Abstract
Based on the fact that alaptide is able to influence the creation and function of keratinocytes, it was supposed that alaptide could be used as a transdermal permeation modifier. Various APIs (bases, acids, salts, neutral molecules, small molecules, steroid-like molecules) were tested on their transdermal permeation in the mixture with micronized and/or nanonized alaptide as a transdermal permeation modifier. Also the influence of the type of formulation (ointment, cream, gel) on the effect of alaptide on skin was investigated intensively. It was observed that under specific conditions alaptide is able to suppress permeation/absorption of compounds through the skin, which can limit the site of action of potentially hazardous/toxic drugs to skin surface. The skin curative activity of alaptide can be helpful in reduction of possible skin irritant/injurious effects of permeating compounds. In transdermal application alaptide causes an increase or a decrease, in dependence on the used concentration, physical state and supporting medium (pharmaceutical formulation), in permeation/absorption of drugs into the skin and/or through the skin. The concentration of the used drug was increased at the place of administration, and/or the systemic concentration was increased, or it was ensured that drugs acted only on the skin surface/in the skin surface layer and did not penetrate into the deeper skin layers or did not have any systemic effect. Although alaptide was found in the 1980s of the twentieth century, even now it has great potential either as an active pharmaceutical ingredient or a permeation modifier.
Dr. Evžen Kasafírek, the “parent” of the alaptide molecule who tragically left us, was an excellent medicinal chemist who was undervalued in his lifetime. He left us many results of his creative work. He educated experts who hold top positions in the world’s largest pharmaceutical companies. We dedicate this article to his memory.
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References
Blažíčková S, Rovenský J, Kasafírek E, Buc M (1996) The immunomodulatory properties of low-molecular tri- and tetrapeptides. Folia Biol 42(1–2):57–59
Brychtová K, Jampílek J, Opatřilová R, Raich I, Farsa O, Csőllei J (2010a) Synthesis, physico-chemical properties and penetration activity of alkyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(2-oxopyrrolidin-1-yl)hexanoates as potential transdermal penetration enhancers. Bioorg Med Chem 18(1):73–79
Brychtová K, Opatřilová R, Raich I, Kalinowski D, Dvořáková L, Plaček L et al (2010b) Investigating the activity of 2-substituted alkyl-6-(2,5-dioxopyrrolidin-1-yl)hexanoates as skin penetration enhancers. Bioorg Med Chem 18(24):8556–8565
Brychtová K, Dvořáková L, Opatřilová R, Raich I, Káčerová S, Plaček L et al (2012) Investigation of substituted 6-aminohexanoates as skin penetration enhancers. Bioorg Med Chem 20(1):86–95
Celis ME, Taleisnik S, Walter R (1971) Regulation of formation and proposed structure of the factor inhibiting the release of melanocyte-stimulating hormone. Proc Natl Acad Sci U S A 68(7):1428–1433
Černíková A, Opatřilová R, Jampílek J (2014a) Rapid informative screening of nano-alaptide as potential transdermal permeation enhancer of acetylsalicylic acid and paracetamol. Mil Med Sci Lett 83(1):34–39
Černíková A, Opatřilová R, Bobál P, Jampílek J (2014b) Rapid screening of permeation of rutin through skin using alaptide enantiomers. ADMET 2(4):248–253
Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M et al (2009) Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol 129(8):1892–1908
Coufalová L, Mrózek L, Rárová L, Plaček L, Opatřilová R, Dohnal J et al (2013) New propanoyloxy derivatives of 5β-cholan-24-oic acid as drug absorption modifiers. Steroids 78(5):435–453
Douša M, Lemr K (2011) Liquid chromatographic method for enantiopurity control of alaptide using polysaccharide stationary phases. J Sep Sci 34(12):1402–1406
Evrard D, Touitou E, Kolusheva S, Fishov Y, Jelinek R (2001) A new colorimetric assay for studying and rapid screening of membrane penetration enhancers. Pharm Res 18(7):943–949
Fang JY, Tsai TH, Hung CF, Wong WW (2004) Development and evaluation of the essential oil from Magnolia fargesii for enhancing the transdermal absorption of theophylline and cianidanol. J Pharm Pharmacol 56(12):1493–1500
Franz TJ (1975) Percutaneous absorption on the relevance of in vitro data. J Invest Dermatol 64(3):190–195
Godwin DA, Michniak BB, Player MR, Sowell JW (1997) Transdermal and dermal enhancing activity of pyrrolidinones in hairless mouse skin. Int J Pharm 155(2):241–250
Harding CR, Scott IR (2002) Stratum corneum moisturizing factors. In: Leyden JJ, Rawling AW (eds) Skin moisturization. Informa Health Care, London, pp 61–80
Herkenne C, Naik A, Kalia YN, Hadgraft J, Guy RH (2006) Pig ear skin ex vivo as a model for in vivo dermatopharmacokinetic studies in man. Pharm Res 23(8):1850–1856
Hliňák Z, Krejčí I, Hondlík J, Yamamoto A (1990) Behavioral consequences of sodium nitrite hypoxia in male rats: amelioration with alaptide treatment. Methods Find Exp Clin Pharmacol 12:385–393
Hliňák Z, Krejčí I (1991) Social recognition in male rats: age differences and modulation by MIF-1 and alaptide. Physiol Res 40(1):59–67
Hliňák Z, Krejčí I (1992) Prolonged social recognition in male rats treated with alaptide or oxiracetam. Behav Pharmacol 3(2):129–131
Hliňák Z, Vinšová J, Kasafírek E (1996) Effect of alaptide, its analogues and oxiracetam on memory for an elevated plus-maze in mice. Eur J Pharmacol 314(1–2):1–7
Hliňák Z, Krejčí I (2005) Oxiracetam pre- but not post-treatment prevented social recognition deficits produced with trimethyltin in rats. Behav Brain Res 161(2):213–219
Hliňák Z, Krejčí I, Hynie S, Klenerová V (2008) Dipeptide “alaptide” prevented impairments in spontaneous behavior produced with trimethyltin in male rats. Neuro Endocrinol Lett 29(6):917–923
Jacobi U, Kaiser M, Toll R, Mangelsdorf S, Audring H, Otberg N et al (2007) Porcine ear skin: an in vitro model for human skin. Skin Res Technol 13(1):19–24
James W, Berger T, Elston D (2006) Andrews’ diseases of the skin: clinical dermatology, 10th edn. Saunders-Elsevier, Philadelphia, pp 5–6
Jampílek J, Opatřilová R, Řezáčová A, Oktábec Z, Pávek P, Král V et al. inventors; University of Veterinary and Pharmaceutical Sciences Brno, Faculty of Pharmacy, assignee (2011) Alaptide: methods of effecting its solubility, membrane penetration and pharmaceutical compositions for human and veterinary applications. Czech Patent application PV 2011-232
Jampílek J, Brychtová K (2012) Azone analogues: classification, design, and transdermal penetration principles. Med Res Rev 32(5):907–947
Jampílek J, Opatřilová R, Dvořáková L. Dohnal, J, inventors; University of Veterinary and Pharmaceutical Sciences Brno, Faculty of Pharmacy, assignee (2012a) Utilization of alaptide as transdermal penetration modifier in pharmaceutical compositions for human and veterinary applications containing glucocorticoids. Czech Patent application PV 2012-72
Jampílek J, Opatřilová R, Dvořáková L, Černíková A, Dohnal J, inventors; University of Veterinary and Pharmaceutical Sciences Brno, Faculty of Pharmacy, assignee (2012b) Utilization of alaptide as transdermal penetration modifier in pharmaceutical compositions for human and veterinary applications containing antimicrobial chemotherapeutics. Czech Patent application PV 2012-511
Jampílek J, Opatřilová R. Coufalová L, Černíková A, Dohnal J, inventors; University of Veterinary and Pharmaceutical Sciences Brno, Faculty of Pharmacy, assignee (2013a) Utilization of alaptide as transdermal penetration modifier in pharmaceutical compositions for human and veterinary applications containing anti-inflammatory drugs and/or antimicrobial chemotherapeutics. WO/2013/020527 A1
Jampílek J, Černíková A, Opatřilová R, Dohnal, J, inventors; University of Veterinary and Pharmaceutical Sciences Brno, Faculty of Pharmacy, assignee (2013b) Utilization of Alaptide as Transdermal Penetration Modifier in Pharmaceutical Compositions for Human and Veterinary Applications Containing Drugs of Central and/or Vegetative Nervous System and/or Sex Hormones or Genital System Modulators. Czech Patent application PV 2013-1000
Jampílek J, Opatřilová R, Řezáčová A, Oktábec Z, Dohnal J, inventors; University of Veterinary and Pharmaceutical Sciences Brno, Faculty of Pharmacy, assignee (2014a) Alaptide: Methods of effecting its solubility, membrane penetration and pharmaceutical compositions for human and veterinary applications. WO/2014/019556 A1
Jampílek J, Opatřilová R, Dvořáková L, Brychtová K, Dohnal J, inventors; University of Veterinary and Pharmaceutical Sciences Brno, Faculty of Pharmacy, assignee (2014b) Utilization of alaptide as transdermal penetration modifier in pharmaceutical compositions for human and veterinary applications containing nonsteroidal anti-inflammatory and/or antipyretic-analgesic drugs. Czech Patent CZ 304915 B6
Julínek O, Setnička V, Řezáčová A, Dohnal J, Vosátka V, Urbanová M (2010) Product of alaptide synthesis: determination of the absolute configuration. J Pharm Biomed Anal 53(4):958–961
Kasafírek E, Vanžura J, Krejčí I, Křepelka J, Dlabač A, Valchář M, inventors; SPOFA – United Pharmaceutical Works & Research Institute for Pharmacy and Biochemistry, assignees (1984 & 1986) 2,5-Piperazinedione derivs. Belgian Patent Belg. 897843. Czechoslovakian Patent CS 231227
Kasafírek E, Šturc A, Roubalová A (1992a) Linear tri- and tetrapeptides acting as prodrugs. Collect Czech Chem Commun 57(1):179–187
Kasafírek E, Rybák M, Krejčí I, Šturs A, Křepela E, Šedo A (1992b) Two-step generation of spirocyclic dipeptides from linear peptide ethyl ester precursors. Life Sci 50(3):187–193
Kasafírek E, Korbová L, Kohout J, Jirásková M, Krejčí I, Galatík A, inventors; SPOFA – United Pharmaceutical Works & Research Institute for Pharmacy and Biochemistry, assignees (1992c) Preparation for local therapy of cutaneous and mucosal lesions. Czechoslovakian Patent CS 276270
Kasafírek E, Krejčí I, Hliňák Z, Valchář M, Dobrovský K, Šturc A et al., inventors; SPOFA – United Pharmaceutical Works & Research Institute for Pharmacy and Biochemistry, assignees (1994) Neuroprotective composition for preventing or treating of central nervous system impairment. United States Patent US 5318973
Katz M, Ben-Shlush I, Kolusheva S, Jelínek R (2006) Rapid colorimetric screening of drug interaction and penetration through lipid barriers. Pharm Res 23(3):580–588
Kezic S, Kammeyer A, Calkoen F, Fluhr JW, Bos JD (2009) Natural moisturizing factor components in the stratum corneum as biomarkers of filaggrin genotype: evaluation of minimally invasive methods. Br J Dermatol 161(5):1098–1104
Korbová L, Čížková J, Kohout J, Kasafírek E, Krejčí I, Vanžura J (1988) Action of cyclo(l-alanyl-1-amino-1-cyclopentanecarbonyl)-alaptide – on experimental gastric ulcers in rats. Cas Lek Cesk 127(51):1574–1577
Korbová L, Kohout J, Kasafírek E (1994) Action of orally administered alaptide on experimental gastric lesions in rats. Ces Slov Gastroenterol 48(4):170–182
Kosař K, Vanžura J (1988) Embryotoxicity of l-prolyl-l-leucyl-glycinamide, cyclo(1-amino-cyclopentanecarbonyl-alanyl) and cyclo(glycyl-leucyl), new potential neuropeptides in chick embryos. Pharmazie 43(10):715–716
Krejčí I, Dlabač A, Vanžura J, Kosnař J (1986) Effect of a spirocyclic cyclodipeptide derivative of MIF on passive avoidance behavior and amnesia in rats. Act Nerv Super 28(4):241–246
Lapka R (1991) Pharmacokinetics and brain entry of alaptide, a novel nootropic agent, in mice, rats and rabbits. J Pharm Pharmacol 43(12):874–876
Maixner J, Rohlíček J, Kratochvíl B, Šturc A (2009) X-ray powder diffraction data for alaptide, 8(S)-methyl-6,9-diazaspiro/4,5/decane-7,10-dione or cyclo(l-Alanyl-1-amino-1-cyclopentan carbonyl), cyclo(l-Ala-Acp). Powder Diffr 24(1):32–34
McGrath JA, Eady RA, Pope FM (2004). Anatomy and Organization of Human Skin. In: Burns T, Breathnach S, Cox N, Griffiths C (eds) Rook’s textbook of dermatology, 7th edn. Blackwell Publishing, Oxford. pp 3.1–3.84
McGrath JA (2012) Profilaggrin, dry skin, and atopic dermatitis risk: size matters. J Invest Dermatol 132(1):10–11
Meyer W, Schwarz K, Neurand K (1978) The skin of domestic mammals as a model for the human skin, with special reference to the domestic pig. Curr Probl Dermatol 7(1):39–52
Minaskanian G, Peck JV, inventors; Whitby Research, Inc., assignee (1992) Penetration enhancers for transdermal delivery of systemic agents. United States Patent US 5142044
Mrózek L, Dvořáková L, Mandelová Z, Rárová L, Řezáčová A, Plaček L et al (2011) Investigation of new acyloxy derivatives of cholic acid and their esters as drug absorption modifiers. Steroids 76(10–11):1082–1097
Mrózek L, Coufalová L, Rárová L, Plaček L, Opatřilová R, Dohnal J et al (2013) New polyfluorothiopropanoyloxy derivatives of 5β-cholan-24-oic acid designed as drug absorption modifiers. Steroids 78(9):832–844
Nedvídková J, Kasafírek E, Nedvídek J, Pacák K, Schreiber V (1994) An analog of MIF, alaptide: effect on serum prolactin, dopamine receptors and growth of rat adenohypophysis. Endocr Res 20(1):39–46
Nedvídková J, Kasafírek E, Nedvídek J, Pacák K, Schreiber V (1994) An analog of MIF, alaptide: effect on serum prolactin, dopamine receptors and growth of rat adenohypophysis. Endocr Res 20(1):39–46
Ni N, El-Sayed MM, Sanghvi T, Yalkowsky SH (2000) Estimation of the effect of NaCl on the solubility of organic compounds in aqueous solutions. J Pharm Sci 89(12):1620–1625
Opatřilová R, Černíková A, Coufalová L, Dohnal J, Jampílek J (2013) In vitro permeation of micronized and nanonized alaptide from semi-solid formulations. Sci World J 2013:Article ID 787283 (8 pages)
Opatřilová R, Jampílek J (2014) Rapid screening of mupirocin skin permeation modification by micronized and nanonized alaptide. ADMET 2(1):56–62
Petersson M, Uvnäs-Moberg K (2004) Prolyl-leucyl-glycinamide shares some effects with oxytocin but decreases oxytocin levels. Physiol Behav 83(3):475–481
Rachakonda VK, Yerramsetty KM, Madihally SV, Robinson RL, Gasem KAM (2008) Screening of chemical penetration enhancers for transdermal drug delivery using electrical resistance of skin. Pharm Res 25(11):2697–2704
Rádl S, Kasafírek E, Krejčí I (1990) Alaptide. Drugs Future 15(5):445–447
Sekkat N, Kalia YN, Guy RH (2002) Biophysical study of porcine ear skin in vitro and its comparison to human skin in vivo. J Pharm Sci 91(11):2376–2381
Sloan KB, Beall HD, Taylor HE, Getz JJ, Villaneuva R, Nipper R, Smith K (1998) Transdermal delivery of theophylline from alcohol vehicles. Int J Pharm 171(2):185–193
Spier HW, Pascher G (1956) Analytical and functional physiology of the skin surface. Hautarzt 7(2):55–60
Šturc A, Kacafírek E, inventors; SPOFA – United Pharmaceutical Works & Research Institute for Pharmacy and Biochemistry, assignees (1992) Process for preparing cyclo-(l-alanyl-1-amino-1-cyclopentanecarbonyl) [alaptide]. Czechoslovakian Patent CS 277132
Vanžura J, Kosař K, Kasafírek E (1986) Inhibition of proliferative activity by cyclic dipeptides: spirocyclic derivatives of 1-aminocyclopentane-carboxylic acid. Toxicol Lett 31(3):189–193
Vinšová J, Kosař K, Kasafírek E (1993) Synthesis and antiproliferative activity of spirocyclic cyclodipeptides, derivatives of 1-amino-1-cyclobutanecarboxylic acid. Collect Czech Chem Commun 58(12):2987–2993
Vinšová J, Kosař K, Kasafírek E (1994) Spirocyclic dipeptides of 1-amino-1-cyclohexanecarboxylic acid. Collect Czech Chem Commun 59(1):195–202
Williams AC, Barry BW (1989) Urea analogues in propylene glycol as penetration enhancers in human skin. Int J Pharm 56(1):43–50
Yamane MA, Williams AC, Barry BW (1995) Terpene penetration enhancers in propylene glycol/water co-solvent systems: effectiveness and mechanism of action. J Pharm Pharmacol 47(12A):978–989
Acknowledgement
This study was supported by the Grant Agency of the Czech Republic (Czech Science Foundation) GAČR P304/11/2246, by the Technology Agency of the Czech Republic TA04010065 and by IGA VFU Brno 302/2015/FaF. Thanks to all our colleagues and numerous graduate and undergraduate students who participated in the evaluation of the discussed alaptide formulations.
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Jampílek, J., Dohnal, J. (2015). Alaptide as Transdermal Permeation Modifier. In: Dragicevic, N., Maibach, H. (eds) Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-47039-8_8
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