Prodrugs of Gestodene for Matrix-Type Transdermal Drug Delivery Systems

Purpose. The aim of this study was to enhance the transdermal absorption of the highly active progestin gestodene from matrix type transdermal delivery systems (TDDS) by formation of prodrugs with improved matrix solubility. Methods. Gestodene esters were synthesized via acylation of the drug with the respective carboxylic anhydrides. Subsequently TDDS were produced using the solvent cast method. Selected formulations were examined with in vitro diffusion experiments using skin of nude mice. Results. One prodrug, gestodene caproate proved to be an oil at ambient temperature and showed a very high solubilty of over 10.5% in the TDDS matrix. Within in vitro penetration studies using those systems the prodrug exhibited a significantly higher transdermal penetration rate than gestodene from reference systems. Furthermore, the prodrug was hydrolyzed to the parent drug to a high extent during the passage of the skin. Conclusions. Designing prodrugs to the requirements of matrix TDDS is an efficient way of enhancing the transdermal drug flux rate.     

Drug Reservoir Composition and Transport of Salmon Calcitonin in Transdermal Iontophoresis

Purpose. The aim of the work was to study iontophoretic transdermal administration of salmon calcitonin (sCt) in rabbits, with particular attention to drug reservoir composition. A dry sCt disc, to be dissolved on the application site, was used for preparing the reservoir for transdermal iontophoresis. As a reference drug reservoir, a pad wetted with drug solution was used. Methods. Experiments were done in rabbits depositing 100 IU of salmon calcitonin on skin and applying anodal iontophoresis. Serum calcium concentration was measured during iontophoresis, passive diffusion and after i.v. administration. Parameters such as pH value and reservoir type were examined. Results. Transdermal iontophoresis of sCt elicited a decrease in the serum calcium level, whereas, in the absence of electric current, no significant fall was measured. Using the reservoir prepared from drug solution, anodal iontophoresis at pH 4.2 was more effective than at pH 7.4, probably due to higher sCt net positive charge. Using the reservoir prepared from dry disc, similar kinetics and extent of drug effect were observed at both pH values. The reservoir prepared from solid drug deposit concentrated sCt next to the skin. Conclusions. Anodal iontophoresis for transdermal calcitonin administration shows therapeutical applicability. The type of reservoir is an important parameter affecting sCt transdermal iontophoresis.     

Chemical Stability of Esters of Nicotinic Acid Intended for Pulmonary Administration by Liquid Ventilation

Purpose. It has been suggested that fluorocarbon liquid may be a unique vehicle for the delivery of drugs directly to the acutely injured lung. A prodrug approach was used as a means of enhancing the solubility of a model drug (nicotinic acid) in the fluorocarbon. The solubility, the chemical stability of the putative prodrugs, and the sensitivity to enzymatic hydrolysis was investigated. Methods. The solubility of each nicotinic acid ester was determined in buffer as a function of pH and in perflubron. The octanol/buffer partition coefficient was determined at pH 7.4. The chemical stability of the putative prodrugs was determined as a function of pH, temperature, buffer content, and ionic strength. In addition, sensitivity of the esters to enzymatic degradation was evaluated. Results. Compared with nicotinic acid, the solubility in perflubron of the esters was significantly enhanced. In aqueous buffers, the esters exhibited pseudo-first order degradation kinetics, with both acid and base catalyzed loss. Studies of the fluorobutyl ester indicate quantitative loss of the putative prodrug and release of the parent nicotinic acid. Porcine esterase accelerated the loss of fluorobutyl ester by a factor of over 200 compared with chemical hydrolysis at pH 7.4. Conclusions. The properties of the fluorinated esters suggest that they may be suitable candidates for further testing as possible prodrugs of nicotinic acid based upon higher solubility in perflubron, rapid release of the parent drug after simple hydrolysis, and sensitivity to the presence of a model esterase enzyme.     

lontophoretic Delivery of Apomorphine I: In Vitro Optimization and Validation

Purpose. To investigate the feasibility of transdermal iontophoretic delivery of apomorphine in patients with Parkinson's disease, transdermal transport rates were optimized and validated across human stratum corneum and freshly dermatomed human skin in vitro. Methods. In all experiments R-apomorphine hydrochloride was applied in the anodal compartment. The effect on the flux of the following parameters was studied, using a flow through transport cell: current density, pH, concentration, ionic strength, osmolarity, buffer strength, temperature and skin type. Results. Transdermal transport of apomorphine was directly controlled by the presence or absence of current. Passive delivery was minimal and no depot effect was observed. A linear relationship was found between current density and steady-state flux. At room temperature the lag time was 30 to 40 minutes. A maximal steady-state flux was obtained when the donor concentration approached maximum solubility. By increasing the temperature of the acceptor chamber to 37°C, the steady-state flux was increased by a factor of 2.3 and the lag time decreased to ± 3 minutes. No effect of osmolarity and buffer strength, and only a small effect of ionic strength and pH on the transport rate were observed. The flux through dermatomed human skin was decreased compared to stratum corneum. This effect was shown not to be caused by skin metabolism. Conclusions. The results obtained in vitroindicate that the iontophoretic delivery of apomorphine can be controlled and manipulated accurately by the applied current. The in vitro flux furthermore depends on the donor composition, temperature and skin type. Under optimized conditions, transport rates resulting in therapeutically effective plasma concentrations are feasible, assuming a one to one in vitro/in vivo correlation.     

Human Skin Permeation of Branched-Chain 3-<Emphasis Type="Italic">O</Emphasis>-Alkyl Ester and Carbonate Prodrugs of Naltrexone

Purpose. Physicochemical characterization and in vitro human skin diffusion studies of branched-chain ester and carbonate prodrugs of naltrexone (NTX) were compared and contrasted with straight-chain ester and carbonate NTX prodrugs.Methods. Human skin permeation rates, thermal parameters, solubilities in mineral oil and buffer, and stabilities in buffer and plasma were determined. Partition coefficients between stratum corneum and vehicle were determined for straight- and branched-chain esters with the same number of carbon atoms.Results. Branched prodrugs had lower melting points, lower buffer solubilities, and higher mineral oil solubilities than NTX. The transdermal flux values from all of these branched prodrugs were significantly lower than flux values from the straight-chain ester and the methyl carbonate prodrugs. Straight-chain prodrugs had higher partition coefficient values and higher calculated thermodynamic activities than their branched-chain counterparts. The prodrug hydrolysis to NTX in buffer and plasma was slower for prodrugs with increased branching.Conclusions. Branched-chain prodrugs with bulky moieties had smaller stratum corneum—vehicle partition coefficients and lower thermodynamic activities that resulted in smaller transdermal flux values than straight-chain prodrugs.     

Synthesis and In Vitro Evaluation of Aminoacyloxyalkyl Esters of 2-(6-methoxy-2-naphthyl)propionic Acid as Novel Naproxen Prodrugs for Dermal Drug Delivery

Purpose. To synthesize and evaluate various novel aminoacyloxyalkyl esters of naproxen (3a-i) and naproxenoxyalkyl diesters of glutamic and aspartic acids (3j-m) as potential dermal prodrugs of naproxen. Methods. The prodrugs 3a-m were synthesized, and their aqueous solubilities, lipophilicities and hydrolysis rates were determined in a buffered solution and in human serum. The permeation of selected prodrugs across excised postmortem human skin was studied in vitro. Results. The aminoacyloxyalkyl prodrugs showed higher aqueous solubilities and similar lipid solubilities, in terms of octanol-buffer partition coefficients (log P_app) at pH 5.0, when compared with naproxen. At pH 7.4 the prodrugs were significantly more lipophilic than naproxen. Prodrugs3a-i showed moderate chemical stability in aqueous solutions at pH 5.0 and were rapidly converted to naproxen in human serum (t_1/2 = 4–19 min). The selected aminoacyloxyalkyl prodrugs possessed a higher flux across the skin than naproxen, with a maximum enhancement of 3-fold compared to naproxen. Prodrugs 3j-mshowed poor aqueous solubility and permeation across the skin. Conclusions. Combinations of adequate aqueous solubility and lipophilicity of naproxen aminoacyloxyalkyl prodrugs having fast rates of enzymatic hydrolysis resulted in improved dermal delivery of naproxen.     

Permeation of Buprenorphine and Its 3-Alkyl-Ester Prodrugs Through Human Skin

Purpose. Homologous 3-alkyl-ester prodrugs (C₂ to C₄) of buprenorphine with decreased crystallinity have been synthesized and evaluated for transdermal delivery commensurate with opioid dependence treatment. Methods. To assess the influence of derivatization on delivery, the permeation of the prodrugs through human skin was determined in vitro. Prodrug metabolism was measured in human blood and skin supernatant in vitro along with chemical hydrolysis controls. The pro-drugs' octanol/water partition coefficients were measured. Results. Without exception, the prodrugs were completely hydrolyzed on passing through the skin and appeared as buprenorphine in the receptor compartment. However, using saturation conditions, in no instance did the buprenorphine flux through skin from a prodrug solution exceed the flux of buprenorphine base itself in vitro. Moreover, the flux of the acetyl ester, the least hydrophobic of the prodrugs, was not significantly elevated upon stripping the skin. Whether in blood or the skin supernatant, the prodrugs hydrolyzed in an apparent first-order fashion and rate constants and half-lives were calculated. Conclusions. We conclude from the results that the prodrugs' very high octanol/water partition coefficients (hydrophobicity) placed them in viable tissue layer controlled diffusion. Consequently, one does not derive the potential flux-increasing benefit of reducing crystallinity that was expected.     

Transdermal iontophoresis of sodium nonivamide acetate I. Consideration of electrical and chemical factors

Transdermal iontophoresis is a process which enhances skin permeation of ionized species by an electrical field as driving force. The aim of this present study was to investigate the transdermal iontophoresis of a newly designed capsaicin derivative, sodium nonivamide acetate (SNA). Studies of electrical and physicochemical factors acting on the kinetics of in vitro iontophoresis were performed. Iontophoresis increased the transdermal penetration flux of SNA as compared to the passive diffusion in this study. Several application modes which possessed the same electrical energy had been researched. The iontophoretic flux of SNA increased following the decrease of donor buffer pH values. This trend could be due to the physiological property of skin and electro-osmotic flow presented. Comparing the various application modes, the discontinuous on/off cyclic current mode showed higher penetration capacity than did continuous mode which was due to the intensity of effective current which would not decay for on/off cyclic application of iontophoresis. The result of the present study is particularly helpful in the development of a SNA transdermal iontophoretic delivery system.     

lontophoretic Delivery of a Telomeric Oligonucleotide

Purpose. To evaluate the feasibility of iontophoretically enhanced transdermal delivery of a phosphorothioate oligonucleotide across hairless mouse skin. Methods. The phosphorothioate sequence, 5-d(TTAGGG)-3 (TAG-6) which mimics the repeat sequence of the telomere was used as a model compound. Iontophoresis was performed on hairless mouse skin using an in vitro flow-through diffusion system. Both 5-FITC and uniformly ³⁵S labeled oligonucleotide were used to monitor transdermal flux. Results. Cathodal delivery of TAG-6 resulted in substantial oligonucleotide flux. The molecular label did not alter transport properties. No flux was measured with either anodal or passive delivery. The oligonucleotide was not degraded as it crossed the skin. Molecular transport was donor condition dependent, with pH and salt concentration both having significant effects. Pre-treating the skin with ethanol reduced iontophoretic transport. Conclusions. These data demonstrate that iontophoresis can enhance transdermal flux of an intact phosphorothioate oligonucleotide and that this penetration is donor condition dependent. Furthermore, iontophoretically enhanced transdermal delivery is a feasible apprach to the administration of phosphorothioate oligonucleotides.     

熊果酸前药的设计合成及抗多发性硬化症活性评价

目的 设计、合成熊果酸前药,以改善熊果酸的水溶性,并对其抗多发性硬化症(multiple sclerosis,MS)活性进行评价。方法 根据前药策略,选取了琥珀酸、二肽氨基酸和艾莎康唑侧链片段,通过缩合、酯化反应等与熊果酸的3位羟基进行结合,采用紫外-可见分光光度法测定前药的水溶性,并建立小鼠实验性自身免疫性脑脊髓炎模型来进行抗MS活性评价。结果 共合成了3个前药,目标化合物的结构经¹H-NMR、¹³C-NMR和LCMS(ESI)进行确证;前药1和2水溶性较熊果酸提升110倍以上,前药3水溶性提升200倍以上;体内抗MS活性结果显示,所得前药化合物的抗MS活性均有一定提高,其中前药1的抗MS活性显著高于熊果酸组,其机制可能是通过抑制外周炎症细胞浸润中枢以及抗脱髓鞘从而发挥抗MS活性;前药1体内代谢结果显示,前药1以原型形式在体内的暴露量为熊果酸的6倍,表明前药1可能主要是以钠盐原型发挥抗MS活性。结论 前药1具有较大的抗MS潜力,值得深入研究。该研究为开发具有抗MS活性的熊果酸前药提供一定依据及有益指导。     

Iontophoretic Delivery of Ropinirole Hydrochloride: Effect of Current Density and Vehicle Formulation

Purpose. The objectives of this work were 1) to establish the feasibility of the transdermal iontophoretic delivery of ropinirole hydrochloride; 2) to investigate the possibility of delivering therapeutic doses of this drug; and 3) to determine the key factors that control ropinirole electrotransport. Methods. A series of in vitro transdermal iontophoretic experiments were instituted to study the effects of drug concentration, co-ion concentration, intensity of current, and application time on ropinirole flux. The convective contribution to ropinirole electrotransport was evaluated by following the transport of the electroosmotic marker mannitol. Results. Ropinirole flux decreased dramatically in the presence of competing ions. This effect was observed even when the molar fraction of the two competing cations was kept constant. Anodal flux of mannitol decreased with drug concentration, indicating a possible alteration of the skin permselectivity. In the absence of competing co-ions, ropinirole transport number reached a maximum value (8-13%). In these conditions, the main factor controlling drug delivery was the intensity of current applied. Conclusions. Transdermal iontophoresis allowed the delivery of therapeutic doses of ropinirole. The dose administered and the input rate were controlled by the judicious choice of the key delivery factors here described.     

Nanoparticles as delivery carriers for anticancer prodrugs

Introduction: Prodrugs are inactive compounds which are metabolized in the body to produce parent active agents. It has been shown that prodrugs hold some advantages over conventional drugs, such as increased solubility, improved permeability and bioavailability, reduced adverse effects and prolonged half-lives. Optimization of the vehicles used is very important in order to employ the advantages of prodrugs. Nanocarriers are currently being widely used as prodrug vehicles because of their ability to enhance storage stability, modulate prodrug release and tumor-targeted delivery and protect against enzymatic attack. This combined approach of prodrugs and nanoparticles has a particular attraction for developing anticancer therapies.

Areas covered: This paper discusses liposomes, polymeric nanoparticles and lipid nanoparticles, which are all carriers commonly used for prodrug encapsulation. Macromolecular prodrugs can spontaneously form self-assembled nanoparticles with no intervention of other additives. This review also describes recent developments in prodrug delivery using nanoparticulate strategies. Pharmacokinetic, pharmacodynamic and cytotoxicity evaluations of anticancer prodrugs are systematically elucidated in this review.

Expert opinion: More profiles involved in animal and clinical studies will encourage the future applicability of prodrug nanocarrier therapy. The possible toxicity associated with nanoparticles is a concern for development of prodrug delivery.     

Transdermal iontophoresis of sodium nonivamide acetate evaluated by in vivo microdialysis and histologic study

By using an intradermal microdialysis technique 22 h after the transdermal iontophoretic delivery of sodium nonivamide acetate (SNA), a synthetic derivative of capsaicin, the amount of SNA in the extracellular space was measured. Transdermal iontophoresis is a process that enhances skin permeation of ionized species by using an electric field as a driving force. Iontophoresis increased the amount of SNA in dialysate compared with passive diffusion in this study. By using various polymers incorporated in formulations, indicated hydrogels showed higher capacity for SNA delivery than solution formulations. This result was possibly attributable to the antinucleant ability of polymers resulting in the increase of thermodynamic activity of SNA in formulations. Pretreatment with isopropyl myristate, a lipophilic penetration enhancer, on rat skin enhanced transdermal delivery of SNA both for passive and iontophoretic penetration, indicating the possibility of reducing the surface area of the administrations site in clinical use. Microscopic examination revealed no or slight changes in the skin after iontophoretic treatment compared with penetration enhancer pretreatment. The histologic results also suggested iontophoretic treatment with 0.5 mA/cm² current density of not more than 7‐h application duration may be acceptable clinically. Drug Dev. Res. 46:87–95, 1999. © 1999 Wiley‐Liss, Inc.     

Enhancement of the Systemic and CNS Specific Delivery of L-Dopa by the Nasal Administration of Its Water Soluble Prodrugs

Purpose. To study the utility of the nasal route for thesystemic delivery of L-dopa using water soluble prodrugs of L-dopa and toexamine if this delivery method will result in preferential delivery to theCNS. Methods. Several alkyl ester prodrugs of L-dopa wereprepared and their physicochemical properties were determined. Invitro hydrolysis rate constants in buffer, rat plasma, rat brainhomogenate, rat CSF, and rat nasal berfusate were determined by HPLC. Invivo nasal experiments were carried out in rats. Levels of L-dopa anddopamine in plasma, CSF, and olfactory bulb were determined using HPLCmethod with electrochemical detection. Results. All the prodrugs showed improved solubility andlipophilicity with relatively fast in vitro conversion in ratplasma. Absorption was fast following nasal delivery of the prodrugs withbioavailability around 90%. Dopamine plasma levels did not changesignificantly following nasal administration of the butyl ester prodrug.Olfactory bulb and CSF L-dopa concentration were higher following nasaldelivery of the butyl ester prodrug compared to an equivalent intravenousdose. Conclusions. Utilization of water soluble prodrugs ofL-dopa via the nasal route in the treatment of Parkinson's disease may havetherapeutic advantages such as improved bioavailability, decreased sideeffects, and potentially enhanced CNS delivery.     

Enhancement of transdermal apomorphine delivery with a diester prodrug strategy

Diester prodrugs of apomorphine, diacetyl apomorphine (DAA), and diisobutyryl apomorphine (DIA) were synthesized, and their partition coefficients, capacity factor (log K′), enzymatic hydrolysis, and in vitro permeation across nude mouse skin were characterized. The lipophilicity of the diesters was between that of apomorphine HCl and the apomorphine base. The prodrugs were chemically stable, but enzymatically unstable in esterase medium, skin homogenate, and human plasma. DAA showed a faster hydrolysis in plasma compared to DIA. Total fluxes (nmol/cm²/h) of the parent drug and prodrug were significantly greater after topical treatment with the diesters in aqueous solutions (water, 30% polyethylene glycol in water, and 30% glycerol in water) compared to treatment with HCl and base forms of apomorphine. DIA flux from deionized water was 51 nmol/cm²/h, which exceeded the flux of apomorphine HCl by 10-fold. The extent of parent drug regeneration after topical application ranged 51-88% and 34-61% for DAA and DIA, respectively, depending on the vehicles selected. Permeation measurements using intact and stratum corneum-stripped skins demonstrated that the viable epidermis/dermis was an important barrier to prodrug permeation. Nano-sized lipid emulsions were also used as carriers for apomorphine and its prodrugs. Diester prodrugs exhibited superior skin permeation compared to the parent drug when formulated into the emulsions. DAA and DIA fluxes from lipid emulsions were 11- and 3-fold higher than that of apomorphine HCl. The results in the present work suggest the feasibility of diester prodrugs for the transdermal delivery of apomorphine.     

In Vivo Evaluation of Acyclovir Prodrug Penetration and Metabolism Through Rat Skin Using a Diffusion/Bioconversion Model

Purpose. In order to evaluate the in vivo penetration of prodrugs which undergo metabolism in skin, we analyzed thein vivo penetration profiles of acyclovir prodrugs based on a two-layer skin diffusion model in consideration of metabolic process. Methods. Acyclovir prodrugs (e.g., valerate, isovalerate and pivarate) were used as model prodrugs and the amounts excreted in urine were measured after percutaneous application. In vivo penetration profiles were then estimated by employing a deconvolution method and the penetration of acyclovir prodrugs was analyzed using a diffusion model. Subsequently, diffusion, partitioning and metabolic parameters were compared under in vitro and in vivo conditions. Results. Although total penetration amounts at the end of the experiment were similar for the three prodrugs, the ratio of intact prodrug to total penetration amount differed significantly. Moreover, the excretion and absorption profiles were also very different for each prodrug. Enzymatic hydrolysis rate constants calculated under in vivo conditions were considerably larger than those obtained in the skin homogenate and in vitro penetration experiments. Conclusions. The present skin diffusion/bioconversion model combined with computer analysis enables us to comprehensively account for diffusion, partitioning and metabolism during in vivo percutaneous absorption. Nevertheless, different enzymatic hydrolysis rate constants obtained under bothin vivo and in vitro conditions demonstrate the difficulty of obtaining accurate values for in vivo enzymatic activity from related in vitro experiments.     

Absorption Rate Limit Considerations for Oral Phosphate Prodrugs

Purpose. To evaluate the potential of phosphate ester prodrugs to significantly improve the absorptive flux of poorly soluble parent drugs. Methods. Absorptive transport studies of parent drugs and their prodrugs were carried out in Caco-2 cells. Prodrugs of parent drugs with variable aqueous solubilities were tested: Hydrocortisone-phosphate/Hydrocortisone, Fosphenytoin/phenytoin, TAT-59/DP-TAT-59, and Entacapone phosphate/Entacapone. Additional absorption studies were carried out in rats. Results. Absorptive fluxes of DP-TAT-59 and phenytoin increased 9.8 or 3.3-fold after dosing TAT-59 and 500 M fosphenytoin, respectively. Hydrocortisone's flux did not increase with hydrocortisone-phosphate at 100 M. Permeability of the highly lipophilic and protein bound compound, DP-TAT-59, was significantly increased with serosal albumin. No permeability increase was observed for the other drugs with albumin. Entacapone phosphate failed to improve the flux of entacapone compared to an entacapone solution, but the prodrug solution did yield higher entacapone plasma levels in rats when compared with an entacapone suspension. Conclusion. Ideal phosphate prodrug candidates are characterized by high permeability and low solubility (BCS Class II drugs). For low dose BCS Class II drug candidates, however, no biopharmaceutical advantage may be gained. Phosphate prodrugs of parent drugs with limited permeability may fail. When screening highly lipophilic parent drugs transport studies should be done with albumin.     

Epidermal Iontophoresis: I. Development of the Ionic Mobility-Pore Model

Purpose. An integrated ionic mobility-pore model for epidermal iontophoresis is developed from theoretical considerations using both the free volume and pore restriction forms of the model for a range of solute radii (r _j ) approaching the pore radii (r _p ) as well as approximation of the pore restriction form for r _j /r _p < 0.4. In this model, we defined the determinants for iontophoresis as solute size (defined by MV, MW or radius), solute mobility, solute shape, solute charge, the Debye layer thickness, total current applied, solute concentration, fraction ionized, presence of extraneous ions (defined by solvent conductivity), epidermal permselectivity, partitioning rates to account for interaction of unionized and ionized lipophilic solutes with the wall of the pore and electroosmosis. Methods. The ionic mobility-pore model was developed from theoretical considerations to include each of the determinants of iontophoretic transport. The model was then used to reexamine iontophoretic flux conductivity and iontophoretic flux-fraction ionized literature data on the determinants of iontophoretic flux. Results. The ionic mobility-pore model was found to be consistent with existing experimental data and determinants defining iontophoretic transport. However, the predicted effects of solute size on iontophoresis are more consistent with the pore-restriction than free volume form of the model. A reanalysis of iontophoretic flux-conductivity data confirmed the model's prediction that, in the absence of significant electroosmosis, the reciprocal of flux is linearly related to either donor or receptor solution conductivity. Significant interaction with the pore walls, as described by the model, accounted for the reported pH dependence of the iontophoretic transport for a range of ionizable solutes. Conclusions. The ionic mobility-pore iontophoretic model developed enables a range of determinants of iontophoresis to be described in a single unifying equation which recognises a range of determinants of iontophoretic flux.     

Transdermal Iontophoretic Delivery of Propofol: A General Anaesthetic in the Form of its Phosphate Salt

The main objective of this study was to investigate the feasibility of delivery of propofol phosphate (PP), a prodrug of propofol, via transdermal route using iontophoresis in combination with chemical permeation enhancers (CPEs). PP, a prodrug, was synthesized and its structure was characterized. In vitro passive and iontophoretic drug transport studies were carried out using Franz diffusion cell across freshly excised hairless rat skin at different concentrations of PP in combination with CPE. Among all the CPEs screened, 0.1% sodium dodecyl sulfate (SDS) increased the passive transdermal flux to 13.43 ± 0.73 μg/(cm² h) from 8.52 ± 0.82 μg/(cm² h) (control). Cathodal iontophoresis in combination with 0.1% SDS synergistically enhanced the flux [249.24 ± 6.12μg/(cm² h)] of PP. The Pharmacokinetic studies were performed in rat model to assess the feasibility of transdermal delivery of PP. The amount of propofol present in plasma samples in control group (passive) was below the detectable levels at all the time points during the study. The plasma concentration—time profile of iontophoresis group of rats was fit to a noncompartmental model and the pharmacokinetic parameters were calculated. These studies suggest the plausibility of achieving therapeutically relevant levels of propofol when delivered via transdermal route by combining iontophoresis with CPE.     

Aryl Ester Prodrugs of Cyclic HPMPC. I: Physicochemical Characterization and In Vitro Biological Stability

Purpose. The chemical, enzymatic, and biological stabilities and physical properties of a series of salicylate and aryl ester prodrugs of the antiviral agent, cyclic HPMPC, were evaluated to support the selection of a lead compound for clinical development. Methods. Chemical stabilities of the prodrugs in buffered solutions at 37°C were determined. Stability was also studied in the presence of porcine liver carboxyesterases (PLCE) at pH 7.4 and 25°C. Tissue stabilities were examined in both human and dog intestinal homogenates, plasmas and liver homogenates. Prodrug and product concentrations were determined by reverse phase HPLC. Results. Chemical degradation of the prodrugs resulted in the formation of both cyclic HPMPC and the corresponding HPMPC monoester. Chemical stability was dependent on the orientation of the exo-cyclic ligand; the equatorial isomers were 5.4- to 9.4-fold more reactive than the axial isomers. In the presence of PLCE, the salicylate prodrugs cleaved exclusively to give cyclic HPMPC and not the HPMPC monoester. In plasma, but not intestinal or liver homogenates, the salicylate esters of cyclic HPMPC cleaved readily with a rate dependent on the chain length of the alkyl ester substituent. Conclusions. The carboxylate function on the salicylate prodrugs of cyclic HPMPC provides an additional handle to chemically modify the lipophilicity, solubility and the biological reactivity of the prodrug. In tissue and enzymatic studies, the major degradation product is cyclic HPMPC. The salicylate ester prodrugs are attractive drug candidates for further in vivo evaluation.