OA18470A - Orodispersible dosage unit containing an estetrol component - Google Patents
Orodispersible dosage unit containing an estetrol component Download PDFInfo
- Publication number
- OA18470A OA18470A OA1201700463 OA18470A OA 18470 A OA18470 A OA 18470A OA 1201700463 OA1201700463 OA 1201700463 OA 18470 A OA18470 A OA 18470A
- Authority
- OA
- OAPI
- Prior art keywords
- estetrol
- dosage unit
- granulation
- granules
- combinations
- Prior art date
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- 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 221
- 229950009589 Estetrol Drugs 0.000 title claims abstract description 217
- 239000007787 solid Substances 0.000 claims abstract description 67
- 239000002245 particle Substances 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 45
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 118
- 238000005469 granulation Methods 0.000 claims description 93
- 230000003179 granulation Effects 0.000 claims description 93
- 239000008187 granular material Substances 0.000 claims description 73
- 239000007788 liquid Substances 0.000 claims description 53
- 238000002156 mixing Methods 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 20
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 18
- 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
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 17
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- 239000011230 binding agent Substances 0.000 claims description 15
- 239000008101 lactose Substances 0.000 claims description 15
- 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 14
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- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 claims description 6
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N Xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 5
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 229950008138 Carmellose Drugs 0.000 claims description 3
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- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- 238000007907 direct compression Methods 0.000 claims description 3
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- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 claims description 2
- CWSZBVAUYPTXTG-UHFFFAOYSA-N 5-[6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxy-5-[4-hydroxy-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OCCO)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 CWSZBVAUYPTXTG-UHFFFAOYSA-N 0.000 claims description 2
- 229920001817 Agar Polymers 0.000 claims description 2
- GZCGUPFRVQAUEE-KCDKBNATSA-N D-(+)-Galactose Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-KCDKBNATSA-N 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims 1
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960001910 lynestrenol Drugs 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229960000606 medrogestone Drugs 0.000 description 1
- 229960004616 medroxyprogesterone Drugs 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- JBVNBBXAMBZTMQ-CEGNMAFCSA-N megestrol Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 JBVNBBXAMBZTMQ-CEGNMAFCSA-N 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229960000270 methylestrenolone Drugs 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229960002831 norgestrienone Drugs 0.000 description 1
- 238000009806 oophorectomy Methods 0.000 description 1
- 230000036220 oral bioavailability Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229950008280 oxymesterone Drugs 0.000 description 1
- 239000011236 particulate material Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 229920001888 polyacrylic acid Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229960001584 promegestone Drugs 0.000 description 1
- 229960004183 quingestanol Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001507 sample dispersion Methods 0.000 description 1
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 230000003637 steroidlike Effects 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
- 229960003410 testosterone decanoate Drugs 0.000 description 1
- 229950003147 testosterone enantate Drugs 0.000 description 1
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- 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
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Abstract
The invention provides an orodispersible solid pharmaceutical dosage unit having a weight between 30 and 1,000 mg, said dosage unit consisting of:• 0.125 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 orodispersible 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 unît 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 sublingual, buccal or sublabial administration of the solid dosage unit.
BACKGROUND OFTHE INVENTION
Estetrol is a human steroid, produced by the fêtai liver during pregnancy only. This natural 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 cstriol by the two enzymes 15a- and 16ahydroxylase. After bîrth 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 risïng concentrations of unconjugated estetrol to about 1 ng/mL (> 3 nmol/L) towards the end of pregnancy. So far the physiologîcal function of estetrol is unknown. The possible use of estetrol as a marker for fêtai well-being has been studied quîte extensively. However, due to the large intra- and inter-individual variation of maternai estetrol plasma levels during pregnancy this appeared not to be feasible.
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 17βestradiol, 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 models. In these models, 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. Surprisîngly, 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 t
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 steroidal 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 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 of the following formulation:
mg | |
Estetrol | 1.5 |
Polyvinylpyrrolidone (Kollidon 25® ex BASF) | 12.5 |
Lactose | 135.795 |
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 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 mentîoned as a suitable mode of administration. Thîs 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 10 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 (Preciro! ®) | 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 15 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 20 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 température or Ît 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 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; 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 the estetrol component and having a volume médian diameter of 2 pm to 50 pm;
• 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 estetrol-containing granules, said granulation liquid containing at least 60 wt.% of liquid solvent;
• removing liquid solvent from the estetrol-containing granules to produce dry estetrolcontaining granules;
• optionally mixing the dry granules with one or more tabletting excipients; and • forming the dry granules or the mixture of the dry granules and the one or more tabletting excipients into a solid dosage unit.
Rapid and complété dissolution of the estetrol component into saliva is essentia! for efficient delivery of the component via sublingual, buccal or sublabia! 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 mucosa! 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 thereof and having a volume médian diameter of 2 pm to 50 pm;
• 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 estetrol-containing granules, said granulation liquid containing at least 60 wt.% of liquid solvent;
• removing liquid solvent from the estetrol-containing granules to produce dry estetrolcontaining granules;
• optionally mixing the dry granules with one or more pharmaceutically acceptable excipients; and • forming the dry granules or the mixture of the dry granules and the one or more tabletting excipients into a solid dosage unit
The production of the estetrol-containing granules in this process may suîtably be carried out, for instance, in a high shear granulator, a low shear granulator or a fluidized bed granulator.
BRIEF DESCRIPTION OF THE FIGURE
Figure 1 illustrâtes the manufacturing process flow chart used in Example 4.
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 the estetrol component and having a volume médian diameter of 2 pm to 50 pm;
• 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 estetrol-containing granules, said granulation liquid containing at least 60 wt.% of liquid solvent;
• removing liquid solvent from the estetrol-containing granules to produce dry estetrolcontaining granules;
• optionally mixing the dry granules with one or more tabletting excipients; and • forming the dry granules or the mixture of the dry granules and the one or more tabletting excipients into a solid dosage unit.
The term ‘estetrol’ as used herein refers to 1,3,5 (10)-estratrien-3,l5a,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.
The term granulation” as used herein, unless indicated otherwise, relates to a process in which primary powder particles are made to adhéré to form larger, multiparticle entities called “granules”.
The term ‘tabletting excipient’ as used herein refers to a pharmaceutically acceptable excipient that can be used in the manufacture of solid dosage units such as tablets.
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 at least 1 wt.%, more preferably 2-25 wt.% and most preferably 2.2-15 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 carboxylic, 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 limited amount of particles with a particle size in excess of 60 pm. Preferably, not more than 10 vol.% of more than 60 pm (D?o), 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 ίο 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 cavity 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 désintégration test according to Ph. Eur. 2.9.1 (“Désintégration of tablets and capsules”) and USP <701> (“Désintégration”), also described in the Examples. The solid dosage unit of the présent invention, when subjected to the aforementioned 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 désintégration test, typically désintégrâtes 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 tensioactive agents, cosolvents, absorption enhancer, superdisintegrants and buffering agents.
The estetrol particles typically represent between 0.5-20 wt.% of the dosage unit. More preferably, the estetrol particles represent 1-18 wt.%, most preferably 5-15 wt.% of the dosage unit.
The solid dosage unit of the présent invention preferably contains 50-99.8 wt.% of watersoluble carbohydrate selected from maltose, fructose, sucrose, lactose, glucose, galactose, trehalose, xylitol, sorbitol, erythritol, maltitol, mannitol, isomalt and combinations thereof.
π
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. Most preferably, the water-soluble carbohydrate is mannitol.
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 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 polyvinylpyrrolidone, crosslinked carmellose and combinations thereof.
The estetrol particles are présent in the solid dosage unit of the présent invention as a component of granules that addîtionally contain one or more granulation excipients.
The dry estetrol-containing granules typically constitute 20-99.9 wt.% of the oral dosage unit. More preferably, these granules represent 50-99.8 wt.%, most preferably 60-99.7 wt.% of the oral dosage unit.
Typically, the dry estetrol-containing granules that contain the estetrol particles hâve a volume médian diameter of 100-4,000 pm, more preferably of 150-1,000 pm and most preferably of200-600 pm.
The dry estetrol-containing granules typically comprise 70-95 wt.% of one or more granulation excipients and 5-30 wt.% of the estetrol component. Even more preferably, these granules comprise 75-90 wt.% of the one or more granulation excipients and 10-25 wt.% of the estetrol component.
Other granulation excipients that may suitably be incorporated into the estetrol-containing granules include water-soluble carbohydrate, diluents/fillers (e.g. calcium salts, microcrystalline cellulose), binders, disintegrating agents, mucoadhesive agents, flavouring, colouring, glidents, lubricants and combinations thereof.
The dry estetrol-containing granules preferably contain at least 20 wt.%, more preferably at least 35 wt.% and most preferably at least 45 wt.% of the water-soluble carbohydrate as defined herein before.
The dry 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.
The dry estetrol-containing granules typically contain 0-20 wt.% of the binder as defined herein before. Even more preferably these granules contain 0.1-15 wt.%, more preferably 0.210 wt.% of the binder.
In accordance with another preferred embodiment, the dry estetrol-containing granules comprise 0.1-20 wt.%, more preferably 0.2-10 wt.% of a disintegrating agent as defined herein before.
Besides dry estetrol-containing granules, the solid dosage unit of the présent invention may suitably contain 0.1-80 wt.%, more preferably 0.2-50 wt.% and most preferably 0.3-40 wt.% of tabletting excipients selected from lactose, mannitol, xylitol, microcrystailine cellulose, starch, croscarmellose sodium, polyvinyl pyrrolidone and combinations thereof. According to one particularly preferred embodiment, the tabletting excipients comprises at least 50 wt.% mannitol. In accordance with another preferred embodiment, the tabletting excipients comprise at least 50 wt.% lactose.
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), I7-deacetyl norgestimate, 19-norprogesterone, acetoxypregnenolone, allylestrenol, anagestone, chlormadinone, cyproterone, demegestone, desogestrel, dienogest, dihydrogesterone, dimethisterone, ethisterone, ethynodiol diacetate, flurogestone acetate, gastrinon, gestodene, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, lynestrenol (=lynoestrenol), medrogestone, medroxyprogesterone, megestrol, melengestrol, nestorone, nomegestrol, nomegestrol-acetate (NOMAC), norethindrone (=norethisterone), norethynodrel, norgestrel (includes d-norgestrel and dlnorgestrel), norgestrienone, normethisterone, progestérone, quingestanol, (17alpha)-17hydroxy-1 l-methylene-19-norpregna-4,15-diene-20-yn-3-one, tibolone, trimegestone, algestone acetophenide, nestorone, promegestone, 17-hydroxyprogesterone esters, 19-nor17hydroxyprogesterone, 17alpha-ethinyl-testosterone, 17alpha-ethinyl-19-nor-testosterone, d17beta-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 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 bucîclate); methyltestosterone; mesterolon; stanozolol; androstenedione; dihydrotestosterone; androstanediol; metenolon; fluoxymesterone; oxymesterone; methandrostenolol; MENT and prodrugs of these compounds. Most preferably 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, 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.
Most preferably, the solid dosage is used in female hormone replacement therapy, especîally to treat vulvovaginal atrophy and/or vasomotor symptoms.
The use of the 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 1-40 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. In 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 unît 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 unît 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 and having a volume médian diameter of 2 pm to 50 pm;
• 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 estetrol-containing granules, said granulation liquid containing at least 60 wt.% of liquid solvent;
• removing liquid solvent from the estetrol-containing granules to produce dry estetrolcontaining granules;
• optionally mixing the dry granules with one or more tabletting excipients; and • forming the dry granules or the mixture of the dry granules and the one or more tabletting excipients into a solid dosage unit.
In the présent process the granulation mixture is preferably produced by combining the estetrol particles with the one or more granulation excipients in a weight ratio that is in the range of 1:2 to 1:1000, more preferably in the range of 1:3 to 1:100 and most preferably in the range of 1:4 to 1:10.
The one or more granulation excipients used in the préparation of the granulation mixture preferably include water-soluble carbohydrate as defined herein before. Preferably, said water-soluble carbohydrate constitutes at least 50 wt.%, more preferably at least 60 wt.% and most preferably at least 80 wt.% of the one or more granulation excipients.
The one or more granulation excipients of the granulation mixture preferably include 0.1-20 wt.%, more preferably 0.15-10 wt.% and most preferably 0.2-5.0 wt.% of binder as defined herein before; ail percentage calculated by weight of the granulation mixture.
The one or more granulation excipients of the granulation mixture may suitably include a disintegrating agent as defined herein before. Preferably, the disintegrating agent constitutes 0.1-20 wt.%, more preferably 0.2-10 wt.% of the granulation mixture.
The 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 most preferably of 1.5:1 to 5:1. The aforementioned weight ratio is calculated on the basis of the total amount of granulation mixture and granulation liquid that is used in the préparation of the dry estetrol-containing granules.
The 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. Most preferably, the granules are prepared in a low shear granulator.
The granulation liquid employed in the présent process preferably contains at least 60 wt.%, more preferably at least 80 wt.% and most preferably at least 90 wt.% of polar solvent selected from water, methanol, éthanol, iso-propanol, acetone and combinations thereof.
According to a particularly preferred embodiment, the granulation liquid contains at least 60 wt.%, more preferably at least 80 wt.% and most preferably at least 90 wt.% of polar solvents selected from water, éthanol and combinations thereof. The polar solvent employed in the granulation liquid preferably contains at least 80 wt.% water, more preferably at least 90 wt.% water.
The granulation liquid employed in the présent process may suitably contain further excipients besides liquid solvent. Examples of such further excipients include binders, disintegrating agents, mucoadhesive agents, colouring, flavouring and combinations thereof.
Preferably, the granulation liquid contains 0.5-40 wt.%, more preferably 1-25 wt.% and most preferably 2-20 wt.% of binder, said binder being selected from cellulose dérivatives, starch and starch dérivatives (e.g. pregelatinized starch), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), agar, gelatin, guar gum, gum Arabie, alginate, polyethylene glycol (PEG), glucose, sucrose, sorbitol and combinations thereof. Preferably, the binder employed in the présent process is selected from cellulose dérivatives, pregelatinized starch, polyvinylpyrrolidone and combinations thereof.
Examples of cellulose dérivatives that may be employed in the dosage unit as binder include hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropylmethylcellulose, methyicellulose, ethylcellulose, carboxymethyl cellulose and combinations thereof.
In the présent process liquid solvent is preferably removed after the 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) to facilitate the removal of liquid solvent during production of the estetrol-containing granules. Typically, the liquid solvent is removed at elevated température (e.g. >50 °C).
The dry estetrol-containing granules produced in the présent process typically hâve a volume médian diameter in the range of 100-4,000 pm. More preferably, the volume médian diameter of these granules is in the range of 200-1,000 pm, most preferably in the range of 200-600 pm.
Examples of the one or more tabletting excipients that are optionally combined with the dry estetrol-containing granules before the forming of the solid dosage unit include lactose, mannitol, xylitol, microcrystalline cellulose, starch, croscarmellose sodium, polyvinyl pyrrolidone and combinations thereof.
Preferably, in the present process the dry estetrol-containing granules are mixed with the one or more tabletting excipients in a weight ratio that is the range of 1:4 to 9:1, more preferably in the range of 1:2.5 to 3:1 and most preferably of 1:1.5 to 1.5 to 1.
In the present process the solid dosage unit may suitably be formed by direct compression or compression moulding. Most preferably, the solid dosage unit is formed by direct compression.
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. The invention is further illustrated by means of the following non-limiting examptes.
EXAMPLES
Dissolution test
The dissolution test described below can be used to study the dissolution behaviour of orodispersibte 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 stir the solution until everything 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 vessets one tablet at the bottom before starting the rotation of the paddles.
• Start the rotation of the paddles immediately.
• Use a stirring 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 of the 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.
Preparation of mobile phase (MP) phosphate buffer • Transfer 1.15 g of NH4H2PO4 (10 mM) into a 1,000 ml 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 injector, a temperature controlled autosampler, column thermostat and Photodiode array detector 2996 (ail by Waters) • Analytîcal colunm: Symmetry Cl8,3.9 x 150 mm, dp = 5 pm (ex Waters) • Guard column: Security guard columg Cl 8,4x3 mm (Phenomenex) • Flow: 1.0 mL/min • Détection: UV @ 280 nm • Column temperature: 30°C • Autosampler temperature: 10°C • Injection volume: 100 pL • Run time: 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 sîze distribution of estetrol monohydratc is performed using a MALVERN MASTERSIZER MICROPLUS laser particle size analyzer.
Préparation of dispersion medium:
• Weigh 1 g of estetrol monohydrate and lg of sorbitan trioleate into a flask.
• A dd 1 litre of n-hexane and mix for at least 1 hour at room température • Filter through a 0.45 pm filter.
Sample préparation:
• Put 100 mg of sample in a 25 mLbeaker.
• 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 arc performed three times using the same dispersion. The final resuit is obtained by averaging the results of the three déterminations.
2t
Example 1
A sublingual tablet is prepared by means of the procedure described below.
A granulation mixture having the composition shown in Table 1 is prepared by dry blending of the ingrédients.
Table 1
Ingrédients | Wt.% |
Milled estetrol1 | 25 |
Mannitol | 40 |
Lactose | 35 |
1 D(v;0.5) = appr. 15 pm
A granulation liquid having the composition shown in Table 2 is prepared by dispersing the pregelatinized starch into the water
Table 2
Ingrédients | Wt.% |
Pregelatinized starch | 2 |
Purified water | 98 |
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.
The granulate so obtained is dried in a vacuum drying oven at 40°C and subsequently screened over a 500 pm sieve.
A tabletting mixture having the composition shown in Table 3 is prepared by mixing the dry granulate with the excipients for 15 minutes (except magnésium stéarate). Magnésium stéarate is added and mixing is continued for an additional 5 minutes.
Table 3
Ingrédients | Wt.% |
Granulated estetrol | 50 |
Lactose | 10 |
Ludiflash ® 2 | 38.5 |
Magnésium stéarate | 1.5 |
A mixture of mannitol (90 wt.%), crospovidone (5 wt.%) and polyvinyl acetate (5 wt.%)
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 granulation mixture having the composition shown in Table 4 is prepared by dry blending ofthe ingrédients.
Table 4
Ingrédients | Wt.% |
Milled estetrol1 | 25 |
Lactose | 75 |
1 D(v,o.5) = appr. 15 pm
A granulation liquid having the composition shown in Table 5 is prepared by dispersing the polyvinylpyrrolidone (PVP) into the water.
Table 5
Ingrédients | Wt.% |
PVP (polyvinylpyrrolidone) | 3 |
Purified water | 97 |
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.
The granulate so obtained is dried in the low shear granulator at 40°C and is subsequently screened over a 500 pm sieve.
A tabletting mixture having the composition shown in Table 6 is prepared by mixing the dry granulate with the excipients for 15 minutes (except magnésium stéarate). Magnésium stéarate is added and mixing is continued for an additional 5 minutes.
Table 6
Ingrédients | Wt.% |
Granulated estetrol | 50 |
Mannitol | 43.5 |
Crospovidone | 5 |
Magnésium stéarate | 1.5 |
The blend is compressed into 80 mg round tablets with diameter 6.5 mm. The estetrol content of these tablets is approximately 10 mg.
Example 3
A sublingual tablet is prepared using the procedure described below.
A granulation mixture having the composition shown in Table 7 is prepared by dry blending of the ingrédients.
Table 7
Ingrédients | Wt.% |
Mîlled estetrol1 | 25 |
Lactose | 75 |
1 D(v,o 5) = appr. 15 pm
A granulation liquid having the composition shown in Table 8 is prepared by dispersing the hydroxypropyl cellulose (HPC) into the water.
Table 8
Ingrédients | Wt.% |
HPC (hydroxypropyl cellulose) | 2 |
Purified water | 97 |
The granulation mixture is granulated in a fluid bed granulator by gradually adding the granulation liquid. The total amount of granulation liquid added amounts to 35% by weight of the granulation mixture.
The granulate so obtained is dried in the fluid bed granulator at 50°C and subsequently screened over a 500 pm sieve.
A tabletting mixture having the composition shown in Table 9 is prepared by mixing the dry granulate with the excipients in Table 9 for 15 minutes (except magnésium stéarate). Magnésium stéarate is added and mixing is continued for an additional 5 minutes.
Table 9
Ingrédients | Wt.% |
Granulated estetrol | 50 |
Mannitol | 43.5 |
Sodium starch glycolate | 5 |
Magnésium stéarate | 1.5 |
The blend is compressed into 80 mg round tablets with diameter 6.5 mm. The estetrol content of these tablets is approximately 10 mg.
Example 4
Seven different sets of sublingual tablets (formulations A to G) were prepared by means of the procedure described below and illustrated in Figure I.
The target amounts of estetrol per tablet were as follows: 100 pg 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.
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.
The estetrol was mixed with a part of the main diluent and screened over a 800 pm screen. AI! other excipients were also screened over a 800 pm screen.
A binder solution of 10% PVP (polyvinylpyrrolidone) in demineralized water was prepared (the PVP concentration in the binder solution used for formulations B, C and F was 15%). Granulation was started by adding the binder solution to the dry mixture consisting of the intragranular excipients (with a batchsize of ± 100 gram). A granulate was formed after 30 seconds of mixing, and subsequently pure demineralized water was added until a suitable granulate was formed (as detected visually, 1 minute of granulation in total).
The granulate was dried ovemight in a vacuum oven at 40°C and subsequently milled over a 800 pm screen. The mixture thus obtained was mixed for 15 minutes with the extragranular excipients (except for magnésium stéarate). Finally, magnésium stéarate was added and mixed for 3 minutes.
Compression was executed using a single punch machine equipped with proper punches (5 mm punch for 30 mg tablets (A and C), 6 mm for 80 mg tablets (E, F and G) and 15 mm for 1000 mg tablets (B and D)).
Disintegration time was quantifîed 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 crushing of tablets”).
The final formulations and corresponding tablet results can be found in Tables 10 and 11 below.
No problems were detected during the experiments, flowability of the blend was good and no sticking was observed.
Table 10 — details of the formulations in Wt.%
Formulation # | A | B | C | D | E | F | G |
Intraerartular | |||||||
Milled Estetrol1 | 0.33 | 24.92 | 25.00 | 0.10 | 12.49 | 12.48 | 12.49 |
Mannitol | 91.17 | 65.89 | 65.49 | 91.90 | 79.25 | 18.99 | |
PVP (polyvinylpyrrolidone) | 2.00 | 2.99 | 3.00 | 2.00 | 2.01 | 1.46 | |
Pregelatinized starch | 1.01 | ||||||
Crospovidone | 4.01 | 4.00 | 4.00 | 4.00 | 4.00 | ||
Lactose | 17.51 | 36.04 | |||||
Déminerai ized water (per 100 gram granulation mixture) | 22 | 26 | 26 | 23 | 19 | 16 | 24 |
Extraaranular | |||||||
Crospovidone | 0.99 | 1.10 | 1.00 | 1.01 | 0.99 | 5.00 | |
Lactose | 10.01 | ||||||
Ludiflash®2 | 38.49 | ||||||
Mannitol | 43.49 | ||||||
Magnésium stéarate | 1.49 | 1.10 | 1.50 | 0.99 | 1.25 | 1.50 | 1.52 |
1 D (,,.0 5)= 15pm n
Containing mannitol (90 wt.%), crospovidone (5 wt.%) and polyvinyl acetate (5 wt.%)
Table 11 - experimentally determined characteristics of the Tablets
Test (average resuit of 6 samples) | Disintegration time | Hardness | Weight |
Formulation # | (min:sec) | (N) | (n»R) |
A | 0:39 | 14.17 | 28.2 |
B | 1:44 | 85.85 | 1058.6 |
C | 1:05 | 28.46 | 30.1 |
D | 0:40 | 66.74 | 1048.9 |
E | 0:32 | 29.70 | 78.9 |
F | 0:41 | 30.97 | 82.2 |
G I 0:33 I 22.69| 78.1
It can be seen that ail tablets were obtained with a final weight close to their target weight and that the disintegration times, even for the largest lg tablets, 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 5
A randomized, open-label, two-period, cross-over, pharmacokinetic study is conducted to compare sublingual bioavailability of 10 mg estetrol administered in one 80 mg tablet (having the same composition as the tablets described in Example 4, Formulation E) 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 basis 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/m (inclusive at the time of the screening).
At the start of the first and the second period 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 estetrol tablet (tablet weight 80 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 12:
Table 12
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 |
• Days9-i3 | 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 13.
Table 13
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 ofthe 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 10 also determined with the help of HPLC/MS/MS.
Results of these analyses show that the bioavailability of sublingually administered estetrol is 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 (5)
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 the estetrol component and having a volume médian diameter of 2 pm to 50 pm;
• 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 estetrol-containing granules, said granulation liquid containing at least 60 wt.% of liquid solvent;
• removing liquid solvent from the estetrol-containing granules to produce dry estetrolcontaining granules;
• optionally mixing the dry granules with one or more tabletting excipients; and • forming the dry granules or the mixture of the dry granules and the one or more tabletting excipients 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 of 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 of the 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 50-99.9 wt.% of water-soluble carbohydrate 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, wherein the dosage unit contains at least 20 wt.% mannitol.
9. 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 polyvinylpyrrolidone, crosslinked carmellose and combinations thereof.
10. 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.
11. Solid dosage unit for the use according to claim 10, said use comprising once daily administration during a period of at least 1 week.
12. Use of an estetrol component for the manufacture of a médicament in the form of a solid dosage unit according to any one of the claims 1-9, for female contraception, said contraception comprising sublingual, buccal or sublabial administration of a dosage unit.
13. 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 12, wherein said contraception comprises once daily administration during a period of at least 1 week.
14. A process of preparing a solid dosage unit according to any one of the preceding claims, 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 and having a volume médian diameter of 2 pm to 50 pm;
• 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 estetrol-containing granules, said granulation liquid containing at least 60 wt.% of liquid solvent;
• removing liquid solvent from the estetrol-containing granules to produce dry estetrolcontaining granules;
• optionally mixing the dry granules with one or more tabletting excipients; and • forming the dry granules or the mixture of the dry granules and the one or more tabletting excipients into a solid dosage unit.
15. Process according to claim 14, wherein the estetrol particles hâve a volume médian diameter of 3-35 pm.
16. Process according to claim 14 or 15, wherein the granulation mixture contains 0.1-20 wt.% of a disîntegrating agent selected from modified starches, croslinked PVP, crosslinked carmellose and combinations thereof.
17. Process according to any one of claims 14-16, wherein the granulation mixture is produced by combîning the estetrol particles with the one or more granulation excipients in a weight ratio that is în the range of 1:4 to 1:1,000.
18. Process according to any one claims 14-17, wherein 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.
*
I
19. Process according to any one of claims 14-18, wherein 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.
20. Process according to any one of claims 14-19, wherein the granulation liquid contains at least 60 wt.% of polar solvent selected from water, methanol, éthanol, iso-propanol, acetone and combinations thereof.
21. Process according to claim 20, wherein the granulation liquid contains at least 60 wt.% of polar solvents selected from water, éthanol and combinations thereof.
22. Process according to claim 20 or 21, wherein the polar solvent contains at least 80 wt.% water.
23. Process according to any one of claims 14-22, wherein the granulation liquid contains 0.250 wt.% of binder, said binder being selected from cellulose dérivatives, starch and starch dérivatives, polyvinyl alcohol, polyvinylpyrrolidone, agar, gelatin, guar gum, gum Arabie, alginate, polyethylene glyvol, glucose, sucrose, sorbitol and combinations thereof.
24. Process according to claim 23, wherein the binder is selected from cellulose dérivatives, pregelatinîzed starch, polyvinylpyrrolidone and combinations therof.
25. Process according to claim 23 or 24, wherein the cellulose dérivatives are selected from hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, carboxymethyl cellulose and combinations thereof.
26. Process according to any one of claims 14-25, wherein the dry estetrol-containing granules hâve a volume médian diameter in the range of 100-4,000 pm.
27. Process according to any one of claims 14-26, wherein the one or more tabletting excipients include lactose, mannitol, xylitol, microcrystalline cellulose, starch, croscarmellose sodium, polyvinyl pyrrolidone and combinations thereof.
5 28. Process according to any one of claims 14-27, wherein the solid dosage unit is formed by direct compression or compression moulding.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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EP15172767.4 | 2015-06-18 |
Publications (1)
Publication Number | Publication Date |
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OA18470A true OA18470A (en) | 2018-11-15 |
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