(12) STANDARD PATENT APPLICATION (11) Application No. AU 2019203067 A1 (19) AUSTRALIAN PATENT OFFICE (54) Title CONTROLLED RELEASE NASAL TESTOSTERONE GELS, METHODS AND PRE­ FILLED MULTI-DOSE APPLICATOR SYSTEMS FOR PERNASAL ADMINISTRATION (51) International Patent Classification(s) A61K9/00 (2006.01) A61K 47/34 (2006.01) A61K9/06 (2006.01) A61K 47/44 (2006.01) A61K 31/568 (2006.01) A61P 5/26 (2006.01) (21) Application No: 2019203067 (22) Date of Filing: 2019.04.30 (43) Publication Date: 2019.05.23 (43) Publication Journal Date: 2019.05.23 (62) Divisional of: 2017204182 (71) Applicant(s) Acerus Pharmaceuticals SRL (72) Inventor(s) Kreppner, Wayne;Fogarty, Siobban;Oberegger, Werner;Maes, Paul Jose Pierre Marie (74) Agent / Attorney Pizzeys Patent and Trade Mark Attorneys Pty Ltd, GPO Box 1374, BRISBANE, QLD, 4001, AU ABSTRACT The present invention relates to intranasal testosterone gels for the controlled release of testosterone into the systemic circulation of males and females for providing constant effective testosterone blood levels, without inducing undesired testosterone spike in blood levels, following pernasal administration. The intranasal testosterone gels of the present invention are safe, convenient to use, well tolerated, stable and easily and reproducibly manufactured on scale up. Moreover, because supra- normal and sub-normal testosterone blood levels are believed to be essentially kept to a minimum or avoided and the testosterone serum levels are believed to remain essentially constant during dose life, i.e., the intranasal testosterone gels of the present invention mimic or restore testosterone blood levels to normal physiologic daily rhythmic testosterone levels, the novel intranasal testosterone gels of the present invention are uniquely suited for testosterone replacement or supplemental therapy and effective for treating males diagnosed with, for example, male testosterone deficiency, such as, low sexual libido, low sexual drive, low sexual activity, low fertility, low spermatogenesis, aspermatogenesis, depression and/or hypogonadism, and females who are diagnosed with, for example, female sexual dysfunction, such as, low sexual libido, low sexual drive, low sexual activity, low amygdala reactivity, low sexual stimulation, hypoactive sexual desire disease ("HSDD"), female sexual arousal disorder and/or anorgasmia. The present invention also relates to methods and pre- filled multi-dose airless applicator systems for pernasal administration of the nasal testosterone gels of the present invention. WO 2012/156822 PCT/IB2012/001127 1/29 2019 Apr 30 2019203067 This data, for application number 2017204182, is current as of 2019-04-30 21:00 AEST WO 2012/156822 PCT/IB2012/001127 1 CONTROLLED RELEASE NASAL TESTOSTERONE GELS, METHODS 2019 AND PRE-FILLED MULTI-DOSE APPLICATOR SYSTEMS FOR PERNASAL ADMINISTRATION Apr 5 30 Field of the Invention [0001] The present invention relates to intranasal testosterone gels for the controlled 10 release of testosterone into the systemic circulation of males and females after pernasal application for providing constant effective testosterone blood levels, without causing unwanted testosterone blood level spikes, over dose life, which are suitable 2019203067 for use in testosterone replacement or supplemental therapy and effective to treat males and females in need of testosterone replacement or testosterone supplemental 15 therapy to treat, for example, male testosterone deficiency or female sexual dysfunction. The present invention also relates to methods and pre-filled multi-dose applicator systems for pernasal administration of the nasal testosterone gels. Background 20 [0002] Nasal drug delivery offers many advantages that include rapid adsorption due to abundant capillary vessels, fast onset of action, avoidance of hepatic first-pass metabolism, utility for chronic medication and ease of administration. [0003] It is known that, in contrast to large and/or ionized molecules, lipophilic 25 pharmaceutical compounds having a sufficiently low molecular weight in general are readily adsorbed by the mucous membrane of the nose. For such drugs it is possible to obtain pharmacokinetic profiles similar to those obtained after intravenous injection. [0004] However, maintaining constant in vivo therapeutic drug concentrations for an 30 extended period of time has been problematic because of the rapid mucociliary clearance of the therapeutic agent from the site of deposition resulting in a short span of time available for absorption and of the presence of enzymes that may cause degradation in the nasal cavity. This data, for application number 2017204182, is current as of 2019-04-30 21:00 AEST WO 2012/156822 PCT/IB2012/001127 2 [0005] Effort has been made to overcome these limitations including the use of bioadhesive systems that increase residence time in the nasal cavity, the use of 2019 enhancers to improve permeability of the nasal membrane or the use of stabilizers that prevent degradation of drugs. Apr 5 30 [0006] For example, in GB 1987000012176, the use of bioadhesive microspheres has been proposed by Ilium and, in PCT/GB98/01147, the use of in-situ gelling pectin formulations by West Pharmaceuticals. 10 [0007] Investigations on the nasal absorption of sexual steroids, rather small and lipophilic compounds, have shown that they are readily absorbed by the mucous 2019203067 membrane of the nose and are found very quickly in serum. Due to this fact, to the short half-life of the compounds and to limited possibilities for formulating nasal application forms with sustained release, sexual steroid use in clinical practice has 15 been limited up to now, because hormone replacement therapy, in general, is a long­ term application. [0008] Several formulations were proposed for these drugs. Thus, in the case of testosterone, which is nearly water-insoluble and somewhat better in vegetable oil, 20 Hussain et al., "Testosterone l73-N,N-dimethylglyc-inate hydrochloride: A prodrug with a potential for nasal delivery of testosterone", J. Pharmaceut. Sei. 91(3): 785-789 (2002), suggested that testosterone might be an ideal candidate for nasal administration, if its solubility in water could be increased. Hussain et al therefore proposed the use of a water-soluble pro-drug, testosterone 17β-Ν,Ν- 25 dimethylglycinate, and found serum levels equal to intravenous administration with peak plasma concentrations within 12 min (25 mg dose) and 20 min (50 mg dose), respectively, and elimination half-lives of about 55 min. It should be mentioned that this speed is not necessary/desirable because sex hormone replacement or supplemental therapy is not an emergency therapy requiring peak plasma 30 concentations immediately following adminsitration. [0009] Ko et al., "Emulsion formulations of testosterone for nasal administration", J. Microencaps., 15(2): 197-205 (1998), proposed the use of charged testosterone WO 2012/156822 PCT/IB2012/001127 3 submicron O/W emulsion formulations (water/Tween80, soybean oil/Span80) based on the hypothesis that increased absorption is possible upon solubilization of the drug 2019 and/or prolongation of the formulation residence time in the nose. Ko et al. found a higher relative bioavailability of the positively (55%) and negatively (51%) charged Apr 5 emulsion compared to the neutral one (37%). Tmax was observed in every case at 30 about 20 min after administration. It is difficult to assess these results because Ko et al. did not take blood samples before application and thus it is not possible to evaluate the differences in the decrease of serum levels, although from a graph it seems that, after intravenous application (hydroalcoholic solution), the level shows the longest 10 elimination half time. In practice, however, such an emulsion is not suitable because the amount of surfactant needed to achieve the droplet size (430 nm) is not acceptable 2019203067 for nasal application. [0010] The solubility of progesterone in water and oil is somewhat comparable to that 15 of testosterone, but investigators have had different approaches. [0011] For example, Cicinelli et al., "Progesterone administration by nasal spray", Fertil Steril 56(1): 139-141 (1991), "Nasally-administered progesterone: comparison of ointment and spray formulations", Maturitas 13(4): 313-317 (1991), "Progesterone 20 administration by nasal sprays in menopausal women: comparison between two different spray formulations", Gynecol Endocrinol 6(4): 247-251 (1992), "Effects of the repetitive administration of progesterone by nasal spray in postmenopausal women", Fertil Steril, 60(6): 1020-1024 (1993) and "Nasal spray administration of unmodified progesterone: evaluation of progesterone serum levels with three different 25 radioimmunoassay techniques", Maturitas 19(1): 43-52 (1994), shows that when progesterone is dissolved in almond oil (20 mg/ml) and administered by nasal spray, this leads to higher progesterone bioavailability than that provided by progesterone dissolved in dimethicone or a PEG-based ointment. After nasal application of progesterone in almond oil Cmax levels were observed after 30 to 60 minutes, 30 decreasing significantly 6 to 8 hours after single administration. [0012] Steege et al. "Bioavailability of nasally administered progesterone", Fertil Steril, 46(4): 727-729 (1986), shows that when progesterone is dissolved in WO 2012/156822 PCT/IB2012/001127 4 polyethylene glycol (200 mg/ml), a Tmax at 30 min is achieved and that the duration of serum level is at least 8 hours but with high variations.