CN102114001A - Orally administered solid preparation containing tolvaptan - Google Patents
Orally administered solid preparation containing tolvaptan Download PDFInfo
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- CN102114001A CN102114001A CN 200910244384 CN200910244384A CN102114001A CN 102114001 A CN102114001 A CN 102114001A CN 200910244384 CN200910244384 CN 200910244384 CN 200910244384 A CN200910244384 A CN 200910244384A CN 102114001 A CN102114001 A CN 102114001A
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- tolvaptan
- oral solid
- solid formulation
- starch
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Abstract
The invention discloses an orally administered solid preparation containing tolvaptan and a preparation method thereof. After micronization, the tolvaptan particles are prepared into the oral solid preparation with pharmaceutically acceptable excipients. More than 90% of the micronized tolvaptan particles has a diameter less than 75 micrometers, and the tolvaptan particles are obtained by wet granulation. The orally administered solid preparation is cinically used for the treatment of hyponatremia.
Description
Technical field
The present invention relates to a kind of oral solid formulation that contains tolvaptan and preparation method thereof, said preparation exists with forms such as tablet, granule, capsule, dispersible tablets.
Background technology
Hyponatremia (hyponatremia) is serum sodium＜135mmol/L, and only reaction is the reduction of sodium concentration in blood plasma, might not represent losing of the interior total sodium amount of body.Overall sodium can be normally or increase is arranged slightly.Hyponatremia can be divided into: the sodium deficiency hyponatremia; Dilutional hyponatremia; The expendable hyponatremia.
Tolvaptan, chemistry (±)-4 by name '-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-o-tolu-m-toluidide, be a kind of vasopressin V2 receptor antagonist (non-peptide class AVP2 receptor antagonist), Na ion concentration in the blood plasma that can raise, help redundant moisture to discharge, strengthen the ability of kidney treating water from urine.Cyclic adenosine monophosphate (cAMP) gathers in the polycystic kidney cell, and it promotes the cyst growth by stimulating secretion of capsule liquid and liner hyperplasia.Tolvaptan is 2 type vasopressin receptor antagonists, can suppress cAMP generation and gathering.FDA has ratified the tolvaptan sheet and has been used for the treatment of dissolubility hyponatremia companion heart failure, liver cirrhosis, vassopressin diacrisis syndromes such as hyponatremia, high Rong He.This product is unique oral type selectivity vasopressin antagonists of getting permission to treat this disease.In clinical research, this product is compared with placebo, has obviously improved the concentration of sodium ion in patient's blood plasma.
The physicochemical property of medicine is one of fundamental of pharmaceutical preparation design.Dissolubility is the basic properties of medicine.For insoluble drug, its stripping is the speed limit process that absorbs, and usually is the main factor that influences bioavailability.Tolvaptan is a kind of active component of water solublity extreme difference, based on this character, the present invention adopts the micronized method of tolvaptan, mix with adjuvant again, wet granule compression tablet, the method not only improves the dissolubility and the dissolution rate of tolvaptan, can promote its absorption in vivo, improve bioavailability, and simple to operate, be suitable for suitability for industrialized production.
Summary of the invention
The invention provides a kind of oral solid formulation that contains tolvaptan and preparation method thereof, with the tolvaptan behind the micronization is active component, add that acceptable accessories is prepared into oral solid formulation, exist with forms such as tablet, granule, capsule and dispersible tablets.
Described tolvaptan percentage by weight in oral solid formulation is 10%-60%.
Can add an amount of pharmaceutically acceptable filler, binding agent, disintegrating agent, lubricant, correctives in the described oral solid formulation.
Described oral solid formulation is characterized in that form of medication can be tablet, granule, capsule, dispersible tablet.
Filler as being fit to tolvaptan oral solid formulation of the present invention comprises: dextrin, glucose, lactose, mannitol, sucrose, starch, ethyl cellulose, microcrystalline Cellulose.Preferred mannitol, lactose, starch, dextrin, pre-paying starch, microcrystalline Cellulose account for the 20%-60% of weight of formulation percentage ratio.
Disintegrating agent as being fit to tolvaptan oral solid formulation of the present invention comprises: carboxymethyl starch sodium, carboxymethylcellulose calcium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone.Preferred carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, shared percentage by weight is 5%-25%.
Tolvaptan oral solid formulation of the present invention, its preparation method is: the tolvaptan crude drug is carried out micronization processes, and the particle diameter that makes its 90% above microgranule is less than 75 microns, then with the filler mix homogeneously; Granulate drying by a common wet granulation technology or a step prilling.Dried particles adds the lubricant mixing, carries out corresponding preparation by dosage form again, gets final product.
The specific embodiment
The present invention is described in further detail below in conjunction with embodiment, but be not limited to following embodiment.Wherein " % " is meant " weight % ".
Embodiment 1
The existence form of this embodiment is a tablet.
| Component | Percentage ratio (%) |
| Tolvaptan | 20.0 |
| Lactose | 52.0 |
| Pre-paying starch | 8.0 |
| Microcrystalline Cellulose | 14.0 |
| The low-substituted hydroxypropyl methylcellulose | 5.0 |
| Magnesium stearate | 1.0 |
| Total | 100 |
Preparation technology: with the tolvaptan micronization, adopt Universalpulverizer, obtain 90% above particle diameter less than 75 microns micropowder.Take by weighing tolvaptan granule that micropowder crosses and recipe quantity lactose, starch, microcrystalline Cellulose, low-substituted hydroxypropyl methylcellulose by recipe quantity and adopt equivalent to progressively increase behind the method mix homogeneously, add 10% starch slurry system soft material, 16 mesh sieves are granulated, drying, mensuration moisture; 24 mesh sieve granulate, the stamping of Φ 6mm scrobicula.
Embodiment 2
The existence form of this embodiment is a tablet.Tolvaptan directly uses without micronization processes.Prescription is formed with embodiment one.
| Component | Percentage ratio (%) |
| Tolvaptan | 20.0 |
| Lactose | 52.0 |
| Pre-paying starch | 8.0 |
| Microcrystalline Cellulose | 14.0 |
| The low-substituted hydroxypropyl methylcellulose | 5.0 |
| Magnesium stearate | 1.0 |
| Total | 100 |
Preparation technology: take by weighing tolvaptan raw material and lactose, starch, microcrystalline Cellulose, low-substituted hydroxypropyl methylcellulose by recipe quantity and adopt equivalent to progressively increase behind the method mix homogeneously, add 10% starch slurry system soft material, 16 mesh sieves are granulated, drying, mensuration moisture; 24 mesh sieve granulate, the stamping of Φ 6mm scrobicula.
Embodiment 3
The existence form of this embodiment is a capsule.
| Component | Percentage ratio (%) |
| Tolvaptan | 30.0 |
| Mannitol | 30.0 |
| Lactose | 34.0 |
| Carboxymethyl starch sodium | 5.0 |
| Pulvis Talci | 1.0 |
| Total | 100 |
Preparation technology: with the tolvaptan micronization, adopt Universalpulverizer, obtain 90% above particle diameter less than 75 microns micropowder.Take by weighing tolvaptan granule that micropowder crosses and recipe quantity mannitol, lactose, carboxymethyl starch sodium by recipe quantity and adopt equivalent to progressively increase behind the method mix homogeneously, add 10% starch slurry system soft material, 16 mesh sieves are granulated, drying, mensuration moisture; 24 mesh sieve granulate promptly get granule.The 4# capsule shells is filled.
Embodiment 4
The existence form of this embodiment is a granule.
| Component | Percentage ratio (%) |
| Tolvaptan | 60.0 |
| Lactose | 25.0 |
| The low-substituted hydroxypropyl methylcellulose | 3 |
| Pre-paying starch | 8.0 |
| Polyvinylpolypyrrolidone | 2.5 |
| Acesulfame potassium | 0.5 |
| Magnesium stearate | 1.0 |
| Total | 100 |
Preparation technology: with the tolvaptan micronization, adopt Universalpulverizer, obtain 90% above particle diameter less than 75 microns micropowder.Take by weighing tolvaptan granule that micropowder crosses and recipe quantity lactose, pre-paying starch, low-substituted hydroxypropyl methylcellulose by recipe quantity.Polyvinylpolypyrrolidone adopts equivalent to progressively increase behind the method mix homogeneously, adds 10% starch slurry system soft material, and 14 mesh sieves are granulated, drying, mensuration moisture; 20 mesh sieve granulate, packing promptly gets granule.
Embodiment 5
The existence form of this embodiment is a dispersible tablet.
| Component | Percentage ratio (%) |
| Tolvaptan | 30.0 |
| Lactose | 40.0 |
| Microcrystalline Cellulose | 15.0 |
| Polyvinylpolypyrrolidone | 6.0 |
| Carboxymethyl starch sodium | 8.0 |
| Magnesium stearate | 1.0 |
| Total | 100 |
Preparation technology: with the tolvaptan micronization, adopt Universalpulverizer, obtain 90% above particle diameter less than 75 microns micropowder.Take by weighing tolvaptan granule that micropowder crosses and recipe quantity lactose, microcrystalline Cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium by recipe quantity and adopt equivalent to progressively increase behind the method mix homogeneously, add 10% starch slurry system soft material, 18 mesh sieves are granulated, drying, mensuration moisture; 30 mesh sieve granulate, the flat stamping of Φ 7mm.
Embodiment 6
Sample to embodiment 1,2,3,4,5 preparations carries out dissolution determination.
Respectively according to embodiment 1,2,3., 4,5 the preparation samples 1,2,3,4,5 carry out determination of dissolution rate, wherein dissolution adopts " second method in 2005 editions two appendix XC dissolution methods of Chinese pharmacopoeia, dissolution medium is the 0.5%SDS aqueous solution of 900mL, rotating speed is 75r/min, the 30min sampling.
By embodiment 1 and 2 dissolution results as can be known, because with the raw material micronization, the dissolution of tolvaptan is increased to 98.52% by 89.36%.As seen to the tolvaptan micronization processes, increase its dissolubility and dissolution, reached the purpose of process modification.
Embodiment 7
Sample to embodiment 1 preparation carries out accelerated stability test, and the result is as follows:
Hence one can see that, and this kind contains the sample dissolution height not only of the oral solid formulation preparation of tolvaptan, quicken 6 months good stabilities, and preparation technology is simple, and be with low cost, is beneficial to exploitation.
Claims (8)
1. oral solid formulation that contains tolvaptan, its feature comprises active component tolvaptan and acceptable accessories.
2. oral solid formulation according to claim 1 is characterized in that active component tolvaptan percentage by weight in oral solid formulation is 10%-60%.
3. acceptable accessories according to claim 1 comprises filler, disintegrating agent, binding agent, lubricant etc.
4. oral solid formulation according to claim 1, the form of medication that it is characterized in that said composition can be tablet, granule, capsule, dispersible tablet.
5. can be in mannitol, lactose, starch, dextrin, pre-paying starch, the microcrystalline Cellulose one or more according to the described filler of claim 3, account for the 20%-60% of weight of formulation percentage ratio.
6. can be in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, the polyvinylpolypyrrolidone one or more according to the described disintegrating agent of claim 3, shared percentage by weight be 5%-25%.
7. oral solid formulation according to claim 1, its preparation method comprises: the tolvaptan crude drug is carried out micronization processes, be mixed in proportion with adjuvant then, adopt wet granulation.
8. the described preparation method of claim 7, comprising: the tolvaptan crude drug is carried out micronization processes, and the particle diameter that makes its 90% above microgranule is mixed in proportion with adjuvant then less than 75 microns, adopts wet granulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910244384 CN102114001A (en) | 2009-12-30 | 2009-12-30 | Orally administered solid preparation containing tolvaptan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910244384 CN102114001A (en) | 2009-12-30 | 2009-12-30 | Orally administered solid preparation containing tolvaptan |
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| CN102114001A true CN102114001A (en) | 2011-07-06 |
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| CN 200910244384 Pending CN102114001A (en) | 2009-12-30 | 2009-12-30 | Orally administered solid preparation containing tolvaptan |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102366412A (en) * | 2011-10-21 | 2012-03-07 | 四川百利药业有限责任公司 | Preparation method of tolvaptan tablet |
| CN105769841A (en) * | 2014-08-12 | 2016-07-20 | 烟台市华文欣欣医药科技有限公司 | Application of syringic acid/4-hydroxy-3,5-dimethoxybenzoic acid in preparing drug for pregnancy termination |
| CN107898759A (en) * | 2017-12-06 | 2018-04-13 | 佛山市腾瑞医药科技有限公司 | A kind of Tolvaptan solid dispersion preparation and preparation method thereof |
| CN107898768A (en) * | 2017-12-06 | 2018-04-13 | 佛山市腾瑞医药科技有限公司 | A kind of tolvaptan soft capsule preparation and its preparation process |
| CN107929249A (en) * | 2017-12-06 | 2018-04-20 | 佛山市腾瑞医药科技有限公司 | A kind of tolvaptan effervescent tablet and preparation method thereof |
| CN108014098A (en) * | 2017-12-06 | 2018-05-11 | 佛山市腾瑞医药科技有限公司 | A kind of tolvaptan fast release micropill preparation, preparation method |
| CN108078933A (en) * | 2017-12-06 | 2018-05-29 | 佛山市腾瑞医药科技有限公司 | A kind of tolvaptan dispersible tablet and preparation method thereof |
-
2009
- 2009-12-30 CN CN 200910244384 patent/CN102114001A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102366412A (en) * | 2011-10-21 | 2012-03-07 | 四川百利药业有限责任公司 | Preparation method of tolvaptan tablet |
| CN102366412B (en) * | 2011-10-21 | 2013-05-15 | 四川百利药业有限责任公司 | Preparation method of tolvaptan tablet |
| CN105769841A (en) * | 2014-08-12 | 2016-07-20 | 烟台市华文欣欣医药科技有限公司 | Application of syringic acid/4-hydroxy-3,5-dimethoxybenzoic acid in preparing drug for pregnancy termination |
| CN107898759A (en) * | 2017-12-06 | 2018-04-13 | 佛山市腾瑞医药科技有限公司 | A kind of Tolvaptan solid dispersion preparation and preparation method thereof |
| CN107898768A (en) * | 2017-12-06 | 2018-04-13 | 佛山市腾瑞医药科技有限公司 | A kind of tolvaptan soft capsule preparation and its preparation process |
| CN107929249A (en) * | 2017-12-06 | 2018-04-20 | 佛山市腾瑞医药科技有限公司 | A kind of tolvaptan effervescent tablet and preparation method thereof |
| CN108014098A (en) * | 2017-12-06 | 2018-05-11 | 佛山市腾瑞医药科技有限公司 | A kind of tolvaptan fast release micropill preparation, preparation method |
| CN108078933A (en) * | 2017-12-06 | 2018-05-29 | 佛山市腾瑞医药科技有限公司 | A kind of tolvaptan dispersible tablet and preparation method thereof |
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Application publication date: 20110706 |