CN117503699A - Aprepitant oral liquid preparation and preparation method - Google Patents
Aprepitant oral liquid preparation and preparation method Download PDFInfo
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- CN117503699A CN117503699A CN202311677055.1A CN202311677055A CN117503699A CN 117503699 A CN117503699 A CN 117503699A CN 202311677055 A CN202311677055 A CN 202311677055A CN 117503699 A CN117503699 A CN 117503699A
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- aprepitant
- oral liquid
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- solution
- liquid formulation
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- 229960001372 aprepitant Drugs 0.000 title claims abstract description 85
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 title claims abstract description 85
- 238000002360 preparation method Methods 0.000 title claims abstract description 64
- 239000007788 liquid Substances 0.000 title claims abstract description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 229930006000 Sucrose Natural products 0.000 claims abstract description 11
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims abstract description 11
- 239000005720 sucrose Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 239000008139 complexing agent Substances 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 8
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims abstract description 8
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical group [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims abstract 2
- 241000289690 Xenarthra Species 0.000 claims abstract 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- 239000008213 purified water Substances 0.000 claims description 18
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 14
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical group CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 14
- 229960003415 propylparaben Drugs 0.000 claims description 11
- 239000000796 flavoring agent Substances 0.000 claims description 10
- 235000013355 food flavoring agent Nutrition 0.000 claims description 10
- 235000003095 Vaccinium corymbosum Nutrition 0.000 claims description 9
- 235000017537 Vaccinium myrtillus Nutrition 0.000 claims description 9
- 235000021014 blueberries Nutrition 0.000 claims description 9
- 240000000851 Vaccinium corymbosum Species 0.000 claims description 8
- 239000003755 preservative agent Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 230000002335 preservative effect Effects 0.000 claims description 6
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 229940124274 edetate disodium Drugs 0.000 claims description 4
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 4
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 4
- 229960002216 methylparaben Drugs 0.000 claims description 4
- 108010011485 Aspartame Proteins 0.000 claims description 3
- 241000167854 Bourreria succulenta Species 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- 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 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 3
- 240000009088 Fragaria x ananassa Species 0.000 claims description 3
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 235000009499 Vanilla fragrans Nutrition 0.000 claims description 3
- 244000263375 Vanilla tahitensis Species 0.000 claims description 3
- 235000012036 Vanilla tahitensis Nutrition 0.000 claims description 3
- 239000000605 aspartame Substances 0.000 claims description 3
- 235000010357 aspartame Nutrition 0.000 claims description 3
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 3
- 229960003438 aspartame Drugs 0.000 claims description 3
- 235000019693 cherries Nutrition 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 3
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 239000012669 liquid formulation Substances 0.000 claims 8
- 239000003814 drug Substances 0.000 abstract description 24
- 239000002775 capsule Substances 0.000 abstract description 22
- 229940100688 oral solution Drugs 0.000 abstract description 20
- 239000004480 active ingredient Substances 0.000 abstract description 6
- 238000010521 absorption reaction Methods 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 230000000857 drug effect Effects 0.000 abstract description 3
- 235000003599 food sweetener Nutrition 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 3
- 238000001727 in vivo Methods 0.000 abstract description 3
- 239000003765 sweetening agent Substances 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 19
- 238000004090 dissolution Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 229940079593 drug Drugs 0.000 description 5
- 239000000463 material Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000009826 distribution Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 208000031481 Pathologic Constriction Diseases 0.000 description 2
- 102100024304 Protachykinin-1 Human genes 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 208000037804 stenosis Diseases 0.000 description 2
- 230000036262 stenosis Effects 0.000 description 2
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 1
- 229940127239 5 Hydroxytryptamine receptor antagonist Drugs 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 1
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 1
- 208000031649 Postoperative Nausea and Vomiting Diseases 0.000 description 1
- 101800003906 Substance P Proteins 0.000 description 1
- 102100037346 Substance-P receptor Human genes 0.000 description 1
- 244000077233 Vaccinium uliginosum Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 229940078646 other antiemetics in atc Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- 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
-
- A—HUMAN NECESSITIES
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- 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
- A61K47/30—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an aprepitant oral liquid preparation and a preparation manufacturing method thereof. 100ml of aprepitant oral liquid comprises 0.50g of aprepitant, 5.00g to 15.00g of solvent, 0.10g to 1.00g of pH regulator, 8.00g to 10.00g of sodium dodecyl sulfate, 3.00g to 5.00g of hydroxypropyl-beta-cyclodextrin, 0.01g to 0.10g of complexing agent and water. The solvent is ethanol, and the complexing agent is disodium edentate. The components are mutually matched to form uniform solution; the medicine is uniformly dispersed in the system, has strong stability, and does not influence the drug effect even if the sweetener such as sucrose is added. Aprepitant in the oral solution is taken as an active ingredient to be uniformly dispersed in the oral solution, the administration dosage can be accurately controlled, excessive treatment or insufficient treatment is avoided, and the administration difficulty of infants is reduced. The oral solution preparation can be released in vitro for 5min to 100%, has a faster release speed than the capsule after being taken, and is beneficial to quick absorption in vivo. The preparation method provided by the invention has the advantages of simple process, short flow, good uniformity of the obtained preparation and low cost, and is suitable for commercial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an aprepitant oral liquid preparation and a preparation manufacturing method thereof.
Background
Aprepitant capsules were marketed by merck in 2003 for the prevention of post-operative nausea and vomiting or for use in combination with other antiemetics to prevent nausea and vomiting due to chemotherapeutic agents. Aprepitant is a selective high-affinity substance P/neurokinin-1 (NK 1) receptor inhibitor, has very low affinity to 5-hydroxytryptamine (5 HT 3), dopamine and corticoid receptors, can pass through the blood brain barrier, occupies the NK-1 receptor in the brain, and has an antiemetic complete control rate which is improved by 14.98% compared with 5-hydroxytryptamine receptor antagonist medicines.
Peak time T after oral aprepitant administration max For 4 hours, the pharmacokinetics of the drug is nonlinear, and the binding rate of plasma protein is more than 95%. Although the aprepitant has very good clinical curative effect, the medicine is BCS IV medicine with very poor solubility, and is difficult to prepare a preparation with higher bioavailability for oral administration. The aprepitant in the current market mainly comprises two dosage forms of capsules and injection, the oral solid administration has slow effect, and the oral solid administration needs to be carried out in advance and for many times so as to ensure the treatment effect; and the injection needs to be used in a specific place. Therefore, there is a need to develop a dosage form with high bioavailability and convenient use.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art.
Disclosure of Invention
The invention aims to solve the problems, and aims to provide an aprepitant oral liquid preparation and a preparation manufacturing method thereof, wherein compared with a capsule, the aprepitant oral liquid preparation greatly improves the dissolution of aprepitant from the preparation, thereby shortening the onset time and improving the bioavailability of aprepitant.
The invention provides an aprepitant oral liquid preparation, which has the characteristics that the 100ml aprepitant oral liquid preparation comprises the following components: aprepitant 0.50g; 5.00 g-15.00 g of solvent; 0.10 g-1.00 g of pH regulator; 8.00 g-10.00 g of sodium dodecyl sulfate; 3.00 g-5.00 g of hydroxypropyl-beta-cyclodextrin; complexing agent 0.01-0.10 g; water, the balance; wherein the solvent is ethanol, and the complexing agent is edetate disodium.
The aprepitant oral liquid preparation provided by the invention can also have the characteristics that the preparation method further comprises the following steps of: 30.00g to 50.00g of flavoring agent; 0.30 g-0.80 g of aromatic; preservative, 0.12 g-0.20 g.
The aprepitant oral liquid preparation provided by the invention can also have the following characteristics: wherein the flavoring agent is one or more of sucrose, sorbitol, mannitol or aspartame.
The aprepitant oral liquid preparation provided by the invention can also have the following characteristics: wherein the flavoring agent is one or more of blueberry essence, orange essence, cherry essence, vanilla essence or strawberry essence.
The aprepitant oral liquid preparation provided by the invention can also have the following characteristics: wherein the preservative is propyl hydroxybenzoate and methyl hydroxybenzoate.
The aprepitant oral liquid preparation provided by the invention can also have the following characteristics: wherein the mass of the propyl hydroxybenzoate is 0.02g, and the mass of the methyl hydroxybenzoate is 0.18g.
The aprepitant oral liquid preparation provided by the invention can also have the following characteristics: wherein the pH regulator is citric acid, and the water is purified water.
The invention also provides a preparation method of the aprepitant oral liquid preparation, which has the characteristics that the preparation method comprises the following steps:
step S1, crushing 0.50g of aprepitant, and taking 100ml of purified water for later use;
step S2, stirring and dissolving 0.01 g-0.02 g of methylparaben and 0.10 g-0.18 g of propylparaben in 20ml of purified water, then adding 30 g-50 g of sucrose for dissolving, then sequentially adding 0.01 g-0.10 g of edetate disodium, 0.3 g-0.8 g of blueberry essence and 3.0 g-5.0 g of hydroxypropyl-beta-cyclodextrin, and stirring and mixing uniformly to obtain a solution A;
step S3, 8 g-10 g of sodium dodecyl sulfate is dissolved in 60ml of purified water, citric acid is added to adjust the pH value to 3.0-3.5, 5 g-15 g of ethanol is added to be stirred and mixed uniformly, and aprepitant obtained in the step S1 is added to be stirred and dissolved to obtain a solution B;
and S4, adding the solution B into the solution A, uniformly mixing, standing to remove bubbles, and adding purified water to dilute to 100ml of constant volume bottle scale marks to obtain the aprepitant oral liquid preparation.
The preparation method of the aprepitant oral liquid preparation provided by the invention can also have the following characteristics: the specific operation of step S1 is as follows: 0.50g of aprepitant was pulverized using a jet mill such that the aprepitant powder had a D90 < 10 microns.
Effects and effects of the invention
The components of the aprepitant oral liquid preparation provided by the invention are mutually matched to form a uniform solution; the medicine is uniformly dispersed in the system, has strong stability, and does not influence the drug effect even if the sweetener such as sucrose is added. And the phenomenon that tablets and capsules are difficult to take due to throat stenosis of infants is overcome, aprepitant serving as an active ingredient is uniformly dispersed in an oral solution preparation, the taking dosage can be accurately controlled, excessive treatment or insufficient treatment is avoided, and the difficulty in taking medicines for infants is reduced. The oral solution can be released in vitro for 5min to 100%, has a faster release rate than aprepitant capsule after administration, and is beneficial to rapid absorption in vivo.
The preparation method provided by the invention has the advantages of simple process, short flow, good uniformity of the obtained oral solution preparation, low cost and suitability for commercial production.
According to the aprepitant oral liquid preparation and the preparation method, compared with a capsule, the oral solution phase greatly improves the dissolution of aprepitant from the preparation, so that the onset time is shortened, and meanwhile, the bioavailability of aprepitant is also improved; and the raw materials are easily available, and the prepared finished product is convenient to carry and take medicine, and has wide market prospect.
Drawings
Fig. 1 is a graph showing the particle size distribution of aprepitant powder according to the present invention.
FIG. 2 shows the saturated solubility of aprepitant in solutions of different pH in screening example 1 of the present invention;
FIG. 3 shows self-made oral solutions and formulations in example 1 of the present inventionDissolution profile in 2.2% SDS aqueous medium.
Detailed Description
In order to make the technical means, creation characteristics, achievement purposes and effects of the invention easy to understand, the aprepitant oral liquid preparation and the preparation manufacturing method of the preparation are specifically described below with reference to examples and drawings.
Unless otherwise indicated, reagents and pharmaceuticals for use in the present invention are commercially available.
The aprepitant oral liquid preparation provided by the invention is prepared by taking 100ml of the prepared aprepitant oral liquid preparation as a weight percentage, and comprises the following components:
aprepitant, 0.50g;
5.00 g-15.00 g of solvent;
0.10 g-1.00 g of pH regulator;
8.00 g-10.00 g of sodium dodecyl sulfate;
3.00 g-5.00 g of hydroxypropyl-beta-cyclodextrin;
complexing agent 0.01-0.10 g;
30.00g to 50.00g of flavoring agent;
0.30 g-0.80 g of aromatic;
0.12 g-0.20 g of preservative;
water, balance.
The flavoring agent is selected from one or more of sucrose, sorbitol, mannitol or aspartame, preferably sucrose.
The flavoring agent is selected from one or more of blueberry essence, orange essence, cherry essence, vanilla essence or strawberry essence; preferably blueberry essence.
The preservative is selected from propyl hydroxybenzoate and methyl hydroxybenzoate. In 100ml of the oral liquid, the mass of the propyl hydroxybenzoate is 0.02g, and the mass of the methyl hydroxybenzoate is 0.18g.
The pH regulator is citric acid, and the water is purified water.
Used in the inventionThe batch number of the capsules is 4523285, and the purified water is purified water specified in Chinese pharmacopoeia; the CAS numbers or manufacturer models for the remaining drugs and agents are as follows:
aprepitant, gilin tandem pharmaceutical limited;
ethanol (absolute ethanol), a new material company of Xinxiang city, xianfeng medicine;
sodium Dodecyl Sulfate (SDS), a company of lakeside hope for pharmaceutical company limited;
propyl hydroxybenzoate, jiangxi Yipu pharmaceutical Co., ltd;
methylparaben, jiangxi Yipu pharmaceutical Co., ltd.
The preparation method of the aprepitant oral liquid preparation comprises the following steps:
step S1, crushing 0.50g of aprepitant by using a jet mill to ensure that the particle size distribution D90 of the aprepitant powder is less than 10 microns, and taking 100ml of purified water for later use.
In this step, the particle size distribution detection is specifically performed as follows: the appropriate amount of aprepitant powder was measured according to the Analysis method using a malvern 3000 laser particle sizer, and the results are shown in fig. 1.
Step S2, stirring and dissolving 0.01 g-0.02 g of methylparaben and 0.10 g-0.18 g of propylparaben in 20ml of purified water, then adding 30 g-50 g of sucrose for dissolving, then sequentially adding 0.01 g-0.10 g of edetate disodium, 0.3 g-0.8 g of blueberry essence and 3.0 g-5.0 g of hydroxypropyl-beta-cyclodextrin, and stirring and mixing uniformly to obtain a solution A.
And S3, dissolving 8-10 g of sodium dodecyl sulfate in 60ml of purified water, adding citric acid to adjust the pH value to 3.0-3.5, adding 5-15 g of ethanol, stirring and mixing uniformly, and then adding the aprepitant obtained in the step S1, stirring and dissolving to obtain a solution B.
And S4, adding the solution B into the solution A, uniformly mixing, standing to remove bubbles, and adding purified water to dilute to 100ml of constant volume bottle scale marks to obtain the aprepitant oral liquid preparation.
The mass of each solvent and raw materials is calculated by 100ml of oral liquid, and in practical application, the mass is calculated according to the volume of the finally prepared oral liquid.
< screening example 1>
The screening example tests the saturated solubility of aprepitant in solutions of different pH to select the appropriate solution for dissolving aprepitant. Citric acid was used to adjust the pH of the solution.
Aprepitant, a company of Jiangsu Huiyuan pharmaceutical industry Co., ltd, was added to aqueous solutions of different pH and SDS concentration at 25℃and placed in a shaker to shake for 24 hours, and the sample was taken to examine the solubility, and the results are shown in Table 1.
TABLE 1 saturation solubility of aprepitant in solutions of different pH values
The results of table 1 can form fig. 2 in the form of a curve.
As can be seen from fig. 2 and table 1, the higher the saturation solubility of aprepitant with the increase of SDS under the same pH conditions. Under the condition of the same SDS addition amount, the saturated solubility gradually increases with the increase of the pH below pH 3.0; at pH3.0 or above, the saturated solubility gradually decreases as the pH increases. In the range of pH 3.0-pH 3.5, the SDS dosage is 4% -12% to meet the requirement of the oral liquid on solubility.
Example 1 ]
100ml of aprepitant oral liquid preparation is prepared by the preparation method, and ingredients are shown in the following table 2:
table 2 composition of oral liquid in example 1
| Name of the name | g/100ml | Action |
| Aprepitant | 5.00 | Active ingredient |
| Sucrose | 30.00 | Flavoring agent |
| Ethanol | 5.00 | Solvent(s) |
| Citric acid | 1.00 | PH regulator |
| Sodium dodecyl sulfate | 8.00 | Solubilizer |
| Hydroxypropyl-beta-cyclodextrin | 3.00 | Solubilizer |
| Edetic acid disodium salt | 0.05 | Complexing agent |
| Blueberry essence | 0.30 | Aromatic agent |
| Propyl hydroxybenzoate | 0.02 | Preservative agent |
| Hydroxy-benzoic acid methyl ester | 0.18 | Preservative agent |
| Purified water | Allowance of | Solvent(s) |
The aprepitant oral liquid preparation prepared in the embodiment is marked as batch number 23071801 and is mixed with aprepitant capsulesLot number 4523285), the specific experimental procedure is as follows:
the dissolution curve detection of the aprepitant oral liquid and the aprepitant capsule is carried out by using a paddle method in a method for measuring the dissolution rate and the release rate of the aprepitant oral liquid and the aprepitant capsule according to the rule 0931 of the 2020 edition of Chinese pharmacopoeia, and the specific method is as follows:
the experimental results are shown in Table 3.
TABLE 3 dissolution results of oral solutions and capsules
The results of Table 3 can be formed into FIG. 3 in the form of a curve. The reference formulation in fig. 3 is the capsule in table 3.
As can be seen from fig. 3 and table 3, the oral liquid showed a rapid release trend, and reached the dissolution plateau for 5 min. The dissolution time is shorter than that of the capsule.
Effects and effects of the examples
Compared with oral solid capsules, the medicine in the oral solution is dispersed in a medium in a molecular form, and has the advantages of large dispersity, quick absorption and quicker play of medicine effect. Because the medicine in the solution exists in a molecular state and can be absorbed by human body without dissolution, the absorption speed of the oral solution preparation is faster than that of the capsule. In the preparation process of the capsule, the active ingredients are wrapped by auxiliary materials or affected by the properties of the auxiliary materials, so that the active ingredients are required to be dissolved and released from the auxiliary materials of the preparation after taking, the dissolution time of the medicine is prolonged, and the oral solution is in a completely dissolved state, so that the bioavailability of the oral solution is higher than that of the capsule.
The oral solution preparation has the greatest advantage of being capable of dividing the dosage at will in clinical medication, and has great convenience in taking medicine for special patients needing to take the dosage according to the weight or the body surface area; for the old and children who are inconvenient to swallow, compared with capsules, the oral solution preparation is more convenient to swallow, and the oral solution preparation is added with proper flavoring agent, so that the oral solution preparation has good taste and greatly improves the medicine taking compliance of patients; when children and old people swallow the capsule, the risk of blocking the trachea exists, and the risk of blocking the medicine can be greatly reduced by the oral solution, so that the safety coefficient of taking medicine is higher.
Therefore, the aprepitant oral liquid preparation and the preparation manufacturing method provided by the embodiment of the invention have the following beneficial effects:
1) The components are mutually matched to form a uniform solution, the taste and sweetness are proper, the blueberry fragrance is provided, and the solution is more suitable for infants to take medicine;
2) The oral solution with the formula has the advantages that the medicine is uniformly dispersed in the system, the stability is strong, and the drug effect is not affected by adding the sweetening agent such as sucrose and the like;
3) The problems that tablets and capsules are difficult to take due to throat stenosis of infants are overcome, aprepitant serving as an active ingredient is uniformly dispersed in an oral solution preparation, the taking dosage can be accurately controlled, excessive treatment or insufficient treatment is avoided, and the aprepitant is prepared into the favorite fruit taste of the infants, caters to the psychological of the infants, and reduces the difficulty of taking the infants;
4) The oral solution is released in vitro for 5min to 100%, has a faster release speed than aprepitant capsules after being taken, and is beneficial to quick absorption in vivo;
5) The processing and manufacturing process is simple, the flow is short, the raw material sources are easy to obtain, the medicine is convenient to carry and use, and the broad market prospect is achieved.
The method has the advantages of simple process, short flow, good uniformity of the obtained oral solution, low cost and suitability for commercial production; and the raw materials are easily available, and the prepared finished product is convenient to carry and take medicine, and has wide market prospect.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (9)
1. An aprepitant oral liquid preparation is characterized in that the aprepitant oral liquid preparation with 100ml comprises the following components:
aprepitant, 0.50g;
5.00 g-15.00 g of solvent;
0.10 g-1.00 g of pH regulator;
8.00 g-10.00 g of sodium dodecyl sulfate;
3.00 g-5.00 g of hydroxypropyl-beta-cyclodextrin;
complexing agent 0.01-0.10 g;
water, the balance;
wherein the solvent is ethanol, and the complexing agent is disodium edentate.
2. Aprepitant oral liquid formulation according to claim 1, characterized in that in 100ml aprepitant oral liquid formulation further comprises:
30.00g to 50.00g of flavoring agent;
0.30 g-0.80 g of aromatic;
preservative, 0.12 g-0.20 g.
3. Aprepitant oral liquid formulation according to claim 2, characterized in that:
wherein the flavoring agent is any one or more of sucrose, sorbitol, mannitol or aspartame.
4. Aprepitant oral liquid formulation according to claim 2, characterized in that:
wherein the aromatic is one or more of blueberry essence, orange essence, cherry essence, vanilla essence or strawberry essence.
5. Aprepitant oral liquid formulation according to claim 2, characterized in that:
wherein the preservative is propyl hydroxybenzoate and methyl hydroxybenzoate.
6. Aprepitant oral liquid formulation according to claim 5, characterized in that:
wherein the mass of the propyl hydroxybenzoate is 0.02g, and the mass of the methyl hydroxybenzoate is 0.18g.
7. Aprepitant oral liquid formulation according to claim 1, characterized in that:
wherein the pH regulator is citric acid, and the water is purified water.
8. The preparation method of the aprepitant oral liquid preparation is characterized by comprising the following steps:
step S1, crushing 0.50g of aprepitant, and taking 100ml of purified water for later use;
step S2, stirring and dissolving 0.01 g-0.02 g of methylparaben and 0.10 g-0.18 g of propylparaben in 20ml of purified water, then adding 30 g-50 g of sucrose for dissolving, then sequentially adding 0.01 g-0.10 g of edetate disodium, 0.3 g-0.8 g of blueberry essence and 3.0 g-5.0 g of hydroxypropyl-beta-cyclodextrin, and stirring and mixing uniformly to obtain a solution A;
step S3, 8 g-10 g of sodium dodecyl sulfate is dissolved in 60ml of purified water, citric acid is added to adjust the pH value to 3.0-3.5, 5 g-15 g of ethanol is added to be stirred and mixed uniformly, and aprepitant obtained in the step S1 is added to be stirred and dissolved to obtain a solution B;
and S4, adding the solution B into the solution A, uniformly mixing, standing to remove bubbles, and adding purified water to dilute to 100ml of constant volume bottle scale marks to obtain the aprepitant oral liquid preparation.
9. The method for manufacturing aprepitant oral liquid formulation according to claim 8, wherein:
the specific operation of step S1 is as follows: 0.50g of aprepitant was pulverized using a jet mill such that the aprepitant powder had a D90 < 10 microns.
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