CN112137989B - Enzalutamide soft capsule quick-release preparation and preparation method thereof - Google Patents
Enzalutamide soft capsule quick-release preparation and preparation method thereof Download PDFInfo
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- CN112137989B CN112137989B CN202011182038.7A CN202011182038A CN112137989B CN 112137989 B CN112137989 B CN 112137989B CN 202011182038 A CN202011182038 A CN 202011182038A CN 112137989 B CN112137989 B CN 112137989B
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- enzalutamide
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- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 229960004671 enzalutamide Drugs 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 239000007901 soft capsule Substances 0.000 title claims abstract description 35
- 239000003814 drug Substances 0.000 claims abstract description 25
- 229940079593 drug Drugs 0.000 claims abstract description 24
- 239000002775 capsule Substances 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 9
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000000725 suspension Substances 0.000 claims abstract description 6
- 239000002562 thickening agent Substances 0.000 claims abstract description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 21
- 238000011049 filling Methods 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 108010010803 Gelatin Proteins 0.000 claims description 8
- 239000008273 gelatin Substances 0.000 claims description 8
- 229920000159 gelatin Polymers 0.000 claims description 8
- 235000019322 gelatine Nutrition 0.000 claims description 8
- 235000011852 gelatine desserts Nutrition 0.000 claims description 8
- 239000011159 matrix material Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000012530 fluid Substances 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 6
- 239000008213 purified water Substances 0.000 claims description 6
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical group CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical group CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000000787 lecithin Substances 0.000 claims description 3
- 235000010445 lecithin Nutrition 0.000 claims description 3
- 229940067606 lecithin Drugs 0.000 claims description 3
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 239000004033 plastic Substances 0.000 claims description 3
- 229920003023 plastic Polymers 0.000 claims description 3
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 abstract description 13
- 239000006185 dispersion Substances 0.000 abstract description 5
- 238000004090 dissolution Methods 0.000 abstract description 5
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 239000002131 composite material Substances 0.000 abstract description 2
- 239000011257 shell material Substances 0.000 description 10
- 241000700159 Rattus Species 0.000 description 7
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 229940123407 Androgen receptor antagonist Drugs 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 239000003936 androgen receptor antagonist Substances 0.000 description 1
- 102000001307 androgen receptors Human genes 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003081 coactivator Effects 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 1
- 230000005937 nuclear translocation Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000002137 ultrasound extraction Methods 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4833—Encapsulating processes; Filling of capsules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to the technical field of medicines, in particular to an enzalutamide soft capsule quick-release preparation and a preparation method thereof. The quick-release preparation of the enzalutamide soft capsule consists of a capsule shell and contents, wherein the contents are suspension containing the enzalutamide, and the quick-release preparation consists of the following raw materials in parts by weight: 40 parts of enzalutamide; 40-60 parts of medium chain triglyceride; 50-100 parts of a thickening agent; 0.3-5 parts of glidant. Aiming at the property characteristics of the enzalutamide drug, the enzalutamide soft capsule quick-release preparation adopts a suspension system to prepare the soft capsule, promotes the dispersion and absorption of the enzalutamide, has good pharmaceutical chemistry and physical stability, and has quick dissolution of active ingredients and high bioavailability; the invention also provides a preparation method of the composite.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an enzalutamide soft capsule quick-release preparation and a preparation method thereof.
Background
Enzalutamide is an androgen receptor antagonist that blocks androgen binding to the androgen receptor and prevents nuclear translocation of ligand receptor complexes and coactivator recruitment, and is a drug for the treatment of castration-resistant prostate cancer. Enzalutamide belongs to a poorly soluble drug, and has low solubility in aqueous solution and solutions with different pH values, so that the preparation form of Enzalutamide is limited. Most of the existing oral solid preparations, tablets or capsules in the market have slower drug dissolution, incomplete dissolution and low bioavailability, and limit the curative effect of the oral preparation.
The patent CN105030685A prepares the enzalutamide into a solid dispersion oral preparation, and the enzalutamide is prepared into the solid dispersion due to poor solubility, so that the preparation process is complex, and the preparation process is further prepared into tablets, so that the cost is high.
The soft capsule is a new formulation developed after tablet and injection, the outer shell of the soft capsule is pressed by gelatin, and liquid medicine is filled in the capsule shell. The preparation has the advantages of quick response, high bioavailability, high curative effect and the like, thereby being more and more favored by markets and patients. The patent CN104857517B is prepared by mixing the content of enzalutamide, caprylic capric acid polyethylene glycol glyceride, butyl hydroxy anisole, butyl hydroxy toluene and enzalutamide to prepare a soft capsule, wherein the method is to heat a carrier to dissolve raw materials, and then filling.
Disclosure of Invention
Aiming at the characteristics of the Enzalutamide drug properties, the invention aims to provide an Enzalutamide soft capsule quick-release preparation, which adopts a suspension system to prepare the soft capsule, promotes the dispersion and absorption of Enzalutamide, has good chemical and physical stability of the drug, quick dissolution of active ingredients and high bioavailability; the invention also provides a preparation method of the composite.
The quick-release preparation of the enzalutamide soft capsule consists of a capsule shell and contents, wherein the contents are suspension containing the enzalutamide, and the quick-release preparation consists of the following raw materials in parts by weight:
the granularity of the enzalutamide bulk drug is D90<10 mu m.
Medium chain triglycerides are used as carriers to promote the absorption of enzalutamide.
The thickener is stearin, and the melting point is less than 37 ℃.
The glidant is lecithin.
The capsule shell comprises gelatin, glycerol and purified water; the mass ratio of gelatin, glycerol and purified water was 1:0.4:1.
The preparation method of the capsule shell material comprises the following steps: adding purified water and glycerol into a gel tank, heating to 60-80deg.C, and stirring until the solution is clear; and adding gelatin, stirring at 60-80deg.C for dissolving, and vacuumizing for removing air bubbles to obtain capsule shell material.
The preparation method of the quick-release preparation of the enzalutamide soft capsule comprises the following steps:
(1) Heating medium chain triglyceride, adding thickener and glidant, and stirring to obtain pseudoplastic matrix fluid;
(2) Adding enzalutamide into the pseudo-plastic matrix fluid, and uniformly stirring to obtain a content with certain fluidity suitable for soft capsule filling;
(3) Making the content and shell material into soft capsule, drying, and picking up pill to obtain quick-release preparation of Enzalutamide soft capsule.
In step (1), the medium chain triglycerides are heated to 50-70 ℃.
Compared with the prior art, the invention has the beneficial effects that:
(1) Aiming at the characteristic of the Enzalutamide drug, the invention adopts a suspension system to prepare the soft capsule, and prepares the pseudoplastic matrix dispersion raw material, so that the raw material drug and the matrix after the disintegration of the capsule shell are in multi-dispersion in the form of liquid drops, thereby not only increasing the dispersibility of the drug after the disintegration of the soft capsule, but also increasing the drug loading capacity and improving the bioavailability of the drug;
(2) The medium chain triglyceride is added into the auxiliary material, so that the absorption of the enzalutamide is obviously improved, the dispersion and the absorption of the enzalutamide can be promoted, and the finally prepared enzalutamide soft capsule quick-release preparation has good pharmaceutical chemical and physical stability, quick dissolution of active ingredients and high bioavailability.
Detailed Description
The invention is further illustrated by means of embodiments.
Examples 1 to 10
In examples 1-10, the composition of the content raw materials of the quick-release preparation of the enzalutamide soft capsule is shown in table 1.
TABLE 1 composition of the content raw materials (in parts by weight) of examples 1-10
The preparation method comprises the following steps:
(1) Heating medium chain triglyceride to 60 ℃, adding stearin and lecithin, and uniformly stirring to obtain a pseudoplastic matrix fluid;
(2) Adding enzalutamide into the pseudo-plastic matrix fluid, and uniformly stirring to obtain a content with certain fluidity suitable for soft capsule filling;
(3) Adding purified water and glycerol into a gel tank according to the mass ratio of gelatin to glycerol to purified water of 1:0.4:1, heating to 70 ℃, and stirring until the solution is clear; adding gelatin, stirring at 70deg.C for dissolving, and vacuumizing to remove air bubbles to obtain capsule shell material;
(4) Making the content and shell material into soft capsule, drying, and picking up pill to obtain quick-release preparation of Enzalutamide soft capsule.
The contents and soft capsules prepared in examples 1 to 10 were evaluated as shown in table 2.
Table 2 contents and soft capsule test results prepared in examples 1 to 10
| Examples | Content mobility | 30 ℃,12 months (physical stability) | Content of | Variation of particle size of raw material |
| Example 1 | Meets the filling requirement | Stable, non-layered | 99.8％ | No change |
| Example 2 | Meets the filling requirement | Stable, non-layered | 99.2％ | No change |
| Example 3 | Meets the filling requirement | Stable, non-layered | 99.7％ | No change |
| Example 4 | Meets the filling requirement | Stable, non-layered | 99.3％ | No change |
| Example 5 | Meets the filling requirement | Stable, non-layered | 99.3％ | No change |
| Example 6 | Meets the filling requirement | Stable, non-layered | 99.8％ | No change |
| Example 7 | Meets the filling requirement | Stable, non-layered | 100.5％ | No change |
| Example 8 | Meets the filling requirement | Stable, non-layered | 99.1％ | No change |
| Example 9 | Meets the filling requirement | Stable, non-layered | 99.0％ | No change |
| Example 10 | Meets the filling requirement | Stable, non-layered | 100.6％ | No change |
Will be solidThe contents prepared in examples 1 to 5 and the negative control sample (without medium chain triglyceride) were respectively fed to SD rats, 30 SD rats were obtained, and the rats were randomly divided into 6 groups of 5 rats each, each with a body weight of 250 g. Fasted for 12 hours before administration, and the water is freely drunk. The negative control and sample Nos. 1-5 of the above examples were orally administered at 40mg/kg, respectively. And 200-300 mu L of intraocular blood is obtained in the 0.5 th, 1 th, 2 nd, 4 th, 6 th, 8 th, 10 th, 12 th, 18 th and 24 th hours after the administration, the intraocular blood is preserved on ice, the supernatant is obtained after centrifugation at 3500 r/min for 10min, then methanol is added for ultrasonic extraction and centrifugation, and the content of the supernatant is detected by HPLC-MS. Statistical analysis of the measured data and calculation of AUC 0-t (μg.h/ml)，C max (ng/ml)，T max And bioavailability.
AUC 0-t The (μg.h/ml) is the area surrounded by the area under the curve (AUC) blood concentration curve versus the time axis at the time of administration, and this parameter is an important index for evaluating the drug absorption degree and reflects the in vivo exposure characteristic of the drug.
C max (ng/ml) is the peak concentration, the highest blood concentration after administration is shown, and the parameter is an important index reflecting the absorption rate and the absorption degree of the drug in the body.
T max For peak time, the time required to reach the drug peak concentration after administration, the parameter reflects the rate of drug entry into the body, and the absorption rate is high and the peak time is short.
The bioavailability is the ratio of the total amount of drug absorbed by the test formulation to the reference formulation, and is used to measure the extent of drug absorption.
The drug absorption in SD rats is shown in Table 3.
TABLE 3 absorption of drug in rats 3 SD
| Examples | AUC 0-t (μg.h/ml) | C max (ng/ml) | T max (h) | F/％ |
| Negative sample | 110 | 5.6 | 6.9 | 26.1 |
| Example 1 | 318 | 15.2 | 6.7 | 78.3 |
| Example 2 | 386 | 17.9 | 6.6 | 90.2 |
| Example 3 | 401 | 18.8 | 6.4 | 95.3 |
| Example 4 | 420 | 19.5 | 6.0 | 96.6 |
| Example 5 | 339 | 16.1 | 6.9 | 94.5 |
As can be seen from table 3: compared with a negative control, the enzalutamide soft capsules prepared by the methods of examples 1-5 have faster absorption in SD rats, higher bioavailability, optimal distribution of examples 2-4 and slightly worse distribution of examples 1 and 5.
Claims (4)
1. An enzalutamide soft capsule quick-release preparation is characterized in that: the capsule consists of a capsule shell and a content, wherein the content is a suspension containing enzalutamide, and the capsule consists of the following raw materials in parts by weight:
40 parts of enzalutamide;
40-60 parts of medium chain triglyceride;
50-100 parts of a thickening agent;
0.3-5 parts of glidant;
the granularity of the enzalutamide bulk drug is D90<10 mu m;
the thickener is stearin, and the melting point is less than 37 ℃;
the glidant is lecithin;
the preparation method of the enzalutamide soft capsule quick-release preparation comprises the following steps:
(1) Heating medium chain triglyceride, adding thickener and glidant, and stirring to obtain pseudoplastic matrix fluid;
(2) Adding enzalutamide into the pseudo-plastic matrix fluid, and uniformly stirring to obtain a content with certain fluidity suitable for soft capsule filling;
(3) Making the content and capsule shell into soft capsule, drying, and picking up pill to obtain quick-release preparation of Enzalutamide soft capsule.
2. The quick release enzalutamide soft capsule formulation of claim 1, wherein: the capsule shell comprises gelatin, glycerol and water.
3. The quick release enzalutamide soft capsule formulation of claim 2, wherein: the mass ratio of gelatin, glycerol and purified water was 1:0.4:1.
4. The quick release enzalutamide soft capsule formulation of claim 1, wherein: in step (1), the medium chain triglycerides are heated to 50-70 ℃.
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| CN202011182038.7A CN112137989B (en) | 2020-10-29 | 2020-10-29 | Enzalutamide soft capsule quick-release preparation and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015022349A1 (en) * | 2013-08-14 | 2015-02-19 | Ratiopharm Gmbh | Dosage form comprising enzalutamide |
| CN104857517A (en) * | 2015-05-14 | 2015-08-26 | 南京海纳医药科技有限公司 | Enzalutamide soft capsule and preparation method thereof |
| CN108078952A (en) * | 2018-03-05 | 2018-05-29 | 瑞阳制药有限公司 | Ethanesulfonic acid Nintedanib soft capsule and preparation method thereof |
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2020
- 2020-10-29 CN CN202011182038.7A patent/CN112137989B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015022349A1 (en) * | 2013-08-14 | 2015-02-19 | Ratiopharm Gmbh | Dosage form comprising enzalutamide |
| CN104857517A (en) * | 2015-05-14 | 2015-08-26 | 南京海纳医药科技有限公司 | Enzalutamide soft capsule and preparation method thereof |
| CN108078952A (en) * | 2018-03-05 | 2018-05-29 | 瑞阳制药有限公司 | Ethanesulfonic acid Nintedanib soft capsule and preparation method thereof |
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