In Vitro Skin Permeation of Morphine Hydrochloride during the Finite Application of Penetration-Enhancing System Containing Water, Ethanol and l-Menthol.

Abstract

We previously discussed the possibility of transdermal application of morphine hydrochloride (MPH) [1][2][3] and examined a mixed solvent system containing water, ethanol (EtOH) and l-menthol (LM) as a skin penetration-enhancing system. [4][5][6][7][8] The phase condition of the system markedly affected the penetration enhancing effect.6) The saturated LM in the applied aqueous solvent system was necessary to obtain a strong enhancing effect, but an excessive amount of LM, which made an o/w emulsion, decreased the enhancing effect. When a finite amount of the system was applied to skin, the system composition on skin changed over time due to the high skin permeability of EtOH. 9,10) The composition change of the system must be considered to design a useful transdermal delivery system containing water, EtOH and LM as penetration enhancers.In this study, a finite amount of the mixed solvent system containing MPH, water, EtOH and LM were applied to excised hairless rat skin, and MPH, EtOH and LM permeation was examined. 1,3-Butylene glycol (BG) was used as one more component to control hydrophilicity or lipophilicity of the mixed system. 11) Five different formulas were used for the application systems (Table 1). Three contained almost saturated LM, and the initial content of LM in the rest was below the limit of solubility of LM. Polyethyleneoxide E-45 (PEO) was used as a neutral polymer to increase viscosity of the systems. MATERIALS AND METHODSMaterials MPH and naloxone hydrochloride were purchased from Takeda Pharmaceutical Co. (Osaka, Japan) and Sigma Chemical Industries (St. Louis, MO, U.S.A.), respectively. LM was purchased from Wako Pure Chemical Industries (Osaka). All other chemicals were of reagent grade and were used without further purification.In Vitro Skin Permeation Experiments The abdominal skin of male WBN/ILA-Ht hairless rats (150-200 g, Ishikawa Laboratory Animals, Saitama, Japan) was excised and mounted in a vertical diffusion cell with a receiver volume of 2.8 ml and an effective diffusion area of 0.95 cm 2 . The receiver cell was filled with distilled water and the cell set was kept at 37°C. Two hundred milligrams of each solution shown in Table 1 was applied to the skin. One milliliter of receiver solution was withdrawn at predetermined times for 24 h to determine concentrations of MPH, LM and EtOH. The same volume of water was added to the receiver compartment to keep the volume constant.Analysis The concentration of MPH was assayed by an HPLC system (pump, LC-9A; UV detector, SPD-6A; Shimadzu Seisakusho, Kyoto, Japan). The column used was a LiChrospher 100 RP-18(e) 5 mm (4.0ϫ250 mm, Kanto Chemical Co., Tokyo, Japan). A mixture of 0.1% phosphoric acid-acetonitrile (65 : 35) containing 5 mM sodium dodecylsulfate was used as the mobile phase, and elution was performed at 40°C with a flow rate of 1.2 ml/min. Aliquots of 200 ml of the receiver solution were withdrawn and mixed with the same volume of methanol containing naloxone hydrochloride as an internal standard, and then the mixture was ce...

Effect of Nerolidol and/or Levulinic Acid on the Thermotropic Behavior of Lipid Lamellar Structures in the Stratum Corneum

“…These enhancers act on intercellular lipid structures in the stratum corneum, reversibly decreasing its barrier function and increasing drug permeability. Many types of enhancers have been investigated, including alcohols, [1][2][3] pyrrolidones, 4,5) surfactants, 6,7) fatty acids, 8,9) and terpenes.…”

“…These enhancers act on intercellular lipid structures in the stratum corneum, reversibly decreasing its barrier function and increasing drug permeability. Many types of enhancers have been investigated, including alcohols, [1][2][3] pyrrolidones, 4,5) surfactants, 6,7) fatty acids, 8,9) and terpenes. 10,11) The modes of action of penetration enhancers include increasing lipid partitioning or diffusion, disturbing lipid structure, and extracting lipids.…”

Effect of Camellia Oil on the Permeation of Flurbiprofen and Diclofenac Sodium through Rat and Pig Skin

“…Permeation of some drugs through skin is enhanced by free fatty acids and terpenes, such as oleic acid 7,8) and l-menthol. 9,10) This means that free fatty acids and terpenes reduce the barrier function of the skin as far as the permeation of drugs is concerned. This conflicts with their use as skin care products.…”

Systemic and strength effects : experimental concentrations of topical menthol.

“…However, many studies report that many terpene compounds, such as menthol, are extremely efficient at penetrating human skin, including the dermal and epidermal layers [32][33][34][35][36]. Terpenes are compounds that are typically derived from essential plan oils, making them rather lipophilic, which allows for easy penetration of cellular membranes [36].…”

“…A range of 10 to 100 fold increases in skin permeation have been observed with the use of topical terpene products [36]. Menthol, in specific, has been show to be effective at skin penetration [34,35]. Martin et al demonstrate that menthol can actually be measured in the bloodstream (19.0 ± 5.4 ng/mL) after topical patch application, and retains a half life of approximately 4.7 hours [34].…”