CN102793929B - Method for preparing stable amorphous drug preparation - Google Patents
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- CN102793929B CN102793929B CN2012103279703A CN201210327970A CN102793929B CN 102793929 B CN102793929 B CN 102793929B CN 2012103279703 A CN2012103279703 A CN 2012103279703A CN 201210327970 A CN201210327970 A CN 201210327970A CN 102793929 B CN102793929 B CN 102793929B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 title abstract description 24
- 229940079593 drug Drugs 0.000 title abstract description 19
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000000463 material Substances 0.000 claims abstract description 24
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 12
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 26
- 229960004891 lapatinib Drugs 0.000 claims description 26
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 22
- 239000004202 carbamide Substances 0.000 claims description 22
- 229960004106 citric acid Drugs 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 6
- 239000007962 solid dispersion Substances 0.000 claims description 6
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 claims description 5
- 229960002303 citric acid monohydrate Drugs 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000000227 grinding Methods 0.000 claims description 2
- 238000007873 sieving Methods 0.000 claims description 2
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- 230000008569 process Effects 0.000 abstract description 6
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- 238000005457 optimization Methods 0.000 abstract description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 abstract description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 abstract description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 abstract description 2
- 239000000600 sorbitol Substances 0.000 abstract description 2
- 230000000087 stabilizing effect Effects 0.000 abstract 2
- 229920002521 macromolecule Polymers 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 24
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- 230000009477 glass transition Effects 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- FZIPCQLKPTZZIM-UHFFFAOYSA-N 2-oxidanylpropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O FZIPCQLKPTZZIM-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 101150039808 Egfr gene Proteins 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
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- 238000009474 hot melt extrusion Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
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- 238000007689 inspection Methods 0.000 description 1
- 229960001320 lapatinib ditosylate Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- AZBFJBJXUQUQLF-UHFFFAOYSA-N n-(1,5-dimethylpyrrolidin-3-yl)pyrrolidine-1-carboxamide Chemical compound C1N(C)C(C)CC1NC(=O)N1CCCC1 AZBFJBJXUQUQLF-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the technical field of drug preparation, in particular to a method for preparing a stable amorphous drug preparation. According to the method, a small quantity of micromolecule auxiliary materials are added to an amorphous pharmaceutical preparation, such as citric acid, succinic acid, sorbitol and the like, which can be used for effectively stabilizing the amorphous pharmaceutical preparation. Compared with macromolecule auxiliary materials, the micromolecule auxiliary materials can have better interaction and compatibility with drug molecules, so that the micromolecule auxiliary materials can be used for better stabilizing the amorphous drug preparation. The invention also provides an optimization method of an amorphous drug preparation prescription, and the optimization process comprises the following steps of: screening proper micromolecule auxiliary materials according to different drugs, and determining an optimal dosage of the screened micromolecule auxiliary materials.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of an amorphous medicine preparation.
Background
In recent years, amorphous drug formulations have received increased attention with the advent of more poorly soluble drugs. The amorphous drug formulation can improve the solubility of poorly soluble drugs, thereby increasing the absorption and bioavailability of the drugs. The amorphous drug preparation has wide application range, and is suitable for the development of early new drugs and the improvement of later preparations.
Amorphous pharmaceutical formulations are generally prepared by dissolving the drug and excipients in a solvent, followed by spray drying and then removing the solvent by lyophilization or rotary evaporation. Another more common method is melt extrusion, where the drug and excipients are melted at high temperature and then rapidly cooled. However, if the preparation process is not appropriate or the formulation is not well prescribed, the drug will crystallize out during the preparation process, and thus an amorphous drug formulation cannot be obtained.
Although amorphous drug formulations have many advantages, amorphous drug formulations are unstable and are metastable and spontaneously crystallize out during storage. Therefore, the preparation of a stable amorphous pharmaceutical preparation has been a problem in the pharmaceutical industry. The current solution is to add a large amount of polymeric excipients to stabilize the amorphous pharmaceutical formulation. The selected polymer material has high glass transition temperature, certain interaction (through hydrogen bond, ionic bond or other modes) with drug molecules and good miscibility. However, the stability of the amorphous drug formulation is still not ideal and the process is relatively complicated.
Disclosure of Invention
The invention aims to provide a method for preparing a stable amorphous pharmaceutical preparation with simple process.
The research of the invention finds that a small amount of micromolecular auxiliary materials (such as citric acid, succinic acid, sorbitol and the like) are added into the formula of the amorphous pharmaceutical preparation during the preparation or storage process, so that the amorphous pharmaceutical preparation can be effectively stabilized. Compared with the macromolecular auxiliary material, the micromolecular auxiliary material and the drug molecules can have better interaction and miscibility. Therefore, the small molecular auxiliary materials can better stabilize the amorphous pharmaceutical preparation. However, the glass transition temperature of the small molecular auxiliary materials is low, and the glass transition temperature of the amorphous pharmaceutical preparation can be reduced by adding a large amount of small molecular auxiliary materials, so that inconvenience is brought to the production of the preparation. Therefore, the prescription needs to be optimized. The optimization process comprises the following steps: screening proper small molecular auxiliary materials according to different medicines; determining the optimal dosage of the screened small molecular auxiliary materials.
The selected small molecular auxiliary materials have good interaction with the medicine. Interactions include hydrogen bonding, ionic bonding, non-polar bonding, and the like. The strength of the interaction can be calculated by a molecular structural formula or obtained by experiments. The more commonly used experimental method is the melting point depression method. The amount of the small molecular auxiliary materials is obtained through experiments. A more straightforward approach is by phase diagram inspection.
The method for preparing the stable amorphous pharmaceutical preparation provided by the invention specifically comprises the following 2 steps:
the preparation method I comprises the following specific steps:
1. dissolving the medicine, the small molecular auxiliary materials and the high molecular auxiliary materials in a proper solvent;
2. removing the solvent by spray drying, freeze drying or rotary evaporation;
3. the obtained solid is stored in a vacuum drier for drying;
4. the resulting solid was ground to a fine powder and then sieved through a 35 mesh sieve.
The preparation method II comprises the following specific steps:
1. mixing the medicine, the small molecular auxiliary material and the high molecular auxiliary material;
2. adding the mixture into a hot-melt extrusion granulator to prepare granules;
3. grinding the obtained solid particles into fine powder, and then sieving the fine powder through a 35-mesh sieve;
4. the resulting powder was stored in a vacuum desiccator for drying.
The amorphous preparation can be easily and successfully prepared by adding the micromolecular auxiliary materials. And can stabilize amorphous formulations during storage and transport.
Drawings
FIG. 1 is a phase diagram of a screening of amorphous urea formulations. The blue triangles represent the resulting solid containing the crystalline form and the red squares represent the resulting solid as an amorphous formulation.
FIG. 2 is a phase diagram of an amorphous urea formulation stored at 40 ℃ and 75% humidity for 3 months. The blue triangles represent the resulting solid containing the crystalline form and the red squares represent the resulting solid as an amorphous formulation.
Fig. 3 is an X-ray diffraction pattern of the prepared lapatinib amorphous formulation.
Figure 4 is the dissolution rate in water of a lapatinib amorphous formulation and a lapatinib drug substance.
Figure 5 is an X-ray diffraction pattern (compared to the start) of an amorphous formulation of lapatinib after storage for 2 weeks at 40 ℃ and 75% humidity.
Detailed Description
The process of the invention is further illustrated by the following specific examples.
Example 1:urea amorphous formulation
Urea has small molecules and is easily crystallized. No amorphous urea has been reported so far. By applying the technology of the patent, the amorphous preparation of urea is successfully prepared and has good stability.
Prescription screening:
1. dissolving urea, citric acid (citric acid) and hydroxypropyl methyl cellulose (HPMC) in methanol, wherein the addition amount of the citric acid is 10-30% of the total weight, and the addition amount of the hydroxypropyl methyl cellulose is 60-80% of the total weight;
2. volatilizing the solvent methanol at normal temperature to obtain an amorphous urea preparation;
3. storing the amorphous urea preparation in a vacuum drier; the temperature is 24-28 ℃, and the preferred temperature is 25 ℃;
microscopy and powder X-ray diffraction were used to determine whether a pure amorphous formulation was obtained. FIG. 1 is a phase diagram of a screening of amorphous urea formulations.
As can be seen from fig. 1, the amorphous form of the formulation can be obtained only with a urea content of less than 10% by weight, without the addition of the small molecule excipient citric acid. With the addition of citric acid, the urea content is up to 60% by weight, and an amorphous preparation can be formed. The resulting amorphous urea formulations were stored at 40 ℃ temperature and 75% humidity for 3 months to study the stability of the formulations. Fig. 2 is a phase diagram of an amorphous urea formulation after storage for 3 months at a temperature of 40 ℃ and a humidity of 75%. As can be seen from fig. 2, the amorphous formulation containing 20% by weight of urea is very stable when 10% or 20% by weight of citric acid is added. Amorphous urea formulations without citric acid, urea crystallizes out after storage for a certain period of time. Therefore, the small molecular auxiliary material citric acid can help the preparation of the urea amorphous preparation and improve the stability of the urea amorphous preparation.
Example 2: amorphous formulations of lapatinib
Lapatinib (lapatinib) is an orally administered small molecule epidermal growth factor (EGFR: ErbB-1, ErbB-2) tyrosine kinase inhibitor for the treatment of advanced or metastatic breast cancer. Lapatinib is a poorly soluble drug with solubility <0.030 mg/mL in water at 25 ℃. Therefore, the bioavailability of lapatinib is low (< 25%). The preparation of amorphous preparation can improve the solubility of lapatinib, thereby improving the bioavailability thereof.
The lapatinib amorphous formulation is formulated as in table 1:
table 1 lapatinib amorphous formulation recipe
| 20120629-2 | 20120629-4 | 20120629-6 | |
| Lapatinib ditosylate | 100mg | 100mg | 500mg |
| PVPK30 | 700mg | 600mg | 3000mg |
| Citric acid monohydrate | --- | 100mg | 500mg |
The preparation method comprises the following steps:
1. lapatinib (lapatinib), PVPK30 and citric acid monohydrate are dissolved in a methanol and water mixed solvent at 54-58 ℃ (preferably 55 ℃). The weight ratio of methanol to water in the mixed solvent is 40:1 v/v;
2. removing the solvent with a rotary evaporator;
3. the obtained solid dispersion is stored in a vacuum drier and dried for 22-26 hours, preferably for 24 hours;
4. the solid dispersion was ground and sieved with a 35-mesh sieve to obtain a solid dispersion powder.
The X-ray diffraction pattern of the prepared lapatinib amorphous preparation is shown in figure 3. It can be seen from figure 3 that 20120629-2 also has a small amount of crystals of lapatinib. 20120629-4 is completely amorphous. Therefore, a small amount of micromolecular auxiliary material, citric acid, is added into the prescription, and the preparation of the amorphous preparation can be facilitated.
20120629-6 is a 20120629-4 magnification prescription. Figure 4 is the dissolution rate of 20120629-6 and lapatinib drug substance in water. From FIG. 4, it can be seen that 20120629-6 has a dissolution rate of up to 150ug/ml in water, which is 5 times higher than that of lapatinib bulk drug. Therefore, the lapatinib amorphous preparation is likely to improve the bioavailability of lapatinib in vivo.
The amorphous lapatinib formulation, 20120629-6, was stored for 2 weeks at 40 ℃ and 75% humidity for stability testing. Figure 5 shows that the lapatinib amorphous formulation is stable under this condition.
Claims (1)
1. A method for preparing the stable amorphous pharmaceutical preparation is characterized in that a proper amount of micromolecular auxiliary materials are added into the formula of the amorphous pharmaceutical preparation;
the preparation method comprises the following specific steps:
(1) dissolving urea, citric acid and hydroxypropyl methyl cellulose in methanol, wherein the addition amount of the citric acid is 10-30% of the total weight, and the addition amount of the hydroxypropyl methyl cellulose is 60-80% of the total weight;
(2) volatilizing the solvent methanol at normal temperature to obtain an amorphous urea preparation;
(3) storing the amorphous urea preparation in a vacuum drier; the temperature is 24 ℃ to 28 ℃;
or,
(1) dissolving lapatinib, PVPK30 and citric acid monohydrate in a mixed solvent of methanol and water at 54-58 ℃, wherein the weight ratio of the methanol to the water in the mixed solvent is 40:1 v/v;
(2) removing the solvent with a rotary evaporator;
(3) the obtained solid dispersion is stored in a vacuum drier for drying for 22-26 hours;
(4) grinding the solid dispersion, and sieving with a 35-mesh sieve to obtain solid dispersion powder; preparing a lapatinib amorphous preparation;
wherein the lapatinib is 100mg, the PVPK30 is 600mg, and the citric acid monohydrate is 100mg, or the lapatinib is 500mg, the PVPK30 is 3000mg, and the citric acid monohydrate is 500 mg.
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| CN2012103279703A CN102793929B (en) | 2012-09-07 | 2012-09-07 | Method for preparing stable amorphous drug preparation |
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Address after: No. 10, Lane 100, Banxia Road, Pudong New Area, Shanghai 200120 Patentee after: Shanghai Aokeda Pharmaceutical Technology Co.,Ltd. Address before: Room 906, No. 781, Cailun Road, Pudong New Area, Shanghai, March 2012 Patentee before: SHANGHAI AUCTA PHARMACEUTICALS Co.,Ltd. |