Dermal delivery

In conclusion, until now insufficent data have been available to define general rules to predict for which drugs liposome encapsulation will be therapeutically beneficial when applied to the skin. It is too early to draw definite conclusions about the advantage of the vise of liposomes over alternative dermal delivery systems in the therapy for drugs designed to exert a pharmacological effect either locally or systemically. 

Testosterone (T.) derivatives for clinical use. T. esters for im. depot injection are T. propionate and T. heptanoate (or enanthate). These are given in oily solution by deep intramuscular injection. Upon diffusion of the ester from the depot, esterases quickly split off the acyl residue, to yield free T. With increasing lipophilicity, esters will tend to remain in the depot, and the duration of action therefore lengthens. A T. ester for oral use is the undecanoate. Owing to the fatty acid nature of undecanoic acid, this ester is absorbed into the lymph, enabling it to bypass the liver and enter, via the thoracic duct, the general circulation. 17-0 Methyltestosterone is effective by the oral route due to its increased metabolic stability, but because of the hepatotoxicity of Cl 7-alkylated androgens (cholestasis, tumors) its use should be avoided. Orally active mesterolone is 1 a-methyl-dihydrotestosterone. Trans-dermal delivery systems for T. are also available. 

In developing protein and peptide trans-dermal delivery systems, one must be mindful of the high interindividual variation in drug absorption across the skin. Large variations in bioavailability have been demonstrated with fentanyl patches, initially intended for postoperative pain relief but later abandoned due to unacceptable variability among individuals receiving the same dose [9]. Response in postoperative patients to the application of a fentanyl patch ranged from ineffective pain relief to severe respiratory depression, and effects were correlated with variations in plasma fentanyl levels [9]. 

Lenaerts et al. (2) prepared a biphasic drug delivery device for tramadol consisting of polyvinyl acetate and polyvinylpyrrolidone having a sustained release for 24 hours. Polyvinylpyrrolidone was also used by Midha et al. (3) in the trans-dermal delivery of atomoxetine. 

Swatschek, D., Schatton, W., Muller, W. E. G., and Kreuter, J. (2002). Microparticles derived from marine sponge collagen (SCMPs) Preparation, characterization and suitability for dermal delivery of all-trans retinol. Eur. ]. Pharm. Biopharm. 54,125-133. 

Godin, B., and E. Touitou. 2002. Intracellular and dermal delivery of polypeptide antibiotic bacitracin, Drug research between information and life sciences, ICCF, 3rd Symposium Abstracts, Bucharest. 

M. Fresta and G. Puglisi, Corticosteroid dermal delivery with skin-lipid liposomes. J. Contr. Rel. 44 141-151 (1997). 

Furhman, L., et al. 1995. Evaluation of several liposomal formulations and preparation techniques for the dermal delivery of phosphorothioate antisense oligonucleotides in hairless mouse skin in vitro. In AAPS Annual Meeting, Miami Beach, FL, USA. 

Honeywell-Nguyen, P. L., and Bouwstra, J. A. (2005), Vesicles as a tool for transdermal and dermal delivery, Drug Discovery Today Technol., 2, 67-74. 

Verma, D. D., Verma, S., Blume, G, and Fahr, A. (2003), Particle size of liposomes influences dermal delivery of substances into skin, Int. J. Pharm., 258,141-151. 

Kasting, G. B., Smith, R. L. and Anderson, B. D. (1992). Prodrugs for dermal delivery Solubility, molecular size, and functional group effects. In Sloan, K. B., ed. Prodrugs Topical and Ocular Drug Delivery. Dekker, New York, pp. 117-161. 

Singh and Roberts [63] have shown that iontophoretic delivery through intact epidermis yields deeper tissue concentrations, identical to that after dermal delivery. Figure 4 shows similar tissue concentrations for lidocaine and salicylate after iontophoretic delivery through intact skin and passive application of these solutes to the dermis. It is therefore concluded that iontophoresis... 

The stratum corneum basically contains a mixture of cholesterol, free fatty acids, and ceramides, placed in multilayers. They mediate both the epidermal permeability barrier and the transdermal delivery of both lipophilic and hydrophilic molecules. Studies have shown that each of the three key lipid classes is required for normal barrier function (32). These reports also show the potential of certain inhibitors of lipid synthesis to enhance the trans-dermal delivery of drugs like lido-caine or caffeine. Thus, the modulation of stratum corneum lipids is an important determinant of the barrier permeability to both hydrophobic and hydrophilic compounds transport and drug penetration. It has been reported that an inverse correlation exists between solute penetration and stratum corneum lipid content (33). 

Modulation of epidermal hpid biosynthesis has been reported to boost dmg delivery. It has also been suggested that it is both the hydrophobic nature of the lipids as well as their tortuous, extracellular localization that are responsible for the restriction in the transport of most molecules across the stratum corneum. The function of this barrier depends on three key lipids cholesterol, fatty acid, or ceramides. Delays of synthesis ceramides in the epidermis have been reported as means of barrier perturbation. Inhibitors of lipid synthesis were used to enhance the trans-dermal delivery of lidocaine or caffeine. Alteration of barrier function was produced by either the fatty acid synthesis inhibitor 5-(tetradecyloxy)-2-fiirancarboxylic acid, the cholesterol synthesis inhibitor fluvastatin, or the cholesterol sulfate, which resulted in a further increase in lidocaine absorption (33). 

Liposomal systems also can form an effective drug reservoir in the upper layers of the skin. This is particularly useful for local skin therapy. Ethosomal carriers composed of phospholipid vesicular systems with alcohols are also effective at enhancing tran -dermal delivery of both lipophilic and hydrophilic compounds. The use of these ethosomes has been used in the delivery of minoxidil to the pilo-sebaceous section of the skin with better results than conventional liposomes. Similar results are reported in clinical studies with acyclovir in a topical therapy treatment of recurrent herpes labialis. Other application reports with ethosomes are patches containing testosterone (37). 

Topical applications in the form of spray also have been reported as vehicles for enhanced frawi-dermal delivery of drugs such as testosterone, estradiol, progesterone, and norethindrone acetate. More effective drug penetration was reported with enhancers padimate and octyl salicylate and compared with laurocapram and oleic acid (38). Other methods reported for enhanced percutaneous drug absorption include iontophoresis (39), ultrasound or sonophoresis (40), and electroporation (41). 

Jain S, Sapre R, Tiwary AK, Jain NK (2005) Proulttaflexible lipid vesicles for effective trans-dermal delivery oflevonorgesttel development, characterization, and performance evaluation. AAPS PharmSciTech 6(3) E513-E522... 

Sinico C, Manconi M, Peppi M, Lai F, Valenti D, Fadda AM (2005) Liposomes as carriers for dermal delivery of tretinoin in vitro evaluation of drug permeation and vesicle-skin interaction. J Control Release 103 123-136... 

It quickly became apparent that such a task would be overwhelming in the short time frame available and that special expertise would be required for certain products such as inhalation and dermal delivery systems. The decision was then made to limit the drug products covered by the guideline to those that included the vast majority of marketed dosage forms, that is, immediate-release and delayed-release tablets, capsules, oral liquids, and parenteral products. 

In a subsequent study, van Hal et al. [40] reported that a decrease in cholesterol content in liquid state bilayers, which increases bilayer fluidity, resulted in an increase in estradiol transport across SC. With confocal laser scanning microscopy, Meuwissen et al. examined the diffusion depth of gel- vs. liquid-state liposomes labeled with fluorescein-dipalmitoylphosphatidylethanolamine (fluorescein-DPPE) with human skin in vitro [41] (Figure 3) and rat skin in vivo [42] and found that the lipophilic label when applied in liquid-state bilayers onto the skin penetrated deeper into the skin than when applied in gel-state liposomes. Recently, Fresta and Puglisi [43] reported that corticosteroid dermal delivery with skin-lipid liposomes was more effective than delivery with phospholipid vesicles, both with respect to higher drug concentrations in deeper skin layers and therapeutic effectiveness. This is a very surprising result, because skin lipid liposomes are rigid and form stacks of lamellae on the surface of the skin [44]. From the previously mentioned studies it seems clear that the thermodynamic state of the bilayer plays a crucial role in the effect of vesicles on dmg transport rate across skin in vitro. 

Drug delivery from LLC phases of oligo(ethylene oxide)-alkyl ether (i.e., (E0) -0-alkyl) surfactants have also been explored but to a much lesser extent than GMO. For example, the L, Qn, and Hu phases of commercial Brij-96 surfactant (i.e., (EO)io-O-oleyl) (Fig. 18) formed with water and other additives, have been explored for release of ephedrine hydrochloride, tenoxi-cam [145], and topical dermal delivery of benzocaine [146]. Work in this area has found that the amount of water swelling the hydrophilic domains of the LLC phase increases drug diffusion and release [145]. In addition to this work, the L phase of the (EO)2i-0-stearyl/oil/water system has been explored for dermal delivery of itraconazole [147] and the L and Hi phases of the (E0)7-0-Ci3 i5 (i.e., Symperonic A7)/water system have been explored for the release of the model drug chlorhexidine diacetate [148]. 

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