BR122020021470B1 - ORODISPERSIBLE DOSAGE UNIT CONTAINING ESTETROL MONOHYDRATE, PREPARATION PROCESS AND USE THEREOF - Google Patents

Abstract

The invention provides an orodispersible solid pharmaceutical dosage unit having a weight between 30 and 1,000 mg, said dosage unit containing at least 100 μg of an estetrol component selected from estetrol, estetrol esters and combinations thereof; wherein the solid dosage unit can be obtained by a process comprising: ? providing an aqueous liquid comprising water, estetrol component and optionally one or more other pharmaceutically acceptable ingredients; ? mixing 1 part by weight of the aqueous liquid with 0.5-20 parts by weight of the carrier particles to produce wet particles; ? remove water from wet particles to produce charged particles; ? optionally mixing the charged particles with one or more tablet excipients; It is ? form the charged particles or mixture of charged particles and one or more tablet excipients into a solid dosage unit. The solid dosage unit is easy to manufacture and perfectly suited for sublingual, buccal or sublabial administration.

Description

TECHNICAL FIELD OF THE INVENTION

[001] The present invention provides an orodispersible solid pharmaceutical dosage unit having a weight of 30 and containing at least 0.1 mg of an estetrol component selected from estetrol, estetrol esters and combinations thereof. This solid dosage unit consists of: • 0.1-25% by weight of estetrol particles containing at least 80% by weight of the estetrol component; and • 75-99.9% by weight of one or more pharmaceutically acceptable ingredients.

[002] The invention also provides a process for preparing the above-mentioned solid dosage unit.

[003] Furthermore, the invention relates to the use of the solid dosage unit in medical treatment, female hormone replacement therapy and female contraception, said use comprising sublingual, buccal or sublabial administration of the solid dosage unit.

BASICS OF THE INVENTION

[004] Estetrol is a human steroid, produced by the fetal liver only during pregnancy. This natural hormone was found in the urine of pregnant women by Diczfalusy and co-workers in 1965. Estetrol has the structure of an estrogenic steroid with four hydroxyl groups. Estetrol is synthesized in the fetal liver from estradiol and estriol by the two enzymes 15a- and 16a- hydroxylase. After birth, the neonatal liver rapidly loses its ability to synthesize estetrol because these two enzymes are no longer expressed.

[005] Estetrol reaches the maternal circulation through the placenta and has already been detected at nine weeks of pregnancy in maternal urine. During the second trimester of pregnancy, high levels were found in maternal plasma, with concentrations of unconjugated estetrol increasing to about 1 ng/mL (> 3 nmol/L) towards the end of pregnancy. Until now, the physiological function of estetrol is unknown. The possible use of estetrol as a marker for fetal well-being has been extensively studied. However, due to the large intra- and inter-individual variation in maternal plasma estetrol levels during pregnancy, this appeared not to be feasible.

[006] Since 2001, estetrol has been widely studied. In humans, estetrol has been shown to have high, dose-proportional oral bioavailability and a long terminal elimination half-life of about 28 hours. Results from in vitro studies have shown that estetrol binds highly selectively to estrogen receptors with a preference for the ERα form of the receptor, unlike the estrogens ethinyl estradiol and 17β-estradiol. Also in contrast to ethinyl estradiol and especially 17β-estradiol, estetrol does not bind to sex hormone binding globulin (SHBG) and does not stimulate SHBG production in vitro.

[007] The properties of estetrol have also been investigated in a series of predictive and well-validated in vivo pharmacological mouse models. In these models, estetrol exhibited estrogenic effects on the vagina, uterus (myometrium and endometrium), body weight, bone mass, bone strength, hot flashes and ovulation (inhibition). All of these effects of estetrol were dose-dependent with maximal effects at comparable dose levels. Surprisingly, estetrol prevented tumor development in a DMBA breast tumor model to an extent and at a dose level similar to the antiestrogen tamoxifen and ovariectomy. This antiestrogenic effect of estetrol in the presence of 17β-estradiol has also been observed in in vitro studies using human breast cancer cells.

[008] Buccal, sublingual or sublabial administration of estetrol is mentioned in a number of patent applications, including WO 2002/094275, WO 2002/094276, WO 2002/094278 and WO 2003/018026. Estetrol containing dosage units for buccal, sublingual or sublabial administration are not described in these publications.

[009] WO 2010/033832 describes an oral dosage form comprising an estriol compound and a pharmaceutically acceptable matrix material, wherein the oral dosage form releases at least about 90% of the estriol compound in a time of less than about 300 seconds when contacted with saliva from the oral and/or sublingual cavity.

[0010] US 2007/286829 describes an orally administered solid dosage form capable of dispensing ethinyl estradiol with improved bioavailability, said solid dosage form comprising (i) about 0.5 μg to about 50 μg of ethinyl estradiol and (ii) an oral dissolution enhancing carrier that provides at least 15% absorption of ethinyl estradiol across the oral mucosa when said solid dosage form is orally administered to the patient with 2 ounces (59.14 mL) of water or less.

[0011] US 6,118,446 describes a buccal dosage unit for administering a combination of steroidal active agents, comprising a compressed tablet of a bioerodible polymeric carrier and therapeutically effective amounts of an androgenic agent selected from testosterone and pharmacologically acceptable esters thereof, a progestin and an estrogen. The examples describe buccal dosage units that were prepared by thoroughly mixing the following components: estrogen, progesterone, androgen, polyethylene oxide, carbomer, and magnesium stearate. Then, the mixture was granulated by means of fluid bed granulation and the granulate thus obtained was pressed into tablets.

[0012] Oral dosage units containing estetrol have been described in several patent publications.

[0013] WO 2002/094276 describes a pharmaceutical composition for use in a method of hormone replacement therapy, which method comprises administering to a person in need of such therapy an effective amount of estetrol, said composition containing practically no progestogen or antiprogestin. WO 2002/094276 describes the preparation of estetrol tablets having a weight of 185 mg, containing 1.5 mg of estetrol, based on the following formulation:

[0014] WO 2002/094275 describes the use of an estetrol in a method for increasing libido in a woman, said method comprising administering to said woman an effective amount of estetrol. Oral administration is mentioned as a suitable mode of administration. This patent application describes the same estetrol tablet as WO 2002/094276.

[0015] WO 2002/094279 describes the use of estetrol in a method of contraception in female mammals, which method comprises oral administration of said estrogenic component and a progestogenic component to a capable female of childbearing age in an amount effective to inhibit ovulation. The following formulation for a 185 mg estetrol tablet is described in this international patent application.

[0016] WO 2003/041718 describes the use of estetrol in a method of hormone replacement in mammals, a method comprising oral administration of estetrol and a progestogenic component to a mammal in an amount effective to prevent or treat symptoms of hypoestrogenism. This patent application describes the same estetrol tablet as WO 2002/094279.

[0017] WO 2007/081206 describes the use of estetrol in a method of treating an acute vascular disorder in a mammal, said method comprising orally administering to said mammal, as needed, an effective amount of estetrol to the mammal. This patent application describes the preparation of hard gelatin capsules, containing 100 mg of estetrol and 25 mg of sildenafil citrate per capsule.

[0018] WO 2008/156365 describes the use of estetrol in the treatment of Meconium Aspiration Syndrome (MAS) in a newborn baby, said treatment comprising administering an effective amount of estrogen to the newborn baby within 7 days after birth. The international patent application describes a suppository for use in newborn babies comprising at least 1 μg of estrogen, said suppository being further characterized by a maximum diameter of less than 10 mm, and a weight of less than 0.5 g. The excipient contained in the suppository may be based on a lipid material that melts at body temperature or may be based on a hydrophilic component that dissolves or disintegrates when it comes into contact with water.

SUMMARY OF THE INVENTION

[0019] The present invention provides an orodispersible solid pharmaceutical dosage unit containing an estetrol component. The dosing unit quickly releases estetrol into an aqueous medium. The solid dosage unit is easy to manufacture and perfectly suited for sublingual, buccal or sublabial administration. Sublingual, buccal and sublabial administration offers the advantages of the estetrol component not having to pass through the digestive system and avoiding first-pass exposure to the liver. Furthermore, these modes of administration provide a rapid onset of action.

[0020] The solid dosage unit according to the present invention has a weight between 30 and 1000 mg and contains at least 100 μg of an estetrol component selected from estetrol, estetrol esters and combinations thereof, and consists of: • 0.1-25% by weight of estetrol particles containing at least 80% by weight of the estetrol component; and • 75-99.9% by weight of one or more pharmaceutically acceptable ingredients.

[0021] This solid dosage can be obtained by a process comprising: • providing estetrol particles containing at least 80% by weight of the estetrol component and having a volume average diameter of 2 μm to 50 μm; • mixing the estetrol particles with one or more granulation excipients to produce a granulation mixture; • mixing the granulation mixture with a granulation liquid to produce granules containing estetrol, said granulation liquid containing at least 60% by weight of liquid solvent; • remove liquid solvent from the estetrol-containing granules to produce dry estetrol-containing granules; • optionally mixing the dry granules with one or more tablet excipients; and • forming the dry granules or mixture of the dry granules and one or more tablet excipients into a solid dosage unit.

[0022] Rapid and complete dissolution of the estetrol component in saliva is essential for efficient dispensing of the component through sublingual, buccal or sublabial administration of the solid dosage unit. It was unexpectedly found that the estetrol component is rapidly released and dispersed in saliva and absorbed through the mucosal lining of the oral cavity if it is present in the solid dosage unit in the form of very small particles.

[0023] The invention also provides a process of preparing the above-mentioned solid dosage unit, said process comprising the steps of: • providing estetrol particles containing at least 80% by weight of an estetrol component selected from estetrol, esters of estetrol and combinations thereof and having a volume average diameter of 2 μm to 50 μm; • mixing the estetrol particles with one or more granulation excipients to produce a granulation mixture; • mixing the granulation mixture with a granulation liquid to produce granules containing estetrol, said granulation liquid containing at least 60% by weight of liquid solvent; • remove liquid solvent from the estetrol-containing granules to produce dry estetrol-containing granules; • optionally mixing the dry granules with one or more pharmaceutically acceptable excipients; and • form the dry granules or mixture of the dry granules and one or more tablet excipients into a solid dosage unit

[0024] The production of estetrol-containing granules in this process can be carried out suitably, for example, in a high shear granulator, a low shear granulator or a fluidized bed granulator.

BRIEF DESCRIPTION OF THE FIGURE

[0025] Figure 1 illustrates the flowchart of the manufacturing process used in Example 2.

DETAILED DESCRIPTION OF THE INVENTION

[0026] A first aspect of the invention relates to an orodispersible solid pharmaceutical dosage unit having a weight between 30 and 1,000 mg, said dosage unit consisting of: • 0.1-25% by weight of estetrol particles containing at least 80% by weight of an estetrol component selected from estetrol, estetrol esters and combinations thereof; and • 75-99.9% by weight of one or more pharmaceutically acceptable ingredients; the solid dosage unit comprising at least 100 μg of the estetrol component; wherein the solid dosage unit can be obtained by a process comprising: • providing estetrol particles containing at least 80% by weight of the estetrol component and having a volume average diameter of 2 μm to 50 μm; • mixing the estetrol particles with one or more granulation excipients to produce a granulation mixture; • mixing the granulation mixture with a granulation liquid to produce granules containing estetrol, said granulation liquid containing at least 60% by weight of liquid solvent; • remove the liquid solvent from the estetrol-containing granules to produce dry estetrol-containing granules; • optionally mixing the dry granules with one or more tablet excipients; and • forming the dry granules or mixture of the dry granules and one or more tablet excipients into a solid dosage unit.

[0027] The term “orodispersible dosage unit”, as used herein, refers to a dosage unit that is intended to rapidly disintegrate in the oral cavity when it comes into contact with saliva and to disperse the estetrol component in the saliva so that it can be absorbed through the mucosal lining of the oral cavity.

[0028] The terms “pharmaceutically acceptable ingredients”, as used herein, include pharmaceutically acceptable excipients and pharmaceutically active ingredients, other than the estetrol component, as defined below.

[0029] The term “sublingual” as used herein refers to the pharmacological route of administration through which the estetrol component diffuses into the blood through tissues under the tongue.

[0030] The term “buccal”, as used herein, refers to the pharmacological route of administration through which the estetrol component diffuses into the blood through the tissues of the buccal vestibule, the area within the mouth between the cheek lining (the mucous membrane buccal) and teeth/gums.

[0031] The term “sublabial”, as used herein, refers to the pharmacological route of administration through which the estetrol component is placed between the lip and the gums.

[0032] The term “granulation” as used herein, unless otherwise indicated, refers to a process in which primary powder particles are made to adhere to form larger multiparticle entities called “granules”.

[0033] The term “tablet excipient” as used herein refers to a pharmaceutically acceptable excipient that can be used in the manufacture of solid dosage units, such as tablets.

[0034] The particle size distribution of the particulate materials used and produced in the present process can be adequately determined by means of laser diffraction.

[0035] Unless otherwise indicated, all percentages mentioned here are percentages by weight.

[0036] Examples of solid dosage units encompassed by the present invention include tablets, tablets, lozenges and films. According to a preferred embodiment, the dosage unit is a tablet, more preferably a compressed tablet.

[0037] The solid dosage unit typically has a weight of between 40 and 500 mg, more preferably between 50 and 300 mg, and most preferably between 70 and 150 mg.

[0038] The solid dosage unit preferably comprises at least 1% by weight, more preferably 2-40% by weight and most preferably 2.2-15% by weight of the estetrol component.

[0039] The amount of the estetrol component contained in the solid dosage unit is preferably within the range of 0.3 to 100 mg, more preferably 0.5 to 40 mg and most preferably 1-20 mg.

[0040] The estetrol component of the present invention is preferably selected from the group consisting of estetrol, estetrol esters, in which the hydrogen atom of at least one of the hydroxyl groups has been replaced by an acyl radical of a carboxylic hydrocarbon, sulfonic acid or sulfamic acid of 1-25 carbon atoms; and combinations thereof. Even more preferably, the estetrol component is estetrol (including estetrol hydrates). More preferably, the estetrol component contained in the dosage unit is estetrol monohydrate.

[0041] The particle size of the estetrol particles in the solid dosage unit must be adequate to achieve sufficient absorption of the estetrol component after sublingual, buccal or sublabial administration. The estetrol particles within the solid dosage unit and (independently) the estetrol particles used in preparing the solid dosage unit preferably have a volume average diameter in the range of 3 μm to 35 μm, more preferably in the range of 4 μm to 25 μm and more preferably in the range of 5 μm to 15 μm.

[0042] The estetrol particles within the solid dosage unit and (independently) the estetrol particles used in preparing the solid dosage unit preferably contain no more than a limited amount of particles with a particle size greater than 60μm. Preferably, not more than 10% by volume greater than 60 μm (D90), more preferably not more than 5% by volume of the estetrol particles have a particle size greater than 60 μm (D95). Even more preferably, not more than 10% by volume of more than 40 μm (D90), more preferably not more than 5% by volume of the estetrol particles have a particle size greater than 40 μm (D95).

[0043] The particle size distribution of the estetrol particles and other particulate materials used in the present process can be suitably determined by means of laser diffraction. The particle size distribution of the estetrol particles within the solid dosage unit can be suitably determined using spectroscopic techniques, for example, Raman mapping.

[0044] The solid dosage unit of the present invention offers the advantage of the estetrol component of being quickly released when the dosage unit is introduced into the oral cavity and comes into contact with saliva. The release rate of the estetrol component of the dosage unit can be suitably determined using the dissolution test described in the Examples, or a disintegration test in accordance with Ph. Eur. 2.9.1 (“Disintegration of Tablets and Capsules”) and USP <701> (“Disintegration”), also described in the Examples. The solid dosage unit of the present invention, when subjected to the above-mentioned dissolution test, normally releases at least 50%, more preferably at least 70% and most preferably at least 80% of the estetrol component after 5 minutes. The solid dosage unit of the present invention, when subjected to the aforementioned disintegration test, typically disintegrates in less than 5 minutes, more preferably in less than 2 minutes, even more preferably in less than 1.5 minutes, even more preferably within less than 1 minute, even more preferably less than 45 seconds, and most preferably less than 30 seconds.

[0045] The estetrol particles employed in the solid dosage unit and in the present process preferably contain at least 90% by weight of the estetrol component, more preferably at least 95% by weight of the estetrol component and most preferably at least 99% estetrol component. In addition to the estetrol component, the estetrol particles may suitably contain pharmaceutically acceptable excipients that aid dispersion of the dosage unit and dissolution and absorption of the estetrol component. Examples of such excipients include surfactants, cosolvents, absorption enhancers, superdisintegrants and buffering agents.

[0046] Estetrol particles typically represent between 0.5-20% by weight of the dosage unit. More preferably, the estetrol particles represent 1-18% by weight, more preferably 5-15% by weight of the dosage unit.

[0047] The solid dosage unit of the present invention preferably contains 50-99.8% by weight of water-soluble carbohydrate, selected from maltose, fructose, sucrose, lactose, glucose, galactose, trehalose, xylitol, sorbitol, erythritol, maltitol, mannitol, isomalt and combinations thereof. More preferably, the water-soluble carbohydrate is selected from lactose, mannitol, erythritol and combinations thereof. Even more preferably, the water-soluble carbohydrate is selected from mannitol, erythritol and combinations thereof. More preferably, the water-soluble carbohydrate is mannitol.

[0048] The solid dosage unit preferably contains at least 20% by weight of mannitol. More preferably, the dosage unit contains 30-70% by weight mannitol, more preferably 40-60% by weight mannitol.

[0049] The water-soluble carbohydrate is preferably contained in the dosage unit in crystalline form. According to another preferred embodiment, the dosage unit contains 0.1-15% by weight, more preferably 0.2 to 10% by weight and most preferably 1-5% by weight of a disintegrating agent selected from modified starches ( for example, sodium salt of carboxymethyl starch), cross-linked polyvinylpyrrolidone, cross-linked carmellose and combinations thereof.

[0050] Estetrol particles are present in the solid dosage unit of the present invention as a component of granules that additionally contain one or more granulation excipients.

[0051] Dry estetrol-containing granules typically constitute 20-99.9% by weight of the oral dosage unit. More preferably, these granules represent 50-99.8% by weight, more preferably 6099.7% by weight of the oral dosage unit.

[0052] Typically, the dried estetrol-containing granules containing the estetrol particles have a volume average diameter of 100 to 4,000 μm, more preferably 150-1,000 μm and most preferably 200-600 μm.

[0053] Dry estetrol-containing granules typically comprise 70-95% by weight of one or more granulation excipients and 5-30% by weight of the estetrol component. Even more preferably, these granules comprise 75-90% by weight of the one or more granulation excipients and 10-25% by weight of the estetrol component.

[0054] Other granulation excipients that can be suitably incorporated into estetrol-containing granules include water-soluble carbohydrate, diluents/fillers (e.g., calcium salts, microcrystalline cellulose), binders, disintegrating agents, mucoadhesive agents, flavorings, colorings, gliding agents, lubricants and combinations thereof.

[0055] The dry estetrol-containing granules preferably contain at least 20% by weight, more preferably at least 35% by weight and most preferably at least 45% by weight of the water-soluble carbohydrate as defined hereinbefore.

[0056] The dried estetrol-containing granules preferably contain at least 30%, more preferably at least 40% and most preferably at least 50% of the water-soluble carbohydrate by weight of the one or more granulation excipients.

[0057] Dry estetrol-containing granules typically contain 0-20% by weight of the binder as defined hereinbefore. Even more preferably, these granules contain 0.1-15% by weight, more preferably 0.2 to 10% by weight of the binder.

[0058] According to another preferred embodiment, the dry estetrol-containing granules comprise 0.1-20% by weight, more preferably 0.2 to 10% by weight of a disintegrating agent as defined hereinbefore.

[0059] In addition to estetrol-containing granules, the solid dosage unit of the present invention may suitably contain 0.1-80% by weight, more preferably 0.250% by weight and most preferably 0.3-40% by weight of tablet excipients selected from lactose, mannitol, xylitol, microcrystalline cellulose, starch, croscarmellose sodium, polyvinyl pyrrolidone and combinations thereof. According to a particularly preferred embodiment, the tablet excipients contain at least 50% by weight mannitol. According to another preferred embodiment, the tablet excipients comprise at least 50% by weight mannitol. According to another preferred embodiment, the tablet excipients comprise 50% by weight lactose.

[0060] The solid dosage unit may contain one or more other pharmaceutically active ingredients in addition to the estetrol component. Examples of such other pharmaceutically active ingredients include steroid hormones. The solid dosage unit of the present invention preferably contains 0.05-10 mg, more preferably 0.1-5 mg of one or more progestins, preferably one or more progestins selected from progesterone, levonorgestrel, norgestimate, norethisterone , norethisterone acetate (NETA), dydrogesterone, drospirenone, 3-beta-hydroxydesogestrel, 3-keto desogestrel (=etonogestrel), 17-deacetyl-norgestimate, 19-norprogesterone, acetoxypregnenolone, allylestrenol, anagestone, chlormadinone, cyproterone, demegestone, desogestrel , dienogest, dihydrogesterone, dimeteristone, ethisterone, ethynodiol diacetate, flurogestone acetate, gastrinon, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, linestrenol (=linoestrenol), medrogestone, medroxyprogesterone, megestrol, melengestrol, nestorone, nomegestrol, nomegestrol acetate (NOMAC) -diene-20-in-3-one, tibolone, trimegestone, algestone acetophenide, nestorone, promegestone, esters of 17-hydroxyprogesterone, 19-nor-17-hydroxyprogesterone, 17-alpha-ethynyl-testosterone, 17alpha-ethynyl-19- nor-testosterone, d-17beta-acetoxy-13beta-ethyl-17alpha-ethynyl-gon-4-en-3-one oxime and prodrugs of these compounds. Preferably, one or more progestins used in accordance with the present invention is(are) selected from the group consisting of progesterone, desogestrel, etonogestrel, gestodene, dienogest, levonorgestrel, norgestimate, norethisterone, norethisterone acetate (NETA), nomegestrol, nomegestrol acetate (NOMAC), drospirenone, trimegestone, nestorone and dihydrogesterone.

[0061] The solid dosage unit according to the present invention preferably contains 0.05-100 mg, more preferably 0.1-50 mg of one or more androgens, preferably one or more androgens selected from testosterone, dehydroepiandrosterone (DHEA); DHEA sulfate (DHEAS); testosterone esters (e.g., testosterone undecanoate, testosterone propionate, testosterone phenylpropionate, testosterone iso-hexanoate, testosterone enanthate, testosterone buchanate, testosterone decanoate, testosterone buciclate); methyltestosterone; mesterolon; stanozolol; androstenedione; dihydrotestosterone; androstanediol; methenolone; fluoxmesterone; oxymeterone; methandrostenolol; MENT and prodrugs of these compounds. More preferably, one or more androgens are selected from the group consisting of testosterone, DHEA and MENT.

[0062] Another aspect of the present invention relates to the use of the above-mentioned solid dosage unit in medical treatment, female hormone replacement therapy or female contraception, said use comprising sublingual, buccal or sublabial administration of the dosage unit. Examples of medical treatment in which the solid dosage unit of the present invention can be suitably used include treatment of osteoporosis and estrogen retroaddition treatment of endometriosis, breast cancer or prostate cancer. According to a preferred embodiment, the solid dosage unit is used in female hormone replacement therapy or female contraception. More preferably, the solid dosage is used in female hormone replacement therapy, especially to treat vulvovaginal atrophy and/or vasomotor symptoms.

[0063] The use of the solid dosage unit in medical treatment, female hormone replacement therapy or female contraception typically comprises sublingual, buccal or sublabial administration of the dosage unit to provide at least 0.1 mg, more preferably 0. 5-100 mg and more preferably 1-40 mg of the estetrol component.

[0064] To treat vulvovaginal atrophy, the dosage unit is preferably administered in an amount sufficient to provide at least 0.1 mg of the estetrol component. More preferably, the dosage unit administered provides at least 0.5 mg, more preferably at least 1 mg of the estetrol component. In the treatment of vulvovaginal atrophy, the dosage unit is preferably administered in an amount that provides not more than 50 mg, more preferably not more than 20 mg and most preferably not more than 10 mg of the estetrol component.

[0065] To treat vasomotor symptoms, the dosage unit is preferably administered in an amount sufficient to provide at least 0.2 mg of the estetrol component. More preferably, the dosage unit administered provides at least 1 mg, more preferably at least 2 mg of the estetrol component. In the treatment of vasomotor symptoms, the dosage unit is preferably administered in an amount that provides not more than 100 mg, more preferably not more than 40 mg and most preferably not more than 20 mg of the estetrol component.

[0066] Typically, these uses of the solid dosage unit comprise daily administration of the dosage unit over a period of at least 1 week, more preferably at least 2 weeks. During these periods, the solid dosage unit is preferably administered to provide a daily dose of at least 0.05 mg, more preferably 0.1-40 mg and most preferably 0.2-20 mg of the estetrol component. .

[0067] To treat vulvovaginal atrophy, the dosage unit is preferably administered to provide a daily dose of at least 0.1 mg of the estetrol component. More preferably, the dosage unit is administered to provide a daily dose of 0.5-20 mg, more preferably 1-10 mg of the estetrol component.

[0068] To treat vasomotor symptoms, the dosage unit is preferably administered to provide a daily dose of at least 0.2 mg of the estetrol component. More preferably, the dosage unit is administered to provide a daily dose of 1-40 mg, more preferably 2-20 mg of the estetrol component.

[0069] Yet another aspect of the invention relates to one for preparing a solid dosage unit as previously described herein, said process comprising the steps of: • providing estetrol particles containing at least 80% by weight of an estetrol component selected from estetrol, estetrol esters and combinations thereof and having a volume average diameter of 2 μm to 50 μm; • mixing the estetrol particles with one or more granulation excipients to produce a granulation mixture; • mixing the granulation mixture with a granulation liquid to produce granules containing estetrol, said granulation liquid containing at least 60% by weight of liquid solvent; • remove liquid solvent from the estetrol-containing granules to produce dry estetrol-containing granules; • optionally mixing the dry granules with one or more tablet excipients; and • forming the dry granules or mixture of the dry granules and one or more tablet excipients into a solid dosage unit.

[0070] In the present process, the granulation mixture is preferably produced by combining the estetrol particles with one or more granulation excipients in a weight ratio that is in the range of 1:2 to 1:1,000, more preferably in the range of 1:3 to 1:100 and more preferably in the range of 1:4 to 1:10.

[0071] The one or more granulation excipients used in preparing the granulation mixture preferably include water-soluble carbohydrate as previously defined herein. Preferably, said water-soluble carbohydrate constitutes at least 50% by weight, more preferably at least 60% by weight and most preferably at least 80% by weight of one or more granulation excipients.

[0072] One or more granulation excipients of the granulation mixture preferably include 0.1-20% by weight, more preferably 0.15-10% by weight and most preferably 0.2-5.0% by weight of binder as previously defined herein; the entire percentage calculated by the weight of the granulation mixture.

[0073] One or more granulation excipients of the granulation mixture may suitably include a disintegrating agent as defined hereinbefore. Preferably, the disintegrating agent constitutes 0.1-20% by weight, more preferably 0.2-10% by weight of the granulation mixture.

[0074] Estetrol-containing granules are preferably produced by mixing the granulation mixture with the granulation liquid in a weight ratio that is in the range of 0.5:1 to 20:1. Even more preferably, the granulation mixture and the granulation liquid are mixed in a weight ratio that is in the range of 0.8:1 to 12:1, even more preferably in the range of 1:1 to 10:1 and more. preferably from 1.5:1 to 5:1. The above-mentioned weight ratio is calculated based on the total amount of granulation mixture and the granulation liquid that is used in preparing the dry estetrol-containing granules.

[0075] Estetrol-containing granules are preferably produced by mixing the granulation mixture with the granulation liquid in a high shear granulator, a low shear granulator or a fluidized bed granulator. More preferably, the granules are prepared in a low shear granulator.

[0076] The granulation liquid used in the present process preferably contains at least 60% by weight, more preferably at least 80% by weight and most preferably at least 90% by weight of polar solvent selected from water, methanol, ethanol , iso-propanol, acetone and combinations thereof.

[0077] According to a particularly preferred embodiment, the granulation liquid contains at least 60% by weight, more preferably at least 80% by weight, and most preferably at least 90% by weight of polar solvents selected from water, ethanol and combinations thereof. The polar solvent used in the granulation liquid preferably contains at least 80% by weight of water, more preferably at least 90% by weight of water.

[0078] The granulation liquid used in the present process may suitably contain other excipients in addition to the liquid solvent. Examples of such additional excipients include binders, disintegrating agents, mucoadhesive agents, coloring agents, flavoring agents and combinations thereof.

[0079] Preferably, the granulation liquid contains 0.5-40% by weight, more preferably 1-25% by weight and most preferably 2-20% by weight of binder, said binder being selected from cellulose derivatives, starch and starch derivatives (e.g., pregelatinized starch, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), agar, gelatin, guar gum, gum Arabic, alginate, polyethylene glycol (PEG), glucose, sucrose, sorbitol, and combinations Preferably, the binder used in the present process is selected from cellulose derivatives, pre-gelatinized starch, polyvinylpyrrolidone and combinations thereof.

[0080] Examples of cellulose derivatives that can be used in the dosage unit as a binder include hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose and combinations thereof.

[0081] In the present process, the liquid solvent is preferably removed after mixing of the granulation mixture with the granulation liquid has been completed. In a preferred embodiment reduced pressure is applied (e.g., less than 200 mbar (20 KPa)) to facilitate removal of the liquid solvent during the production of the estetrol-containing granules. Typically, the liquid solvent is removed at elevated temperature (e.g. > 50°C).

[0082] The dried estetrol-containing granules produced in the present process typically have a volume average diameter in the range of 100-4,000 μm. More preferably, the volume average diameter of these beads is in the range of 200-1,000 μm, more preferably in the range of 200-600 μm.

[0083] Examples of one or more tablet excipients that are optionally combined with the dried estetrol-containing granules prior to forming the solid dosage unit include lactose, mannitol, xylitol, microcrystalline cellulose, starch, croscarmellose sodium, polyvinyl pyrrolidone and combinations thereof .

[0084] Preferably, in the present process, the estetrol-containing granules are mixed with one or more tablet excipients in a weight ratio that is in the range of 1:4 to 9:1, more preferably in the range of 1:2, 5 to 3:1 and more preferably 1:1.5 to 1.5 to 1.

[0085] In the present process, the estetrol-containing granule can be suitably formed by direct compression or compression molding. More preferably, the solid dosage unit is formed by direct compression.

[0086] The solid dosage units obtained by the present method can be packaged in different ways. Preferably, the dosage units are packaged in a blister pack containing at least 14 dosage units.

[0087] The invention is further illustrated by means of the following non-limiting examples.

EXAMPLES Dissolution test

[0088] The dissolution test described below can be used to study the dissolution behavior of orodispersible dosage units.

Dissolving apparatus

[0089] • VanKel VK 7010 or VK 7025 paddle and basket dissolution tester, VK 8000 autosampler, 1000 mL dissolution vessels and micron pore filters (35 pins).

Dissolving medium

[0090] • Transfer 9,000 ml of demineralized water to a 10,000 ml volumetric flask.

[0091] • Add 68.05 g of KH2PO4 and 8.96 g of NaOH and stir the solution until everything dissolves.

[0092] • Mix the solution and adjust the pH to 6.8 with NaOH or phosphoric acid, if necessary and make up the volume with demineralized water.

Dissolution procedure

[0093] • Transfer 900 ml of dissolution medium to each vessel of the paddle apparatus.

[0094] • Assemble the device, heat the medium to 37 ± 0.5°C and remove the thermometer.

[0095] • Place a tablet at the bottom of each of the six vessels before starting to rotate the blades.

[0096] • Start rotating the blades immediately.

[0097] • Use a stirring speed of 50 rpm.

[0098] • Take 5 ml samples from the dissolution vessels after 5, 10, 20, 30, 45, 60, 75 and 90 minutes for a complete dissolution profile. Take the sample from a position halfway between the surface of the dissolution medium and the top of the paddle and not less than 10 mm from the vessel wall. The removed dissolution volume is not replaced by fresh dissolution medium.

[0099] Estetrol concentrations in the samples were determined using HPLC using estetrol loading solutions as a reference.

Preparation of mobile phase (MP) phosphate buffer

[00100] • Transfer 1.15 g of NH4H2PO4 (10 mM) into 1,000 ml of demineralized water, dissolve it and adjust the pH to 3.0 with phosphoric acid.

HPLC apparatus

[00101] • Alliance 2695 separation module consisting of a quaternary solvent dispensing system, a variable volume injector, a temperature-controlled autosampler, a column thermostat, and a 2996 photodiode array detector (all from Waters)

[00102] • Analytical column: Symmetry C18, 3.9 x 150 mm, dp = 5 μm (ex Waters)

[00103] • Protection column: C18 safety protection column, 4x3 mm (Phenomenex)

[00104] • Flow: 1.0 mL/min

[00105] • Detection: UV @ 280 nm

[00106] • Column temperature: 30°C

[00107] • Autosampler temperature: 10°C

[00108] • Injection volume: 100 μL

[00109] • Execution time: 12 min. Elution gradient

[00110] Dissolution tests are carried out in triplicate.

Particle Size Measurements

[00111] The particle size distribution of estetrol monohydrate is performed using a MALVERN MASTERSIZER MICROPLUS laser particle size analyzer.

Preparation of the dispersion medium:

[00112] • Weigh 1 g of estetrol monohydrate and 1 g of sorbitan trioleate into a flask.

[00113] • Add 1 liter of n-hexane and mix for at least 1 hour at room temperature

[00114] • Filter through a 0.45 μm filter.

Sample preparation:

[00115] • Place 100 mg of sample in a 25 mL beaker.

[00116] • Add a few drops of dispersion medium.

[00117] • Mix carefully with a glass rod to suspend the powder well.

[00118] • Add 10 mL of dispersion medium.

[00119] • Run the analysis with the sample dispersion unit speed at 3000-3500 rpm.

Analysis:

[00120] Particle size measurements are performed three times using the same dispersion. The final result is obtained by averaging the results of the three determinations.

Example 1

[00121] A sublingual tablet is prepared using the procedure described below.

[00122] A granulation mixture having the composition shown in Table 1 is prepared by dry combining the ingredients. Table 1 D(v; o.5): approx. 15 μm

[00123] A granulation liquid having the composition shown in Table 2 is prepared by dispersing pregelatinized starch in water Table 2

[00124] The granulation mixture is granulated in a high shear granulator by gradually adding the aqueous granulation liquid. The total amount of granulation liquid added amounts to 25% by weight of the granulation mixture.

[00125] The granulate thus obtained is dried in a vacuum drying oven at 40°C and subsequently sieved through a 500 μm sieve.

[00126] A mixture of tablets having the composition shown in Table 3 is prepared by mixing the dry granulate with the excipients for 15 minutes (except magnesium stearate). Magnesium stearate is added and mixing is continued for an additional 5 minutes. Table 3 2 A mixture of mannitol (90% by weight), crospovidone (5% by weight) and polyvinyl acetate (5% by weight)

[00127] The tablet mixture is pressed into 80 mg round tablets having a diameter of 6.5 mm. The estetrol content of these tablets is approximately 10 mg.

Example 2

[00128] A sublingual tablet is prepared using the procedure described below and illustrated in Figure 1.

[00129] A granulation mixture having the composition shown in Table 4 is prepared by dry combining the ingredients. Table 4 1 D(v; 0.5) = approx. 15μm

[00130] A granulation liquid having the composition Table 5 is prepared by dispersing polyvinylpyrrolidone (PVP) in water. Table 5

[00131] The granulation mixture is granulated in a low shear granulator by gradually adding the granulation liquid. The total amount of granulation liquid added amounts to 25% by weight of the granulation mixture.

[00132] The granulate thus obtained is dried in the low shear granulator at 40°C and is subsequently sieved through a 500 μm sieve.

[00133] A mixture of tablets with the composition shown in Table 6 is prepared by mixing the dry granulate with the excipients for 15 minutes (except magnesium stearate). Magnesium stearate is added and mixing continues for another 5 minutes. Table 6

[00134] The combination is pressed into 80 mg round tablets with a diameter of 6.5 mm. The estetrol content of these tablets is approximately 10 mg.

Example 3

[00135] A sublingual tablet is prepared using the procedure described below.

[00136] A granulation mixture having the composition shown in Table 7 is prepared by dry mixing the ingredients. Table 7 1 D(v; 0.5) = approx. 15μm

[00137] A granulation liquid having the composition shown in Table 8 is prepared by dispersing hydroxypropyl cellulose (HPC) in water. Table 8

[00138] The granulation mixture is granulated in a fluidized bed granulator by gradually adding the granulation liquid. The total amount of granulation liquid added amounts to 35% by weight of the granulation mixture

[00139] The granulate thus obtained is dried in the fluidized bed granulator at 50°C and subsequently sieved through a 500 μm sieve.

[00140] A mixture of tablets having the composition shown in Table 9 is prepared by mixing the dry granulate with the excipients in Table 9 for 15 minutes (except magnesium stearate). Magnesium stearate is added and mixing continues for another 5 minutes. Table 9

[00141] The combination is pressed into 80 mg round tablets with a diameter of 6.5 mm. The estetrol content of these tablets is approximately 10 mg.

Example 4

[00142] Seven different sets of sublingual tablets (formulations A to G) were prepared using the procedure described below and illustrated in Figure 1.

[00143] The target amounts of estetrol per tablet were as follows: 100 μg for formulation A, 250 mg for formulation B, 7.5 mg for formulation C, 1 mg for formulation D, and 10 mg for formulations E, F and G .

[00144] The target weights for the tablets were as follows: 30 mg for formulations A and C, 1000 mg for formulations B and D and 80 mg for formulations E, F and G.

[00145] Estetrol was mixed with part of the main diluent and sieved through an 800 μm sieve. All other excipients were also screened on an 800 μm sieve.

[00146] A 10% PVP (polyvinylpyrrolidone) binder solution in demineralized water was prepared (the concentration of PVP in the binder solution used for formulations B, C and F was 15%).

[00147] Granulation was initiated by adding the binder solution to the dry mixture consisting of the intragranular excipients (with a batch size of ± 100 grams). A granule was formed after 30 seconds of mixing, and subsequently pure demineralized water was added until a suitable granule was formed (as detected visually, 1 minute of granulation in total).

[00148] The granulate was dried overnight in a vacuum oven at 40°C and subsequently ground through an 800 μm sieve. The mixture thus obtained was mixed for 15 minutes with extragranular excipients (except magnesium stearate). Finally, magnesium stearate was added and mixed for 3 minutes.

[00149] Compression was performed using a single punching machine equipped with appropriate perforations (5 mm perforation for 30 mg tablets (A and C), 6 mm for 80 mg tablets (E, F and G) and 15 mm for 1,000 mg tablets (B and D)).

[00150] Disintegration time was quantified according to the known protocol described in Ph. Eur. 2.9.1 (“Disintegration of tablets and capsules”) and in USP <701> (“Disintegration”) using water as the specified liquid.

[00151] Hardness was measured using the known protocol described in Ph. Eur. 2.9.8 (“Tablet Crushing Resistance”).

[00152] The final formulations and corresponding tablet results can be found in Tables 10 and 11 below.

[00153] No problems were detected during the experiments, the fluidity of the combination was good and no adhesion was observed. Table 10 - details of formulations in % by weight 1 D (v; 0.5) = 15 μm 2 containing mannitol (90% by weight), crospovidone (5% by weight) and polyvinyl acetate (5% by weight) Table 11 - experimentally determined characteristics of tablets Test (average result of 6 samples) Disintegration time Hardness Weight

[00154] It can be seen that all tablets were obtained with a final weight close to their target weight and that the disintegration times, even for the larger 1g tablets, were very small, according to the sublingual administration route, buccal or sublabial intended for these tablets.

[00155] Finally, the hardness of all tablets was within a very acceptable range.

Example 5

[00156] A randomized, open-label, two-period, crossover pharmacokinetic study is conducted to compare the sublingual bioavailability of 10 mg of estetrol administered in an 80 mg tablet (with the same composition as the tablets described in Example 4, Formulation E ) with oral availability of estetrol contained in an 83 mg tablet containing 10 mg of estetrol. These tablets are administered sublingually and orally to healthy volunteers under fasting conditions.

[00157] Ten healthy individuals are selected based on the following criteria: age between 45 and 65 years (inclusive), non-smokers or ex-smokers (at least 6 months before dosing), body mass index (BMI) = 18, 5 to 30 kg/m2 (including at the time of sorting).

[00158] At the beginning of the first and second periods of the study, between 07:00 am and 07:28 am, 5 subjects receive a single dose of the sublingual formulation of estetrol by administering one tablet of estetrol (tablet weight of 80 mg, 10 mg estetrol) and 5 subjects receive a single oral dose of the oral estetrol formulation by administering one estetrol tablet (83 mg tablet weight; 10 mg estetrol), taken together with 200 ml of water.

[00159] It is necessary for individuals to fast for at least 10 hours before administering the tablet and for at least 4 hours after administration. Drinking water or beverages is not permitted within one hour before administering the drug. Subjects are given 200 ml of water 1 hour before and 2 hours after tablet administration. Subjects are free to drink water and fruit tea starting 4 hours after tablet administration. Standardized meals are provided 10.5 hours before and 4, 6, 9 and 13 hours after tablet administration.

[00160] The sequence of events that occurs during the first and second period is shown in Table 12: Table 12

[00161] The blood and urine sampling schedule used in this study is shown in Table 13. Table 13

[00162] The concentration of estetrol in the collected blood samples is determined using HPLC/MS/MS. The concentrations of glucuronidated estetrol (D ring) in urine samples are also determined with the help of HPLC/MS/MS.

[00163] The results of these analyzes show that the bioavailability of estetrol administered sublingually is comparable or even superior to estetrol administered orally. Furthermore, the data suggest that sublingually administered estetrol has improved bioavailability compared to orally administered estetrol. Sublingual estetrol has less impact on a liver function parameter.

Claims (24)

1. Orodispersible solid pharmaceutical dosage unit having a weight between 30 and 1,000 mg, said dosage unit characterized by the fact that it consists of: • 0.1-25% by weight of estetrol particles containing at least 90% by weight of estetrol monohydrate, said estetrol particles being present in said dosage unit as a component of granules additionally containing one or more granulation excipients; and • 75-99.9% by weight of one or more pharmaceutically acceptable ingredients; the solid dosage unit comprising at least 100 μg of estetrol monohydrate; wherein the solid dosage unit can be obtained by a process comprising: • providing estetrol particles containing at least 90% by weight estetrol monohydrate and having a volume average diameter of 3 μm to 35 μm; • mixing the estetrol particles with one or more granulation excipients to produce a granulation mixture; • mixing the granulation mixture with a granulation liquid to produce granules containing estetrol, said granulation liquid containing at least 60% by weight of liquid solvent; • remove liquid solvent from the estetrol-containing granules to produce dry estetrol-containing granules; • optionally, mixing the dry granules with one or more tablet excipients; and • forming the dry granules or mixture of the dry granules and one or more tablet excipients into a solid dosage unit. 2. Dosage unit according to claim 1, characterized in that the dosage unit has a weight between 40 and 500 mg. 3. Dosage unit according to claim 1 or 2, characterized in that the dosage unit contains 0.5-25% by weight of estetrol monohydrate. 4. Dosage unit according to any one of claims 1 to 3, characterized in that the dosage unit contains 0.3-100 mg of estetrol monohydrate. 5. Dosage unit according to any one of claims 1 to 4, characterized by the fact that the one or more pharmaceutically acceptable ingredients comprise a progestin selected from the group consisting of: progesterone, desogestrel, etonogestrel, gestodene, dienogestel, levonorgestrel , norgestimate, norethisterone, norethisterone acetate (NETA), nomegestrol, nomegestrol acetate (NOMAC), drospirenone, trimegestone, nestorone and dydrogesterone. 6. Dosage unit according to any one of claims 1 to 5, characterized by the fact that the progestin is 0.05-10 mg of drospirenone. 7. Dosage unit according to any one of claims 1 to 6, characterized in that the dosage unit contains 50-99.9% by weight of water-soluble carbohydrates selected from maltose, fructose, sucrose, lactose, glucose, galactose, trehalose, xylitol, sorbitol, erythritol, maltitol, mannitol, isomalt and combinations thereof. 8. Dosage unit according to claim 7, characterized in that the dosage unit contains at least 20% by weight of mannitol. 9. Dosage unit according to any one of claims 1 to 8, characterized in that the dosage unit contains 0.1-20% by weight of a disintegrating agent selected from modified starches, cross-linked polyvinylpyrrolidone, cross-linked carmellose and combinations thereof. 10. Process for preparing a solid dosage unit as defined in any one of claims 1 to 9, said process characterized in that it comprises the steps of: • providing estetrol particles containing at least 90% by weight of estetrol monohydrate and having a volume average diameter of 3 μm to 35 μm; • mixing the estetrol particles with one or more granulation excipients to produce a granulation mixture; • mixing the granulation mixture with a granulation liquid to produce granules containing estetrol, said granulation liquid containing at least 60% by weight of liquid solvent; • remove liquid solvent from the estetrol-containing granules to produce dry estetrol-containing granules; • optionally, mixing the dry granules with one or more tablet excipients; and • forming the dry granules or mixture of the dry granules and one or more tablet excipients into a solid dosage unit. 11. Process according to claim 10, characterized in that the granulation mixture contains 0.1-20% by weight of a disintegrating agent selected from modified starches, cross-linked PVP, cross-linked carmellose and combinations thereof. 12. Process according to any one of claims 10 or 11, characterized in that the granulation mixture is produced by combining the estetrol particles with one or more granulation excipients in a weight ratio that is in the range of 1 :4 to 1:1,000. 13. Process according to any one of claims 10 to 12, characterized in that the estetrol-containing granules are produced by mixing the granulation mixture with the granulation liquid in a weight ratio that is in the range of 0.5: 1 to 20:1. 14. Process according to any one of claims 10 to 13, characterized in that the estetrol-containing granules are produced by mixing the granulation mixture with the granulation liquid in a high shear granulator, a low shear granulator of a fluidized bed granulator. 15. Process according to any one of claims 10 to 14, characterized in that the granulation liquid contains at least 60% by weight of polar solvent selected from water, methanol, ethanol, isopropanol, acetone and combinations thereof. 16. Process according to claim 15, characterized in that the granulation liquid contains at least 60% by weight of polar solvents selected from water, ethanol and combinations thereof. 17. Process according to claim 15 or 16, characterized in that the polar solvent contains at least 80% by weight of water. 18. Process according to any one of claims 10 to 17, characterized by the fact that the granulation liquid contains 0.2-50% by weight of binder, said binder being selected from cellulose derivatives, starch and derivatives of starch, polyvinyl alcohol, polyvinylpyrrolidone, agar, gelatin, guar gum, gum arabic, alginate, polyethylene glycol, glucose, sucrose, sorbitol and combinations thereof. 19. Process according to claim 18, characterized in that the binder is selected from cellulose derivatives, pregelatinized starch, polyvinylpyrrolidone and combinations thereof. 20. Process according to claim 18 or 19, characterized in that the cellulose derivatives are selected from hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose and combinations thereof. 21. Process according to any one of claims 10 to 20, characterized by the fact that the dried estetrol-containing granules have a volume average diameter in the range of 100-4,000 μm. 22. Process according to any one of claims 10 to 21, characterized in that one or more tablet excipients include lactose, mannitol, xylitol, microcrystalline cellulose, starch, croscarmellose sodium, polyvinyl pyrrolidone and combinations thereof. same. 23. Process according to any one of claims 10 to 22, characterized in that the solid dosage unit is formed by direct compression or compression molding. 24. Use of the solid dosage unit as defined in any one of claims 1 to 9, characterized by the fact that it is in the manufacture of a pharmaceutical composition for female contraception or for female hormone replacement therapy, wherein said composition is for administration sublingual, buccal or sublabial dosage unit.