OA18501A - Orodispersible dosage unit containing an estetrol component. - Google Patents
Orodispersible dosage unit containing an estetrol component. Download PDFInfo
- Publication number
- OA18501A OA18501A OA1201700476 OA18501A OA 18501 A OA18501 A OA 18501A OA 1201700476 OA1201700476 OA 1201700476 OA 18501 A OA18501 A OA 18501A
- Authority
- OA
- OAPI
- Prior art keywords
- dosage unit
- estetrol
- combinations
- solid dosage
- component
- Prior art date
Links
- AJIPIJNNOJSSQC-NYLIRDPKSA-N Estetrol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)[C@@H]4O)O)[C@@H]4[C@@H]3CCC2=C1 AJIPIJNNOJSSQC-NYLIRDPKSA-N 0.000 title claims abstract description 195
- 229950009589 Estetrol Drugs 0.000 title claims abstract description 189
- 239000007787 solid Substances 0.000 claims abstract description 66
- 239000002245 particle Substances 0.000 claims abstract description 57
- 238000000034 method Methods 0.000 claims abstract description 33
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 92
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 claims description 17
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 17
- 239000000594 mannitol Substances 0.000 claims description 17
- 235000010355 mannitol Nutrition 0.000 claims description 17
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 15
- HEBKCHPVOIAQTA-SCDXWVJYSA-N Xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 15
- 229960002675 Xylitol Drugs 0.000 claims description 15
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 15
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 15
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 15
- 239000000811 xylitol Substances 0.000 claims description 15
- 235000010447 xylitol Nutrition 0.000 claims description 15
- -1 magnésium stéarate Chemical compound 0.000 claims description 13
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 claims description 11
- 239000008101 lactose Substances 0.000 claims description 11
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 10
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- 239000000546 pharmaceutic aid Substances 0.000 claims description 9
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 9
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 8
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 7
- UNXHWFMMPAWVPI-QWWZWVQMSA-N D-Threitol Natural products OC[C@@H](O)[C@H](O)CO UNXHWFMMPAWVPI-QWWZWVQMSA-N 0.000 claims description 7
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 7
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- UNXHWFMMPAWVPI-ZXZARUISSA-N Erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 7
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 4
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- VQHSOMBJVWLPSR-WUJBLJFYSA-N Maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 3
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N Trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 3
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- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(E)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 claims description 3
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- WWYNJERNGUHSAO-XUDSTZEESA-N Previfem Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 5
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- IIVBFTNIGYRNQY-YQLZSBIMSA-N Nomegestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 IIVBFTNIGYRNQY-YQLZSBIMSA-N 0.000 description 4
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- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229960003410 testosterone decanoate Drugs 0.000 description 1
- 229950003147 testosterone enantate Drugs 0.000 description 1
- VOCBWIIFXDYGNZ-IXKNJLPQSA-N testosterone enanthate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCC)[C@@]1(C)CC2 VOCBWIIFXDYGNZ-IXKNJLPQSA-N 0.000 description 1
- 229960000746 testosterone undecanoate Drugs 0.000 description 1
- 150000003515 testosterones Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960001023 tibolone Drugs 0.000 description 1
- 238000004450 types of analysis Methods 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
Abstract
The invention provides an orodispersible solid pharmaceutical dosage unit having a weight between 30 and 1,000 mg, said dosage unit consisting of: • 0.1-25 wt. % of estetrol particles containing at least 80 wt. % of an estetrol component selected from estetrol, estetrol esters and combinations thereof; and • 75-99.9 wt.% of one or more pharmaceutically acceptable ingredients; the solid dosage unit comprising at least 100 µg of the estetrol component; and wherein the solid dosage unit can be obtained by a process comprising wet granulation of estetrol particles having a volume weighted average particle size of 2 µm to 50 µm. The solid dosage unit is easy to manufacture and perfectly suited for sublingual, buccal or sublabial administration.
Description
The présent invention provides an orodispersîble solid pharmaceutical dosage unit having a weight of 30-1,000 mg 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 wt.% of estetrol particles containing at least 80 wt.% of the estetrol component; and • 75-99.9 wt.% of one or more pharmaceutically acceptable ingrédients.
The invention also provides a process of preparing the aforementioned solid dosage unit.
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 15 sublingual, buccal or sublabiat administration of the said dosage unit..
BACKGROUND OF THE INVENTION
Estetrol is a human steroid, produced by the fêtai liver during pregnancy only. This natural 20 hormone was discovered in urine of prégnant women by Diczfalusy and coworkers in 1965.
Estetrol has the structure of an estrogenic steroid with four hydroxyl groups. Estetrol is synthesized in the fêtai liver from estradiol and estriol by the two enzymes 15a- and 16ahydroxylase. After birth the néonatal liver rapidly loses its capacity to synthesize estetrol because these two enzymes are no longer expressed.
Estetrol reaches the maternai circulation through the placenta and was already detected at nine weeks of pregnancy in maternai urine. During the second trimester of pregnancy high levels were found in maternai plasma, with steadily rising concentrations of unconjugated estetrol to about 1 ng/mL (> 3 nmol/L) towards the end of pregnancy. So far the physiological function 30 of estetrol îs unknown. The possible use of estetrol as a marker for fêtai well-being has been studied quite extensively. However, due to the large intra- and inter-individual variation of maternai estetrol plasma levels during pregnancy this appeared not to be feasîble.
Since 2001 estetrol has been studied extensively. In humans estetrol was shown to hâve a high and dose-proportional oral bioavailability and a long terminal élimination half-life of about 28 hours. Results from in vitro studies showed that estetrol binds highly sélective to the estrogen receptors with preference for the ERa form of the receptor, unlike the estrogens ethinyl estradiol and 17p-estradiol. Also in contrast with ethinyl estradiol and especially with Ι7βestradiol, estetrol does not bind to sex hormone binding globulin (SHBG) and does not stimulate the production of SHBG in vitro.
The properties of estetrol hâve also been investigated in a sériés of prédictive, well validated pharmacological in vivo rat modeis. In these modeis, estetrol exhibited estrogenic effects on the vagina, the utérus (both myometrium and endometrium), body weight, bone mass, bone strength, hot flushes and on ovulation (inhibition). Ail these effects of estetrol were dosedependent with maximum effects at comparable dose levels. Surprisingly, estetrol prevented tumour development in a DMBA mammary tumour model to an extent and at a dose level similar to the anti-estrogen tamoxifen and to ovariectomy. This anti-estrogenic effect of estetrol in the presence of 17P-estradiol has also been observed in in vitro studies using human breast cancer cells.
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.
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 of the buccal and/or sublingual cavity.
US 2007/286829 describes an orally administered solid dosage form capable of delivering ethinyl estradiol with improved bioavailability, said solid dosage form comprising (i) about 0.5 pg to about 50 pg of ethinyl estradiol and (ii) an oral dissolution enhancing carrier that provides for at least 15% absorption of the ethinyl estradiol through the oral mucosa when said solid dosage form is orally administered to the patient with 2 ounces of water or less.
US 6,117,446 describes a buccal dosage unit for administering a combination of stéroïdal active agents, comprising a compressed tablet of a bioerodible polymeric carrier and therapeutically effective amounts of an androgénie 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, progestogen, androgen, polyethylene oxide, carbomer and magnésium 5 stéarate. Next, the mixture was granulated by means of fluid bed granulation and the granulate so obtained was pressed into tablets.
Oral dosage units containing estetrol hâve been described in several patent publications.
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 a therapy an effective amount of estetrol, said composition containing virtually no progestogen or anti-progestin, WO 2002/094276 describes the préparation of estetrol tablets having a weight of 185 mg, containing 1.5 mg estetrol, on the basis ofthe following formulation:
| mg | |
| Estetrol | 1.5 |
| Polyvinylpyrrolidone (Kollidon 25® ex BASF) | 12.5 |
| Lactose | 135.795 |
| Microcrystalline cellulose (Avicel PH 10l ®) | 26.25 |
| Glyceryl palmitostearate (Precirol ®) | 2.775 |
| Anhydrous colloïdal silica (Aerosil 200 ®) | 1.0 |
| Crospovidone (Polyplasdone XL ®) | 4.0 |
| Coloring agent | 0.18 |
WO 2002/094275 describes the use of an estetrol in a method of 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.
WO 2002/094279 describes the use of estetrol in a method of contraception in mammalian females, which method comprises the oral administration of said estrogenic component and a progestogenic component to a female of childbearing capability in an effective amount to inhibit ovulation. The following formulation for a 185 mg estetrol tablet is described in this international patent application.
| mg | |
| Estetrol | 1.5 |
| Levonorgestrel | 0.15 |
| Polyvinylpyrrolidone (Kollidon 25® ex BASF) | 13.5 |
| Lactose | 135.645 |
| Microcrystalline cellulose (Avicel PH 101 ®) | 26.25 |
| Glyceryl palmitostearate (Precirol ®) | 2.775 |
| Anhydrous colloïdal silica (Aerosil 200 ®) | 1.0 |
| Crospovidone (Polyplasdone XL ®) | 4.0 |
| Coloring agent | 0.18 |
WO 2003/041718 describes the use of estetrol in a method of hormone replacement in mammals, which method comprises the oral administration of estetrol and a progestogenic component to a mammal in an effective amount to prevent or treat symptoms of hypoestrogenism. This patent application describes the same estetrol tablet as WO 2002/094279.
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, upon demand, an effective amount of the estetrol to the mammal. This patent application describes the préparation of hard gélatine capsules, containing 100 mg estetrol and 25 mg sildenafil citrate per capsule.
WO 2008/156365 describes the use of estetrol in the treatment of Méconium Aspiration Syndrome (MAS) in a newbom infant, said treatment comprising administering an effective amount of estrogen to said newbom infant within 7 days after birth. The international patent application describes a suppository for use in newbom infants comprising at least 1 pg of estrogen, said suppository further being 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 lipid material that melts at body temperature or it may be based on a hydrophilic component that dissolves or disintegrates when it cornes into contact with water.
SUMMARY OF THE INVENTION
The présent invention provides an orodispersible solid pharmaceutical dosage unit containing an estetrol component. The dosage unit rapidly releases the estetrol in aqueous environment. The solid dosage unit is easy to manufacture by direct compression and perfectly suited for sublingual, buccal or sublabial administration. Sublingual, buccal and sublabial administration each offer the advantages that the estetrol component does not hâve to pass through the digestive system and avoids first-pass liver exposure. Furthermore, these modes of administration provide a rapid onset of action.
The solid dosage unit according to the présent invention has a weight between 30 and 1,000 mg and contains at least 100 pg of an estetrol component selected from estetrol, estetrol esters and combinations thereof; and consists of:
• 0.1-25 wt.% of estetrol particles containing at least 80 wt.% of the estetrol component; and • 75-99.9 wt.% of one or more pharmaceutically acceptable ingrédients.
This solid dosage is obtainable by a process comprising:
• providing estetrol particles containing at least 80 wt.% of an estetrol component selected from estetrol, estetrol esters and combinations thereof, said estetrol particles having a volume médian diameter in the range of 2 pm to 50 pm;
• preparing a dry blend by mixing the estetrol particles with one or more pharmaceutically acceptable ingrédients; and • compressing the dry blend into a solid dosage unit.
Rapid and complété dissolution of the estetrol component into saliva is essential for efficient delivery of the component via sublingual, buccal or sublabial administration of the solid dosage unit. The inventors hâve unexpectedly found that the estetrol component is rapidly released and dispersed into saliva and absorbed through the mucosat lining of the oral cavity if it is présent in the solid dosage unit in the form of very small particles.
The invention also provides a process of preparing the aforementioned solid dosage unit, said process comprising the steps of:
• providing estetrol particles containing at least 80 wt.% of an estetrol component selected from estetrol, estetrol esters and combinations thereof, said estetrol particles having a volume médian diameter in the range of 2 pm to 50 pm;
• preparing a dry blend by mixing 1 part by weight of the estetrol particles with 2-1,000 parts by weight of one or more pharmaceutically acceptable excipients; and • compressing the dry blend into a solid dosage unit.
BRIEF DESCRIPTION OF THE FIGURE
Figure 1 illustrâtes the manufacturing process flow chart used in Example 3.
DETAILED DESCRIPTION OFTHE INVENTION
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 wt.% of estetrol particles containing at least 80 wt.% of an estetrol component selected from estetrol, estetrol esters and combinations thereof; and • 75-99.9 wt.% of one or more pharmaceutically acceptable ingrédients; the solid dosage unit comprising at least 100 pg of the estetrol component; wherein the solid dosage unit can be obtained by a process comprising:
• providing estetrol particles containing at least 80 wt.% of an estetrol component selected from estetrol, estetrol esters and combinations thereof, said estetrol particles having a volume médian diameter in the range of 2 pm to 50 pm;
• preparing a dry blend by mixing the estetrol particles with one or more pharmaceutically acceptable excipients; and • compressing the dry blend into a solid dosage unit.
The term ‘estetrol’ as used herein refers to 1,3,5 (10)-estratrien-3,15a,16a,17p-tetrol or 15ahydroxyestriol as well as hydrates of estetrol, e.g. estetrol monohydrate.
The term ‘orodispersible dosage unit’ as used herein refers to a dosage unit that is designed to rapidly disintegrate in the oral cavity when it cornes into contact with saliva and to disperse the estetrol component into the saliva so it may be absorbed through the mucosal lining of the oral cavity.
The terms ‘pharmaceutically acceptable ingrédients’ as used herein include both pharmaceutically acceptable excipients and pharmaceutically active ingrédients other than the estetrol component, as further defined below.
The term ‘sublingual’ as used herein refers to the pharmacological route of administration by which the estetrol component diffuses into the blood through tissues under the tongue.
The term ‘buccal’ as used herein refers to the pharmacological route of administration by which the estetrol component diffuses into the blood through tissues of the buccal vestibule, the area inside the mouth between the lining of cheek (the buccal mucosa) and the teeth / gums.
The term ‘sublabial' as used herein refers to the pharmacological route of administration by which the estetrol component is placed between the lip and the gingiva.
Unless indicated otherwise, ail percentages mentioned herein are percentages by weight.
Examples of solid dosage units encompassed by the présent invention include tablets, dragees, lozenges and films. In accordance with a preferred embodiment, the dosage unit is a tablet, most preferably a compressed tablet.
The solid dosage unit typically has a weight between 40 and 500 mg, more preferably between 50 and 300 mg, and most preferably between 70 and 150 mg.
The solid dosage unit preferably comprises 0.5-25 wt.%, more preferably 1-20 wt.% and most preferably 1.2-15 wt.% ofthe estetrol component.
The amount of the estetrol component contained in the solid dosage unit preferably lies within the range of 0.3-100 mg, more preferably of 0.5-40 mg and most preferably of 1 -20 mg.
The estetrol component of the présent invention preferably is selected from the group consisting of estetrol, esters of estetrol wherein the hydrogen atom of at least one of the hydroxyl groups has been substituted by an acyl radical of a hydrocarbon carboxyiic, sulfonic acid or sulfamic acid of 1-25 carbon atoms; and combinations thereof. Even more preferably, the estetrol component is estetrol (including estetrol hydrates). Most preferably, the estetrol component contained in the dosage unit is estetrol monohydrate.
The particle size of the estetrol particles in the solid dosage unit should be adéquate for achieving 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 the préparation of the solid dosage unit preferably hâve a volume médian diameter in the range of 3 pm to 35 pm, more preferably in the range of 4 pm to 25 pm and most preferably in the range of 5 pm to 15 pm.
The estetrol particles within the solid dosage unit and (independently) the estetrol particles used in the préparation of the solid dosage unit preferably contain not more than a Iimited amount of particles with a particle size in excess of 60 pm. Preferably, not more than 10 vol.% of more than 60 pm (Dço), more preferably not more than 5 vol.% of the estetrol particles hâve a particle size of more than 60 pm (D95). Even more preferably, not more than 10 vol.% of more than 40 pm (D90), more preferably not more than 5 vol.% of the estetrol particles hâve a particle size of more than 40 pm (D95).
The particles size distribution of the estetrol particles, and of other particulate materials used in the présent process, may suitably be determined by means of laser diffraction. The particle size distribution of the estetrol particles within the solid dosage unit can suitably be determined using spectroscopic techniques, e.g. Raman mapping.
The solid dosage unit of the présent invention offers the advantage that the estetrol component is rapidly released when the dosage unit is introduced into the oral c a vit y and cornes into contact with saliva. The rate of release of the estetrol component from the dosage unit can suitably be determined using the dissolution test described in the Examples, or a disintegration test according to 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 présent invention, when subjected to the aforementîoned dissolution test, typically 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 présent invention, when subjected to the aforementioned disintegration test, typically disintegrates within less than 5 minutes, more preferably within less than 2 minutes, still more preferably within less than 1,5 minutes, still more preferably within less than 1 minute, still more preferably within less than 45 seconds, and most preferably within less than 30 seconds.
The estetrol particles employed in the solid dosage unit and in the présent process preferably contain at least 90 wt.% of the estetrol component, more preferably at least 95 wt.% of the estetrol component and most preferably at least 99 wt.% of the estetrol component. Besides the estetrol component, the estetrol particles can 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 microcrystalline cellulose, tensioactive agents, cosolvents, absorption enhancer, superdisintegrants and buffering agents.
The estetrol particles typically represent between 0.5-35 wt.% of the dosage unit. More preferably, the estetrol particles represent 1-22 wt.%, most preferably 1.2-15 wt.% ofthe dosage unit.
The dosage unit of the présent invention preferably contains 50-99.5 wt.%, more preferably 55-90 wt.% and most preferably 60-88 wt.% of filler selected from maltose, fructose, sucrose, lactose, glucose, galactose, trehalose, xylitol, sorbitol, erythritol, maltitol, mannitol, isomalt, microcrystalline cellulose, calcium salts (e.g. calcium phosphates) and combinations thereof.
According to a particularly preferred embodiment, the dosage unit contains 30-99.5 wt.%, more preferably 50-90 wt.% and most preferably 60-80 wt.% of filler selected from lactose, xylitol, sorbitol, erythritol, mannitol, microcrystalline cellulose and combinations thereof.
Advantageously, the dosage unit contains at least 20 wt.% of sugar alcohol selected from mannitol, xylitol and combinations thereof. More preferably, the dosage unit contains 30-90 wt.% of sugar alcohol selected from mannitol, xylitol and combinations therof. Most preferably, the dosage unît contains 40-80 wt.% of sugar alcohol selected from mannitol, xylitol and combinations thereof.
Dosage unit according to any one of the preceding claims, wherein the dosage unit contains 0.1-20 wt.%, more preferably 0.2-10 wt.% and most preferably 1-5 wt.% of a disintegrating agent selected from modified starches (e.g. sodium sait of carboxymethyl starch), crosslinked polyvinyl pyrrolidone, crosslinked carmefiose and combinations thereof.
The combination of estetrol particles, filler and disintegrating agent typically constitutes at least 70 wt.% of the solid dosage unit. More preferably, said combination constitutes at least 80 wt.% and most preferably at least 90 wt.% of the dosage unit.
The solid dosage unit of the présent invention preferably contains 0-60 wt.%, more preferably 5-40 wt.% and most preferably 10-35 wt.%microcrystanine cellulose.
According to another preferred embodiment, the dosage unit contains 0.1-2 wt.%, more preferably 0.2-1.5 wt.% and most preferably 0.5-1 wt.% of lubricant selected from sodium stearyl fiimarate, magnésium stéarate, stearic acid, sodium lauryl sulfate, talc, polyethylene glycol, calcium stéarate and mixtures thereof.
Other excipients that may suitably be incorporated in the dosage include mucoadhesive agents, flavouring, colouring, sweeteners (other than sweet tasting filters), glidents and combinations thereof.
The solid dosage unit may contain one or more other pharmaceutically active ingrédients besides the estetrol component. Examples of such other pharmaceutically active ingrédients include steroid hormones. The solid dosage unit of the présent invention preferably contains 0.05-10 mg, more preferably 0.1-5 mg of one or more progestogens, preferably one or more progestogens selected from progestérone, levonorgestrel, norgestimate, norethisterone, norethisteron-acetate (ΝΕΤΑ), dydrogesterone, drospirenone, 3-beta-hydroxydesogestrel, 3keto desogestrel (=etonogestrel), 17-deacetyl norgestimate, 19-norprogesterone, acetoxypregnenolone, allylestrenol, anagestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, flurogestone acetate, gastrinon, gestodene, gestrinone, hydroxym ethyl progestérone, hydroxyprogesterone, lynestrenol (=lynoestrenol), medrogestone, medroxyprogesterone, megestrol, melengestrol, nestorone, nomegestrol, nomegestrol-acetate (NOMAC), norethindrone (=norethisterone), norethynodrel, norgestrel (includes d-norgestrel and dl18501 norgestrel), norgestrienone, normethisterone, progestérone, quingestanol, (17a!pha)-17hydroxy-11 -methylene-1 9-norpregna-4,l 5-diene-20-yn-3 -one, tibolone, trimegestone, algestone acetophenide, nestorone, promegestone, 17-hydroxyprogesterone esters, 19-nor17hydroxyprogesterone, 17alpha-ethinyl-testosterone, 17alpha-ethinyl-19-nor-testosterone, d5 17beta-acetoxy-13beta-ethyl-17alpha-ethinyl-gon-4-en-3-one oxime and prodrugs of these compounds. Preferably the one or more progestogens used in accordance with the présent invention is selected from the group consisting of progestérone, desogestrel, etonogestrel, gestodene, dienogest, levonorgestrel, norgestimate, norethisterone, norethisteron-acetate (ΝΕΤΑ), nomegestrol, nomegestrol-acetate (NOMAC), drospirenone, trimegestone, nestorone 10 and dydrogesterone.
The solid dosage unit according to the présent 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, déhydroépiandrostérone (DHEA); DHEA-sulphate (DHEAS);
testosterone esters (e.g. testosterone undecanoate, testosterone propionate, testosterone phenylpropionate, testosterone isohexanoate, testosterone enantate, testosterone bucanate, testosterone decanoate, testosterone buciclate); methyltestosterone; mesterolon; stanozolol; androstenedione; dihydrotestosterone; androstanediol; metenolon; fluoxymesterone; oxymesterone; methandrostenolol; MENT and prodrugs of these compounds. Most preferably 20 the one or more androgens are selected from the group consisting of testosterone, DHEA and MENT.
Another aspect of the présent invention relates to the use of the aforementioned solid dosage unit in medical treatment, in female hormone replacement therapy or in female contraception, 25 said use comprising sublingual, buccal or sublabial administration of the dosage unit.
Examples of medical treatment in which the solid dosage unit of the présent invention may suitably be used include treatment of osteoporosis and estrogen add-back treatment in endometriosis, breast cancer or prostate cancer. In accordance with a preferred embodiment, the solid dosage unit is used in female hormone replacement therapy or female contraception. 30 Most preferably, the solid dosage is used in female hormone replacement therapy, especially to treat vulvovaginal atrophy and/or vasomotor symptoms.
The use ofthe solid dosage unit in medical treatment, in female hormone replacement therapy or in 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 most preferably
-40 mg of the estetrol component.
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 administered dosage unit provides at least 0.5 mg, most preferably at least 1 mg of the estetrol component. ln the treatment of vulvovaginal atrophy the dosage unit is preferably administered in an amount that provides no more than 50 mg, more preferably not more than 20 mg and most preferably not more than 10 mg of the estetrol component.
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 administered dosage unit provides at least 1 mg, most preferably of 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 no more than 100 mg, more preferably not more than 40 mg and most preferably not more than 20 mg of the estetrol component.
Typically, these uses of the solid dosage unit comprise once daily administration of the dosage unit during a period of at least 1 week, more preferably of 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 of 0.1-40 mg and most preferably of 0,2-20 mg of the estetrol component.
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, most preferably of 1-10 mg of the estetrol component.
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, most preferably 2-20 mg of the estetrol component.
Yet another aspect of the invention relates to a process of preparing a solid dosage unit as described herein before, said process comprising the steps of:
• providing estetrol particles containing at least 80 wt.% of an estetrol component selected from estetrol, estetrol esters and combinations thereof, said estetrol particles having a volume médian diameter in the range of 2 pm to 50 pm;
• preparing a dry btend by mixing 1 part by weight of the estetrol particles with 2-1,000 parts by weight of one or more pharmaceutically acceptable excipients; and • compressing the dry btend into a solid dosage unit.
The process of the présent invention preferably does not comprise addition of liquid solvent during or after the combining of the estetrol particles and the one or more pharmaceutically 10 acceptable excipients.
In the présent process the dry blend that is compressed into a solid dosage unit is preferably produced by combining the estetrol particles with the one or more pharmaceutically acceptable excipients in a weight ratio that is in the range of 1:3 to 1:500, more preferably in 15 the range of 1:4 to 1:100 and most preferably in the range of 1:5 to 1:10.
The dry blend that is compressed into the solid dosage unit preferably contains 50-99.5 wt.%, more preferably 55-90 wt.% and most preferably 60-88 wt.% of fïller as defined herein before.
According to a particularly preferred embodiment the dry btend contains 30-99.5 wt.%, more preferably 50-90 wt.% and most preferably 60-80 wt.% of fïller selected from lactose, xylitol, sorbitol, erythritol, mannitol, microcrystalline cellulose and combinations thereof.
Sugar alcohol selected from mannitol, xylitol and combinations thereof is advantageously contained in the dry blend in a concentration of at least 20 wt.%. More preferably, said sugar alcohol is contained in the dry blend in a concentration of 30-90 wt.%, most preferably of 4080 wt.%.
According to another preferred embodiment, the dry blend contains 0.1-20 wt.%, more preferably 0.2-10 wt.% and most preferably 1-5 wt.% of a disintegrating agent selected from modified starches, croslinked polyvinylpyrrolidone, crosslinked carmellose and combinations thereof.
The combination of estetrol particles, filler and disintegrating agent typically constitutes at least 70 wt.% of the dry blend. More preferably, said combination constitutes at least 80 wt.% and most preferably at least 90 wt.% of the dry blend.
The solid dosage unit of the présent invention preferably contains 0-60 wt.%, more preferably 5-40 wt.% and most preferably 10-35 wt.% microcrystalline cellulose.
The dry blend employed in the présent process preferably contains 0-60 wt.%, more preferably 5-40 wt.% and most preferably 10-35 wt.% microcrystalline cellulose.
The dry blend that is compressed into the solid dosage unit preferably contains 0.1-2 wt.%, more preferably 0.2-1.5 wt.% and most preferably 0.5-1 wt.% of lubricant selected from sodium stearyl fumarate, magnésium stéarate, stearic acid, sodium lauryl sulfate, talc, polyethylene glycol, calcium stéarate and mixtures thereof.
The dry blend is preferably compressed into a solid dosage unit by means of direct compression.
The solid dosage units obtained by the présent method can be packaged in different ways. Preferably, the dosage units are packaged in a blister pack containing at least 14 dosage units.
The invention is further illustrated by means of the following non-Iimiting examples.
EXAMPLES
Dissolution test
The dissolution test described below can be used to study the dissolution behaviour of orodispersible dosage units.
Dissolution apparatus • Paddle and basket dissolution tester VanKel VK 7010 or VK 7025, autosampler VK 8000, 1000 mL dissolution vessels and porous micron filters (35 pin)
Dissolution Medium • Transfer 9,000 ml of demineralised water into a volumétrie flask of 10,000 ml.
• Add 68.05 g of KH2PO4 and 8.96 g NaOH and stîr the solution until everythîng is dissolved.
• Mix the solution and adjust the pH to 6.8 with NaOH or phosphoric acid, if necessary and make up to volume with demineralised water.
Dissolution Procedure • Transfer 900 ml of Dissolution Medium into each vessel of the paddle apparatus.
• Assemble the apparatus, warm the medium to 37 ± 0.5 °C, and remove the thermometer.
• Place in each of the six vessels one tablet at the bottom before starting the rotation ofthe paddles.
• Start the rotation of the paddles immediately.
• Use a stîrring speed of 50 rpm.
• Take samples of 5 ml from the dissolution vessels after 5, 10, 20, 30, 45, 60, 75 and 90 minutes for a complété dissolution profile. Take the sample from a position midway between the surface of the dissolution medium and the top ofthe paddle blade and not less than 10 mm from the vessel wall. The removed dissolution volume is not replaced by fresh dissolution medium.
Estetrol concentrations in the samples were determined by means of HPLC using estetrol stock solutions as a reference.
Préparation of mobile phase (MP) phosphate buffer • Transfer 1.15 g of NH4H2PO4 (10 mM) into a 1,000 mi of demineralised water, dissolve it and adjust the pH to 3.0 with phosphoric acid.
HPLC apparatus • Alliance 2695 Séparations module consisting of a quatemary solvent delivery system, a variable volume injecter, a température controlled autosampler, column thermostat and Photodiode array detector 2996 (ail by Waters) • Analytical colunm: Symmetry CI8,3.9 x 150 mm, dp = 5 μτη (ex Waters) • Guard column: Security guard columg C18,4x3 mm (Phenomenex) • Flow: 1.0 mL/min • Détection: UV @ 280 nm • Column température: 30°C • Autosampler température: 10°C • Injection volume: 100 pL • Runtime: 12 min
Elution gradient
| Time (min) | Acetonitrile (%) | Phosphate buffer (%) |
| 0 | 20 | 80 |
| 9 | 75 | 25 |
| 10 | 20 | 80 |
| 12 | 20 | 80 |
The dissolution tests are conducted in triplicate.
Particle size measurements
Particle size distribution of estetrol monohydrate is performed using a MALVERN MASTERSiZER MiCROPLUS laser particle size analyzer.
Préparation of dispersion medium:
• Weigh 1 g of estetrol monohydrate and 1g of sorbitan trioleate into a flask.
• A dd 1 litre of n-hexane and mix for at least i hour at room température • Filter through a 0.45 pm filter.
Sample préparation:
• Put 100 mg of sample in a 25 mL beaker.
• Add some drops of dispersion medium.
• Mix carefully with a glass rod to suspend well the powder.
• Add 10 mLof dispersion medium.
• Perform the analysis with the sample dispersion unit's speed at 3000-3500 rpm.
Analysis:
Particle size measurements are performed three times using the same dispersion. The final resuit is obtained by averaging the results of the three déterminations.
Exemple 1
A sublingual tablet is prepared by means of the procedure described below.
A tabletting mixture having the composition shown in Table 1 is prepared by dry blending, using a low shear mixer.
Table 1
| Ingrédients . | Wt.% |
| Milled estetrol1 | 12.5 |
| Mannitol | 47.5 |
| Lactose | 30 |
| PVP (polyvinylpyrrolidone) | 4 |
| Sodium crosscarmellose | 4 |
| Flavour | 0.5 |
| Aspartame | 1 |
| Magnésium stéarate | 0.5 |
1 D(v.o.s)= 15pm
The tabletting mixture is compressed into 80 mg round tablets with a diameter of 6.5 mm. The estetrol content of these tablets is 10 mg.
Example 2
A sublingual tablet is prepared by means of the procedure described below.
A tabletting mixture having the composition shown in Table 2 is prepared by dry blending using a low shear mixer.
Table 2
| Ingrédients | Wt.% |
| Milled estetrol1 | 12.5 |
| Mannitol | 37.5 |
| Xylitol | 10 |
| Microcrystaliine cellulose | 33 |
| Sodium starch glycolate | 5 |
| Flavour | 0.5 |
| Aspartame | 1 |
| Magnésium stéarate | 0.5 |
* D(V,os)= I5pm
The tabletting mixture is compressed into 80 mg round tablets with a diameter of 6.5 mm. The estetrol content of these tablets is 10 mg.
Example 3
Five different sets of sublingual tablets (formulations A to E) were prepared by means of the procedure described below and illustrated în Figure 1.
The target amounts of estetrol per tablet were as follows: 100 pg for formulation A, 1 mg for formulation B, and 10 mg for formulations C, D and E.
The target weights for the tablets were as follows: 30 mg for formulation A, lOOOmg for formulation B, and 80 mg for formulations C, D and E.
The estetrol was mixed with a part of the main diluent and screened over a 800 pm screen. ΑΠ other excipients were also screened over a 800 pm screen.
The materials were weighed and transferred into the mixing container (except for magnésium stéarate) and mixed for 15 minutes. Finally, magnésium stéarate was added and mixed for a further 3 minutes.
Compression was executed using a single punch machine equipped with a proper punch (5 mm punch for 30 mg tablets (A), 6 mm for 80 mg tablets (C, D and E) and 15 mm for 1000 mg tablets (B)).
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.
Hardness was measured using the known protocol described in Ph. Eur. 2.9.8 (“Résistance to 5 crushing of tablets”).
The final formulations and corresponding tablet results can be found in Tables 3 and 4 below.
Ail formulations were prepared and processed into tablets without encountering any spécifie 10 difficulties. It should be noted that a good flowing diluent was used in ail formulations to overcome flowability issues and that the concentration of magnésium stéarate was at least 1.5% to avoid sticking.
1 D (v.os)= 15pm
Table 3 — details of the formulations In Wt.%
| Formulation # | A | B | C | D | E |
| Milled Estetrol1 | 0.33 | 0.1 | 12.50 | 12.40 | 12.35 |
| Mannitol | 83.14 | 83.47 | 71.00 | 48.47 | 38.62 |
| Maize starch | 10.01 | 10.00 | 10.00 | ||
| Crospovidone | 5.01 | 5.01 | 4.99 | ||
| Lactose | 29.68 | ||||
| PVP (polyvinylpyrrolidone) | 3.98 | ||||
| Sodium crosscarmellose | 3.98 | ||||
| Xylitol DC | 9.91 | ||||
| Microcrystalline cellulose | 32.66 | ||||
| Sodium starch glycolate | 4.97 | ||||
| Magnésium stéarate | 1.51 | 1.51 | 1.50 | 1.49 | 1.48 |
Table 4 - experimentally determined characteristics of the Tablets
| Test (average resuit of 6 samples) | Disintegration time | Hardness | Weight |
| Formulation # | (min:sec) | (N) | (mg) |
| A | 0:53 | 39.57 | 33.22 |
| B | 1:07 | 86.07 | 1060.37 |
| C | 0:39 | 57.49 | 81.16 |
| D | 0:39 | 42.71 | 78.48 |
| E | 0:38 | 37.29 | 76.49 |
It can be seen that al! tablets were obtained with a final weight close to their target weight and that the disintegration times, even for the largest 1 g tablet, were very short, in accordance with the intended sublingual, buccal or sublabial administration route for these tablets. Finally, the hardness of ail tablets was within a very acceptable range.
Example 4
A randomized, open-label, two-period, cross-over, pharmacokinetic study is conducted to compare sublingual bîoavailability of 10 mg estetrol administered in one 100 mg tablet with oral availability of estetrol contained in a 83 mg tablet containing 10 mg estetrol. These tablets are administered sublingually and orally to healthy female volunteers under fasting conditions.
Ten healthy female subjects are selected on the basîs ofthe following criteria: âge of 45-65 years (inclusive), nonsmokers or past smokers (at least 6 months before dosing), body-mass index (BMI) = 18.5 to 30 kg/m2 (inclusive at the time of the screening).
The composition of the 100 mg sublingual tablets is described in Table 5 below.
TableS
| Quantity (Wt.%) | Function | |
| Milled Estetrol1 | 10 | Active ingrédient |
| Ludiflash®4' | 84 | Diluent/binder/super disintegrant |
| Kollidon CL-SF®3 | 3 | Super disintegrant |
| Magnésium stéarate | 3 | Lubricant |
2 A mixture of mannitol (90 wt.%), Kollidon CL-SF® 3 (5 wt.%) and Kollicoat® SR30D (a polyvinyl acetate dispersion in povidone) (5 wt.%) 3 crospovidone superfine grade
These tablets hâve a very fast disintegration time (of 40 seconds on average).
At the start ofthe first and the second period ofthe study, between 07:00 am and 07:28 am, 5 subjects receive a single dose ofthe sublingual formulation of estetrol by administering one estetrol tablet (tablet weight 100 mg; 10 mg estetrol) and 5 subjects receive a single oral dose ofthe oral estetrol formulation by administering one estetrol tablet (tablet weight 83 mg; 10 mg estetrol), ingested together with 200 ml water.
Subjects are required to fast for at least 10 hours prior to tablet administration and for at least 4 hours after administration. Drinking of water or beverages is not permitted within 1 hour before the drug administration. Subjects receive 200 ml of water 1 hour prior to and 2 hours after tablet administration. Subjects are free to drink water and fruit tea from 4 hours following the tablet administration. Standardized meals are provided 10.5 hours before and 4, 6,9, and 13 hours after tablet administration.
The sequence of events that occurs during the first and second period is shown in Table 6:
Table 6
| Event | |
| First period | |
| • Day 1 | Confinement from 19:00 |
| • Day 2 | Dosing, blood and urine sampling, confinement |
| • Day 3 | Exit procedure, confinement till 8 am |
| • Days 4-8 | Retum visits |
| • Days 9-13 | Wash out |
| Second period | |
| • Day 14 | Confinement from 19:00 |
| • Day 15 | Dosing, blood and urine sampling, confinement |
| • Day 16 | Exit procedure, confinement till 8 am |
| • Days 17-21 | Retum visits |
| • Days 22-26 | Wash out |
| • Day 27 | Administration of a progestin |
| • Day 28 | Phone call, progestin withdrawal test check |
The blood and urine sampling schedule used in this study is shown in Table 7.
Table 7
| Blood sampling | Blood collection (4 ml) is performed prior to administration of the tablet (0), and subsequently 0:10,0:15,0:20,0:25,0:30,0:35,0:40,0:45,0:50,0:55, 1:00, 1:10, 1:20, 1:30, 2, 3,4,6, 10, 16, 24,48,72,96, 120, 144 hours after administration. Total number of blood collections in each period is 27. |
| Urine sampling | Urine collection is performed prior to administration of the tablet and 2,4,8, 12,24,48,72,96, 120 and 144 hours after administration. Total number of urine collections in each period is 11. |
The estetrol concentration in the collected blood samples is determined by means of HPLC/MS/MS. The concentrations of glucuronided estetrol (D-ring) in the urine samples is also determined with the help of HPLC/MS/MS.
Results of these analyses show that the bioavailability of sublingually administered estetrol is 5 comparable or even superior to orally administered estetrol. Furthermore, the data suggest that sublingually administered estetrol has an earlier bioavailability compared to orally administered estetrol. Sublingual estetrol has less impact on a liver function parameter.
Claims (15)
1. An orodispersible solid pharmaceutical dosage unit having a weight between 30 and 1,000 mg, said dosage unit consisting of:
• 0.1-25 wt.% of estetrol particles containing at least 80 wt.% of an estetrol component selected from estetrol, estetrol esters and combinations thereof; and • 75-99.9 wt.% of one or more pharmaceutically acceptable ingrédients; the solid dosage unit comprising at least 100 pg of the estetrol component; wherein the solid dosage unit can be obtained by a process comprising:
• providing estetrol particles containing at least 80 wt.% of an estetrol component selected from estetrol, estetrol esters and combinations thereof, said estetrol particles having a volume médian diameter in the range of 2 pm to 50 pm;
• preparing a dry blend by mixing the estetrol particles with one or more pharmaceutically acceptable excipients; and • compressing the dry blend into a solid dosage unit.
2. Dosage unit according to claim 1, wherein the dosage unit has a weight between 40 and 500 mg.
3. Dosage unit according to claim 1 or 2, wherein the dosage unit contains 0.5-25 wt.% of the estetrol component.
4. Dosage unit according to any one of the preceding claims, wherein the dosage unit contains 0.3-100 mg ofthe estetrol component.
5. Dosage unit according to any one of the preceding claims, wherein the estetrol component is estetrol.
6. Dosage unit according to any one of the preceding claims, wherein the estetrol particles hâve a volume médian diameter of 3-35 pm.
7. Dosage unit according to any one of the preceding claims, wherein the dosage unit contains 50-99.5 wt.% of filler selected from maltose, fructose, sucrose, lactose, glucose, galactose, trehalose, xylitol, sorbitol, erythritol, maltitol, mannitol, isomalt, microcrystalline cellulose, calcium salts and combinations thereof.
8. Dosage unit according to claim 7, wherein the dosage unit contains 50-99.5 wt.% of filler selected from lactose, xylitol, sorbitol, erythritol, mannitol, microcrystalline cellulose and combinations thereof.
9. Dosage unit according to claim 7 or 8, wherein the dosage unit contains at least 20 wt.% of sugar alcohol selected from mannitol, xylitol and combinations thereof.
10. Dosage unit according to any one of the preceding claims, wherein the dosage unit contains 0.1-20 wt.% of a disintegrating agent selected from modified starches, crosslinked polyvinyl pyrrolidone, crosslinked carmellose and combinations thereof.
11. Dosage unit according to any one of the preceding claims, wherein the dosage unit contains 0-60 wt.% of microcrystalline cellulose.
12. Dosage unit according to any one of the preceding claims, wherein the dosage unit contains 0.1-2 wt.% of lubricant selected from sodium stearyl fumarate, magnésium stéarate, stearic acid, sodium lauryl sulfate, talc, polyethylene glycol, calcium stéarate and mixtures thereof.
13. A solid dosage unit according to any one of the preceding claims for use in medical treatment or for use in female hormone replacement therapy, said use comprising sublingual, buccal or sublabial administration of the dosage unit.
14. Solid dosage unit for the Use according to claim 13, said use comprising once daily administration during a period of at least 1 week.
15. Use of an estetrol component for the manufacture of a médicament in the form of a solid dosage unit according to any one of claims 1-12, for female contraception, said contraception comprising sublingual, buccal or sublabial administration of the dosage unit.
16. Use of an estetrol component for the manufacture of a médicament in the form of a solid dosage unit, for female contraception, according to claim 15, wherein said contraception comprises once daily administration during a period of at least 1 week.
17. A process of preparing a solid dosage unit according to any one of claims 1-12, said process comprising the steps of:
• providing estetrol particles containing at least 80 wt.% of an estetrol component selected from estetrol, estetrol esters and combinations thereof, said estetrol particles having a volume médian diameter in the range of 2 pm to 50 pm;
• preparing a dry blend by mixing 1 part by weight of the estetrol particles with 2-1,000 parts by weight of one or more pharmaceutically acceptable excipients; and • compressing the dry blend into a solid dosage unit.
18. Process according to claim 17, wherein the process does not comprise addition of liquid solvent during or after the combining of the estetrol particles and the one or more pharmaceutically acceptable excipients.
19. Process according to claim 17 or 18, wherein the estetrol particles hâve a volume médian diameter of 3-35 pm.
20. Process according to any one of claims 17-19, wherein the dry blend contains 50-99.5 wt.% of a Aller selected from maltose, fructose, sucrose, lactose, glucose, galactose, trehalose, xylitol, sorbitol, erythritol, maltitol, mannitol, isomalt, microcrystalline cellulose, calcium salts and combinations thereof.
21. Process according to claim 20, wherein the dosage unit contains 50-99.5 wt.% of filler selected from lactose, xylitol, sorbitol, erythritol, mannitol, microcrystalline cellulose and combinations thereof.
22. Process according to claim 20 or 21, wherein the dry blend contains at least 20 wt.% of sugar alcohol selected from mannitol, xylitol and combinations thereof.
23. Process according to any one of claims 17-22, wherein the dry blend contains 0.1-20 wt.% 5 of a disintegrating agent selected from modified starches, crosslinked polyvinylpyrrotidone, crosslinked carmellose and combinations thereof.
24. Process according to any one of claims 17-23, wherein the dosage unit contains 0-60 wt.% of microcrystalline cellulose.
25. Process according to any one of claims 17-24, wherein the dry blend contains 0.1-2 wt.% of lubricant selected from sodium stearyl fumarate, magnésium stéarate, stearic acid, sodium lauryl sulfate, talc, polyethylene glycol, calcium stéarate and mixtures thereof.
15 26. Process according to any one of claims 17-25, wherein the solid dosage unit is formed by direct compression.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP15172747.6 | 2015-06-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA18501A true OA18501A (en) | 2018-12-04 |
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