CN110664812B - Pharmaceutical composition containing imidazo isoindole derivative - Google Patents
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Abstract
The invention relates to a pharmaceutical composition containing an imidazoisoindole derivative. Specifically, the pharmaceutical composition comprises a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof and an acidic substance. The pharmaceutical composition has improved bioavailability
Description
Technical Field
The invention relates to a pharmaceutical composition containing an imidazoisoindole derivative and a preparation method thereof.
Background
Indoleamine-pyrrole-2,3-dioxygenase (IDO) is a monomeric iron-containing heme protein consisting of 403 amino acid residues, including two folded alpha-helical domains, a large domain containing a catalytic pocket in which a substrate can interact with IDO in a hydrophobic manner. IDO is an enzyme that catalyzes the conversion of tryptophan into formylkynurenine, is widely distributed in tissues other than liver of human and other mammals (rabbits and mice), is the only rate-limiting enzyme that catalyzes the catabolism of tryptophan other than liver, and tryptophan is an amino acid necessary for cell maintenance, activation and proliferation, and is also an essential component constituting proteins. IDO is closely related to various cytokines such as Interferon (IFN), interleukin (IL), tumor necrosis factor and the like, and can activate IDO under certain conditions. On one hand, IDO causes local tryptophan depletion, so that T-cells are arrested in the middle stage of G1, and the proliferation of the T-cells is inhibited; on the other hand, IDO catalyzes the main product of tryptophan metabolism and canine urea to induce T-cell apoptosis by oxygen free radical mediated changes in intracellular oxidants and antioxidants, which is an inherent immunosuppressive mechanism existing in the body. A large number of studies at present show that IDO is highly expressed in leukemia cells, so that local T cell proliferation is inhibited, T-cell mediated immune reaction is inhibited, T-cell activation signal transduction is inhibited, and the attack of tumor cells escaping from an immune system is mediated. It has been found that most human tumors constitutively express IDO. Therefore, IDO is a potential target for cancer immunotherapy.
The IDO inhibitor has good application prospect in the pharmaceutical industry as a medicament. WO2016169421 discloses a structurally novel, highly potent and low-toxic selective IDO inhibitor compound having excellent effects and effects, especially excellent drug absorption activity, which is chemically named (S) -2- (4- (4- (4- (6-fluoro-5H-imidazo [5,1-a ] isoindol-5-yl) piperidin-1-yl) phenyl) -1H-pyrazol-1-yl) ethanol and has a chemical structure shown in formula (I),
in the research, the compound shown in the formula (I) is prepared into the pharmaceutical composition, and the bioavailability is insufficient. Even if the dosage of the composition is increased, the bioavailability is not obviously improved, which brings difficulty to the clinical application of the compound shown in the formula (I).
Disclosure of Invention
In order to solve the above technical problems, it is an object of the present invention to provide a pharmaceutical composition comprising a compound represented by formula (I), which has improved bioavailability.
The invention provides a pharmaceutical composition which comprises a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof and an acidic substance.
In certain embodiments, the acidic material has a pH of no greater than 3 when prepared as a 0.1mol/L aqueous solution.
The acidic substance may be an organic or inorganic acid, and may be, for example, one or more of hydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfuric acid, methanesulfonic acid, acetic acid, propionic acid, malonic acid, oxalic acid, gluconic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, pyruvic acid, hydroxybutyric acid, adipic acid, salicylic acid, embonic acid, phthalic acid, aspartic acid, glutamic acid, mandelic acid, benzoic acid and ascorbic acid, preferably citric acid and/or tartaric acid. The acidic material may be present in an amount ranging from 1% to 70%, preferably from 5% to 60%, more preferably from 10% to 55%, based on the total weight of the composition.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a cyclodextrin.
The cyclodextrin may be alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin or derivatives thereof. Known cyclodextrin derivatives include, but are not limited to, sulfoalkyl ether cyclodextrin derivatives, alkyl ether cyclodextrin derivatives (e.g., methyl, ethyl, and propyl ether cyclodextrins), hydroxyalkyl cyclodextrin derivatives, sulfanyl ether cyclodextrin derivatives, carboxylated cyclodextrin derivatives (e.g., succinyl- β -cyclodextrin, etc.), sulfated cyclodextrin derivatives, and the like. For example, the cyclodextrin may be sulfobutyl- β -cyclodextrin, hydroxypropyl- β -cyclodextrin, hydroxyethyl- β -cyclodextrin, glucosyl- β -cyclodextrin, methyl- β -cyclodextrin. The cyclodextrin may be present in an amount ranging from 1% to 70%, preferably from 5% to 60%, more preferably from 10% to 55%, based on the total weight of the composition.
In the pharmaceutical composition of the present invention, the content of the compound represented by the formula (I) may range from 1% to 30%, preferably from 5% to 25%, based on the total weight of the composition.
In certain embodiments, the pharmaceutical compositions of the present invention further comprise a filler, which may be one or more of microcrystalline cellulose, mannitol, pregelatinized starch, lactose and the like. The filler is present in an amount of about 10% to about 70% based on the total weight of the composition.
In certain embodiments, the pharmaceutical composition of the present invention further comprises a disintegrant, which may be one or more of croscarmellose sodium, starch, sodium carboxymethyl starch, and crospovidone. The disintegrant may be present in an amount of 1% to 30% based on the total weight of the composition.
In certain embodiments, the pharmaceutical composition of the present invention further comprises a binder, which may be one or more of hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, methyl cellulose, and the like. The binder content may be 0.5% to 15% based on the total weight of the composition.
In certain embodiments, the pharmaceutical compositions of the present invention further comprise a lubricant, which may be one or more of magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, aerosil, talc, colloidal silica. The lubricant may be present in an amount of 0.5% to 5% based on the total weight of the composition.
In certain embodiments, the pharmaceutical composition of the present invention is an oral formulation, preferably a tablet or capsule.
In another aspect of the present invention, there is provided a pharmaceutical composition comprising:
1) A compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably in an amount of from 1% to 30%, preferably from 5% to 25%, by weight of the total composition;
2) An acidic substance selected from one or more of hydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfuric acid, methanesulfonic acid, acetic acid, propionic acid, malonic acid, oxalic acid, gluconic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, pyruvic acid, hydroxybutyric acid, adipic acid, salicylic acid, pamoic acid, phthalic acid, aspartic acid, glutamic acid, mandelic acid, benzoic acid and ascorbic acid, preferably citric acid and/or tartaric acid, preferably in an amount of from 1% to 70%, preferably from 5% to 60%, more preferably from 10% to 55%, based on the total weight of the composition.
3) A filler selected from one or more of microcrystalline cellulose, mannitol, pregelatinized starch, lactose, and the like, preferably in an amount of 10% to 70% based on the total weight of the composition;
4) A disintegrant selected from one or more of croscarmellose sodium, starch, sodium carboxymethyl starch, and crospovidone, preferably in an amount of 1% to 30% based on the total weight of the composition;
5) A binder selected from one or more of hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, methyl cellulose, etc., preferably in an amount of 0.5-15% based on the total weight of the composition;
6) A lubricant selected from one or more of magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, aerosil, talc, colloidal silicon dioxide, preferably in an amount of 0.5% to 5% by weight of the total composition.
In another aspect of the present invention, there is provided a pharmaceutical composition comprising:
1) A compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably in an amount of from 1% to 30%, preferably from 5% to 25%, by weight of the total composition;
2) A cyclodextrin selected from sulfobutyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin or methyl-beta-cyclodextrin, preferably in an amount of from 1% to 70%, preferably from 5% to 60%, more preferably from 10% to 55%, based on the total weight of the composition.
3) A filler selected from one or more of microcrystalline cellulose, mannitol, pregelatinized starch, lactose, and the like, preferably in an amount of 10% to 70% based on the total weight of the composition;
4) A disintegrant selected from one or more of croscarmellose sodium, starch, sodium carboxymethyl starch, and crospovidone, preferably in an amount of 1% to 30% based on the total weight of the composition;
5) A binder selected from one or more of hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, methyl cellulose, etc., preferably in an amount of 0.5-15% based on the total weight of the composition;
6) A lubricant selected from one or more of magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, aerosil, talc, colloidal silicon dioxide, preferably in an amount of 0.5% to 5% by weight based on the total weight of the composition.
The content of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof in the pharmaceutical composition can be 1-1000mg, preferably 10-500mg, and more preferably 20-200mg.
In another aspect, the present invention provides a method for preparing the pharmaceutical composition of the present invention, comprising the step of mixing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients.
For example, the method may comprise the step of mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with an acidic substance and one or more pharmaceutically acceptable excipients.
For example, the method may comprise the step of mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with a cyclodextrin and one or more pharmaceutically acceptable excipients.
The pharmaceutical compositions of the present invention may be prepared by methods well known in the art. For example, in the case of granules, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and an excipient, a binder, a disintegrant, a wetting agent, and the like may be mixed as needed, and subjected to stirring granulation, extrusion granulation, rotary granulation, one-step spray granulation, and the like, or may be subjected to direct dry granulation. In addition, the medicine can also be prepared by a micro-pill medicine application mode. In addition, the particles may be granulated and pulverized as necessary. Further, the granules may be added with excipients, disintegrants, binders, antioxidants, colorants, etc. and tabletted to tablets or directly filled into capsules.
The pharmaceutical composition of the present invention can be used for preventing and/or treating and preventing diseases with pathological features of IDO mediated tryptophan metabolic pathway. These diseases include infection by viruses such as AIDS, cell infections such as lyme disease and streptococcal infection, neurodegenerative disorders (e.g., alzheimer's disease, huntington's disease and parkinson's disease), autoimmune diseases, depression, anxiety, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer), ocular disease states (e.g., cataracts and age-related yellowing), and autoimmune diseases, wherein the cancer may be selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
The compound shown in the formula (I) or the pharmaceutically acceptable salt thereof can be in any form, and specific forms include but are not limited to: amorphous, random crystalline, hydrate, solvate, and the like.
The invention unexpectedly greatly improves the bioavailability of the composition by adding the acidic substance or the cyclodextrin into the composition, and is beneficial to the drug effect of the drug.
Drawings
FIG. 1 is a graph of in vitro dissolution profiles of the formulations obtained in examples 1-3;
FIG. 2 is a graph showing the simulated administration dissolution profiles of the formulations obtained in examples 1 to 3;
FIG. 3 is a graph of simulated dosing dissolution for the formulation obtained in example 4;
fig. 4 is a graph comparing the mean plasma concentration-time curves of the formulations obtained in examples 1, 2 and 4 in humans.
Detailed Description
Example 1: prescription without adding acidic substance
A compound medicine composition formula (mass percent) shown in formula (I):
mixing the compound represented by the formula (I), lactose, microcrystalline cellulose and croscarmellose sodium, adding an aqueous solution of polyvinylpyrrolidone, performing wet granulation by a granulator, performing fluidized bed drying, performing dry granulation by the granulator, adding magnesium stearate, mixing, tabletting, and coating with a film coating premix to prepare tablets of the compound represented by the formula (I) having a specification of 100 mg.
Example 2: prescription for adding citric acid
A compound medicine composition formula (mass percent) shown in formula (I):
mixing the compound shown in the formula (I), lactose, microcrystalline cellulose and crosslinked polyvinylpyrrolidone, adding ethanol water solution of polyvinylpyrrolidone, performing wet granulation by using a granulator, performing fluidized bed drying, and performing dry granulation by using the granulator; crushing citric acid, performing one-step granulation by adopting ethanol water solution, and performing dry granulation; the granules of the compound represented by the formula (I) after wet granulation, the granules after citric acid granulation, crospovidone (added) and magnesium stearate were mixed, tableted, and coated with a film-coating premix to prepare tablets of the compound represented by the formula (I) having a specification of 100 mg.
Example 3: prescription for adding tartaric acid
A compound medicine composition formula (mass percent) shown in formula (I):
according to the method of example 2, tablets containing 100mg of the compound represented by the formula (I) were prepared.
Example 4: formula of adding sulfobutyl-beta-cyclodextrin
A compound of formula (I) pharmaceutical composition formula (45 tablets):
mixing the compound shown in formula (I), lactose, microcrystalline cellulose, croscarmellose sodium, sulfobutyl-beta-cyclodextrin and polyvinylpyrrolidone, adding magnesium stearate, mixing, and tabletting.
Example 5: in vitro dissolution test
In vitro dissolution measurements were performed on the tablet samples obtained in examples 1-3 according to the second method of 0931, the four general guidelines of the chinese pharmacopoeia 2015 year edition. 1000ml of 0.08% sodium lauryl sulfate in pH4.5 acetate buffer was used as the dissolution medium and dissolution tests were performed at 37. + -. 0.5 ℃ and a paddle speed of 75rpm, the test results are shown in FIG. 1.
The results show that the tablets of examples 1-3 were completely and well dissolved within 45 min.
Example 6: simulated drug delivery test
The tablet samples obtained in examples 1 to 4 were subjected to a simulated administration test according to the second method of the four general rules 0931 of the year edition of the chinese pharmacopoeia 2015. 6 tablets obtained in examples 1 to 4 were charged, respectively, and dissolution test was carried out at 37. + -. 0.5 ℃ and 75rpm using 50ml of hydrochloric acid with pH of 3.0 +100ml of purified water as dissolution medium, as shown in Table 1, and the test results are shown in FIGS. 2 and 3.
TABLE 1
The results show that, although the in vitro dissolution test was acceptable, the sample of example 1 to which no acidic substance was added did not substantially dissolve under the dissolution method simulating the administration of a drug to a human; on the other hand, the samples of examples 2 and 3, to which the acidic substance was added, were able to dissolve out 85% or more within 45min, and were good in dissolution. The sample of example 4, to which cyclodextrin was added, was able to dissolve more than 85% within 45min, and was good in dissolution. The excellent dissolution of the preparation in a simulated in-vivo environment is beneficial to the absorption of the medicine by a human body and increases the bioavailability.
Example 7
The pharmacokinetic parameters of the drug were determined in healthy humans using the tablet samples of example 1, example 2 and example 4. A single oral administration of 6 tablet samples (non-crossover) was performed on healthy male subjects who received a flat light diet late in the day before the test, fasted to the next morning after dinner and orally administered the test drug 200ml warm water on an empty stomach early in the morning of the test day. After the subjects took the drugs for two cycles, venous blood was collected at the time points of the experimental design, and the elapsed blood concentration of TCS in whole blood was measured by LC-MS/MS, the mean blood concentration-time curve is shown in fig. 4, and the mean AUC and Cmax data are shown in table 2 below.
TABLE 2
From the results, it can be seen that the tablet of example 1 has good in vitro dissolution, but poor in vivo bioavailability. The bioavailability of the tablet of example 2 with citric acid was high, and the AUC was 3 times higher than that of the tablet without the acidic substance. The addition of the acidic substance greatly improves the exposure of the medicine in vivo and enhances the medicine effect. The bioavailability of the example 4 tablet is greatly improved compared with the example 1 tablet, and the individual difference is obviously improved.
Claims (5)
1. A pharmaceutical composition comprising (amounts based on the total weight of the composition):
1) 1-30% of a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof;
2) An acidic substance selected from citric acid and/or tartaric acid, in an amount of 10% -55%;
3) A filling agent, which is selected from one or more of microcrystalline cellulose, mannitol, pregelatinized starch and lactose, and the content is 10-70%;
4) Disintegrating agent, selected from one or more of croscarmellose sodium, starch, sodium carboxymethyl starch and crospovidone, with a content of 1% -30%;
5) The adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and methylcellulose, and the content of the adhesive is 0.5 to 15 percent;
6) A lubricant selected from one or more of magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, superfine silica powder, pulvis Talci, and colloidal silicon dioxide, with a content of 0.5% -5%,
2. the pharmaceutical composition of claim 1, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is present in an amount of 5% to 25%.
3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition is an oral formulation.
4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is a tablet or capsule.
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Citations (3)
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WO2016169421A1 (en) * | 2015-04-21 | 2016-10-27 | 江苏恒瑞医药股份有限公司 | Imidazo isoindole derivative, preparation method therefor and medical use thereof |
WO2018072743A1 (en) * | 2016-10-21 | 2018-04-26 | 苏州盛迪亚生物医药有限公司 | Use of pd-1 antibody conjugated with ido inhibitor in preparing anti-tumor drug |
WO2018072742A1 (en) * | 2016-10-21 | 2018-04-26 | 江苏恒瑞医药股份有限公司 | Crystalline form of free base of imidazo isoindole derivative and preparation method therefor |
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WO2016169421A1 (en) * | 2015-04-21 | 2016-10-27 | 江苏恒瑞医药股份有限公司 | Imidazo isoindole derivative, preparation method therefor and medical use thereof |
WO2018072743A1 (en) * | 2016-10-21 | 2018-04-26 | 苏州盛迪亚生物医药有限公司 | Use of pd-1 antibody conjugated with ido inhibitor in preparing anti-tumor drug |
WO2018072742A1 (en) * | 2016-10-21 | 2018-04-26 | 江苏恒瑞医药股份有限公司 | Crystalline form of free base of imidazo isoindole derivative and preparation method therefor |
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