximately 447/0.7 (652/1.4) for t=0-8 (0-24)h; tmax approximately 1 h), arguably in non-diffusive fashion. Ketoprofen from Diractin moreover disappears from body periphery slower (t1/2,a) approximately 4-6 h), owing to sustained drug release from the carriers in target tissue. Final clearance always proceeds via plasma (tmax approximately 4 h). Epicutaneous application of ketoprofen in conventional gels or the carrier-based formulation thus leads to different local accumulations and clearances. Ketoprofen from Diractin achieves more desirable biodistribution and clearance, arguably due to spontaneous carrier-mediated drug transport across the skin, which ensures local and relatively long-lasting drug deposition into peripheral target tissues.     

Pharmacokinetic Studies of Methotrexate in Plasma and Synovial Fluid Following IV Bolus and Topical Routes of Administration in Dogs

Purpose. The pharmacokinetic properties of methotrexate (MTX) in the plasma and synovial fluid (SF) after bolus IV and topical administration were studied in dogs to assess the feasibility of topical delivery of MTX for the treatment of rheumatoid arthritis. Methods. A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and topically applied on the elbow and stifle joints of dogs. SF was collected by inserting a needle with syringe into the joint space. Drug concentrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. Results. Peak MTX concentrations in SF occurrred at 38 ± 5 min following bolus IV dose, indicating the presence of a substantial diffusion barrier between the plasma and SF. The plasma/SF concentration ratios of 1.16 ± 0.25 were maintained after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 ± 1.2 hr) and SF (12.7 ± 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 ± 0.21 hr) was longer than that in plasma (2.56 ± 0.20 hr), probably due to the slow distribution of MTX to SF. After topical dose, MTX concentrations in plasma reached the steady state at ~4 hr, lasting for ~20 hr.The bioavailability of MTX from the gel was 11.8 ± 3.3% of the applied dose, but muscle tissues beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical difference in SF concentrations of MTX between drug treated and untreated joints 24 hr after topical dose. Conclusions. Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation. Methods. A MTX gel in Poloxamer 407 containing an absorption enhancer was formulated and topically applied on the elbow and stifle joints of dogs. SF was collected by inserting a needle with syringe into the joint space. Drug concentrations in the plasma, SF and muscle tissues were determined using a HPLC method with fluorimetric detection. Results. Peak MTX concentrations in SF occurrred at 38 ± 5 min following bolus IV dose, indicating the presence of a substantial diffusion barrier between the plasma and SF. The plasma/SF concentration ratios of 1.16 ± 0.25 were maintained after the attainment of distribution equilibrium between the two compartments. The t1/2 values in the plasma (11.2 ± 1.2 hr) and SF (12.7 ± 3.7 hr) were similar during the elimination phase, while the MRT in SF (3.24 ± 0.21 hr) was longer than that in plasma (2.56 ± 0.20 hr), probably due to the slow distribution of MTX to SF. After topical dose, MTX concentrations in plasma reached the steady state at ~4 hr, lasting for ~20 hr.The bioavailability of MTX from the gel was 11.8 ± 3.3% of the applied dose, but muscle tissues beneath the gel application site had significantly higher levels of MTX than untreated muscle tissues. There was no statistical difference in SF concentrations of MTX between drug treated and untreated joints 24 hr after topical dose. Conclusions. Topical delivery of MTX in a hydrophilic gel achieved a sustained C/t profile in plasma and higher drug levels in muscle tissues underneath the dosing site, implicating the potential therapeutic value of the topical formulation.