CN102869343B - low concentration meloxicam tablets - Google Patents
low concentration meloxicam tablets Download PDFInfo
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- CN102869343B CN102869343B CN201180022413.4A CN201180022413A CN102869343B CN 102869343 B CN102869343 B CN 102869343B CN 201180022413 A CN201180022413 A CN 201180022413A CN 102869343 B CN102869343 B CN 102869343B
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- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Ilacox Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 title claims abstract description 79
- 229960001929 meloxicam Drugs 0.000 title claims abstract description 78
- 239000007787 solid Substances 0.000 claims abstract description 28
- 238000003825 pressing Methods 0.000 claims abstract description 19
- 239000000843 powder Substances 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 239000000796 flavoring agent Substances 0.000 claims description 19
- 235000013355 food flavoring agent Nutrition 0.000 claims description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 239000000945 filler Substances 0.000 claims description 15
- 229910000460 iron oxide Inorganic materials 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- 239000000314 lubricant Substances 0.000 claims description 12
- 239000003002 pH adjusting agent Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 9
- 239000003086 colorant Substances 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 6
- 150000008064 anhydrides Chemical class 0.000 claims description 6
- 235000015278 beef Nutrition 0.000 claims description 6
- 239000000377 silicon dioxide Substances 0.000 claims description 6
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate dihydrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 238000005469 granulation Methods 0.000 claims description 4
- 230000003179 granulation Effects 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 claims description 3
- BOJFTTGNERPKTO-UHFFFAOYSA-N calcium;icosanoic acid Chemical compound [Ca].CCCCCCCCCCCCCCCCCCCC(O)=O BOJFTTGNERPKTO-UHFFFAOYSA-N 0.000 claims description 3
- -1 flowing regulator Substances 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims 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 claims description 2
- 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 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 claims description 2
- 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 2
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 2
- 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 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 2
- 235000011010 calcium phosphates Nutrition 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 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 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 238000004513 sizing Methods 0.000 claims 9
- 238000007873 sieving Methods 0.000 claims 3
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Chemical group [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims 2
- 239000002245 particle Substances 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 1
- 239000000686 essence Substances 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 235000011194 food seasoning agent Nutrition 0.000 claims 1
- 238000005453 pelletization Methods 0.000 claims 1
- 239000004575 stone Substances 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 abstract description 10
- 239000003826 tablet Substances 0.000 description 141
- JEIPFZHSYJVQDO-UHFFFAOYSA-N Iron(III) oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 9
- 229920002261 Corn starch Polymers 0.000 description 7
- 239000008120 corn starch Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 5
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drugs Drugs 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- LZNWYQJJBLGYLT-UHFFFAOYSA-N 4-hydroxy-2-methyl-1,1-dioxo-N-pyridin-2-ylthieno[2,3-e]thiazine-3-carboxamide Chemical compound OC=1C=2SC=CC=2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 LZNWYQJJBLGYLT-UHFFFAOYSA-N 0.000 description 1
- 208000001187 Dyskinesias Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010017577 Gait disturbance Diseases 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N Meglumine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010048592 Musculoskeletal disease Diseases 0.000 description 1
- 206010028391 Musculoskeletal pain Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 208000000399 Procedural Pain Diseases 0.000 description 1
- YIBNHAJFJUQSRA-YNNPMVKQSA-N Prostaglandin H2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2C\C=C/CCCC(O)=O YIBNHAJFJUQSRA-YNNPMVKQSA-N 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010038683 Respiratory disease Diseases 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- BMQVRJOWNGSIEG-UHFFFAOYSA-L calcium;icosanoate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCCCC([O-])=O BMQVRJOWNGSIEG-UHFFFAOYSA-L 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 229940051164 ferric oxide yellow Drugs 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- LDHBWEYLDHLIBQ-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide;hydrate Chemical compound O.[OH-].[O-2].[Fe+3] LDHBWEYLDHLIBQ-UHFFFAOYSA-M 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000011218 segmentation Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
Abstract
The present invention relates to by the solid tablet of powder direct pressing, it comprises the meloxicam being dispersed in this tablet and one or more excipient, and this tablet can be fractured into two, three and/or four unit, and each unit all contains the active ingredient of equivalent.
Description
Invention field
The present invention relates to new oral delivery form comprising alienable meloxicam (Meloxicam) tablet and preparation method thereof.
Background of invention
Meloxicam (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) is NSAID (non-steroidal anti-inflammatory drug) NSAID of former times health (oxicam) family.The medicine inhibitory enzyme PGH2 synzyme of these types, also referred to as cyclo-oxygenase or COX.Meloxicam has antiinflammatory, brings down a fever and analgetic properties.
Meloxicam and sodium salt and meglumine salt thereof are described in EP 0002482.As shown in EP 0945134, single active ingredient has low aqueous solubility, and this patent is also disclosed the pH dependent solubility of meloxicam and salt thereof.Meloxicam has the most different form of medication, the tablet (EP 1385483 and GB2455875) manufactured including solution (EP 1299107), suspension (EP 1066029), water-soluble granular (EP 1558262), the tablet (EP 1942902) by the granule manufacture containing meloxicam or the mixture of powders by direct pressing.
It is an object of the invention to develop solid Meloxicam Tablets acceptant, masticable, even for special low concentration, this tablet allows also to accurately be administered meloxicam.
Accompanying drawing explanation
The figure of tablet of Figure 1A: 1mg meloxicam chewable tablets and size.
The figure of tablet of Figure 1B: 2.5mg meloxicam chewable tablets and size.
Fig. 2: include figure of tablet and the fracture recess of size.
Detailed Description Of The Invention
Surprisingly it has been discovered that solid Meloxicam Tablets acceptant, masticable can be prepared by the method for the present invention, even for special low concentration, allowing also to accurately be administered meloxicam, the method is carried out by direct pressing powder and without any granulation step.
This tablet is administered to companion animals (such as cat and dog), the dog of following body weight: 1kg to 70kg, 1kg to 60kg, 1kg to 50kg, 1kg to 40kg, 1kg to 30kg, 1kg to 20kg, 1kg to 10kg.This tablet is administered to the animal suffering from acute and the inflammation of chronic musculoskeletal disease and pain, to treat or to alleviate these diseases.Other indication includes the dyskinesia, limping, respiratory disorder, the pain of such as postoperative pain, heating and inflammation.
The present invention relates to by the solid tablet of powder direct pressing, it comprises meloxicam or its pharmaceutically acceptable salt and one or more excipient, being characterised by that this tablet can be fractured into two, three and/or four unit, each unit all contains the active ingredient of equivalent.Tablet is characterised by that meloxicam is dispersed in tablet.In another embodiment, the present invention relates to by the solid tablet of powder direct pressing, it comprises meloxicam or its pharmaceutically acceptable salt and one or more excipient, these excipient are perfectly even scattered in tablet, this tablet can be fractured into two, three and/or four unit, being preferably two or four, more preferably two, each unit all contains the active ingredient of equivalent.Tablet contains selected from following excipient: filler, disintegrating agent, pH adjusting agent, coloring agent, flowing regulator (flow regulator), lubricant and flavoring agent.
At least one in excipient is selected from following filler/disintegrating agent: starch (such as (but not limited to) corn starch), microcrystalline Cellulose, calcium phosphate, lactose, maltodextrin, mannitol, sorbitol, crospolyvinylpyrrolidone and sodium carboxymethyl cellulose, preferably starch and microcrystalline Cellulose.When starch is filler/disintegrating agent, then its concentration is selected from every tablet 150mg to 450mg, it is preferably every tablet 150 to 300mg, 160 to 290mg, 170 to 280mg, 170 to 270mg, 180 to 260mg, 170 to 250mg, 190 to 240mg, 200 to 240mg, 210 to 240mg, 220 to 240mg and 230 to 240mg, more preferably every tablet 235.0mg, these concentration are particularly preferred in the tablet containing 1mg meloxicam.Another preferred concentration is selected from every tablet 200 to 450mg, 210 to 440mg, 220 to 430mg, 230 to 420mg, 240 to 410mg, 250 to 400mg, 260 to 390mg, 270 to 380mg, 280 to 370mg, 290 to 360mg, 300 to 360mg, 310 to 360mg, 320 to 360mg, 330 to 360mg, 340 to 360mg and 350 to 360mg, being preferably every tablet 351.5mg, these concentration are particularly preferred in every tablet contains the tablet of 2.5mg meloxicam.
The concentration of the second filler/disintegrating agent is selected from every tablet 300 to 800mg, the most every tablet 300 to 600mg, 300 to 500mg, 400 to 500mg, the most every tablet 400mg, and these concentration are particularly preferred in the tablet containing 1mg meloxicam.Another preferred concentration is selected from every tablet 400 to 800mg, 500 to 700mg, 500 to 600mg and every tablet 600mg, and these concentration are particularly preferred in every tablet contains the tablet of 2.5mg meloxicam.
The coloring agent used in tablets includes iron oxide brown (ferric oxide brown) and/or iron oxide yellow (ferric oxide yellow), preferably iron oxide brown and iron oxide yellow.The concentration of each coloring agent is in the range of every tablet 2 to 8mg, and preferred concentration is selected from every tablet 3 to 5mg, every tablet 3 to 4mg and every tablet 3.2mg, and these concentration are particularly preferred in the tablet containing 1mg meloxicam.Another preferred concentration is selected from every tablet 3 to 8mg, every tablet 4 to 6mg, every tablet 3 to 5mg and every tablet 4.8mg, and these concentration are particularly preferred in every tablet contains the tablet of 2.5mg meloxicam.
Tablet contains selected from following pH adjusting agent: tartaric acid, maleic acid and Trisodium citrate dihydrate, preferably Trisodium citrate dihydrate.The concentration of pH adjusting agent is in the range of 50mg to 150mg, the preferred concentration of pH adjusting agent is selected from the tablet containing 1mg meloxicam, every tablet 50 to 100mg, 50 to 90mg, 50 to 80mg, 50 to 70mg, 60 to 90mg, 60 to 80mg and 60 to 70mg, the most every tablet 65.6mg.Another preferred concentration is selected from every tablet 75 to 150mg, 85 to 140mg, 85 to 130mg, 85 to 120mg, 85 to 110mg, 85 to 100mg, 90 to 150mg, 90 to 140mg, 90 to 130mg, 90 to 120mg, 90 to 110mg, 90 to 100mg and every tablet 98.4mg, and these concentration are particularly preferred in every tablet contains the tablet of 2.5mg meloxicam.
Tablet is possibly together with selected from following flowing regulator: Talcum, anhydride silica and lubricant, preferably anhydride silica.The concentration of flowing regulator is in the range of 2 to 8mg, the preferred concentration of flowing regulator is selected from every tablet 2 to 6mg, 3 to 6mg, 3 to 5mg, 3 to 4mg, 2 to 5mg and 2 to 4mg, and even more preferably 4mg, these concentration are particularly preferred in the tablet containing 1mg meloxicam.Another preferred concentration is selected from every tablet 4 to 8mg, 5 to 8mg, 6 to 8mg, 6 to 7mg, 5 to 7mg, 4 to 7mg, 4 to 6mg, 5 to 6mg and every tablet 6mg, and these concentration are particularly preferred in every tablet contains the tablet of 2.5mg meloxicam.
Tablet is possibly together with selected from following lubricant: Polyethylene Glycol (macrogol, polyethylene glycol), stearic acid, aluminium stearate, arachidic acid calcium (calcium arachinat) and magnesium stearate, it is preferably stearic acid, aluminium stearate, arachidic acid calcium and magnesium stearate, most preferably magnesium stearate.The concentration of lubricant is in the range of every tablet 5 to 15mg, the preferred concentration of lubricant is selected from every tablet 5 to 10mg, 5 to 9mg, 5 to 8mg, 6 to 10mg, 6 to 9mg, 6 to 8mg, 7 to 10mg, 7 to 9mg, 7 to 8mg and every tablet 8mg, and these concentration are particularly preferred in the tablet containing 1mg meloxicam.Another preferred concentration of lubricant is selected from every tablet 8 to 15mg, 8 to 14mg, 8 to 13mg, 8 to 12mg, 9 to 15mg, 9 to 14mg, 9 to 13mg, 9 to 12mg, 10 to 15mg, 10 to 14mg, 10 to 13mg, 10 to 12mg, 11 to 15mg, 11 to 14mg, 11 to 13mg, 11 to 12mg and every tablet 12mg, and these concentration are particularly preferred in every tablet contains the tablet of 2.5mg meloxicam.
Flavoring agent is preferably Artificial Beef flavoring agent, and its concentration is in the range of every tablet 40 to 160mg.The preferred concentration of flavoring agent is selected from every tablet 40 to 100mg, 50 to 100mg, 60 to 100mg, 70 to 100mg, 80 to 100mg and every tablet 80mg, and these concentration are particularly preferred in the tablet containing 1mg meloxicam.Another preferred concentration of flavoring agent is selected from every tablet 90 to 160mg, 100 to 150mg, 110 to 140mg, 110 to 130mg and every tablet 120mg, and these concentration are particularly preferred in every tablet contains the tablet of 2.5mg meloxicam.
According to the present invention, tablet contains 0.5 to 5mg meloxicam and tablet weight is 500mg to 2000mg.Tablet preferably comprises 0.5mg to 5mg meloxicam, and total tablet weight is 500mg to 2000mg, and tablet diameters is in the range of 10mm to 20mm.Additionally, tablet is highly preferred in the range of 3mm to 8mm, more preferably 4mm to 8mm, 5.3mm to 7.3mm or 4.5mm to 6.5mm, even more preferably 5mm, 5.5mm or 6.3mm.The meloxicam amount of every tablet is preferably 1mg to 4mg, more preferably 1mg to 3mg or 1.5mg to 2.5mg, even more preferably 1mg and 2.5mg.The gross weight of tablet in the range of 500 to 2000mg, preferably 700 to 1500mg, most preferably 800mg and 1200mg.In a preferred embodiment, the gross weight of the tablet containing 0.5mg to 1.8mg meloxicam is about 500mg to 900mg, and diameter is in the range of 10 to 15mm.The even more preferably tablet containing 0.5mg to 1.8mg meloxicam, its gross weight is about 500mg to 900mg, and diameter is in the range of 10mm to 15mm, and height is in the range of 4.5mm to 6.5mm.In another preferred embodiment, the gross weight of the tablet containing 1.9 to 5mg meloxicam is 900 to 2000mg, and a diameter of 15mm to 20mm.The even more preferably tablet containing 1.9 to 5mg meloxicam, its gross weight is 900mg to 2000mg, a diameter of 15mm to 20mm, and thickness is in the range of 5.3mm to 7.3mm.In the especially preferred embodiment of the present invention, tablet contains the 1mg meloxicam being dispersed in the total tablet weight of 800mg, and/or is dispersed in the 2.5mg meloxicam in the tablet that gross weight is 1200mg.Flavoring agent accounts for the 2% to 15% of tablet total weight amount.According to the present invention, the most preferably every 800mg tablet of tablet contains 1mg meloxicam, and flavoring agent content is every tablet 10 weight %, or the every tablet of tablet contains 2.5mg meloxicam, and tablet total weight amount is 1200mg, and flavoring agent content is every tablet 10 weight %.Flavoring agent according to the present invention is preferably Artificial Beef flavoring agent.
According on the other hand, tablet has the shape as illustrated in Figure 1A and 1B and Fig. 2.Generally, tablet contains 0.5mg to 5mg meloxicam, and total tablet weight is 500mg to 2000mg.The size of tablet is represented by its diameter (in the range of 10mm to 20mm) and height (in the range of 3mm to 8mm) thereof.Preferably, the gross weight of the tablet containing 1mg meloxicam is 500mg to 900mg；Diameter is in the range of 10mm to 20mm, 11mm to 18mm, 12mm to 17mm, 13mm to 16mm, 14mm to 15mm, and another preferred scope is 12mm to 15mm；And height is in the range of 4mm to 8mm, 5mm to 7mm, 5mm to 6mm, preferably 5mm to 6mm.Being especially preferably the tablet as illustrated in Figure 1A, it contains the meloxicam that concentration is every tablet 1.0mg, and the gross weight of tablet is 800mg, and a diameter of 14mm and height are 5.5mm.Preferably, the gross weight of the tablet containing 2.5mg meloxicam is 900 to 2000mg；Diameter is in the range of 10mm to 20mm, 11mm to 18mm, 12mm to 17mm, 13mm to 16mm, 14mm to 15mm, and another preferred scope is 15mm to 18mm or 15mm to 17mm；And height is in the range of 4mm to 8mm, 5mm to 7mm, 5mm to 6mm, another preferred scope is 5mm to 8mm.Being especially preferably tablet as illustrated in Figure 1B, it contains the meloxicam that concentration is every tablet 2.5mg, and the gross weight of tablet is 1200mg, and a diameter of 16mm and height are 6.3mm.
As shown in Figure 1A and 1B, tablet has fracture recess/score line, and it makes tablet can fragment into two unit, owing to meloxicam is uniformly distributed in tablets, therefore obtains two unit containing equivalent meloxicam.
According on the other hand, tablet has orthogonal two fracture recess/score line, as illustrated in fig. 2.Therefore, tablet can the quartering, obtain four or two unit containing equivalent meloxicam, be only possible to accomplish only because meloxicam is uniformly distributed in tablets.
Solid preparation according to the present invention is the direct pressing tablet without any granulation step.Active ingredient in solid preparation is preferably the meloxicam in free alkali form.
In contrast to the prior art, according to the tablet of the present invention by powder direct pressing piece agent is manufactured, thus the active ingredient meloxicam of available low content.Additionally, tablet has large scale, owing to this large scale can make animal be easier to pick up tablet, so needing this size.Additionally, this size makes tablet be easier to segmentation, in order to reach the accurate administration of medicine in the case of low dosage is administered, so this size is the most critically important.Such as, as it has been described above, a diameter of 14mm of the tablet containing 1mg meloxicam, and a diameter of 16mm of the tablet containing 2.5mg meloxicam.As it has been described above, the concentration of active drug composition is the lowest and is considered marginal value, this shows that the concentration range of meloxicam is difficult to produce the wherein equally distributed bolus of active ingredient.
Even if surprisingly it has been discovered that the concentration of active ingredient is relatively low, the manufacture method of the present invention also can make meloxicam be uniformly distributed.The method can manufacture the described tablet dividing and can ensure that accurately administration.As it has been described above, final tablet is preferably carved with fracture recess/score line, it guarantees that user is easier and tablet is fractured into two panels, three and/or four.Direct pressing method comprises the following steps:
1) premixing meloxicam and the filler/disintegrating agent of 10-50%, it is preferably 20% to 40%, more preferably 25-35%, even more preferably 33%, then through suitably screening, its screen size is 0.6 to 1.5mm, preferably 0.7 to 1.4mm, more preferably 0.8 to 1.3mm, even more preferably selected from following screen size: 0.6mm, 0.8mm, 1.0mm and 1.5mm.
2) premixing pH adjusting agent and one or more coloring agent, then through suitably screening, its screen size is 0.6 to 1.5mm, preferably 0.7 to 1.4mm, more preferably 0.8 to 1.3mm, even more preferably selected from following screen size: 0.6mm, 0.8mm, 1.0mm and 1.5mm.
3) filler/disintegrating agent (preferably 60% to 80% of 90-50% is mixed, more preferably 60-70%, even more preferably 67%), the second filler/disintegrating agent, flowing regulator, lubricant and artificial flavoring, then through suitably screening, its screen size is 0.6 to 1.5mm, it is preferably 0.7 to 1.4mm, more preferably 0.8 to 1.3mm, even more preferably selected from following screen size: 0.6mm, 0.8mm, 1.0mm and 1.5mm.
4) it is blended in step 1) and 2) the middle mixture obtained, then through suitably screening, its screen size is 0.6 to 1.5mm, it is preferably 0.7 to 1.4mm, more preferably 0.8 to 1.3mm, even more preferably selected from following screen size: 0.6mm, 0.8mm, 1.0mm and 1.5mm.
5) step 3 finally it is blended in) and 4) the middle mixture obtained, then through suitably screening, its screen size is 0.6 to 1.5mm, it is preferably 0.7 to 1.4mm, more preferably 0.8 to 1.3mm, even more preferably selected from following screen size: 0.6mm, 0.8mm, 1.0mm and 1.5mm.
6) by step 5) in obtain mixture of powders be pressed into tablet.
Direct pressing method preferably includes following steps:
1) premixing meloxicam and the corn starch of 10-50%, it is preferably 20% to 40%, more preferably 25-35%, the corn starch of even more preferably 33%, then through suitably screening, its screen size is 0.6 to 1.5mm, preferably 0.7 to 1.4mm, more preferably 0.8 to 1.3mm, even more preferably selected from following screen size: 0.6mm, 0.8mm, 1.0mm and 1.5mm.
2) premixing Trisodium citrate dihydrate, iron oxide brown and iron oxide yellow, then through suitably screening, its screen size is 0.6 to 1.5mm, it is preferably 0.7 to 1.4mm, more preferably 0.8 to 1.3mm, even more preferably selected from following screen size: 0.6mm, 0.8mm, 1.0mm and 1.5mm.
3) corn starch (preferably 60% to 80% of 90-50% is mixed, more preferably 60-70%, the corn starch of even more preferably 67%), microcrystalline Cellulose, anhydride silica, magnesium stearate and Artificial Beef flavoring agent, then through suitably screening, its screen size is 0.6 to 1.5mm, it is preferably 0.7 to 1.4mm, more preferably 0.8 to 1.3mm, even more preferably selected from following screen size: 0.6mm, 0.8mm, 1.0mm and 1.5mm.
4) it is blended in step 1) and 2) the middle mixture obtained, then through suitably screening, its screen size is 0.6 to 1.5mm, it is preferably 0.7 to 1.4mm, more preferably 0.8 to 1.3mm, even more preferably selected from following screen size: 0.6mm, 0.8mm, 1.0mm and 1.5mm.
5) step 3 finally it is blended in) and 4) the middle mixture obtained, then through suitably screening, its screen size is 0.6 to 1.5mm, it is preferably 0.7 to 1.4mm, more preferably 0.8 to 1.3mm, even more preferably selected from following screen size: 0.6mm, 0.8mm, 1.0mm and 1.5mm.
6) by 5) in the mixture of powders that obtains be pressed into tablet.
Therefore, according on the other hand, it is provided that comprising the solid tablet of meloxicam or its pharmaceutically acceptable salt, wherein this solid tablet can be obtained by the direct pressing method of mixture of powders, and the method comprises step 1 as above to 6.
According on the other hand, it is provided that comprise the solid tablet of meloxicam or its pharmaceutically acceptable salt, the one or multi-step during wherein the manufacture of this solid tablet comprises method step 1 to 6 as above as described in this article.Such as, this manufacture method comprises step 1, step 1+4, step 1+4+6 or step 1+4+5+6.
According on the other hand, it is provided that the method manufacturing solid tablet, wherein the method is preferably made up of to 6 step 1 as above.
Manufacture method
The description of following manufacture method should be regarded as another embodiment, and therefore should not be construed as restrictive.
The first step of manufacture method is premixing active ingredient (such as meloxicam or its medicine and pharmacology active salt) and partial starch, then sieves.Owing to meloxicam or its pharmaceutically acceptable salt total amount in tablet mixture are relatively low; therefore need to carry out follow-up mixing with the revolution of e.g., from about 900, to guarantee that active ingredient is uniformly distributed in substrate after adding another screened mixture containing sodium citrate and ferrum oxide.Finally, add the mixture of screened microcrystalline Cellulose, meat flavor, remaining starch, colloidal silica anhydrous and magnesium stearate, then make mixing container rotate e.g., from about 350 turns finally to mix.
By final mixture direct pressing piece agent.
Embodiment
I. gross weight is the composition of the tablet comprising 1mg meloxicam and 10% flavoring agent of 800mg.
| Composition | Mg/ sheet |
| Meloxicam | 1.0 |
| Trisodium citrate dihydrate | 65.6 |
| Corn starch | 235.0 |
| Iron oxide brown | 3.2 |
| Iron oxide yellow | 3.2 |
| Microcrystalline Cellulose | 400.0 |
| Manufactured powder's beef flavoring agent | 80.0 |
| Anhydride silica | 4.0 |
| Magnesium stearate | 8.0 |
| Amount to | 800.0 |
II. gross weight is the composition of the tablet comprising 2.5mg meloxicam and 10% flavoring agent of 1200mg.
| Composition | Mg/ sheet |
| Meloxicam | 2.5 |
| Trisodium citrate dihydrate | 98.4 |
| Corn starch | 351.5 |
| Iron oxide brown | 4.8 |
| Iron oxide yellow | 4.8 |
| Microcrystalline Cellulose | 600.0 |
| Manufactured powder's beef flavoring agent | 120.0 |
| Anhydride silica | 6.0 |
| Magnesium stearate | 12.0 |
| Amount to | 1200.0 |
Claims (16)
1., by the solid tablet of powder direct pressing, it comprises meloxicam or it pharmaceutically may be used
The salt accepted and one or more excipient, wherein the powder of this direct pressing is without step of pelletizing
Suddenly, the powder of described direct pressing sieves through the sieve that suitable step sizing is 0.6 to 1.5mm,
And comprise the meloxicam particle having equal to or less than selected step sizing, and described tablet can
Being fractured into two, three and/or four unit, each unit all contains the active component of equivalent.
2. solid tablet as claimed in claim 1, it is characterised in that the step sizing of described sieve is 1.0
To 1.5mm.
3. such as the solid tablet of claim 1 or 2, it is characterised in that meloxicam is dispersed
In described tablet.
4. the solid tablet as any one of claims 1 to 3, it is characterised in that described figuration
Agent is selected from filler, disintegrating agent, pH adjusting agent, coloring agent, flowing regulator, lubricant
And flavoring agent.
5. solid tablet as claimed in claim 4, it is characterised in that described coloring agent is iron oxide brown
And/or iron oxide yellow.
6. solid tablet as claimed in claim 4, it is characterised in that described pH adjusting agent is selected from winestone
Acid, maleic acid and Trisodium citrate dihydrate.
7. solid tablet as claimed in claim 4, it is characterised in that described flowing regulator is selected from sliding
Stone, anhydride silica and lubricant.
8. solid tablet as claimed in claim 4, it is characterised in that described lubricant is selected from poly-second two
Alcohol, stearic acid, aluminium stearate, arachidic acid calcium and magnesium stearate.
9. the solid tablet as any one of claim 1-8, it is characterised in that described excipient
In at least one be selected from following filler/disintegrating agent: calcium phosphate, lactose, Fructus Hordei Germinatus stick with paste
Essence, mannitol, sorbitol, crospolyvinylpyrrolidone, sodium carboxymethyl cellulose, starch
And microcrystalline Cellulose.
10. the solid tablet as any one of claim 1-9, it comprises 0.5 to 5mg U.S. Lip river
Former times health and tablet weight are 500mg to 2000mg.
11. solid tablets as any one of claim 1-10, its amount of comprising is total tablet weight
The flavoring agent of 2 to 15 weight % of amount.
12. solid tablets as any one of claim 1-11, it is characterised in that described seasoning
Agent is Artificial Beef flavoring agent.
13. solid tablets as any one of claim 1-12, it is characterised in that described solid
Preparation contains the meloxicam in free alkali form.
14. 1 kinds without any granulation step direct pressing method, it comprises the following steps:
1) premixing meloxicam and the filler/disintegrating agent of 10-50%, then sieve through suitable
Divide the sieve screening of a size of 0.6 to 1.5mm；
2) premixing pH adjusting agent and one or more coloring agent, then through suitable step sizing
It it is the sieve screening of 0.6 to 1.5mm；
3) the mixing filler/disintegrating agent of 90-50%, the second filler/disintegrating agent, flow adjustment
Agent, lubricant and artificial flavoring, the sieve screening of the most screened a size of 0.6 to 1.5mm；
4) it is blended in step 1) and 2) the middle mixture obtained, then through suitable step sizing it is
The sieve screening of 0.6 to 1.5mm；
5) step 3 finally it is blended in) and 4) the middle mixture obtained, then through suitably sieving chi
Very little be 0.6 to 1.5mm sieve screening；And
6) by step 5) in obtain mixture of powders be pressed into tablet, wherein said tablet can
Being fractured into two, three and/or four unit, each unit all contains the active component of equivalent.
The direct pressing method of 15. such as claim 14, wherein said step includes:
1) premixing meloxicam and the filler/disintegrating agent of 33%, then through suitably sieving chi
Very little be 0.6 to 1.5mm sieve screening；
2) premixing pH adjusting agent and one or more coloring agent, then through suitable step sizing
It it is the sieve screening of 0.6 to 1.5mm；
3) mixing 67% filler/disintegrating agent, the second filler/disintegrating agent, flowing regulator,
Lubricant and artificial flavoring, then sieve through the sieve that suitable step sizing is 0.6 to 1.5mm
Point；
4) it is blended in step 1) and 2) the middle mixture obtained, then through suitable step sizing it is
The sieve screening of 0.6 to 1.5mm；
5) step 3 finally it is blended in) and 4) the middle mixture obtained, then through suitably sieving chi
Very little be 0.6 to 1.5mm sieve screening；And
6) by step 5) in obtain mixture of powders be pressed into tablet, wherein said tablet can
Being fractured into two, three and/or four unit, each unit all contains the active component of equivalent.
16. solid tablets comprising meloxicam or its pharmaceutically acceptable salt, wherein this is solid
Body tablet can be by obtaining without any granulation step direct pressing method such as claims 14 or 15
, wherein said tablet is by powder direct pressing, and wherein the powder of this direct pressing is through suitably
Step sizing is the sieve screening of 0.6 to 1.5mm, and comprises and have equal to or less than selected screening chi
Very little meloxicam particle, and described tablet can be fractured into two, three and/or four unit,
Each unit all contains the active component of equivalent.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10162015.1 | 2010-05-05 | ||
| EP10162015 | 2010-05-05 | ||
| PCT/EP2011/056610 WO2011138197A2 (en) | 2010-05-05 | 2011-04-27 | Novel low concentration meloxicam tablets |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102869343A CN102869343A (en) | 2013-01-09 |
| CN102869343B true CN102869343B (en) | 2016-12-14 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101277701A (en) * | 2005-09-30 | 2008-10-01 | 贝林格尔·英格海姆维特梅迪卡有限公司 | Pharmaceutical preparation containing meloxicam |
| CN101632640A (en) * | 2009-06-15 | 2010-01-27 | 陶灵刚 | Meloxicam liposome and pharmaceutical composition thereof |
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101277701A (en) * | 2005-09-30 | 2008-10-01 | 贝林格尔·英格海姆维特梅迪卡有限公司 | Pharmaceutical preparation containing meloxicam |
| CN101632640A (en) * | 2009-06-15 | 2010-01-27 | 陶灵刚 | Meloxicam liposome and pharmaceutical composition thereof |
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