US 20150297733A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0297733 A1 Oberegger et al. (43) Pub. Date: Oct. 22, 2015
(54) CONTROLLED RELEASE TOPICAL A647/22 (2006.01) TESTOSTERONE FORMULATIONS AND A647/4 (2006.01) METHODS A6M 35/00 (2006.01) A647/26 (2006.01) (71) Applicant: TRIMEL BIOPHARMA SRL, A647/02 (2006.01) Durants, Christ Church (BB) A647/38 (2006.01) A647/32 (2006.01) (72) Inventors: Werner Oberegger, Waterdown (CA); A619/00 (2006.01) Paul José Pierre Marie Maes, Visé A647/10 (2006.01) (BE) (52) U.S. Cl. CPC ...... A61K 47/44 (2013.01); A61 K9/0014 (21) Appl. No.: 14/442,949 (2013.01); A61 K3I/568 (2013.01); A61 K 47/22 (2013.01); A6 IK 4 7/14 (2013.01); A6IK (22) PCT Filed: Nov. 14, 2013 47/0 3:38: A6 IK 47/26 38. A61 K 47/02 (2013.01); A61 K47/38 (2013.01); A61 K (86). PCT No.: PCT/B2O13AOO2913 47/32 (2013.01); A61M35/003 (2013.01) S371 (c)(1), (2) Date: May 14, 2015 (57) ABSTRACT O O The present invention relates to testosterone topical formula Related U.S. Application Data tions, especially high testosterone concentration formula (60) Provisional application No. 61/729,304, filed on Nov. tions, such as between about 6% to about 15% w/w or higher, 21, 2012, provisional application No. 61/726,564, for the controlled release of testosterone into the systemic filed on Nov. 14, 2012. circulation of males and females for providing constant effec tive testosterone blood levels, without inducing undesired Publication Classification testosterone spike in blood levels or testosterone transfer ence, following topical administration. The present invention (51) Int. Cl. also relates to methods and pre-filled multi-dose airless appli A6 IK 47/44 (2006.01) cator systems for pernasal administration of the nasal test A6 IK3I/568 (2006.01) osterone gels of the present invention
1. O Patent Application Publication Oct. 22, 2015 Sheet 1 of 29 US 2015/0297733 A1
FIG. 1 Patent Application Publication Oct. 22, 2015 Sheet 2 of 29 US 2015/0297733 A1
FG. 2 Patent Application Publication Oct. 22, 2015 Sheet 3 of 29 US 2015/0297733 A1
FG. 3 Patent Application Publication Oct. 22, 2015 Sheet 4 of 29 US 2015/0297733 A1
FG. 4 Patent Application Publication Oct. 22, 2015 Sheet 5 of 29 US 2015/0297733 A1
FU 15 MLPOL (-) BARRE
... PSTON 15 ML. (-) Patent Application Publication Oct. 22, 2015 Sheet 6 of 29 US 2015/0297733 A1
XXX. Capot SP 15 ( ) & X OVERCAP SP 5
Poussoir Digital ( )
* - DIGITALACTUATOR
A Bague SP15 ( ) SNAP ON SP5
Joint de coi ( ) Neck Gasket
isme VP39/140 HTA Ø14.7 ( ) MECHANISM VP39/140 HTA 214.7
228,230,15MM-8: Patent Application Publication Oct. 22, 2015 Sheet 7 of 29 US 2015/0297733 A1
FG. 7A
FG. 7B Patent Application Publication Oct. 22, 2015 Sheet 8 of 29 US 2015/0297733 A1
FG. 8B Patent Application Publication Oct. 22, 2015 Sheet 9 of 29 US 2015/0297733 A1
Patent Application Publication Oct. 22, 2015 Sheet 10 of 29 US 2015/0297733 A1
~~~~*****No.
§ø±3.5
Patent Application Publication Oct. 22, 2015 Sheet 11 of 29 US 2015/0297733 A1
Patent Application Publication Oct. 22, 2015 Sheet 12 of 29 US 2015/0297733 A1
Apparatus A (E)-- ()^^. ()ra?-- ()wn ()-- (Dr^ | 1 - Apparatus B
O GO GO G. XXXXaaXAasaxaaaaaaaaaaaaaaaaaXaaXaXXXXXX-AAAAAaaaaaaaaaaaaaaaaaaaaaaaaaa.
F.G. 12
Amount of estosterone Released Coriparison s -- Low # IMP11001 X - A Low #E0-007 s 3 O O O 2OO . 1 OOOs
Time (min)
F.G. 13 Patent Application Publication Oct. 22, 2015 Sheet 13 of 29 US 2015/0297733 A1
Time (hr) F.G. 14 Patent Application Publication Oct. 22, 2015 Sheet 14 of 29 US 2015/0297733 A1
saxx-xxxi. sasakaxx-xx-assassssssssssssssssssssessssssss No eatient BSc device "TBS-isyring 500 &aasaxx-xxx-xxxxxxxxxxaxxxxxxxx-xxxxaaaaaaaXXXXXXXXXXXX. arraxxxxxxxxxxaaaaaaaaaaaaaaaaaaxxxx,
**** O O:
O
Time (hr)
F.G. 15
Á?suapK?i?qeqoud
FIG. 16 Patent Application Publication Oct. 22, 2015 Sheet 15 of 29 US 2015/0297733 A1
Sobilité de a testostérone dias différents wéicies a 32C et 50°C (expré en portentage dissos)
O
------exox's S
2. 3 to "gs g" s :
F.G. 17
F.G. 18 Patent Application Publication Oct. 22, 2015 Sheet 16 of 29 US 2015/0297733 A1
Corpound Activity
Testosteroie Weighing
Caiculation of Fecessary Active ingredients and Quality an Ont excipients Control
Castro is Prefix
Mixing of testosterone
estosterone in Castor oil
fixture
Mixingis until dissolved testosterone |Appearance
fixture i s rs Homogenization Oleoy polyoxylglycerides
awaxaaaaaa-awo-sease
Mixture Mixte 3.
w Homogenization Appearance s
Coiloida's icon dioxide
F.G. 19 Patent Application Publication Oct. 22, 2015 Sheet 17 of 29 US 2015/0297733 A1
Compound Activity Control
&&easaaaaaaassaa-exas&ex-xxxx swarasww.xxxxxxv-xxxxsw8 aarara
estosterose Weighing Quality Calculation of necessary T Active ingredients and Contro amount excipients
xxx xxxxxxx xxxxx xxxx-xxx-xx-s-s-s-s-s-s-s-s-s-s-s-s-s-s-s-s Dimethy isosorbide Pre-Mix Stage Mixing of dimethy isosorbide and Diethyleneglycol ethy diethyleneglycol ethy ether ether aaaaaarxxxxxaaaaaaaaaaaaaaaaaaaasax
xxxxxxxxxxxxxx-xxxx. Pre-Mix Stage Pre-Mix Stage Mixing speed s SaxxxxxYYY :- Mixing of Pre-Mix + Time Povicione and powidone + copovidone Temp Copowidore until completely dissolved Sasa
saaaas SaaaaaXaaaaaaaaa.
Pre-Mix Stage Pre-Mix Stage it
ca Add hydroxypropy cellulose to Pre-Mix until Solution is Hydroxypropy cellulose clear
Mo Pre-Mix Stage Active fixture Mixing speed r Add testosterone to Pre- ite Mix Liti testosteroie w Temp - Testosterone has dissolved X-axaaaaaaaaaaa-K&ax-XXXXXXXXaxaawaaaaaa. t FIG. 20A Patent Application Publication Oct. 22, 2015 Sheet 18 of 29 US 2015/0297733 A1
wrwa Preparation of Buik Ge. Mixing speed Add Active Mixture to
castor oil and mix. Cool Time Active Extre mixture to 40°C and
r colloidal silicon dioxide Appearance
d S. SEE D Castrof Oi dia+Coloida is issolvedfree of entrapped and solution air. ASSay
Cool to 30°C prior to impurities transfer into s SfS Container Wiscosity
Bik (Ge FE into syringes. Fling of Clinical Package in sealed Slippies aluminium foil pouches.
exax Assassesssssssssssssssssssssssssssss VV FG, 2OB
ww. 're * x, x-rx rx raw way was x-ax as W. is w:
Sixxx.
8 o' 1214 16, 1820 22 24 Time after administration (h) FIG. 21 Patent Application Publication Oct. 22, 2015 Sheet 19 of 29 US 2015/0297733 A1
as a ------a ------sa------exe-a-
A *************<<<<<<<<<<<<<.››.››
w
!**********************************<<<<<<<<~~~~.~~~~~~,~~~~'+'~~~~~~~~,~~~
s: ZZ"SOH-)
>>--~~~~40099
……*******æ*
c ***~~~~#00gz f Lifia, eucaesose Patent Application Publication Oct. 22, 2015 Sheet 20 of 29 US 2015/0297733 A1
as
00:009
w
fi essed 8.93sogse Patent Application Publication Oct. 22, 2015 Sheet 21 of 29 US 2015/0297733 A1
Oct. 22, 2015 Sheet 22 of 29 US 2015/0297733 A1
(usific) uosnia Patent Application Publication Oct. 22, 2015 Sheet 23 of 29 US 2015/0297733 A1
***
----~--~~~~~~~