MXPA01001985A - Immediate release tablet - Google Patents
Immediate release tabletInfo
- Publication number
- MXPA01001985A MXPA01001985A MXPA/A/2001/001985A MXPA01001985A MXPA01001985A MX PA01001985 A MXPA01001985 A MX PA01001985A MX PA01001985 A MXPA01001985 A MX PA01001985A MX PA01001985 A MXPA01001985 A MX PA01001985A
- Authority
- MX
- Mexico
- Prior art keywords
- formulation
- oral administration
- thrombin inhibitor
- molecular weight
- low molecular
- Prior art date
Links
- 239000000203 mixture Substances 0.000 claims abstract description 50
- 239000003868 thrombin inhibitor Substances 0.000 claims abstract description 30
- 238000009472 formulation Methods 0.000 claims abstract description 29
- 101700006801 THBI Proteins 0.000 claims abstract description 23
- 239000000945 filler Substances 0.000 claims abstract description 21
- 230000001419 dependent Effects 0.000 claims abstract description 13
- 239000007884 disintegrant Substances 0.000 claims abstract description 10
- 239000007787 solid Substances 0.000 claims abstract description 4
- 229920002472 Starch Polymers 0.000 claims description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 10
- 239000000314 lubricant Substances 0.000 claims description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 9
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 9
- 235000019698 starch Nutrition 0.000 claims description 9
- 239000008107 starch Substances 0.000 claims description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 7
- 235000010980 cellulose Nutrition 0.000 claims description 7
- 229920002678 cellulose Polymers 0.000 claims description 7
- 239000001913 cellulose Substances 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 7
- 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 6
- 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 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 208000005189 Embolism Diseases 0.000 claims description 4
- 239000004471 Glycine Substances 0.000 claims description 4
- 208000001435 Thromboembolism Diseases 0.000 claims description 4
- -1 hydroxyimino Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
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- 230000000069 prophylaxis Effects 0.000 claims description 3
- 235000000346 sugar Nutrition 0.000 claims description 3
- 238000005550 wet granulation Methods 0.000 claims description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
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- 241000124008 Mammalia Species 0.000 claims 1
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- 238000004090 dissolution Methods 0.000 abstract description 19
- 150000001875 compounds Chemical class 0.000 description 30
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- 229940045902 sodium stearyl fumarate Drugs 0.000 description 7
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(E)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 7
- 238000002156 mixing Methods 0.000 description 6
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
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- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
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- 229910052623 talc Inorganic materials 0.000 description 5
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- 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 description 3
- 230000002378 acidificating Effects 0.000 description 3
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- 101710010431 shlA Proteins 0.000 description 3
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- CDPROXZBMHOBTQ-SJORKVTESA-N 2-[[(2R)-3-cyclohexyl-1-[(2S)-2-[3-(diaminomethylideneamino)propylcarbamoyl]piperidin-1-yl]-1-oxopropan-2-yl]amino]acetic acid Chemical compound NC(N)=NCCCNC(=O)[C@@H]1CCCCN1C(=O)[C@H](NCC(O)=O)CC1CCCCC1 CDPROXZBMHOBTQ-SJORKVTESA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 229950003291 Inogatran Drugs 0.000 description 2
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 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 description 2
- 229940100445 WHEAT STARCH Drugs 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229940078499 tricalcium phosphate Drugs 0.000 description 2
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 description 2
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L Calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 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 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
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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 description 1
- 229950003499 FIBRIN Drugs 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- 206010016948 Food interaction Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 230000035536 Oral bioavailability Effects 0.000 description 1
- 229940100486 RICE STARCH Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M Sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 240000001016 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 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
- 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 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- DKWNMCUOEDMMIN-PKOBYXMFSA-N melagatran Chemical compound C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@H](NCC(O)=O)C2CCCCC2)CC1 DKWNMCUOEDMMIN-PKOBYXMFSA-N 0.000 description 1
- 229960002137 melagatran Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
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- 229920001206 natural gum Polymers 0.000 description 1
- KREXGRSOTUKPLX-UHFFFAOYSA-N octadecanoic acid;zinc Chemical compound [Zn].CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O KREXGRSOTUKPLX-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
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- 229920000642 polymer Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
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- 239000002904 solvent Substances 0.000 description 1
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
A new oral IR formulation in solid form for a low molecular weight thrombin inhibitor having pH dependent dissolution, characterized in that the formulation comprises a filler or a combination of fillers having disintegrant properties in an amount higher than 35%w/w of the formulation.
Description
IMMEDIATE RELEASE TABLET
Field of the invention
The invention concerns a solid dosage form of a low molecular weight thrombin inhibitor formulated as tablets for immediate release (IR) as well as a process for manufacturing them. The invention also concerns the medical use of the formulation in the prophylaxis and / or treatment of thromboembolism.
BACKGROUND OF THE INVENTION
The thrombin inhibitor used in the formulation of the present invention is a low molecular weight drug with pH-dependent solubility. It is characterized by a low solubility at a basic pH which increases dramatically in the protonated form at acidic pH. Thus, for administration in conventional IR formulations, rapid dissolution of the drug is obtained at acidic pH while markedly lower solution is obtained at neutral pH. This variation in the dissolution is not acceptable for a safe, efficient and convenient therapy. REF.127445
The present invention provides an immediate release formulation based on conventional manufacturing processes with careful selection of the excipients that provide a solution that is not, or is very little dependent on the pH.
Several different ways have been suggested in order to prepare solid dosage forms of immediate release.
Lach an (The Theory and practice of industrial pharmacy 1989, 343, appA) describes the composition and manufacture of two different standard granulates for IR tablets. These two compositions gave very poor quality of the granules, which gave unacceptable tablets with very low hardness. These compositions did not work with the low molecular weight thrombin inhibitors used in connection with the present invention. The tablets did not meet the definition of rapidly dissolving the pharmaceutical product presented in "Guidance for Industry." Waiver of in vivo Bioavailibility and Bioequivalents Studies for Immediate Relays Solids Dosage Forms Containing Certain Active Moieties / Active Ingredients Base on Biopharmaceutics Classification
System. "Tablets should release 85% or more of the amount set in 30 minutes.
Description of the invention
It has now been found that thrombin inhibitors based on low molecular weight peptides with pH-dependent solubility - including their salts - can be formulated as IR tablets with no or very little pH-dependent dissolution.
Accordingly, the object of the present invention is to provide a new pharmaceutical formulation comprising a thrombin inhibitor based on a low molecular weight peptide formulated as an IR tablet with no or very low pH-dependent dissolution and a process for the preparation of such formulations.
The thrombin inhibitors mentioned in this application are thrombin inhibitors based on low molecular weight peptides with pH-dependent solubility. The term "thrombin inhibitor based on low molecular weight peptides" should be understood by those skilled in the art to include thrombin inhibitors with one to four peptide bonds, and / or
molecular weight less than 1000, and includes those described generically and, more preferably, specifically in the document reviewed by Claesson in Blood Coagul. Fibrin (1994) 5, 411, as well as those set forth in U.S. Patent No. 4,346,078; International Patent Applications WO 97/23499, WO 97/02284, WO 97/46577, WO 98/01422, WO 93/05069, WO 93/11152, WO 95/23609, WO 95/35309, WO 96/25426, WO 94/29336, WO 93/18060 and WO 95/01168; and European Patent Applications Nos. 623,596, 648 780, 468 231, 559 046, 641 779, 185 390, 526 877, 542 525, 195 212, 362 002, 364 344, 530 167, 293 881, 686 642, 669 317 and 601 459.
Preferred thrombin inhibitors based on low molecular weight peptides include those collectively known as "gatrans". Particular gatrans that may be mentioned include HOOC-CH2 (R) Cha-Pic-Nag-H
(known as inogatran; see International Patent Application WO 93/11152 and the list of abbreviations herein) and HOOC-CH2- (R) Cgl-Aza-Pab-H (known as nelagatran; see the International Patent application. WO
94/29336 and the list of abbreviations herein.) Thrombin inhibitors based on preferred low molecular weight peptides are selected from the group consisting of inogatran, (Glycine, N- [2- [2 - [[[] 3 - [(aminoimino-
methyl) amino] propyl] amino] carbonylj-l -piperidyl] -1-cyclohexylmethyl) -2-oxoethylJ-, [2R- [2S] J-), melagatran,
(glycine, N- [2- [2- [[[[4- (aminoiminomethyl) phenylj-methyl] amino] carbonyl] -l-acetidinyl] -l-cyclohexyl-2-oxoethyl] -, [2R- [2S]] ] -) and compound A, (glycine, N- [1-cyclohexyl -2- [2 - [[[[4- (hydroxyimino) aminomethyl] -phenyl] methyl] amino] carbonyl] -! - acetidinyl] -2 -oxoethyl] -, ethyl ester, [S- (R *, S *)] -).
The preferred low molecular weight thrombin inhibitor, Compound A is effective for the treatment of thromboembolism. Compound A is described in International Patent Application WO 97/23499. Compound A is a low molecular weight thrombin inhibitor with good oral bioavailability, low variability and limited food interaction. No solid dosage form containing this inhibitor has been published.
In order to produce tablets that provide a solution in which there is or is very little pH dependence, Compound A should have a particle size of less than 300 μm, preferably less than 150 μm and with a preferred average particle size less than 80 μm. With another low molecular weight thrombin inhibitor with low solubility at basic pH and pH-dependent solubility
the particle size requirements will depend on the level of low solubility.
It has been found that by carefully selected excipients the pH-dependent solution could be reduced and give a tablet release of more than 85% in 30 minutes acidic as well as neutral environment. This, in spite of Compound A which has an extremely pH-dependent solubility.
The formulation according to the invention comprises the thrombin inhibitor, a filler, or a combination of fillers, said filler / fillers having disintegrating properties (due to foaming) and, optionally, non-foaming disintegrating fillers, binders and / or lubricants.
The amount of filler / fillers having disintegrant properties constitutes more than 35% (w / w), preferably more than 50% (w / w) of the formulation.
Some excipients can serve multiple purposes, for example being a filler and a disintegrant at the same time. An excipient used in higher amounts of 35% is in the invention defined as a filler
but that contributes with other important properties for the formulation, for example disintegration, binder or lubrication.
The filler with disintegrating properties is selected from the group consisting of cellulose per se (such as microcrystalline cellulose), microfine cellulose) starch per se (such as corn starch, sodium starch glycolate, potato starch, wheat starch).
The non-foaming fillers are selected from the group of sugars (such as mannitol, sorbitol, dextrose, xylitol, sucrose, lactose).
The disintegrant is selected from the group consisting of cellulose per se (such as microcrystalline cellulose, microfine cellulose, cross-linked sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose), starch per se (such as sodium starch glycolate, pre-gelatinized starch, corn starch, starch). of potato, rice starch, wheat starch) and others (such as cross-linked polyvinylpyrrolidone, cation exchange resin).
The binder is selected from the group consisting of cellulose per se (such as sodium carboxymethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), polymers (such as polyvinyl pyrrolidone, polyethylene glycol), gelatins (such as hydrolyzed gelatin), and traditional binders (such as starch, natural gums).
The lubricant is selected from the group consisting of insoluble lubricants (such as magnesium stearate, calcium stearate, zinc stearate, stearic acid, oils, talc, sodium stearyl fumarate), and soluble lubricants such as polyethylene glycol, sodium benzoate, sodium lauryl sulfate).
In the formulation according to the invention the different constituents are preferably included in the following proportions, calculated in weight percent of the finished tablet;
Thrombin inhibitor: 1-35%, preferably 1-15
Filling: 35-90%, preferably 45-80%, when it comes to 50-90% microcrystalline cellulose, preferably 60-80% and more preferably 72-76%,
when it comes to a non-sponge filling 0-50% when it is mannitol 0-15%, preferably 5-10%.
Disintegrant: 0-35%, preferably 7-35%, when it is sodium starch glycolate 3- 20%, preferably 5-10%.
Binder: 0-15%, preferably 4-12%, when it is polyvinylpyrrolidone 3-15%, preferably 5-10%.
Lubricant: 0 - 5%, preferably 0.5 - 1.5%, when dealing with sodium stearyl fumarate 0.5 - 1.5% preferably more than 1%.
In the invention it was found that a formulation comprising the active component with a particle size of less than 150 μm and an average particle size of less than 89 μm, fillers (for example microcrystalline cellulose (50-90%, preferably 74%), mannitol (0-15%, preferably 8.5%) disintegrant (for example, sodium starch glycolate 3-20%, preferably 8.5%), moistened with a suitable binder (for example polyvinylpyrrolidone K 90 (3-15%, preferably. %) and final mixing with the lubricant
Suitable (eg, sodium stearyl fumarate (0.5-1.5%, preferably 1%) provides a tablet having good technical properties and a very low pH-dependent dissolution.
The formulations according to the invention can preferably be prepared either by direct compression or by the wet granulation technique.
Direct compression
A low molecular weight thrombin inhibitor is mixed with the filler (s) and, if necessary, with the disintegrant. This mixture is then mixed with the lubricant and compressed into the tablets.
Wet granulation
A low molecular weight thrombin inhibitor is mixed with the filler (s), and if necessary with the disintegrant. The mixture is then moistened with a suitable solvent in which the binder can dissolve. After drying the granulate is ground and then mixed with the lubricant and compressed into tablets.
Practical examples
EXAMPLE 1 Solution of the drug of the tablets according to the invention
The IR tablets of the thrombin inhibitor, Compound A, is prepared by mixing Compound A, microcrystalline cellulose, sodium starch glycolate and mannitol. The mixture was moistened with an appropriate amount of polyvinylpyrrolidone K 90 dissolved in water. After drying, the granulate is milled and then mixed with sodium stearyl fumarate and compressed into tablets.
Tablet
Compound A 24 Microcrystalline cellulose (MCC pH 101) 140 Sodium starch glycolate 16 Mannitol 16 Polyvinylpyrrolidone K 90 15 Water in sufficient quantity Sodium stearyl fumarate
Punches: 9 mm Tablet weight: 213 mg
Hardness 110N
The obtained tablets were analyzed with respect to dissolution of Compound A using a USP No. 2 USP (paddle), 100 rpm, 500 ml. The dissolution medium used had a temperature of 37 ° C. Two different dissolution media were used, 0.1 M HCl pH 1 and phosphate buffer at pH 6.8 (ionic strength of 0.1). The amount of compound A released was determined by UV-spectrometry.
The results are shown in figure 1. After 30 minutes the amount of dissolved compound A was 94% (average n = 3) in 0.1 M HCl and 94% (average n = 3) in phosphate buffer at pH 6.8.
Example lb. Dissolution of the drug of the tablets according to the invention
The IR tablets of the thrombin inhibitor,
Compound A was prepared by mixing Compound A, microcrystalline cellulose and corn starch and the mixture was wetted with an appropriate amount of corn starch.
(pasta) . After drying the granulate was milled and then mixed with cross-linked polyvinylpyrrolidone. Finally the
Sodium stearyl fumarate was added by mixing and the granulate was compressed into tablets.
mg / tablet
Compound A 30 Microcrystalline cellulose 115 Corn starch 55 Corn starch (paste) 6 Water sufficient amount Polyvinylpyrrolidone withdraculated 10 Sodium stearyl fumarate 2.2
Punches: 8.5 mm Weight of the tablet 219 mg Hardness: 110N
The obtained tablets were analyzed for dissolution of Compound A according to the method described in Example 1. The results are shown in Figure 2. After 30 minutes the amount of Compound A dissolved was 100%.
(average n = 3) in 0.1 M HCl and 97% (average n = 3) in phosphate buffer pH 6.8.
Example 2. Drug dissolution of the tablets according to the reference
Lachman (The theory and practice of industrial pharmacy 1986,343, appA) describes another composition and elaboration of a standard granulate for an IR tablet. IR tablets of thrombin inhibitor, Compound A were prepared according to this method by mixing Compound A, tricalcium phosphate and the mixture was wetted with pre-gelatinized corn starch dissolved in water. After drying the granulate was milled and then mixed with talc. Finally, the mineral oil was added to the mixture and the granulate was compressed into tablets.
mg / tablet
Compound A 24 Tricalcium phosphate 100 Pregelatinized starch 15 Water (sufficient amount) Talcum 60 Mineral oil, lightweight 4
Punches: 9 mm Tablet weight: 198 mg
Hardness: 12N
The obtained tablets were analyzed for dissolution of compound A according to the method described in Example 1. The results are shown in figure 2. After 30 minutes the amount of compound A dissolved was 40%
(average n = 3) in 0.1 M HCl and 5% (average n = 3) in phosphate buffer pH 6.8.
Example 3. Drug dissolution of the tablets according to the reference
Lachman (The theory and practice of industrial pharmacy 1986,343, appA) describes the composition and elaboration of another "standard" granulate for an IR tablet. The tro Bina inhibitor tablets, Compound A were prepared according to this method by mixing Compound A, lactose and the mixture was wetted with starch dissolved in water.
After drying the granulate was milled and then mixed with dry starch and talcum. Finally, the mineral oil was added to the mixture and the granulate was compressed into tablets.
mg / tablet
Compound A 24 Lactose 110 Starch (paste) 5 Starch 28 Talc 28 Mineral oil 50 cps 11
Punches: 9 mm Weight of tablets 206 mg Hardness: 10 N
The obtained tablets were analyzed for dissolution of compound A according to the method described in Example 1. The results are shown in figure 3. After 30 minutes the amount of dissolved compound A was 100% (average n = 3) in HCl 0.1 M and 74% (average n = 3) in phosphate buffer pH 6.8.
Brief description of the Figures
Figure 1: Dissolution of the thrombin inhibitor, Compound A of the tablets according to the invention as
described in Example 1. (No figure is given for example Ib).
Figure 2: Dissolution of the thrombin inhibitor, Compound A of the tablets according to the reference as described in Example 2.
Figure 3: Dissolution of the thrombin inhibitor, Compound A of the tablets according to the reference as described in Example 3.
Conclusion (Examples)
From the examples, it is obvious that a sufficient quality of the product is not achieved when using a "standard" granulate. Whether the technical properties are bad [Example 2 and 3,] and / or the phosphate buffer solution pH 6.8 does not meet the definition of a product that rapidly dissolves a drug in Guidance for Industry. Waiver of in Vivo Bioavailability and Bioequivalents Studies for Immediate Relay Solids Dosage Forms Containing System. With the formulation according to the invention the dissolution is rapid in both media and the technical properties are excellent.
It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.
Having described the invention as above, it is claimed as property in the following:
Claims (12)
1. A formulation for oral administration, in solid form, of immediate release of a thrombin inhibitor based on a low molecular weight peptide having pH-dependent solubility which is characterized in that the formulation comprises a filler or a combination of fillers having disintegrating properties in an amount greater than 35% by weight of the formulation, selected from the group consisting of a cellulose per se and a starch per se.
2. A formulation for oral administration according to claim 1, characterized in that the formulation optionally contains a sugar, a disintegrant, a binder and / or a lubricant.
3. A formulation for oral administration according to any of the preceding claims which is characterized in that the thrombin inhibitor has a particle size of less than 300 μm, preferably less than 150 μm and a preferred average particle size of less than 80 μm.
4. A formulation for oral administration according to any of the preceding claims which is characterized in that it comprises a combination of microcrystalline cellulose and mannitol.
5. A formulation for oral administration according to claim 4, characterized in that the microcrystalline cellulose constitutes 50-90% (by weight) of the formulation.
6. A formulation for oral administration according to claim 4, characterized in that the mannitol constitutes 0-15% (by weight) of the formulation.
7. A formulation for oral administration according to any of the preceding claims which is characterized in that the thrombin inhibitor is glycine, N- [1-cyclohexyl-2- [2- [[[[4- [(hydroxyimino) aminomethyl] -phenyl] methyl] amino] carbonyl] -1-acetyidinyl] -2-oxoethyl] -, ethyl ester, [S- (R *, S *)] -).
8. A formulation for oral administration according to any of the preceding claims for use in therapy.
9. The use of a thrombin inhibitor based on a low molecular weight peptide, a filler or a combination of fillers having disintegrating properties in an amount greater than 35% by weight according to claim 1 in the manufacture of a formulation for prophylaxis and / or thrombo-embolism treatment.
10. A method for prophylaxis and / or treatment of thromboembolism which is characterized in that a therapeutically effective amount of a formulation according to claim 1 is administered to a mammal in need of such treatment.
11. A process for the preparation of a formulation for oral administration of immediate release according to claim 1 which is characterized in that the preparation is by direct compression or by wet granulation techniques.
12. Use of a filler selected from the group consisting of a cellulose derivative, and a starch derivative, optionally a sugar, a disintegrant, a binder and / or a lubricant in the preparation of a formulation of. immediate release for administration oral, containing a thrombin inhibitor based on a low molecular weight peptide having pH-dependent solubility.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9802973-9 | 1998-09-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA01001985A true MXPA01001985A (en) | 2001-12-04 |
Family
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