US 2016O256473A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0256473 A1 Merkus (43) Pub. Date: Sep. 8, 2016 (54) OROMUCOSAL LIQUIDESTRADIOL Publication Classification COMPOSITIONS (51) Int. Cl. (71) Applicant: INNOTESTO BVBA, Kasterlee (BE) A613 L/565 (2006.01) A647/4 (2006.01) (72) Inventor: Franciscus Wilhelmus Henricus Maria A647/10 (2006.01) Merkus, Kasterlee (BE) A619/00 (2006.01) A619/08 (2006.01) (21) Appl. No.: 15/155,410 (52) U.S. C. 1-1. CPC ............... A61 K3I/565 (2013.01); A61 K9/006 (22) Filed: May 16, 2016 (2013.01); A61 K9/08 (2013.01); A61K 47/10 Related U.S. Application Data (2013.01); A61 K47/14 (2013.01) (63) Continuation of application No. 14/370,435, filed on (57) ABSTRACT Jul. 2, 2014, filed as application No. PCT/EP2013/ 050110 on Jan. 4, 2013. The present invention relates to low dose estradiol solutions for oromucosal administration Suitable in replacement (30) Foreign Application Priority Data therapy or suppletion of low estradiol levels and also for preventing, alleviating or treating symptoms associated with Jan. 4, 2012 (GB) ................................... 12OOO62.6 low endogenous levels of estradiol in female Subjects. US 2016/0256473 A1 Sep. 8, 2016 OROMUCOSAL LIQUIDESTRADIOL 0007 Formulations of dimethyl-3-cyclodextrin com COMPOSITIONS plexes of 17 B-estradiol and/or progesterone in an aqueous solution for nasal application have been described in EP 0001. The present invention relates to low dose estradiol 0349091. One such formulation containing 17 B-estradiol Solutions for oromucosal administration Suitable in replace complexed in methylated-p-cyclodextrin has been authorized ment therapy or suppletion of low estradiol levels and also for for medical use under the trade name AerodiolTM. This nasal preventing, alleviating or treating symptoms associated with spray product, administered in a low dose of 300 ug/day, was low endogenous levels of estradiol in female Subjects. as effective as a 2 mg oral tablet/day in treating menopausal symptoms. It showed reduced adverse effects, i.e. fewer inci BACKGROUND OF THE INVENTION dences of mastalgia and withdrawal bleedings. Furthermore, beneficial effects on Some lipid parameters, on markers of 0002 Current estradiol therapy includes oral, transder bone resorption, bone formation and bone mineral density mal, injectable and vaginal formulations. Transdermal deliv were reported. Finally, less breast tenderness was found with ery comprises patches, gels, lotions and sprays, while Vaginal intranasal administration of estradiol as compared to oral products include Suppositories, creams, and rings. treatment. 0003) Estradiol, when taken orally as tablets, pills or cap 0008 Because of the side effects of frequent nasal admin Sules, is converted for a large part to estrone after absorption istration, AerodiolTM is recommended for once daily admin in the gastrointestinal tract and metabolism in the liver (first istration in a high dose resulting in high peak estradiol levels. pass metabolism). This causes an imbalance in the estradiol/ These are reached within 10-30 min. and the levels return to estrone ratio, which is normally 1:1 in premenstrual women. 10% of the peak value in about two hours after administration This imbalance is mainly responsible for a change in lipids (Devissaguet et al., Eur. J. Drug Metabol. Pharmacokinetics and clotting factors. Non-oral products (transdermal, vaginal) 1999; 24; 265-271). This means that once daily intranasal avoid this hepatic first-pass metabolism and therefore are administration of AerodiolTM results in a “pulsatile' profile, considered first choice in estradiol Suppletion. comprising one large peak per day, followed by a period 0004. In general, it is advisable to use the lowest dose of during which estradiol levels remain at a low level. Peak the hormone estradiol possible, because overdosing may lead levels after administration of 300 g estradiol by the required to side effects related to unphysiological hormone levels. quantity of AerodiolTM nasal spray reach values of 1400 Low-dose non-oral products are first choice because of (1) the pg/ml. Normal estradiol levels differ slightly per laboratory, low-dose administered, (2) the physiological ratio between but range from 100-500 pg/ml during a menstrual cycle. This levels of estradiol and its metabolite estrone, and (3) as a means that the peak level of 1400 pg/ml, obtained with nasal consequence the decreased risk of adverse effects. The use of AerodiolTM, is about 3 times higher than the highest normal very low doses may also be beneficial as opposed treatment levels in premenopausal women. (continuous or cyclic co-administration of a progestogen) is 0009. A further disadvantage related to nasal administra not an absolute requirement because the endometrium does tion is that the access to the nasal mucosa can be compro not proliferate upon administration of very low doses of estra mised in instances such as common cold or allergy resulting diol. in a running or blocked nose. This results in inconsistent or 0005. In the research into new estradiol products, non-oral even no nasal absorption. The product characteristics of administration has been considered, including products for AerodiolTM teach that in that instance the patient, should nasal and oromucosal administration. U.S. Pat. No. 5,955, administer a double dose of AerodiolTM via the oromucosal 098 discloses a buccal aerosol spray, comprising a propellant route to reach similar estradiol serum levels. 50-95%, a non-polar solvent 5-50%, the active drug com 0010 Moreover, nasal administration may give rise to pound 0.001-15% (including estradiol), and a flavoring agent local side effects in the nose, such as local irritation, itching, 0.05-5%. U.S. Pat. No. 6,110,486 discloses a buccal spray rhinorrhoea, Sneezing and nosebleeds. Multiple nasal admin containing estradiol, dissolved in a pharmacologically istrations increase these undesired side effects. acceptable polar solvent, comprising in weight '% of total 0011. It is a first object of the invention to avoid nasal composition: polar solvent 75-99.8%, active compound 0.68 administration of estradiol and the side effects associated 40%. As solvents for the sprays there are used low molecular therewith. weight polyethylene glycols (PEG) of 200-1000 MW (pref 0012. It is a second object of the invention to provide an erably 200-600) and also low molecular weight alcohols and estradiol composition for oromucosal administration that polyols, such as glycerin and water. Illustrated is a spray does not require the administration of high doses of estradiol. formulation containing estradiol and 85% polyethylene gly Such as for example the double dose required for oromucosal col. However, this solvent has a bitter, burning taste in the administration of AerodiolTM. mouth, making a spray, based mainly on Such an ingredient, 0013 Further, it is an object of the invention to provide a poorly acceptable for chronic use. new dosage regimen for estradiol administration that pro 0006 US 2011/0097405 discloses an oromucosal estra vides a physiological pharmacokinetic profile approaching diol product, which is absorbed mainly in the oral cavity and normal estradiol plasma levels. A particular object is the not in the gastro-intestinal tract. It is a water-soluble film, provision of a dosage regimen with low estradiol peak levels, called wafer. Such wafers containing estradiol in a low dose in particular a regimen that keeps the highest estradiol levels dissolve quickly in the mouth, thereby releasing estradiol. under 500 pg/ml, and avoids the high peak serum levels seen which then can be absorbed via the oromucosal route. Buccal with the administration of existing nasal formulations. tablets comprisingestradiol are disclosed in EP 0371466 and 0014. It is also an object of the invention to provide a new WO 2010/089078. Medicated papers for oromucosal admin and improved dosage form comprising a low dose estradiol istration containing estradiol and a cyclodextrinare described formulation, for application to the oral mucosa, that (1) deliv in EP 1867 321. ers a similar or better bioavailability than nasal administra US 2016/0256473 A1 Sep. 8, 2016 tion, (2) provides a dosage form whereby the dose can be (0023 The dose may have a volume of 10 ul to 300 ul of individualized, (3) with a flexible dosage frequency and (4) said solution, preferably 25ul to 100 ul—for example 25ul, offers better patient compliance. 50 ul or 100 ul. 0024. The oromucosal administration can be by a spray, a SUMMARY OF THE INVENTION dosage pen or a device delivering drops. Thus in a further aspect, the invention provides a dosage form comprising a 0015. In one aspect, the present invention relates to a non spray, a dosage pen or a device delivering drops containing aqueous (or Substantially non-aqueous) solution containing the solution as specified herein. 0.01-0.9% (w/v) of estradiol, or an equivalent amount of a 0025. The estradiol solutions of the invention can be used pharmaceutically acceptable hydrate or ester thereof, 5-30% in a dosage regimen that can be individually adapted by one or (v/v) of a C-C alcohol and 70-95% (v/v) of an ester of a more of the following: 1. by the dose as such, 2. the volume of C-C alcohol and a C-C fatty acid for use in the treatment the sprays or drops, 3. the number of sprays or drops, 4. by a of a human female with decreased estradiol levels by oromu single or multiple administration, 5. at one or more points in cosal administration of a dose of said solution, said dose time, and 6. by the frequency of the daily administrations. The containing 0.01-0.3 mg of estradiol, or an equivalent amount Solution may be administered according to the regimens of a pharmaceutically acceptable hydrate or an ester thereof.