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(12) Patent Application Publication (10) Pub. No.: US 2011/0245215 A1 Carrara Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0245215 A1 Carrara Et Al US 20110245215A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0245215 A1 Carrara et al. (43) Pub. Date: Oct. 6, 2011 (54) TRANSIDERMAL DELIVERY SYSTEMIS FOR (60) Provisional application No. 60/453,604, filed on Mar. ACTIVE AGENTS 11, 2003, provisional application No. 60/510,613, filed on Oct. 10, 2003, provisional application No. (75) Inventors: Dario Norberto R. Carrara, 60/510,613, filed on Oct. 10, 2003. Oberwil (CH); Arnaud Grenier, Steinbrunn le Haut (FR): Celine (30) Foreign Application Priority Data Besse, Saint Louis (FR); Stephen M. Simes, Long Grove, IL (US); Aug. 3, 2000 (EP) ......................... PCT/EPOO/O7533 Leah M. Lehman, Green Oaks, IL (US) Publication Classification (51) Int. Cl. (73) Assignee: ANTARES PHARMA, IPL, AG A6II 3/568 (2006.01) A6IP5/26 (2006.01) (21) Appl. No.: 13/106,715 A6IP 5/00 (2006.01) (52) U.S. Cl. ........................................................ S14/178 (22) Filed: May 12, 2011 (57) ABSTRACT Related U.S. Application Data A formulation for transdermal or transmucosal administra (63) Continuation of application No. 13/044,447, filed on tion of an active agent. The formulation includes an active Mar. 9, 2011, which is a continuation of application agent and a delivery vehicle comprising a C to C alkanol, a No. 12/614,216, filed on Nov. 6, 2009, which is a polyalcohol, and a permeation enhancer of monoalkyl ether continuation-in-part of application No. 10/798,111, of diethylene glycol present in an amount Sufficient to provide filed on Mar. 10, 2004, said application No. 12/614, permeation enhancement of the active agent through dermal 216 is a continuation-in-part of application No. or mucosal surfaces. The formulation is substantially free of 11/755,923, filed on May 31, 2007, which is a continu long-chain fatty alcohols, long-chain fatty acids, and long ation-in-part of application No. 1 1/371,042, filed on chain fatty esters in order to avoid undesirable odor and Mar. 7, 2006, now Pat. No. 7,335,379, which is a irritation effects caused by Such compounds during use of the continuation of application No. PCT/EP04/11175, formulation. Also, the active agent is testosterone that is filed on Oct. 6, 2004, said application No. 1 1/755,923 present in an amount of about 1%, the alkanol is ethanol that is a continuation-in-part of application No. 1 1/634, is present in an amount of about 46.28% to about 47.5% of the 005, filed on Dec. 4, 2006, now Pat. No. 7,404,965, formulation; the polyalcohol is propylene glycol that is which is a continuation of application No. 10/343,570, present in an amount of about 6% of the formulation; and the filed on May 19, 2003, now Pat. No. 7,214,381, filed as permeation enhancer is diethylene glycol monoethyl ether application No. PCT/EP01/09007 on Aug. 3, 2001. that is present in an amount of about 5% of the formulation. Patent Application Publication Oct. 6, 2011 Sheet 1 of 11 US 2011/0245215 A1 -- fi :- 8: 8 r s ea sess : - askx i &isi & S.SS . a.s is - a0 is s 3.S. -o- 98-A 0% -e- 86-A 86 x orror & ris & Patent Application Publication Oct. 6, 2011 Sheet 2 of 11 US 2011/0245215 A1 isy Seii.33. -- is ess as -e- isy siggs: ...if S - - ay 3, Case (88 g. it is is is is a 22 is iiie (loirs. Six's Application F.C. 3A i -- Cay ites: 2: . sis -- Ray Case 3.3 g x-- ayi-fixese (, jig. s - - lay Cosa .38 g. A w S.S airs. Sixx agiaioi Patent Application Publication Oct. 6, 2011 Sheet 3 of 11 US 2011/0245215 A1 -- tag glose 8.8 s. -- ay Coxe .22s. -- isy -foss 4-g -H- ayi is ess E.88. s irregiosis. Sixespitation FIG. 3C 3. Šarišy Rafi is sess, SS finis is G. 3D Patent Application Publication Oct. 6, 2011 Sheet 4 of 11 US 2011/0245215 A1 w retire --EHE-E-8&is a--A- a-- risyi: singsassis close is geoisy -o-e-3-kirias siliate dose, 3.5g geaisy - -e- - isfay 4: initiate aise is geaisy M e-ray - fruise tisse, .5 sies, s ': - . s as a s' SS. ------ *ray : fisiiigis gies.& 35&#8 gsay rts .ka : -Yowa-a-a-N--* Year -8 x ----aw --- sess-r ris"-stir-r -E-EHE-3 stay is is seis s feet --a-A- a-- is day i: single dose, 59 geay -&----- (stay initiiie assig sistasy f -(-e-&- a stay is: Niiga aass, is gsay 8:risy - Riisease, ig ga'ay fe say Sigis is iss, 3S is say & s & s re-s? a. *-i- or st ... Sites fit FIG, 3F Patent Application Publication Oct. 6, 2011 Sheet 5 of 11 US 2011/0245215 A1 is - s wass s 8 S - 25 & s i. s --. is S. 3. $g Fine is Patent Application Publication Oct. 6, 2011 Sheet 6 of 11 US 2011/0245215 A1 s also Fine fi FIG. 4C Tisis fi F.G. (D Patent Application Publication Oct. 6, 2011 Sheet 7 of 11 US 2011/0245215 A1 y g Ss f s - n -e “ - we co - - - W - a-- - - asr sar-r r E-Šs -S -wrix---.ti-ps.uwe------ ass-axY aa. Six SS 3- 3. SS: is f FIG, IE Patent Application Publication Oct. 6, 2011 Sheet 8 of 11 US 2011/0245215 A1 S.s: wa r •S S. s s m E---8- ---Šil. SS gas-a-stro--: S. n s w i-Er Š-seats Patent Application Publication Oct. 6, 2011 Sheet 9 of 11 US 2011/0245215 A1 . -e-Es-Eis- a seatient s Patent Application Publication Oct. 6, 2011 Sheet 10 of 11 US 2011/0245215 A1 orx Raseiba S is mo (.625g/day (0.325 mg estradioi Y -- i.S./isyff, rig astracio Y -- 3.5g/clay i.Stig estradio S&S8:S $88&; is & $8: iss: 3 $East of resissisi. FIG. A Patent Application Publication Oct. 6, 2011 Sheet 11 of 11 US 2011/0245215 A1 SSS. Šassis ::sis $S: $8 $'s sek -a- Facebo -- .333's as f.3°S fig &srcial -(- .25g/clay O. Sing estradio -say is gig &SE&isi £8ssie $88-g i88& is $88: 3 is $. US 2011/02452.15 A1 Oct. 6, 2011 TRANSIDERMAL DELIVERY SYSTEMIS FOR 0005. In addition to reduced levels of endogenous steroid ACTIVE AGENTS hormones Such as those described above, adrenal insuffi ciency leads to reduced levels of dehydroepiandrosterone CROSS-REFERENCE TO RELATED (DHEA) in men and women. The adrenal glands are also APPLICATIONS involved in the production of many hormones in the body, 0001. This application is a continuation of application Ser. including DHEA and sex hormones such as estrogen and No. 13/044,447 filed Mar. 9, 2011, which is a continuation of testosterone. Consequently, adrenal insufficiency can lead to application Ser. No. 12/614,216 filed Nov. 6, 2009, which is a reduced levels of DHEA and sex hormones which can lead to continuation-in-part of application Ser. No. 10/798,111 filed the clinical symptoms described above. Mar. 10, 2004, which claims the benefit of each of application 0006 Although steroid hormone concentrations may be No. 60/453,604 filed Mar. 11, 2003 and 60/510,613 filed Oct. restored to normal or near-normal levels by hormone replace 10, 2003. Application Ser. No. 12/614,216 is also a continu ment therapy, the current forms of treatment (i.e., oral, intra ation-in-part of application Ser. No. 1 1/755,923 filed May 31, muscular, Subcutaneous, transdermal patches and topical for 2007, which is a continuation-in-part of U.S. patent applica mulations) have several disadvantages. For example, orally tion Ser. No. 1 1/371,042 filed Mar. 7, 2006, now U.S. Pat. No. administered testosterone is largely degraded in the liver, and 7.335,379, which is a continuation of International applica tion no. PCT/EP2004/011175 filed Oct. 6, 2004, which is therefore not a viable option for hormone replacement claims the benefit of U.S. provisional patent application No. since it does not allow testosterone to reach systemic circu 60/510,613, filed Oct. 10, 2003. Application Ser. No. 1 1/755, lation. Further, analogues of testosterone modified to reduce 923 is also a continuation-in-part of U.S. patent application degradation (e.g., methyltestosterone and methandros tenolone) have been associated with abnormalities to liver Ser. No. 1 1/634,005 filed Dec. 4, 2006, now U.S. Pat. No. function, such as elevation of liver enzymes and conjugated 7,404.965, which is a continuation of application Ser. No. bilirubin. Injected testosterone produces wide peak-to-trough 10/343,570 filed May 19, 2003, now U.S. Pat. No. 7,214,381, variations in testosterone concentrations that do not mimic which is the U.S. national stage of International application the normal fluctuations of testosterone making maintenance no. PCT/EP01/09007 filed Aug. 3, 2001 which claims prior of physiological levels in the plasma difficult. Testosterone ity to International application no. PCT/EP00/07533 filed injections are also associated with mood Swings and Aug. 3, 2000. Each prior application is expressly incorpo increased serum lipid levels. Injections require large needles rated herein in its entirety by reference thereto. for intramuscular delivery, which leads to diminished patient compliance due to discomfort. Commonly, estrogen is often TECHNICAL FIELD administered orally. This route of administration has been 0002 The present invention relates to a novel transdermal also associated with complications related to hormone or transmucosal pharmaceutical formulation comprising at metabolism, resulting in inadequate levels of circulating hor least one active ingredient and a solvent system.
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