CN115887395A - Enzalutamide solid dispersion preparation and preparation method and application thereof - Google Patents
Enzalutamide solid dispersion preparation and preparation method and application thereof Download PDFInfo
- Publication number
- CN115887395A CN115887395A CN202211449254.2A CN202211449254A CN115887395A CN 115887395 A CN115887395 A CN 115887395A CN 202211449254 A CN202211449254 A CN 202211449254A CN 115887395 A CN115887395 A CN 115887395A
- Authority
- CN
- China
- Prior art keywords
- enzalutamide
- solid dispersion
- carrier
- mass ratio
- surfactant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 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 130
- 229960004671 enzalutamide Drugs 0.000 title claims abstract description 127
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title claims abstract description 44
- 239000004094 surface-active agent Substances 0.000 claims abstract description 22
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims abstract description 18
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 18
- 229920000193 polymethacrylate Polymers 0.000 claims abstract description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 30
- 238000009472 formulation Methods 0.000 claims description 24
- 235000019359 magnesium stearate Nutrition 0.000 claims description 19
- 239000000377 silicon dioxide Substances 0.000 claims description 19
- 235000012239 silicon dioxide Nutrition 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000001694 spray drying Methods 0.000 claims description 15
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 14
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 14
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 14
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 239000000314 lubricant Substances 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 13
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 12
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 12
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 12
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 12
- 239000000945 filler Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 8
- 239000007884 disintegrant Substances 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 8
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 229960001866 silicon dioxide Drugs 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
- 238000000889 atomisation Methods 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 5
- 230000000762 glandular Effects 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- -1 tween-40 Polymers 0.000 claims description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 2
- 229940057948 magnesium stearate Drugs 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
- 229920000053 polysorbate 80 Polymers 0.000 claims description 2
- NWZBFJYXRGSRGD-UHFFFAOYSA-M sodium;octadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOS([O-])(=O)=O NWZBFJYXRGSRGD-UHFFFAOYSA-M 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 27
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 238000001514 detection method Methods 0.000 description 13
- 229940079593 drug Drugs 0.000 description 7
- 239000007901 soft capsule Substances 0.000 description 7
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 108010052832 Cytochromes Proteins 0.000 description 3
- 102000018832 Cytochromes Human genes 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 102000001307 androgen receptors Human genes 0.000 description 2
- 108010080146 androgen receptors Proteins 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 231100000405 induce cancer Toxicity 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000025308 nuclear transport Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229940085728 xtandi Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses an enzalutamide solid dispersion preparation, and a preparation method and application thereof. The enzalutamide solid dispersion preparation contains an enzalutamide solid dispersion and a pharmaceutically acceptable excipient, wherein the enzalutamide solid dispersion comprises enzalutamide, a carrier and a surfactant, and the mass ratio of the enzalutamide to the carrier is 1: 1.0-3.0; the carrier is hydroxypropyl methyl cellulose acetate succinate and/or polymethacrylate. The preparation has high dissolution rate, high dissolution speed, good stability, low carrier dosage, simple preparation process, recyclable organic solvent and low production cost.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to an enzalutamide solid dispersion preparation, and a preparation method and application thereof.
Background
Enzalutamide is an androgen receptor inhibitor, and can competitively inhibit the binding of androgen to a receptor, and can inhibit the nuclear transport of androgen receptor and the interaction of the receptor with DNA. In vitro experimental studies show that enzalutamide can inhibit unlimited proliferation of glandular cancer cells and induce cancer cell apoptosis through gene expression, and enzalutamide can reduce tumor volume in a model experiment of mouse prostate cancer xenograft. The major metabolite of enzalutamide is N-demethylenzalutamide, which exhibits similar inhibitory activity in vitro as enzalutamide. The medicine is metabolized in vivo and is rapidly absorbed after administration, blood plasma concentration reaches Cmax within 1-2h, average end t1/2 is 3-10d, and main metabolic enzymes are cytochrome 2C8 and cytochrome 3A4. When the product is used, the use of a medicine with strong competitive effect on cytochrome 2C8 target spots is avoided as much as possible.
Enzalutamide drugs were co-developed by Medivation and Astelai (Aspellas) and approved by the FDA for the treatment of advanced prostate cancer (cancer-resistant cancer) at 8 months of 2012, under the trade name Xtandi, which is an oral softgel formulation. The relative molecular mass is 464.4, the CAS registry number is 915087-33-1, and the structure is shown as the following formula:
enzalutamide is a low-dissolution and low-permeability medicine, belongs to BCS IV class, and is a soft capsule formulation developed by Anstelai company for ensuring better bioavailability, but the preparation produced by the method has low dissolution rate and low bioavailability, and because the stability of the Enzalutamide is poor, the stability of the Enzalutamide is improved by adding BHT and BHA composite antioxidant, but the two antioxidants have poor clinical safety, and the soft capsule preparation process is complex and has higher cost.
Disclosure of Invention
The invention aims to overcome the problem of slow dissolution rate of enzalutamide in vivo. Therefore, the invention provides an enzalutamide solid dispersion, a solid dispersion preparation and a preparation method thereof. The solid dispersion preparation provided by the invention has the advantages of high dissolution rate, high dissolution speed, good stability, lower carrier dosage, simple preparation process, recyclable organic solvent and low production cost.
The invention provides an enzalutamide solid dispersion preparation which contains an enzalutamide solid dispersion and a pharmaceutically acceptable excipient, wherein the enzalutamide solid dispersion comprises enzalutamide, a carrier and a surfactant, and the mass ratio of the enzalutamide to the carrier is 1: 1.0-3.0;
the carrier is hydroxypropyl methyl cellulose acetate succinate and/or polymethacrylate;
the mass ratio of the enzalutamide to the surfactant is 1: 0.01-0.075;
the surfactant is one or more of Tween-20, tween-40, tween-80 and sodium stearyl sulfate;
the pharmaceutically acceptable excipient comprises a filler and a disintegrant;
the filler is microcrystalline cellulose;
the disintegrant is croscarmellose sodium.
Preferably, the carrier is hydroxypropylmethylcellulose acetate succinate.
Preferably, the mass ratio of the enzalutamide to the carrier is 1: 1.0-1.3, and further preferably, the mass ratio of the enzalutamide to the carrier is 1: 1.25.
Preferably, the carrier is hydroxypropyl methyl cellulose acetate succinate, and the mass ratio of the enzalutamide to the carrier is 1: 1.25.
Preferably, the surfactant is Tween-20.
Preferably, the mass ratio of the enzalutamide to the surfactant is 1: 0.025-0.05; more preferably 1:0.0375.
preferably, the pharmaceutically acceptable excipient further comprises a lubricant.
Preferably, the lubricant is one or more of magnesium stearate, silicon dioxide and talcum powder; further preferably, the lubricant is magnesium stearate and silicon dioxide.
Preferably, the mass ratio of the enzalutamide to the filler is 1.0 to 3.0, such as 1: 1.25.
Preferably, the mass ratio of the enzalutamide to the disintegrant is 1.
Preferably, the mass ratio of the enzalutamide to the lubricant is 1.
Preferably, when the lubricant is magnesium stearate and silicon dioxide, the mass ratio of magnesium stearate to silicon dioxide is 2:3.
preferably, the pharmaceutically acceptable excipients are microcrystalline cellulose, silicon dioxide, croscarmellose sodium and magnesium stearate.
Preferably, the enzalutamide solid dispersion preparation consists of enzalutamide, a carrier, a surfactant and a pharmaceutically acceptable excipient.
Preferably, the enzalutamide solid dispersion preparation comprises the following components in parts by mass: 1 part of enzalutamide; 1-3 parts of a carrier; 0.01 to 0.075 part of surfactant; 1-3 parts of a filling agent; 0.05 to 0.5 portion of disintegrating agent; 0.05-0.5 part of lubricant;
preferably, the enzalutamide solid dispersion formulation consists of the following components: 1 part of enzalutamide; 1.25 parts of hydroxypropyl methyl cellulose acetate succinate; tween-20.0375 weight portions; 1.25 parts of microcrystalline cellulose; 0.075 part of silicon dioxide; 0.125 part of croscarmellose sodium; 0.05 part of magnesium stearate.
Preferably, the solid dispersion formulation of enzalutamide is a tablet.
The invention also provides a preparation method of the enzalutamide solid dispersion preparation, which comprises the following steps:
(1) Mixing a carrier, a surfactant, enzalutamide and a solvent, and carrying out spray drying to obtain an enzalutamide solid dispersion;
(2) Adding a pharmaceutically acceptable excipient to the enzalutamide solid dispersion;
the technological parameters of the spray drying are as follows: the air inlet temperature is 105-135 ℃, the air outlet temperature is 40-90 ℃, the feeding speed is 6-12 g/min, and the atomization pressure is 0.2-0.5 Mpa.
The carrier, the surfactant and the pharmaceutically acceptable excipient are as described in any one of the present invention.
Preferably, the solvent is one or more of water, ethanol and acetone; more preferably, the solvent is a mixture of acetone and ethanol; further preferably, the acetone and ethanol volume ratio is 2:3.
Preferably, the process parameters of the spray drying are as follows: the air inlet temperature is 110-130 deg.C (e.g. 120 deg.C), the air outlet temperature is 50-80 deg.C (e.g. 60 deg.C), the feeding speed is 7-10 g/min, and the atomizing pressure is 0.2-0.5 MPa. Further preferably, the process parameters of the spray drying are as follows: the air inlet temperature is 115-125 ℃, the air outlet temperature is 55-65 ℃, the feeding speed is 9g/min, and the atomization pressure is 0.3-0.4 MPa.
Preferably, the preparation method of the enzalutamide solid dispersion preparation comprises the following steps:
(1) Mixing a carrier with the solvent to obtain a carrier solution;
(2) Mixing a surfactant with the carrier solution to obtain a mixed solution;
(3) Dispersing the enzalutamide in the mixed solution, and performing spray drying to obtain an enzalutamide solid dispersion;
(4) Adding a pharmaceutically acceptable excipient to the enzalutamide solid dispersion.
The invention also provides application of the enzalutamide solid dispersion preparation in preparing a medicament for treating glandular cancer, wherein the glandular cancer is preferably prostatic cancer, and more preferably advanced prostatic cancer.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
1) Compared with the enzalutamide soft capsule, the tablet prepared by spray drying has better solubility and dissolution rate, thereby improving the bioavailability of the enzalutamide in vivo;
2) The enzalutamide tablet provided by the invention contains a film coating, and enzalutamide is not easy to oxidize and degrade, so that the quality stability of the preparation is improved;
3) The enzalutamide solid dispersion provided by the invention has a lower moisture value, and the risk of crystal phase conversion of the bulk drug is greatly reduced;
4) The prescription and the preparation method provided by the invention can better fit a reference preparation;
5) The invention has simple preparation process, recyclable organic solvent and low production cost.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. Experimental procedures without specifying specific conditions in the following examples were selected in accordance with conventional procedures and conditions, or in accordance with commercial instructions.
Example 1
1) Respectively taking 50g of polyoxyethylene, polymethacrylate, PEG8000 and hydroxypropyl methyl cellulose acetate succinate, dissolving into 167ml of acetone-ethanol mixed solution (the volume ratio of acetone-ethanol is 2:3), and respectively adding 1.5g of Tween-20 to obtain a carrier solution;
2) Respectively adding 40g of enzalutamide bulk drug into the four carrier solutions, stirring until the mixture is clear, and then carrying out spray drying, wherein the air inlet temperature is controlled to be 120 ℃, the air outlet temperature is controlled to be 60 ℃, the feeding speed is 9g/min, and the atomization pressure is 0.4MPa, so as to obtain four enzalutamide solid dispersions;
3) Respectively adding 50g of microcrystalline cellulose, 3g of silicon dioxide, 5g of croscarmellose sodium and 2g of magnesium stearate into the four enzalutamide solid dispersions, uniformly mixing and tabletting to obtain four enzalutamide solid dispersion tablets;
1. and (3) dissolution rate detection: taking 6 tablets prepared in the example 1 and 6 tablets of original enzalutamide soft capsules (21E 1209, anstalat) and enzalutamide tablets (19007Y 1, anstalat), respectively, and detecting according to a dissolution detection method in the second part of the appendix of the 2020 edition of Chinese pharmacopoeia, wherein the dissolution detection conditions are as follows: paddle, 50rpm, pH1.0 dissolution medium.
The dissolution results are shown in the following table:
from the above results, it can be seen that the four tablets prepared in example 1 are significantly superior to the original ground soft capsule dosage form in terms of dissolution rate and dissolution speed, and the tablet with hydroxypropylmethylcellulose acetate succinate as the carrier is slightly superior to the original ground tablet in terms of dissolution rate and dissolution speed.
2. Water absorption detection of enzalutamide solid dispersion tablets: the four solid dispersions of enzalutamide prepared in example 1 were placed under acceleration conditions (40 ℃,75% rh) for 30 days, and sampled for water content values at 0, 5, 10, 20, and 30 days, respectively.
The detection result of the water content value of the solid dispersion tablet is as follows:
because, during storage of a drug in a solid dispersion, if the hygroscopicity is large, the moisture content in the drug increases, and the amorphous phase of the drug may be transformed into a thermodynamically stable crystalline phase, which may result in a decrease in the dissolution rate of the drug and influence in vivo absorption. The water absorption detection result shows that the water content value of the hydroxypropyl methyl cellulose acetate succinate batch is slowly increased under the condition of 30 days of acceleration; like the benoxalutamide tablets, the amount of water increase of the hydroxypropylmethylcellulose acetate succinate batch was slightly lower than the reference formulation. Considering that the solid dispersion has a higher risk of amorphous phase transformation to crystalline phase under the condition of high moisture value, hydroxypropyl methylcellulose acetate succinate is most preferable as the solid dispersion carrier.
3. Stability test
The four enzalutamide solid dispersion preparations, enzalutamide tablets and enzalutamide soft capsules in example 1 were placed together at 40 ℃ and 75% rh for 3 months, and samples were taken at 0 day, 10 days, 30 days and 90 days to test the substances. The results are shown in the following table.
And (3) related substance detection results:
the results show that the impurity content of the four enzalutamide solid dispersion preparations is lower than that of the soft capsule, wherein the impurities of hydroxypropyl methylcellulose acetate succinate and polymethacrylate preparations in batches are slowly increased, and the stability of the enzalutamide solid dispersion preparations is better than that of enzalutamide tablets. As a result of combining the dissolution rate and the moisture value, the hydroxypropyl methyl cellulose acetate succinate has better effect as a solid dispersion carrier.
Example 2
Enzalutamide tablets consist of:
the preparation method comprises the following steps:
1) Dissolving 100g of hydroxypropyl cellulose acetate succinate in 334mL of acetone and ethanol (the volume ratio of acetone to ethanol is 2:3), and dissolving 3g of Tween-20 in the mixed solution to obtain a carrier solution;
2) Dispersing 80g of enzalutamide in the carrier solution, stirring until the carrier solution is clear, and then carrying out spray drying;
controlling spray drying parameters: the air inlet temperature is 120 ℃, the air outlet temperature is 60 ℃, the liquid spraying speed is 9g/min, and the atomizing pressure is 0.4MPa, so that the enzalutamide solid dispersion is obtained;
3) 100g of microcrystalline cellulose, 6g of silicon dioxide, 10g of croscarmellose sodium and 4g of magnesium stearate are added into the enzalutamide solid dispersion, and the mixture is uniformly mixed and tableted.
Example 3
1) Taking 50g of six parts of hydroxypropyl methyl cellulose acetate succinate in parallel, respectively dissolving in 167ml of acetone-ethanol mixed solution (the volume ratio of acetone-ethanol is 2:3), and respectively adding 1.5g of Tween-20 to obtain a carrier solution;
2) Adding 40g of enzalutamide raw material medicine into the carrier solution, stirring until the mixture is clear, and then carrying out spray drying:
preparation 1: controlling the air inlet temperature to be 120 ℃, the air outlet temperature to be about 60 ℃, the feeding speed to be 9g/min and the atomizing pressure to be 0.4MPa to obtain the enzalutamide solid dispersion;
preparation 2: controlling the air inlet temperature to be 100 ℃, the air outlet temperature to be about 60 ℃, the feeding speed to be 9g/min and the atomizing pressure to be 0.4MPa to obtain the enzalutamide solid dispersion;
preparation 3: controlling the air inlet temperature to be 140 ℃, the air outlet temperature to be about 60 ℃, the feeding speed to be 9g/min and the atomizing pressure to be 0.4MPa to obtain the enzalutamide solid dispersion;
preparation 4: controlling the air inlet temperature to be 120 ℃, the air outlet temperature to be about 60 ℃, the feeding speed to be 5g/min and the atomizing pressure to be 0.4MPa to obtain the enzalutamide solid dispersion;
preparation 5: controlling the air inlet temperature to be 120 ℃, the air outlet temperature to be about 60 ℃, the feeding speed to be 13g/min and the atomizing pressure to be 0.4MPa to obtain the enzalutamide solid dispersion;
preparation 6: controlling the air inlet temperature to be 120 ℃, the air outlet temperature to be about 60 ℃, the feeding speed to be 9g/min and the atomizing pressure to be 0.6MPa to obtain the enzalutamide solid dispersion;
3) Respectively adding 50g of microcrystalline cellulose, 3g of silicon dioxide, 5g of croscarmellose sodium and 2g of magnesium stearate into six parts of enzalutamide solid dispersion, uniformly mixing and tabletting to obtain an enzalutamide solid dispersion tablet;
and (3) dissolution rate detection: taking 6 tablets of the tablets prepared in the example 3 and 6 tablets of enzalutamide (19007Y 1, ansteletai) respectively, detecting according to a dissolution detection method in the appendix of the second part of Chinese pharmacopoeia 2020 edition, wherein the dissolution detection conditions are as follows: paddle method, 50rpm, pH1.0 dissolution medium.
The results show that batches were similar to the reference formulation except that the dissolution of the formulation 2 and 5 batches did not fit the reference formulation. Wherein formulation 1 batch is more similar to the reference formulation and has a slightly better release rate than the reference formulation, thus spray process parameters for formulation 1 batch are preferred.
Example 4
1) Respectively dissolving 50g of each of four parts of hydroxypropyl methyl cellulose acetate succinate in 167ml of acetone-ethanol mixed solution (the volume ratio of acetone-ethanol is 2:3), and adding 1.5g of Tween-20 to obtain a carrier solution;
2) Respectively adding 40g of enzalutamide raw material medicine into the four carrier solutions, stirring until the mixture is clarified, and then carrying out spray drying, wherein the air inlet temperature is controlled to be 120 ℃, the air outlet temperature is controlled to be 60 ℃, the feeding speed is 9g/min, and the atomization pressure is 0.4MPa, so as to obtain four enzalutamide solid dispersions;
3) Tablets were prepared with the following excipients, respectively:
batch 1: adding 50g of microcrystalline cellulose, 3g of silicon dioxide, 5g of croscarmellose sodium and 2g of magnesium stearate, uniformly mixing, and tabletting to obtain an enzalutamide solid dispersion tablet;
batch 2: adding 50g of lactose, 3g of silicon dioxide, 5g of croscarmellose sodium and 2g of magnesium stearate, uniformly mixing and tabletting to obtain the enzalutamide solid dispersion tablet;
batch 3: adding 50g of corn starch, 3g of silicon dioxide, 5g of croscarmellose sodium and 2g of magnesium stearate, uniformly mixing and tabletting to obtain an enzalutamide solid dispersion tablet;
batch 4: adding 50g of microcrystalline cellulose, 3g of silicon dioxide, 5g of carboxymethylcellulose calcium and 2g of magnesium stearate, uniformly mixing and tabletting to obtain the enzalutamide solid dispersion tablet.
And (3) dissolution rate detection: taking 6 tablets of the tablet prepared in the example 4 and 6 tablets of enzalutamide (19007Y 1, ansteletai) respectively, detecting according to a dissolution detection method in the appendix of the second part of Chinese pharmacopoeia 2020 edition, wherein the dissolution detection conditions are as follows: paddle, 50rpm, pH1.0 dissolution medium.
The results show that with lactose and corn starch as fillers, the tablet dissolution rate is slow and the end-point release is incomplete; when carboxymethylcellulose calcium is used as a disintegrant, the dissolution rate is slightly slower than that of croscarmellose sodium, and the end-point release is incomplete. Therefore, microcrystalline cellulose is selected as a filler, and croscarmellose sodium is selected as a disintegrating agent.
Claims (11)
1. An enzalutamide solid dispersion preparation which contains an enzalutamide solid dispersion and a pharmaceutically acceptable excipient, wherein the enzalutamide solid dispersion comprises enzalutamide, a carrier and a surfactant, and the mass ratio of the enzalutamide to the carrier is 1: 1.0-3.0;
the carrier is hydroxypropyl methyl cellulose acetate succinate and/or polymethacrylate;
the mass ratio of the enzalutamide to the surfactant is 1: 0.01-0.075;
the surfactant is one or more of Tween-20, tween-40, tween-80 and sodium stearyl sulfate;
the pharmaceutically acceptable excipient comprises a filler and a disintegrant;
the filler is microcrystalline cellulose;
the disintegrant is croscarmellose sodium.
2. The formulation of solid dispersions of enzalutamide according to claim 1, characterized in that it satisfies one or more of the following conditions:
(1) The carrier is hydroxypropyl methyl cellulose acetate succinate;
(2) The mass ratio of the enzalutamide to the carrier is 1: 1.0-1.3;
(3) The surfactant is Tween-20;
(4) The mass ratio of the enzalutamide to the surfactant is 1: 0.025-0.05;
(5) The mass ratio of the enzalutamide to the filler is 1.0-3.0;
(6) The mass ratio of the enzalutamide to the disintegrant is 1.05-0.4;
(7) The pharmaceutically acceptable excipient further comprises a lubricant.
3. The formulation of solid dispersions of enzalutamide according to claim 2, characterized in that it satisfies one or more of the following conditions:
(1) The mass ratio of the enzalutamide to the carrier is 1: 1.25;
(2) The mass ratio of the enzalutamide to the surfactant is 1:0.0375;
(3) The lubricant is one or more of magnesium stearate, silicon dioxide and talcum powder;
(4) The mass ratio of the enzalutamide to the lubricant is 1.
4. The formulation of solid dispersions of enzalutamide according to claim 3, characterized in that it satisfies one or more of the following conditions:
(1) The carrier is hydroxypropyl methyl cellulose acetate succinate, and the mass ratio of the enzalutamide to the carrier is 1: 1.25;
(2) The lubricant is magnesium stearate and silicon dioxide;
(3) The mass ratio of the enzalutamide to the filler is 1: 1.25;
(4) The mass ratio of the enzalutamide to the disintegrant is 1: 0.125;
(5) The mass ratio of the enzalutamide to the lubricant is 1: 0.125;
(6) When the lubricant is magnesium stearate and silicon dioxide, the mass ratio of the magnesium stearate to the silicon dioxide is 2:3;
(7) The pharmaceutically acceptable excipients are microcrystalline cellulose, silicon dioxide, croscarmellose sodium and magnesium stearate.
5. The enzalutamide solid dispersion formulation of any one of claims 1-4, wherein the enzalutamide solid dispersion formulation consists of enzalutamide, a carrier, a surfactant, and a pharmaceutically acceptable excipient.
6. The enzalutamide solid dispersion formulation of claim 1, comprising the following parts by mass of components: 1 part of enzalutamide; 1-3 parts of a carrier; 0.01 to 0.075 part of surfactant; 1-3 parts of a filling agent; 0.05 to 0.5 portion of disintegrating agent; 0.05-0.5 part of lubricant;
and/or the enzalutamide solid dispersion preparation is a tablet.
7. The enzalutamide solid dispersion formulation of claim 5, wherein the enzalutamide solid dispersion formulation consists of: 1 part of enzalutamide; 1.25 parts of hydroxypropyl methyl cellulose acetate succinate; tween-20.0375 parts; 1.25 parts of microcrystalline cellulose; 0.075 part of silicon dioxide; 0.125 part of croscarmellose sodium; 0.05 part of magnesium stearate.
8. A method of preparing a formulation of solid dispersion of enzalutamide according to any one of claims 1 to 7, comprising the steps of:
(1) Mixing a carrier, a surfactant, enzalutamide and a solvent, and carrying out spray drying to obtain an enzalutamide solid dispersion;
(2) Adding a pharmaceutically acceptable excipient to the enzalutamide solid dispersion;
the technological parameters of the spray drying are as follows: the air inlet temperature is 105-135 ℃, the air outlet temperature is 40-90 ℃, the feeding speed is 6-12 g/min, and the atomization pressure is 0.2-0.5 Mpa;
the carrier, the surfactant and the pharmaceutically acceptable excipient are as defined in any one of claims 1 to 7.
9. The method of preparing the formulation of solid dispersions of enzalutamide according to claim 8, characterized in that it satisfies one or more of the following conditions:
(1) The solvent is one or more of water, ethanol and acetone; more preferably, the solvent is a mixture of acetone and ethanol; further preferably, the acetone and ethanol volume ratio is 2:3;
(2) The technological parameters of the spray drying are as follows: the air inlet temperature is 110-130 ℃, the air outlet temperature is 5-80 ℃, the feeding speed is 7-10 g/min, and the atomization pressure is 0.2-0.5 Mpa.
10. The process for the preparation of solid dispersion formulation of enzalutamide according to claim 8 or 9, characterized in that it comprises the following steps:
(1) Mixing a carrier with the solvent to obtain a carrier solution;
(2) Mixing a surfactant with the carrier solution to obtain a mixed solution;
(3) Dispersing the enzalutamide in the mixed solution, and performing spray drying to obtain an enzalutamide solid dispersion;
(4) Adding a pharmaceutically acceptable excipient to the enzalutamide solid dispersion.
11. Use of the enzalutamide solid dispersion formulation according to any one of claims 1 to 7 in the preparation of a medicament for the treatment of glandular cancer, preferably prostate cancer, more preferably advanced prostate cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211449254.2A CN115887395A (en) | 2022-11-18 | 2022-11-18 | Enzalutamide solid dispersion preparation and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211449254.2A CN115887395A (en) | 2022-11-18 | 2022-11-18 | Enzalutamide solid dispersion preparation and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115887395A true CN115887395A (en) | 2023-04-04 |
Family
ID=86477449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211449254.2A Pending CN115887395A (en) | 2022-11-18 | 2022-11-18 | Enzalutamide solid dispersion preparation and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115887395A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105358535A (en) * | 2012-09-11 | 2016-02-24 | 梅迪维新***医疗股份有限公司 | Formulations of enzalutamide |
-
2022
- 2022-11-18 CN CN202211449254.2A patent/CN115887395A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105358535A (en) * | 2012-09-11 | 2016-02-24 | 梅迪维新***医疗股份有限公司 | Formulations of enzalutamide |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1407894A (en) | Pharmaceutical composition | |
| JP2012501971A (en) | Co-crystals and pharmaceutical formulations containing co-crystals | |
| CN104888228A (en) | Sorafenib tosylate solid dispersion body and preparation method thereof | |
| CN110812365A (en) | Composition, preparation method and preparation thereof | |
| TWI747906B (en) | A new crystal form of dapagliflozin, its preparation method and use thereof | |
| EP2050436A1 (en) | Pharmaceutical composition containing dutasteride | |
| CN105434386A (en) | Sustained release tablet containing high water-soluble active ingredients and preparation method thereof | |
| CN117547534A (en) | Nicorandil sustained release preparation and preparation method thereof | |
| CN114302712B (en) | Acipimox multi-unit sustained-release pellet tablet and preparation method thereof | |
| CN101277681B (en) | Oral solid pharmaceutical formulation of the tribulin inhibitor indibulin | |
| JP3037393B2 (en) | Method for producing solid drug for oral administration | |
| CN103191065A (en) | Celecoxib new formulation and preparation method thereof | |
| CN106511291A (en) | Acotiamide hydrochloride controlled release tablet and preparation method thereof | |
| CN115887395A (en) | Enzalutamide solid dispersion preparation and preparation method and application thereof | |
| CN104415034B (en) | A kind of imidafenacin pharmaceutical composition and preparation method thereof | |
| JP7448275B2 (en) | Orbit Azin Fumarate Enteric Coated Pellets, Method of Preparation and Use thereof | |
| CN112569190B (en) | Oral administration preparation of pulsatilla chinensis saponin B4 and preparation method thereof | |
| CN115919793A (en) | Orlistat capsule preparation and preparation method thereof | |
| CN115463097A (en) | Preparation process of tacrolimus slow-release intermediate particles | |
| CN115124420A (en) | Rhein and matrine eutectic crystal hydrate, preparation method, composition and application thereof | |
| CN112315914A (en) | Lenalidomide pharmaceutical composition and preparation method thereof | |
| CN106902097A (en) | A kind of pharmaceutical composition for improving drug bioavailability | |
| CN106715404A (en) | Anhydrous crystalline free base form of 6-{2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]ethoxy}-3-ethoxy-1,2-benzisoxazole | |
| US20130045253A1 (en) | Oral antidepressant formulation with reduced excipient load | |
| CN115227660B (en) | Metformin hydrochloride sustained release tablet and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20230404 |