CN104873474A - Methanesulfonic acid dabigatran oral solid preparation - Google Patents
Methanesulfonic acid dabigatran oral solid preparation Download PDFInfo
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- CN104873474A CN104873474A CN201510253943.XA CN201510253943A CN104873474A CN 104873474 A CN104873474 A CN 104873474A CN 201510253943 A CN201510253943 A CN 201510253943A CN 104873474 A CN104873474 A CN 104873474A
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- Prior art keywords
- methanesulfonic acid
- acid dabigatran
- dabigatran etcxilate
- poloxamer
- coating
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Abstract
The invention provides a methanesulfonic acid dabigatran oral solid preparation; the prescription is as follows: the methanesulfonic acid dabigatran oral solid preparation comprises a core and an outer layer; the core contains 0.05-0.2g of methanesulfonic acid dabigatran, 0.05-0.2g of poloxamer, 0.01-0.04g of croscarmellose sodium, 0-0.2g of microcrystalline cellulose, 0-0.2g of lactose, 0-0.02g of hydroxypropylcellulose, 0-0.02g of silicon dioxide, and 0-0.02g of magnesium stearate; a process comprises the following steps of: pre-processing methanesulfonic acid dabigatran and poloxamer to prepare solid powder or particles, and then, preparing the oral solid preparation with other prescription accessories; the oral solid preparation prepared by the invention is capable of increasing the bioavailability of methanesulfonic acid dabigatran in a human body (more than or equal to 15%); simultaneously, antacid is not added into the preparation; gastrointestinal irritation is reduced; compliance of stomach and duodenal ulcer patients is increased; simultaneously, the compatibility of the medicinal raw materials and the accessories is increased; and the drug stability is increased.
Description
Technical field
The present invention relates to medical art, particularly a kind of methanesulfonic acid dabigatran etcxilate oral solid formulation.
Background technology
The chemical name 3-of methanesulfonic acid dabigatran etcxilate (Dabigatran etexilate mesylate) [(2-{ [4-(own oxygen carbonylamino-imino-methyl)-phenyl amino]-methyl }-1-methyl isophthalic acid H-benzimidazole-5-carbonyl)-pyridine-2-base-amino]-ethyl propionate mesylate, molecular formula C
34h
41n
7o
5cH
4o
3s, relative molecular mass 723.84.Methanesulfonic acid dabigatran etcxilate is a kind of novel non-peptide class direct thrombin inhibitor, and Nikkei U.S. FDA approval October 19 in 2010 suffers stroke for reducing nonvalvular atrial fibrillation patient and to treat with the prevention of risk of systemic embolism.Methanesulfonic acid dabigatran etcxilate have can oral, potent, without the need to features such as special Medication monitor, drug interaction are few, there is good potential applicability in clinical practice.Methanesulfonic acid dabigatran etcxilate dissolubility in various organic solvent is better, wherein maximum with the apparent solubility in dichloromethane, but the dissolubility of methanesulfonic acid dabigatran etcxilate in water is minimum.The apparent solubility of methanesulfonic acid dabigatran etcxilate reduces with the increase of solution ph, and the dissolubility in pH 1.0 solution reaches 13.49 mg mL
-1, 1.89 mg mL are about when pH 2.0
-1, be 156 μ g mL when pH 3.0
-1, almost insoluble in the buffer of pH > 5.The lgP 4.17 of methanesulfonic acid dabigatran etcxilate, its lgD value has significant pH value dependency.Methanesulfonic acid dabigatran etcxilate has good dissolubility in the stomach environment of pH 1.0 ~ 3.0, but permeable membrane is inadequate, may have good permeable membrane in the fluid environment of pH 3.0 ~ 8.0.Present stage, methanesulfonic acid dabigatran etcxilate oral administration biaavailability is lower, is only 3% ~ 7%.
Disclose the Orally administered dispensing dosage form of 3-[(2-{ [4-(own oxygen carbonylamino-imino-methyl)-phenyl amino]-methyl }-1-methyl isophthalic acid H-benzimidazole-5-carbonyl)-pyridine-2-base-amino]-ethyl propionate and salt thereof at patent CN1638771.A, which disclose a kind of graininess preparation.This granule is that spherical/spherical core district comprises organic acid and skin comprises active substance haply.The advantage of the drug-delivery preparation made like this is isolated for making organic acid and active substance have living space by sealing coat, another advantage as above-mentioned grain structure is that after using this medicament, organic acid is just dissolved in solution, then produce a kind of acid miniclimate of solubilized active substance, thus reach the feature under different pH with identical bioavailability.But the absolute bioavailability of said preparation is only about 6.4%, the bioavailability of the human body of methanesulfonic acid dabigatran etcxilate is had no and significantly improves.
Summary of the invention
For prior art above shortcomings, the object of the present invention is to provide a kind of methanesulfonic acid dabigatran etcxilate oral solid formulation, said preparation can significantly improve the bioavailability of product after oral, the absolute bioavailability of said preparation is greater than about 15%, and the bioavailability that this technology prepares preparation is 2 times that patent CN1638771.A technology prepares the bioavailability of preparation.
To achieve these goals, technical scheme of the present invention is: just adopt comminution by gas stream or torching mark to process after being mixed homogeneously with poloxamer proper proportion by active component methanesulfonic acid dabigatran etcxilate again, allow methanesulfonic acid dabigatran etcxilate fully contact with poloxamer, and then adjuvant is prepared into preparation.
According to such scheme, in this preparation unit dosage, core contains methanesulfonic acid dabigatran etcxilate 0.05g ~ 0.20g, poloxamer 0.05g ~ 0.20g, cross-linking sodium carboxymethyl cellulose 0.01 ~ 0.04g, microcrystalline Cellulose 0 ~ 0.20g, lactose 0 ~ 0.20g, hyprolose 0 ~ 0.02g, silicon dioxide 0 ~ 0.02g, magnesium stearate 0 ~ 0.02g.
Methanesulfonic acid dabigatran etcxilate 0.1269g, poloxamer 0.12g, cross-linking sodium carboxymethyl cellulose 0.016g, microcrystalline Cellulose 0.096g, lactose 0.04g, hyprolose 0.004g, silicon dioxide 0.004g, magnesium stearate 0.004g is preferably according to this preparation prescription of such scheme.
Methanesulfonic acid dabigatran etcxilate 0.1730g, poloxamer 0.15g, cross-linking sodium carboxymethyl cellulose 0.02g, microcrystalline Cellulose 0.12g, lactose 0.05g, hyprolose 0.0053g, silicon dioxide 0.005g, magnesium stearate 0.005g is preferably according to this preparation prescription of such scheme.
Can be following steps according to this preparation process thereof of such scheme:
A, supplementary material pre-treatment: take methanesulfonic acid dabigatran etcxilate and poloxamer according to recipe quantity, mixing all with, pulverize together with jet mill;
B, granulation: by steps A material and cross-linking sodium carboxymethyl cellulose, lactose, microcrystalline Cellulose, hyprolose in wet mixing pelletizer, add appropriate purified water and granulate;
C, drying: by step B material, with fluid bed, dry, granulate after dry;
D, always to mix: step C material, recipe quantity silicon dioxide, magnesium stearate mix homogeneously;
E, tabletting: in step C in material and tablet machine, calculate tablet unit dose weight, tabletting;
F, coating: by plain sheet good for tabletting, with coating in high-efficiency coating, coating weight gain about about 1%;
G, packaging.
Also can be following steps according to this preparation process thereof of such scheme:
A, supplementary material pre-treatment: take methanesulfonic acid dabigatran etcxilate and poloxamer according to recipe quantity, mixing all with, hot-melt extruded;
B, granulation: steps A material is mixed homogeneously with cross-linking sodium carboxymethyl cellulose, lactose, microcrystalline Cellulose, hyprolose, silicon dioxide, magnesium stearate;
C, tabletting: in step B in material and tablet machine, calculate tablet unit dose weight, tabletting;
D, coating: by plain sheet good for tabletting, with coating in high-efficiency coating, coating weight gain about about 1%;
E, packaging.
Detailed description of the invention
Clinical trial
To totally 24 each capsules of volunteer containing 110mg(in dabigatran etcxilate) active substance, carry out the clinical trial of bioavailability according to preparation made in embodiment 1.In a branch of therapy, make without any volunteer treated in advance Orally administered composition on an empty stomach.And in another branch that treatment is sent out, make this same volunteer oral 40mg omeprazole (a day twice) in advance, time-consuming 3 days to increase phase gastric acid pH, then just Orally administered composition; During administration invention formulation, continue to use omeprazole.
Its degree of absorption is determined by the excretion of quantitative test methanesulfonic acid dabigatran etcxilate in urine.
With do not use any compared with the medication of Therapeutic Method, after omeprazole pretreat, its Relative biological can availability be 96%, and both absolute bioavailabilities are respectively 15.3%, 14.7%.
Under similar dispensing condition, after the treatment of same omeprazole, formed and the preparation manufactured according to patent CN1638771.A technology, the patented technology used shown in following table prepares exact ingredient ratio.With do not use any compared with the medication of Therapeutic Method, after omeprazole pretreat, its Relative biological can availability be 92%, both absolute bioavailabilities are respectively 6.5%, 6.0%.
* dabigatran etcxilate 110mg is equivalent to
Therefore, compared with the preparation prepared with existing patent CN1638771.A technology, the application of the invention can improve the bioavailability (bioavailability improves about about 2.5) of methanesulfonic acid dabigatran etcxilate, the preparation simultaneously using the present invention to prepare is the same with preparation prepared by patent CN1638771.A, and human bioavailability and gastric acid pH have nothing to do.Again, use in invention formulation composition, not containing antacid composition, stimulation can not be brought to gastric ulcer and duodenal ulcer patients, improve patient compliance.
Following examples are for illustration of the present invention:
Embodiment 1
Prepared by A, methanesulfonic acid dabigatran etcxilate and mixtures of poloxamers
Methanesulfonic acid dabigatran etcxilate crosses 80 mesh sieves, mixes (rotating speed 20rpm, 15min) to mixing homogeneously with graininess poloxamer in V-Mixer.Mix homogeneously material is pulverized in jet mill (rotating forward, 40HZ), make the mean diameter of material: D90 20um; D50 10um.Material collection is in the container being lined with double-layer polyethylene film bag.
B, granulation
The cross-linking sodium carboxymethyl cellulose of steps A material and recipe quantity, lactose, microcrystalline Cellulose are added suitable quantity of water in wet mixing pelletizer; soft material processed; soft material crosses 20 mesh sieves in Fast granulate machine, and dressing, after granulate, material collection is in the container being lined with double-layer polyethylene film bag.
C, drying
By the wet granular after step B granulate in fluid bed, first use the little wind of cool breeze 5 minutes, post-heating is dry; baking temperature 60 DEG C ± 5 DEG C; material granulate in Fast granulate machine after dry, granule crosses 20 mesh sieves, and after granulate, material collection is in the container being lined with double-layer polyethylene film bag.
D, always to mix
After step C granulate, material and recipe quantity silicon dioxide, magnesium stearate are always mixed in V-Mixer, and total mixed machine mixing (rotating speed 20rpm, 15min) is to mix homogeneously, and after mixing, material collection is in the container being lined with double-layer polyethylene film bag.
E, tabletting: in step C in material and tablet machine, calculate tablet unit dose weight, tabletting;
F, coating: by plain sheet good for tabletting, with coating in high-efficiency coating, coating weight gain about about 1%;
G, packaging.
Embodiment 2
The preparation of A, methanesulfonic acid dabigatran etcxilate and poloxamer solid dispersion
Methanesulfonic acid dabigatran etcxilate (the particle diameter: D90 20um of recipe quantity; D50 10um) and poloxamer, always mix in V-Mixer, total mixed machine mixing (rotating speed 20rpm, 15min) is to mix homogeneously, and after mixing, material collection is in the container being lined with double-layer polyethylene film bag.
Added by material in hot-melt extruded machine, design temperature is 80 DEG C, carries out hot-melt extruded, and after extruded material cooling, granulate (sieve number 20 mesh sieve) in Fast granulate machine, after granulate, material collection is in the container being lined with double-layer polyethylene film bag.
B, always to mix
Steps A material and cross-linking sodium carboxymethyl cellulose, lactose, microcrystalline Cellulose, silicon dioxide, magnesium stearate one are arised from V-Mixer and mix (rotating speed 20rpm, 15min) to mixing homogeneously, after mixing, material collection is in the container being lined with double-layer polyethylene film bag.
C, tabletting: in step B in material and tablet machine, calculate tablet unit dose weight, tabletting;
D, coating: by plain sheet good for tabletting, with coating in high-efficiency coating, coating weight gain about about 1%;
E, packaging.
Claims (6)
1. a methanesulfonic acid dabigatran etcxilate oral formulations, comprise the coatings outside label and label, in the tablet of unit dose, label contains methanesulfonic acid dabigatran etcxilate 0.05g ~ 0.20g, poloxamer 0.05g ~ 0.20g, cross-linking sodium carboxymethyl cellulose 0.01 ~ 0.04g, microcrystalline Cellulose 0 ~ 0.20g, lactose 0 ~ 0.20g, hyprolose 0 ~ 0.02g, silicon dioxide 0 ~ 0.02g, magnesium stearate 0 ~ 0.02g.
2. this oral solid formulation technique is crude drug--methanesulfonic acid dabigatran etcxilate and adjuvant----poloxamer; anticipate (two materials by after two mixing of materials together comminution by gas stream or two material hot-melt extrudeds) and prepare solid particle or powder, be then prepared into oral solid formulation with all the other adjuvants.
3. the methanesulfonic acid dabigatran etcxilate oral formulations according to claims 1, it is characterized in that described preparation, containing methanesulfonic acid dabigatran etcxilate 0.1269g, poloxamer 0.12g, cross-linking sodium carboxymethyl cellulose 0.016g, microcrystalline Cellulose 0.096g, lactose 0.04g, hyprolose 0.004g, silicon dioxide 0.004g, magnesium stearate 0.004g in unit dose.
4. the methanesulfonic acid dabigatran etcxilate oral formulations according to claims 1, it is characterized in that described preparation, containing methanesulfonic acid dabigatran etcxilate 0.1730g, poloxamer 0.15g, cross-linking sodium carboxymethyl cellulose 0.02g, microcrystalline Cellulose 0.12g, lactose 0.05g, hyprolose 0.0053g, silicon dioxide 0.005g, magnesium stearate 0.005g in unit dose.
5. the methanesulfonic acid dabigatran etcxilate oral solid formulation technique according to claims 1, is characterized in that, comprise the following steps:
A, supplementary material pre-treatment: take methanesulfonic acid dabigatran etcxilate and poloxamer according to recipe quantity, mixing all with, pulverize together with jet mill;
B, granulation: by steps A material and cross-linking sodium carboxymethyl cellulose, lactose, microcrystalline Cellulose, hyprolose in wet mixing pelletizer, add appropriate purified water and granulate;
C, drying: by step B material, with fluid bed, dry, granulate after dry;
D, always to mix: step C material, recipe quantity silicon dioxide, magnesium stearate mix homogeneously;
E, tabletting: in step C in material and tablet machine, calculate tablet unit dose weight, tabletting;
F, coating: by plain sheet good for tabletting, with coating in high-efficiency coating, coating weight gain about about 1%;
G, packaging.
6. the methanesulfonic acid dabigatran etcxilate oral solid formulation technique according to claims 1, its feature exists
In, comprise the following steps:
A, supplementary material pre-treatment: take methanesulfonic acid dabigatran etcxilate and poloxamer according to recipe quantity, mixing all with, hot-melt extruded;
B, always to mix: steps A material is mixed homogeneously with cross-linking sodium carboxymethyl cellulose, lactose, microcrystalline Cellulose, hyprolose, silicon dioxide, magnesium stearate;
C, tabletting: in step B in material and tablet machine, calculate tablet unit dose weight, tabletting;
D, coating: by plain sheet good for tabletting, with coating in high-efficiency coating, coating weight gain about about 1%;
E, packaging.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510253943.XA CN104873474A (en) | 2015-05-19 | 2015-05-19 | Methanesulfonic acid dabigatran oral solid preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510253943.XA CN104873474A (en) | 2015-05-19 | 2015-05-19 | Methanesulfonic acid dabigatran oral solid preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104873474A true CN104873474A (en) | 2015-09-02 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510253943.XA Pending CN104873474A (en) | 2015-05-19 | 2015-05-19 | Methanesulfonic acid dabigatran oral solid preparation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105534939A (en) * | 2015-12-29 | 2016-05-04 | 郑州大明药物科技有限公司 | Dabigatran etexilate mesylate oral solid preparation and preparation method thereof |
| CN106491553A (en) * | 2016-12-09 | 2017-03-15 | 吉林省博大伟业制药有限公司 | A kind of new synthesis process of dabigatran etexilate methanesulfonate |
| CN111902161A (en) * | 2018-04-04 | 2020-11-06 | 上海汉都医药科技有限公司 | Pharmaceutical composition containing dabigatran etexilate and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011110478A1 (en) * | 2010-03-08 | 2011-09-15 | Ratiopharm Gmbh | Dabigatran etexilate-containing pharmaceutical composition |
-
2015
- 2015-05-19 CN CN201510253943.XA patent/CN104873474A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011110478A1 (en) * | 2010-03-08 | 2011-09-15 | Ratiopharm Gmbh | Dabigatran etexilate-containing pharmaceutical composition |
Non-Patent Citations (1)
| Title |
|---|
| 张柏清等: "《陶瓷工业机械设备》", 31 January 2013 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105534939A (en) * | 2015-12-29 | 2016-05-04 | 郑州大明药物科技有限公司 | Dabigatran etexilate mesylate oral solid preparation and preparation method thereof |
| CN106491553A (en) * | 2016-12-09 | 2017-03-15 | 吉林省博大伟业制药有限公司 | A kind of new synthesis process of dabigatran etexilate methanesulfonate |
| CN111902161A (en) * | 2018-04-04 | 2020-11-06 | 上海汉都医药科技有限公司 | Pharmaceutical composition containing dabigatran etexilate and preparation method thereof |
| CN111902161B (en) * | 2018-04-04 | 2023-12-15 | 上海汉都医药科技有限公司 | Pharmaceutical composition containing dabigatran etexilate and preparation method thereof |
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Application publication date: 20150902 |
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