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Phosphodiesterase Inhibitors Applied Via the Transvaginal Route for the Treatment of Infertility

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Phosphodiesterase Inhibitors Applied Via the Transvaginal Route for the Treatment of Infertility (19) TZZ __T (11) EP 2 724 716 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 153(4) EPC (43) Date of publication: (51) Int Cl.: 30.04.2014 Bulletin 2014/18 A61K 9/00 (2006.01) A61K 9/06 (2006.01) A61K 47/10 (2006.01) A61K 47/18 (2006.01) (2006.01) (2006.01) (21) Application number: 12742928.0 A61K 47/32 A61P 15/08 (22) Date of filing: 20.06.2012 (86) International application number: PCT/ES2012/070453 (87) International publication number: WO 2012/175775 (27.12.2012 Gazette 2012/52) (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • Pardina Palleja, María Carmen GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO 08022 Barcelona (ES) PL PT RO RS SE SI SK SM TR •Vaz-Romero Uña, Miguel Ángel 08017 Barcelona (ES) (30) Priority: 23.06.2011 ES 201131059 (74) Representative: Sugrañes Patentes y Marcas (71) Applicants: Calle Provenza 304 • Pardina Palleja, María Carmen 08008 Barcelona (ES) 08022 Barcelona (ES) •Vaz-Romero Uña, Miguel Ángel 08017 Barcelona (ES) (54) PHOSPHODIESTERASE INHIBITORS APPLIED VIA THE TRANSVAGINAL ROUTE FOR THE TREATMENT OF INFERTILITY (57) The present invention relates to a new applica- vaginal administration of a phosphodiesterase inhibitor tion of phosphodiesterase inhibitors for couple infertility immediately before and/or after coitus. It also relates to treatment which forms an effective alternative to the in- dosage forms suitable for the intravaginal administration vasive assisted reproductive techniques such as conju- of phosphodiesterase inhibitors. gal artificial insemination and which consists of the trans- EP 2 724 716 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 724 716 A1 Description Technical Field 5 [0001] The present invention relates to an alternative to the invasive assisted reproductive techniques for infertility treatment by administrating a phosphodiesterase inhibitor transvaginally. State of the Prior Art 10 [0002] In developed countries it is calculated that approximately 15% of the couples wishing to conceive a child have difficulties for achieving same. A couple is considered infertile if the couple was incapable of conceiving after having unprotected sexual relationships for at least 12 months. As described, for example, in the document by Dohle et al., Guidelines on Male Infertility (update 2010) published by the European Association of Urology, it is estimated that a male infertility factor is found in approximately 50% of the infertile couples. Male infertility is mainly caused by poor 15 semen quality due to causes which may be very heterogeneous therefore, in practice, the cause of male infertility is often unknown and is often referred to as idiopathic infertility. In these cases, an empirical medical treatment can be resorted to but said treatments tend to be long with varying effectiveness and are always accompanied by the risk of side effects associated with any prolonged oral pharmacological treatment. Therefore, it is often considered that the best option for these couples is to resort to assisted reproductive techniques in attempt to have offspring. 20 [0003] Assisted reproductive techniques which infertile couples tend to resort to are conjugal artificial insemination (CAI) and in vitro fertilization (IVF). CAI consists of inseminating the semen of the couple itself previously subjected to a sperm capacitation process by intrauterine route so that the sperm acquire the ovule fertilizing capacity. IVF is based on extracting oocytes from the woman and fertilizing them in vitro with sperm from the partner which are also previously capacitated. 25 [0004] Even though the assisted reproductive techniques have become a very common practice in our society over the last decades they still have a series of drawbacks. [0005] First, assisted reproductive techniques are invasive techniques which necessarily require medical intervention to achieve conception and which can be troublesome for couples, beside the fact that, inevitably, pregnancy stops being the result of spontaneous sexual intercourse between a couple. Furthermore, said techniques have a high cost and a 30 moderate percentage of success. Therefore, the article by Hernández et al., Registro de IAC-IAD de la Sociedad Española de Fertilidad (CAI-AID Register of the Spanish Society of Fertility). Year 2003, Revista Iberoamericana de Fertilidad y Reproducción Humana (Iberoamerican Magazine of Human Fertility and Reproduction), 2007, 24 (4): 229-240, for example, compiles the data from insemination registers (conjugal artificial insemination CAI and artificial insemination by donor or AID) collected by the Spanish Society of Fertility in 2003 from the data supplied by 95 centers throughout 35 Spain, and it is observed that for couple insemination or CAI, the pregnancy rate is 14.7%. For the above reasons, it is found that many couples are reluctant to undergo the assisted reproductive techniques. [0006] Within the scope of assisted reproductive techniques, the state of the art describes the in vitro use of pentoxi- fylline, a non-specific phosphodiesterase enzyme inhibitor, for the treatment of sperm samples due to its sperm motility improving capacity for the purpose of improving the capacitation of sperm intended to be used in said techniques either 40 for in vitro fertilization or for artificial insemination, as described, for example, in the article by Minhas et al., Effectiveness of pentoxifylline in semen preparation for intrauterine insemination, Hum. Reprod., 1996, 11 (6): 1236-9. [0007] Likewise, the in vitro effect of selective phosphodiesterase PDE1 and PDE4 inhibitors in sperm extracts has also been studied. Selective PDE4 inhibitors increase sperm motility whereas selective PDE1 inhibitors stimulate acro- some reaction, such as described in the article by Fisch et al., Enhancement of motility and acrosome reaction in human 45 spermatozoa: differential activation by type specific phosphodiesterase inhibitors, Hum. Reprod. 1998; 13 (5): 1248-54. [0008] On the other hand, the article by Aparicio et al., Pentoxifylline (BL 191) by oral administration in the treatment of asthenozoospermia, Andrology, 1980,12 (3): 228-31, describes the oral administration of pentoxifylline for treating men with asthenozoospermia or low sperm motility. Said article describes a study where a high dose of pentoxifylline was administrated to a group of 15 infertile men with asthenozoospermia, 1200 mg daily for four months. A substantial 50 improvement in sperm motility of the subjects treated was observed, and 2 pregnancies (13.3%) were counted after the treatment. However, treatment with oral pentoxifylline, as typically occurs with any continuous pharmacological treatment, entails a certain risk of adverse effects, particularly, among other possible side effects, it has been described that pentoxifylline can induce hypotension and arrhythmias. Spanish Patent Application ES-A-2245609 describes that pen- toxifylline or its metabolites can cause mutagenic effects. 55 [0009] International Patent Application WO-A-2004/037262 describes the transvaginal administration of phosphodi- esterase inhibitors for the purpose of stimulating female sexual desire. [0010] Therefore, there is still a need to provide an alternative for treating couple infertility, simple to use and non- invasive, respecting couple intimacy and the natural conception process, while being effective, safe and economical. 2 EP 2 724 716 A1 Object of the Invention [0011] The object of the invention is the use of a phosphodiesterase inhibitor for preparing a medicament intended for the transvaginal treatment of couples with infertility. 5 [0012] Another object of the invention is a phosphodiesterase inhibitor for use in the transvaginal treatment of couples with infertility. [0013] Another object of the invention is a pharmaceutical composition of a phosphodiesterase inhibitor. [0014] Another object of the invention is a kit including the composition of a phosphodiesterase inhibitor. 10 Detailed Description of the Invention [0015] The purpose of the present invention is to provide a phosphodiesterase inhibitor administered transvaginally for use in treatment of couples with infertility. [0016] The authors of the present invention have developed a new use for phosphodiesterase inhibitors through 15 transvaginal administration, which is significantly effective for infertility treatment, providing a safe, economical and easy- to-use treatment, whereby it forms an efficient and non-invasive alternative to the assisted reproductive methods. Phosphodiesterase inhibitors 20 [0017] Phosphodiesterase inhibitors are a group of drugs which inhibit the action of the enzymes from the family of cyclic-nucleotide phosphodiesterases (PDEs) that catalyze the hydrolysis of the inner phosphate bond of the cyclic monophosphate nucleotides cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate). Thus Phosphodiesterase inhibitors act inhibiting the metabolism of second intercellular messengers cAMP and cGMP. [0018] The family of phosphodiesterases is made up of 11 groups sequentially known as phosphodiesterase 1 (PDE1) 25 to phosphodiesterase 11 (PDE11). Such drugs are selective inhibitors, i.e., drugs specifically inhibiting some of said groups, as well as other drugs which are known as non-specific or non-selective phosphodiesterase inhibitors, i.e., drugs simultaneously inhibiting more than one phosphodiesterase, have been described. [0019] Within the scope of the present invention, the term phosphodiesterase
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