CN111840245A - Dabigatran etexilate pharmaceutical composition and preparation method thereof - Google Patents
Dabigatran etexilate pharmaceutical composition and preparation method thereof Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Abstract
The invention particularly relates to a dabigatran etexilate pharmaceutical composition, which comprises the following components: 1) contains an organic acid layer prepared by coating organic acid, adhesive and antisticking agent on the outer layer; 2) an isolation layer is arranged outside the organic acid layer; 3) an upper medicine layer which is prepared by mixing dabigatran etexilate containing an active ingredient or pharmaceutically acceptable salt or hydrate thereof, an anti-sticking agent and a binding agent is arranged outside the isolation layer; 4) and a protective layer is arranged outside the upper medicine layer. The dabigatran etexilate composition prepared by the invention can be stably dissolved out in the in-vivo absorption process, so that good bioavailability is achieved.
Description
Technical Field
The invention relates to the field of medicines, in particular to a dabigatran etexilate pharmaceutical composition and a preparation method thereof.
Background
The chemical name of the dabigatran etexilate active substance is 3- [ (2- { [4- (hexyloxycarbonylamino-imino-methyl) -phenylamino ] -methyl } -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino ] -propionic acid ethyl ester, and salts and hydrates thereof. The chemical structure of dabigatran etexilate is shown in the following scheme I. It is a novel synthetic non-peptide thrombin inhibitor, a prodrug of dabigatran (dabigatran), and is mainly used for preventing postoperative venous thrombosis. Dabigatran etexilate is converted in vivo into dabigatran having direct anticoagulant activity after oral, gastrointestinal absorption. dabigatran binds to the fibrin-specific binding site of thrombin, preventing cleavage of fibrinogen to fibrin, thereby blocking the final step of the coagulation cascade network and thrombus formation.
Because only a trace amount of dabigatran etexilate is dissolved out in a medium with pH being more than 4, the acidic environment is beneficial to the dissolution and the in vivo absorption of the main active ingredient dabigatran etexilate from the pharmaceutical preparation.
Application No. 201310047056.8, entitled pharmaceutical composition containing dabigatran etexilate or a salt and hydrate thereof, discloses an active substance pellet core material, an isolation layer, an organic acid layer, and an isolation layer or an outer coating layer arranged outside the organic acid layer in this order, wherein dabigatran etexilate is pH dependent, the lower the pH, the better the solubility, and the patent fails to promote the dissolution of dabigatran etexilate by wrapping the active ingredient pellet core material in the organic acid layer, because the organic acid layer dissolves relatively quickly.
Disclosure of Invention
The invention aims to solve the problems in the prior art and provides a dabigatran etexilate pharmaceutical composition which can be stably dissolved out in the in-vivo absorption process so as to achieve good bioavailability.
In order to achieve the purpose, the invention adopts the following technical scheme:
a dabigatran etexilate pharmaceutical composition comprising: 1) contains an organic acid layer prepared by coating organic acid, adhesive and antisticking agent on the outer layer; 2) an isolation layer is arranged outside the organic acid layer; 3) an upper medicine layer which is prepared by mixing dabigatran etexilate containing an active ingredient or pharmaceutically acceptable salt or hydrate thereof, an anti-sticking agent and a binding agent is arranged outside the isolation layer; 4) and a protective layer is arranged outside the upper medicine layer.
In the composition, the organic acid is selected from pharmaceutically acceptable acids and hydrates or acid salts thereof, and the organic acid is one or more of tartaric acid, fumaric acid, malic acid, citric acid, succinic acid and amino acid; preferably tartaric acid; further, the amino acid is selected from acidic amino acids; the acidic amino acid comprises aspartic acid and glutamic acid.
In the composition, the pill core is tartaric acid pill core. The combination of the tartaric acid pill core and the tartaric acid is favorable for promoting the dissolution of the active ingredient dabigatran etexilate or the pharmaceutically acceptable salt or hydrate thereof. The tartaric acid pill core is adopted as a special pill core, which is helpful for stably keeping the pH value at a proper value and promoting the dissolution of the active ingredients.
The pellet core of the pellet can also adopt a blank pellet core, and the amount of the organic acid is correspondingly required to be adjusted and increased. The invention selects tartaric acid, because the pellet core is a blank pellet core and does not contain tartaric acid, the corresponding amount of tartaric acid is screened again.
The tartaric acid pellet core selected by the invention is an outsourcing product, the tartaric acid and HPMC are used as components, and the tartaric acid pellet core is prepared by extrusion spheronization equipment through pellets with the size of 0.60-0.71 mm.
The mass sum of the organic acids in the organic acid layer accounts for 34-38% of the total prescription mass; preferably 36%. The organic acid herein includes tartaric acid contained in the core of the pellet.
The adhesive used in the invention is one or more of HPMC, HPC, PVP and EC; preferably HPMC or HPC.
The anti-sticking agent used in the invention is one or more of superfine silica gel powder, talcum powder and magnesium stearate; preferably aerosil.
The isolating layer or the protective layer is prepared by mixing a pharmaceutically acceptable adhesive and an anti-sticking agent; further, the pharmaceutically acceptable binder comprises HPMC, HPC, PVP, and/or EC; the pharmaceutically acceptable anti-sticking agent comprises aerosil, talcum powder and/or magnesium stearate.
The composition of the invention can be prepared into capsule preparations.
The invention also provides a preparation method of the dabigatran etexilate pharmaceutical composition, which comprises the following steps:
1) coating the acid layer coating liquid containing organic acid, adhesive and antisticking agent on the pellet core by a fluidized bed to prepare organic acid layer pellet core;
2) coating the isolating layer coating liquid containing adhesive and antisticking agent onto the organic acid layer pellet core in fluidized bed to obtain isolating layer pellet core;
3) coating the coating liquid containing adhesive and active ingredients on the isolated layer pill core by a fluidized bed to obtain a pill core with a medicinal layer;
4) Coating the protective layer coating solution containing adhesive and antisticking agent on the pellet core via fluidized bed to obtain pellet core.
Finally, the pellet cores prepared into the granular pellets are transferred into capsules to be prepared into capsule preparations, and the capsules are prepared by adopting conventional capsule materials such as gelatin and the like.
In order to ensure the stability of the medicine and increase the effective period, the surface of the medicine can be coated with a protective layer, and the coating layer is prepared from a pharmaceutically acceptable polymer, a binding agent and an anti-sticking agent.
Specifically, the organic acid layer, the isolation layer, the medicine applying layer and the protective layer are respectively prepared by a fluidized bed process:
organic acid layer: dissolving Arabic gum in purified water, adding L-tartaric acid after dissolving completely, adding colloidal silicon dioxide after dissolving completely, stirring well to obtain coating liquid of tartaric acid layer, and coating the coating liquid on tartaric acid pill core. And (4) putting the tartaric acid pellet cores into a bottom-spraying coating pan, drying after coating, sieving, and screening out coarse and fine pellets.
Coating parameters: the inlet air temperature is set to be 40-70 ℃, the atomization pressure is 1.5-2.8 bar, and the rotation speed of the liquid feed pump is 20-150 rpm.
Isolation layer: dispersing hydroxypropyl methylcellulose into purified water, adding ethanol after completely dissolving, stirring, adding pulvis Talci, and stirring to obtain coating solution of the isolation layer. Coating the coating solution on the pellets coated with tartaric acid solution. And (3) putting the tartaric acid layer coated pellets into a bottom spray coating pan, drying after coating, sieving, and screening out coarse and fine pellets.
Coating parameters: the inlet air temperature is set to be 35-50 ℃, the atomization pressure is 1.6-2.8 bar, and the rotation speed of the liquid feed pump is 20-200 rpm.
A medicine applying layer: sieving hydroxypropyl cellulose with a 20-mesh sieve, dispersing into isopropanol, stirring until the hydroxypropyl cellulose is completely dissolved, adding talcum powder and dabigatran etexilate mesylate raw materials (micropowder) to completely disperse the hydroxypropyl cellulose and the dabigatran etexilate mesylate, stirring uniformly, shearing the coating liquid at a high speed for 10min, and circulating every 30min to obtain the coating liquid of the upper medicine layer. Coating the coating solution on the pellets coated with the isolating layer. And (4) putting the pellets coated with the isolating layer into a bottom-spraying coating pan, drying after coating, sieving, and screening out coarse pellets and fine pellets.
Coating parameters: setting the air inlet temperature to be 35-55 ℃, the atomization pressure to be 1.8-2.8 bar, and maintaining the air outlet volume to be 1400m3The rotation speed of the liquid supply pump is 20-400 rpm.
Protective layer: dispersing hydroxypropyl methylcellulose into purified water, adding ethanol after the hydroxypropyl methylcellulose is completely dissolved, uniformly stirring, adding talcum powder, and uniformly stirring to obtain a coating solution of a protective layer. The coating solution is coated on the pellets which are coated with the medicine layer. And (3) putting the pellets coated with the upper medicine layer into a bottom spray coating pan, drying after coating, sieving, and screening out coarse and fine pellets.
Coating parameters: the inlet air temperature is set to be 35-50 ℃, the atomization pressure is 1.8-2.8 bar, and the rotation speed of the liquid supply pump is 20-300 rpm.
The invention has the beneficial effects that:
firstly, the dabigatran etexilate composition prepared by the invention can be stably dissolved out in the in-vivo absorption process, thereby achieving good bioavailability.
Secondly, the pellet core of the finally prepared product is high in roundness by optimizing the formula process and the preparation process of the composition, the average value of a self-made sample is 0.94 and is 0.80 higher than the average value of an original ground medicament (reference preparation), the product prepared by the invention is more beneficial to uniform dissolution of active ingredients, the in-vitro dissolution RSD is smaller than that of the reference preparation, the self-made sample is stable, the in-vivo variation is reduced compared with that of the reference, and the number of required cases during in-vivo BE test can BE reduced.
Drawings
FIG. 1 is a dissolution profile of a reference formulation;
FIG. 2 is a dissolution profile of a formulation of the present invention;
FIG. 3 is a graph of dissolution profiles including a spacer layer;
FIG. 4 is a microscopic view of the reference formulation;
FIG. 5 is an electron microscope image of a home-made product;
fig. 6 is a schematic diagram of a home-made product.
In fig. 6, 1 is a pellet core; 2 is an organic acid layer; 3 is an isolation layer; 4 is a medicine layer; and 5 is a protective layer.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
According to the pH solubility curve of the bulk drug, the solubility is obviously increased when the pH is less than 3.0, so that in order to increase the solubility of the bulk drug, an acidic microenvironment needs to be provided for the bulk drug to achieve the effect of solubilization, tartaric acid is selected to achieve the purpose, and the dosage of the tartaric acid needs to be screened. Samples were prepared according to different tartaric acid pellet cores and L-tartaric acid dosages in the following formula table, and the tartaric acid pellet cores and L-tartaric acid dosages were finally obtained by comparing dissolution curves in the citrate buffer solution with pH3.0 and the acetate buffer solution with pH4.5, and the dissolution results are shown in Table 1.
*Solvents removed during the process
The preparation process comprises the following steps:
organic acid layer: dissolving 0.65kg of Arabic gum into 8.80kg of purified water, adding 2.89kg of L-tartaric acid after complete dissolution, adding 0.49kg of colloidal silica after complete dissolution, stirring uniformly to obtain a coating solution of a tartaric acid layer, and coating the coating solution on a tartaric acid pill core. 8.84kg of tartaric acid pellet cores are put into a bottom spray coating pan, dried after coating, sieved and screened to remove coarse and fine pellets.
Coating parameters: the inlet air temperature is set to be 45-70 ℃, the atomization pressure is 1.5-2.8 bar, and the rotation speed of the liquid supply pump is 20-150 rpm.
Isolation layer: dispersing 0.33kg of hydroxypropyl methylcellulose into 3.50kg of purified water, adding 26.40kg of ethanol after the hydroxypropyl methylcellulose is completely dissolved, uniformly stirring, adding 2.06kg of talcum powder, and uniformly stirring to obtain the coating liquid of the isolating layer. Coating the coating solution on the pellets coated with tartaric acid solution. And (3) putting the tartaric acid layer coated pellets into a bottom spray coating pan, drying after coating, sieving, and screening out coarse and fine pellets.
Coating parameters: the inlet air temperature is set to be 35-50 ℃, the atomization pressure is 1.6-2.8 bar, and the rotation speed of the liquid feed pump is 20-200 rpm.
A medicine applying layer: 2.61kg of hydroxypropyl cellulose is sieved by a 20-mesh sieve and dispersed into 151.10kg of isopropanol, after the hydroxypropyl cellulose is stirred overnight and completely dissolved, 0.47kg of talcum powder and 13.06kg of dabigatran etexilate mesylate raw material (micropowder) are added to be completely dispersed and stirred uniformly, the coating solution is sheared at high speed for 10min, and circulation is carried out every 30min, so as to obtain the coating solution of the upper medicine layer. Coating the coating solution on the pellets coated with the isolating layer. And (4) putting the pellets coated with the isolating layer into a bottom-spraying coating pan, drying after coating, sieving, and screening out coarse pellets and fine pellets.
Coating parameters: setting the air inlet temperature to be 35-55 ℃, the atomization pressure to be 1.8-2.8 bar, and maintaining the air outlet volume to be 1400m3The rotation speed of the liquid supply pump is 20-400 rpm.
Protective layer: dispersing 0.23kg of hydroxypropyl methylcellulose into 1.73kg of purified water, adding 13.08kg of ethanol after the hydroxypropyl methylcellulose is completely dissolved, uniformly stirring, adding 0.38kg of talcum powder, and uniformly stirring to obtain the coating liquid of the protective layer. The coating solution is coated on the pellets which are coated with the medicine layer. And (3) putting the pellets coated with the upper medicine layer into a bottom spray coating pan, drying after coating, sieving, and screening out coarse and fine pellets.
Coating parameters: the inlet air temperature is set to be 35-50 ℃, the atomization pressure is 1.8-2.8 bar, and the rotation speed of the liquid supply pump is 20-300 rpm.
The applicant examined the dissolution of the product obtained according to the invention at various pH values and the results are given in table 1.
TABLE 1 dissolution at different pH values
The applicant further investigated the stability of the pharmaceutical composition of the present application through experiments, which were conducted as follows:
the sample and reference preparation capsule prepared by the method are naked and put under the conditions of illumination, 40 +/-5 ℃ and 60 +/-5 ℃ for influencing factor test, and the dissolution curve and related substances in pH2.0 are detected, wherein the dissolution conditions are as follows: basket method, 100rpm, dissolution medium 0.01NHCl (ph2.0), dissolution medium volume: 900ml, sampling time: to 45 minutes, the results are shown in Table 2.
The related substance detection method comprises the following steps: chromatographic conditions are as follows: a chromatographic column (recommended to be Phenomenex Gemini C18, 4.6X 250mm, 5 mu m or a chromatographic column with equivalent efficiency) with octadecylsilane chemically bonded silica as a filler, a 0.2% ammonium acetate solution (the pH value is adjusted to 4.3 by glacial acetic acid) as a mobile phase A, acetonitrile as a mobile phase B, and gradient elution is carried out according to the following table;
column temperature 35 ℃, flow rate 1.0ml/min, detection wavelength: the detection wavelengths are 242nm, 310nm and 340nm by using DAD or a detector with equivalent performance. The DBC-Z6 detection wavelength is 310nm, the peak area of other impurities (all calculated according to unknown impurities) is calculated by selecting the peak area at the wavelength with the strongest absorption in the three wavelengths, and the result is shown in Table 3.
TABLE 2 stability under different conditions
Where the product of lot 011803 was prepared as prescribed in DB170617 JL.
TABLE 3
From the above dissolution results and the results of the related substances, the pharmaceutical composition of the present invention is more stable than the reference formulation.
The applicant further investigated the effect of the protective layer formation on the stability of the pharmaceutical composition, and the experimental results were as follows:
weight gain screening of different protective layers:
the weight gain of the protective layer was screened and determined by determining the dissolution profile of each example at ph2.0 for weight gain and the ratio of HPMC and talc. The protective layer formulation of each example is shown in Table 4, and the dissolution at pH2.0 is shown in Table 5.
TABLE 4 protective layer recipe
TABLE 5 dissolution at pH2.0
The applicant further measured the roundness of the drug:
the contents of the reference formulation and the home-made sample were taken separately, 20 pellets were taken randomly, the minor and major diameters of the pellets were measured separately using a microscope, and the minor/major diameters (where the major diameter is closer to more rounded, i.e., the major diameter is closer to 1 more rounded) were calculated, the average value of the reference formulation was 0.80, and the average value of the home-made sample was 0.94, and the specific test results are shown in table 6 below.
TABLE 6 measurement results
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be made by those skilled in the art without inventive work within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope defined by the claims.
Claims (10)
1. A pharmaceutical composition of dabigatran etexilate, comprising: 1) contains an organic acid layer prepared by coating organic acid, adhesive and antisticking agent on the outer layer; 2) an isolation layer is arranged outside the organic acid layer; 3) an upper medicine layer which is prepared by mixing dabigatran etexilate containing an active ingredient or pharmaceutically acceptable salt or hydrate thereof, an anti-sticking agent and a binding agent is arranged outside the isolation layer; 4) and a protective layer is arranged outside the upper medicine layer.
2. The pharmaceutical dabigatran etexilate composition according to claim 1, wherein: the organic acid in the organic acid layer is selected from pharmaceutically acceptable acid and hydrate or acid salt thereof; the organic acid is one or more of tartaric acid, fumaric acid, malic acid, citric acid, succinic acid and amino acid; preferably tartaric acid; further, the amino acid is selected from acidic amino acids.
3. The pharmaceutical dabigatran etexilate composition according to claim 1, wherein: the pill core in the organic acid layer is a tartaric acid pill core.
4. The pharmaceutical dabigatran etexilate composition according to claim 1, wherein: the adhesive in the organic acid layer is one or more of HPMC, HPC, PVP and EC; preferably HPMC or HPC.
5. The pharmaceutical dabigatran etexilate composition according to claim 1, wherein: the anti-adhesion agent in the organic acid layer is one or more of superfine silica gel powder, talcum powder and magnesium stearate; preferably aerosil.
6. The pharmaceutical dabigatran etexilate composition according to claim 1, wherein: the mass sum of the organic acids in the organic acid layer accounts for 34-38% of the total prescription mass; preferably 36%.
7. The pharmaceutical dabigatran etexilate composition according to claim 1, wherein: the isolating layer or the protective layer is prepared by mixing a pharmaceutically acceptable adhesive and an anti-sticking agent; the pharmaceutically acceptable binder comprises HPMC, HPC, PVP, and/or EC; the pharmaceutically acceptable anti-sticking agent comprises aerosil, talcum powder and/or magnesium stearate.
8. The pharmaceutical dabigatran etexilate composition according to claim 1, wherein: the composition can be prepared into capsules.
9. A preparation method of a dabigatran etexilate pharmaceutical composition is characterized by comprising the following steps:
1) coating the acid layer coating liquid containing organic acid, adhesive and antisticking agent on the pellet core by a fluidized bed to prepare organic acid layer pellet core;
2) Coating the isolating layer coating liquid containing adhesive and antisticking agent onto the organic acid layer pellet core in fluidized bed to obtain isolating layer pellet core;
3) coating the coating liquid containing adhesive and active ingredients on the isolated layer pill core by a fluidized bed to obtain a pill core with a medicinal layer;
4) coating the protective layer coating solution containing adhesive and antisticking agent on the pellet core via fluidized bed to obtain pellet core.
10. The process for the preparation of the pharmaceutical composition of dabigatran etexilate according to claim 9, characterized in that:
coating parameters in step 1): setting the air inlet temperature to be 40-70 ℃, the atomization pressure to be 1.5-2.8 bar and the rotation speed of the liquid supply pump to be 20-150 rpm;
coating parameters in step 2): setting the air inlet temperature to be 35-50 ℃, the atomization pressure to be 1.6-2.8 bar and the rotation speed of a liquid supply pump to be 20-200 rpm;
coating parameters in step 3): setting the air inlet temperature to be 35-55 ℃, the atomization pressure to be 1.8-2.8 bar, and maintaining the air outlet volume to be 1400m3The rotation speed of the liquid supply pump is 20-400 rpm above the hour;
step 4), coating parameters: the inlet air temperature is set to be 35-50 ℃, the atomization pressure is 1.8-2.8 bar, and the rotation speed of the liquid supply pump is 20-300 rpm.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2024175037A1 (en) * | 2023-02-21 | 2024-08-29 | 广州玻思韬控释药业有限公司 | Pellet of dabigatran etexilate or pharmaceutically acceptable salt thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2024175037A1 (en) * | 2023-02-21 | 2024-08-29 | 广州玻思韬控释药业有限公司 | Pellet of dabigatran etexilate or pharmaceutically acceptable salt thereof |
| WO2024175036A1 (en) * | 2023-02-21 | 2024-08-29 | 广州玻思韬控释药业有限公司 | Pellet of dabigatran etexilate or pharmaceutically acceptable salt thereof |
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| CN111840245B (en) | 2023-07-18 |
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