Synthesis and In Vitro Evaluation of Aminoacyloxyalkyl Esters of 2-(6-methoxy-2-naphthyl)propionic Acid as Novel Naproxen Prodrugs for Dermal Drug Delivery (original) (raw)
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Synthesis of Naproxen pro-drugs for enhanced transdermal absorption
2014
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as Naproxen have been used for a long time for the treatment of acute and chronic inflammation conditions. However, the oral administration of NSAIDs for a long time can cause gastric mucosal damage, which may result in ulceration and bleeding. Therefore, the development of a transdermal drug delivery (TDD) system of NSAIDs is of a great interest as it decreases GIT side effect and provides a constant release of drug in a determined period of time. Moreover, one of the important parameters of TTD is improving the permeability of the drug through human skin, since the stratum corneum layer of the epidermis prevents the permeability of various drugs and the naproxen in particular. In this present paper, we have successfully synthesized and characterized various ester derivatives of naproxen (methyl, ethyl, propyl, butyl, pentyl and hexyl esters) that have more suitable physicochemical properties for TDD and the butyl ester derivative has been formulated into liquid formulation for topical administration. The formulation was tested for stability according to ICH guidelines. No change in the initial appearance was observed during three months of study at room temperature & at 40 °C. The assay and pH were within the international standard limits during the period of the study. So, stable topical formulation of naproxen ester has been obtained.
In vitro evaluation of acyloxyalkyl esters as dermal prodrugs of ketoprofen and naproxen
Journal of Pharmaceutical Sciences, 1998
A series of acyloxyalkyl esters of ketoprofen and naproxen were synthesized and investigated as topical prodrugs with the aim of improving the dermal delivery of the drugs. In addition, some hydroxyalkyl esters of ketoprofen and naproxen were synthesized as possible intermediates of acyloxyalkyl prodrugs. All of the prodrugs were more lipophilic than their parent molecules, as evaluated by drug partitioning between 1-octanol and phosphate buffer at pH 7.4 (log Papp). However, their solubilities in aqueous solutions decreased markedly compared with the parent molecules. The prodrugs were stable toward chemical hydrolysis in aqueous solutions (pH 7.4), but were hydrolyzed to the parent drug both in 80% human serum and in human skin homogenate, with half-lives ranging from 4 to 137 min and from 13 to 403 min, respectively. The abilities of the selected naproxen acyloxyalkyl prodrugs to deliver naproxen through excised human skin were evaluated. Generally, the prodrugs showed similar dermal delivery as the parent drug through cadaver skin. In the present series of lipophilic prodrugs of naproxen, the prodrug with the highest aqueous solubility was the most effective prodrug to deliver naproxen through the skin.
Novel Naproxen Salts with Increased Skin Permeability
Pharmaceutics
The paper presents the synthesis, full identification, and characterization of new salts-L-proline alkyl ester naproxenates [ProOR][NAP], where R was a chain from ethyl to butyl (including isopropyl). All obtained compounds were characterized by Nuclear Magnetic Resonance (NMR), Fourier transform infrared spectroscopy (FTIR), X-ray powder diffractometry (XRD), and in vitro dissolution studies. The specific rotation, phase transition temperatures (melting point), and thermal stability were also determined. In addition, their lipophilicity, permeability, and accumulation in pigskin were determined. Finally, toxicity against mouse L929 fibroblast cells was tested. The obtained naproxen derivatives showed improved solubility and higher absorption of drug molecules by biological membranes. Their lipophilicity was lower and increased with the increase in the alkyl chain of the ester. The derivative with isopropyl ester had the best permeability through pigskin. The use of L-proline isopro...
Pharmaceutical Research, 2010
Purpose This work probed the topical delivery and skinstaining properties of a novel co-drug, naproxyl-dithranol (Nap-DTH), which comprises anti-inflammatory (naproxen) and anti-proliferative (dithranol) moieties. Method Freshly excised, full-thickness porcine ear skin was dosed with saturated solutions of the compounds. After 24 h, the skin was recovered and used to prepare comparative depth profiles by the tape-stripping technique and to examine the extent of skin staining. Results Depth profiles showed that Nap-DTH led to a 5-fold increase in drug retention in the skin compared to dithranol. The application of Nap-DTH also demonstrated improved stability, resulting in lower levels of dithranol degradation products in the skin. Furthermore, significantly less naproxen from hydrolysed Nap-DTH permeated into the receptor phase compared to naproxen when applied alone (0.08± 0.03 nmolcm -² and 180±60 nmolcm -², respectively). Moreover, the reduced staining of the skin was very apparent for Nap-DTH compared to dithranol. Conclusions Topical delivery of Nap-DTH not only improves the delivery of naproxen and dithranol, but also reduces unwanted effects of the parent moieties, in particular the skin staining, which is a major issue concerning the use of dithranol.
Prodrug Strategy for Enhancing Drug Delivery via Skin
Current Drug Discovery Technologies, 2006
Skin as a route for drug delivery has been extensively investigated. However, because of the predominant barrier function of stratum corneum in skin, the clinical application is limited. One strategy to solve this problem of drug permeation via skin is the use of prodrugs. Prodrugs are inactive compounds which are metabolized either chemically or enzymatically in a controlled or predictable manner to its parent active drug. Prodrugs can enhance dermal/transdermal drug delivery via different mechanisms, including increased skin partitioning, increased aqueous solubility, and reduced crystallization, etc. Besides the prodrug itself, the optimization of vehicle is important as well. The prodrug partitioning between skin and vehicle as well as prodrug-vehicle interaction may influence the enhancing efficacy on skin permeation. This review explores the synthesis and enhancing mechanisms of prodrugs for topical drug delivery. The prodrugs categorized by the therapeutic use of the parent drugs, including anticancer drugs, analgesics, anti-inflammatory drugs and vitamins, are systemically introduced in this review.
Journal of Pharmaceutical Sciences, 1995
Stereoselective hydrolysis of two ester prodrugs of propranolol, isovaleryl propranolol (IV-PL) and cyclopropanoyl propranolol (CP-PL), was studied in Tris-HCI buffer (pH 7.4) containing 0.15 M KCI, skin and liver homogenates, 5% plasma in Tris-HCI buffer, skin cytosol and microsomes, and liver cytosol and microsomes. The hydrolysis rate constants of (R)-isomers of the prodrugs were 1.1–30.3 times greater than those of the respective (S)-isomers in tissue preparations. Skin showed considerable metabolic activity and very high stereoselectivity (R/S ratio: 7.3–30.3). The hydrolyzing capacities of buffer and different tissue preparations per milligram of protein content were in the following increasing order: buffer < skin homogenate < plasma < liver homogenate. The studies with microsomes and cytosol indicated that the esterases, which are responsible for the hydrolysis of prodrugs, were mainly present in the cytosolic and microsomal fractions of skin and liver, respectively. There was a good correlation between the octanol–buffer partition coefficients of propranolol and its prodrugs and the skin partition coefficient. In vitro stereoselective penetration of propranolol and the prodrugs through full-thickness hairless mouse skin was evaluated with flow-through diffusion cells. Although the concentration of propranolol was 14–22 times greater than those of the prodrugs in the donor chamber, the steady-state flux of propranolol isomers [10.72 and 10.64 μg/cm2.h for (R)- and (S)-isomers, respectively] were similar to those of CP-PL [10.80 and 10.78 μg/cm2.h for (R)- and (S)-isomers, respectively] and even lower than those of IV-PL [14.51 and 14.33 μg/cm2.h for (R)- and (S)-isomers, respectively]. Moreover, the permeability coefficients of IV-PL [2.82 × 10−3 and 2.78 × 10−3 cm/h for (R)- and (S)-isomers, respectively] and CP-PL (1.29 × 10−3 cm/h for each isomer) were 14–30-fold greater than those of propranolol isomers (0.09 × 10−3 cm/h for each isomer). The diffusion coefficients of all the compounds were similar, but their solvent membrane distribution coefficients differed greatly and proved that the higher permeability coefficients of the prodrugs were due to the higher affinity of the prodrugs for skin. Neither propranolol nor the prodrugs showed stereoselective penetration. However, highly stereoselective hydrolysis occurred during penetration of the prodrugs, and the R/S ratios of the cumulative amount of delivered propranolol in 12 h were 11 and 13 for IV-PL and CP-PL, respectively. A skin irritation test was performed in Japanese white male rabbits and no irritation was observed. In conclusion, the hairless mouse skin possesses highly stereoselective esterase activity, and IV-PL and CP-PL might be promising prodrugs for transdermal delivery of higher amounts of drug from a much lower initial concentration compared with propranolol.
Bioorganic & Medicinal Chemistry, 2002
Aminocarbonyloxymethyl esters 3 based on (S)-amino acid carriers were synthesised and evaluated as potential prodrugs of carboxylic acid agents. In addition, the compounds were evaluated as topical prodrugs with the aim of improving the dermal delivery of two non-steroidal anti-inflammatory agents: naproxen and flufenamic acid. The lipophilicities of these compounds were determined and their hydrolyses in aqueous solutions and in human plasma were examined. Compounds 3 containing a secondary carbamate group were hydrolysed at pH 7.4 by two different routes: (i) direct nucleophilic attack at the ester carbonyl carbon leading to the release of the parent carboxylic acid and (ii) intramolecular rearrangement involving an O!N acyl migration, leading to the formation of the corresponding amide. The rearrangement pathway is highly dependent on the size of the carboxylic acid and amino acid substituents, being eliminated when the amino acid is valine or leucine. In contrast, compounds 3 decomposed in plasma exclusively through ester hydrolysis, most releasing the parent carboxylic acid quantitatively with half-lives shorter than 5 min. The permeation of selected prodrugs across excised postmortem human skin was studied in vitro. All prodrugs evaluated exhibited a lower flux than the corresponding parent carboxylic acid. The poor skin permeation observed for compounds 3 is most probably due to their low aqueous solubility and high partition coefficient. #
International Journal of Pharmaceutics, 2005
Various amide prodrugs of ketorolac were synthesized and their rat skin permeation characteristics were determined. The solubility of the prodrugs in propylene glycol (PG) was determined at 37 • C while lipophilicity was obtained as 1-octanol/water partition coefficient (log P) and capacity factor (k ) using HPLC. Stability of the prodrugs in rat skin homogenate, plasma and liver homogenate was investigated to observe the enzymatic degradation. Rat skin permeation characteristics of the prodrugs saturated in PG were investigated using the Keshary-Chien permeation system at 37 • C. The log P value of the prodrugs increased up to 4.28 with the addition of various alkyl chain to ketorolac which has a log P of 1.04. Good linear relationship between log P and capacity factor was observed (r 2 = 0.89). Amide prodrugs were converted to ketorolac only in rat liver homogenate. However, the skin permeation rate of amide prodrugs did not significantly increase, probably due to their low aqueous solubility. Chemical modification of the ketorolac amide prodrug and/or the selection of proper vehicle to increase aqueous solubility would be necessary for an effective transdermal delivery of ketorolac.
Preparation and Evaluation of Microemulsion Formulations of Naproxen for Dermal Delivery
Naproxen (Np) is an example of a non-steroidal anti-inflammatory drug (NSAID) commonly used for the reduction of pain and inflammation. In order to develop an alternative formulation for the topical administration of Np, microemulsions were evaluated as delivery vehicles. Four formulations were prepared using isopropyl myristate (IPM) as oil phase, Span 80, Labrafil M, Labrasol, Cremophor EL as surfactants, ethanol as co-surfactant and distilled water or 0.5 N NaOH solution as aqueous phase. The final concentration of Np in the microemulsion system was 100 mg/g (w/w). The physicochemical properties such as electrical conductivity, droplet size, viscosity, pH and phase inversion temperature of microemulsions were measured. Stability tests of the formulations were also performed at 5 2, 25 2 and 40 2°C. The abilities of various microemulsions and selected commercial (C) formulation to deliver Np through the skin were evaluated in vitro using diffusion cells fitted with rat skins. The in vitro permeation data showed that microemulsions increased the permeation rate of Np between 4.335–9.040 times over the C formulation. Furthermore Np successfully permeated across the skin from the microemulsion with the highest flux rate (1.347 0.005 mg·cm 2·h 1) from a formulation (M4Np) consisting of IPM (2.36 g), Labrosol (0.13 g), Span 80 (0.62 g), ethanol (5.23 g), 0.5 N NaOH solution (0.66 g) and Np (1 g). According to the histological investigations, no obvious skin irritation was observed for the studied microemulsions. These results indicate that the microemulsion formulation may be appropriate vehicles for the topical delivery of Np.
Synthesis and comparative skin permeability of atenolol and propranolol esters
Journal of Drug Delivery Science and Technology, 2005
The prodrug approach is one of the methods which have been evaluated for improving the systemic delivery of pharmacologically active compounds. ln the present study, we have synthesized ester prodrugs of atenolol and propranolol by adding alkyl side chains to the β-hydroxy function of the drug with the objective of enhancing their lipophilicity. In vitro skin permeability study in excised mice skin showed that the prodrugs permeate freely through the skin than the respective drug moieties and significant flux enhancement (6.2-fold) was observed in both cases. In the case of atenolol, the highest permeability coefficient was shown by capriate (C 10 side chain) where as in propranolol the highest permeability was recorded with caproate ester (C 6 side chain). The difference in permeability may be attributed to their difference in the intrinsic lipophilicities.