CN102793929A - Method for preparing stable amorphous drug preparation - Google Patents
Method for preparing stable amorphous drug preparation Download PDFInfo
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- CN102793929A CN102793929A CN2012103279703A CN201210327970A CN102793929A CN 102793929 A CN102793929 A CN 102793929A CN 2012103279703 A CN2012103279703 A CN 2012103279703A CN 201210327970 A CN201210327970 A CN 201210327970A CN 102793929 A CN102793929 A CN 102793929A
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- amorphous state
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- adjuvant
- carbamide
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- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- 238000000034 method Methods 0.000 title claims abstract description 27
- 239000003814 drug Substances 0.000 title claims abstract description 25
- 229940079593 drug Drugs 0.000 title abstract description 15
- 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 36
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 22
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 4
- 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 claims abstract description 3
- 239000000600 sorbitol Substances 0.000 claims abstract description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 46
- 239000002671 adjuvant Substances 0.000 claims description 27
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 23
- 239000004202 carbamide Substances 0.000 claims description 23
- 235000013877 carbamide Nutrition 0.000 claims description 23
- 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 23
- 229960004891 lapatinib Drugs 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
- 239000007962 solid dispersion Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- -1 hydroxypropyl Chemical group 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 3
- LTUDISCZKZHRMJ-UHFFFAOYSA-N potassium;hydrate Chemical compound O.[K] LTUDISCZKZHRMJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000002390 rotary evaporation Methods 0.000 claims description 3
- 238000001694 spray drying Methods 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 238000009474 hot melt extrusion Methods 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims 1
- 238000000227 grinding Methods 0.000 claims 1
- 239000001384 succinic acid Substances 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 7
- 230000003993 interaction Effects 0.000 abstract description 6
- 238000012216 screening Methods 0.000 abstract description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 abstract description 2
- 229920002521 macromolecule Polymers 0.000 abstract description 2
- 238000005457 optimization Methods 0.000 abstract 2
- 230000000087 stabilizing effect Effects 0.000 abstract 2
- 238000005516 engineering process Methods 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000004017 vitrification Methods 0.000 description 3
- 241001289753 Graphium sarpedon Species 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000003287 optical effect Effects 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
- 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
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 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
- 238000001727 in vivo Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 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
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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 field of medicine preparing technology, be specifically related to a kind of method for preparing of amorphous state pharmaceutical preparation.
Background technology
In recent years, along with the appearance of many more insoluble drugs, amorphous state pharmaceutical preparation obtains increasing concern.Amorphous state pharmaceutical preparation can improve the dissolubility of insoluble drug, thereby increases the absorption and the bioavailability of medicine.Amorphous state pharmaceutical preparation applied range is applicable to the exploitation of early stage new drug and the improvement of later stage preparation.
The pharmaceutical preparation of preparation amorphous state, usual method is to be dissolved in medicine and adjuvant in the solvent earlier, uses spray drying then, again through lyophilization or rotary evaporation, removes and desolvates.Also having a kind of method relatively more commonly used is to melt extrusion molding, at high temperature melts medicine and adjuvant earlier, then cooling fast.If but preparation technology is improper or preparation prescription is bad, medicine can crystallize out in the preparation process, thereby can not get amorphous state pharmaceutical preparation.
Though amorphous state pharmaceutical preparation has a lot of advantages, amorphous state pharmaceutical preparation is very unstable, and it is in metastable condition, can spontaneous crystallizing out in storage process.Therefore prepare a stable amorphous state pharmaceutical preparation is the difficult problem of pharmacy circle always.Solution commonly used at present is to add a large amount of high polymer adjuvants to stablize amorphous state pharmaceutical preparation.Selected macromolecule material should have higher vitrification point, can and drug molecule certain interaction (through hydrogen bond, ionic bond or other modes) and compatibility are preferably arranged.But handle like this, the stability of amorphous state pharmaceutical preparation is still not ideal enough, and technology is more complicated also.
Summary of the invention
The objective of the invention is to propose the simple preparation of a kind of technology and stablize the method for amorphous state pharmaceutical preparation.
The present invention finds after deliberation, no matter in preparation or storage process, in the prescription of amorphous state pharmaceutical preparation, adds a spot of micromolecule adjuvant (like citric acid, succinic acid, sorbitol etc.), can effectively stablize amorphous state pharmaceutical preparation.Compare with high polymer adjuvant, micromolecule adjuvant and drug molecule can have better interaction and compatibility.Therefore, the micromolecule adjuvant can better be stablized amorphous state pharmaceutical preparation.But the vitrification point of micromolecule adjuvant is lower, add a large amount of micromolecule adjuvants the vitrification point of amorphous state pharmaceutical preparation is reduced, thereby production is made troubles to preparation.So prescription need be optimized.Optimizing process comprises: according to the suitable micromolecule adjuvant of different drug screening; Confirm to filter out the optimum amount of micromolecule adjuvant.
Selected micromolecule adjuvant should have good interaction with medicine.Interaction comprises hydrogen bond, ionic bond, nonpolar bond etc.The interaction power can be calculated or pass through experiment and obtain through molecular structural formula.Experimental technique relatively more commonly used is that fusing point reduces method.The used in amounts of micromolecule adjuvant will obtain through testing.More direct method is to investigate through phasor.
The method of amorphous state pharmaceutical preparation is stablized in the preparation that the present invention proposes, and specifically can have following 2 kinds:
Method for preparing I, concrete steps are:
1. with medicine, micromolecule adjuvant and high polymer adjuvant are dissolved in the suitable solvent;
2. use spray drying, the method for lyophilization or rotary evaporation is removed and is desolvated;
3. resulting solid is kept at and carries out drying in the vacuum desiccator;
4. the solid abrasive with gained becomes fine powder, crosses 35 purpose sieves then.
Method for preparing II, concrete steps are:
1. hybrid medicine, micromolecule adjuvant and high polymer adjuvant;
2. add hot melt extrusion granulator machine to said mixture, make granule;
3. the solid particle that grinds gained becomes fine powder, crosses 35 purpose sieves then;
4. resulting powder is kept at and carries out drying in the vacuum desiccator.
Adding the micromolecule adjuvant can be than the preparation amorphous state preparation that is easier to success.And can make the amorphous state preparation in storage and transportation, keep stable.
Description of drawings
Fig. 1 is the screening phasor of carbamide amorphous state preparation.On behalf of the gained solid, blue triangle contain crystal formation, and it is the amorphous state preparation that red square is represented the gained solid.
Fig. 2 is the phasor of condition after following 3 months that carbamide amorphous state preparation is stored in 40 ℃ of temperature and 75% humidity.On behalf of the gained solid, blue triangle contain crystal formation, and it is the amorphous state preparation that red square is represented the gained solid.
Fig. 3 is the Lapatinib amorphous state formulation X optical diffraction figure that makes.
Fig. 4 is Lapatinib amorphous state preparation and the dissolution of Lapatinib crude drug in water.
The X-ray diffraction pattern (with the comparison of beginning) that Fig. 5 is a Lapatinib amorphous state preparation after storing for 2 weeks under the condition of 40 ℃ and 75% humidity.
The specific embodiment
Through specific embodiment, further introduce the inventive method below.
Embodiment 1:Carbamide (urea) amorphous state preparation
The molecule of carbamide is very little, is easy to crystallization.Also do not report amorphous state carbamide at present.Use the technology of this patent, the amorphous state preparation of carbamide is by the preparation of success, and good stability is arranged.
Prescription screening:
1. carbamide, citric acid (citric acid) and hydroxypropyl emthylcellulose (HPMC) are dissolved in the methanol, wherein, the addition of citric acid is 10 %～30 % of gross weight, and the addition of hydroxypropyl emthylcellulose is 60 %～80 % of gross weight;
2. solvent methanol volatilizees at normal temperatures, obtains carbamide amorphous state preparation;
3. carbamide amorphous state preparation is kept in the vacuum desiccator; Temperature is 24 ℃ ~ 28 ℃, preferred 25 ℃;
Detect whether obtain pure amorphous state preparation with microscope and powder x-ray diffraction.Fig. 1 is the screening phasor of carbamide amorphous state preparation.
Can see from Fig. 1, not add micromolecule adjuvant citric acid, only be lower than under the situation of gross weight 10%, just can obtain the amorphous state preparation at urea content.Added citric acid, urea content still can form the amorphous state preparation up to gross weight 60%.The carbamide amorphous state preparation that obtains is stored in the condition of 40 ℃ of temperature and 75% humidity and studies stability of formulation over following 3 months.Fig. 2 is the phasor of carbamide amorphous state preparation after storing 3 months under the condition of 40 ℃ of temperature and 75% humidity.As can beappreciated from fig. 2, when the citric acid that adds gross weight 10% or 20%, the amorphous state preparation that contains gross weight 20% carbamide is very stable.The carbamide amorphous state preparation that does not have citric acid, after storing certain hour, carbamide can crystallize out.This shows that micromolecule adjuvant citric acid can help the preparation of carbamide amorphous state preparation and improve carbamide amorphous state stability of formulation.
Embodiment 2: Lapatinib amorphous state preparation
Lapatinib (lapatinib) is a kind of oral micromolecule epidermal growth factor (EGFR:ErbB-1, ErbB-2) tyrosine kinase inhibitor, late period that is used to treat or metastatic breast cancer.Lapatinib belongs to insoluble drug, and dissolubility is < 0.030 mg/>mL in 25 ° of C water.Therefore, the bioavailability of Lapatinib lower (< 25%).Be prepared into the dissolubility that the amorphous state preparation can improve Lapatinib, thereby improve its bioavailability.
Lapatinib amorphous state preparation prescription such as table 1:
Table 1 Lapatinib amorphous state preparation prescription
| ? | 20120629-2 | 20120629-4 | 20120629-6 |
| Two p-methyl benzenesulfonic acid Lapatinibs | 100mg | 100mg | 500mg |
| PVPK30 | 700mg | 600mg | 3000mg |
| Monohydrate potassium | --- | 100mg | 500mg |
Method for preparing is following:
1. Lapatinib (lapatinib), PVPK30 and monohydrate potassium are dissolved in the methanol and water mixed solvent of 54 ℃ ~ 58 ℃ (preferred 55 ℃).The weight ratio of first alcohol and water is 40:1 v/v in the mixed solvent;
2. remove with Rotary Evaporators and desolvate;
3. the solid dispersion that obtains is kept in the vacuum desiccator dry 22 ~ 26 hours, preferred dry 24 hours;
4. the abrasive solid dispersion is crossed 35 mesh sieves, obtains the solid dispersion powder.
The Lapatinib amorphous state formulation X optical diffraction figure that makes is as shown in Figure 3.As can beappreciated from fig. 3 20120629-2 also has the crystal of a spot of Lapatinib.20120629-4 is an amorphous state completely.Therefore in prescription, add a spot of micromolecule adjuvant, citric acid can help to prepare noncrystal preparation.
20120629-6 is the prescription that 20120629-4 amplifies.Fig. 4 is 20120629-6 and the dissolution of Lapatinib crude drug in water.As can beappreciated from fig. 4 the dissolution of 20120629-6 in water is 5 times of Lapatinib crude drug dissolution up to 150ug/ml.So Lapatinib amorphous state preparation probably improves Lapatinib bioavailability in vivo.
Lapatinib amorphous state preparation, 20120629-6 are placed on to store under the condition of 40 ℃ and 75% humidity investigated its stability tests in 2 weeks.Fig. 5 shows that Lapatinib amorphous state preparation is stable with this understanding.
Claims (5)
1. one kind prepares the method for stablizing amorphous state pharmaceutical preparation, it is characterized in that in the prescription of amorphous state pharmaceutical preparation, adding an amount of micromolecule adjuvant.
2. method according to claim 1 is characterized in that said micromolecule adjuvant is citric acid, succinic acid or sorbitol.
3. method according to claim 1 and 2 is characterized in that concrete steps are:
(1) with medicine, micromolecule adjuvant and high polymer adjuvant are dissolved in the suitable solvent;
(2) use spray drying, the method for lyophilization or rotary evaporation is removed and is desolvated;
(3) resulting solid is kept at and carries out drying in the vacuum desiccator;
(4) solid abrasive with gained becomes fine powder, crosses 35 purpose sieves then;
Perhaps
(1) hybrid medicine, micromolecule adjuvant and high polymer adjuvant;
(2) add hot melt extrusion granulator machine to said mixture, make granule;
(3) solid particle of grinding gained becomes fine powder, crosses 35 purpose sieves then;
(4) resulting powder is kept at and carries out drying in the vacuum desiccator.
4. method according to claim 1 is characterized in that concrete steps are:
(1) carbamide, citric acid and hydroxypropyl emthylcellulose are dissolved in the methanol, wherein, the addition of citric acid is 10%～30 % of gross weight, and the addition of hydroxypropyl emthylcellulose is 60 %～80 % of gross weight;
(2) solvent methanol volatilizees at normal temperatures, obtains carbamide amorphous state preparation;
(3) carbamide amorphous state preparation is kept in the vacuum desiccator; Temperature is 24 ℃ ~ 28 ℃.
5. method according to claim 1 is characterized in that concrete steps are:
(1) Lapatinib, PVPK30 and monohydrate potassium are dissolved in 54 ℃ ~ 58 ℃ the methanol and water mixed solvent, and the weight ratio of first alcohol and water is 40:1 v/v in the mixed solvent;
(2) remove with Rotary Evaporators and desolvate;
(3) solid dispersion that obtains is kept in the vacuum desiccator dry 22--26 hour;
(4) abrasive solid dispersion is crossed 35 mesh sieves, obtains the solid dispersion powder.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10774067B2 (en) | 2014-08-08 | 2020-09-15 | Chugai Seiyaku Kabushiki Kaisha | Amorphous form of tetracyclic compound |
| WO2024186765A1 (en) * | 2023-03-03 | 2024-09-12 | Aems Corp. | Amorphous solid composition, methods and uses thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1591121A1 (en) * | 2000-12-14 | 2005-11-02 | Ortho-Mcneil Pharmaceutical, Inc. | Steroid hormone products comprising a stabilizing agent in non-crystalline form |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1591121A1 (en) * | 2000-12-14 | 2005-11-02 | Ortho-Mcneil Pharmaceutical, Inc. | Steroid hormone products comprising a stabilizing agent in non-crystalline form |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10774067B2 (en) | 2014-08-08 | 2020-09-15 | Chugai Seiyaku Kabushiki Kaisha | Amorphous form of tetracyclic compound |
| TWI718102B (en) * | 2014-08-08 | 2021-02-11 | 日商中外製藥股份有限公司 | Amorphous body of tetracyclic compound |
| WO2024186765A1 (en) * | 2023-03-03 | 2024-09-12 | Aems Corp. | Amorphous solid composition, methods and uses thereof |
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