ZA200503479B - Pharmaceutical tablets containing tibolone and a coating - Google Patents
Pharmaceutical tablets containing tibolone and a coating Download PDFInfo
- Publication number
- ZA200503479B ZA200503479B ZA200503479A ZA200503479A ZA200503479B ZA 200503479 B ZA200503479 B ZA 200503479B ZA 200503479 A ZA200503479 A ZA 200503479A ZA 200503479 A ZA200503479 A ZA 200503479A ZA 200503479 B ZA200503479 B ZA 200503479B
- Authority
- ZA
- South Africa
- Prior art keywords
- coating
- tablets
- sugar
- tablet
- tibolone
- Prior art date
Links
- 238000000576 coating method Methods 0.000 title claims description 67
- WZDGZWOAQTVYBX-XOINTXKNSA-N tibolone Chemical compound C([C@@H]12)C[C@]3(C)[C@@](C#C)(O)CC[C@H]3[C@@H]1[C@H](C)CC1=C2CCC(=O)C1 WZDGZWOAQTVYBX-XOINTXKNSA-N 0.000 title claims description 63
- 239000011248 coating agent Substances 0.000 title claims description 62
- 229960001023 tibolone Drugs 0.000 title claims description 58
- 239000007888 film coating Substances 0.000 claims description 40
- 238000009501 film coating Methods 0.000 claims description 40
- 235000000346 sugar Nutrition 0.000 claims description 35
- 101000764229 Rattus norvegicus Mitochondrial import receptor subunit TOM40 homolog Proteins 0.000 claims description 27
- 238000009495 sugar coating Methods 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 14
- 108010010803 Gelatin Proteins 0.000 claims description 10
- 229920000159 gelatin Polymers 0.000 claims description 10
- 239000008273 gelatin Substances 0.000 claims description 10
- 235000019322 gelatine Nutrition 0.000 claims description 10
- 235000011852 gelatine desserts Nutrition 0.000 claims description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 9
- 229930006000 Sucrose Natural products 0.000 claims description 9
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 7
- 229920003086 cellulose ether Polymers 0.000 claims description 6
- 235000011187 glycerol Nutrition 0.000 claims description 6
- 239000004014 plasticizer Substances 0.000 claims description 6
- 239000005720 sucrose Substances 0.000 claims description 6
- 229920002554 vinyl polymer Polymers 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 229920003157 Eudragit® RL 30 D Polymers 0.000 claims description 2
- 230000003019 stabilising effect Effects 0.000 claims 4
- 101100390778 Drosophila melanogaster Fitm2 gene Proteins 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 122
- 239000000203 mixture Substances 0.000 description 25
- 239000006185 dispersion Substances 0.000 description 17
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 10
- 239000007857 degradation product Substances 0.000 description 9
- 239000000454 talc Substances 0.000 description 9
- 229910052623 talc Inorganic materials 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 8
- 239000008187 granular material Substances 0.000 description 8
- 238000006317 isomerization reaction Methods 0.000 description 8
- 235000019698 starch Nutrition 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000008107 starch Substances 0.000 description 7
- 229960004793 sucrose Drugs 0.000 description 7
- 239000008199 coating composition Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- -1 nonparelis Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 230000000087 stabilizing effect Effects 0.000 description 5
- 239000004408 titanium dioxide Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- 229920003119 EUDRAGIT E PO Polymers 0.000 description 3
- 229920003139 Eudragit® L 100 Polymers 0.000 description 3
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 3
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 3
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 3
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 235000013681 dietary sucrose Nutrition 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 229920000058 polyacrylate Polymers 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007940 sugar coated tablet Substances 0.000 description 3
- 239000001069 triethyl citrate Substances 0.000 description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 3
- 235000013769 triethyl citrate Nutrition 0.000 description 3
- 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 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 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000007891 compressed tablet Substances 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 235000013980 iron oxide Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000000873 masking effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000009498 subcoating Methods 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-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 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 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 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 229920003163 Eudragit® NE 30 D Polymers 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-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 description 1
- 239000002775 capsule Substances 0.000 description 1
- OIQPTROHQCGFEF-UHFFFAOYSA-L chembl1371409 Chemical compound [Na+].[Na+].OC1=CC=C2C=C(S([O-])(=O)=O)C=CC2=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 OIQPTROHQCGFEF-UHFFFAOYSA-L 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
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- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229960005191 ferric oxide Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 108010025899 gelatin film Proteins 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
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- 230000003993 interaction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical class OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
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- 235000019423 pullulan Nutrition 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 150000003431 steroids Chemical group 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Description
PHARMACEUTICAL TABLETS CONTAINING TIBOLONE AND A COATING
The present invention relates to a pharmaceutical tablet comprising an amount of from 0.1 to 10% by weight of tibolone.
Compositions comprising tibolone, the chemical name of which is (7a, 17a)-17- hydroxy-7-methyi-19-nor-17-pregn-5(10)-en-20-yn-3-one (also denoted as Org OD 14) and a pharmaceutically acceptable solid carrler have been described in EP 389035.
A known formulation for tibolone is a 100 mg tablet having 2.5 mg of tibolone contained therein, a relatively small amount (e.g. approx. 1% by weight) of pharmaceutically acceptable auxiliaries, and a carrier making up the body of the tablet. The carrier typically is composed of approx. 10% by weight of starch, e.g. potato starch, and approx. 80% by weight of lactose. Tablets of 100 mg containing 2.5 mg of tibolone are available in medical practice under the name of Livial®.
Upon long-term storage of tibolone-containing tablets degradation products of tibolone appear. The major degradation product is (70, 170)-17-hydroxy-7-methyl- 19-nor-17-pregn-4-en-20-yn-3-one (Org OM38). OM38 differs from tibolone in that the double bond in the steroid skeleton is located between positions 4 and §, whereas In tibolone it is located between positions 5 and 10. This isomerization product Is identified as the major impurity in tibolone and in tibolone-containing tablets and limits (at a maximum of 5% by weight of OM38) the approved shelf life of the presently available Livial® tablets to @ maximum of two years. Considerable advantage is achieved in prolonging the shelf life of tibolone-containing tablets. It is therefore advantageous to find means to reduce the formation of OM38 and to provide more stable tibolone tablets with respect to the amount of OM38 formed after storage.
The problem of reducing OM38 formation in tibolone and tibolone-containing products was addressed earfier in WO 00/23460, providing high purity tibolone containing less than 0.5% by weight of OM38, and in WO 98/47517, providing a composition comprising tibolone and a pharmaceutically acceptable carrier, said carrier having a high starch content, i.e. more than 10%, preferably at least 40% by weight. Despite these contributions to the art, there still is a need to further improve the shelf life of tibolone tablets and for attematives to the solutions presented in WO 00/23460 and WO 98/47517.
In accordance with the present invention a stabilized pharmaceutical tablet comprising an amount of from 0.1 to 10% by weight of tibolone provided with a coating is made available for the first time. Surprisingly, such a tablet has a lower content of OM38 after storage, in particular after several months of storage, than a similar tablet without a coating. it is unexpected that a coating reduces the formation of the tibolone-derived isomerisation degradation product OM38.
The present invention further resides in an unexpected new use of a coating for stabilizing a pharmaceutical tablet comprising an amount of from 0.1 to 10% by weight of tibolone. :
In the context of the present invention with the term “stabilized” thus is meant “stabilized with respect to the formation of OM38 upon storage.” Hence, the coating of tibolone-containing tablets serves to reduce the formation of OM38 as : compared to uncoated tablets. Further, in the context of the present invention the term “tablets” is meant to refer to “sofid dosage forms” which can technically be provided with a coating and which typically are applied for oral administration.
Thus, apart from compressed or molded tablets, powders, granules, nonparelis, and capsules are also comprised in the tem “tablets.” Compressed tablets, however, are the most frequently used solid dosage forms.
Incidentally, in WO 98/47517 reference is made to provide tablets of tibolone with a film coat if required {see page 5, lines 14-16). The tablets made in accordance with WO 98/47517 make use of a pharmaceutically acceptable carrier containing more than 10%, preferably at least 40% by weight of starch. In this document, no teaching or suggestion is made with respect to the technical effect of a coating on the formation of OM38 during storage of tibolone-containing tablets. Tibolone tablets stabilized by application of a coating are neither disclosed nor exemplified in this document. With respect to the words “if required” In fine 14 it should be noted that the Livial® tablets that are currently on the market are neither coated nor require a coating with a view to typical reasons for coating pharmaceutical tablets (taken from Remington, page 894, cited below), i.e. protecting the drug from its surrounding environment (particularly air, moisture, and light), masking of unpleasant taste or odor, increasing the ease by which the product can be ingested by a patient, improving product identity, facilitating handling, improving product appearance, reducing the risk of interaction between incompatible components, improving product mechanical integrity or modifying drug release.
Further, WO 98/47517 only mentions a film coat and makes no reference to any other type of coating.
In the context of the present invention with “coating” is meant any coating which achieves a stabilizing effect with respect to the formation of OM38 upon storage of a coated tablet as compared to an uncoated tablet. Whether or not a costing achieves a stabilizing effect can easlly be determined by one skilled in the art on the basis of the present specification. The amount of OM38 present in a tablet is determined via HPLC analysis in a conventional way.
Suitable examples of coatings that can be used in accordance with the present invention include a film coating, a sugar coating, a sugar film coating, for exampte, a sugar film coating according fo US 2002/0044970, and a “wrap” costing according to US 5146730. The compositions of these coatings and the methods and equipment by which they are applied onto tablets are well-known to a person skilled in the art and they are described, for example, by Stuart C. Porter in
Chapter 46: Coating of pharmaceutical dosage forms in Remington: The Science and Practice of Pharmacy; 20th ed., 2000; Alfonso R. Gennaro, Editor, Lippincott
Williams & Wilkins; Baltimore, USA, as well as in US 2002/0044970 and US 5146730. Preference Is given to aqueous coating compositions, including mixtures of water and an organic solvent such as an alcohol. Most preferably, coating compositions containing water as the only solvent or vehicle are used.
In particular, the coating to be used in accordance with the present invention is a sugar coating, a sugar film coating or a “wrap” coating. Particularly, the coating of the present invention is a film coating, a sugar coating or a sugar film coating. Ina preferred embodiment of the present invention the coating is a sugar coating or a sugar film coating. The sugar coating may be used with or without a seal coat and/or subcoat
With respect to a film coating, the present inventors have found that not all film coatings give the desired stabilizing effect on tibolone tablets. In particular,
tibolone tablets coated with Eudragit® E PO and Eudragit® L100, which are acrylic polymer-containing coatings used for moisture protection, taste and odor masking and for drug delivery in the jejenum, respectively, showed a higher content of OM38 after storage as compared to uncoated tablets. Accordingly, these film coating should not be used.
As explained in Chapter 46 of Remington (cited above), the major components in any film coating formulation usually consist of a polymer, a plasticizer, a colorant, and a solvent. In accordance with the present invention, a plasticizer and a colorant are optional ingredients and — as stated above - the solvent or vehicle preferably is an aqueous solvent or vehicle or most preferably it is water.
Sultable examples of polymers include cellulose ethers, such as hydroxypropyl cellulose, methylcellulose, and ethylcellulose, and particularly hydroxypropyl methylcellulose. Suitable cellulose ether-containing coating compositions are commercially available under the name of Sepifilm™, Opadry®, and Aquacoat®. .
Acrylic polymers such as methacrylate and methyl methacrylate copolymers, vinyl polymers such as polyvinyl alcohol and polyvinyl pyrrolidone, gelatin or starches, may also be used. Suitable acrylic polymer-containing coating compositions are commercially available under the name of Eudragit®. Suitable vinyl polymer- containing coating compositions are commercially available under the name of
Opaglos®, Opalux™, and Opadry®. In particular in accordance with the present invention use Is made of a cellulose ether, a vinyl polymer or gelatin, more in particular a cellulose ether or a vinyl polymer.
Typical plasticizers include glycerin (or glycerol), propylene glycol, polyethylene glycol, triacetin (or glyceryl triacetate), acetylated monoglyceride, citrate esters (e.g. triethyl citrate), and phthalate esters (e.g. diethyl phthalate). Prefered plasticizers are glycerin or glycerol, propylene glycol, and polyethylene glycol.
As explained in Chapter 46 of Remington (cited above), a sugar coating typically consists of a seal coating or sealing, a subcoating, and a sugar coating. In said latter sugar coating a polymer typically is not present. In accordance with the present invention the seal coating and the subcoating are optional coatings and need not be used in combination with a sugar coating in order to obtain the technical effect of the present invention. In particular, the ‘ stabilizing effect on
OM38 formation can already be observed in sugar coated tablets without a seal coat and/or subcoat.
The sugar used in a sugar coating typically is sucrose (or saccharose), but other 5 saccharides such as glucose, fructose, and lactose or polyalcohols such as sorbitol, mannitol, and xylitol may also be used in accordance with the present invention. Either one or more sugars may be used in accordance with the invention. Preferably, the sugar comprises sucrose.
A sugar film coating is a coating comprising a polymer and a sugar as defined above. For example, the sugar film coating according to US 2002/0044970 makes use of an aqueous sugar coating liquid containing 30-54% by weight of saccharides (preferably sucrose), 2-10% by weight of polyethylene glycol, and 0.2- 29% by weight of polyvinyl pyrrolidone, giving rise fo a mono Jayered sugar coated . tablet. JP 2001026534 describes a sugar film coat comprising sucrose, pullulan, and hydroxypropyl methyicellulose. Based on this, a person skilled in the art will find no trouble in making suitable variations in a sugar film coating. :
The “wrap” coating according to US 5146730 typically makes use of a water-based gelatin preparation having about 45% by weight of gelatin and about 8% by weight of a plasticizer (glycerin and/or sorbitol). With the method of US 5146730, tablets are enrobed or “wrapped” in a gelatin coating formed by application of respective layers of elastic gelatin film to opposite sides of the tablet The applied gelatin layers conform tightly to the tablet surface, bond securely to the tablet, and are sealed together in essentially edge-to-edge manner at a seal line which extends around the tablet at a desired place on the tablet. The coating is applied by feeding a tablet into a cavity formed between a pair of dies over two elastic self-adherent films. A tablet, which is enveloped in this manner between the films is finally coated by sealing the films to each other along the lines contiguous to the tablet.
Instead of gelatin, (modified) starches, alginates, modified gelatin, acrylates, polyvinyl pyrrolidone, cellulose derivatives both esters and ethers, and polysiloxanes may also be used. The details of this method and of the “wrap” coating composition are described in US 5146730.
The coating to be used in accordance with the present invention typically also contains pharmaceutically acceptable auxiliaries such as arabic gum (or acadia),
calcium carbonate, magnesium stearate, talc, china clay, and/or titanium dioxide.
Such auxiliaries may be used in conventional quantities if desired. A colorant may also be used if desired.
As is known to the person skilled in the art of coating and as exemplified in the examples below, either one or more than one coating layers may be used and if more than one layer is used, the layers may be of the same or different composition. Particularly, in accordance with the present invention a single layer coating is used.
If desired, the coated pharmaceutical tablet of the present invention can be subjected to smoothing, polishing or printing as Is known in the art
The pharmaceutical tablets to be used in accordance with the present invention may vary in weight and/or in tibolone content. Particularly, 100 mg tablets : containing 2.5 mg of tibolone (i.e. 2.5% by weight) are cumrentiy on the market and 65 mg tablets containing 1.25 mg of tibolone (i.e. 1.9% by weight) are currently under investigation. Results on both are provided in the examples given below.
The pharmaceutically acceptable carrer may vary in composition and be composed of approx. 10% by weight of starch and approx. 80% by weight of lactose, or contain higher amounts of starch as described in WO 98/47617. In particular, the carrier contains less than 40%, more In particular 10% or less by weight of starch. In a preferred embodiment of the invention, stabilized coated
Livial® tablets are provided.
The present invention is illustrated by the following Examples.
Example 1
Tablets of 65 mg total weight, containing 1.25 mg of tibolone, were prepared from purified tibolone. The latter was obtained according to the method described In
WO 00/23460.
A basic granulate, consisting of 10% potato starch and 80% lactose, was manufactured in a Fluid Bed Granulator, using a starch mucilage as binding liquid.
Uncoated tibolone tablets 65 mg tablets having the composition: 1.25 mg tibolone, 63.29 mg basic granulate, 0.13 mg ascorbyl palmitate, and 0.33 mg magnesium stearate, were prepared as follows: approximately 10% of the basic granulate was premixed with tibolone and ascorbyl palmitate. After screening the premix through a 250 um sleve, the rest of the basic granulate was added and mixing was continued. Finally, magnesium stearate was admixed and the final mixture was tabletted to tablets with a diameter of 5 mm.
Film coating
Tablets prepared as described above were provided with a film coat (1.2 mg per tablet) having the following composition: 0.75 mg hydroxypropyl methyl cellulose
E15, 0.15 mg polyethylene glycol 400, 0.11 mg titanium dioxide, and 0.19 mg talc.
An aqueous dispersion of the coating excipients was sprayed onto the tablets using standard film coating equipment (Accela Cota™ 24") at a rotation speed of the coating pan of 12.5 rpm, an inlet temperature of approx. 60°C, and an airflow of approx. 300 m*hour.
Sugar coating
A batch of approx. 16 kg of tablets film coated as described above (now having the function of a seal coat) was further provided with a sugar-containing subcoat, a sugar-containing layering powder, and a sugar coat.
For application of the coats, tablets were added to a sugar coat pan. The rotating pan had a diameter of about 0.7 m and a rotation speed of 42 rpm. Room conditions were 21°C and 46% relative humidity.
A subcoat consisting of an aqueous 60.2 w/w % dispersion of approx. 20% arabic gum and approx. 80% saccharose was added manually to the tablets in the sugar coat pan step by step. After each addition, a total of a few hundred grams of a layering powder consisting of 64.3% talc, 21.4% calcium carbonate, 7.1% - saccharose, and 7.1% titanium dioxide was added manually. Between the addition of subcoat and layering powder, the tablets were dried in open air without forced drying. After finalizing the subcoat (subcoat and layering powder approx. 26 mg per tablet), a sugar coat dispersion with the composition indicated in Table 1 was added in a number of sequential steps and finally the batch of sugar coated tablets was dried (sugar coat approx. 39 mg per tablet).
Table 1 [Saccherose [436
Glycoro1865% |04
The amount of the components are provided in weight percentages of the total weight of the composition.
Sugar coatingll
A batch of 8 kg of tablets film coated as described above was provided with a sugar coat, but now without a subcoat, as described above.
Tablets prepared and coated as described above were packed in open brown glass bottles and were subjected to the storage condition of 25°C and 60% relative humidity (RH) or 40°C and ambient relative humidity.
After six months, the amount of the isomerization degradation product OM38 was measured in the tablets via HPLC analysis as a percentage of the declared amount of tibolone in the tablets. The results are depicted in Table 2.
Table 2 a it (%oMms _ |sp@ |%omss [sp®
Uncosted tablets 283 loo ess [002
Fimooated ___ |246 {00s [a3 000 ‘Sugarcosted! __ |232 002 [ste Joos (Sugarcostedl [239 [001 [344 [005 "RH is Relative Humidity of the environment.
2 gp is the standard deviation in the mean obtained from three measurements from pooled tablets of 10 tablets per pool.
The results in Table 2 show that the coating of tibolone tablets in accordance with the present invention results in a decrease in the formation of the isomerization degradation product OM38 and thus leads io stabilized tibolone tablets. Sugar coating gave better results than just film coating. :
Example 2
Sugar coating .
A batch of approx. 20 kg of uncoated tablets (65 mg, see Example 1) was provided with a sugar coat.
For application of the coat, tablets were added to a conventional film coat pan equipped with an air bypass (Dumoulin IDA 30 X). The rotating pan had a diameter : of about 1 m and a rotation speed of 3 to 5 rpm.
A sugar coat dispersion with the composition indicated in Table 3 was added in a number of sequential steps until a sugar coat of approx. 35 mg per tablet was reached and finally the batch of sugar coated tablets was dried and analysed as described in Example 1. The results after two months of storage are depicted in
Table 4.
Table 3 (Arabicgum [18 [Saccharcse 1605
Tale [30 (Ttanumdioxide 09 ‘Sunsetyellow [0.002
Purified water [348 total 100 [Comaubawax® [01 n5 9 Added after the application of the coat to obtain a shiny appearance
The amount of the components are provided in weight percentages of the total waelght of the composition.
Table 4 = (%omas__ [sp? [Uncoated tablets _____|265 [009 (Sugercoated [168 [002
SD is the Standard deviation in the mean obtained from three measurements from pooled tablets of 10 tablets per pool.
The results in Table 4 show that the coating of tibolone tablets in accordance with the present invention results in a decrease in the formation of the isomerization degradation product OM38 and thus leads to stabilized tibolone tablets. : Example 3
Tablets of 100 mg total weight, containing 2.5 mg of tibolone, were prepared following the procedure described in Example 1.
Uncoated tibolone tablets 100 mg tablets with a diameter of 8 mm having the composition: 2.5 mg tibolone, 96.8 mg basic granulate, 0.2 mg ascorby! palmitate, and 0.5 mg magnesium stearate, were prepared as described in Example 1.
Film coating
Tablets prepared as described above were provided with a film coat (1.51 mg per tablet) having the following composition: 0.94 mg hydroxypropyl methyi cellulose
E15, 0.19 mg polyethylene glycol 400, 0.14 mg titanium dioxide, and 0.24 mg talc.
An aqueous dispersion of the coating excipients was sprayed onto the tablets : using standard film coating equipment (Accela Cota™ 24) at a rotation speed of the coating pan of 12.5 rpm, an inlet temperature of approx. 60°C, and an airflow of approx. 300 m>hour.
Sugar coating
A batch of 14 kg of tablets film coated as described above was provided with a sugar coat in the same manner 8s described in ‘Sugar coat I' of Example 1 (approx. 35 mg per tablet of subcoat and layering powder and approx. 8 mg per tablet of sugar coat).
The tablets were analysed as described in Example 1 and the results after six months of storage are depicted in Table 5.
Table 5
At 25°C, 60% RH" | At 40°C, ambient RH %OM38 | |%OM38
Uncoated tablets sor | lees
Fimooated ___ |274 | lass ‘Sugarcosted _ |272 | [383
RH is Relative Humidity of the environment.
The results in Table 5 show that the coating of tibolone tablets in accordance with the present invention results in a decrease In the formation of the isomerization degradation product OM38 and thus leads to stabilized tibolone tablets.
Example 4
Tablets of 65 mg total weight, containing 0.625 mg of tibolone, were prepared following the procedure described in Example 1.
Uncoated tibolone tablets 65 mg tablets having the composition: 0.625 mg tibolone, 63.9 mg basic granulate, 0.13 mg ascorbyl palmitate, and 0.325 mg magnesium stearate, were prepared as described in Example 1.
Film coating
Tablets prepared as described above were provided with a film coat having the following composition: 5.2 mg Opadry® AMB, consisting of polyvinyl alcohol, titanium dioxide, talc, iron oxide yellow, lecithin, xanthan gum and Iron oxide red.
An aqueous dispersion (solids content 15 wiw%) of the coating excipients was sprayed onto the tablets using standard film coating equipment (Glatt® GC300) at a rotation speed of the coating pan of approx. 15 rpm, an inlet temperature of approx. 60°C, and an airflow of approx. 100 mhour.
Film coating Il
Tablets prepared as described above were provided with a film coat having the following composition: 6.2 mg Sepifilm™ LP770, consisting of hydroxypropyl methylcellulose, stearic acid, and talc. An aqueous dispersion (solids content 8 wiw%) of the coating excipients was sprayed onto the tablets using standard film coating equipment (Glatt® GC300) at a rotation speed of the coating pan of approx. 15 rpm, an inlet temperature of approx. 60°C, and an alrfiow of approx. 100 m>hour.
The tablets were analysed as described in Example 1 and the results after six months of storage are depicted in Table 6.
Table 6
At 25°C, 80% RH" AL 40°C, 40% RH lwomss |sp? |%omss [sD®
Uncoated tablets
Film coated | (as [002 [1069 04
Film coated ! (351 [006 [577 |005 1) RH is Relative Humidity of the environment. 2 SD is the standard deviation in the mean obtained from three measurements from pooled tablets of 10 tablets per pool.
The results in Table 8 show that the coating of tibolone tablets in accordance with the present invention results in a decrease in the formation of the isomerization degradation product OM38 and thus leads to stabllized tibolone tablets.
Uncoated tibolone tablets 65 mg tablets with a diameter of 5 mm having the composition: 0.644 mg tibolone, 63.9 mg basic granulate, 0.13 mg ascorbyi palmitate, and 0.325 mg magnesium stearate, were prepared following the procedure described in Example 1.
Film coating
Tablets prepared as described above were provided with 5.2 mg per tablet of a film coat having the following composition: 3.07 mg Eudragit® E PO, 0.31 mg sodium lauryl sulfate, 0.78 mg stearic acid, and 1.04 mg magnesium stearate. An aqueous dispersion (solids content 16 wiw%) of the coating excipients was sprayed onto the tablets using standard film coating equipment (Glatt® GC300) at a rotation speed of the coating pan of approx. 15 rpm, an inlet temperature of approx. 45°C, and an airflow of approx. 100 mhour.
Film coating i
Tablets prepared as described above were provided with 52 mg per tablet of a film coat using an aqueous film coat dispersion having the following composition (in wiw% of the total dispersion): 11.1% Eudragit® L 100, 5.6% triethyl citrate, 3.7% 1N NHs, 74% purified water, and 5.6% talc. The aqueous dispersion was sprayed onto the tablets using standard film coating equipment (Glatt® GC300) at a rotation speed of the coating pan of approx. 20 rpm, an inlet temperature of approx. 45°C, and an airfiow of approx. 80 mhour. 18
Film coating lil
Tablets prepared as described above were provided with 5.2 mg per tablet of a film coat using an aqueous film coat dispersion having the following composition (in wiw% of the total dispersion): 39.2% Eudragit® RL 30D, 2.4% triethyl citrate, 52.5% purified water, and 5.9% talc. The aqueous dispersion was sprayed onto the tablets using standard film coating equipment (Glati® GC300) at a rotation speed of the coating pan of approx. 15 rpm, an inlet temperature of approx. 45°C, and an alrflow of approx. 80 m*/hour.
Flim coating IV "Tablets prepared as described above were provided with 5.2 mg per tablet of a film coat using an aqueous film coat dispersion having the following composition (in wiw% of the total dispersion): 41 .7% Eudragit® NE 30D, 45.8% purified water, and 12.5% talc. The aqueous dispersion was sprayed onto the tablets using standard film coating equipment (Glatt® GC300) at a rotation speed of the coating pan of approx. 20 rpm, an inlet temperature of approx. 45°C, and an airflow of approx. 80 m*hour.
The tablets were analysed as described in Example 1 and the results after two months of storage are depicted in Table 7.
Table 7 ar ‘womss _ |sp? |%omss [sp?
Uroamambles [172 [oot lazr loo
Fimocoated| _____ l26s [00s ert loor
Fimcoatedl [805 [006 [889 [038
Fimooatedll 1127 oor laos [005
FimooatedV______ [170 Joo [ass |oo2
RH is Relative Humidity of the environment. 2 SD is the standard deviation in the mean obtained from three measurements from pooled tablets of 10 tablets per pool.
The results in Table 7 show that not all coatings of tibolone tablets result in a decrease in the formation of the isomerization degradation product OM38, in particular when using Eudragit® E PO or Eudragit® L 100 worse results were obtained as compared to uncoated tablets.
Claims (12)
1. A stabilised pharmaceutical tablet comprising an amount of from 0.1 to 10% by weight of tibolone provided with a coating, wherein said coating ‘achieves a stabilising effect with respect to the formation of OM38 upon storage of a coated tablet as compared to an uncoated tablet, with the proviso that when said coating is a film coating, the fitm coating contains a cellulose ether, a vinyl polymer or gelatin.
2. A tablet according to claim 1, wherein the coating is a film coating, a sugar coating, a sugar film coating or a ‘wrap’ coating.
3. A tablet according to claim 2, wherein the coating is a sugar coating or a sugar film coating.
4. A tablet according to claim 3, wherein the sugar comprises sucrose.
5. A tablet according to any one of claims 1-4, wherein the coating contains a plasticizer selected from the group consisting of glycerin, propylene glycol, and polyethylene glycol.
6. A stabilised pharmaceutical tablet comprising an amount of from 0.1 to 10% by weight of ‘tibolone provided with a film coating comprising Eudragit RL 30D, wherein said coating achieves a stabilising effect with respect to the formation of OM38 upon storage of a coated tablet as compared to an uncoated tablet.
7. Use of a coating for stabilising a pharmaceutical tablet comprising an amount of from 0.1 to 10% by weight of tibolone, wherein said coating achieves a stabilising effect with respect to the formation of OM38 upon storage of a coated tablet as compared to an uncoated tablet, with the proviso that when said coating is a film coating, the film coating contains a cellulose ether, a vinyl polymer or gelatin.
8. Use according to claim 7, wherein the coating is a film coating, a sugar coating, a sugar film coating or a ‘wrap’ coating.
9. Use according to claim 8, wherein the coating is a sugar coating or a sugar film coating.
10. Use according to claim 9, wherein the sugar comprises sucrose. AMENDED SHEET
PCT/EP2003/050829
11. A tablet as claimed in claim 1, substantially as herein described with reference to and as illustrated in any of the examples.
12. Use as claimed in claim 7, substantially as herein described with reference to and as illustrated in any of the examples. AMENDED SHEET
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