CN104623684A - Preparation method of Empagliflozin and mannitol composition - Google Patents
Preparation method of Empagliflozin and mannitol composition Download PDFInfo
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- CN104623684A CN104623684A CN201510071399.7A CN201510071399A CN104623684A CN 104623684 A CN104623684 A CN 104623684A CN 201510071399 A CN201510071399 A CN 201510071399A CN 104623684 A CN104623684 A CN 104623684A
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Abstract
The invention provides a preparation method of an Empagliflozin and mannitol composition. The preparation method comprises the following steps: mixing Empagliflozin and mannitol, performing hot-melting granulation, and mixing with other pharmaceutically acceptable carriers to obtain an oral solid preparation. The Empagliflozin and mannitol composition prepared by using the method is stable and controllable in quality and fast to dissolve.
Description
Technical field
The invention belongs to medical art, be specifically related to the preparation method of a kind of En Gelie clean mannitol compositions and obtain the clean oral solid formulation of En Gelie by the method.
Background technology
Type ii diabetes becomes the disease of increased popularity, and its high-frequency complication (as diabetic foot, blindness, renal failure etc.) not only has influence on the quality of life of patient, and likely causes the shortening in life-span.
En Gelie clean (empagliflozin) is the white-2(SGLT-2 of a kind of oral sodium glucose co-transporter 2) inhibitor.SGLT-2 is the transporter that primary responsibility absorbs that from Glomerular filtrate glucose enters body circulation again, by suppressing SGLT-2, En Gelie only to decrease kidney to filtering absorbing again of glucose, and reduces the kidney threshold value of glucose, thus adds the excretion of glucose in urine.This product is used for
the glycemic control of patients with type Ⅰ DM adult patient, is researched and developed jointly by Boehringer Ingelheim company and Li Lai company, obtains European Union's approval in May, 2014, obtains U.S. FDA approval in August, 2014.
The clean chemical name of En Gelie is: (1S)-1,5-dehydration-1-C-[the chloro-3-of 4-[[4-[[(3S)-tetrahydrochysene-3-furyl] oxygen base] phenyl] methyl] phenyl]-D-Glucose alcohol.
En Gelie is that white is extremely light yellow only, no hygroscopicity powder.Atomic water-soluble, be insoluble in methanol, be slightly soluble in ethanol and acetonitrile, dissolve in 50% acetonitrile solution, be dissolved in toluene hardly.In view of En Gelie is only poorly soluble, after often needing to carry out pulverizing micronization, carry out the production of the solid orally ingestible such as tablet or capsule again to increase the dissolubility of medicine.
Patent CN102387783A discloses a kind of preparation method preparing the clean sheet of En Gelie, by the particle diameter of the clean raw material of control En Gelie to reach the effect improving dissolution, particularly reaches less granularity and can reach good result of extraction.And reach this granularity and need to carry out micronization to medicine, this needs special mechanical activation comminution or Jet Mill, more loaded down with trivial details in production, reduces production efficiency.Medicine is in micronization process in addition, medicine is easily in atmosphere floating, the contact area of direct labor and medicine is caused greatly to increase, therefore special preventer is needed, otherwise concerning workman healthy be also disadvantageous, and when Dust Capacity is increased to a certain degree in environment, easily cause blast, concerning production, also have certain potential safety hazard.
Therefore be still necessary to provide a kind of method, avoid using Jet Mill, the clean dissolubility of En Gelie can be improved again, be applicable to commercially producing.
Summary of the invention
The invention provides the preparation method of the clean mannitol compositions of a kind of En Gelie, by En Gelie, clean and mannitol hot melt is granulated, be be prepared into the clean mannitol compositions of En Gelie by torching mark, only after treatment, inventor finds that medicine has good dissolution rate to En Gelie.Its dissolution rate is obviously faster than without the medicine after this PROCESS FOR TREATMENT.
En Gelie only in this preparation method due to needs heating and melting, therefore do not limit too much the particle diameter that the En Gelie fed intake is clean, this greatly reduces cost and the technological requirement of raw material production.
Mannitol is widely used in pharmaceutical preparation, mainly in tablet or capsule as filler or diluent.It is soluble in water, and fusing point is 166-168 DEG C.
The invention provides the preparation method of the clean mannitol compositions of a kind of En Gelie, comprise following steps:
A. En Gelie is clean and mannitol mixing, obtains mixture;
B. heated by said mixture, make it melting, stir, cooling obtains compositions.
Concrete operations are as follows:
En Gelie is mixed with mannitol only, heating makes the clean and mannitol melting of En Gelie, under agitation, clean and the mannitol of En Gelie merges mutually, after cooling, form the complex of the clean and mannitol of En Gelie, as required, optionally carry out pulverizing obtaining suitable particle diameter, carry out follow-up preparation process process.By this technique, En Gelie is processed only, because En Gelie is clean and mannitol mutually merges to disperse, be equivalent to the specific surface area improving medicine, and mannitol dissolubility is better, therefore can promote the dissolution rate of medicine.
The clean fusing point of En Gelie is 150 DEG C.Mannitol fusing point is 166-168 DEG C.In heating and melting process, twin screw hot melt extruder can be selected to be prepared.Can design temperature be generally 175-200 DEG C, preferred 175-190 DEG C, preferred temperature range be 175-185 DEG C.
The similar hot-melt extruded legal system of this technique is for solid dispersion, but it is not exclusively equivalent, the polymer carrier that mainly general solid dispersion preparation uses, it generally has certain viscosity, such as commodity are called the copolyvidone of Kollidon VA64, Plasdone S 630, the polyvidone PVP of different viscosities grade, hyprolose HPC, hypromellose HPMC etc.In fusion method preparation process, medicine melts, and polymer carrier molding melten glass state, medicine and macromolecular material merge, cool after form solid dispersion.
In order to ensure that medicine and carrier reach good syncretizing effect, the ratio of general polymer carrier and medicine reaches more than 2 times, for this product, because pharmaceutical specifications is 25mg, therefore polymer carrier at least needs more than 50mg, and carrier often has certain viscosity, the cohesive material of high-load like this act as the effect of binding agent, therefore there is certain difficulty for preparation process process.Mainly need to add relatively large disintegrating agent, this can bring slice, thin piece moisture-sensitive to affect stability, or ensures that the weight of tablet is comparatively large, to control polymer carrier in necessarily less ratio, suitable to guarantee medicine disintegration speed.
And the present invention uses mannitol as carrier material, it is not the carrier material that general solid dispersions technique uses, it self usually as a kind of filler, not there is viscosity and not there is disintegrative yet, and it is soluble in water, character and macromolecular material tool are very different, and these character determine its and are relatively applicable to follow-up preparation process process, heavy or without the need to increasing more disintegrating agent in prescription without the need to controlling larger sheet.
Clean and the mannitol of En Gelie is after hot-melt extruded, solid mass can be formed again after cooling, pulverized by mechanical activation comminution or grinding means, the ratio of general control crushing rear material 80% is between 40-100 order, this is the particle size range that a conventional formulation technique uses, and can be easily prepared from by general disintegrating apparatus.
The present invention has screened the ratio of the clean and mannitol of En Gelie.Find along with mannitol ratio increase time, in the compositions of formation, the clean dissolution rate of En Gelie promotes thereupon.This may be because mannitol ratio increases, and in the clean mannitol complex of En Gelie of formation, the clean degree of scatter of En Gelie improves, and mannitol is the good adjuvant of a kind of water dissolution, and therefore the dissolution velocity of complex Chinese medicine can promote.
Therefore according to the present invention, En Gelie weight ratio that is clean and mannitol is 1:4 to 1:10, preferred 1:6 to 1:8.Prepare compositions according to this ratio, be follow-uply conveniently prepared into the tablet or capsule with comparatively approrpiate wts.
Because medicine is carried out melting by preparation method provided by the invention, therefore be not strict with for the granularity that the En Gelie fed intake is clean, this is for the technique of preparation, relatively simply, without the need to only carrying out mechanical activation comminution or comminution by gas stream to En Gelie, cost and production time are saved.
After obtaining the clean mannitol compositions of En Gelie, after can further mixing with adjuvant, be prepared into tablet or capsule formulation etc.Optionally adjuvant comprises filler, binding agent, disintegrating agent, lubricant etc.Also optionally add other active component and form compound preparation.
Be applicable to the filler of solid preparation of the present invention including, but not limited to mannitol, lactose, microcrystalline Cellulose, starch, corn starch, partially pregelatinized starch, sucrose, lactose, glucose, dextrin, calcium hydrogen phosphate, dalcium biphosphate, maltose alcohol etc.
Be applicable to the binding agent of solid preparation of the present invention including, but not limited to polyvidone, copolyvidone, hypromellose, hyprolose etc.
Be applicable to the disintegrating agent of solid preparation of the present invention including, but not limited to cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.
Be applicable to the lubricant of solid preparation of the present invention including, but not limited to magnesium stearate, sodium stearyl fumarate etc.
Tablet of the present invention optionally carries out film coating.Coating membrane increases weight as 2%-5% usually, coating membrane by: film former, plasticizer, pigment etc. form.Also commercially available coating powder can be selected to carry out coating.
The clean mannitol complex of En Gelie prepared by the present invention, can obtain suitable particle diameter by pulverizing or grinding technics, direct compression technique therefore can be adopted to carry out the production of tablet, or fill capsule after directly mixing with medical additive.
Also wet granulation process can be adopted in addition to produce, clean for En Gelie mannitol compositions is mixed with other adjuvants, add ethanol, water or other wetting agent and carry out pelletize, and it is dry, mix after adding lubricant or other adjuvants after screening, material after mixing is carried out the preparation of tablet or capsule.
Also dry method granulation processes can be adopted in addition to produce, clean for En Gelie mannitol compositions is mixed with other adjuvants, adopt roll-in method to prepare ribbon, mix after adding lubricant or other adjuvants after crushing and screening, material after mixing is carried out the preparation of tablet or capsule.
Below can adopting, in table, prescription carries out material proportion.
The clean composition quality of En Gelie provided by the invention is stablized, and tablet made further, capsule have good In Vitro Dissolution performance, and the method for the compositions of preparation is simple, clean, is applicable to suitability for industrialized production.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but be not limited to following embodiment.For proving the advantage of this technology, the En Gelie that embodiment 1-4 feeds intake is the raw material of comparative example 2 only, and its particle diameter is D90=149 μm.Being meant to of particle diameter D90 " particle diameter corresponding when accounting for total amount 90% on cumulative percentage rate curve " is generally adopt laser diffractometry to detect gained.
The clean crude drug of comparative example 1: En Gelie, it is gained after comminution by gas stream, and its particle diameter is D90=24 μm.
The clean crude drug of comparative example 2: En Gelie, its particle diameter is D90=149 μm.
embodiment 1
The preparation of the clean mannitol compositions of En Gelie:
Join in hot-melt extruded machine after taking the clean and 40g mannitol mixing of 10g En Gelie, temperature is set to 175 DEG C, after extruding, and after taking out cooling, employing mechanical crusher is pulverized, and crushing rear material is crossed 40 mesh sieves.
embodiment 2
The preparation of the clean mannitol compositions of En Gelie:
Join in hot-melt extruded machine after taking the clean and 60g mannitol mixing of 10g En Gelie, temperature is set to 185 DEG C, after extruding, and after taking out cooling, employing mechanical crusher is pulverized, and crushing rear material is crossed 40 mesh sieves.
embodiment 3
The preparation of the clean mannitol compositions of En Gelie:
Join in hot-melt extruded machine after taking the clean and 80g mannitol mixing of 10g En Gelie, temperature is set to 200 DEG C, after extruding, and after taking out cooling, employing mechanical crusher is pulverized, and crushing rear material is crossed 40 mesh sieves.
embodiment 4
The clean mannitol compositions preparation of En Gelie:
Join in hot-melt extruded machine after taking the clean and 100g mannitol mixing of 10g En Gelie, temperature is set to 200 DEG C, after extruding, and after taking out cooling, employing mechanical crusher is pulverized, and crushing rear material is crossed 40 mesh sieves.
Stripping result: the compositions of getting embodiment 1 ~ 4 preparation being equivalent to the clean 25mg of En Gelie, with the clean crude drug of En Gelie in 25mg comparative example 1,2 in the pH1.0 medium of 900ml, carry out stripping curve mensuration under adopting paddle method 50rpm condition, stripping result (unit %) is as follows:
From embodiment 1-4 and comparative example 1-2, after treatment, dissolution rate can obviously promote medicine.Its dissolution rate is equivalent to or faster than the dissolution rate of comparative example 1 Chinese medicine (medicine after comminution by gas stream).
embodiment 5
The preparation of the clean sheet of En Gelie, prescription is as follows:
The clean mannitol compositions of En Gelie prepared by the embodiment 1 that prescription 1 uses, the clean mannitol compositions of En Gelie prepared by the embodiment 2 that prescription 2 uses, the clean mannitol compositions of En Gelie prepared by the embodiment 3 that prescription 3 uses, the clean mannitol compositions of En Gelie prepared by the embodiment 4 that prescription 4 uses, the particle diameter that the En Gelie of prescription 5 use is clean is D90=24 μm, the particle diameter that the En Gelie of prescription 6 use is clean is D90=149 μm, and technique is carried out mixing rear direct compression by above-mentioned material.
Solid preparation Dissolution experiments:
Get prescription 1-6 sample, the former sheet that grinds is in the pH1.0 medium of 900ml only for En Gelie, and carry out stripping curve mensuration under adopting paddle method 50rpm condition, result is as follows:
As can be seen from the table above: use D90=149 μm of its result of extraction of prescription 1-4 containing En Gelie clean mannitol compositions to be all better than the En Gelie former result of extraction of coarse grain footpath prescription 6 grinding sheet and do not use the clean mannitol compositions of En Gelie only.
Claims (10)
1. the preparation method of the clean mannitol compositions of Yi Zhong En Gelie, is characterized in that: comprise following steps:
A. En Gelie is clean and mannitol mixing, obtains mixture;
B. heated by said mixture, make it melting, stir, cooling obtains the clean mannitol compositions of En Gelie.
2. the preparation method of the clean mannitol compositions of En Gelie according to claim 1, is characterized in that: described En Gelie weight ratio that is clean and mannitol is 1:4 to 1:10, preferred 1:6 to 1:8.
3. the preparation method of the clean mannitol compositions of En Gelie according to claim 1, is characterized in that: described step b adopts hot-melt extruded machine heating and melting to granulate.
4. the preparation method of the clean mannitol compositions of En Gelie according to claim 1, is characterized in that: described heating-up temperature is 175-200 DEG C, preferred 175-190 DEG C, more preferably 175-185 DEG C.
5. the oral solid formulation that Yi Zhong En Gelie is clean, is characterized in that: obtain the clean mannitol compositions of En Gelie containing the described preparation method of one of with good grounds claim 1-4.
6. oral solid formulation according to claim 5, is characterized in that: this solid preparation is also containing one or more combinations of filler, binding agent, disintegrating agent and lubricant.
7. oral solid formulation according to claim 5, is characterized in that: described filler is selected from following one or more: mannitol, lactose, microcrystalline Cellulose, starch, corn starch, partially pregelatinized starch, sucrose, lactose, glucose, dextrin, calcium hydrogen phosphate, dalcium biphosphate and maltose alcohol.
8. oral solid formulation according to claim 5, is characterized in that: described binding agent is selected from polyvidone, copolyvidone, hypromellose and hyprolose.
9. oral solid formulation according to claim 5, is characterized in that: described disintegrating agent is selected from cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose.
10. oral solid formulation according to claim 5, is characterized in that: described lubricant is selected from magnesium stearate, sodium stearyl fumarate.
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| CN201510071399.7A CN104623684B (en) | 2015-02-11 | 2015-02-11 | Preparation method of engletin mannitol composition |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016169534A1 (en) * | 2015-04-24 | 2016-10-27 | Zentiva, K. S. | Solid forms of amorphous empagliflozin |
| CN111214450A (en) * | 2020-04-23 | 2020-06-02 | 上海翰森生物医药科技有限公司 | Empagliflozin tablet and preparation process thereof |
| CN112618495A (en) * | 2020-12-29 | 2021-04-09 | 青岛黄海制药有限责任公司 | Empagliflozin dry suspension and preparation method thereof |
| EP4299054A1 (en) | 2022-06-29 | 2024-01-03 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A tablet comprising empagliflozin |
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| WO2011039337A1 (en) * | 2009-10-02 | 2011-04-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof |
| CN102316861A (en) * | 2009-02-13 | 2012-01-11 | 贝林格尔.英格海姆国际有限公司 | Pharmaceutical composition comprising linagliptin and optionally a sglt2 inhibitor, and uses thereof |
| CN102387783A (en) * | 2009-02-13 | 2012-03-21 | 贝林格尔.英格海姆国际有限公司 | Pharmaceutical composition comprising glucopyranosyl diphenylmethane derivatives, pharmaceutical dosage form thereof, process for their preparation and uses thereof for improved glycemic control in a patient |
| WO2014195966A2 (en) * | 2013-05-30 | 2014-12-11 | Cadila Healthcare Limited | Amorphous form of canagliflozin and process for preparing thereof |
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2015
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| CN102316861A (en) * | 2009-02-13 | 2012-01-11 | 贝林格尔.英格海姆国际有限公司 | Pharmaceutical composition comprising linagliptin and optionally a sglt2 inhibitor, and uses thereof |
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| WO2011039337A1 (en) * | 2009-10-02 | 2011-04-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016169534A1 (en) * | 2015-04-24 | 2016-10-27 | Zentiva, K. S. | Solid forms of amorphous empagliflozin |
| CN111214450A (en) * | 2020-04-23 | 2020-06-02 | 上海翰森生物医药科技有限公司 | Empagliflozin tablet and preparation process thereof |
| CN112618495A (en) * | 2020-12-29 | 2021-04-09 | 青岛黄海制药有限责任公司 | Empagliflozin dry suspension and preparation method thereof |
| CN112618495B (en) * | 2020-12-29 | 2022-06-14 | 青岛黄海制药有限责任公司 | Empagliflozin dry suspension and preparation method thereof |
| EP4299054A1 (en) | 2022-06-29 | 2024-01-03 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A tablet comprising empagliflozin |
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