CN115227663A - Dabigatran etexilate mesylate capsule and preparation method thereof - Google Patents
Dabigatran etexilate mesylate capsule and preparation method thereof Download PDFInfo
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- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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Abstract
The invention aims to provide a dabigatran etexilate mesylate capsule and a preparation method thereof, wherein the dabigatran etexilate mesylate capsule comprises contents and a hard capsule shell, and the contents comprise 130-150 parts of tartaric acid pill core, 5-6 parts of hydroxypropyl methylcellulose, 5-6 parts of talcum powder, 165-180 parts of dabigatran etexilate mesylate and 25-35 parts of hydroxypropyl cellulose. The dissolution rate of the dabigatran etexilate capsule in a 0.01N hydrochloric acid solution dissolution medium for 45min is more than 90%, the dissolution rate is high, and the clinical curative effect is stable; stable quality, no obvious change of dissolution after being placed for 6 months under accelerated condition, slow increase of impurities, and less than 1 percent of total impurities.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a dabigatran etexilate capsule and a preparation method thereof.
Background
Dabigatran etexilate mesylate has the chemical name of beta-alanine, N- [ [2- [ [ [4- [ [ [ (hexyloxy) carbonyl ] amino ] iminomethyl ] phenyl ] amino ] methyl ] -1-methyl-1H-benzimidazol-5-yl ] carbonyl ] -N-2-pyrimidine-, ethyl ester and mesylate, and the chemical structure of the dabigatran etexil mesylate is shown in a formula I, is an oral direct thrombin inhibitor developed by the company Boringer GmbH and is mainly used for: (1) prevention of stroke in patients with non-valvular atrial fibrillation; (2) Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) prevention in patients who have been treated with anticoagulant medication by injection for 5-10 days; (3) already treated patients reduce the risk of recurrence of DVT and PE; (4) prevention of DVT and PE after hip replacement.
The dabigatran etexilate is a new generation oral anticoagulant drug Direct Thrombin Inhibitors (DTIs), can provide effective, predictable and stable anticoagulant effects, simultaneously has less drug interaction, no drug-food interaction, does not need routine blood coagulation function monitoring or dose adjustment, and has very wide clinical application.
The solubility of the dabigatran etexilate mesylate is pH-dependent and is almost insoluble in a medium with the pH value being more than 4.0, so that the acidic environment is favorable for the main active ingredient of the dabigatran etexilate to be dissolved out of a pharmaceutical preparation and absorbed in vivo. However, the active ingredient is not stable on storage under acidic conditions and is easily degraded.
Disclosure of Invention
The inventor of the invention is dedicated to research on the dabigatran etexilate capsules and the preparation process thereof, and unexpectedly discovers the dabigatran etexilate capsules and the preparation process thereof, and the prepared dabigatran etexilate capsules have stable quality, obviously improved dissolution rate and stable clinical curative effect.
In order to achieve the purpose, the invention provides the following technical scheme:
firstly, the invention provides a dabigatran etexilate capsule, which comprises a content and a hard capsule shell, wherein the content comprises the following components in parts by weight:
the main component of the hard capsule shell is HPMC, and the water content is lower than 6.0%.
Furthermore, the particle size of the tartaric acid pill core is 600-800 mu m.
Furthermore, the talcum powder is 600 meshes.
Further, the hydroxypropyl methylcellulose is 2% aqueous solution (20 ℃) and has the viscosity of 3-6mPa & s; hypromellose having a viscosity of 5 mPas is preferably used as a 2% aqueous solution (20 ℃).
Further, the hydroxypropyl cellulose is 5% aqueous solution (25 ℃) of hydroxypropyl cellulose with the viscosity of 75-150mPa & s.
Furthermore, the dabigatran etexilate capsule contains 100-150mg of dabigatran etexilate, preferably 110mg and 150mg.
Further, the invention provides a dabigatran etexilate capsule which contains the following components in parts by weight:
173 parts of dabigatran etexilate mesylate is equivalent to 150 parts of dabigatran etexilate.
Furthermore, the invention provides a preparation method of the dabigatran etexilate capsule.
A preparation method of dabigatran etexilate capsules is characterized by using a fluidized bed granulator and comprising the following steps:
(1) Preparation of an isolating layer containing a tartaric acid pill core:
the isolation layer comprises:
the preparation method comprises the following steps:
(1) preparation of an isolation layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder in absolute ethyl alcohol and purified water;
(2) liquid spraying: setting the air inlet temperature of the fluidized bed granulator to be 55.0 +/-5.0 ℃; control the air inlet amount to 2000 +/-500 m 3 H; controlling the liquid spraying speed to be 140-220 g/min; the atomization pressure is 0.20-0.30 Mpa; and (3) spraying the isolating layer solution prepared in the step (1) onto a tartaric acid pill core at the material temperature of 41.0 +/-3 ℃ to obtain the pellet 1 containing the isolating layer.
(3) And (3) drying: setting the air inlet temperature at 22-27 ℃, drying the pellets 1 prepared in the step (2), and sampling to determine the Loss On Drying (LOD) until the LOD is less than or equal to 1.50 percent (105 ℃,10 min).
(2) Preparation of the active layer
The active layer comprises the following components:
(1) preparation of a liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain liquid medicine;
(2) liquid spraying: setting the air inlet temperature of the fluidized bed granulator to be 35.0 +/-5.0 ℃; control the air inlet amount to 2000 +/-500 m 3 H; controlling the liquid spraying speed to be 140-220 g/min; the atomization pressure is 0.20-0.30 Mpa; spraying the liquid medicine prepared in the step (1) to an isolation layer containing a tartaric acid pill core at the material temperature of 29.0 +/-3 ℃ to obtain a pellet 2 containing active ingredients;
(3) and (3) drying: setting the air inlet temperature to be 22-27 ℃, drying the pellets 2 prepared in the step (2), and sampling to determine the Loss On Drying (LOD) until the LOD is less than or equal to 1.50 percent (105 ℃,10 min).
(3) Subpackaging: subpackaging into capsule shells to obtain the dabigatran etexilate capsules.
In the step (1) of preparing the isolating layer containing the tartaric acid pill core, the step (2) of spraying liquid is carried out, and the air inlet temperature is 55 ℃.
In the step (1) of preparing the isolating layer containing the tartaric acid pill core, the step (2) of spraying liquid, wherein the spraying speed is 180g/min.
In the step (1) of preparing the isolating layer containing the tartaric acid pill core, and in the step (2), the liquid is sprayed, and the atomization pressure is 0.25Mpa.
In the step (1) of preparing the isolating layer containing the tartaric acid pill core, the step (3) of drying is carried out, and the air inlet temperature is 25 ℃.
In the step (2) of preparing the active layer, the air inlet temperature is 35 ℃, and in the step (2), the liquid is sprayed.
In the step (2) of preparing the active layer, the material temperature is 29 ℃, and in the step (2) of spraying liquid, the material temperature is controlled to be 29 ℃.
And (3) drying in the step (2) of preparing the active layer, wherein the air inlet temperature is 25 ℃.
LOD is loss on drying, and the determination method is that the loss on weight of a sample is reduced after drying for 10min at 105 ℃.
The invention has the beneficial technical effects that:
(1) The dabigatran etexilate capsule provided by the invention has the dissolution rate of more than 90% in a 0.01N hydrochloric acid solution dissolution medium for 45min, is high in dissolution rate and stable in clinical curative effect.
(2) The dabigatran etexilate capsule provided by the invention has stable quality, the dissolution rate does not change obviously after the capsule is placed for 6 months under an accelerated condition, the impurities grow slowly, and the total impurities are all lower than 1%.
Detailed Description
The invention discloses a dabigatran etexilate capsule and a preparation method thereof, and the method can be realized by combining the relevant principles of pharmaceutical preparations and properly improving the process parameters by taking the contents of the invention as reference. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention.
For a better understanding of the invention, and not as a limitation on the scope thereof, all numbers expressing quantities, percentages, and other numerical values used in this application are to be understood as being modified in all instances by the term "about". At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials and the like used in the following examples are commercially available unless otherwise specified.
The dissolution curve measuring method comprises the following steps:
(1) Dissolution medium: 0.01N hydrochloric acid solution.
(2) A dissolution device: (ii) a Basket method; rotating speed: 100 revolutions per minute; volume of medium: 900ml; temperature: 37.0 +/-0.5 ℃; sampling volume: 7ml;
(3) Sampling time: 10. 15, 20, 30 and 45min;
(4) The standard is as follows: a. taking 12 tablets of each of the sample and the reference preparation prepared in the example respectively, and measuring the dissolution curves of the tablets; b. taking the average dissolution value of each time point on the two curves, and calculating a similarity factor (f 2); c. no more than one sampling point with the drug dissolution amount exceeding 85 percent; d. the elution amount at the first sampling time point (5 minutes) should not exceed 20% relative to the standard deviation, and the elution amounts at the remaining sampling time points should not exceed 10% relative to the standard deviation.
And (3) auxiliary material sources:
the structural formula of impurities in the dabigatran etexilate capsule is as follows:
impurity 1:
the molecular formula is as follows: c 27 H 29 N 7 O 3
Impurity 2:
the molecular formula is as follows: c 32 H 37 N 7 O 5
Impurity 3:
the molecular formula is as follows: c 34 H 41 N 7 O 5
Impurity 4:
the molecular formula is as follows: c 29 H 31 N 7 O 5
Impurity 5:
the molecular formula is as follows: c 34 H 40 N 6 O
Example 1: dabigatran etexilate capsules
1. The prescription composition is as follows:
10000 capsules are dosed according to the prescription to prepare the dabigatran etexilate capsules, which are the same as the following.
2. The preparation method comprises the following steps:
(1) Preparation of an isolating layer containing a tartaric acid pill core:
(1) preparation of an isolation layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder in absolute ethyl alcohol and purified water;
(2) liquid spraying: setting the air inlet temperature of the fluidized bed granulator to be 55 ℃; controlling the air inlet amount to be 2000/h; controlling the liquid spraying speed to be 180g/min; the atomization pressure is 0.25Mpa; and (3) spraying the isolating layer solution prepared in the step (1) onto the tartaric acid pill core at the material temperature of 41 ℃ to obtain the pellet 1 containing the isolating layer.
(3) And (3) drying: the pellet 1 prepared in the step (2) was dried with the inlet air temperature set at 25 deg.c, and the Loss On Drying (LOD) was measured by sampling until the LOD was 1.2% (105 deg.c, 10 min).
(2) Preparation of the active layer:
(1) preparation of a liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain a liquid medicine;
(2) liquid spraying: setting the air inlet temperature of the fluidized bed granulator to be 35.0 ℃; controlling the air inlet amount to be 2000/h; controlling the liquid spraying speed to be 180g/min; the atomization pressure is 0.25Mpa; spraying the liquid medicine prepared in the step (1) to an isolation layer containing a tartaric acid pill core at the material temperature of 29 ℃ to obtain a pellet 2 containing active ingredients;
(3) and (3) drying: setting the air inlet temperature at 25 ℃, drying the pellets 2 prepared in the step (2), and sampling to determine the Loss On Drying (LOD) until the LOD is 1.2% (105 ℃,10 min).
(3) Subpackaging: subpackaging into HPMC capsule shell with water content of 5.5% to obtain capsule containing 150mg of dabigatran etexilate.
3. And (3) detection results: the results of the dissolution curve test in 0.01n hcl are shown in table 1.
Table 1: dissolution Profile of dabigatran etexilate capsules prepared in example 1
| Time | Amount of elution | RSD |
| /min | (％) | (％) |
| 10 | 13 | 12.5 |
| 15 | 56 | 8.3 |
| 20 | 77 | 6.5 |
| 30 | 97 | 1.0 |
| 45 | 98 | 0.2 |
Example 2: dabigatran etexilate capsules
1. The prescription composition is as follows:
2. the preparation method comprises the following steps:
(1) Preparation of an isolating layer containing a tartaric acid pill core:
(1) preparation of an isolation layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder in absolute ethyl alcohol and purified water;
(2) liquid spraying: setting the air inlet temperature of the fluidized bed granulator to be 50 ℃; the air inlet volume is controlled to be 2500m < 3 >/h; controlling the liquid spraying speed to be 220g/min; the atomization pressure is 0.30Mpa; and (3) spraying the isolating layer solution prepared in the step (1) onto the tartaric acid pill core at the material temperature of 44 ℃ to obtain the pellet 1 containing the isolating layer.
(3) And (3) drying: the inlet air temperature was set at 22 ℃, the pellets 1 prepared in step (2) were dried, and a sample was taken to determine Loss On Drying (LOD) to an LOD of 1.5% (105 ℃,10 min).
(2) Preparation of active layer:
(1) preparation of a liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain a liquid medicine;
(2) liquid spraying: setting the air inlet temperature to be 30 ℃; the air inlet volume is controlled to be 2500m < 3 >/h; controlling the liquid spraying speed to be 220g/min; the atomization pressure is 0.30Mpa; spraying the liquid medicine prepared in the step (1) to an isolation layer containing a tartaric acid pill core at the material temperature of 32 ℃ to obtain a pellet 2 containing active ingredients;
(3) and (3) drying: setting the air inlet temperature at 22 ℃, drying the pellets 2 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is 1.5% (105 ℃,10 min).
(3) Subpackaging: subpackaging into HPMC capsule shell with water content of 4.3% to obtain capsule containing 150mg of dabigatran etexilate.
3. And (3) detection results: the results of the dissolution curve test in 0.01n hcl are shown in table 2.
Table 2: dissolution profile of dabigatran etexilate capsules prepared in example 2
| Time | Amount of elution | RSD |
| /min | (％) | (％) |
| 10 | 16 | 13.4 |
| 15 | 54 | 7.2 |
| 20 | 73 | 6.6 |
| 30 | 92 | 4.2 |
| 45 | 98 | 1.8 |
Example 3: dabigatran etexilate capsules
1. The prescription composition is as follows:
2. the preparation method comprises the following steps:
(1) Preparation of an isolating layer containing a tartaric acid pill core:
(1) preparing an isolation layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder in absolute ethyl alcohol and purified water;
(2) liquid spraying: setting the air inlet temperature of the fluidized bed granulator to be 60 ℃; control the air intake quantity to 1500m 3 H; controlling the liquid spraying speed to be 140g/min; the atomization pressure is 0.20Mpa; and (3) spraying the isolating layer solution prepared in the step (1) onto the tartaric acid pill core at the material temperature of 38 ℃ to obtain the pellet 1 containing the isolating layer.
(3) And (3) drying: the pellet 1 prepared in step (2) was dried with the inlet air temperature set at 27 deg.c, and the Loss On Drying (LOD) was measured by sampling until the LOD was 1.0% (105 deg.c, 10 min).
(2) Preparation of the active layer:
(1) preparation of a liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain liquid medicine;
(2) liquid spraying: setting the air inlet temperature to be 40 ℃; control the air intake quantity to 1500m 3 H; controlling the liquid spraying speed to be 140g/min; the atomization pressure is 0.20Mpa; the atomization pressure is 0.20-0.30 Mpa; spraying the liquid medicine prepared in the step (1) to an isolating layer containing a tartaric acid pill core at the material temperature of 26 ℃ to obtain a pellet 2 containing active ingredients;
(3) and (3) drying: setting the air inlet temperature at 27 ℃, drying the pellets 2 prepared in the step (2), and sampling to determine the Loss On Drying (LOD) until the LOD is 1.0% (105 ℃,10 min).
(3) Subpackaging: subpackaging into HPMC capsule shell with water content of 3.8% to obtain capsule containing 150mg of dabigatran etexilate.
3. And (3) detection results: the results of the dissolution curve test in 0.01n hcl are shown in table 3.
Table 3: dissolution profile of dabigatran etexilate capsules prepared in example 3
| Time | Amount of elution | RSD |
| /min | (％) | (％) |
| 10 | 21 | 14.0 |
| 15 | 51 | 6.9 |
| 20 | 67 | 5.8 |
| 30 | 84 | 3.0 |
| 45 | 97 | 2.3 |
Example 4: dabigatran etexilate capsules
1. The prescription composition is as follows:
2. the preparation method comprises the following steps:
(1) Preparation of an isolating layer containing a tartaric acid pill core:
(1) preparation of an isolation layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder in absolute ethyl alcohol and purified water;
(2) liquid spraying: setting the air inlet temperature of the fluidized bed granulator to be 52 ℃; control the air inlet quantity of 1800m 3 H; controlling the liquid spraying speed to be 160g/min; the atomization pressure is 0.23Mpa; and (3) spraying the isolating layer solution prepared in the step (1) onto the tartaric acid pill core at the material temperature of 40 ℃ to obtain the pellet 1 containing the isolating layer.
(3) And (3) drying: the pellet 1 prepared in the step (2) was dried with the inlet air temperature set at 25 deg.c, and the Loss On Drying (LOD) was measured by sampling until the LOD was 1.4% (105 deg.c, 10 min).
(2) Preparation of the active layer
(1) Preparation of a liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain a liquid medicine;
(2) liquid spraying: setting the air inlet temperature to be 33.0 ℃; control the air inlet quantity of 1800m 3 H; controlling the liquid spraying speed to be 160g/min; the atomization pressure is 0.23Mpa; spraying the liquid medicine prepared in the step (1) to an isolating layer containing a tartaric acid pill core at the material temperature of 27 ℃ to obtain a pellet 2 containing active ingredients;
(3) and (3) drying: setting the air inlet temperature at 25 ℃, drying the pellets 2 prepared in the step (2), and sampling to determine the Loss On Drying (LOD) until the LOD is 1.3 percent (105 ℃,10 min).
(3) Subpackaging into HPMC capsule shell with water content of 5.6% to obtain capsule containing 110mg of dabigatran etexilate.
3. And (3) detection results: the results of the dissolution curve test in 0.01n hcl are shown in table 4.
Table 4: dissolution profile of dabigatran etexilate capsules prepared in example 4
| Time | Amount of elution | RSD |
| /min | (％) | (％) |
| 10 | 22 | 13.1 |
| 15 | 60 | 8.3 |
| 20 | 79 | 7.1 |
| 30 | 92 | 4.5 |
| 45 | 96 | 3.7 |
Example 5: dabigatran etexilate capsules
1. The prescription composition is as follows:
2. the preparation method comprises the following steps:
(1) Preparation of an isolating layer containing a tartaric acid pill core:
(1) preparation of an isolation layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder in absolute ethyl alcohol and purified water;
(2) liquid spraying: setting the air inlet temperature of the fluidized bed granulator to be 58 ℃; controlling the air inlet quantity to be 2300/h; controlling the liquid spraying speed to be 210g/min; the atomization pressure is 0.27Mpa; and (3) spraying the isolating layer solution prepared in the step (1) onto the tartaric acid pill core at the material temperature of 42 ℃ to obtain the pellet 1 containing the isolating layer.
(3) And (3) drying: the pellet 1 prepared in the step (2) was dried with the inlet air temperature set at 25 deg.c, and the Loss On Drying (LOD) was measured by sampling until the LOD was 1.3% (105 deg.c, 10 min).
(2) Preparation of the active layer:
(1) preparation of a liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain liquid medicine;
(2) liquid spraying: setting the air inlet temperature to be 37.0 ℃; controlling the air inlet quantity to be 2300/h; controlling the liquid spraying speed to be 210g/min; the atomization pressure is 0.27Mpa; spraying the liquid medicine prepared in the step (1) to an isolating layer containing a tartaric acid pill core at the material temperature of 31 ℃ to obtain a pellet 2 containing active ingredients;
(3) and (3) drying: setting the air inlet temperature at 25 ℃, drying the pellets 2 prepared in the step (2), and sampling to determine the Loss On Drying (LOD) until the LOD is 1.3 percent (105 ℃,10 min).
(3) Subpackaging: subpackaging into HPMC capsule shell with water content of 5.5% to obtain capsule containing 150mg of dabigatran etexilate.
3. And (3) detection results: the results of the dissolution curve test in 0.01n hcl are shown in table 5.
Table 5: dissolution profile of dabigatran etexilate capsules prepared in example 5
| Time | Amount of elution | RSD |
| /min | (％) | (％) |
| 10 | 17 | 14.2 |
| 15 | 57 | 9.0 |
| 20 | 81 | 6.8 |
| 30 | 95 | 4.2 |
| 45 | 98 | 2.8 |
Comparative example 1: effect of hydroxypropylcellulose on dissolution
1. The prescription composition is as follows:
the amounts or viscosities of hydroxypropylcellulose are varied, see table below, otherwise as in example 1
| Comparative example | Hydroxypropyl cellulose | The dosage of hydroxypropyl cellulose |
| Comparative examples 1 to 1 | Hydroxypropyl cellulose 3 | 30 |
| Comparative examples 1 to 2 | Hydroxypropyl cellulose 4 | 30 |
| Comparative examples 1 to 3 | Hydroxypropyl cellulose 3 | 20 |
| Comparative examples 1 to 4 | Hydroxypropyl cellulose 1 | 50 |
| Comparative examples 1 to 5 | Hydroxypropyl cellulose 1 | 20 |
2. The preparation method comprises the following steps: the same as in example 1.
3. And (3) detection results: the results of the dissolution curve test in 0.01n hcl are shown in table 6.
Table 6: dissolution profile of dabigatran etexilate capsules prepared in comparative example 1
The stability and dissolution behavior of the dabigatran etexilate capsules are influenced by the dosage or viscosity of the hydroxypropyl cellulose:
(1) The dissolution behavior of the dabigatran etexilate is influenced by the hydroxypropyl celluloses with different viscosities, when the viscosity of the hydroxypropyl methylcellulose is high (such as comparative examples 1-1 and 1-2), namely the viscosity of a 5% aqueous solution (25 ℃) exceeds 150mPa & s, the dissolution of the prepared dabigatran etexilate capsules in 0.01N hydrochloric acid becomes slow, the dissolution rate is lower than 80% after 45min, and the dissolution rate is low. And the dissolution rate difference of the same batch of capsules is large, the relative standard deviation of dissolution exceeds 20% at 10min, and the relative standard deviation of dissolution exceeds 10% at 15min, so that the dissolution is unstable.
(2) The dissolution behavior of dabigatran etexilate is influenced by the dosage of hydroxypropyl cellulose, when the dosage of hydroxypropyl cellulose is larger (as comparative examples 1-4), namely more than 30 parts by weight, the dissolution of the prepared dabigatran etexilate capsule in 0.01N hydrochloric acid becomes slow, the dissolution rate is lower than 90% after 45min, and the dissolution rate is slow; when the dosage of hypromellose is small (as comparative examples 1-5), the prepared dabigatran etexilate capsule dissolves faster in 0.01N hydrochloric acid, the dissolution rate after 45min is 99%, but the stability is poor (see table 11 of example 6), and after 6 months of acceleration, the impurity 5 is higher than 1.0%; the total impurities are higher than 2%. Thus, a 5% solution of hydroxypropylcellulose in water (25 ℃) has a viscosity of 75 to 150 mPas; the weight portion is 25-35 portions.
Comparative example 2: effect of hypromellose on dissolution
1. The prescription composition is as follows:
the hypromellose was used in different amounts or viscosities, as shown in the table below, otherwise as in example 1.
| Comparative example | Hydroxypropyl methylcellulose | Dosage of hydroxypropyl methylcellulose |
| Comparative example 2-1 | Hydroxypropyl methylcellulose 3 | 5.5 |
| Comparative examples 2 to 2 | Hydroxypropyl methylcellulose 4 | 5.5 |
| Comparative examples 2 to 3 | Hydroxypropyl methylcellulose | 3 |
| Comparative examples 2 to 4 | Hydroxypropyl methylcellulose | 8 |
2. The preparation method comprises the following steps: the same as in example 1.
3. And (3) detection results: the results of measurement of the dissolution curve in 0.01n hcl are shown in table 7.
Table 7: dissolution profile of dabigatran etexilate capsules prepared in comparative example 2
The dosage or viscosity of hypromellose affects the stability and dissolution behavior of dabigatran etexilate capsules:
(1) The dissolution behavior of the dabigatran etexilate is influenced by the hydroxypropyl methylcellulose with different viscosities, when the viscosity of the hydroxypropyl methylcellulose is large (such as comparative example 2-1 and comparative example 2-2), namely the viscosity of a 2% aqueous solution (20 ℃) exceeds 6mPa & s, the dissolution of the prepared dabigatran etexilate capsule in 0.01N hydrochloric acid becomes slow, the dissolution rate is lower than 80% after 45min, and the dissolution is slow. And the dissolution rate difference of the same batch of capsules is large, the relative standard deviation of dissolution exceeds 20% at 10min, and the relative standard deviation of dissolution exceeds 10% at 15min, so that the dissolution is unstable.
(2) The dissolution behavior of dabigatran etexilate is influenced by the dosage of the hypromellose, when the dosage of the hypromellose is larger (as in comparative examples 2-4), namely more than 6 parts by weight, the dissolution of the prepared dabigatran etexilate capsule in 0.01N hydrochloric acid becomes slow, the dissolution rate is lower than 90% after 45min, and the dissolution is slow. And the dissolution rate difference of the same batch of capsules is large, the relative standard deviation of dissolution at 10min exceeds 20%, and the dissolution is unstable.
(3) The dosage of the hypromellose influences the dissolution behavior of the dabigatran etexilate, and is lower than 5 parts by weight when the dosage of the hypromellose is smaller (as in comparative examples 2-3); the prepared dabigatran etexilate capsules are fast in dissolution in 0.01N hydrochloric acid, the dissolution rate is 99% after 45min, but the stability is poor (see table 11 of example 6), and after 6 months of acceleration, the impurity 5 is higher than 1.0%; the total impurities are higher than 2%.
Thus, a 2% solution of hypromellose in water (20 ℃) has a viscosity of 3-6 mPas; preferably a 2% aqueous solution (20 ℃) having a viscosity of 5 mPas; the parts by weight are preferably 5 to 6 parts.
Comparative example 3: influence of the Material temperature during the preparation of the active layer
1. The prescription composition is as follows: the same as in example 1.
2. The preparation method comprises the following steps:
the material temperature in the "(2) spray liquid" in the preparation of the active layer in the step (2) is shown in the following table, and other preparation methods are the same as in example 1.
| Comparative example | (2) during preparation of the active layer in step (2) ((2) spray liquid) "material temperature |
| Comparative example 3-1 | The material temperature is 37 DEG C |
| Comparative examples 3 and 2 | The material temperature is 40 DEG C |
3. And (3) detection results: the results of measurement of the dissolution curve in 0.01n hcl are shown in table 8.
Table 8: dissolution profile of dabigatran etexilate capsules prepared in comparative example 3
Comparative analysis examples 1 to 5 and comparative example 3 revealed that: the material temperature influences the stability of the product in the preparation process of the active layer, and the dissolution rate of the product is not influenced. When the material temperature in the preparation process of the active layer is higher than 32 ℃, such as 37 ℃ in a comparative example 3-1 and 40 ℃ in a comparative example 3-2, the prepared related substances of the dabigatran etexilate capsules increase faster, and after the acceleration for 6 months, the impurity 5 is higher than 1.0 percent; the total impurities are all higher than 2%. Therefore, the temperature of the materials in the preparation process should not be higher than 32 ℃, and is preferably 29.0 +/-3 ℃.
Comparative example 4: influence of LOD control during preparation
1. The prescription composition is as follows: the same as in example 1.
2. The preparation method comprises the following steps:
LOD value in "(3) Dry" in the production process is shown in the following table, and other production methods are the same as in example 1.
3. And (3) detection results: the results of the dissolution curve test in 0.01n hcl are shown in table 9.
Table 9: dissolution profile of dabigatran etexilate capsules prepared in comparative example 4
Comparative analysis examples 1-5 and comparative example 4 show that: the control of the drying weight loss in the preparation process influences the stability of the product and does not influence the dissolution rate of the product. The LOD value in the isolating layer containing the tartaric acid pellet core in the step (1) and the LOD value in the preparation of the active layer in the step (2) both influence the stability of the dabigatran etexilate capsule (Table 11 of the specific example 6), when the LOD value is higher than 1.5%, the growth of related substances of the prepared dabigatran etexilate capsule is faster, and after the acceleration for 6 months, the impurity 5 is higher than 1.0%; the total impurities are all higher than 2%. The LOD value during the preparation should therefore be less than 1.5%.
Comparative example 5: the dabigatran etexilate mesylate capsule is prepared according to Chinese patent CN03805473.6
1. The prescription composition is as follows: the same as example 2 in Chinese patent CN 03805473.6.
2. The preparation method comprises the following steps: the same as example 2 in Chinese patent CN 03805473.6.
3. And (3) detection results: the results of the dissolution curve test in 0.01n hcl are shown in table 10.
Table 10: dissolution profile of dabigatran etexilate capsules prepared in comparative example 5
| Time | Amount of elution | RSD |
| /min | (％) | (％) |
| 10 | 16 | 25.8 |
| 15 | 58 | 14.7 |
| 20 | 83 | 7.1 |
| 30 | 94 | 5.2 |
| 45 | 97 | 1.8 |
Comparative analysis examples 1-5 and comparative example 5 know: the dabigatran etexilate mesylate capsule prepared according to the example 2 in the Chinese patent CN03805473.6 has the dissolution rate of 97 percent after 45min in 0.01N hydrochloric acid and is fast in dissolution. However, the difference of dissolution rates of the capsules in the same batch is large, the relative standard deviation of dissolution exceeds 20% at 10min, and the relative standard deviation of dissolution exceeds 10% at 15min, so that the dissolution is unstable. The prepared dabigatran etexilate capsule related substances grow faster, and after the substance is accelerated for 6 months, the total impurities are higher than 1.0%.
Example 6: stability test
Examples 1 to 5, comparative examples 1 to 6, comparative examples 2 to 3, comparative examples 3 to 1 to 3 to 2, and comparative examples 4 to 1 to 4 to 3, the dabigatran etexilate capsules prepared at a temperature of 40 ℃. + -. 2 ℃; the samples were taken at 75% + -5% (accelerated) relative humidity for 6 months and at the end of 0 and 6 months, and the results of the measurements of the relevant substances, dissolution rates, etc. are shown in Table 11.
Table 11: stability test results table
As can be seen from Table 11, after the dabigatran etexilate capsule prepared by the invention is placed for 6 months under an accelerated condition, the dissolution rate does not change obviously, the increase of impurities is slow, and the impurities 1-5 are all lower than 0.15%; the total impurities are all less than 1%. Therefore, the dabigatran etexilate capsule provided by the invention has the advantages of good dissolution effect and stable quality.
Claims (10)
1. The dabigatran etexilate mesylate capsule comprises a content and a hard capsule shell, wherein the content comprises the following components in parts by weight:
the main component of the hard capsule shell is HPMC, and the water content is lower than 6.0%; the particle size of the tartaric acid pill core is 600-800 μm; the talcum powder is sieved by a 600-mesh sieve; the hydroxypropyl methylcellulose is 2% hydroxypropyl methylcellulose with the viscosity of water solution of 3-6mPa & s; the hydroxypropyl cellulose is 5% hydroxypropyl cellulose with water solution viscosity of 75-150 mPa.s.
2. The dabigatran etexilate mesylate capsule of claim 1, wherein the hypromellose is a 2% aqueous solution of hypromellose having a viscosity of 5 mPa-s.
3. The dabigatran etexilate mesylate capsule according to claim 1 or 2, wherein the content comprises the following components in parts by weight:
4. the dabigatran etexilate mesylate capsule according to claim 1 or 2, wherein the dabigatran etexilate capsule contains 100 to 150mg, preferably 110mg, 150mg of dabigatran etexilate.
5. A process for the preparation of dabigatran etexilate mesylate capsules according to claim 1 or 2, wherein a fluid bed granulator is used, comprising the steps of:
(1) Preparing an isolating layer containing the tartaric acid pill core:
the isolation layer comprises:
the preparation method comprises the following steps:
(1) preparing an isolation layer solution: dissolving and dispersing hydroxypropyl methylcellulose and talcum powder in absolute ethyl alcohol and purified water;
(2) liquid spraying: setting the air inlet temperature of the fluidized bed granulator to be 55.0 +/-5.0 ℃; control the air inlet amount to 2000 +/-500 m 3 H; controlling the liquid spraying speed to be 140-220 g/min; the atomization pressure is 0.20-0.30 Mpa; the temperature of the materials is 41.0 +/-3 ℃, and the materials prepared in the step (1) are isolatedSpraying the layer solution on the tartaric acid pill core to obtain a pellet 1 containing an isolation layer;
(3) and (3) drying: setting the air inlet temperature to be 22-27 ℃, drying the pellets 1 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is less than or equal to 1.50 percent (105 ℃,10 min);
(2) Preparation of the active layer
Comprises the following components:
(1) preparing a liquid medicine: dissolving dabigatran etexilate mesylate and hydroxypropyl cellulose in isopropanol to obtain a liquid medicine;
(2) liquid spraying: setting the air inlet temperature of the fluidized bed granulator to be 35.0 +/-5.0 ℃; control the air inlet amount to 2000 +/-500 m 3 H; controlling the liquid spraying speed to be 140-220 g/min; the atomization pressure is 0.20-0.30 Mpa; spraying the liquid medicine prepared in the step (1) to an isolation layer containing a tartaric acid pill core at the material temperature of 29.0 +/-3 ℃ to obtain a pellet 2 containing active ingredients;
(3) and (3) drying: setting the air inlet temperature to be 22-27 ℃, drying the pellets 2 prepared in the step (2), sampling and measuring the Loss On Drying (LOD) until the LOD is less than or equal to 1.50 percent (105 ℃,10 min);
(3) Subpackaging: subpackaging into capsule shells to obtain the dabigatran etexilate capsules.
6. The method according to claim 5, wherein in the step (1) of preparing the isolating layer containing the tartaric acid pellet core, the liquid is sprayed, and the inlet air temperature is 55 ℃.
7. The process according to claim 5, wherein the step (1) of preparing the barrier layer comprising tartaric acid pellets comprises the step of (2) spraying a liquid at a speed of 180g/min.
8. The method of claim 5, wherein in the step (1) of preparing the barrier layer comprising tartaric acid pellets and in the step (2) of spraying the liquid, the atomization pressure is 0.25MPa.
9. The method according to claim 5, wherein in the step (2) of preparing the active layer, the liquid is sprayed at a material temperature of 29 ℃.
10. The method according to claim 5, wherein in the step (2) of preparing the active layer, the drying step is performed in step (3), and the temperature of the inlet air is 25 ℃.
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| WO2025046547A1 (en) * | 2023-09-01 | 2025-03-06 | Glenmark Pharmaceuticals Limited | A stable solid oral dosage form of dabigatran |
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