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Ep 2229936 B1 (19) TZZ ¥_T (11) EP 2 229 936 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/14 (2006.01) A61K 9/51 (2006.01) 06.05.2015 Bulletin 2015/19 A61K 9/107 (2006.01) A61K 9/48 (2006.01) A61K 31/568 (2006.01) (21) Application number: 09003370.5 (22) Date of filing: 09.03.2009 (54) Nanonized testosterone formulations for improved bioavailability Nanonisierte Testosteronformulierungen für verbesserte Bioverfügbarkeit Formules de testostérone de taille nano pour une meilleure biodisponibilité (84) Designated Contracting States: (74) Representative: UEXKÜLL & STOLBERG AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Patentanwälte HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL Beselerstrasse 4 PT RO SE SI SK TR 22607 Hamburg (DE) (43) Date of publication of application: (56) References cited: 22.09.2010 Bulletin 2010/38 EP-A- 1 698 329 WO-A-00/67728 WO-A-2007/103294 DE-A1- 19 825 856 (73) Proprietor: PharmaSol GmbH DE-A1- 19 932 157 US-A1- 2002 119 916 12307 Berlin (DE) US-B1- 6 814 959 (72) Inventors: • BAGCHUS W M ET AL: "IMPORTANT EFFECT OF • Keck, Cornelia FOOD ON THE BIOAVAILABILITY OF ORAL 12161 Berlin (DE) TESTOSTERONE UNDECANOATE" • Muchow, Marc PHARMACOTHERAPY, BOSTON, US, vol. 23, no. 67292 Kirchheimbolanden (DE) 3, 1 January 2003 (2003-01-01), pages 319-325, XP001147255 ISSN: 0277-0008 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 229 936 B1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 229 936 B1 2 Description other persons (especially children) to get into contact with thegel. If skincontact with untreated persons is expected, State of the Art: showering beforehand is strongly advised. Otherwise it bears the risk of transferring the drug to them and can [0001] In general products for testosterone delivery 5 result (in case of females) in androgenisation. Side ef- can be divided into two groups: Products for injection and fects are skin irritations. Due to inter- and intraindividual other products which include oral, buccal, and transder- differences in skin permeation the flux of drug can greatly mal systems. vary and is almost impossible to predict. Transdermal [0002] The crucial problem is the very high first pass patches are also widely used and available on the mar- effect of natural testosterone taken orally, about 99% of 10 kets worldwide. Depending on the delivery system, one the drug are immediately metabolised by liver enzymes or even two patches have to by applied simultaneously and do not reach the circulation. and have to be carried for two to four days. Severe skin [0003] To bypass this problem several approaches irritations are a common phenomenon. The systems for have been made: The first attempt was the methylisation use on the torso are still available while the formulations of testosterone, which hindered liver enzymes from in- 15 for application on the scrotum have been discontinued: activating it. Although application of methyltestosterone While absorption of testosterone via scrotum skin is bet- lead to a pronounced serum testosterone level, it was ter, it contains high concentration of esterases that lead found to be very liver toxic and was therefore withdrawn to a high concentration of dihydrotestosterone after ap- (C. Wang et al., Investigation, treatment and monitoring plication. Furthermore compliance was low: Shaving of of late-onset hypogonadism in males, Int. J. Androl. 32, 20 the scrotum was necessary, problems with adhesion of 1-10 (2008); F. C. Wu, Steroidogenesis and androgen the patches and skin irritations occurred (J. C. Findlay et use and abuse, Bailliere’s Clin. Endocrinol. Metab. 6, al., Treatment of primary hypogonadism in men by the 403-737 (1992)). However, other testosterone esters are transdermal administration of testosterone, J. Clin. En- better tolerated. There is a variety of testosterone deliv- docrinol. Metab. (68) 369-373 (1989)). While the problem ery systems on the market consisting of testosterone or 25 of high dihydrotestosterone levels does not occur with its esters, however they all have clear disadvantages. non-scrotum patches, skin irritation is even more pro- [0004] The first group are injections. In general injec- nounced with these formulations. In general it can be tions are not patient-convenient. Intravenous injection is concluded that transdermal systems exhibit delivery performed with an aqueous suspension of testosterone. problems and are not very patient convenient. Due to rapid degradation of the molecule by enzymes, 30 [0006] The use of subcutaneous implants is also the- several injections per day are necessary to maintain a oretically possible. There is only one subcutaneous prod- sufficiently high serum level of the hormone. As a result uct commercially available, which is only sold in the the products have been discontinued (Androlan Aqueo- U.S.A.: Testopel pellets. They are implanted under the sus; Andesterone Suspension, both USA) Roughly half skin and release the drug continuously over a four to six a dozen testosterone preparations for interamuscular in- 35 months time period. A microsurgery has to be performed jection are on the market in the U.S.A., France and Ger- to put the 3.4x9mm pellets into their desired place of ac- many. Those products consist of an oily solution of a tion. Furthermore once administered the release rate of testosterone ester (mostly testosterone enantate or tes- testosterone is difficult to adjust. Risks and side effects tosteroneundecanoate). After intramuscular injectionthe are: Extrusion, bleeding, and inflammations/infections at hormone is liberated from the oil during a period of 6 to 40 the site of implantation (F. Jockenhovel et al., Pharma- 12 weeks. However, more than 10% of the patients suffer cokinetics and pharmacodynamics of subcutaneous tes- from pain at the site of injection. Even more critical, once tosterone implants in hypogonadal men. Clin. Endocri- administered, the dose cannot be adapted which carries nol. (Oxf.) 45:61-71 (1996)). Apart from the implantation the risk of overdosing - especially with patients that start procedure being not patient-friendly, it is difficult to ter- with a testosterone replacement therapy (M. A. Mackey, 45 minate a treatment. The low number of these products Tolerability of intramuscular injections of testosterone es- on the market clearly reflects the little suitablility of this ter, in oil vehicle. Hum. Reprod. 10:862-865 (1995)). delivery approach. [0005] Transdermal systems available for application [0007] Buccal administration of testosterone is onto the skin are gels and patches. They can be classified achieved by the use of a tablet (bioadhesive delivery sys- by their site of application: Systems which are applied on 50 tem), which has to be placed on the gum. A buccal for- the torso and systems for the scrotum. Transdermal gels mulation (Striant) is currently marketed in the U.S., Great are preparations of testosterone and sometimes contain Britain and The Netherlands. Sufficiently high serum lev- also permeation enhancers like cyclopentadecanolide or els can only be achieved if the product is constantly ap- high concentrations of alcohol. They are applied at least plied and changed every 12 hours. (H. Zhang et al., oral once a day and they need to dry on the skin. The patient 55 mucosal drug delivery-clinical pharmacokinetics and has to wait for 5 to 10 minutes after application for the therapeutic applications. Clin. Pharmacokinet. (41) formulation to dry. Hands have to be carefully washed 661-680 (2002)). The buccal tablet does not always stay and the site of administration has to be covered to avoid in place. Tooth brushing, eating and drinking often loos- 2 3 EP 2 229 936 B1 4 ens it. It is also unintentionally swallowed without even caused by the drug not lymphatically absorbed but pass- noticing it. Side effects that have been described are: ing the liver. This can also be achieved when having an Headache, gingivitis and irritations of the gum and dys- oral formulation with higher bioavailability. This invention geusia (taste perversion). Regular gum examination is provides a nanonized formulation which fulfils this. The strongly advised (Striant patient information, 5 ht-formulation can be used for testosterone derivatives, e.g. tp://www.striant.com/Consum- esters, but also for the original testosterone molecule. In er/patient_info/patient_info.asp, accessed 04/03/09). addition the nanonized formulations can be potentially [0008] Thereare a varietyof otherformulation attempts applied for dermal delivery or nasal administration. like nasal spray, pulmonary delivery or ultrasound en- hanced transdermal transport. Those attempts have not 10 Aim of invention: made it to the market yet. [0009] After revieing the disadvabntages of the various [0013] Aim of the invention was to reduce the single delivery routes, the oral route has clear advantages. Is dose of testosteronundecanoate (TU) from 2 units (cap- is patient-convenient with no side effects such as injec- sules) - as used in the commercial product Andriol Tes- tion pain. In contrast to i.m. injections, treatment can be 15 tocaps® - to one unit by replacing the oil formulation of terminated. TU by one which shows identical - or ideally higher - [0010] However, as outlined above, the first pass effect bioavalibility (BA) but requires less application volume. limits the amount of testosterone reaching the circulation A single dose improves patient compliance, reduces dramatically. To overcome this problem, capsules filled costs of the health system caused by non-compliance with a solution of testosterone undecanoate in an oily 20 and increases the convenience of the patient in therapy.
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