CN117224522B - Pharmaceutical composition, preparation method thereof and pharmaceutical preparation - Google Patents
Pharmaceutical composition, preparation method thereof and pharmaceutical preparation Download PDFInfo
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- CN117224522B CN117224522B CN202311524088.2A CN202311524088A CN117224522B CN 117224522 B CN117224522 B CN 117224522B CN 202311524088 A CN202311524088 A CN 202311524088A CN 117224522 B CN117224522 B CN 117224522B
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 80
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000000825 pharmaceutical preparation Substances 0.000 title abstract description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 160
- 239000004094 surface-active agent Substances 0.000 claims abstract description 86
- 239000004064 cosurfactant Substances 0.000 claims abstract description 25
- 239000004480 active ingredient Substances 0.000 claims abstract description 23
- -1 polyoxyethylene Polymers 0.000 claims abstract description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 13
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 13
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 10
- 239000004359 castor oil Substances 0.000 claims abstract description 10
- 235000019438 castor oil Nutrition 0.000 claims abstract description 10
- 125000005456 glyceride group Chemical group 0.000 claims abstract description 10
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims abstract description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000002148 esters Chemical class 0.000 claims abstract description 8
- BKVAAWMQOQLENB-UHFFFAOYSA-N 15-hydroxy stearic acid Chemical compound CCCC(O)CCCCCCCCCCCCCC(O)=O BKVAAWMQOQLENB-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229920002675 Polyoxyl Polymers 0.000 claims abstract description 5
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 5
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 3
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 claims abstract description 3
- 239000000194 fatty acid Substances 0.000 claims abstract description 3
- 229930195729 fatty acid Natural products 0.000 claims abstract description 3
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- 229920000136 polysorbate Polymers 0.000 claims abstract description 3
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- 239000007787 solid Substances 0.000 claims description 7
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- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 4
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 2
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
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- 238000004090 dissolution Methods 0.000 abstract description 22
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- 239000000523 sample Substances 0.000 description 34
- 238000012360 testing method Methods 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
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- 241000700159 Rattus Species 0.000 description 3
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- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 101100248253 Arabidopsis thaliana RH40 gene Proteins 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 238000010812 external standard method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
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- FPLYNRPOIZEADP-UHFFFAOYSA-N octylsilane Chemical group CCCCCCCC[SiH3] FPLYNRPOIZEADP-UHFFFAOYSA-N 0.000 description 2
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- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000271309 Aquilaria crassna Species 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 101000656751 Haloarcula marismortui (strain ATCC 43049 / DSM 3752 / JCM 8966 / VKM B-1809) 30S ribosomal protein S24e Proteins 0.000 description 1
- 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 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
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- 239000007884 disintegrant Substances 0.000 description 1
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- 229940088679 drug related substance Drugs 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
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- 239000007902 hard capsule Substances 0.000 description 1
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- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
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- 239000003960 organic solvent Substances 0.000 description 1
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- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
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- 229930003799 tocopherol Natural products 0.000 description 1
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- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of pharmaceutical preparations, and relates to a pharmaceutical composition which comprises one or more of Bragg furan, a first type of surfactant and a cosurfactant selected from a second type of surfactant and a cosurfactant; the weight ratio of the first surfactant to the second surfactant is 0.4:1-5:1, and the weight ratio of the first surfactant to the cosurfactant is 0.1:1-6:1; the first class of surfactants is selected from the group consisting of polyethylene glycol 15-hydroxystearate, castor oil polyoxyl esters, tween and polyoxyethylene hydrogenated castor oil; the second class of surfactants is selected from caprylic capric polyethylene glycol glyceride, oleoyl polyoxyethylene glyceride and span; the cosurfactant is selected from propylene glycol, polyethylene glycol, polyglycerol fatty acid esters and diethylene glycol monoethyl ether. Also relates to a preparation method of the pharmaceutical preparation and the pharmaceutical composition. The pharmaceutical composition is submicron emulsion or microemulsion particles, has good emulsifying state, high active ingredient content, low impurity content, long-term stability, quick dissolution and good pharmacokinetic effect.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition and a preparation method thereof, and a pharmaceutical preparation.
Background
Bragg furan (buagakura), chemical name (1R, 6S, 9R) 6,10,10-trimethyl-2-butyl-oxatricyclo [7.2.1.0 ] 1,6 ]The twelve-2-alkene is a derivative of agarofuran which is a chemical component in agalloch eaglewood, and is prepared by a chemical synthesis method. Bragg furan showed anxiolytic effect in various animal tests and has low toxic and side effects.
The Bragg furan is oily at the temperature, has poor water solubility and unstable quality, can be obviously degraded after being placed at room temperature for 3 months, and needs to be placed in a refrigerator (2-8 ℃) during long-term storage. The dissolution rate of the bragg furan affects its oral absorption efficiency. The solid dispersion of the Bragg furan is prepared by a researcher by adopting a solid dispersion technology, so that the in-vitro dissolution of the Bragg furan can be improved, the medicine solidification is realized, the stability of the Bragg furan is improved, and the Bragg furan is convenient to store for a long time. However, a large amount of organic solvent is required in the preparation of the solid dispersion, which has special requirements on the production environment, and the solvent residue of the final product is controlled through a certain process step.
Thus, there is a need for a new pharmaceutical composition of Bragg furan that overcomes the above-described deficiencies in the prior art.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition containing active ingredient of the Bragg furan, which has good emulsifying state in water or in vivo, can spontaneously form submicron emulsion particles or micro emulsion particles and has good absorption effect; the pharmaceutical composition has high active ingredient content, low impurity content, high stability, long-term stability, rapid dissolution, and good pharmacokinetic effect. It is a further object of the present invention to provide a pharmaceutical formulation comprising the above pharmaceutical composition. It is still another object of the present invention to provide a method for preparing the above pharmaceutical composition.
To achieve the above object, the first aspect of the present invention relates to a pharmaceutical composition comprising active ingredient spread furan, a first type of surfactant and one or more selected from a second type of surfactant and cosurfactants; wherein,
the weight ratio of the first type of surfactant to the second type of surfactant is 0.4:1-5:1 (e.g., 0.7:1, 0.8:1, 1:1, 1.5:1, 2:1, 2.4:1, 3:1, 3.5:1, 4:1, 4.3:1, 4.8:1, 5:1), and/or the weight ratio of the first type of surfactant to the co-surfactant is 0.1:1-6:1 (e.g., 0.5:1, 0.8:1, 1:1, 1.5:1, 2:1, 2.5:1, 2.7:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.2:1, 5.5:1, 5.8:1, 6:1);
the first surfactant is selected from one or more of 15-hydroxystearic acid polyethylene glycol ester, castor oil polyoxyl ester, tween and polyoxyethylene hydrogenated castor oil; the second class of surfactants are selected from one or more of caprylic/capric polyethylene glycol glyceride, oleoyl polyoxyethylene glyceride and span; the cosurfactant is selected from one or more of propylene glycol, polyethylene glycol, polyglycerol fatty acid ester and diethylene glycol monoethyl ether.
In some embodiments of the first aspect of the present invention, the first class of surfactants is selected from one or more of polyethylene glycol 15-hydroxystearate, castor oil polyoxyl ester (35), tween 80, tween 20 and polyoxyethylene 40 hydrogenated castor oil.
In some embodiments of the first aspect of the present invention, the second class of surfactants is selected from one or more of caprylic capric polyethylene glycol glyceride, oleoyl polyoxyethylene glyceride, and span 80.
In some embodiments of the first aspect of the invention, the active ingredient bragg furan is present in the pharmaceutical composition in an amount of greater than 0% and less than or equal to 40%, for example 0.5%, 1%, 2%, 3%, 4%, 5%, 7%, 9%, 10%, 12%, 15%, 17%, 18%, 20%, 22%, 23%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 37%, 38%, 40% by weight.
In some embodiments of the first aspect of the invention, the first class of surfactants is present in the pharmaceutical composition in an amount of 20% to 90% by weight, for example 21%, 23%, 25%, 27%, 30%, 33%, 35%, 37%, 40%, 42%, 45%, 46%, 50%, 52%, 54%, 55%, 57%, 58%, 60%, 62%, 65%, 67%, 68%, 70%, 72%, 74%, 76%, 80%, 83%, 85%, 87%, 89%, 90%.
In some embodiments of the first aspect of the invention, the pharmaceutical composition comprises a bragg furan, a first class of surfactants and a co-surfactant, wherein the amount of the bragg furan in the pharmaceutical composition is 5% -30% by weight, such as 7%, 9%, 10%, 12%, 15%, 17%, 18%, 20%, 21%, 23%, 25%, 27%, 29%, 30%.
In some embodiments of the first aspect of the invention, the first class of surfactants is present in the pharmaceutical composition in an amount of 25% to 90% by weight, e.g., 27%, 30%, 33%, 35%, 37%, 40%, 43%, 45%, 47%, 50%, 52%, 55%, 58%, 60%, 63%, 65%, 67%, 70%, 72%, 75%, 77%, 80%, 83%, 85%, 88%, 90%.
In some embodiments of the first aspect of the invention, the pharmaceutical composition comprises active ingredient as a first class of surfactants and a second class of surfactants, wherein the weight content of the first class of surfactants in the pharmaceutical composition is 15% -40%, for example 17%, 19%, 20%, 22%, 25%, 27%, 30%, 31%, 33%, 35%, 37%, 38%, 39%, 40%.
In some embodiments of the first aspect of the invention, the first class of surfactants is present in the pharmaceutical composition in an amount of 20% to 50% by weight, for example 22%, 24%, 25%, 27%, 30%, 33%, 35%, 38%, 40%, 42%, 43%, 45%, 47%, 49%, 50%.
In some embodiments of the first aspect of the invention, the pharmaceutical composition further comprises a cosurfactant.
In some embodiments of the first aspect of the present invention, the pharmaceutical composition is any one of the following:
A. the pharmaceutical composition comprises the following components in percentage by weight:
5% -30% (e.g., 7%, 9%, 10%, 12%, 15%, 17%, 18%, 20%, 21%, 23%, 25%, 27%, 29%, 30%) of Bragg furan
First class of surfactants 25% -90% (e.g., 27%, 30%, 33%, 35%, 37%, 40%, 43%, 45%, 47%, 50%, 52%, 55%, 58%, 60%, 63%, 65%, 67%, 70%, 72%, 75%, 77%, 80%, 83%, 85%, 88%, 90%)
Cosurfactants 5% -60% (e.g. 7%, 9%, 10%, 11%, 12%, 15%, 18%, 20%, 23%, 25%, 27%, 30%, 33%, 35%, 38%, 40%, 43%, 46%, 48%, 50%, 52%, 55%, 57%, 59%, 60%);
B. the pharmaceutical composition comprises the following components in percentage by weight:
15% -40% (e.g., 17%, 19%, 20%, 22%, 25%, 27%, 30%, 31%, 33%, 35%, 37%, 38%, 39%, 40%)
20% -50% (e.g., 22%, 24%, 25%, 27%, 30%, 33%, 35%, 38%, 40%, 42%, 43%, 45%, 47%, 49%, 50%) of a first class of surfactants
A second class of surfactants 10% -45% (e.g., 12%, 15%, 17%, 19%, 20%, 22%, 24%, 25%, 27%, 30%, 33%, 35%, 38%, 40%, 42%, 43%, 45%);
preferably, the pharmaceutical composition further comprises 10% -35% by weight of cosurfactants, e.g. 12%, 15%, 17%, 19%, 20%, 22%, 24%, 25%, 27%, 30%, 33%, 35%.
In some embodiments of the first aspect of the invention, the pharmaceutical combination further comprises a pharmaceutical excipient other than the surfactant and the cosurfactant.
In some embodiments of the first aspect of the present invention, the pharmaceutical excipients other than the surfactant and cosurfactant are selected from one or more of an oil phase, a solvent, an antioxidant, a filler, a binder, a disintegrant, a lubricant, a coating material.
In some embodiments of the first aspect of the present invention, the pharmaceutical excipients other than the surfactant and cosurfactant are selected from one or both of an oil phase and an antioxidant.
In some embodiments of the first aspect of the present invention, the oil phase may be 12% -15% by weight of the pharmaceutical composition.
In the present invention, antioxidants include, but are not limited to, butyl hydroxyanisole, dibutyl hydroxytoluene, tocopherols, and the like.
In some embodiments of the first aspect of the present invention, the antioxidant may be present in the pharmaceutical composition in an amount of 0% to 0.2% by weight.
The second aspect of the present invention relates to a pharmaceutical formulation comprising the pharmaceutical composition according to the first aspect of the present invention.
In some embodiments of the second aspect of the invention, the pharmaceutical formulation is a solid oral formulation.
In some embodiments of the second aspect of the present invention, the solid oral formulation is selected from one or more of granules, tablets (e.g., dispersible tablets, effervescent tablets, sustained-release tablets, etc.), pills, and capsules (e.g., hard capsules, soft capsules, sustained-release capsules, etc.).
A third aspect of the invention relates to a method for preparing a pharmaceutical composition according to the first aspect of the invention, comprising the steps of:
the active ingredient spread furan is mixed with one or more of a first class of surfactants, a co-surfactant and a second class of surfactants.
In some embodiments of the third aspect of the invention, the oil phase and the antioxidant are added and mixed with the other materials during mixing.
In some embodiments of the third aspect of the invention, the active ingredient, the bragg furan, is in a liquid state during mixing. The Bragg furan is solid at the temperature of 2-8 ℃ and can be gradually melted into oily liquid at the room temperature of 25 ℃. Preferably, the temperature is maintained at not less than 25℃ (e.g., 37℃) prior to and during mixing.
In some embodiments of the third aspect of the invention, the first type of surfactant is in a liquid state during mixing.
The invention has the beneficial effects that:
1. the pharmaceutical composition can spontaneously form submicron emulsion particles with the average particle diameter of 100-1000 nm or below 100nm in water or in vivo, has good emulsifying state, and has excellent in vivo absorption effect.
2. The pharmaceutical composition of the invention has high stability, high content of active ingredients and low content of impurities.
3. After the accelerated test, the average particle size, the dissolution rate, the content of active ingredients and the content of impurities of the pharmaceutical composition have no obvious change, which proves that the pharmaceutical composition can be kept stable for a long time.
4. The active ingredient of the pharmaceutical composition of the invention, namely the Bragg furan, can be rapidly dissolved out.
5. The pharmaceutical composition has good pharmacokinetic effect.
6. The preparation method of the pharmaceutical composition has no special requirements on production environment, is simple and convenient, and is suitable for industrialized popularization.
Drawings
In order that the invention may be more readily understood, a more particular description of the invention will be rendered by reference to specific embodiments thereof that are illustrated in the appended drawings, in which
FIG. 1 is an in vitro dissolution profile of a Bragg furan capsule (samples 1-5, 28 and drug substance) prepared according to the method of example 6 of the present invention;
FIG. 2 is an in vitro dissolution curve of an accelerated test of a Bragg furan capsule (sample 3) prepared in example 6 of the present invention;
FIG. 3 is an in vitro dissolution profile of an accelerated test of a Bragg furan capsule (control sample 7) prepared in example 6 of the present invention;
FIG. 4 is a graph showing the plasma concentration versus time of pharmacokinetic experiments for the Bragg furan capsules (sample 1) prepared in example 6 of the present invention and the control drug.
Description of the embodiments
Embodiments of the present invention will now be described more fully hereinafter with reference to the accompanying examples, in which it is shown, however, that the examples are shown, and in which the invention is practiced. The following description of at least one exemplary embodiment is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The following reagents or materials are shown in table 1 for english names, chinese names and commodity information.
TABLE 1
Example 1: preparation of pharmaceutical compositions containing Bragg furan
Pharmaceutical compositions containing bragg furan were prepared according to the formulations shown in table 2, giving samples 1-11. The preparation method comprises the following steps:
(1) Weighing a prescribed amount of Bragg furan, and heating and melting at about 37 ℃ for later use;
(2) Heating Kolliphor ELP at about 60deg.C to melt;
(3) Adding the above components into Bragg furan according to the prescription, and mixing at about 37deg.C.
Table 2 formulations for samples 1-11
Example 2: preparation of pharmaceutical compositions containing Bragg furan
Pharmaceutical compositions containing bragg furan were prepared according to the formulations shown in table 3, giving samples 12-16. The preparation method comprises the following steps:
(1) Weighing a prescribed amount of Bragg furan, and heating and melting at about 37 ℃ for later use;
(2) Heating Kolliphor ELP/Kolliphor HS 15/Kolliphor RH40 at about 60deg.C to melt for use;
(3) Adding the above components into Bragg furan according to the prescription, and mixing at about 37deg.C.
TABLE 3 formulations for samples 12-16
Example 3: preparation of pharmaceutical compositions containing Bragg furan
Pharmaceutical compositions containing bragg furan were prepared according to the formulations shown in table 4, giving samples 17-21. The preparation method comprises the following steps:
(1) Weighing a prescribed amount of Bragg furan, and heating at about 37 ℃ to melt for later use;
(2) Heating Kolliphor HS15 at about 60deg.C to melt for use;
(3) Adding the above components into Bragg furan according to the prescription, and mixing at about 37deg.C.
Table 4 formulations for samples 17-21
Example 4: preparation of pharmaceutical compositions containing Bragg furan
Pharmaceutical compositions containing bragg furan were prepared according to the formulations shown in table 5, giving samples 22-24. The preparation method comprises the following steps:
(1) Weighing a prescribed amount of Bragg furan, and heating at about 37 ℃ to melt for later use;
(2) Heating Kolliphor RH40 at 60deg.C to melt;
(3) Adding the above components into Bragg furan according to the prescription, and mixing at about 37deg.C.
Table 5 formulations for samples 22-24
Example 5: preparation of pharmaceutical compositions containing Bragg furan
According to the formulation shown in Table 6, a pharmaceutical composition containing Bragg furan was prepared, giving samples 25-30. The preparation method comprises the following steps:
(1) Weighing a prescribed amount of Bragg furan, and heating at about 37 ℃ to melt for later use;
(2) Adding the above components into Bragg furan according to the prescription, and mixing at about 37deg.C.
Table 6 formulations of samples 25-30
Example 6: preparation of Bragg furan capsules or tablets
(1) And (3) directly filling the Bragg furan pharmaceutical composition prepared in the examples 1-5 into liquid-filled capsules to obtain Bragg furan capsules, wherein each Bragg furan capsule contains 15mg.
(2) The pharmaceutical compositions of the bragg furans prepared in examples 1-5 were solidified and then filled into a common gelatin hollow capsule. The solid auxiliary material colloidal silicon dioxide is directly mixed with the Bragg furan pharmaceutical composition (the weight ratio of the pharmaceutical composition to the colloidal silicon dioxide is 1.5:1-2:1) for solidification, so as to realize adsorption solidification. And filling the mixed particles into capsules to obtain the Bragg furan capsules, wherein each granule contains 15mg of Bragg furan.
(3) The pharmaceutical compositions of the Bragg furan prepared in examples 1-5 are dissolved in water together with a proper amount of water-soluble auxiliary materials such as lactose, mannitol and the like, and solidified particles are obtained through spray drying or fluidized bed granulation and the like. Adding proper amount of cross-linked sodium carboxymethylcellulose and magnesium stearate into the prepared solid particles, and mixing. And filling the granules into capsules to obtain the Bragg furan capsules, wherein each granule contains 15mg of Bragg furan.
(4) Directly tabletting the granules prepared in (2) or (3) to obtain the Bragg furan tablet, wherein each tablet contains 15mg of Bragg furan.
Comparative example 1
On the basis of sample 12 of example 2, the cosurfactant was replaced with an equal weight of a first class of surfactants, the remainder being unchanged, to give control sample 1;
based on sample 12 of example 2, the first type of surfactant was replaced with an equal weight of cosurfactant, the remainder being unchanged, giving control sample 2.
The formulations of sample 12 and control samples 1-2 are shown in Table 7.
TABLE 7
Comparative example 2
Based on sample 30 of example 5, the weight ratio of the first type surfactant to the cosurfactant was kept unchanged, and the loading of the active ingredient was increased to 16.7%, 18.2%, 20%, respectively, with the remainder unchanged, to obtain control samples 3-5.
The formulations of sample 30 and control samples 3-5 are shown in Table 8.
TABLE 8
Comparative example 3
Based on sample 3 of example 1, the first type of surfactant was replaced with an equal weight of the second type of surfactant, the remainder being unchanged, to obtain control sample 6;
based on sample 3 of example 1, the second type surfactant was replaced with an equal weight of the first type surfactant, the remainder being unchanged, to obtain a control sample 7;
the formulations of sample 3 and control samples 6-7 are shown in Table 9a.
TABLE 9a
Based on sample 19 of example 3, the first type of surfactant was replaced with an equal weight of the second type of surfactant, the remainder being unchanged, to obtain control sample 8;
the formulations of sample 19 and control sample 8 are shown in Table 9b.
TABLE 9b
Based on sample 24 of example 4, the first type of surfactant was replaced with an equal weight of the second type of surfactant, the remainder being unchanged, to obtain control sample 9;
the formulations of sample 24 and control sample 9 are shown in Table 9c.
TABLE 9c
Based on sample 26 of example 5, the first type of surfactant was replaced with an equal weight of the second type of surfactant, the remainder being unchanged, to give control sample 10;
based on sample 26 of example 5, the second type surfactant was replaced with an equal weight of the first type surfactant, the remainder being unchanged, to give control sample 11;
the formulations of sample 26 and control samples 10-11 are shown in Table 9d.
TABLE 9d
Comparative example 4
Based on sample 19 of example 3, the weights of the first type surfactant and the second type surfactant were kept unchanged, and the loading of the active ingredient was increased to 35.8% and 40.3%, respectively, and the remainder was unchanged, to obtain control samples 12 to 13.
The formulations of sample 19 and control samples 12-13 are shown in Table 10.
Table 10
Comparative example 5
Based on sample 22 of example 4, the total weight of the first and second surfactants was kept unchanged, and the weight ratios of the first and second surfactants were adjusted to 13:1 and 0.25:1, respectively, with the remainder unchanged, to obtain control samples 14-15.
The formulations of sample 22 and control samples 14-15 are shown in Table 11.
TABLE 11
Test case
1. Emulsion state observation and particle size measurement:
the sample was added to about 20 times by weight of 37℃water, the emulsified state of the sample in water was observed after stirring, the appearance of the sample was again observed after centrifugation at 3500rpm for 20 minutes, and the results are shown in Table 12.
If no delamination occurred after centrifugation of the sample, the particle size distribution (refractive index of the test object 1.59, absorptivity 0.01) was measured by a Markov nanosize meter, and the average particle size and Polydispersity (PI) were recorded.
2. Determination of the active ingredient content:
taking a certain amount of capsules (75 mg equivalent to Bragg furan) prepared in example 6, taking out the content, placing the content into a 50mL brown measuring flask, adding ethanol, shaking for 5 minutes to dissolve and dilute the content to a scale, and shaking the content uniformly; then precisely measuring 1mL, placing in a 10mL brown measuring flask, adding ethanol for dilution to a scale, shaking uniformly, filtering, and taking the subsequent filtrate as a sample solution. Another 15mg of the reference Bragg furan was taken, dissolved in 100mL of ethanol and diluted to a solution containing 0.15mg of Bragg furan per 1mL of ethanol as a reference solution. Precisely measuring 10 μl of each of the control solution and the sample solution, and injecting into a liquid chromatograph, wherein the chromatographic conditions are as follows according to high performance liquid chromatography (four general rules 0512 in the year of Chinese pharmacopoeia 2020): chromatographic column: octyl silane bonded silica gel is used as a filler; mobile phase: acetonitrile: water=80:20 (volume ratio); flow rate: 1.0 mL/min -1 The method comprises the steps of carrying out a first treatment on the surface of the Column temperature: 40 ℃; detection wavelength: 196nm; sample injection amount: 10. Mu.L; the chromatogram was recorded and the content of active ingredient in the capsule content was calculated as peak area according to the external standard method.
Wherein X is the content of active ingredients in the content of the capsule; a is that s The main peak area of the sample solution; cs is the concentration of the contents (mg/ml) in the test solution; f is a correction factor; w is the average weight of the capsule contents (mg, calculated by dividing the total weight of the contents by the number of capsules in this test); m is m a Standard weight of the capsule contents (mg, 15mg in this test); d, d s Dilution with the test sample (50×10=500 in this test); m is m s Total weight (mg) of the capsule contents taken; a is that r Is the main peak area of the reference substance solution; cr is the concentration (mg/ml) of the reference substance solution; m is m r Is the weight (mg) of the reference substance; p (P) r The purity of the reference substance; d, d r The dilution factor was the control (100-fold in this test).
3. Determination of impurity content:
taking a certain amount of capsules (equivalent to 15mg of Bragg furan) prepared in example 6, taking out the content, placing the content into a centrifuge tube, adding about 2.5mL of 1mol/L sodium hydroxide solution, swirling for 20min, adding about 7.5mL of n-hexane, swirling for about 10min after full mixing, centrifuging for 25min by using a centrifugal force of 3200rpm, and taking supernatant to obtain a sample solution. The test solution was diluted 200-fold as a 0.5% control solution.
Precisely measuring a blank solvent (n-hexane), a sample solution and a control solution, and injecting 10 mu L of each solution into a liquid chromatograph, and measuring according to high performance liquid chromatography (four general rules 0512 in the year 2020 edition of Chinese pharmacopoeia) under the following chromatographic conditions: chromatographic column: octyl silane bonded silica gel is used as a filler; mobile phase: acetonitrile: water=72:28 (volume ratio); flow rate: 1.0 mL/min -1 The method comprises the steps of carrying out a first treatment on the surface of the Column temperature: 40 ℃; detection wavelength: 196nm and 240nm; sample injection amount: 10 mu L.
Recording the chromatogram to 2 times of the retention time of the main component chromatogram peak, and starting integration in the sample solution chromatogram for 5.7 min; calculating the impurity content in the capsule content by self-contrast method with the relative response factor added, wherein the relative response factor of the impurity with the 0.27 times of the retention time of the main component chromatographic peak is 1.1, and the relative response factor of the impurity with the 0.59 times of the retention time of the main component chromatographic peak is 2.1; if other impurity peaks are shown, the impurity content in the capsule content is calculated by a self-contrast method. The same retention time positions at 196nm and 240nm respond simultaneously, with the largest one participating in the calculation, without repeating the calculation.
Wherein: f is the relative response factor of the impurity; a is that r Peak area of the bragg furan in the control solution; a is that s Peak area of impurities in the sample solution; d, d r Dilution with control solution (n-hexane is not miscible with sodium hydroxide solution in this test, only n-hexane has a dilution effect, so d) r 7.5×200=1500 times); d, d s The dilution factor of the test sample (7.5 times in the test, only n-hexane was used for dilution).
The results of items 1-3 above are shown in Table 12.
TABLE 12 test results for samples 1-30 and control samples 1-15
"/" indicates no detection.
As can be seen from table 12:
the pharmaceutical composition can spontaneously form submicron emulsion or submicron emulsion with the average particle size of 100-1000 nm or below 100nm in water, has good particle size uniformity and good emulsifying state, and has high active ingredient content and low impurity content.
Compared with the pharmaceutical composition singly adopting the first class of surfactants or singly adopting the cosurfactants, the pharmaceutical composition adopting the first class of surfactants and the cosurfactants has good emulsification state and does not generate layering phenomenon;
compared with a pharmaceutical composition which adopts excessive drug loading and simultaneously comprises a first type surfactant and a cosurfactant, the pharmaceutical composition adopting the first type surfactant and the cosurfactant has good emulsification state and does not generate layering phenomenon;
compared with the pharmaceutical composition singly adopting the second class surfactant, the pharmaceutical composition adopting the first class surfactant and the second class surfactant has good emulsification state and does not generate layering phenomenon;
compared with the pharmaceutical composition singly adopting the first-class surfactant, the pharmaceutical composition adopting the first-class surfactant and the second-class surfactant has smaller average particle size and lower impurity content;
compared with a pharmaceutical composition which adopts excessive drug loading and simultaneously comprises the first and second class surfactants, the pharmaceutical composition adopting the first and second class surfactants has better emulsification state, smaller average particle size, better particle size uniformity and lower impurity content;
compared with the medicine composition with the too high or too low proportion of the first and second class surfactants, the medicine composition adopting the first and second class surfactants has good emulsifying state and does not generate layering phenomenon.
4. Determination of in vitro dissolution profile:
the dissolution rate and release rate were measured by the dissolution rate and release rate measurement method (second method of the fourth edition of the chinese pharmacopoeia 2020 edition, rule 0931).
The pharmaceutical composition is filled into capsules according to 15mg specification, the capsules are filled into sedimentation baskets, 500mL of 0.5% sodium dodecyl sulfate solution is taken as a dissolution medium, the rotation speed is 100 revolutions per minute, the operation is performed according to the law, 5mL is sampled at 5, 10, 15, 20, 30 and 45 minutes, and the liquid is supplemented by 5mL. Filtering, and taking the subsequent filtrate as a sample solution. Taking 75mg of a Bragg furan reference substance, placing into a 25mL brown measuring flask, adding ethanol to dilute to a scale, and shaking uniformly; 1.0mL of the mixture is precisely measured and filled into capsules, the capsules are placed in a 100mL brown measuring flask, 0.5% sodium dodecyl sulfate solution is added for dilution to a scale, and the mixture is shaken uniformly to serve as a reference solution (0.03 mg of the mixture is contained in each 1mL of the mixture). And respectively precisely measuring 20 mu L of a reference substance solution and 20 mu L of a test substance solution, injecting into a high performance liquid chromatograph, recording peak areas, and calculating the dissolution rate by an external standard method. The auxiliary material interference test results show that the dissolution medium and the capsule shell have no interference to the in-vitro dissolution detection.
The in vitro dissolution profiles of samples 1-5, 28 and the capsules prepared by filling the bulk drug with the bragg furan (see method of example 6) were determined as shown in fig. 1. The results show that the in-vitro dissolution rate and the in-vitro dissolution degree of the pharmaceutical composition are obviously increased compared with those of the raw materials, and each sample has the characteristic of quick dissolution.
5. Acceleration test:
packaging the raw material medicine of the Bragg furan after filling into a hollow capsule by an aluminum bag, placing under an acceleration test condition (40+/-2 ℃ and RH75% +/-5%) for 3 months, sampling and measuring the content of active ingredients and the content of impurities respectively in 0 month, 1 month and 3 months, and the results are shown in Table 13;
the bragg furan capsules prepared in example 6 (samples 1 to 5) were packed in aluminum bags, placed under accelerated test conditions (40±2 ℃ C., 75% ±5%) for 3 months, sampled for 0 month, 1 month and 3 months respectively to determine the content of active ingredient, the content of impurity and the average particle size, and the in vitro dissolution curves of the bragg furan capsules of sample 3 for 0 month, 1 month and 3 months respectively were determined, and the determination methods were the same as those of items 1 to 4 above, and the results are shown in Table 14 and FIG. 2.
A control sample 7 was used to prepare a Bragg furan capsule according to the method of example 6, the Bragg furan capsule was packed in an aluminum bag, and placed under accelerated test conditions (40.+ -. 2 ℃ C., 75%.+ -. 5% RH) for 3 months, and samples were taken for 0 month and 1 month, respectively, to determine in vitro dissolution profiles, and the determination method was the same as that of item 4, and the results are shown in FIG. 3.
TABLE 13 accelerated test results of crude drug Bragg furan
/>
TABLE 14 accelerated test results of Bragg Furan capsules
The results show that the content of active ingredients in the bulk drug of the Bragg furan is obviously reduced and the content of impurities is obviously increased within 3 months in an acceleration test; the dissolution rate of the control sample 7 in vitro is obviously reduced after accelerating for 1 month; in the accelerated test, the content of active ingredients, the content of impurities, the average particle size and the dissolution rate of the Bragg furan capsule are not obviously changed within 3 months, and the dissolution rate is not obviously reduced, so that the stability of the pharmaceutical composition is better.
6. Pharmacokinetic experiments:
SD rats were randomly divided into 2 groups, and the solid dispersion preparation method of sample 1 and control drug in example 1 (refer to patent CN 202111481813.3) was respectively administered by gavage, wherein a drug composition containing about 10% of the Bragg furan was prepared from Bragg furan and povidone K30, the administration amount was 16mg/kg based on the Bragg furan, and blood was taken from the jugular vein of the rats at each time point of 5min, 10min, 20min, 40min, 1h, 2h, 4h, 6h, 8h, 24h after administration, the blood concentration was measured by LC-MS/MS, and the chromatographic conditions were as follows:
the gradient elution was carried out using a HALO 90 AQ-C18 column (2 μm, 3X 30 mm), a sample injection amount of 10. Mu.L, and a flow rate of 0.6mL/min with solvent A (water containing 5% by weight of acetonitrile, 0.1% by weight of formic acid) and solvent B (water containing 95% by weight of acetonitrile, 0.1% by weight of formic acid) as mobile phases according to Table 15.
TABLE 15
The plasma concentration versus time curve is shown in fig. 4.
According to the curve, using WinNonlin software and adopting non-atrioventricular model to calculate pharmacokinetic parameters, and plasma peak time, peak concentration and AUC after oral administration of positive control medicine aqueous solution to rat 0-∞ 0.5h, 104ng/mL and 239 h.ng/mL respectively; administration of drugsPeak time to peak, peak concentration to peak and AUC after sample 1 in example 1 0-∞ 0.334h, 143ng/mL and 298 h.ng/mL, respectively. The results show that the in vivo pharmacokinetics of the prepared Bragg furan pharmaceutical composition is not obviously different from that of the control medicine.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.
Claims (6)
1. A pharmaceutical composition comprising an active ingredient, a first class of surfactants, and one or more selected from the group consisting of a second class of surfactants and cosurfactants; wherein,
the weight ratio of the first class of surfactants to the second class of surfactants is 0.4:1-5:1, and/or the weight ratio of the first class of surfactants to the cosurfactants is 0.1:1-6:1;
the first surfactant is selected from one or more of 15-hydroxystearic acid polyethylene glycol ester, castor oil polyoxyl ester, tween and polyoxyethylene hydrogenated castor oil; the second class of surfactants are selected from one or more of caprylic/capric polyethylene glycol glyceride, oleoyl polyoxyethylene glyceride and span; the cosurfactant is selected from one or more of propylene glycol, polyethylene glycol, polyglycerol fatty acid ester and diethylene glycol monoethyl ether;
and, the pharmaceutical composition is any one of the following:
A. the pharmaceutical composition comprises the following components in percentage by weight:
5% -30% of Bragg furan;
25% -90% of a first surfactant;
5% -60% of cosurfactant;
B. the pharmaceutical composition comprises the following components in percentage by weight:
15% -40% of Bragg furan;
20% -50% of a first surfactant;
10% -45% of a second class of surfactants;
C. the pharmaceutical composition comprises the following components in percentage by weight:
15% -40% of Bragg furan;
20% -50% of a first surfactant;
10% -45% of a second class of surfactants;
10% -35% of cosurfactant.
2. The pharmaceutical composition of claim 1, wherein the first type of surfactant is selected from one or more of 15-hydroxystearic acid polyethylene glycol ester, castor oil polyoxyl ester 35, tween 80, tween 20 and polyoxyethylene 40 hydrogenated castor oil;
the second class of surfactants is selected from one or more of caprylic capric polyethylene glycol glyceride, oleoyl polyoxyethylene glyceride and span 80.
3. The pharmaceutical composition according to claim 1 or 2, further comprising pharmaceutical excipients other than surfactants and cosurfactants.
4. A pharmaceutical formulation comprising the pharmaceutical composition of any one of claims 1 to 3.
5. The pharmaceutical formulation of claim 4, which is a solid oral formulation; the solid oral preparation is selected from one or more of granules, tablets, pills and capsules.
6. A method of preparing the pharmaceutical composition of claim 1 or 2, comprising the steps of:
the active ingredient spread furan is mixed with one or more of a first class of surfactants, a co-surfactant and a second class of surfactants.
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| CN103585137A (en) * | 2013-11-12 | 2014-02-19 | 中国药科大学 | Paeonol lyotropic liquid crystal self-emulsified preparation and preparation method thereof |
| CN109414403A (en) * | 2016-07-11 | 2019-03-01 | 因泰克制药有限公司 | Oral Gastroretentive formulations and application thereof |
| WO2023012322A1 (en) * | 2021-08-05 | 2023-02-09 | Pharvaris Gmbh | Lipid-based composition for oral administration of bradykinin b2-receptor antagonists |
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| CN103585137A (en) * | 2013-11-12 | 2014-02-19 | 中国药科大学 | Paeonol lyotropic liquid crystal self-emulsified preparation and preparation method thereof |
| CN109414403A (en) * | 2016-07-11 | 2019-03-01 | 因泰克制药有限公司 | Oral Gastroretentive formulations and application thereof |
| WO2023012322A1 (en) * | 2021-08-05 | 2023-02-09 | Pharvaris Gmbh | Lipid-based composition for oral administration of bradykinin b2-receptor antagonists |
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