CN110013468B - AZD9291 deuterated derivative pharmaceutical preparation - Google Patents
AZD9291 deuterated derivative pharmaceutical preparation Download PDFInfo
- Publication number
- CN110013468B CN110013468B CN201810017685.9A CN201810017685A CN110013468B CN 110013468 B CN110013468 B CN 110013468B CN 201810017685 A CN201810017685 A CN 201810017685A CN 110013468 B CN110013468 B CN 110013468B
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- Prior art keywords
- azd9291
- deuterated derivative
- deuterated
- pharmaceutical preparation
- methyl
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- 229960003278 osimertinib Drugs 0.000 title claims abstract description 55
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 25
- 239000003085 diluting agent Substances 0.000 claims abstract description 13
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 10
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 10
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- 239000000203 mixture Substances 0.000 claims description 6
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical group CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 4
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- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002160 maltose Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000004300 potassium benzoate Substances 0.000 description 1
- 235000010235 potassium benzoate Nutrition 0.000 description 1
- 229940103091 potassium benzoate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical group [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
The invention provides an AZD9291 deuterated derivative medicinal preparation and a preparation method thereof, the medicinal preparation comprises an AZD9291 deuterated derivative or pharmaceutically acceptable salt thereof and a diluent, wherein D of the AZD9291 deuterated derivative or pharmaceutically acceptable salt thereof is90Is 20-280 μm. The AZD9291 deuterated derivative pharmaceutical preparation obtained by the invention has high dissolution rate and good stability, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an AZD9291 deuterated derivative medicinal preparation and a preparation method thereof.
Background
Non-small cell lung cancer includes squamous cell carcinoma (phosphorus), adenocarcinoma, large cell carcinoma, which grows and divides slowly compared to small cell carcinoma, with diffuse metastases relatively late, with non-small cell lung cancer accounting for 80% of all lung cancers, with approximately 75% of patients finding it in the middle and late stages. Epidermal Growth Factor (EGFR) is a receptor type tyrosine kinase, is an important regulator of cell growth, differentiation and survival, and can effectively control or delay the development of non-small cell type lung cancer by inhibiting the EGFR. There are currently many EGFR inhibitors (e.g., gefitinib, erlotinib), but prolonged use results in EGFR activating mutations, which have increased affinity for small molecule tyrosine kinase inhibitors and decreased affinity for adenosine triphosphate relative to wild-type EGFR, ultimately resulting in resistance to the inhibitor.
AZD9291 is disclosed in Chinese patent 201280033773.9 under the chemical name N- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide with the following chemical formula:
AZD9291 was developed successfully by Aslicon and it is a drug that selectively inhibits strongly certain mutant forms of EGFR. Compared with numerous competitors against EGFR mutations as well, AZD9291 has a distinct advantage: it can not only inhibit the EGFR mutation causing carcinogenesis, but also can continuously inhibit the EGFR mutation causing drug resistance. But it is easily demethylated by metabolism in vivo, increases the burden of liver metabolism, causes hepatotoxicity, and causes short half-life of pharmacokinetic properties in vivo, and finally affects anticancer activity of the drug.
CN104140418A shows that the disadvantages that AZD9291 is easy to be metabolized and demethylated in vivo and has short half-life of pharmacokinetics can be improved by carrying out deuteration on AZD 9291. However, the deuterated AZD9291 compounds have low in vivo solubility, are pH dependent, precipitate from solution as the drug passes through the gastrointestinal tract, cause a change in the extent and/or rate of absorption of the drug, are unstable, and present an increased risk of side effects.
Therefore, the AZD9291 deuterated derivative pharmaceutical preparation which has high in-vivo dissolution speed, good bioavailability and stable quality and is easy to prepare is needed at present.
Disclosure of Invention
The invention provides an AZD9291 deuterated derivative pharmaceutical preparation with high dissolution rate, good bioavailability and good stability and a preparation method thereof.
The invention firstly provides an AZD9291 deuterated derivative medicinal preparation which comprises an AZD9291 deuterated derivative or pharmaceutically acceptable salt thereof and a diluent, wherein the AZD9291 deuterated derivative is a compound shown as a formula (I), and the AZD9291 deuterated derivative or pharmaceutically acceptable salt thereof is D90Is 20-280 μm in diameter,
wherein:
R1is selected from methyl or methyl of 1 to 3 deuterated atoms;
R2is selected from methyl or methyl of 1 to 3 deuterated atoms;
R3is selected from methyl or methyl of 1 to 3 deuterated atoms;
R4is selected from methyl or methyl of 1 to 3 deuterated atoms;
R5is selected from methyl or methyl of 1 to 3 deuterated atoms;
R1、R2、R3、R4and R5At least one of the groups is selected from methyl groups having 1 to 3 deuterated atoms.
Preferably, the active ingredient in the AZD9291 deuterated derivative pharmaceutical preparation is selected from:
(1) n- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1- (D)3-methyl) indol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide;
(2) n- (2- { 2-dimethylaminoethyl-methylamino } -4- (D)3-methoxy) -5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide;
(3) n- (2- { 2-dimethylaminoethyl- (D)3-methyl) amino } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide;
(4) n- (2- { 2-bis (D)3-methyl) aminoethyl-methylamino } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide;
(5) n- (2- {2- [ methyl (D)3-methyl) amino]Ethyl-methylamino } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide.
More preferred is N- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1- (D)3-methyl) indol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide.
Through multiple experimental researches, the inventor finds that through controlling the derivative of AZD9291 deuterationThe particle size of the compound or the pharmaceutically acceptable salt thereof can effectively enhance the dissolution rate of the pharmaceutical preparation, and even if the pharmaceutical preparation only contains the pharmaceutically active ingredients and the diluent, the ideal dissolution effect can be achieved. Also, the present inventors have found that selection D90When the particle size of the active ingredient is within the range of 20 to 280 μm, the prepared pharmaceutical preparation can ensure good dissolution effect, has good quality stability, and does not cause decomposition and deliquescence due to the small particle size of the active ingredient.
Preferably, D of the AZD9291 deuterated derivative or the pharmaceutically acceptable salt thereof as the active ingredient in the AZD9291 deuterated derivative pharmaceutical preparation9020-160 μm; more preferably, D of the active ingredient AZD9291 deuterated derivative or pharmaceutically acceptable salt thereof90Is 20-100 μm.
In the AZD9291 deuterated derivative pharmaceutical preparation, a pharmaceutically acceptable salt can be formed by using an inorganic acid or an organic acid. For example, a pharmaceutically acceptable salt can be formed using an inorganic acid, such as one selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. It is also possible to use inorganic acids, for example selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. A preferred pharmaceutically acceptable salt is the mesylate salt.
The AZD9291 deuterated derivative pharmaceutical preparation also contains one or two of a disintegrant and a solubilizer.
The AZD9291 deuterated derivative pharmaceutical preparation comprises the following components in percentage by mass:
wherein the content of the pharmaceutically acceptable salt of the AZD9291 deuterated derivative is calculated by using the AZD9291 deuterated derivative.
The AZD9291 deuterated derivative pharmaceutical preparation also contains a lubricant; the dosage of each component is calculated by mass percent as follows:
wherein the content of the pharmaceutically acceptable salt of the AZD9291 deuterated derivative is calculated by using the AZD9291 deuterated derivative.
In another technical scheme, the AZD9291 deuterated derivative pharmaceutical preparation comprises an active ingredient N- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1- (D)3-methyl) indol-3-yl) pyrimidin-2-yl]The composition comprises a methanesulfonic acid salt of amino } phenyl) prop-2-enamide, a diluent, a disintegrating agent and a lubricant, wherein the preferable mass percentage of the dosage of each component is as follows:
wherein N- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1- (D)3-methyl) indol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide methanesulfonate in an amount of N- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1- (D)3-methyl) indol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide.
The formula dosage is screened according to the scheme, and the more preferable mass percentage of the dosage of each component of the AZD9291 deuterated derivative pharmaceutical preparation is as follows:
wherein N- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1- (D)3-methyl) indol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide methanesulfonate in an amount of N- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1- (D)3-methyl) indol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide.
The diluent in the invention can be one or more selected from microcrystalline cellulose, lactose, mannitol, calcium carbonate, calcium phosphate, calcium sulfate, fructose, sugar alcohol, magnesium carbonate, magnesium oxide, dextrin, maltose, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, glucose and the like.
The disintegrating agent can be selected from one or more of croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethylcellulose sodium, sodium carboxymethyl starch, sodium starch glycolate, dry starch, alginic acid, sodium alginate, etc.
The solubilizer can be one or more selected from polysorbate, poloxamer, polyoxyethylene alkyl ether, sorbitan monolaurate, polyoxyethylene lauryl ether, polyhydroxy 15 stearate, polyoxylglyceride, pyrrolidone, sodium lauryl sulfate, caprylic glyceride, etc.
The lubricant is selected from one or more of calcium stearate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, palmitoyl stearyl glyceride, magnesium stearate, polyethylene glycol, potassium benzoate, sodium fumarate, stearic acid, pulvis Talci, glyceryl tribehenate, and silica gel.
In the AZD9291 deuterated derivative pharmaceutical preparation, the preferable diluent is a mixture of microcrystalline cellulose and mannitol, the preferable disintegrant is low-substituted hydroxypropyl cellulose, and the preferable lubricant is sodium stearate fumarate.
The AZD9291 deuterated derivative pharmaceutical preparation can be prepared by adopting a common method in the prior art, and comprises wet granulation, dry granulation, direct tabletting and the like; the invention also provides a preparation method of the AZD9291 deuterated derivative pharmaceutical preparation, which comprises the following steps:
a. uniformly mixing AZD9291 deuterated derivatives shown in formula (I) or pharmaceutically acceptable salts thereof with a diluent, and performing dry granulation to obtain medicine granules;
b. tabletting the drug granules prepared in the step a.
The step a of the preparation method also comprises the step of adding one or two of a disintegrating agent and a solubilizing agent; step b also comprises the step of adding a lubricant.
By the invention of9020-280 mu m AZD9291 deuterated derivative or pharmaceutically acceptable salt thereof is used as a pharmaceutical active ingredient, can effectively improve the dissolution rate of insoluble drugs and promote absorption and utilization. The ideal dissolution effect can be achieved by only adding the diluent into the medicinal preparation without adding the disintegrating agent, so that the medicinal volume of unit dose is reduced, and the compliance of patients is improved.
Detailed Description
In the following examples:
compound A represents N- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1- (D)3-methyl) indol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide;
compound B represents N- (2- { 2-dimethylaminoethyl-methylamino } -4- (D)3-methoxy) -5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide;
compound C represents N- (2- { 2-dimethylaminoethyl- (D)3-methyl) amino } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide;
compound D represents N- (2- { 2-bis (D)3-methyl) aminoethyl-methylamino } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide;
compound E represents N- (2- {2- [ methyl (D)3-methyl) amino]Ethyl-methylamino } -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide;
compound F represents N- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1- (D)2-methyl) indol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide.
Example 1
The preparation process comprises the following steps:
a. mixing compound A, microcrystalline cellulose and mannitol, and granulating by dry method to obtain medicinal granule;
b. tabletting the drug granules prepared in the step a.
Example 2
The preparation process comprises the following steps:
a. fully and uniformly mixing the mesylate of the compound A, microcrystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose, and performing dry granulation to obtain medicine granules;
b. and c, uniformly mixing the medicine particles obtained in the step a with sodium stearyl fumarate, and tabletting.
Example 3
The preparation process comprises the following steps:
a. mixing compound C, lactose, croscarmellose sodium, sodium starch glycolate, sodium lauryl sulfate and polysorbate, and granulating by dry method to obtain medicinal granule;
b. and c, uniformly mixing the medicine granules obtained in the step a with glyceryl behenate, and tabletting.
Example 4
The preparation process comprises the following steps:
a. mixing compound D, sorbitol, crospovidone and poloxamer, and granulating by dry method to obtain medicinal granule;
b. and c, uniformly mixing the medicine particles obtained in the step a with calcium stearate and polyethylene glycol, and tabletting.
Example 5
The preparation process comprises the following steps:
a. mixing compound E, mannitol, calcium carbonate and sodium carboxymethyl starch, and dry granulating to obtain medicinal granule;
b. tabletting the drug granules in the step a.
Example 6
The preparation process comprises the following steps:
a. mixing the mesylate of the compound B, lactose, dextrin, low-substituted hydroxypropyl cellulose and polyoxyethylene lauryl alcohol ether, and granulating by dry method to obtain medicinal granules;
b. tabletting the drug granules in the step a.
Example 7
The preparation process comprises the following steps:
a. fully and uniformly mixing fumarate of the compound F, cane sugar, magnesium oxide and sodium starch glycolate, and performing dry granulation to obtain medicine granules;
b. and c, uniformly mixing the medicine particles obtained in the step a with the superfine silica gel powder, and tabletting.
Example 8
The preparation process comprises the following steps:
a. mixing the mesylate of the compound A, microcrystalline cellulose, mannitol and crospovidone uniformly, and granulating by a dry method to obtain medicine granules;
b. and c, uniformly mixing the medicine particles obtained in the step a with sodium fumarate, and tabletting.
Example 9
The preparation process comprises the following steps:
a. fully and uniformly mixing the mesylate of the compound A, microcrystalline cellulose, maltose and low-substituted hydroxypropyl cellulose, and performing dry granulation to obtain medicine granules;
b. and c, uniformly mixing the medicine particles obtained in the step a with sodium stearyl fumarate, and tabletting.
Example 10
The preparation process comprises the following steps:
a. fully and uniformly mixing the mesylate of the compound A, microcrystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose, and performing dry granulation to obtain medicine granules;
b. and c, uniformly mixing the medicine particles obtained in the step a with sodium stearyl fumarate, and tabletting.
Example 11
The preparation process comprises the following steps:
a. mixing the mesylate of the compound A, calcium phosphate, lactose and low-substituted hydroxypropyl cellulose, and granulating by a dry method to obtain medicinal granules;
b. and c, uniformly mixing the medicine granules obtained in the step a with talcum powder, and tabletting.
Dissolution determination
The formulations of examples 1 to 11 were subjected to dissolution (%) measurement according to the dissolution measurement method (second Paddle method in Chinese pharmacopoeia 2015 edition) using 900ml of pH6.8 phosphate buffer as dissolution medium at 50 rmp. The results are shown in Table 1.
From the above data, the AZD9291 deuterated derivative pharmaceutical preparation prepared by the method of the invention has a cumulative dissolution rate of more than 90% in 10 minutes, and D of the active ingredient in examples 1, 4, 5, 10 and 1190When the particle size is selected from 20-100 μm, the accumulative dissolution rate in 10 minutes can reach 97%, and the particle size can be completely dissolved within 60 minutes.
Stability detection
The tablets of examples 1 to 11 were continuously kept at 40. + -. 2 ℃ and RH75% +/-5% for 6 months, and the total impurity content (%) of the AZD9291 deuterated derivatives was measured by HPLC for 0 day and 6 months, and the results are shown in Table 2.
As can be seen from the data in Table 2, the AZD9291 deuterated derivative pharmaceutical preparation prepared by the method has good stability, and the total impurity content in the preparation is basically unchanged after an accelerated test for 6 months.
Comparative example 1
The components and amounts of comparative examples 1(a) to 1(e), and the preparation method are the same as example 2.
Dissolution determination
The dissolution (%) of the formulations of comparative examples 1(a) -1(e) was determined according to the dissolution determination method (second method slurry method in chinese pharmacopoeia 2015 edition) using 900ml of ph6.8 phosphate buffer as dissolution medium at 50rpm, and compared with the dissolution data of example 2, and the results are shown in table 3.
From the above comparative data, D90When the thickness is 20-280 μm, the AZD9291 deuterated derivative preparation has good dissolution effect. When D is present90Less than 20, e.g., 10 μm in example 1(a), the dissolution rate of the prepared pharmaceutical preparation is reduced due to the decrease of the active ingredient particles and the increase of the specific surface area, which results in decomposition, deliquescence, etc. When D is present90If the particle size is larger than 280 μm, as in 320 μm of example 1(e), the AZD9291 deuterated derivative has poor solubility and the drug particles are too large, so that the prepared drug preparation has low dissolution rate.
Stability detection
The tablets of comparative examples 1(a) -1(e) were simultaneously allowed to stand at 40. + -. 2 ℃ and RH75% + -5% for 6 months, and the total impurity contents (%) of the AZD9291 deuterated derivatives were measured by high performance liquid chromatography for 0 day and 6 months, and compared with the impurity contents data of the AZD9291 deuterated derivatives for 0 day and 6 months of example 2, and the results are shown in Table 4.
From the above table, it can be seen that D is a deuterated derivative of AZD929190The range is selected to be less than 20, for example, when 10 μm is used in example 1(a), the prepared pharmaceutical preparation is unstable; and D90When the range is selected to be 20-280 mu m, the prepared medicinal preparation can ensure good stability.
Comparative example 2
The preparation method is the same as example 1.
Dissolution determination
Dissolution (%) was measured according to the dissolution measurement method (second method of pharmacopoeia of China 2015 edition) using 900ml of phosphate buffer solution with pH6.8 as dissolution medium at 50rpm for the formulation of comparative example 2, and the results are shown in Table 5 in comparison with the dissolution data of example 1.
From the above comparative data, it can be seen that D is appropriately used90The particle size can effectively improve the solubility of the AZD9291 deuterated derivative, and the ideal dissolution effect can be achieved by only adding a diluent into the medicinal preparation without adding a disintegrating agent.
Claims (4)
1. An AZD9291 deuterated derivative pharmaceutical preparation is characterized by comprising mesylate of AZD9291 deuterated derivative, a diluent, a disintegrant and a lubricant; the dosage of each component is calculated by mass percent as follows: 10-30% of mesylate of AZD9291 deuterated derivative, 65-85% of diluent, 1-10% of disintegrant and 0.5-1.5% of lubricant; wherein the content of the mesylate of the AZD9291 deuterated derivative is calculated as the AZD9291 deuterated derivative; the AZD9291 deuterated derivative is N- (2- { 2-dimethylaminoethyl-methylamino } -4-methoxy-5- { [4- (1- (D3-methyl) indol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide; d of mesylate of the AZD9291 deuterated derivative90Is 20-280 μm.
2. The pharmaceutical preparation according to claim 1, wherein the amount of each component is calculated as: 20% of mesylate of AZD9291 deuterated derivative, 74% of diluent, 5% of disintegrant and 1% of lubricant; wherein the content of the mesylate of the AZD9291 deuterated derivative is calculated as the AZD9291 deuterated derivative.
3. The pharmaceutical formulation of claim 1, wherein the diluent is a mixture of microcrystalline cellulose and mannitol; the disintegrant is low-substituted hydroxypropyl cellulose.
4. The pharmaceutical formulation of claim 1, wherein the lubricant is sodium stearyl fumarate.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103006608A (en) * | 2012-12-04 | 2013-04-03 | 姚俊华 | Drug composition containing gefitinib |
| WO2014028914A1 (en) * | 2012-08-17 | 2014-02-20 | Beta Pharma, Inc. | Deuterated icotinib derivatives |
| CN105848647A (en) * | 2014-01-02 | 2016-08-10 | 阿斯利康(瑞典)有限公司 | Pharmaceutical compositions comprising AZD9291 |
| CN106176752A (en) * | 2015-05-07 | 2016-12-07 | 石药集团中奇制药技术（石家庄）有限公司 | ceritinib pharmaceutical composition |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014028914A1 (en) * | 2012-08-17 | 2014-02-20 | Beta Pharma, Inc. | Deuterated icotinib derivatives |
| CN103006608A (en) * | 2012-12-04 | 2013-04-03 | 姚俊华 | Drug composition containing gefitinib |
| CN105848647A (en) * | 2014-01-02 | 2016-08-10 | 阿斯利康(瑞典)有限公司 | Pharmaceutical compositions comprising AZD9291 |
| CN106176752A (en) * | 2015-05-07 | 2016-12-07 | 石药集团中奇制药技术（石家庄）有限公司 | ceritinib pharmaceutical composition |
Non-Patent Citations (1)
| Title |
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| 氘代AZD9291的合成;康芳圆等;《合成化学》;20161231;第24卷(第3期);第263-265页 * |
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