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 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 /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. deliv were reported. Finally, less 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 after absorption istration, AerodiolTM is recommended for once daily admin in the and in the (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. 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 . 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 ) 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 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 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 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. described above. 0016. In another aspect, the present invention relates to a 0026. In one embodiment, the solutions of the invention or solution containing 0.01-0.9% (w/v) of estradiol, or an for use in the invention contain 10-30% ethanol (v/v), 70-90% equivalent amount of a pharmaceutically acceptable hydrate of isopropyl myristate or isopropyl palmitate and 0.01-0.9% or ester thereof, 5-30% (v/v) of a C-C alcohol and 70-95% estradiol, or an equivalent amount of a pharmaceutically (V/v) of an ester of a C-C alcohol and a C-C fatty acid for use in the manufacture of a medicament for the treatment of a acceptable hydrate or ester thereof. human female with reduced estradiol levels by oromucosal 0027. In one embodiment, the solutions of the invention or administration of a dose of said solution, said dose containing for use in the invention contain 0.01-0.5% (w/v) estradiol or 0.01-0.3 mg of estradiol, or an equivalent amount of a phar an equivalent amount of a pharmaceutically acceptable maceutically acceptable hydrate or ester thereof. hydrate or ester thereof. 0028. In yet another aspect, the present invention relates to 0017. The solutions of the invention may be administered a solution comprising estradiol, or an equivalent amount of a in a predetermined quantity by a number of administrations, pharmaceutically acceptable hydrate or ester thereof, as either at one point in time or at more points in time, selected specified herein, for the treatment, prevention or relief, or for such that the resulting estradiol serum levels mimic the use in the manufacture of a medicament for use in the treat normal levels throughout the day. Suitably, the solutions of ment, prevention or relief, of symptoms in a human female the invention may be administered in Such a manner as to caused by insufficient endogenous production of . restore the female's estradiol serum levels to normal values. Examples of these symptoms include headaches, , 0018. In accordance with these aspects of the invention, vasomotor symptoms (hot flushes), symptoms of urogenital therefore the dose may be administered by single or multiple atrophy, decrease in bone mineral density, and administrations as described below. The dose may have a increased risk or incidence of bone fractures. volume of 10 ul to 300 ul of said solution, preferably 25ul to 0029. In yet another aspect, the present invention relates to 100 ul—for example 25ul, 50 ul or 100 ul. a method of treating, preventing or relieving symptoms in a 0019. The human female may be treated with a dose of human female caused by insufficient endogenous production said solution at one or more points in time. The solutions of of estrogen, said method comprising the oromucosal admin the invention may be administered once daily or multiple istration of a solution comprising estradiol or an equivalent times daily, for example two, three, four, five or six doses per amount of a pharmaceutically acceptable hydrate or ester day. In some embodiments, multiple administrations may be thereof, as specified herein. Examples of these symptoms are given at regular periods of time, e.g. every hour or every two, as cited above. three, or four hours. 0030. In yet another aspect of the present invention, there 0020. In one embodiment, the dose may be administered is provided a solution of estradiol, as specified herein, for use intermittently in a time period that is in the range of 1 to 4 in the treatment or manufacture of a medicament for use in the hours, in particular at equal time intervals, for example at treatment of decreased estradiol levels in a human female by intervals of about 1, or 2, or 3, or of 4 hours. administration at one or more points in time via the oromu 0021 Typically, the solutions may be administered by 1-6 cosal route of a predetermined quantity of said solution by a doses per day, for example 1, 2, 3, 4, 5 or 6 doses per day, or single or multiple administration, said predetermined quan by 1-4 doses per day, or by 1-2 doses per day. tity representing a dose of 0.01-0.3 mg of estradiol, in a 0022. In a different aspect, the present invention relates to volume in the range of 10 ul to 300 preferably 25 ul to 100 a method of treatment of a human female with reduced estra ul for example 2550 ul or 100 ul. Administration of estra diol levels, said method comprising administering oromucos diol in this manner has been found to cause a controlled ally to a human female patient in need thereof, at one or more increase of estradiol serum levels that is proportional to the points in time, a dose of a solution containing 0.01-0.9% amount of estradiol administered. (w/v) of estradiol, or an equivalent amount of a pharmaceu 0031. In yet another aspect of the invention, there is pro tically acceptable hydrate or ester thereof, 5-30% (v/v) of a vided a non-aqueous (or Substantially non-aqueous) Solution C-C alcohol and 70-95%(v/v) of an esterofa C-C alcohol containing 0.01-0.9% (w/v) of estradiol, or an equivalent and a Cs-C fatty acid; wherein said dose is given by single amount of a pharmaceutically acceptable hydrate or ester or multiple administration and comprises 0.01-0.3 mg of thereof, 5-30% (v/v) of a C-C alcohol and 70-95% (v/v) of estradiol, or an equivalent amount of a pharmaceutically an ester of a C-C alcohol and a Cs-C fatty acid for use in acceptable hydrate or ester thereof. the treatment of a human female with hot flushes; wherein US 2016/0256473 A1 Sep. 8, 2016

said solution is administered by oromucosal, preferably buc 14, 16, 18, 20 or 22 ) such as, e.g. myristic acid, cal, buccomaxillary or buccogingival, administration as soon palmitic acid, , arachidic acid or oleic acid. C-C, as the hot flushes occurata dosage of 0.01-0.3 mg estradiol in alcohols comprise alcohols having from 2 to 6 carbon atoms a volume of said solution in the range 10-300 ul, preferably 25 (e.g. 2, 3, 4, 5 or 6 carbon atoms), in particular the C-C- ul to 100 ul; for example 25ul, 50 ul or 100 ul. alcohols as specified herein, as well as the homologs with 6 0032. In yet another aspect of the invention there is pro carbonatoms Such as hexanol, also including diols and triols, vided a solution of estradiol, as specified herein, for use in the Such as ethanol, isopropanol, propylene glycol, and glycerol. treatment or manufacture of a medicament for use in the 0043. Examples of of Cs-C fatty acids and C-C, treatment of decreased estradiol levels in a postmenopausal alcohols include isopropyl myristate, isopropyl palmitate and human female by administration at one or more points in time isopropyl Stearate. Examples of vegetable are sesame , via the oromucosal route of a predetermined quantity of said corn oil, castor oil and olive oil. Solution by a single or multiple administration ; Said prede 0044) The term “non-aqueous(or substantially non-aque termined quantity representing a dose of 0.01-0.3 mg of estra ous) as used herein means that the solution does not contain diol, thereby to elevate and/or keep the estradiol level in the water, or only a small amount of water, Such as less than 5%, female higher than 20, higher than 30, higher than 40 or or less than 3%, or less than 1%. higher than 50 pg/ml, and lower than 500 pg/ml, especially 0045. The term “v/v” refers to volume per volume, and between 50-500 pg/ml, during a required period of time. “w/v' to weight per volume. 0033. In yet another aspect, the present invention relates to 0046. The term “about’, when used in relation to a numeri a non-aqueous (or Substantially non-aqueous) solution con cal value, has the meaning generally understood in the rel taining 0.01-0.9% (w/v) of estradiol, or an equivalent amount evant art. In certain embodiments the term “about may be of a pharmaceutically acceptable hydrate or ester thereof, left out or may be interpreted to mean the numerical value 5-30% (v/v) of a C-C alcohol and 70-90% (v/v) of an ester +10%; or +5%; or +2%; or +1%. of a C-C alcohol and a C-C fatty acid. 0047. The present invention solution is administered oro 0034. In some embodiments, the C-C alcohol may be mucosally. This means the solution in a specific dose or ethanol and the ester of a C-C alcohol and a C-C fatty Volume is administered to the oral cavity and the active drug acid may be isopropyl myristate or isopropyl palmitate. Substance is Subsequently absorbed via one or more of the oromucosal (lingual, Sublingual, buccal, gingival, and pala DETAILED DESCRIPTION OF THE INVENTION tal) membranes. 0035) Any reference cited herein is hereby incorporated 0048. The solutions of the invention may be conveniently by reference. self-administered by the patient or administered by a physi 0036. As used herein, the term “subject” refers to a human cian, carer or nurse. being. The terms “subject' and “patient” are used inter 0049. The solutions may be administered in a single or changeably. multiple administration, meaning that a certain dose amount 0037. The terms “level”, “serum level”, “blood level, of estradiol is administered all at once or in one or more “plasma leveland “blood serum level” are used herein inter Sub-doses. For example, one puff of a spray Solution may be changeably. administered, representing the full desired dose, or one, two 0038. As used herein, the term “oromucosal” refers to or more puffs of a smaller dose may be administered, prefer buccal, buccomaxillary Sublingual, gingival, buccogingival ably shortly after one another. and palatal. 0050. In particular embodiments of this invention, the 0039. The term “solutions’ refers to solutions that are solutions contain from 0.01-0.9% (w/v), or from 0.05-0.8% liquid at ambient and body temperature. (w/v), or from 0.1-0.7% (w/v), or from 0.2-0.6% (w/v), or 0040. When used herein, the term “estradiol means from 0.3-0.5% (w/v), or from 0.1-0.4% (w/v), or from 0.1-0. 17-alpha-estradiol or 17-beta-estradiol. Preferred in the 3% (w/v) of estradiol or an equivalent amount of a pharma present invention is estradiol is in the form of 17-beta-estra ceutically acceptable hydrate or ester thereof. diol. The terms “estradiol and “estradiol derivatives” are 0051. The quantity of estradiol to be administered typi intended to cover estradiol itself as well as any pharmaceuti cally may be determined after measuring the estradiol serum cally acceptable hydrates, esters or derivatives thereof. The concentrations. Depending on the results of these measure term “pharmaceutically acceptable esters of estradiol refers ments, the physician can decide to prescribe an estradiol to esters of estradiol Such as, for example, , Solution of lower or higher concentration and/or the dosing , estradiol phenylpropionate, estradiol propi regimen can be individually adapted by either the dose as onate, estradiol enanthate, , estradiol such, or the Volume of the administrations, or the number of benzoate, , and estradiol administrations, or the frequency of daily administrations. Sulfamate. 0052. In particular embodiments of this invention, the 0041. The term "C-C alcohol refers to alcohols having solution contains from 5-30% (v/v), or from 10-30% (v/v), or from two to five carbon atoms, e.g. 2, 3, 4 or 5 carbon atoms. from 5-25% (v/v), or from 10-25% (v/v), or from 15-25% Particular subgroups of these are the monohydric saturated (v/v) of the C-Cs alcohol, preferably ethanol. branched or non-branched C-C alcohols such as for 0053. In the solutions of the present invention containing example ethanol. 1-propanol, isopropanol, butanol, pentanol ethanol, when presentina concentration of at least 10% (v/v), or the dihydric alcohols such as propylene glycol, or trihydric the ethanol not only acts as solvent, but also as an effective alcohols such as glycerol. antimicrobial preservative. This is advantageous because it 0042. The phrase “pharmaceutically acceptable esters of makes the use of and inclusion of other preservatives in Such Cs-C fatty acids and C-C alcohols' refers to Such esters Solutions Superfluous. and also includes Vegetable oils. Cs-C fatty acids comprise 0054. In one embodiment the solutions contain from fatty acids having from 8 to 22 carbon atoms (e.g. 8, 10, 12. 5-40% (v/v), or from 5-35% (v/v) of the C-C alcohol. Solu US 2016/0256473 A1 Sep. 8, 2016

tions with ethanol concentrations exceeding 30% (v/v) may increase of the estradiol blood serum levels that is propor cause irritation or other side effects, but these can be allevi tional to the amount of estradiol administered. ated by adding certain ingredients. 0063. The controlled increase of estradiol serum levels 0055. In particular embodiments of this invention, the may be between about 150-300 pg/ml for each 0.05 mg of solution contains from 70-95% (v/v) of an ester of a C estradiol administered, or between about 75-150 pg/ml for alcohol and a Cs fatty acid, or from 75-90% or from 80-8% each 0.025 mg of estradiol administered. of Such esters. 0064. The dosing regimen with the estradiol solutions of 0056. As mentioned above, the solutions of the invention this invention may avoid the administration of large doses may be administered in a predetermined quantity by a number thereby causing a peak level of estradiol, well above normal of administrations, either at one point in time or at more levels. The present dosing regimen avoids the local side points in time, selected Such that the resulting estradiol blood effects associated with frequent nasal administrations. Such serum levels mimic the normal levels throughout the day. as local irritation, itching, rhinorrhoea, Sneezing and nose Thus, the solutions of the invention may be administered in a bleeds. In addition, with the solutions of this invention lower predetermined quantity and by a number of administrations, doses can be administered as compared with aqueous cyclo either at one point in time or at more points in time, to increase dextrin formulations of estradiol, in particular the AerodiolTM the estradiol serum levels to normal values, in particular to formulation. levels that are higher than 20 pg/ml, or serum levels that are in 0065. The dosage regimen for estradiol administration of the range of 10-500 pg/ml, 50-100 pg/ml, or 100-500 pg/ml. the invention provides a physiological pharmacokinetic pro In one embodiment said serum levels are maintained for more file close to normal estradiol plasma levels. The dosage regi than 3 hours, preferably maintained at a level of higher than men of the invention moreover shows lower estradiol peak 20pg/ml for 3 hours. levels, while keeping the highest estradiol levels under 500 0057 The solutions of the invention may be administered pg/ml, and avoids the high peak serum levels seen with the once daily or multiple times daily, for example two, three, administration of nasal formulations. four, five or six times per day. In particular, multiple admin 0066. The present estradiol dose regimen (1) delivers a istrations may be given at regular periods of time, e.g. every similar or better bioavailability than nasal administration, (2) provides a dosage form whereby the dose can be individual hour or every two, three, or four hours. ized, (3) with a flexible dosage frequency, and (4) offers better 0058. In one embodiment, the dose may be administered patient compliance. intermittently in a time period that is in the range of 1 to 4 0067. In another embodiment, the solutions of the inven hours, in particular at equal time intervals, for example at tion comprise a further active drug Substance, Such as proges intervals of about 1, or 2, or 3, or of 4 hours. terone or another progestogen compound, for example in a 0059. The solution may be administered by 1-6 adminis range of 0.1-5% (w/v), 0.5-4% (w/v), 1-3% (w/v/) or 1.5%- trations per day, for example 1, 2, 3, 4, 5 or 6 administrations 2.5% (w/v). per day, or by 1-4 per day administrations, or by 1-2 admin 0068. In some embodiments, the solvent in the solutions of istrations per day. the invention may consist or consist essentially of 5-30% 0060. The solutions of the invention may be administered (v/v) of a C-C alcohol and 70-90% (v/v) of an ester of a in various ways, for instance by a spray or as drops. Devices C-C alcohol and a Cs-C fatty acid. In other embodiments, that can be used are (sterile or non-sterile) multi-dose or the solutions of the invention the solvent may consist or unit-dose containers or multi-dose or unit-dose sprays or drop consist essentially of 0.01-0.9% (w/v) of estradiol or an devices or any other container or pen from which a specific equivalent amount of a pharmaceutically acceptable hydrate volume of e.g. 25ul, 50 ul etc. can be transferred to the oral or ester thereof, 5-30% (v/v) of a C-C alcohol and 70-90% cavity. Devices to administer the estradiol solutions of the (v/v) of an ester of a C-C alcohol and a Cs-C fatty acid. invention include glass bottles with a spray device, but any 0069. In addition, the solutions of the invention may also other device (with or without the use of propellants) for include a Sweetener or flavoring agent, for example in a administration of Volumes in the range of 25ul to 120 ul, e.g. concentration of 1-5% (w/v), Examples of sweeteners or fla 25ul, 50 ul, 70 ul, 90 ul, 100 ul or 120 ul. When using a spray, Voring agents can be found in the pharmaceutical literature. any kind of device known in the art having a capacity in the For instance Saccharin can be added to the Solutions. Any of range of about 25-200 ul per dose (or puff), e.g., about 50, 75, the ingredients to be added preferably are in the list of GRAS 100, 125, 150, 175 ul. Also drop dispensers or dosage pens (generally regarding as being safe) list of chemicals used in may be suitable to administer the solutions to the oral cavity pharmaceutical preparations and those that are currently of the patient. allowed in topical and parenteral formulations. 0061. In certain embodiments, the present invention solu 0070. In other embodiments the present invention solution tion comprises per dosage Volume, administered for example may contain also antioxidants, viscosity enhancers, viscosity per drops, dosage pen, or spray, a dose of estradiol in the range modulators, Surfactants and excipients regulating the adher of 10-300 ug of estradiol, such as 25-300 g of estradiol, e.g. ence of the solution the mucous membranes in the oral cavity. 50-300 ug of estradiol. Typically the dose per dose comprises All those excipients are known from the pharmaceutical lit 10-200 ug of estradiol, such as 10-100 ug of estradiol or erature (for instance Remington: The Science and Practice of 25-100 ug of estradiol. As a daily dose total amounts of Pharmacy, 21th edition, PA Lippincott Williams & Wilkins, 100-600 ug of estradiol, preferably 100-300 lug of estradiol 2005). may be administered. 0071. A propellant may be added where the solution is 0062. This invention also relates to the use of a solution of adapted for delivery in spray form. Suitable propellants estradiol, as specified herein, in the treatment of decreased include hydrogen-containing chlorofluorocarbons, hydro estradiol levels in a female by oromucosal administration of a gen-containing fluorocarbons such as heptafluoroethane, predetermined quantity of said solution, causing a controlled dimethylfluoropropane, tetrafluoropropane, butane, isobu US 2016/0256473 A1 Sep. 8, 2016 tane, dimethyl ether, diethyl ether and any other non-CFC and (0079 Serum progesterone levels from 5 to 30 ng/ml (15 CFC propellants. A preferred propellant is 1,1,1,2-tetrafluo 90 nmol/L) are considered representative of luteal phase roethane (HFA 134a). progesterone levels, but also levels of 2-20 ng/ml (6-60 nmol/ 0072 The present invention relates to a solution of estra L) can be found in the literature. No specific levels needed to diol for use in the treatment of decreased estradiol levels in a provide an adequate endometrial protection to estrogen female subject by administration via the oromucosal route of replacement therapy in postmenopausal women are known, a predetermined quantity of said solution, by a single or but are expected to be approximately 2 ng/ml and higher. multiple administration, at one or more points in time, said 0080. In a further aspect, the invention provides a formu quantity representing a dose of 0.01-0.3 mg of estradiol, lation in the form of a solution as described herein, compris thereby causing an increase of the estradiol serum levels that ing a non-aqueous Solution of progesterone in a concentration is proportional to the amount of estradiol administered. of 0.1-5% for oromucosal administration. By administration 0073. In another aspect, the present invention relates to an of a predetermined quantity of said solution, by a single or estradiol Solution, as specified herein, for treating, alleviat multiple administration, at one or more points in time, said ing, relieving, or preventing a physical condition in a female quantity, representing a dose of 0.1-3 mg of progesterone, it is Subject caused by deficient (insufficient) endogenous blood possible to obtain an increase of the progesterone serum levels of estradiol. Such as headaches, nausea, depression, levels that is proportional to the amount of progesterone vasomotor symptoms (hot flushes), symptoms of urogenital administered. The increase in progesterone serum level may atrophy, loss of , decrease in bone mineral density, be approximately 0.3-2 ng/ml per 0.1 mg progesterone (or osteoporosis or increased risk or incidence of bone fractures. approximately 1-6 mmol/L per 0.1 mg progesterone). 0074. In a preferred embodiment of the invention, the 0081 Embodiments of this invention concern for instance female subject to be treated is a woman with a deficient (too 1.5% (w/v) progesterone oromucosal Solutions comprising low) level of estradiol, which is common during the meno 150 mg progesterone, 3.0 ml ethanol, and 7.0 ml ml isopropyl pause and postmenopause. In women in the reproductive age, myristate. 100 ul of such solutions represents 1.5 mg of normal estradiol levels range from 100-500 pg/ml during progesterone, 50 ul represents 0.75 mg, while 25ul represents different parts of the menstrual cycle. 0.375 mg progesterone. 0075. In early , estradiol levels are lower than I0082. Other embodiments concern liquid solutions con 100 pg/ml and in late menopause decrease to 10-20 pg/ml. taining progesterone dissolved in solvents comprising etha Value ranges of normal estradiol levels under 100 pg/ml can nol and/or other C-C alcohols and esters ofisopropyl alco be associated with hot flushes, and may signal menopause. hol and/or other C-C alcohols and Cs-C fatty acids. Menopause is the end of menstruation, which results from a I0083. Such formulations can be administered indepen reduced production of estrogen. During the menopause the dently from the estradiol administration, or at the same time. number of follicles falls below a certain threshold, the ovaries I0084 Compositions in the form of a solution containing can no longer produce mature follicles and sex hormones. As both estradiol and progesterone may be useful products for a consequence the ability to reproduce ends with menopause. treating postmenopausal women with an intact endometrium The average age at which women go through the menopause and Such compositions may also be useful contraceptive is about 45-50 years. Because life expectancy is getting products. I0085 Hence, in a further aspect, there is provided a non longer, women can now expect to be for a large part of their aqueous (or Substantially non-aqueous) solution containing lives in the post-menopausal stage. 0.01-0.9% (w/v) of estradiol, or an equivalent amount of a 0.076 Inafurther embodiment of the invention, the female pharmaceutically acceptable hydrate, or ester thereof, and 0.1 subject to be treated with the estradiol solution according to to 5% (w/v) of progesterone, 10-30% (v/v) or 5-40% (v/v) of the invention is a hysterectomised woman. After total hyster a C-C alcohol, and 70-90% (v/v) or 60-95%(v/v) of an ester ectomy with removal of both ovaries, hormone production of ofa C-C alcohol and a Cs-C fatty acid, for the treatment of (estradiol) and (progesterone) stops a female with reduced estradiol levels, or for the manufacture completely. of a medicament for the treatment of a female with reduced 0077. In women with an intact endometrium the use of estradiol levels, by oromucosal administration of a dose of estradiol monotherapy stimulates the proliferation of the said solution, said dose containing 0.01-0.3 mg of estradiolor endometrium. It is important to realize that also the opposing an equivalent amount of a pharmaceutically acceptable effect of progesterone, which terminates the proliferation of hydrate, or an ester thereof, and also containing 0.1-3 mg of the endometrium, is absent in postmenopausal women. Since progesterone, by single or multiple administration, at one or hyperplasia of the endometrium is a risk factor in the devel more points in time. opment of , the endometrium of women on 0086. Another aspect concerns a non-aqueous (or Substan estradiol monotherapy should be protected by co-administer tially non-aqueous) solution containing 0.01-0.9% (w/v) of ing a progestogen, continuously or in a cyclic dosage regi estradiol, or an equivalent amount of a pharmaceutically acceptable hydrate, or ester thereof, and 0.1 to 5% (w/v) of C. progesterone, 10-30% (v/v) of a C-C alcohol, and 70-90% 0078. It may therefore be advantageous to use a progest (v/v) of an ester of a C-C alcohol and a Cs-C fatty acid. erone solution for oromucosal co-administration in post I0087. One embodiment concerns a non-aqueous (or sub menopausal women in combination with the estradiol solu stantially non-aqueous) solution containing 0.01-0.9% (w/v) tions of the present invention. Such progesterone solution can of estradiol, or an equivalent amount of a pharmaceutically for instance be a solution containing 0.1-5% (w/v) progest acceptable hydrate, or ester thereof, and 0.1 to 5% (w/v) of erone in a solvent comprising 10-30% (v/v) of a C-C alco progesterone, 10-30% (v/v) of ethanol, and 70-90% (v/v) of hol and 70-90% (v/v) of an ester of a C-C alcohol and a isopropyl myristate. Cs-C fatty acid, e.g. a solution of ethanol and isopropyl I0088. The invention also concerns a product comprising or myristate. In particular embodiments, said solution contains containing a solution of estradiol, as specified herein, and a 0.5-4% (w/v), or 1-3% (w/v) progesterone. Solution of progesterone, as described herein, as a combined US 2016/0256473 A1 Sep. 8, 2016 preparation for simultaneous, separate or sequential use for Example 6 the treatment of a female with reduced estradiol levels. 0089. The solutions of the present invention are superior in Estradiol Levels Upon Administration of Solutions enhancing the oromucosal absorption of estradiol. The of the Invention. present invention consists of a solution that is completely water-free, contains ethanolenisopropyl myristate (or palmi I0121 Ranges of normal estradiol levels are expressed in tate), and these components all contribute to the oromucosal ng/1 or pg/ml of estradiol (272 ng/l=272 pg/ml=1 nmol/l). absorption efficiency and total bioavailability of estradiol I0122. In women in the reproductive age, normal estradiol being Surprisingly twice as good as the oromucosal levels range from 100-500 pg/ml during different parts of the AerodiolTM administration. menstrual cycle. 0090 The invention is illustrated by the following, non I0123. In early menopause, estradiol levels are lower than limiting, examples. 100 pg/ml and in late menopause decrease to 10-20 pg/ml. Value ranges of normal estradiol levels under 100 pg/ml can EXAMPLES be associated with hot flushes, and may signal menopause. 0.124. These experiments were carried out in individual Example 1 cases in postmenopausal women. Serum levels of estradiol were measured 30 minutes (between 25-35 minutes) after Estradiol Spray 0.3% administering several doses of estradiol (by administering the buccal sprays described in examples 1 and 3). Results: 0091) Estradiol 30 mg 0092 Ethanol 2 ml 0093) Isopropyl Myristate 8 ml Estradiol-dose Formulation Estradiol level Increase per 101g 0094) 100 ul=300 ug 25 Jug (example 3) 101 pg/ml 40 pg/ml 0.095 50 ul=150 ug 150 g (example 1) 715 pg/ml 48 pg/ml 0096 25ul=75ug 75 ug (example 1) 339 pg/ml 45 pg/ml 150 g (example 1) 704 pg/ml 47 pg/ml Example 2 100 g (example 3) 412 pg/ml 41 pg/ml 75 ug (example 3) 302 pg/ml 40 pg/ml Estradiol Spray 0.2% 0097. Estradiol 20 mg 0.125. The increase of the estradiol serum level per 10 ug 0098. Ethanol 1.5 ml estradiol dose was found to vary between about 40-50 pg/ml. 0099 Isopropyl Myristate 8.5 ml For instance the increase is about 700 pg/ml per 150 ug 0100 100 ul=200 ug estradiol dose. 0101 50 ul=100 ug 0.126 These levels were compared with the levels from the 0102 25ul=50 ug literature achieved with nasal AerodiolTM, which is an aque ous solution of an estradiol-cyclodextrin complex. The mean Example 3 peak serum level (Cmax) obtained with AerodiolTM is approximately 1400 pg/ml after a dose of 300 ug estradiol, Estradiol Spray 0.1% given as 2 nasal sprays of 150 Lug (one in each nostril), and this level is between 600-800 pg/ml after a single nasal spray of (0103) Estradiol 10 mg 150 ug estradiol (Devissaguet et al. Eur. J. Drug Metabol. 01.04 Ethanol 1 ml Pharmacokinetics 1999:24:265-271). 0105 Isopropyl Palmitate 9 ml 0127 Serum estradiol levels obtained after oromucosal 0106 100 ul=100 ug administration of the present invention Solutions are very 01.07 50 ul=50 ug similar, indicating that the estradiol amount absorbed from 0108) 25ul=25 ug the oromucosal spray in the oral cavity is similar to the amounts of estradiol absorbed in the nose upon nasal admin Example 4 istration of the product AerodiolTM. I0128. However, the published product characteristics of Estradiol Spray 0.05% AerodiolTM disclose, that when AerodiolTM is taken (in women with a blocked nose) by the oromucosal route, the 0109 Estradiol 5 mg estradiol absorption, and thus the Cmax and AUC are reduced 0110 Ethanol 2 ml to 50%. Women with a blocked nose have to take a double 0111 Isopropyl Palmitate 8 ml amount of the AerodiolTM spray. This means that the estradiol 0112 100 ul=50 ug from the solutions of the present invention is absorbed via the 0113 50 ul=25 ug oromucosal route twice as good, which is a Surprising result 0114 20 ul-10 ug (Table 1). Example 5 TABLE 1 Estradiol Spray 0.4% Comparison of AUC and Cmax using a similar dose of estradiol 0115 Estradiol 40 mg FORMULATION AUC Cmax 0116 Ethanol 1.5 ml Aerodiol TM taken as nasal spray 100% 100% 0117 Isopropyl Myristate 8.5 ml (aqueous) 0118 100 ul=400 ug Aerodiol TM taken as oromucosal spray SO% SO% 0119 50 ul=200 ug (aqueous) 0120 25ul=100 ug US 2016/0256473 A1 Sep. 8, 2016

TABLE 1-continued 1-20. (canceled) 21. A method of treating a human female patient having Comparison of AUC and Cmax using a similar dose of estradiol reduced estradiol levels, said method comprising administer FORMULATION AUC Cmax ing oromucosally to a human female patient in need thereof one or more doses of a solution comprising 0.01-0.9% (w/v) Estradioloromucosal spray 100% 100% of estradiol, or an equivalent amount of a pharmaceutically (present invention, non-aqueous) acceptable hydrate or ester thereof, 5-30% (v/v) of ethanol and 70-95% (v/v) of an ester of a Calcohol and a Cs fatty 0129. In other experiments 4 postmenopausal women acid; wherein said dose comprises 0.01-0.3 mg of estradiol, or received as a buccal spray 2x25ul estradiol 0.2% (example an equivalent amount of a pharmaceutically acceptable 2), representing a dose of 100 ug estradiol. Serum levels of hydrate or ester thereof, wherein the solution is administered estradiol during 3 hours were as follows (Table 2): 1-6 times per day by spray, by drops or by a dosage pen, and wherein the Solution does not contain water. TABLE 2 22. The method according to claim 21, wherein a volume Time in Mean estradiol Standard Deviation between about 10-500 ul of the estradiol solution is adminis minutes level in pg/ml (SD) in pg/ml tered per dose. 23. The method according to claim 21, wherein said dose is O 45 (40) 10 285 (85) administered intermittently in a time period in the range 1 to 15 416 (114) 4 hours. 30 483 (98) 24. The method according to claim 21, wherein the eleva 40 468 (61) 60 364 (48) tion and control of the estradiol levels in the female patient 90 275 (46) results in treating, preventing or relieving symptoms caused 120 172 (38) by insufficient endogenous production of estrogen, such as 18O 120 (32) headaches, nausea, vasomotor symptoms (hot flushes), symptoms of urogenital atrophy, decrease in bone mineral density, osteoporosis and increased risk or incidence of bone CONCLUSIOSN fractures. 0130. The results show that the mean estradiol level 25. The method according to claim 21, wherein the solution remains above 100 pg/ml for more than 3 hours, indicating comprises 10-30% (v/v) of ethanol and 70-90% (v/v) of said that a dosage regimen comprising a dose of 100 g estradiol ester. administered oromucosally, using a spray bottle containing 26. The method according to claim 21, wherein the C the present invention solution (example 2), is protecting alcohol is selected from ethanol. 1-propanol, isopropanol, women for more than 3 hours from hot flushes, which are butanol, pentanol, hexanol, propylene glycol, and glycerol; associated with levels under 100 pg/ml. This protection and the Cs fatty acid is selected from myristic acid, palm would be even longer if the hot flushes are associated with itic acid, Stearic acid, arachidic acid and oleic acid. estradiol levels under 50 pg/ml. 27. The method according to claim 21, wherein the ester of 0131 Further, whena oromucosal dose of 100 ugestradiol the Cs fatty acid and C alcohol is isopropyl myristate, would have been given 2-4 times a day, with a dosing interval isopropyl palmitate or isopropyl Stearate. of 3-4 hours, for most of the day, women would be protected 28. The method according to claim 21, wherein the ester of from hot flushes, associated with estradiol levels under 50 or the Cs fatty acid and C alcohol is a vegetable oil, such as 100 pg/ml sesame oil, corn oil, castor oil or olive oil. 0132) The results also provide evidence, that the AUC 29. The method according to claim 21, comprising 0.01-0. (Area Under the Curve of the serum levels) measured after two, three or four estradiol oromucosal administrations of 9% of estradiol (w/v), 10 -30% (v/v) ethanol (v/v) and respectively 150 Lig, 100 g and 75ug is approximately simi 70-90% (v/v) isopropyl myristate. lar to the total AUC after nasal estradiol application of 300 ug 30. The method according to claim 21, wherein the ratio of nasal estradiol (AerodiolTM). This indicates that the oromu the Volumes of said ethanol to said ester of a C- alcohol and cosal estradiol spray described in the present invention is a C fatty acid is 30:70, 25:75, 20:80, 15:85, or 10-90 bioequivalent to the nasal AerodiolTM product that has been (v/v%). approved by the regulatory authorities in in 2001.