CN115770248A - Ivabradine hydrochloride preparation and preparation method thereof - Google Patents
Ivabradine hydrochloride preparation and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an ivabradine hydrochloride preparation and a preparation method thereof. The ivabradine hydrochloride preparation comprises ivabradine hydrochloride, cyclodextrin, chloride and pharmaceutically acceptable auxiliary materials. According to the invention, by adopting an inclusion technology, cyclodextrin is preferably selected as an inclusion material to be combined with the ivabradine hydrochloride form inclusion compound, so that the solubility of the medicine is increased, the dissolution rate of the medicine is improved, and the bioavailability is improved.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an ivabradine hydrochloride preparation and a preparation method thereof.
Background
Ivabradine hydrochloride belongs to the selective inhibition of cardiac pacing IF current, has selective effect on sinus node and has no effect on intracardiac conduction, myocardial contraction or ventricular repolarization. The ivabradine hydrochloride has the simple heart rate reducing effect, and is used for symptomatic treatment of chronic stable angina pectoris accompanied by normal sinus rhythm, contraindication to beta-blocker or intolerance.
The ivabradine stable drug has the characteristic of poor solubility, and in order to improve the dissolution rate of the crystal form drug in a preparation, the prior art usually adopts a micronization technology, a solid dispersion technology, a surfactant solubilization technology, an inclusion technology and the like. However, in the storage of the preparation, the medicine is easy to be converted into a crystal form, which not only influences the dissolution of the medicine, but also causes the increase of impurities and brings hidden troubles to clinical medication. In addition, in the prior art, most of the auxiliary materials contain lactose, and some patients suffering from galactose intolerance, primary intestinal lactase deficiency or glucose-lactose malabsorption cannot use the auxiliary materials, so that the audience population is reduced.
Chinese patent CN101559228A discloses a pharmaceutical composition for treating hyperlipidemia complicated with chronic stable angina pectoris, which comprises ivabradine hydrochloride, atorvastatin calcium, beta-cyclodextrin and pharmaceutically acceptable auxiliary materials, wherein the weight ratio of the ivabradine hydrochloride to the beta-cyclodextrin is 1:4-8-20, and the pharmaceutical composition has a good synergistic effect in treating stable angina pectoris accompanied with hyperlipidemia, and has a good blood fat reducing effect and a good hemorheology influence effect on the hyperlipidemia.
WO2015/001133A1 discloses a pharmaceutical composition comprising a complex of ivabradine in amorphous form or a pharmaceutically acceptable salt thereof unsubstituted β -cyclodextrin and pharmaceutically acceptable excipients in a weight ratio of ivabradine to β -cyclodextrin of 1:1-1. Also disclosed is a method for preparing the composition by dissolving and evaporating the solvent.
Disclosure of Invention
The invention overcomes the defects of the prior art, provides the ivabradine hydrochloride preparation with high dissolution rate and high stability, solves the problem of low dissolution rate of the ivabradine hydrochloride by a cyclodextrin inclusion technology, improves the stability of the preparation, reduces the impurity content and improves the safety of the medicine.
Specifically, the technical scheme of the invention is as follows:
the invention aims to provide an ivabradine hydrochloride inclusion compound which comprises ivabradine hydrochloride, cyclodextrin and chloride.
The second purpose of the invention is to provide a preparation method of the ivabradine hydrochloride clathrate compound, which comprises the following steps: preparing cyclodextrin into saturated solution at 5-10 deg.C, adding ivabradine hydrochloride dissolved in ethanol, mixing, stirring at 5-10 deg.C for 0.5-1.5 hr, adding chloride, stirring at 15-25 deg.C for 0.5-1.5 hr, cooling, concentrating, washing, and drying.
The third purpose of the invention is to provide an ivabradine hydrochloride preparation, which comprises ivabradine hydrochloride, cyclodextrin, chloride and pharmaceutically acceptable auxiliary materials, namely the ivabradine hydrochloride preparation prepared from the prepared ivabradine hydrochloride clathrate compound and the pharmaceutically acceptable auxiliary materials.
Further, the ivabradine hydrochloride preparation comprises but is not limited to granules, mixture, tablets, capsules, pills, powder, syrup, microcapsules and paste, preferably tablets and capsules.
Furthermore, the ivabradine hydrochloride is alpha-crystal form, beta d-crystal form, y-crystal form, epsilon-crystal form, s-crystal form and amorphous ivabradine hydrochloride.
Further, the cyclodextrin is one of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin and methyl-beta-cyclodextrin.
Preferably, the cyclodextrin is one of alpha-cyclodextrin, hydroxypropyl-beta-cyclodextrin and methyl-beta-cyclodextrin.
Thermal analysis shows that the ivabradine hydrochloride can generate an absorption peak at 185-210 ℃, the crystallization degree of the ivabradine hydrochloride can be greatly reduced or disappeared after the drug is included with the cyclodextrin, the absorption peak disappears, the inventor identifies the phase of the inclusion compound by a DSC method, and a large number of experiments prove that the absorption peak disappears after the alpha-crystal form, the beta d-crystal form, the y-crystal form, the epsilon-crystal form, the s-crystal form and the amorphous ivabradine hydrochloride are included with the alpha-cyclodextrin, the hydroxypropyl-beta-cyclodextrin and the methyl-beta-cyclodextrin, thereby proving that the inclusion is successful and forming the high-quality inclusion compound.
Further, the chloride is sodium chloride or/and potassium chloride. The inventor unexpectedly finds that in the inclusion process, a proper amount of chloride is added, so that the encapsulation rate can be improved to a certain extent, and importantly, the stability of the preparation can be obviously improved, the ivabradine hydrochloride can be effectively prevented from being degraded to form impurities, and the quality of the ivabradine hydrochloride preparation can be improved.
Specifically, the weight ratio of the ivabradine hydrochloride to the cyclodextrin is 1.
Specifically, the weight ratio of the ivabradine hydrochloride to the chloride is 1.
Further, the pharmaceutically acceptable auxiliary materials are selected from a plurality of fillers, diluents, disintegrants, lubricants, binders, wetting agents, flavoring agents, stabilizers and pH regulators.
Specifically, the filler is selected from one or more of dextrin, microcrystalline cellulose, pregelatinized starch, sucrose, mannitol, calcium bicarbonate, calcium sulfate and calcium carbonate, and is preferably microcrystalline cellulose and mannitol. Based on the consideration that most of the auxiliary materials in the prior art contain a large amount of lactose, and some patients with galactose intolerance, primary intestinal lactase deficiency or glucose-lactose malabsorption cannot use the auxiliary material, so that the audience population is reduced, the invention tries to replace the filler, and unexpectedly discovers that the mannitol and the microcrystalline cellulose can not only completely replace the lactose in the auxiliary materials, but also have the effect of improving the dissolution of the ivabradine hydrochloride to a certain extent under the condition that the weight ratio is 1:1.
The fourth purpose of the invention is to provide a method for preparing the ivabradine hydrochloride preparation, which comprises the following steps: the ivabradine hydrochloride clathrate compound is prepared by adding pharmaceutically acceptable auxiliary materials into the ivabradine hydrochloride clathrate compound according to the preparation formulation and the preparation process required by the preparation formulation.
Compared with the prior art, the invention has the beneficial effects that:
(1) According to the invention, through an inclusion technology, the cyclic compound with a cavity structure, such as alpha-cyclodextrin, hydroxypropyl-beta-cyclodextrin and methyl-beta-cyclodextrin, is preferably used as a host, ivabradine hydrochloride is used as an object, an inclusion compound is formed through van der Waals force, and the proportion of the host and the object is preferably selected, so that the solubility of the medicine is increased, the dissolution rate of the medicine is improved, and the bioavailability is improved.
(2) According to the invention, by introducing chloride into the inclusion technology and controlling the proportion, the encapsulation rate and the drug-loading rate of the ivabradine hydrochloride inclusion compound are improved to a certain extent, a good foundation is laid for further preparation of the preparation, the degradation of the ivabradine hydrochloride can be prevented, the content of related substances of the preparation is low, the stability is high, the long-term storage is facilitated, and the shelf life is prolonged.
(3) According to the invention, through preferably selecting auxiliary materials, microcrystalline cellulose and mannitol are found to be capable of improving the dissolution of ivabradine hydrochloride to a certain extent and improving the bioavailability.
Drawings
FIG. 1: single factor test for influence of cyclodextrin kind on encapsulation efficiency and drug loading rate of inclusion compound
FIG. 2: identification of Ivabradine hydrochloride clathrate by thermal analysis (DSC curve)
FIG. 3: single factor test for influence of cyclodextrin and ivabradine hydrochloride ratio on drug loading of inclusion compound
FIG. 4: single factor test for the Effect of the Cyclodextrin to Ivabradine hydrochloride ratio on the Inclusion Rate of the Inclusion Compound
FIG. 5: single factor test for the Effect of Cyclodextrin to chloride ratio on drug Loading of Inclusion Compounds
FIG. 6: single factor test for the Effect of Cyclodextrin to chloride ratio on Inclusion Rate
FIG. 7: the preparation stability (long-term test) of the Ivabradine hydrochloride Lei Dingpian and the Ivabradine hydrochloride sold in the market
FIG. 8: the preparation stability (accelerated test) of the Ivabradine hydrochloride Lei Dingpian and the commercially available Ivabradine hydrochloride tablet
FIG. 9: effect of Cyclodextrin to chloride ratio on formulation stability (Long term test)
FIG. 10: effect of Cyclodextrin to chloride ratio on formulation stability (accelerated test)
FIG. 11: dissolution rates of the Ivabrax hydrochloride Lei Dingpian and the Ivabrax hydrochloride tablet sold in the market
FIG. 12: influence of selection of auxiliary materials on dissolution rate of ivabradine hydrochloride tablets
Detailed Description
In order to make the purpose and technical solution of the present invention more clear, the present invention is further described with reference to the following examples, but the scope of the present invention is not limited to these examples, and the examples are only used for explaining the present invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true scope of the invention.
Example 1: ivabradine hydrochloride clathrate compound
Amorphous ivabradine hydrochloride 5.5g
Hydroxypropyl-beta-cyclodextrin 3.85g
Potassium chloride 1.1g
The preparation method comprises the following steps:
preparing cyclodextrin into a saturated solution at the temperature of 10 ℃, adding ivabradine hydrochloride dissolved by ethanol, adding the solution into the cyclodextrin saturated solution, stirring for 1h at the temperature of 10 ℃, adding chloride, stirring for 1h at the temperature of 20 ℃, cooling, concentrating, washing and drying to obtain 10.03g of the ivabradine hydrochloride inclusion compound, wherein the drug-loading rate is 49.85 percent and the encapsulation rate is 90.90 percent.
Example 2: ivabradine hydrochloride clathrate compound
Amorphous ivabradine hydrochloride 8.3g
Methyl-beta-cyclodextrin 6.64g
Potassium chloride 1.66g
The preparation method comprises the following steps:
preparing cyclodextrin into a saturated solution at the temperature of 10 ℃, adding ivabradine hydrochloride dissolved by ethanol, adding the solution into the cyclodextrin saturated solution, stirring for 1h at the temperature of 10 ℃, adding chloride, stirring for 1h at the temperature of 15 ℃, cooling, concentrating, washing and drying to obtain 15.77g of the ivabradine hydrochloride inclusion compound, wherein the drug loading rate is 47.55 percent and the encapsulation rate is 90.36 percent.
Example 3: ivabradine hydrochloride inclusion compound
Amorphous ivabradine hydrochloride 5.6g
3.85g of alpha-cyclodextrin.
Potassium chloride 1.1g
The preparation method comprises the following steps:
preparing cyclodextrin into a saturated solution at the temperature of 5 ℃, adding ivabradine hydrochloride dissolved by ethanol, adding the solution into the cyclodextrin saturated solution, stirring for 1h at the temperature of 5 ℃, adding chloride, stirring for 1h at the temperature of 25 ℃, cooling, concentrating, washing and drying to obtain 10.22g of ivabradine hydrochloride inclusion compound, wherein the drug loading is 48.92 percent and the encapsulation rate is 89.28 percent.
Example 4: ivabradine hydrochloride tablets (1000 tablets)
The preparation method comprises the following steps:
the ivabradine hydrochloride clathrate compound prepared in the example 1, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and aerosil are respectively crushed, sieved, uniformly mixed and tabletted according to the formula.
Example 5: ivabradine hydrochloride capsule (1000 granules)
The preparation method comprises the following steps:
taking a proper amount of water as a wetting agent, respectively crushing and sieving the ivabradine hydrochloride clathrate compound, mannitol, calcium bicarbonate, crospovidone, magnesium stearate and starch in the formula amount of the example 1, pouring the crushed materials into a wet mixing granulator, stirring the mixture to obtain wet granules, and filling the wet granules into capsules to obtain the ivabradine hydrochloride capsule.
Example 6: the influence of the cyclodextrin species on the encapsulation efficiency and the drug loading capacity of the inclusion compound is researched
A: alpha-cyclodextrin
B: beta-cyclodextrin
C: gamma-cyclodextrin
D: hydroxypropyl-beta-cyclodextrin
E; methyl-beta-cyclodextrin
The formula dosage and the preparation process are the same as those of example 1, three parallel experiments are carried out, the ivabradine hydrochloride clathrate compound is prepared, and the encapsulation rate and the drug-loading rate are measured.
As shown in fig. 1, the ivabradine hydrochloride can be synthesized into an inclusion compound by selecting alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin and methyl-beta-cyclodextrin as inclusion materials, and further, the ivabradine hydrochloride is better loaded by taking the alpha-cyclodextrin, the hydroxypropyl-beta-cyclodextrin and the methyl-beta-cyclodextrin as inclusion materials, the drug loading rate is 49.85%, and the encapsulation rate is 90.90%.
Example 6: identification of inclusion compound by thermal analysis method
By differential scanning calorimetry at a temperature of 150-255 deg.C at 10 K.min -1 The temperature change rate of (a) was subjected to thermal analysis of the inclusion compound. The situation that the alpha-crystal form ivabradine hydrochloride, the beta d-crystal form ivabradine hydrochloride, the y-crystal form ivabradine hydrochloride, the epsilon crystal form ivabradine hydrochloride, the s crystal form ivabradine hydrochloride, the amorphous form ivabradine hydrochloride and cyclodextrin form an inclusion compound is explored. Since ivabradine hydrochloride generates an absorption peak at 185-210 ℃, and the degree of crystallization of the drug is greatly reduced or disappeared after the drug is included with cyclodextrin, the absorption peak cannot be detected on a thermogram, as shown in fig. 2, no absorption peak appears on a DSC curve of the inclusion compound of examples 1-3, thus proving that the inclusion compound is formed. (the heat absorption peak curves of examples 1 to 3 in FIG. 1 slightly overlap, but do not affect the explanation of the technical effect of the present invention). In addition, DSC tests are also carried out by the inventors of the inclusion compounds of other crystal forms, and no absorption peak appears.
Example 7: the influence of the ratio of cyclodextrin to ivabradine hydrochloride on the encapsulation rate and the drug loading rate of the inclusion compound is researched
A: ivabradine hydrochloride: hydroxypropyl- β -cyclodextrin =1
B: ivabradine hydrochloride: hydroxypropyl- β -cyclodextrin =1
C: ivabradine hydrochloride: hydroxypropyl- β -cyclodextrin =1
D: ivabradine hydrochloride: hydroxypropyl-beta-cyclodextrin =1:1
E; ivabradine hydrochloride: hydroxypropyl- β -cyclodextrin =1:0.2
F: ivabradine hydrochloride: hydroxypropyl- β -cyclodextrin =1:1.5
G: ivabradine hydrochloride: hydroxypropyl- β -cyclodextrin =1:2
The formula dosage and the preparation process are the same as those of example 1, three parallel experiments are carried out, the ivabradine hydrochloride clathrate compound is prepared, and the encapsulation rate and the drug-loading rate are measured.
As can be seen from fig. 3 and 4, ivabradine hydrochloride: the weight ratio of hydroxypropyl-beta-cyclodextrin =1 is 0.5-1, and the ivabradine hydrochloride inclusion compound has high drug loading, high entrapment rate and good repeatability.
Example 8: the influence of the ratio of cyclodextrin to chloride on the inclusion compound encapsulation rate and the drug loading rate is explored
A: ivabradine hydrochloride: potassium chloride =1
B: ivabradine hydrochloride: potassium chloride =1
C: ivabradine hydrochloride: potassium chloride: sodium chloride =1
D: ivabradine hydrochloride: sodium chloride =1:0.1
E; ivabradine hydrochloride: sodium chloride =1:0.2
F: ivabradine hydrochloride: chloride =1:0
The formula dosage and the preparation process are the same as those of example 1, three parallel experiments are carried out, the ivabradine hydrochloride clathrate compound is prepared, and the encapsulation rate and the drug-loading rate are measured.
From fig. 5-6, it can be seen that the addition of chloride has less influence on the encapsulation efficiency and drug loading of the ivabradine hydrochloride clathrate, but in the case of ivabradine hydrochloride: the weight ratio of chloride =1 to 0.1-0.2, the drug loading and encapsulation rate of the ivabradine hydrochloride clathrate compound is slightly higher.
Example 9: the preparation stability of the Ivabrane hydrochloride Lei Dingpian and the commercial Ivabrane hydrochloride tablet is researched
And (3) accelerated test: the test sample is placed for 6 months under the conditions of commercial package temperature of 40 +/-2 ℃ and relative humidity of 75% +/-5%, and is respectively sampled at the end of 1 month, 2 months, 3 months and 6 months during the test period to measure the content of related substances.
And (3) long-term test: according to the commercial package, the sample is placed under the conditions that the temperature is 25 +/-2 ℃ and the relative humidity is 60% +/-10%, and the samples are respectively taken at 0 month, 3 months, 6 months, 9 months, 12 months, 24 months and 36 months during the test period, and the content of the related substances is detected.
Fig. 7 and 8 show the results of the long-term stability test and the accelerated stability test of the ivabradine hydrochloride Lei Dingpian of example 4 and the commercially available ivabradine hydrochloride tablets, respectively, which show that the stability of the ivabradine hydrochloride tablet of the present invention is higher than that of the commercially available ivabradine hydrochloride tablet.
Example 10: the effect of the ratio of cyclodextrin to chloride on the stability of the formulations was investigated
A: ivabradine hydrochloride: potassium chloride =1
B: ivabradine hydrochloride: potassium chloride =1
C: ivabradine hydrochloride: potassium chloride: sodium chloride =1
D: ivabradine hydrochloride: sodium chloride =1:0.1
E; ivabradine hydrochloride: chloride =1:0
F: ivabradine hydrochloride: chloride =1:0.05
G: ivabradine hydrochloride: sodium chloride =1:0.5
The formula dosage and the preparation process are the same as those in the examples 1 and 4, the ivabradine hydrochloride tablets are prepared, the contents of relevant substances in long-term tests and accelerated tests are measured, and the influence of chloride in the inclusion compound on the stability of the preparation is researched.
Figure 9-10 results of long term, accelerated tests of stability of the formulations show that the stability of the formulations in ivabradine hydrochloride: chloride =1: the preparation prepared by the ivabradine hydrochloride inclusion compound prepared within the weight ratio range of 0.2 can obviously improve the stability of the preparation and reduce the content of related substances.
Example 11: dissolution rate of the Ivabrax hydrochloride Lei Dingpian and the Ivabrax hydrochloride tablet sold in the market
Figure 11 shows that after the ivabradine hydrochloride and the cyclodextrin form the inclusion compound, the medicine release speed of the ivabradine hydrochloride can be adjusted, the medicine release process is smooth, and meanwhile, the dissolution of the ivabradine hydrochloride is improved, so that the bioavailability is improved, and the dissolution rate reaches 98.7% in 30 min.
Example 12: influence of selection of auxiliary materials on dissolution rate of ivabradine hydrochloride tablets
The ivabradine hydrochloride clathrate compound prepared in the example 1, the filler, the disintegrant and the glidant are respectively crushed, sieved, uniformly mixed and tabletted into 1000 tablets according to the formula. The dissolution of group A, B, C ivabradine hydrochloride tablets was tested.
Based on the consideration that the auxiliary materials in the prior art mostly contain a large amount of lactose, and some patients suffering from galactose intolerance, primary intestinal lactase deficiency or glucose-lactose malabsorption cannot use the auxiliary materials, so that the audience population is reduced, the invention specially replaces the filler, and unexpectedly discovers that the dissolution of the ivabradine hydrochloride can be improved to a certain extent by adding mannitol and microcrystalline cellulose 1:1, and the specific figure is 12.
Claims (10)
1. The ivabradine hydrochloride preparation is characterized by comprising the ivabradine hydrochloride, cyclodextrin, chloride and pharmaceutically acceptable auxiliary materials.
2. The ivabradine hydrochloride formulation according to claim 1, wherein the ivabradine hydrochloride is in the α -crystalline form, the β d-crystalline form, the y-crystalline form, the e-crystalline form, the s-crystalline form, the amorphous ivabradine hydrochloride.
3. Ivabradine hydrochloride formulation according to claim 1, wherein the cyclodextrin is one of a-cyclodextrin, β -cyclodextrin, γ -cyclodextrin, hydroxypropyl- β -cyclodextrin, methyl- β -cyclodextrin.
4. Ivabradine hydrochloride formulation according to claim 3, wherein the cyclodextrin is one of a-cyclodextrin, hydroxypropyl- β -cyclodextrin, methyl- β -cyclodextrin.
5. Ivabradine hydrochloride formulation according to claim 1, wherein the chloride is sodium chloride or/and potassium chloride.
6. Ivabradine hydrochloride formulation according to claim 1, wherein the ratio by weight of ivabradine hydrochloride to cyclodextrin is between 1 and 0.5 and 1.
7. Ivabradine hydrochloride formulation according to claim 1, wherein the ratio in parts by weight of ivabradine hydrochloride to chloride is from 1.
8. Ivabradine hydrochloride formulation according to claim 1, wherein the pharmaceutically acceptable auxiliary material is selected from the group consisting of fillers, diluents, disintegrants, lubricants, binders, wetting agents, flavoring agents, stabilizers, pH regulators.
9. Ivabradine hydrochloride formulation according to claim 8, wherein the filler is selected from one or more of dextrin, microcrystalline cellulose, pregelatinized starch, sucrose, mannitol, calcium bicarbonate, calcium sulfate, calcium carbonate.
10. A process for the preparation of ivabradine hydrochloride formulation according to claim 1, characterized in that it comprises the following steps:
(1) Preparing an ivabradine hydrochloride clathrate compound: preparing cyclodextrin into saturated solution at 5-10 deg.C, adding ivabradine hydrochloride dissolved in ethanol, mixing, stirring at 5-10 deg.C for 0.5-1.5 hr, adding chloride, stirring at 15-25 deg.C for 0.5-1.5 hr, cooling, concentrating, washing, and drying to obtain the final product;
(2) Preparation of ivabradine hydrochloride preparation: adding pharmaceutically acceptable adjuvants, and making into desired dosage form.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015001133A1 (en) * | 2013-12-12 | 2015-01-08 | Synthon B.V. | Pharmaceutical composition comprising amorphous ivabradine |
| WO2021203377A1 (en) * | 2020-04-09 | 2021-10-14 | 比卡生物科技（广州）有限公司 | Bendamustine composition and use thereof |
| CN114159398A (en) * | 2021-03-22 | 2022-03-11 | 南京艾德加生物制药科技有限公司 | Procaterol hydrochloride oral solid composition and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015001133A1 (en) * | 2013-12-12 | 2015-01-08 | Synthon B.V. | Pharmaceutical composition comprising amorphous ivabradine |
| WO2021203377A1 (en) * | 2020-04-09 | 2021-10-14 | 比卡生物科技（广州）有限公司 | Bendamustine composition and use thereof |
| CN114159398A (en) * | 2021-03-22 | 2022-03-11 | 南京艾德加生物制药科技有限公司 | Procaterol hydrochloride oral solid composition and preparation method thereof |
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