| Transdermal and dermal delivery system (TDDS) is an emerging field ofpharmaceutical sciences, it is in a front position as new technology and formulations,Transdermal delivery of drug can penetrate through the stratum corneum of the skinabsorbed by the capillaries into blood circulation. The active agent achieves effectiveplasma concentration which in turn has the role of prevention or treatment of diseaseof the organizations or lesions. Transdermal drug delivery can be used for thetreatment of systemic diseases and skin localized diseases. For the topical treatment oflocalized skin diseases, retarder would maximize skin retention and minimize skinpenetration due to a better treatment of dermatological disorders and less potentialsystematic side effect of the applied active agent.Metronidazole is an anti-infective medicine, which is selectively taken up byanaerobic bacteria and sensitive protozoa, and it has been reported to be the activepharmaceutical ingredient in a number of prescription drugs for the treatment ofrosacea and acne. However, more than1%of patients take place common adversedrug reactions, associated with systemic metronidazole therapy. The aim of this studyis to investigate penetration retardant in the formulations of MTZ, and to study theresorption and penetration of metronidazole from the topical formulations.In this paper, the local administration system of MTZ was studied. Weinvestigated the physical and chemical properties of drug molecules, established the invitro high performance liquid chromatography (HPLC) analysis method, and studiedmass balance of in vitro metronidazole permeation. The presence of retarder1,4-cyclohexanediol and1,2-hexanediol in the formulations of MTZ significantlyreduced the flux of applied MTZ without reducing the retention of MTZ indermatological relevant epidermal layer. It was demonstrated that the ratio ofretardation effect decreased form40%to30%(w/w), when reduced the concentrationof1,2-hexanediol from25%to4%. When the concentration of1,2-hexanediol wasreduced to1%, the ratio of retardation effect decreased to15%(w/w). Moreover, therewas no retardation effect of the formulation was observed when only contained1,4-cyclohexanediol compared to the control. It was found that a combination of1,2-hexanediol and1,4-cyclohexanediol showed a synergistic retardation effect onpercutaneous absorption of MTZ.Furthermore, the study was also carried out to investigate the1,2-hexanediol on mechanistic aspect of the retardation effect. For the synergistic retarder,1,2-hexanediol has two hydroxyl groups which could from H-bonding interaction withboth1,4-cyclohexanediol and ceramide. The hydrophobic alkyl chain in1,2-hexanediol could intercalate into the skin lipids. This complex could disrupt the SCbilayer due to the lipophilic chain in1,2-hexanediol and carry1,4-cyclohexanediolinto the SC layer. The intercalated1,4-cyclohexanediol and1,2-hexanediol complexcould form two-sided H-bonding (H-bond crosslinking) with neighboring ceramidemolecules, creating a crosslinked network. This network could condense the SC lipidsand make the skin less permeable, leading to penetration retardation of MTZ. In orderto study the effect of chain length in1,2-alkanediol, replaced the1,2-propanediol (3carbons),1,2-butanediol (4carbons),1,2-pentanediol (5carbons) and1,2-heptanediol (7carbons). It was demonstrated that only1,2-heptanediol with1,4-cyclohexanediol had significant retardant effect, and proved this speculativerationality. Elucidation of the retardation mechanism would help us to provide anexperimental basis for the discovery and in-depth study of the retarder, and provides atheoretical basis for practical application. |
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