US 20070042030A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0042030 A1 Cevc (43) Pub. Date: Feb. 22, 2007 (54) PREPARATION FOR THE APPLICATION OF Mar. 6, 1991 (DE).............................................. 4107 153 AGENTS IN MINI-DROPLETS Mar. 6, 1991 (DE).............................................. 4107 152 Aug. 22, 1991 (WO)........................... PCT/EP91/O1596 (75) Inventor: Gregor Cevc, Heinstetten (DE) Publication Classification Correspondence Address: EDWARDS & ANGELL, LLP (51) Int. Cl. P.O. BOX SS874 A 6LX 9/27 (2006.01) BOSTON, MA 02205 (US) (52) U.S. Cl. ............................................ 424/450; 977/907 (73) Assignee: IDEA AG, Munchen (DE) (57) ABSTRACT (21) Appl. No.: 11/481,804 The invention relates to a preparation for the application of 1-1. agents in the form of minuscule droplets of fluid, in par (22) Filed: Jul. 5, 2006 ticular provided with membrane-like structures consisting of Related U.S. Application Data one or several layers of amphiphilic molecules, or an AV amphiphilic carrier Substance, in particular for transporting (63) Continuation of application No. 09/621,574, filed on the agent into and through natural barriers such as skin and Jul. 21, 2000, which is a continuation of application similar materials. The preparation contains a concentration No. 07/844 644 filed on Apr. 23, 1992, now aban- of edge active substances which amounts to up to 99 mol-% doned. sy is s s of the agent concentration which is required for the induc tion of droplet solubilization. Such preparations are suitable, (30) Foreign Application Priority Data for example, for the non-invasive applications of antidia betics, in particular of insulin. The invention, moreover, Aug. 24, 1990 (DE).............................................. 4O26833 relates to the methods for the preparation of such formula Aug. 24, 1990 (DE).............................................. 4O26834 tions. 12 600 MEANSIZE 10 500 e S as y 400 e Éf 5 g 300 S o 2 3E sc d in M 200 l s s ? 100 O 1 2 3 4 O 1 2 3 4. S100/OAC (mol/mol) Patent Application Publication Feb. 22, 2007 Sheet 1 of 21 US 2007/0042030 A1 s XX as O E S Co o O O O O o 9 O O Co O O O S CO tr cy CN ver Nee s Sn S2 3ONWISIS (+) Ha Patent Application Publication Feb. 22, 2007 Sheet 2 of 21 US 2007/0042030 A1 C s N 2 a. s 2 S 8 S. 8 S. S. S. C as CN co r cr) N y Ye CD (uu) aWWIO s l O as S2 CMO N C/O 2 C l d o o o O o o O Cd o O O Co C CO O r cr) cN w (uuu) LWWIO Patent Application Publication Feb. 22, 2007 Sheet 3 of 21 US 2007/0042030 A1 N CO Z CC as -- H ---- 1S - S o o O Co o O as g S. S S S2 5 CY (uu). NOLIVIAO OWONWLS "YLWWIOf O U 3. o CC 9 CD l 8 o SN Se CO CO s C O ONWISIS32 (+)Hd Patent Application Publication Feb. 22, 2007 Sheet 5 of 21 US 2007/0042030 A1 N CVO 2 CC O d as O E ar s o o O o O o 9 o o O O O S r cr) cN were uu) NOLIVIAOO-VONVLS' 3.13WVIO s ONWISIS Patent Application Publication Feb. 22, 2007 Sheet 6 of 21 US 2007/0042030 A1 N CfO 2. CC U s S. i S 8 s(uu) NOLIVIAOO&WONWLS5 & "WWI8 & S. - U H is O O Vs a 8 o SN S2 o co r on O 3ONVISISY "(...)Hd Patent Application Publication Feb. 22, 2007 Sheet 7 of 21 US 2007/0042030 A1 O vs. OO g N to is 5 CD c C CD - 5(5. l ? CN O ve O 2 CS NOILWW&O IOISA-OW Patent Application Publication Feb. 22, 2007 Sheet 8 of 21 US 2007/0042030 A1 Co qs g R CVO 2 n CC 2 s <CL s as . E Co S o C - co C o c. 9 D O l) O O E (uu) LWWIO g ONWISISR Patent Application Publication Feb. 22, 2007 Sheet 9 of 21 US 2007/0042030 A1 O as S a (uu) NOLIVIN3Os OVONVIS'y5 & 13WVIO 8 & U L - C C/O O O CD - CD 9. S o ONWISIS Patent Application Publication Feb. 22, 2007 Sheet 10 of 21 US 2007/0042030 A1 | t SNN 22 N 2 III 2 s s III 2 S (%)XWildn NIXIS Patent Application Publication Feb. 22, 2007 Sheet 11 of 21 US 2007/0042030 A1 e (%) OOO19 NISOO Patent Application Publication Feb. 22, 2007 Sheet 12 of 21 US 2007/0042030 A1 CfO s O CO 1. CO5 H CN q O (%)OOO19 NISOO Patent Application Publication Feb. 22, 2007 Sheet 13 of 21 US 2007/0042030 A1 : s3. s s s C O L O ld s vs v s CP/5u) OOOTNINOIL3 id3O3SOOn 19 Patent Application Publication Feb. 22, 2007 Sheet 14 of 21 US 2007/0042030 A1 U N CMO Z CC d s O S S Cd Co Co O O o S2 C Cd C O O S r cyd CN v aua WN CD OdO sa : l nal O C v CO L CO C . Cl co fa d E N. ONWISIS Patent Application Publication Feb. 22, 2007 Sheet 15 of 21 US 2007/0042030 A1 O N Z CC ; s S o O 92 o o lc) d S. S 5 \ (uu) NOILWINO OWONWLS "YLWWIO S. U o stS. e 3 do ONWISISS Patent Application Publication Feb. 22, 2007 Sheet 16 of 21 US 2007/0042030 A1 o r D cy O cr) 2 O e es C C Lo 9 CVO O CS S n1 s O s s S. vs. D S Co • C CN Co CD CO On 2 to 8 ve CVO Z O S2 CAP S O O CO O LO O v- O O CN N. cs CN ve O O (uu OOv) OO Patent Application Publication Feb. 22, 2007 Sheet 17 of 21 US 2007/0042030 A1 g 2 - D CVO 2 s s 2 CC 4 ? s O N1 n1 S O d O O s S2 ve g (IP/5u)OOO19 NINOILldO3SOOn 19 Patent Application Publication Feb. 22, 2007 Sheet 18 of 21 US 2007/0042030 A1 Co OC) r 4. S3 - CY) d CMO Z 3.t D CC 2 &gO S. O cN se N1 S. S wim O CN vo C O CN t CP/5u) OOO19 NINOIL31d303SOOnt) Patent Application Publication Feb. 22, 2007 Sheet 19 of 21 US 2007/0042030 A1 33. C d P O v s s cd s O LO Co O s S2 t g Cip?bu) OOO19 NINOIL lO3SOOn 19 Patent Application Publication Feb. 22, 2007 Sheet 20 of 21 US 2007/0042030 A1 o CY) 2 - D CO 4. S H Z CC 2 ?a d O Na 2 1. S2 9 to c O s 2 sCo Ltdis stO (p/6u) OOO19 NINOldO3SOOnt) Patent Application Publication Feb. 22, 2007 Sheet 21 of 21 US 2007/0042030 A1 : sgs Z - O s CO 2 H Z CC Z O s O Na L 1. s (p/6u) OOO19 NINOLTdOSOOnTS) US 2007/0042030 A1 Feb. 22, 2007 PREPARATION FOR THE APPLICATION OF to simply add chemical penetration enhancers to the mixture AGENTS IN MINI-DROPLETS of agent and other molecules; applications to human skin were the only case in which additives were sometimes 0001. The present invention relates to a novel type of applied in advance, in the form of an organic solution. The preparations Suitable for the application of different agents reason for this application form was the current concept for in the form of a minuscule droplet or, in particular, a vesicle the action of penetration enhancers: to date one has studied, consisting of one or a few membrane-like amphiphile discussed, and believed that, in general, any facilitated agent assemblies. These can mediate the transport of agents into penetration is a consequence of skin fluidization, on the one and through a series of natural permeability barriers or hand (Golden et al., (1987) J. Pharm. Sci. 76, 25-28). (This through the constrictions in Such barriers; for example, phenomenon is normally associated with a destruction of the through intact skin or similar organs. The invention further skin Surface and of its protective shield and thus is undes relates to a procedure for the large-scale production of Such ired.) On the other hand, it has been shown that some agents carriers. As a special example, non-invasive application of can permeate through skin in the form of low-molecular antidiabetics is described for the case of insulin. weight complexes with added molecules (Green et al., 0002 The application of various agents is often ham (1988) Int. J. Pharm. 48, 103-111). pered by the presence of barriers with a low permeability to 0006 Methods deviating from the ones already described Such agents. Owing to skin impermeability, for example, have brought little improvement to date. The use of lipoidal many common therapeutic agents must be applied per os or carriers, the liposomes, on intact skin, which has been parenterally (i.v., i.m., i.p.). Intrapulmonary and intranasal theoretically discussed by several authors, was mainly applications of aerosols, the use of rectal formulations, gels aimed at modifying the agent's pharmacokinetics (Patel, for mucous applications, or use of occular formulations are Bioch. Soc. Trans. 609th Meeting, 13, 513-517, 1985, only practicable in certain areas and not for all types of Mezei, M.