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1Hol=C2 Light Water (C2 > C1) Patent Application Publication May 1, 2008 US 2008/O103092 A1 5 (1H2O=C2

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1Hol=C2 Light Water (C2 > C1) Patent Application Publication May 1, 2008 US 2008/O103092 A1 5 (1H2O=C2 US 20080 103092A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0103092 A1 Pomytkin et al. (43) Pub. Date: May 1, 2008 (54) METHODS FOR INTRADERMAL, Publication Classification TRANSIDERMAL, ORTRANSMUCOSAL DELIVERY OF BIOLOGICALLY ACTIVE (51) Int. Cl. SUBSTANCES A6II 47/02 (2006.01) A6II 38/02 (2006.01) (76) Inventors: Igor Anatolievich Pomytkin, Moscow A6IR 48/00 (2006.01) (RU); Sergey Pavlovich Soloviev, (52) U.S. Cl. .................................... 514/8: 514/2: 514/769 Moscow (RU) (57) ABSTRACT Correspondence Address: NOTARO AND MICHALOS This invention relates to method for intradermal, transdermal 1OO DUTCH HILL ROAD or transmucosal delivering a biologically active Substance to a mammal in need thereof, which method comprises a step of SUTE 110 co-administering to said mammal with the biologically active ORANGEBURG, NY 10962-2100 (US) Substance an effective amount of an absorption enhancer, which is water comprising from about 99.760 to about 10 (21) Appl. No.: 11/817,919 99.999% of light isotopologue H, 0 and up to 100% of residual isotopologues H, '70, H., '80, HH'0, HH'70, (22) PCT Filed: Mar. 11, 2005 'HH'0, H, O, H, '70, and H 0. Such biologically (86) PCT NO.: PCT/RUOS/OO108 active substance is selected from the group consisting of drugs, physiologically active peptides, physiologically active S371(c)(1), proteins, glycoproteins, nucleic acid, nutrients, vitamins, and (2), (4) Date: Nov. 15, 2007 minerals. 5 1Hol=C2 Light Water (C2 > C1) Patent Application Publication May 1, 2008 US 2008/O103092 A1 5 (1H2O=C2 Light Water (C2 > C1) Licuid US 2008/O 103092 A1 May 1, 2008 METHODS FOR INTRADERMAL, TRANSDERMAL wherein the level of light water isotopologue 'H'Ois about ORTRANSMUCOSAL DELIVERY OF 99.7317% (Vienna Standard Mean Ocean Water, VSMOW), BIOLOGICALLY ACTIVE SUBSTANCES and wherein total level of all eight heavy isotopologues com prising at least one heavy isotopes H, O, and 'O is about TECHNICAL FIELD 0.2683% (e.g. 0.199983% 'H'O, 0.0372% 'H'7O, 0.031069% 'HH 'O, 0.0000623% HH 'O, and 0001. The present invention relates to human or animal 0.0000116% "HHO). Rothman et al., J. Quant. Spectrosc. healthcare. More specifically, the present invention relates to Radiat. Transfer, 1998, 60, 665. Rothman et al., J. Quant. method for intradermal, transdermal or transmucosal deliv Spectrosc. Radiat. Transfer, 2003, 82, p. 9. The abundance of ering a bioactive Substance to a mammal in need thereof. water isotopologues in natural water slightly varies on Earth district and climatic conditions and is expressed typically as BACKGROUND OF THE INVENTION the deviation, Ö, relative to the international VSMOW stan 0002 Transdermal or transmucosal delivery is an alterna dard. The natural water enriched maximally by major light tive method of systemic delivery of biologically active sub water isotopologue 'H'O was founded in Antarctica (Stan stances that offers several advantages over both injectable and dard Light Antarctic Precipitation, SLAP), wherein said enteral methods. Biologically active Substances that are 6-values of residual heavy isotopes are 6H-415.5%0, Ö''O- absorbed through the oral mucosa or skin directly enter the 28.1%0, and 8'O-53.9%0 that corresponds to the 99.757% systemic circulation, bypassing the gastrointestinal tract and level of light water isotopologue 'H'O. R. van Trigt, Laser first-pass metabolism in the liver. This results in rapid onset of Spectrometry for Stable Isotope Analysis of Water Biomedical action via a more comfortable and convenient delivery route and Paleoclimatological Applications, 2002, Groningen: than the intravenous route. However, the transdermal or trans University Library Groningen, p. 50. Thus, water with the mucosal delivery of biologically active substances is limited abundance of light water isotopologue 'H'O more than by barrier function of skin and mucosa that lows absorption of 99.757% is not found in nature. the Substance. Especially, the mucosa and skin presents a 0008 Complete depletion of natural water of deuterium barrier to the penetration of hydrophilic substances with high comprising isotopologues (HHO, HH7O, HHO, molecular weight such as peptides, proteins, and nucleic 'H'O, HO, and HO) provides water enriched by acids. light water isotopologue 'H'O to the level never more than 0003 Intradermal delivery of biologically active sub 99.76%, since total level of these deuterium-comprising iso stances into deeper layers of the skin is frequently limited by topologues in water is below 0.031%. Thus, water with con barrier function of skin. Accordingly, biologically active Sub tent of light water isotopologue 'H'O more than 99.76% stances although proved effective for treating skin disorders, can be prepared in industrial scale by methods providing have limited effects resulting from only partial penetration depletion of natural water of heavy isotopologues H.O. into the skin. Especially, the outer layers of skin present a HO, H2H16O. H?H7O, H2H18O, *H, O, *H,7O, barrier to the penetration of hydrophilic substances with high and H.O. molecular weight such as peptides, proteins, and nucleic 0009 Unexpectedly, we discovered that water enriched by acids. light water isotopologue 'H'O to the level unknown in 0004 Thus, there is the great need in effective and safe nature (from 99.760 to 99.999%) increases absorption of methods for intradermal, transdermal or transmucosal deliv biologically active Substances into and through skin and ering a biologically active Substance to a mammal in need mucosa as compared to water with natural levels of light thereof. water isotopologue 'H'O (from 99.710 to 99.757%). 0005 Methods for enhancing the intradermal, transdermal 0010. It is an object of the present invention to provide a and transmucosal delivery of active agents are known in the method for intradermal, transdermal or transmucosal deliv art. In one approach, promoters of absorption (absorption ering a biologically active Substance to a mammal in need enhancers) are included in the active agent-containing formu thereof, which method comprises a step of co-administering lation. Zatz, J. L., Modification of Skin Permeation by Sur to said mammal with the biologically active Substance an face-Active Agents in Skin Permeation Fundamentals and effective amount of an absorption enhancer, which is water Application, 149-162 (1993); and Barry, B. W., “Properties comprising from about 99.760 to about 99.999% of light That Influence Percutaneous Absorption in Dermatological isotopologue 'H'O and up to 100% of residual isotopo Formulations,' Percutaneous Absorption, 127-233 (1983). logues 'H'7O, HO, H2H16O. H2H7O, H2H18O, Surface active agents phosphatidylcholine and Sodium gly 2H, O, 2H, 17O, and 2H8O. cocholate are examples of absorption promoters. However, addition of these Surface active agents results in only a slight BRIEF DESCRIPTION OF THE DRAWINGS to moderate enhancement of permeability at the expense of 0011 FIG. 1 is a schematic side view of an apparatus for damaging the barrier tissue. the manufacturing the water comprising from about 99.760 to 0006 Thus, there is the great need in effective and safe about 99.999% of light isotopologue 'H'O and up to 100% absorption enhancers for intradermal, transdermal or trans of residual isotopologues 'H'7O, 'H'O, "HHO, mucosal delivering a biologically active Substance, especially H2H7O, H2H16O. 1H2H1 O, 'H, O, *H,7O, and hydrophilic, to a mammal in need thereof. 2H.O. 0007 Natural water is a composition of nine water isoto pologues ('H'O, 'H'7O, 'H'O, "HHO, HH7O, DISCLOSURE OF INVENTION HHO, H, O, H, 7O, H, 'O) formed by stable iso 0012 The present invention provides a method for intra topes of hydrogen (H and H) and oxygen ("O, O, 'O), dermal, transdermal or transmucosal delivering a biologically US 2008/O 103092 A1 May 1, 2008 active Substance to a mammal in need thereof, which method antidiabetic agents, antidiarrheal agents, antidiuretic agents, comprises a step of co-administering to said mammal with the antidotes, antidy skinetic agents, antidysmenorrheal agents, biologically active Substance an effective amount of an antiemetic agents, antifibrinolytic agents, antifibrotic agents, absorption enhancer, which is water comprising from about antifungal agents, antiglaucoma agents, antihemorrhagic 99.760 to about 99.999% of light isotopologue 'H'O and up agents, antihistaminic agents, antihypercalcemic agents, to 100% of residual isotopologues 'H' O, H, O, antyhyperglycemic agents, antihyperlipidemic agents, anti 1H2H1 O, H2H7O, 1H2H1 O, PH, O, PH,7O, and hypertensive agents, antihyperthyroid agents, antihyperuri *H, O. cemic agents, antihypocalcemic agents, antihypoglycemic agents, antihypotensive agents, anti-inflammatory agents, 0013 As used herein, the term “isotopologue' is in accor anti-Kawasaki disease agents, antimalarial agents, antime dance with IUPAC Compendium of Chemical Terminology themoglobinemic agents, antimigraine agents, antimyastenic 2nd Edition (1997) and refers to a molecular entity that differs agents, antineoplastic agents, antineuralgic agents, only in isotopic composition (number of isotopic Substitu antineutropenic agents, antipanic agents, antipolyneuropathy tions), e.g. 'H'O, "HHO, and "H.O. agents, antiprotozoal agents, antipsoriatic agents, antipsy 0014 Herein and after, term “light water refers to water chotic agents, antipyretic agents, antirheumatic agents, anti comprising from about 99.760 to about 99.999% of light Seborrheic agents, antispasmodic agents, antithrombotic
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