WO2008082124A1 - Stabilized pharmaceutical drug of atorvastatin - Google Patents
Stabilized pharmaceutical drug of atorvastatin Download PDFInfo
- Publication number
- WO2008082124A1 WO2008082124A1 PCT/KR2007/006785 KR2007006785W WO2008082124A1 WO 2008082124 A1 WO2008082124 A1 WO 2008082124A1 KR 2007006785 W KR2007006785 W KR 2007006785W WO 2008082124 A1 WO2008082124 A1 WO 2008082124A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- atorvastatin
- pharmaceutical drug
- drug
- oral administration
- polyethylene oxide
- Prior art date
Links
- 229940079593 drug Drugs 0.000 title claims abstract description 47
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 title abstract description 26
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 title abstract description 26
- 229960005370 atorvastatin Drugs 0.000 title abstract description 26
- 229920000642 polymer Polymers 0.000 claims abstract description 21
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 16
- 238000003860 storage Methods 0.000 claims abstract description 13
- 239000002552 dosage form Substances 0.000 claims abstract description 5
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical class CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 claims description 13
- 239000003826 tablet Substances 0.000 claims description 12
- 239000008187 granular material Substances 0.000 claims description 11
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229960000502 poloxamer Drugs 0.000 claims description 4
- 229920001983 poloxamer Polymers 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000007902 hard capsule Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 abstract description 12
- 238000000576 coating method Methods 0.000 abstract description 8
- 230000003647 oxidation Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 230000020477 pH reduction Effects 0.000 abstract description 3
- 238000000354 decomposition reaction Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 13
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- FQCKMBLVYCEXJB-MNSAWQCASA-L atorvastatin calcium Chemical compound [Ca+2].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1.C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 FQCKMBLVYCEXJB-MNSAWQCASA-L 0.000 description 4
- 229940002661 lipitor Drugs 0.000 description 4
- 230000000087 stabilizing effect Effects 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 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 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- GNWCZBXSKIIURR-UHFFFAOYSA-N (2-docosanoyloxy-3-hydroxypropyl) docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCCCCCCCCCCCC GNWCZBXSKIIURR-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960001770 atorvastatin calcium Drugs 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- -1 glyceryl fatty acid Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229920003087 methylethyl cellulose Polymers 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Definitions
- the present invention relates to a stabilized atorvastatin-containing pharmaceutical drug for oral administration, and more particularly to an atorvastatin-containing pharmaceutical drug for oral administration, which prepared by coating atorvastatin with a polymer containing polyethylene oxide group and preventing the conditions for acidification (mechanism of atorvastatin decomposition) and outer surroundings for oxidation, thereby providing improved storage stability and improving the quality of goods during the shelf life even in the same dosage form with the conventional pharmaceutical drug.
- Atorvastatin or its pharmaceutically acceptable salts is a selective and competitive inhibitor of HMG-CoA reductase, and has been used as a therapeutic agent for treatment of hyperlipidemia.
- Atorvastatin exists in various forms such as crystalline, liquid-crystalline, noncrystalline and amorphous forms.
- Crystalline form of atorvastatin calcium is disclosed in U.S. patent No.5,969,156 (crystalline forms 1, 2 and 4), and in U.S. patent No. 6,121,461 (crystalline form 3).
- U.S. patent No. 6,605,729 also discloses the crystalline forms 5-19 of atorvastatin.
- WO 03/000235 Pfizer
- WO 03/000292 Pfizer
- WO 2005/065656 Pfizer
- WO 2006/059224 Warner-Lambert Company
- U.S. patent No. 6,558,659 Teva Pharmaceutical Industries Ltd.
- U.S. patent No. 6,569,463 Lipocine, Inc.
- WO 2005/065656 discloses a stabilizing method of mixing amorphous drugs and poloxamer (weight ratio of 1 : 1) along with polymers.
- the present invention discloses a method of stabilizing atorvastatin pharmaceutical drug regardless of crystalline form by coating atorvastatin calcium salt with a predetermined amount of a polymer containing polyethylene oxide group. Further, the present invention is different from the conventional patents in that the stabilization of atorvastatin may be ensured even when the amount of the polymer is reduced by more than 80 wt%.
- the present inventors have exerted extensive researches to overcome the aforementioned problems, and finally developed a pharmaceutical drug for oral administration with improved storage stability by coating atorvastatin calcium salt (regardless of its crystalline form) with a predetermined amount of a polymer containing polyethylene oxide group, while maintaining the level of drug release as high as that of the conventional pharmaceutical drug, thereby completing the present invention.
- the present invention aims to provide a pharmaceutical drug for oral administration with improved storage stability, which is prepared by coating atorvastatin calcium salt with a polymer containing polyethylene oxide group.
- the present invention relates to a pharmaceutical drug for oral administration with improved storage stability, which comprises 5-10 wt% of an active ingredient, i.e., atorvastatin calcium salt relative to the weight of a tablet and 10-20 wt% of a polymer containing polyethylene oxide group relative to the weight of the active ingredient.
- an active ingredient i.e., atorvastatin calcium salt relative to the weight of a tablet
- a polymer containing polyethylene oxide group relative to the weight of the active ingredient.
- Various impurities are produced during the manufacture of a pharmaceutical drug for oral administration due to the reactions of acidification and oxidation.
- the present invention provides an atorvastatin-containing pharmaceutical drug for oral administration, which prepared by coating crystalline or noncrystalline atorvastatin calcium salt with a polymer containing polyethylene oxide group.
- a pharmaceutical drug herein may be developed into the same dosage form with the conventional pharmaceutical drug, while ensuring sufficient storage stability and improving the quality of goods during the shelf life.
- a polymer containing polyethylene oxide group is used for improving the storage stability of an atorvastatin pharmaceutical drug. This is because polyethylene oxide has a relatively high oxidisability. Atorvastatin reacts with oxygen in air, thereby generating epoxide impurities. Polyethylene oxide is oxidized faster than an atorvastatin due to the higher oxidisability of an atorvastatin, thus improving the storage stability of an atorvastatin pharmaceutical drug.
- the polymer containing polyethylene oxide group include polyethylene oxide, poloxamer, polyethylene glycol, gelucire or the derivatives thereof.
- Preferable examples are poloxamer and polyethylene glycol.
- the aforementioned polymer may be contained in the amount of 10-20 wt% relative to the weight of atorvastatin. When the amount is less than 10 wt%, it may be difficult to control the generation of impurities. When it is higher than 20 wt%, it may be difficult to manufacture it into a tablet form.
- the polymer may be coated onto atorvastatin according to any conventional method such as, without limitation, a spray-dry, a melt extrusion and preferably a hot-melt method.
- the conventional pharmaceutically acceptable ingredients for the preparation of excipient granules such as a diluent, a disintegrant and a binder may also be contained in the amount of 2- 70 wt% relative to the weight of the final composition.
- a typical pharmaceutical drug for oral administration may be formulated by adding 0.5- 2 wt% of a lubricant and 1-4 wt% of a coating agent preferably in a dosage form of powders, granules, hard capsules or tablets.
- Examples of a pharmaceutically acceptable disintegrant include hydroxypropyl cellulose, crospovidone, sodium starch glycolate and croscarmellose sodium. A disintegrant herein may also be appropriately selected among the conventional ones.
- Examples of a pharmaceutically acceptable binder include povidone, copovidone and celluloses.
- Examples of a pharmaceutically acceptable lubricant include magnesium stearate, sodium stearyl fumarate, talc, esters of glyceryl fatty acid and glycerol dibehenate.
- ⁇ lubricant herein may also be appropriately selected among the conventional ones.
- Examples of a pharmaceutically acceptable coating agent include polyvinyl alcohol, hydroxypropylmethyl cellulose, methyl cellulose and ethyl cellulose.
- prepared pharmaceutical drug for oral administration containing atorvastatin calcium salt is superior to the conventional pharmaceutical drug in storage stability, thereby enabling to extend the shelf life and improve the goods quality.
- an atorvastatin-containing pharmaceutical drug for oral administration of the present invention comprises a predetermined amount of a polymer containing polyethylene oxide group, thereby improving storage stability and increasing goods quality and the shelf life, while maintaining a similar level of drug release to the level of the conventional pharmaceutical drug.
- Figure 1 shows the dissolution patterns of a commercially available pharmaceutical drug and a drug of Example 2 in distilled water (DW).
- Figure 2 shows the dissolution patterns of a commercially available pharmaceutical drug and a drug of Example 7 in distilled water (DW).
- Excipient granules were prepared with a high-shear mixer [YC-SEP-S MG ⁇ 3J, Yenchen] by using the excipients as shown in Table 1.
- the excipient granules were dried, and sieved with a 30-sized sieve.
- Main drug was coated with polymer with the high-shear mixer, and mixed with the excipient granules.
- Round-shaped tablets were prepared with a single tableting machine [ERWEKA Corp. ] by post-mixing lubricant was post-mixed.
- Film-coated tablets were prepared with a coating machine [Sejong Mechanics] by using coating agents dissolved in distilled water. [Table 1 ]
- Excipient granules were prepared with a high-shear mixer [YC-SEP-S MG-3J, Yenchen] by using the excipients as shown in Table 2.
- the excipient granules were dried, and sieved with a #30 mesh screen.
- An active ingredient was coated with polymer with the high-shear mixer, and mixed with the excipient granules.
- Round-shaped tablets were prepared with a single tableting machine [ERWEKA Corp. ] by post-mixing lubricant was post-mixed.
- Film-coated tablets were prepared with a coating machine [Sejong Mechanics] by using coating agents dissolved in distilled water.
- a tablet with the same content with a commercially available Lipitor [Pfizer] used as a control drug herein was prepared by using amorphous raw material.
- Granules were obtained by mixing atorvastatin calcium salt (amorphous) 20 mg, calcium carbonate 66 mg, microcrystalline cellulose 120 mg, lactose 65.61 mg, croscarmellose sodium 18 mg, polysorbate 80 1.2 mg, hydroxypropyl cellulose 6 mg and magnesium stearate 1.5 mg, followed by tabulation.
- a tablet with the same content with a commercially available Lipitor [Pfizer] used as a control drug herein was prepared by using crystalline form 8 raw material.
- Granules were obtained by mixing atorvastatin calcium salt (crystalline form type 8) 20 mg, calcium carbonate 66 mg, microcrystalline cellulose 120 mg, lactose 65.61 mg, croscarmellose sodium 18 mg, polysorbate 80 1.2 mg, hydroxypropyl cellulose 6 mg and magnesium stearate 1.5 mg, followed by tabulation.
- Stability test was conducted by using tablets prepared in Examples 1-8 and Comparative Examples 1-2 under the conditions described in the guidelines of ICH (International Conference on Harmonization).
- the conditions of long-term test was 25 0 C and 60% RH.
- the conditions of accelerated test was 40 0 C and 75% RH.
- Impurities were analyzed with a HPLC, and the contents of total impurities were compared. Tables 3-5 show the increase in the amount of impurities relative to the initial amount.
- Tables 3-4 indicate that the tablets of Examples show an improvement in storage stability than the pharmaceutical drugs of Comparative Examples.
- Dissolution test was conducted by using the atorvastatin calcium salt tablets of Examples 2 and 7 and the commercially available Lipitor 20 mg tablet [Pfizer] as described in Korea Pharmacopoeia and according to the paddle method (50 rpm).
- the volume of dissolution solution was 900 mL.
- the sampling time was 5, 10, 15 and 30 minutes, respectively, during the dissolution test.
- Dissolution solution (4 mL) was separated and filtered through a membrane filter (0.45 ⁇ m), and used as a test solution. Analysis was carried out by absorption spectrophotometry, and wave length was 244 nm.
- Figures 1 and 2 show that a pharmaceutical drug of the present invention has a dissolution rate that is equivalent to that of the commercially available pharmaceutical drug.
- an atorvastatin-containing pharmaceutical drug for oral administration of the present invention comprises a predetermined amount of a polymer containing polyethylene oxide group. Accordingly, a drug herein enables to improve the storage stability and extend the guarantee period, thereby increasing the quality of goods, while maintaining the level of drug release equivalent to the level of the conventional pharmaceutical drug.
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a stabilized atorvastatin-containing pharmaceutical drug for oral administration, and more particularly to an atorvastatin-containing pharmaceutical drug for oral administration, which prepared by coating atorvastatin with a polymer containing polyethylene oxide group and preventing the conditions for acidification (mechanism of atorvastatin decomposition) and outer surroundings for oxidation, thereby enabling to ensure improved storage stability and improve the quality of goods during the shelf life even in the same dosage form with the conventional pharmaceutical drug.
Description
[DESCRIPTION] [Invention Title] Stabilized pharmaceutical drug of atorvastatin
[Technical Field]
The present invention relates to a stabilized atorvastatin-containing pharmaceutical drug for oral administration, and more particularly to an atorvastatin-containing pharmaceutical drug for oral administration, which prepared by coating atorvastatin with a polymer containing polyethylene oxide group and preventing the conditions for acidification (mechanism of atorvastatin decomposition) and outer surroundings for oxidation, thereby providing improved storage stability and improving the quality of goods during the shelf life even in the same dosage form with the conventional pharmaceutical drug.
[Background Art]
Atorvastatin or its pharmaceutically acceptable salts is a selective and competitive inhibitor of HMG-CoA reductase, and has been used as a therapeutic agent for treatment of hyperlipidemia. A compound disclosed in U.S. patent No. 5,273,995, i.e., [(R-(R*, R*)]-2-(4-fluorophenyl)-
/3,δ,dihydroxy-5-(l-methylethyl)-3-phenyl-4-(phenylamino)-carbonyl- IH- pyrrole-1-heptanoic acid calcium salt (2:1) is currently commercially available under the registered trademark of Lipitor.
Atorvastatin exists in various forms such as crystalline, liquid-crystalline, noncrystalline and amorphous forms. Crystalline form of atorvastatin calcium is disclosed in U.S. patent No.5,969,156 (crystalline forms 1, 2 and 4), and in U.S. patent No. 6,121,461 (crystalline form 3). U.S. patent No. 6,605,729 also discloses the crystalline forms 5-19 of atorvastatin.
U.S. patent No. 5,686,104 (Warner-Lambert Company, Innovator); U.S. patent No.6,126,971 (Warner-Lambert Company); U.S. patent No.7,030,151 (Lek Pharmaceuticals d. d.)i and WO 2003/0175338 (Ranbaxy Pharmaceuticals Inc.) disclose the methods of stabilizing atorvastatin, which easily decomposes under an acidic condition, by creating alkali or basic circumstances. There have also been other stabilizing methods using polymers in WO
03/000235 (Pfizer); WO 03/000292 (Pfizer); WO 2005/065656 (Pfizer); WO 2006/059224 (Warner-Lambert Company); U.S. patent No. 6,558,659 (Teva Pharmaceutical Industries Ltd.); and U.S. patent No. 6,569,463 (Lipocine, Inc.). In particular, WO 2005/065656 (Pfizer) discloses a stabilizing method of mixing amorphous drugs and poloxamer (weight ratio of 1 : 1) along with polymers.
However, unlike the aforementioned conventional techniques, the present invention discloses a method of stabilizing atorvastatin pharmaceutical drug regardless of crystalline form by coating atorvastatin calcium salt with a predetermined amount of a polymer containing polyethylene oxide group. Further, the present invention is different from the conventional patents in that the stabilization of atorvastatin may be ensured even when the amount of the polymer is reduced by more than 80 wt%.
[Disclosure]
[Technical Problem]
Therefore, the present inventors have exerted extensive researches to overcome the aforementioned problems, and finally developed a pharmaceutical drug for oral administration with improved storage stability by coating atorvastatin calcium salt (regardless of its crystalline form) with a predetermined amount of a polymer containing polyethylene oxide group, while maintaining the level of drug release as high as that of the conventional pharmaceutical drug, thereby completing the present invention.
Accordingly, the present invention aims to provide a pharmaceutical drug for oral administration with improved storage stability, which is prepared by coating atorvastatin calcium salt with a polymer containing polyethylene oxide group.
[Technical Solution] The present invention relates to a pharmaceutical drug for oral administration with improved storage stability, which comprises 5-10 wt% of an active ingredient, i.e., atorvastatin calcium salt relative to the weight of a tablet and 10-20 wt% of a polymer containing polyethylene oxide group relative to the weight of the active ingredient. Hereunder is provided a detailed description of the present invention.
Various impurities are produced during the manufacture of a pharmaceutical drug for oral administration due to the reactions of acidification and oxidation. To overcome the problems, the present invention provides an atorvastatin-containing pharmaceutical drug for oral administration, which prepared by coating crystalline or noncrystalline atorvastatin calcium salt with a polymer containing polyethylene oxide group. A pharmaceutical drug herein may be developed into the same dosage form with the conventional pharmaceutical drug, while ensuring sufficient storage stability and improving the quality of goods during the shelf life. In the present invention, a polymer containing polyethylene oxide group is used for improving the storage stability of an atorvastatin pharmaceutical drug. This is because polyethylene oxide has a relatively high oxidisability. Atorvastatin reacts with oxygen in air, thereby generating epoxide impurities. Polyethylene oxide is oxidized faster than an atorvastatin due to the higher oxidisability of an atorvastatin, thus improving the storage stability of an atorvastatin pharmaceutical drug. Examples of the polymer containing polyethylene oxide group include polyethylene oxide, poloxamer, polyethylene glycol, gelucire or the derivatives thereof. Preferable examples are poloxamer and polyethylene glycol. The aforementioned polymer may be contained in the amount of 10-20 wt% relative to the weight of atorvastatin. When the amount is less than 10 wt%, it may be difficult to control the generation of impurities. When it is higher than 20 wt%, it may be difficult to manufacture it into a tablet form.
The polymer may be coated onto atorvastatin according to any conventional method such as, without limitation, a spray-dry, a melt extrusion and preferably a hot-melt method. The conventional pharmaceutically acceptable ingredients for the preparation of excipient granules such as a diluent, a disintegrant and a binder may also be contained in the amount of 2- 70 wt% relative to the weight of the final composition. A typical pharmaceutical drug for oral administration may be formulated by adding 0.5- 2 wt% of a lubricant and 1-4 wt% of a coating agent preferably in a dosage form of powders, granules, hard capsules or tablets.
Examples of a pharmaceutically acceptable disintegrant include hydroxypropyl cellulose, crospovidone, sodium starch glycolate and croscarmellose sodium. A disintegrant herein may also be appropriately
selected among the conventional ones. Examples of a pharmaceutically acceptable binder include povidone, copovidone and celluloses. Examples of a pharmaceutically acceptable lubricant include magnesium stearate, sodium stearyl fumarate, talc, esters of glyceryl fatty acid and glycerol dibehenate. Λ lubricant herein may also be appropriately selected among the conventional ones. Examples of a pharmaceutically acceptable coating agent include polyvinyl alcohol, hydroxypropylmethyl cellulose, methyl cellulose and ethyl cellulose.
Thus prepared pharmaceutical drug for oral administration containing atorvastatin calcium salt is superior to the conventional pharmaceutical drug in storage stability, thereby enabling to extend the shelf life and improve the goods quality.
[Advantageous Effects] As described above, an atorvastatin-containing pharmaceutical drug for oral administration of the present invention comprises a predetermined amount of a polymer containing polyethylene oxide group, thereby improving storage stability and increasing goods quality and the shelf life, while maintaining a similar level of drug release to the level of the conventional pharmaceutical drug.
[Description of Drawings]
Figure 1 shows the dissolution patterns of a commercially available pharmaceutical drug and a drug of Example 2 in distilled water (DW). Figure 2 shows the dissolution patterns of a commercially available pharmaceutical drug and a drug of Example 7 in distilled water (DW).
[Best Mode]
[Mode for Invention] The present invention is described more specifically by the following
Examples. Examples herein are meant only to illustrate the present invention, but they should not be construed as limiting the scope of the claimed invention.
Examples 1-4
Excipient granules were prepared with a high-shear mixer [YC-SEP-S MG~3J, Yenchen] by using the excipients as shown in Table 1. The excipient granules were dried, and sieved with a 30-sized sieve. Main drug was coated with polymer with the high-shear mixer, and mixed with the excipient granules. Round-shaped tablets were prepared with a single tableting machine [ERWEKA Corp. ] by post-mixing lubricant was post-mixed. Film-coated tablets were prepared with a coating machine [Sejong Mechanics] by using coating agents dissolved in distilled water. [Table 1 ]
Examples 5-8
Excipient granules were prepared with a high-shear mixer [YC-SEP-S MG-3J, Yenchen] by using the excipients as shown in Table 2. The excipient granules were dried, and sieved with a #30 mesh screen. An active ingredient was coated with polymer with the high-shear mixer, and mixed
with the excipient granules. Round-shaped tablets were prepared with a single tableting machine [ERWEKA Corp. ] by post-mixing lubricant was post-mixed. Film-coated tablets were prepared with a coating machine [Sejong Mechanics] by using coating agents dissolved in distilled water.
[Table 2]
Comparative Example 1
A tablet with the same content with a commercially available Lipitor [Pfizer] used as a control drug herein was prepared by using amorphous raw material. Granules were obtained by mixing atorvastatin calcium salt (amorphous) 20 mg, calcium carbonate 66 mg, microcrystalline cellulose 120 mg, lactose 65.61 mg, croscarmellose sodium 18 mg, polysorbate 80 1.2 mg, hydroxypropyl cellulose 6 mg and magnesium stearate 1.5 mg, followed by
tabulation.
Comparative Example 2
A tablet with the same content with a commercially available Lipitor [Pfizer] used as a control drug herein was prepared by using crystalline form 8 raw material. Granules were obtained by mixing atorvastatin calcium salt (crystalline form type 8) 20 mg, calcium carbonate 66 mg, microcrystalline cellulose 120 mg, lactose 65.61 mg, croscarmellose sodium 18 mg, polysorbate 80 1.2 mg, hydroxypropyl cellulose 6 mg and magnesium stearate 1.5 mg, followed by tabulation.
Test Example 1 '■ stability test
Stability test was conducted by using tablets prepared in Examples 1-8 and Comparative Examples 1-2 under the conditions described in the guidelines of ICH (International Conference on Harmonization). The conditions of long-term test was 25 0C and 60% RH. The conditions of accelerated test was 40 0C and 75% RH.
Impurities were analyzed with a HPLC, and the contents of total impurities were compared. Tables 3-5 show the increase in the amount of impurities relative to the initial amount.
[Table 3] Stability Test of Comparative Example 1, Examples 1, 2 and 4 (6 months)
Tables 3-4 indicate that the tablets of Examples show an improvement in storage stability than the pharmaceutical drugs of Comparative Examples.
Test Example 2: dissolution rate test
Dissolution test was conducted by using the atorvastatin calcium salt tablets of Examples 2 and 7 and the commercially available Lipitor 20 mg tablet [Pfizer] as described in Korea Pharmacopoeia and according to the paddle method (50 rpm). The volume of dissolution solution was 900 mL.
The sampling time was 5, 10, 15 and 30 minutes, respectively, during the dissolution test. Dissolution solution (4 mL) was separated and filtered through a membrane filter (0.45 μm), and used as a test solution. Analysis was carried out by absorption spectrophotometry, and wave length was 244 nm.
Figures 1 and 2 show that a pharmaceutical drug of the present invention has a dissolution rate that is equivalent to that of the commercially available pharmaceutical drug.
[Industrial Applicability]
As described above, an atorvastatin-containing pharmaceutical drug for oral administration of the present invention comprises a predetermined amount of a polymer containing polyethylene oxide group. Accordingly, a drug herein enables to improve the storage stability and extend the guarantee period, thereby increasing the quality of goods, while maintaining the level of drug release equivalent to the level of the conventional pharmaceutical drug.
Claims
[CLAIMS] [Claim 1]
A pharmaceutical drug comprising atorvastatin calcium salt as an active ingredient for oral administration with improved storage stability, the pharmaceutical drug further comprising 10-20 wt% of a polymer relative to the weight of the atorvastatin calcium salt.
[Claim 2]
The pharmaceutical drug of claim 1, wherein the polymer comprises polyethylene oxide group.
[Claim 3]
The pharmaceutical drug of claim 2, wherein the polymer is selected from the group consisting of polyethylene oxide, poloxamer, polyethylene glycol, Gelucire and its derivatives.
[Claim 4] The pharmaceutical drug of claim 1, wherein the atorvastatin calcium salt is crystalline or noncrystalline.
[Claim 5]
The pharmaceutical drug of claim 1, which is formulated into a dosage form selected from the group consisting of powders, granules, hard capsules and tablets.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020060138231A KR20080062430A (en) | 2006-12-29 | 2006-12-29 | Oral administration formulation containing atorvastatin with excellent storage stability |
| KR10-2006-0138231 | 2006-12-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2008082124A1 true WO2008082124A1 (en) | 2008-07-10 |
Family
ID=39588745
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2007/006785 WO2008082124A1 (en) | 2006-12-29 | 2007-12-24 | Stabilized pharmaceutical drug of atorvastatin |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR20080062430A (en) |
| WO (1) | WO2008082124A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011154755A1 (en) | 2010-06-08 | 2011-12-15 | Nanoform Cardiovascular Therapeutics Ltd. | Nanostructured atorvastatin, its pharmaceutically acceptable salts and compositions of them, process for the preparation thereof and pharmaceutical compositions containing them |
| CN105030728A (en) * | 2015-09-22 | 2015-11-11 | 青岛华之草医药科技有限公司 | Medicinal atorvastatin calcium composition capsules for treating coronary heart disease |
| CN105343024A (en) * | 2015-11-05 | 2016-02-24 | 石家庄市华新药业有限责任公司 | Atorvastatin calcium tablet and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005065656A2 (en) * | 2003-12-31 | 2005-07-21 | Pfizer Products Inc. | Stabilized pharmaceutical solid compositions of low-solubility drugs, poloxamers, and stabilizing polymers |
| WO2006059224A1 (en) * | 2004-12-02 | 2006-06-08 | Warner-Lambert Company Llc | Pharmaceutical compositions of amorphous atorvastatin and process for preparing same |
| WO2006087404A1 (en) * | 2005-02-16 | 2006-08-24 | Ercros Industrial, S.A. | Stabilised amorphous calcium atorvastatin and production method thereof |
-
2006
- 2006-12-29 KR KR1020060138231A patent/KR20080062430A/en not_active Ceased
-
2007
- 2007-12-24 WO PCT/KR2007/006785 patent/WO2008082124A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005065656A2 (en) * | 2003-12-31 | 2005-07-21 | Pfizer Products Inc. | Stabilized pharmaceutical solid compositions of low-solubility drugs, poloxamers, and stabilizing polymers |
| WO2006059224A1 (en) * | 2004-12-02 | 2006-06-08 | Warner-Lambert Company Llc | Pharmaceutical compositions of amorphous atorvastatin and process for preparing same |
| WO2006087404A1 (en) * | 2005-02-16 | 2006-08-24 | Ercros Industrial, S.A. | Stabilised amorphous calcium atorvastatin and production method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011154755A1 (en) | 2010-06-08 | 2011-12-15 | Nanoform Cardiovascular Therapeutics Ltd. | Nanostructured atorvastatin, its pharmaceutically acceptable salts and compositions of them, process for the preparation thereof and pharmaceutical compositions containing them |
| CN105030728A (en) * | 2015-09-22 | 2015-11-11 | 青岛华之草医药科技有限公司 | Medicinal atorvastatin calcium composition capsules for treating coronary heart disease |
| CN105343024A (en) * | 2015-11-05 | 2016-02-24 | 石家庄市华新药业有限责任公司 | Atorvastatin calcium tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20080062430A (en) | 2008-07-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2010210123B2 (en) | Process for the preparation of a pharmaceutical composition comprising ezetimibe | |
| US20090196932A1 (en) | Pharmaceutical compositions of atorvastatin | |
| JP2011506373A (en) | Pharmaceutical composition | |
| AU2010242938A2 (en) | Fixed dose drug combination formulations | |
| US20090005425A1 (en) | Complex Formulation Comprising Amlodipine Camsylate And Simvastatin and Method For Preparation Thereof | |
| US20080248115A1 (en) | Combinations of statins and anti-obesity agent | |
| US20080038332A1 (en) | Stable pharmaceutical formulation comprising atorvastatin calcium | |
| WO2023012817A1 (en) | A pharmaceutical composition comprising combination of dapagliflozin and sitagliptin | |
| WO2008082124A1 (en) | Stabilized pharmaceutical drug of atorvastatin | |
| AU2014293807B2 (en) | Combination Formulation Containing Sustained Release Metformin And Immediate Release HMG-COA Reductase Inhibitor | |
| US20150037414A1 (en) | Stable controlled release pharmaceutical compositions containing fenofibrate and pravastatin | |
| US20140248345A1 (en) | Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with atorvastatin | |
| CA2534910C (en) | Stable controlled release pharmaceutical compositions containing fenofibrate and pravastatin | |
| US20120165386A1 (en) | Stable oral pharmaceutial composition of atorvastatin | |
| WO2024095137A1 (en) | Pharmaceutical composition of empagliflozin and process thereof | |
| EP4188338A1 (en) | Bilayer tablet comprising ezetimibe and atorvastatin | |
| EP2779999A2 (en) | Pharmaceutical formulations comprising atorvastatin and glimepiride | |
| AU2005210117A1 (en) | Hypocholesterolemic compositions comprising a statin and an antiflatulent agent | |
| KR101302306B1 (en) | complex for improving, alleviating, treating or preventing of hyperlipidemia | |
| KR20200015758A (en) | Pharmaceutical composition | |
| WO2021019499A1 (en) | Solid oral multiple-unit immediate release compositions, methods and uses thereof | |
| KR101072600B1 (en) | Stable pharmaceutical composition comprising fluvastatin and method for preparing the same | |
| AU2003254428B2 (en) | Stable controlled release pharmaceutical compositions containing Fenofibrate and Pravastatin | |
| KR20090048023A (en) | Oral combinations containing amlodipine besylate and atorvastatin calcium | |
| KR100715114B1 (en) | Pharmaceutical Compositions for Diabetes Treatment |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 07851746 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 07851746 Country of ref document: EP Kind code of ref document: A1 |