CN111514146A - Pharmaceutical composition containing posaconazole - Google Patents
Pharmaceutical composition containing posaconazole Download PDFInfo
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- CN111514146A CN111514146A CN202010348551.2A CN202010348551A CN111514146A CN 111514146 A CN111514146 A CN 111514146A CN 202010348551 A CN202010348551 A CN 202010348551A CN 111514146 A CN111514146 A CN 111514146A
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- posaconazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a pharmaceutical composition of posaconazole, which comprises a posaconazole crystal I and a posaconazole crystal Y, wherein the weight ratio of the posaconazole crystal I to the posaconazole crystal Y is 1:1-1:1.5, the posaconazole crystal I is micronized, the posaconazole crystal Y is unmicronized, the average particle size of the micronized posaconazole crystal I is 6-8 mu m, the median particle size is 2-4 mu m, the average particle size of the non-micronized posaconazole crystal Y is 8.5-12 mu m, and the median particle size is 4.5-8 mu m. The in vitro bacteriostasis test result of the pharmaceutical composition of the posaconazole provided by the invention on mucor circinelloides, polyspora polyculta and fusarium solani is higher than the bacteriostasis effect of the posaconazole which is singly used on the market, and the MIC value is lower.
Description
Technical Field
The invention relates to the field of medicine, in particular to a pharmaceutical composition containing posaconazole as an active pharmaceutical ingredient.
Background
Posaconazole (posaconazole) is a derivative of itraconazole, belongs to a broad-spectrum triazole antifungal drug, and is developed and produced by the company mosasando; the oral suspension is approved by European drug evaluation agency (EMEA) and American Food and Drug Administration (FDA) respectively in 2005 and 2006 for treating fungal infection, is approved by imported registration of China national food and drug administration (HSA) obtained in 2013, and is mainly used for preventing invasive aspergillus and candida infections including patients who have graft-versus-host disease (GVHD) after receiving Hematopoietic Stem Cell Transplantation (HSCT) or hematological malignancy patients who have chemotherapy to cause chronic neutropenia, and treating oropharyngeal candidiasis including itraconazole and/or fluconazole refractory to oropharyngeal candidiasis [1 ]. Subsequently, the FDA successively approved the marketing of posaconazole sustained-release tablets and intravenous solutions.
However, the Minimum Inhibitory Concentrations (MICs) of posaconazole on mucor circinelloides, polyspora prolifera and fusarium solani on the market are all more than 16 mu g/ml.
Disclosure of Invention
Based on this, there is a need for a pharmaceutical composition comprising posaconazole as an active pharmaceutical ingredient with a high bacteriostatic effect.
A pharmaceutical composition of posaconazole, comprising posaconazole crystal I and posaconazole crystal Y, wherein the weight ratio of posaconazole crystal I to posaconazole crystal Y is 1:1-1:1.5, posaconazole crystal I is micronized, posaconazole crystal Y is unmicronized, the average particle size of micronized posaconazole crystal I is 6-8 μm, the median particle size is 2-4 μm, the average particle size of unmicronized posaconazole crystal Y is 8.5-12 μm, and the median particle size is 4.5-8 μm.
Wherein the grinding time of the microcrystallization of the posaconazole crystal I is 15-30 min.
Wherein the pharmaceutical composition of posaconazole is prepared by the following method:
1) preparation of posaconazole crystal I: adding 2g of posaconazole into a mixed solvent of 18mL of ethyl acetate and 5mL of ethanol, heating to 80 ℃, dissolving and clarifying, then cooling to 20 ℃ within 1.5 hours, crystallizing, preserving heat at 20 ℃, and filtering to obtain 1.4g of posaconazole with the yield of 70%, wherein the crystal form is the crystal form I through XRD detection;
2) microcrystallization treatment of posaconazole crystal I: grinding the prepared posaconazole crystal I for 20min to obtain a microcrystallized posaconazole crystal I with the average particle size of 7.3 mu m;
3) preparation of posaconazole crystal Y: and (3) heating 2g of the posaconazole crystal II at 175 ℃ for 10min to completely convert the posaconazole crystal II into a posaconazole crystal Y, and detecting the crystal form to be the crystal form Y by XRD. The average particle size of the posaconazole crystal Y is 9.6 mu m, and the median particle size is 7.9 mu m;
4) mixing the microcrystallized posaconazole crystal I and the posaconazole crystal Y in a weight ratio of 1:1.
Wherein the MIC value of the pharmaceutical composition of posaconazole to mucor circinelloides is 8, the MIC value of Cisidomide is 7.5, and the MIC value of Fusarium solani is 9.5.
Wherein the pharmaceutical composition of posaconazole is prepared by the following method:
1) preparation of posaconazole crystal I: adding 3g of posaconazole into a mixed solvent of 27mL of ethyl acetate and 12mL of methanol, heating to 75 ℃, dissolving and clarifying, then cooling to 25 ℃ within 2 hours, crystallizing, keeping the temperature at 25 ℃ and filtering to obtain 2.4g of posaconazole, wherein the yield is 80%, and the crystal form is the crystal form I through XRD detection;
2) microcrystallization treatment of posaconazole crystal I: grinding the prepared posaconazole crystal I for 31min to obtain a microcrystallized posaconazole crystal I with the average particle size of 6.6 mu m;
3) preparation of posaconazole crystal Y: heating 8g of posaconazole crystal I at 180 ℃ for 15min to completely convert the posaconazole crystal I into a posaconazole crystal Y, detecting the crystal form as a crystal form Y by XRD, wherein the average particle size of the posaconazole crystal Y is 8.7 mu m, and the median particle size is 7.6 mu m;
4) mixing the microcrystallized posaconazole crystal I and the posaconazole crystal Y in a weight ratio of 1: 1.3.
Wherein the MIC value of the pharmaceutical composition of posaconazole to mucor circinelloides is 5.6, the MIC value of Cisidomide is 7.1, and the MIC value of Fusarium solani is 8.4.
The pharmaceutical composition of posaconazole according to claim 1, wherein: the pharmaceutical composition of posaconazole is prepared by the following method:
1) preparation of posaconazole crystal I: adding 8g of posaconazole into a mixed solvent of 72mL of methyl acetate and 30mL of methanol, heating to 80 ℃, dissolving and clarifying, then cooling to 20 ℃ within 1.5 hours, crystallizing, preserving heat at 20 ℃, and filtering to obtain 7.3g of posaconazole with the yield of 91%, wherein the crystal form is the crystal form I through XRD detection;
2) microcrystallization treatment of posaconazole crystal I: grinding the prepared posaconazole crystal I for 40min to obtain a microcrystallized posaconazole crystal I with the average particle size of 6.0 mu m;
3) preparation of posaconazole crystal Y: heating 20g of posaconazole crystal I at 175 ℃ for 19min to completely convert the posaconazole crystal I into a posaconazole crystal Y, detecting the crystal form as a crystal form Y by XRD, wherein the average particle size of the posaconazole crystal Y is 9 microns, and the median particle size is 7.5 microns;
4) mixing the microcrystallized posaconazole crystal I and the posaconazole crystal Y in a weight ratio of 1: 1.5.
Wherein the MIC value of the pharmaceutical composition of posaconazole to mucor circinelloides is 6.2, the MIC value of Cisidomide is 6.6, and the MIC value of Fusarium solani is 9.0.
Wherein the MIC value of the posaconazole composition of the microcrystallized posaconazole crystal I and the posaconazole crystal Y for mucor circinelloides is 5.4-10, the MIC value of Fusarium multiforme is 6-9, and the MIC value of Fusarium solani is 7-10.
The in vitro bacteriostasis test result of the combination of the microcrystallized posaconazole crystal I and the microcrystallized posaconazole crystal Y on the trichoderma circinelloides, polyspora polycephala and fusarium solani is higher than the bacteriostasis effect of the posaconazole alone used in the market, and the MIC value is lower.
Detailed Description
The pharmaceutical composition of posaconazole comprises a posaconazole crystal I and a posaconazole crystal Y, wherein the weight ratio of the posaconazole crystal I to the posaconazole crystal Y is 1:1-1:1.5, wherein the posaconazole crystal I is micronized, the posaconazole crystal Y is unmicronized, the micronized posaconazole crystal I has an average particle size of 6 to 8 μm, and the median particle size is 2 to 4 μm. The mean particle size of the unmicronised posaconazole crystals Y is between 8.5 and 12 μm and the median particle size is between 4.5 and 8 μm.
Grinding conditions are as follows:
in order to avoid the crystal structure of the posaconazole crystal Y from being damaged in the grinding process, the non-microcrystallized posaconazole crystal Y is adopted. The grinding time for the microcrystallization of the posaconazole crystal I is 15-30 min.
Example 1
1) Preparation of posaconazole crystal I: adding 2g of posaconazole into a mixed solvent of 18mL of ethyl acetate and 5mL of ethanol, heating to 80 ℃, dissolving and clarifying, then cooling to 20 ℃ within 1.5 hours, crystallizing, preserving heat at 20 ℃, and filtering to obtain 1.4g of posaconazole with the yield of 70%, wherein the crystal form is the crystal form I through XRD detection.
2) Microcrystallization treatment of posaconazole crystal I: and (3) grinding the prepared posaconazole crystal I for 20min to obtain a microcrystallized posaconazole crystal I with the average particle size of 7.3 mu m.
3) Preparation of posaconazole crystal Y: and (3) heating 2g of the posaconazole crystal I at 175 ℃ for 10min to completely convert the posaconazole crystal I into a posaconazole crystal Y, and detecting the crystal form to be the crystal form Y by XRD. The average particle size of the posaconazole crystal Y was 9.6. mu.m, and the median particle size was 7.9. mu.m.
4) Mixing the microcrystallized posaconazole crystal I and the posaconazole crystal Y in a weight ratio of 1:1.
Example 2
1) Preparation of posaconazole crystal I: adding 3g of posaconazole into a mixed solvent of 27mL of ethyl acetate and 12mL of methanol, heating to 75 ℃, dissolving and clarifying, then cooling to 25 ℃ within 2 hours, crystallizing, preserving heat at 25 ℃ and filtering to obtain 2.4g of posaconazole, wherein the yield is 80%, and the crystal form is the crystal form I through XRD detection.
2) Microcrystallization treatment of posaconazole crystal I: and grinding the prepared posaconazole crystal I for 31min to obtain a microcrystallized posaconazole crystal I with the average particle size of 6.6 mu m.
3) Preparation of posaconazole crystal Y: and (3) heating 8g of the posaconazole crystal II at 180 ℃ for 15min to completely convert the posaconazole crystal II into a posaconazole crystal Y, and detecting the crystal form as a crystal form Y by XRD. The average particle size of the posaconazole crystal Y was 8.7. mu.m, and the median particle size was 7.6. mu.m.
4) Mixing the microcrystallized posaconazole crystal I and the posaconazole crystal Y in a weight ratio of 1: 1.3.
Example 3
1) Preparation of posaconazole crystal I: adding 8g of posaconazole into a mixed solvent of 72mL of methyl acetate and 30mL of methanol, heating to 80 ℃, dissolving and clarifying, then cooling to 20 ℃ within 1.5 hours, crystallizing, preserving heat at 20 ℃, and filtering to obtain 7.3g of posaconazole with the yield of 91%, wherein the crystal form is the crystal form I through XRD detection.
2) Microcrystallization treatment of posaconazole crystal I: and grinding the prepared posaconazole crystal I for 40min to obtain a microcrystallized posaconazole crystal I with the average particle size of 6.0 mu m.
3) Preparation of posaconazole crystal Y: heating 20g of posaconazole crystal I at 175 ℃ for 19min to completely convert the posaconazole crystal I into a posaconazole crystal Y, detecting the crystal form as a crystal form Y by XRD, wherein the average particle size of the posaconazole crystal Y is 9 microns, and the median particle size is 7.5 microns;
4) mixing the microcrystallized posaconazole crystal I and the posaconazole crystal Y in a weight ratio of 1: 1.5.
Bacteriostatic experiments:
the MIC value of the posaconazole composition containing the microcrystallized posaconazole crystal I and the posaconazole crystal Y for mucor circinelloides is 5.4-10, the MIC value of the Fusarium multiformes is-6-9, and the MIC value of the Fusarium solani is 7-10.
Experimental strains: mucor circinelloides, Fusarium polyspora, Fusarium solani. The experimental drugs were pharmaceutical compositions of posaconazole obtained in examples 1 to 3, respectively.
In-vitro antibacterial activity determination:
minimal Inhibitory Concentrations (MICs) of Mucor circinelloides, Fusarium polytrichum, and Fusarium solani were performed with reference to the M27-A3 protocol established by the American society for Clinical and Laboratory Standards Institute (CLSI).
And (3) testing results: the pharmaceutical composition of posaconazole of example 1 had a MIC value of 8 for mucor circinelloides, a MIC value of 7.5 for fusarium solani and a MIC value of 9.5 for fusarium solani.
The pharmaceutical composition of posaconazole of example 2 had a MIC value of 5.6 for mucor circinelloides, 7.1 for fusarium verticillicivorum, and 8.4 for fusarium solani.
The MIC value of the pharmaceutical composition of posaconazole of example 3 for mucor circinelloides was 6.2, the MIC value for fusarium verticillicicola was 6.6, and the MIC value for fusarium solani was 9.0.
The in vitro bacteriostasis test result of the combination of the microcrystallized posaconazole crystal I and the microcrystallized posaconazole crystal Y on the trichoderma circinelloides, polyspora polycephala and fusarium solani is higher than the bacteriostasis effect of the posaconazole alone used in the market, and the MIC value is lower.
In light of the foregoing description of preferred embodiments in accordance with the invention, it is to be understood that numerous changes and modifications may be made by those skilled in the art without departing from the scope of the invention. The technical scope of the present invention is not limited to the contents of the specification, and must be determined according to the scope of the claims.
Claims (9)
1. A pharmaceutical composition of posaconazole, characterized in that: the pharmaceutical composition of posaconazole comprises posaconazole crystal I and posaconazole crystal Y, wherein the weight ratio of the posaconazole crystal I to the posaconazole crystal Y is 1:1-1:1.5, the posaconazole crystal I is micronized, the posaconazole crystal Y is not micronized, the average particle size of the micronized posaconazole crystal I is 6-8 mu m, the median particle size is 2-4 mu m, the average particle size of the non-micronized posaconazole crystal Y is 8.5-12 mu m, and the median particle size is 4.5-8 mu m.
2. The pharmaceutical composition of posaconazole according to claim 1, wherein: the grinding time for the microcrystallization of the posaconazole crystal I is 15-30 min.
3. The pharmaceutical composition of posaconazole according to claim 1, wherein: the pharmaceutical composition of posaconazole is prepared by the following method:
1) preparation of posaconazole crystal I: adding 2g of posaconazole into a mixed solvent of 18mL of ethyl acetate and 5mL of ethanol, heating to 80 ℃, dissolving and clarifying, then cooling to 20 ℃ within 1.5 hours, crystallizing, preserving heat at 20 ℃, and filtering to obtain 1.4g of posaconazole with the yield of 70%, wherein the crystal form is the crystal form I through XRD detection;
2) microcrystallization treatment of posaconazole crystal I: grinding the prepared posaconazole crystal I for 20min to obtain a microcrystallized posaconazole crystal I with the average particle size of 7.3 mu m;
3) preparation of posaconazole crystal Y: and (3) heating 2g of the posaconazole crystal II at 175 ℃ for 10min to completely convert the posaconazole crystal II into a posaconazole crystal Y, and detecting the crystal form to be the crystal form Y by XRD. The average particle size of the posaconazole crystal Y is 9.6 mu m, and the median particle size is 7.9 mu m;
4) mixing the microcrystallized posaconazole crystal I and the posaconazole crystal Y in a weight ratio of 1:1.
4. The pharmaceutical composition of posaconazole according to claim 3, wherein: the MIC value of the pharmaceutical composition of posaconazole to mucor circinelloides is 8, the MIC value of Cisidosia infestans is 7.5, and the MIC value of Fusarium solani is 9.5.
5. The pharmaceutical composition of posaconazole according to claim 1, wherein: the pharmaceutical composition of posaconazole is prepared by the following method:
1) preparation of posaconazole crystal I: adding 3g of posaconazole into a mixed solvent of 27mL of ethyl acetate and 12mL of methanol, heating to 75 ℃, dissolving and clarifying, then cooling to 25 ℃ within 2 hours, crystallizing, keeping the temperature at 25 ℃ and filtering to obtain 2.4g of posaconazole, wherein the yield is 80%, and the crystal form is the crystal form I through XRD detection;
2) microcrystallization treatment of posaconazole crystal I: grinding the prepared posaconazole crystal I for 31min to obtain a microcrystallized posaconazole crystal I with the average particle size of 6.6 mu m;
3) preparation of posaconazole crystal Y: heating 8g of posaconazole crystal I at 180 ℃ for 15min to completely convert the posaconazole crystal I into a posaconazole crystal Y, detecting the crystal form as a crystal form Y by XRD, wherein the average particle size of the posaconazole crystal Y is 8.7 mu m, and the median particle size is 7.6 mu m;
4) mixing the microcrystallized posaconazole crystal I and the posaconazole crystal Y in a weight ratio of 1: 1.3.
6. The pharmaceutical composition of posaconazole according to claim 5, wherein: the MIC value of the pharmaceutical composition of posaconazole to mucor circinelloides is 5.6, the MIC value of Cisidomide is 7.1, and the MIC value of Fusarium solani is 8.4.
7. The pharmaceutical composition of posaconazole according to claim 1, wherein: the pharmaceutical composition of posaconazole is prepared by the following method:
1) preparation of posaconazole crystal I: adding 8g of posaconazole into a mixed solvent of 72mL of methyl acetate and 30mL of methanol, heating to 80 ℃, dissolving and clarifying, then cooling to 20 ℃ within 1.5 hours, crystallizing, preserving heat at 20 ℃, and filtering to obtain 7.3g of posaconazole with the yield of 91%, wherein the crystal form is the crystal form I through XRD detection;
2) microcrystallization treatment of posaconazole crystal I: grinding the prepared posaconazole crystal I for 40min to obtain a microcrystallized posaconazole crystal I with the average particle size of 6.0 mu m;
3) preparation of posaconazole crystal Y: heating 20g of posaconazole crystal I at 175 ℃ for 19min to completely convert the posaconazole crystal I into a posaconazole crystal Y, detecting the crystal form as a crystal form Y by XRD, wherein the average particle size of the posaconazole crystal Y is 9 microns, and the median particle size is 7.5 microns;
4) mixing the microcrystallized posaconazole crystal I and the posaconazole crystal Y in a weight ratio of 1: 1.5.
8. The pharmaceutical composition of posaconazole of claim 7, wherein: the MIC value of the pharmaceutical composition of posaconazole to mucor circinelloides is 6.2, the MIC value of Cisidomide is 6.6, and the MIC value of Fusarium solani is 9.0.
9. The pharmaceutical composition of posaconazole of claim 7, wherein: the MIC value of the posaconazole composition for crystallizing the posaconazole crystal I and the posaconazole crystal Y against mucor circinelloides is 5.4-10, the MIC value of the Fusarium dormitogens is 6-9, and the MIC value of the Fusarium solani is 7-10.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1988887A (en) * | 2004-05-28 | 2007-06-27 | 先灵公司 | Injectable pharmaceutical suspension comprising posaconazole |
| CN102046172A (en) * | 2008-06-02 | 2011-05-04 | 桑多斯股份公司 | Pharmaceutical compositions containing a crystalline form of posaconazole |
| WO2017180714A1 (en) * | 2016-04-12 | 2017-10-19 | University Of Kansas | ANTIFUNGAL ACTIVITY OF lRON SEQUESTERING POLYMERS |
| WO2018022802A1 (en) * | 2016-07-26 | 2018-02-01 | University Of Southern California | Selective bromodomain inhibition of fungal bdf1 |
| CN108567782A (en) * | 2018-07-05 | 2018-09-25 | 江苏先声药业有限公司 | A kind of posaconazole externally-applied medicinal composition, preparation method and the usage |
-
2020
- 2020-04-28 CN CN202010348551.2A patent/CN111514146A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1988887A (en) * | 2004-05-28 | 2007-06-27 | 先灵公司 | Injectable pharmaceutical suspension comprising posaconazole |
| CN102046172A (en) * | 2008-06-02 | 2011-05-04 | 桑多斯股份公司 | Pharmaceutical compositions containing a crystalline form of posaconazole |
| WO2017180714A1 (en) * | 2016-04-12 | 2017-10-19 | University Of Kansas | ANTIFUNGAL ACTIVITY OF lRON SEQUESTERING POLYMERS |
| WO2018022802A1 (en) * | 2016-07-26 | 2018-02-01 | University Of Southern California | Selective bromodomain inhibition of fungal bdf1 |
| CN108567782A (en) * | 2018-07-05 | 2018-09-25 | 江苏先声药业有限公司 | A kind of posaconazole externally-applied medicinal composition, preparation method and the usage |
Non-Patent Citations (1)
| Title |
|---|
| 王思卜等: ""泊沙康唑对临床来源接合菌的体外抗菌活性研究"", 《中国真菌学杂志》 * |
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