Synthesis, Stability and In Vitro Dermal Evaluation of Aminocarbonyloxymethyl Esters as Prodrugs of Carboxylic Acid Agents (original) (raw)
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Physicochemical properties and permeation across mouse skin of non-steroidal anti-inflammatory drugs
Mediterr J Pharm Pharm Sci, 2021
The skin provides an effective barrier and only limited number of drugs can penetrate in adequate amounts. This study aims to identify the relationship between the physicochemical properties and permeation across mouse skin of non-steroidal anti-inflammatory drugs in view of their feasibility to transdermal delivery. Biphenylacetic acid, diclofenac base, diclofenac sodium, indomethacin and piroxicam are the drugs studied. Number of physicochemical properties studies were performed. Drug permeation studies across hairless mouse skin were carried out using an in-vitro finite dosing diffusion cell. The relationship between physicochemical properties of the drugs studied and their percutaneous penetration was studied. Purity for the compounds studied ranged from 99.09% to 100% in which 99.89% purity was obtained for diclofenac base. At 7.4, the % ionized of piroxicam was found to be 95.12%, while for other drugs were in the range of 98.01% and 99.96%. The true partition coefficient values in the n-octanol/water system are in the range of 1.85 and 2.85, while in the n-octanol/phosphate system ranged from 2.14 to 3.70. Observed solubility in water, phosphate buffer and noctanol ranged from 0.033 to 0.322, 0.202 to 0.329 mg per ml, and 2.19 to 16.10 mg per ml, respectively. A linear relationship was found between water solubility and melting point between steady-state rates of permeation across intact and viable skin, between n-octanol solubility and maximum predicted flux and between molecular volume and the ratio of maximum predicted flux. Predicted flux calculated was compared with the experimental data which resulted in a high correlation. Physicochemical criteria which were determined the feasibility of nonsteroidal anti-inflammatory drugs studied for transdermal delivery were identified. The relationships obtained in this study provide an essential physical and chemical properties that govern transport of non-steroidal anti-inflammatory drugs across hairless mouse skin.
International journal of pharmaceutics, 2006
The percutaneous penetration-enhancing effects of glycolic acid, lactic acid and sodium lauryl sulphate through the human epidermis was investigated using 5-fluorouracil as a hydrophilic model permeant and three compounds belonging to the phenylalcohols: 2-phenyl-ethanol, 4-phenyl-butanol and 5-phenyl-pentanol. The lipophilicity values of the compounds ranged from log Poct -0.95 to 2.89. The effect of the enhancer concentration was also studied. Skin pretreatment with aqueous solutions of the three enhancers did not increase the permeability coefficient of the most lipophilic compound (log Poct = 2.89). For the other compounds assayed, the increase in the permeability coefficients depended on the concentration used in skin pretreatment, and on the lipophilicity of the compounds tested-and was always greater for the most hydrophilic compound (5-fluorouracil), for which lactic acid exerted a greater enhancer effect than glycolic acid or sodium lauryl sulphate. Primary irritation testi...
Evaluation of skin permeation and accumulation profiles of a highly lipophilic fatty ester
Archives of Pharmacal Research, 2008
Purpose: Classic penetration enhancement/retardation methods for improved dermal drug delivery primarily focus on coapplied chemicals aided alterations in skin accumulation/permeation profile, and in many cases, this has been achieved by compromising the systemic absorption/toxicities of penetrant/enhancer/retarder. In this study, higher dermal accumulation without systemic absorption of ketorolac and its fatty esters (esters) will be achieved by synthesizing lipophilic fatty ester soft prodrugs of ketorolac. Methods: Ketorolac decenoate (C10:1), dodecenoate (C12:1) and palmitoleate (C16:1) were synthesized and evaluated for their lipophilicity, enzymatic hydrolysis, chemical stabilities, and skin permeation and accumulation profiles using the combination of common permeation enhancing techniques such as the use of lipophilic receptor solution, enhancer pretreatment of skins, removal of stratum corneum and delipidization of skins etc. Results: Esters were highly lipophilic, chemically stable, enzymatically unstable in hairless mouse skin/liver homogenates and impermeable into the receptor solution.
Human skin permeation of 3- O -alkyl carbamate prodrugs of naltrexone
Journal of Pharmaceutical Sciences, 2009
N-Monoalkyl and N,N-dialkyl carbamate prodrugs of naltrexone (NTX), an opioid antagonist, were synthesized and their in vitro permeation across human skin was determined. Relevant physicochemical properties were also determined. Most prodrugs exhibited lower melting points, lower aqueous solubilities, and higher oil solubilities than NTX. The flux values from N-monoalkyl carbamate prodrugs were significantly higher than those from NTX and N,N-dialkyl carbamates. The melting points of N-monoalkyl carbamate prodrugs were quite low compared to the N,N-dialkyl carbamate prodrugs and NTX. Heats of fusion for the N,N-dialkyl carbamate prodrugs were higher than that for NTX. N-Monoalkyl carbamate prodrugs had higher stratum corneum/vehicle partition coefficients than their N,N-dialkyl counterparts. Higher percent prodrug bioconversion to NTX in skin appeared to be related to increased skin flux. N,N-Dialkyl carbamate prodrugs were more stable in buffer and in plasma than N-monoalkyl carbamate prodrugs. In conclusion, N-monoalkyl carbamate prodrugs of NTX improved the systemic delivery of NTX across human skin in vitro. N,N-Dialkyl substitution in the prodrug moiety decreased skin permeation and plasma hydrolysis to the parent drug. The cross-sectional area of the carbamate head group was the major determinant of flux of the N-monoalkyl and N,N-dialkyl carbamate prodrugs of NTX.
Journal of Pharmaceutical Sciences, 2001
The permeability of compromised skin barrier was investigated in vitro using acetone-disrupted hairless mouse skin as a model membrane. The effect of compound lipophilicity was studied using sucrose, caffeine, hydrocortisone, estradiol, and progesterone as model compounds. The results demonstrated that permeability barrier disruption by acetone treatment signi®cantly enhanced the permeability of the skin to both hydrophilic and amphipathic compounds, including sucrose, caffeine and hydrocortisone. This effect was more prominent with caffeine and hydrocortisone at different transepidermal water loss (TEWL) levels. Acetone treatment, however, didn't appear to alter the percutaneous penetration of highly lipophilic compounds, such as estradiol and progesterone. The characteristics of skin permeability were described by parabolic relationships between log P WS (permeability coef®cient of whole skin) and log K O/W (octanol/water partition coef®cient) at different degrees of permeability barrier disruption. The optimal log K O/W of compounds for skin penetration appeared to decrease with an increase in TEWL levels. The maximal permeability achieved was similar through skin displaying different TEWL levels. In an attempt to explore the underlying mechanisms for the changes in skin permeability, the stratum corneum/ normal saline partition coef®cients of water, caffeine, and hydrocortisone either decreased or remained unaffected with an increase in TEWL. Electron microscopic examinations have revealed reductions in stratum corneum lipid content and alterations in intercellular membrane structures as a result of acetone treatment, whereas negligible changes in the number of horny layers were observed by safranin staining of the stratum corneum. We have concluded that the enhancement in skin permeability to both hydrophilic and amphipathic compounds by acetone treatment arose mainly because of the increase in stratum corneum diffusivity at higher TEWL levels. The results imply the possibility of using both TEWL and drug lipophilicity to predict alterations in skin permeability and hence the dose adjustment of topically applied medication for patients with impaired skin barrier function. ß
Journal of Pharmaceutical Sciences, 2015
As a continuing effort to understand the skin permeation behavior of weak acids and bases, the objectives of the present study were to evaluate skin permeation of nonsteroidal anti-inflammatory drugs (NSAIDs) under the influence of pH, investigate the mechanism of pH effect, and examine a previous hypothesis that the effective skin pH for drug permeation is different from donor solution pH. In vitro permeability experiments were performed in side-by-side diffusion cells with diclofenac, ibuprofen, flurbiprofen, ketoprofen, and naproxen and human skin. The donor solution pH significantly affected skin permeation of NSAIDs, whereas no effect of the receiver pH was observed. Similar to previous observations, the apparent permeability coefficient versus donor solution pH relationships deviated from the predictions (fractions of unionized NSAIDs) according to the acid/base theory. The influences of the viable epidermis barrier, polar pathway transport, ion permeation across skin, and effective skin pH were investigated. The effective pH values for skin permeation determined using the NSAIDs (weak acids) in this study were different from those obtained previously with a weak base at the same donor solution pH conditions, suggesting that the observed permeability-pH relationships could not be explained solely by possible pH differences between skin and donor solution.
Biological & Pharmaceutical Bulletin, 2007
The purpose of this study was to evaluate the physicochemical properties, skin permeation and accumulation profiles of model lipophilic ketorolac fatty ester (esters) prodrugs. Ketorolac linoleate (C18:2), oleate (C18:1) and stearate (C18:0) were evaluated for their solubility, capacity factor, enzymatic hydrolysis, chemical stability, and skin permeation and accumulation profiles using the combination of common permeation enhancing techniques such as the use of supersaturated solution of permeants in the enhancer vehicle, lipophilic receptor solution, enhancer pretreatment of skins, removal of stratum corneum and delipidization of skins etc. Esters were highly lipophilic, chemically stable for the duration of observation, enzymatically unstable in hairless mouse skin/liver homogenates and plasma, and impermeable into the receptor solution. Absence of skin permeation, relative enzymatic stability during permeation and chemical stability of these esters could delineate preliminary possibilities for designing safer topical agents without systemic absorption.
The AAPS Journal, 2013
The purpose of this study was to determine the ability and the safety of a series of alkylammonium C12-gemini surfactants to act as permeation enhancers for three model drugs, namely lidocaine HCl, caffeine, and ketoprofen. In vitro permeation studies across dermatomed porcine skin were performed over 24 h, after pretreating the skin for 1 h with an enhancer solution 0.16 M dissolved in propylene glycol. The highest enhancement ratio (enhancement ratio (ER)=5.1) was obtained using G12-6-12, resulting in a cumulative amount of permeated lidocaine HCl of 156.5 μg cm −2. The studies with caffeine and ketoprofen revealed that the most effective gemini surfactant was the one with the shorter spacer, G12-2-12. The use of the latter resulted in an ER of 2.4 and 2.2 in the passive permeation of caffeine and ketoprofen, respectively. However, Azone was found to be the most effective permeation enhancer for ketoprofen, attaining a total of 138.4 μg cm −2 permeated, 2.7-fold over controls. This work demonstrates that gemini surfactants are effective in terms of increasing the permeation of drugs, especially in the case of hydrophilic ionized compounds, that do not easily cross the stratum corneum. Skin integrity evaluation studies did not indicate the existence of relevant changes in the skin structure after the use of the permeation enhancers, while the cytotoxicity studies allowed establishing a relative cytotoxicity profile including this class of compounds, single chain surfactants, and Azone. A dependence of the toxicity to HEK and to HDF cell lines on the spacer length of the various gemini molecules was found.
Journal of Pharmaceutical Research International, 2021
Skin penetration enhancement technology is a rapidly evolving area that will greatly increase the quantity of transdermal drug delivery medications. Penetration enhancers are used to facilitate the movement of drugs through the skin barrier. Numerous methods exist for extending partition enhancement. The enhancers' contact with the polar head of the lipid groups is the potential means for increasing the penetration. Penetration enhancers improve the amount of free water molecules between the bilayer, leading to an improvement of the polar drug diffusion cross section. This article focuses on the different compounds assessed for improving penetration activity like sulphoxides, azones, pyrrolidones, alcohols and alkanols, glycols, surfactants and terpenes.
Human Skin Permeation of Branched-Chain 3-O-Alkyl Ester and Carbonate Prodrugs of Naltrexone
Pharmaceutical Research, 2005
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. Straightchain 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.