CN114588107A - Ibuprofen lysine salt injection and preparation method thereof - Google Patents
Ibuprofen lysine salt injection and preparation method thereof Download PDFInfo
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- CN114588107A CN114588107A CN202210353999.2A CN202210353999A CN114588107A CN 114588107 A CN114588107 A CN 114588107A CN 202210353999 A CN202210353999 A CN 202210353999A CN 114588107 A CN114588107 A CN 114588107A
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- Prior art keywords
- injection
- lysine salt
- solution
- ibuprofen lysine
- cyclodextrin
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- 229960001680 ibuprofen Drugs 0.000 title claims abstract description 114
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 title claims abstract description 109
- 239000007924 injection Substances 0.000 title claims abstract description 60
- 238000002347 injection Methods 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 44
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 42
- 229960004853 betadex Drugs 0.000 claims abstract description 42
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 40
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 40
- 239000000243 solution Substances 0.000 claims description 102
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- 238000011049 filling Methods 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- 239000008215 water for injection Substances 0.000 claims description 35
- 238000003756 stirring Methods 0.000 claims description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 239000000377 silicon dioxide Substances 0.000 claims description 14
- 235000012239 silicon dioxide Nutrition 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000012528 membrane Substances 0.000 claims description 8
- IHHXIUAEPKVVII-APFIOPMWSA-N (2s)-2,6-diaminohexanoic acid;(2r)-2-[4-(2-methylpropyl)phenyl]propanoic acid Chemical class NCCCC[C@H](N)C(O)=O.CC(C)CC1=CC=C([C@@H](C)C(O)=O)C=C1 IHHXIUAEPKVVII-APFIOPMWSA-N 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000011068 loading method Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract description 2
- 230000006866 deterioration Effects 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 35
- 229930182555 Penicillin Natural products 0.000 description 10
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 10
- 229940049954 penicillin Drugs 0.000 description 10
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 8
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 8
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 5
- 229940093181 glucose injection Drugs 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000008354 sodium chloride injection Substances 0.000 description 5
- 239000004472 Lysine Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000018977 lysine Nutrition 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 208000003278 patent ductus arteriosus Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- PYHRZPFZZDCOPH-QXGOIDDHSA-N (S)-amphetamine sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C[C@H](N)CC1=CC=CC=C1.C[C@H](N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-QXGOIDDHSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000002028 premature Effects 0.000 description 2
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- IHHXIUAEPKVVII-ZSCHJXSPSA-N [(1s)-5-amino-1-carboxypentyl]azanium;2-[4-(2-methylpropyl)phenyl]propanoate Chemical compound OC(=O)[C@@H](N)CCCC[NH3+].CC(C)CC1=CC=C(C(C)C([O-])=O)C=C1 IHHXIUAEPKVVII-ZSCHJXSPSA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides ibuprofen lysine salt injection and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The injection contains ibuprofen lysine salt, beta-cyclodextrin and pH regulator. The injection has the advantages of easy storage, transportation, good stability, no deterioration, and convenient clinical application.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to ibuprofen lysine salt injection and a preparation method thereof.
Background
The ibuprofen lysine salt is a compound of ibuprofen and lysine, is a water-soluble medicament, and has strong antipyretic, analgesic and anti-inflammatory effects. The ibuprofen lysine salt overcomes the defect of poor water solubility of the original ibuprofen, is quicker to dissolve out and quicker to take effect, has related preparations of the ibuprofen lysine salt on the market abroad, and is only injection in 2 companies at present.
The ibuprofen lysine salt is a compound prepared from ibuprofen and lysine, exists in the form of ibuprofen and lysine in vivo after administration, and plays the same pharmacological action as ibuprofen. Ibuprofen is a non-steroidal anti-inflammatory drug applied to clinical application in the 70 th of the 20 th century, is an inhibitor of cyclooxygenase in prostate synthesis, is mainly used for clinically relieving symptoms such as light to moderate postoperative pain, dysmenorrhea, headache and the like, and is also used for treating various arthritis, gout and fever caused by various reasons. In addition, ibuprofen has been widely used in the treatment of patent ductus arteriosus in newborn or premature infants, and studies have reported that ibuprofen has similar or even stronger therapeutic effect, better safety and less renal damage compared with indomethacin. The ibuprofen lysine salt injection has obvious clinical advantages and great product potential.
The ibuprofen lysine salt injection is a non-steroidal medicament. The product is used for closing Patent Ductus Arteriosus (PDA) with clinical significance to premature infants with body weight of 500-1500 g and gestational age of no more than 32 weeks. The former company of this injection was called RECORDATI corporation of Italy (Likang, Italy) from the FDA site, and the manufacturer also called X-GEN Pharmaceuticals, Inc.
The prescription of original developer company RECORDATI company is simple, and the description is as follows: ibuprofen lysine is a clear sterile preservative-free solution (±) -ibuprofen L-lysine salt which is the active ingredient. (±) -ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID). L-lysine is used in the manufacture of water-soluble pharmaceutical product salts suitable for intravenous administration. Ibuprofen lysine contained 17.1mg ibuprofen lysine (equivalent to 10mg (±) -ibuprofen) per ml of ibuprofen lysine in USP water for injection. The pH is adjusted to 7.0 with sodium hydroxide or hydrochloric acid.
Disclosure of Invention
The invention aims to provide the ibuprofen lysine salt injection which has good stability, is not easy to deteriorate and is easy to store. The ibuprofen lysine salt is used as an active ingredient, the formula of the injection is screened and optimized, cyclodextrin is mainly added into the formula, and the beta-cyclodextrin is determined to be suitable for the ibuprofen lysine salt injection by screening alpha-cyclodextrin and beta-cyclodextrin.
The active component ibuprofen lysine is protected by complexing, and the stability of ibuprofen lysine salt prepared into injection is successfully solved, so that the invention is completed.
The technical problem of the invention is realized by the following technical scheme.
The invention provides an ibuprofen lysine salt injection which contains ibuprofen lysine salt, beta-cyclodextrin and a pH regulator.
Wherein the molar ratio of the ibuprofen lysine salt to the beta-cyclodextrin in the ibuprofen lysine salt injection is 3.3: 1-2.2: 1, preferably 2.8: 1,2.76: 1,2.62:1.
The pH value of the ibuprofen lysine salt injection is 6.5-7.5, and preferably 7.0.
In the ibuprofen lysine salt injection, 1710mg of ibuprofen lysine salt is contained in every 100mL of injection in the formula, and 1800 mg-2500 mg of beta-cyclodextrin is contained in the injection.
In some embodiments, the ibuprofen lysine salt injection comprises 1710mg ibuprofen lysine salt and 2100mg β -cyclodextrin per 100mL injection solution, and the pH is 7.0.
The invention provides a preparation method of the ibuprofen lysine salt injection, which comprises the following steps:
(1) dissolving beta-cyclodextrin in sodium hydroxide solution;
(2) adding ibuprofen lysine salt into water for injection to form an ibuprofen lysine salt aqueous solution;
(3) and adding the ibuprofen lysine salt aqueous solution into the beta-cyclodextrin aqueous solution to form an ibuprofen lysine salt-beta-cyclodextrin complex solution.
The preparation method of the ibuprofen lysine salt injection comprises the following steps:
(1) adding beta-cyclodextrin of a formula amount into 100ml of water for injection, stirring and dissolving, adjusting the pH value to 9.0-10.0 by using 1mol/L sodium hydroxide solution, heating the solution to 40-50 ℃, and stirring for about 1 hour to obtain a solution I;
(2) adding ibuprofen lysine salt with the prescription amount into 900ml of water for injection, and stirring for 5 minutes at room temperature to obtain a solution II;
(3) adding the solution II into the solution 1, continuously stirring for 30 minutes to ensure that the beta-cyclodextrin fully includes ibuprofen lysine salt, and then adjusting the pH value to 6.8-7.2 by using 1mol/L hydrochloric acid to obtain a solution III;
(4) filtering the solution III with 0.45 μm and 0.22 μm filter membrane, controlling the loading amount to be 2.15ml +/-0.05 ml, filling nitrogen before and after filling, filling into 2ml colorless medium borosilicate vials coated with silicon dioxide, wherein the rubber plug adopts a coated rubber plug.
The invention provides an ibuprofen lysine salt injection, which contains ibuprofen lysine salt and beta-cyclodextrin, wherein each 1000mL of the injection contains 17100mg (1000 mg counted by ibuprofen) of the ibuprofen lysine salt and 21000mg of the beta-cyclodextrin, the pH value of the injection is about 7.0, and the injection is prepared by the following method, wherein the preparation method comprises the following steps: (1) adding beta-cyclodextrin of a prescription amount into 100ml of water for injection, stirring and dissolving, adjusting the pH value to 9.5 by using 1mol/L sodium hydroxide solution, heating the solution to 45 ℃, and stirring for about 1 hour to obtain a solution I; (2) adding ibuprofen lysine salt with the prescription amount into 900ml of water for injection, and stirring for 5 minutes at room temperature to obtain a solution II; (3) adding the solution II into the solution 1, continuously stirring for 30 minutes to ensure that the beta-cyclodextrin fully includes ibuprofen lysine salt, and then adjusting the pH value to 7.0 by using 1mol/L hydrochloric acid to obtain a solution III; (4) filtering the solution III with 0.45 μm and 0.22 μm filter membrane, controlling the loading amount to be 2.15ml +/-0.05 ml, filling nitrogen before and after filling, filling into 2ml colorless medium borosilicate vials coated with silicon dioxide, wherein the rubber plug adopts a coated rubber plug.
The specific implementation mode is as follows:
the present invention will be described in further detail with reference to the following embodiments, but the present invention is not limited to these embodiments.
Example 1
Recipe 1-1:
ibuprofen lysine salt 17.1g (10 g calculated as ibuprofen, 0.0485mol)
alpha-Cyclodextrin 15.5g (0.0159mol)
Adding water for injection to 1000ml
(1) The alpha-cyclodextrin with the prescription amount is added into 100ml of water for injection, stirred and dissolved, the pH value is adjusted to 9.5 by 1mol/L sodium hydroxide solution, and the solution is heated to 45 ℃ and stirred for about 1 hour to obtain solution I.
(2) The prescribed amount of ibuprofen lysine salt was added to 900ml of water for injection, and stirred at room temperature for 5 minutes to obtain solution II.
(3) Adding the solution II into the solution 1, continuing stirring for 30 minutes, and adjusting the pH value to 6.6 by using 1mol/L hydrochloric acid to obtain a solution III.
(4) Filtering the solution III with 0.45 μm and 0.22 μm, controlling the filling amount to be 2.15ml +/-0.05 ml, filling nitrogen before and after filling, and filling into 2ml colorless medium borosilicate film-coated penicillin bottles coated with silicon dioxide.
Prescription 1-2
Ibuprofen lysine salt 17.1g (10 g calculated as ibuprofen, 0.0485mol)
alpha-Cyclodextrin 13.5g (0.0139mol)
Adding water for injection to 1000ml
(1) The alpha-cyclodextrin with the prescription amount is added into 100ml of water for injection, stirred and dissolved, the pH value is adjusted to 9.5 by 1mol/L sodium hydroxide solution, and the solution is heated to 45 ℃ and stirred for about 1 hour to obtain solution I.
(2) The prescribed amount of ibuprofen lysine salt was added to 900ml of water for injection, and stirred at room temperature for 5 minutes to obtain solution II.
(3) Adding the solution II into the solution 1, continuing stirring for 30 minutes, and adjusting the pH value to 6.6 by using 1mol/L hydrochloric acid to obtain a solution III.
(4) Filtering the solution III with 0.45 μm and 0.22 μm, controlling the filling amount to be 2.15ml +/-0.05 ml, filling nitrogen before and after filling, and filling into 2ml colorless medium borosilicate film-coated penicillin bottles coated with silicon dioxide.
Prescription 1-3
Ibuprofen lysine salt 17.1g (10 g calculated as ibuprofen, 0.0485mol)
Alpha-cyclodextrin 11.5g (0.0118mol)
Adding water for injection to 1000ml
(1) The alpha-cyclodextrin with the prescription amount is added into 100ml of water for injection, stirred and dissolved, the pH value is adjusted to 9.5 by 1mol/L sodium hydroxide solution, and the solution is heated to 45 ℃ and stirred for about 1 hour to obtain solution I.
(2) The prescribed amount of ibuprofen lysine salt was added to 900ml of water for injection, and stirred at room temperature for 5 minutes to obtain solution II.
(3) Adding the solution II into the solution 1, continuing stirring for 30 minutes, and adjusting the pH value to 6.6 by using 1mol/L hydrochloric acid to obtain a solution III.
(4) Filtering the solution III with 0.45 μm and 0.22 μm, controlling the filling amount to be 2.15ml +/-0.05 ml, filling nitrogen before and after filling, and filling into 2ml colorless medium borosilicate film-coated penicillin bottles coated with silicon dioxide.
Example 2
Prescription 2:
ibuprofen lysine salt 17.1g (calculated as ibuprofen, 10g)
Beta-cyclodextrin 18.0g
Adding water for injection to 1000ml
(1) Adding the beta-cyclodextrin of the prescription amount into 100ml of water for injection, stirring and dissolving, adjusting the pH value to 9.5 by using 1mol/L sodium hydroxide solution, heating the solution to 45 ℃, and stirring for about 1 hour to obtain a solution I.
(2) The prescribed amount of ibuprofen lysine salt was added to 900ml of water for injection, and stirred at room temperature for 5 minutes to obtain solution II.
(3) Adding the solution II into the solution 1, continuing stirring for 30 minutes, and adjusting the pH value to 6.6 by using 1mol/L hydrochloric acid to obtain a solution III.
(4) Filtering the solution III with 0.45 μm and 0.22 μm, controlling the filling amount to be 2.15ml +/-0.05 ml, filling nitrogen before and after filling, and filling into 2ml colorless medium borosilicate film-coated penicillin bottles coated with silicon dioxide.
Example 3
The effect of different cyclodextrins on the stability of ibuprofen lysine salt was compared in example 1 and example 2, which were examined at a high temperature of 60 ℃ for one month.
By comparing example 1 with example 2, the influence factors (60 ℃) are obviously larger than those of the sample of example 2 in the examination of the substances related to example 1, and the beta-cyclodextrin plays a role in protecting the ibuprofen lysine salt serving as the active ingredient than the alpha-cyclodextrin.
Example 4
Prescription 4:
ibuprofen lysine salt 17.1g (calculated as ibuprofen 10g)
Beta-cyclodextrin 20.0g
Adding water for injection to 1000ml
(1) Adding the beta-cyclodextrin of the prescription amount into 100ml of water for injection, stirring and dissolving, adjusting the pH value to 9.5 by using 1mol/L sodium hydroxide solution, heating the solution to 45 ℃, and stirring for about 1 hour to obtain a solution I.
(2) The prescribed amount of ibuprofen lysine salt was added to 900ml of water for injection, and stirred at room temperature for 5 minutes to obtain solution II.
(3) Adding the solution II into the solution 1, continuing stirring for 30 minutes, and adjusting the pH value to 6.8 by using 1mol/L hydrochloric acid to obtain a solution III.
(4) Filtering the solution III with 0.45 μm and 0.22 μm filter membrane, controlling the filling amount to be 2.15ml +/-0.05 ml, filling nitrogen before and after filling, and filling in 2ml colorless medium borosilicate film-coated penicillin bottles coated with silicon dioxide.
Example 5
Prescription 5:
ibuprofen lysine salt 17.1g (calculated as ibuprofen, 10g)
Beta-cyclodextrin 21.0g
Adding water for injection to 1000ml
(1) Adding beta-cyclodextrin of a prescription amount into 100ml of water for injection, stirring and dissolving, adjusting the pH value to 9.5 by using 1mol/L sodium hydroxide solution, heating the solution to 45 ℃, and stirring for about 1 hour to obtain a solution I.
(2) The prescribed amount of ibuprofen lysine salt was added to 900ml of water for injection, and stirred at room temperature for 5 minutes to obtain solution II.
(3) Adding the solution II into the solution 1, continuing stirring for 30 minutes, and adjusting the pH value to 7.0 by using 1mol/L hydrochloric acid to obtain a solution III.
(4) Filtering the solution III with 0.45 μm and 0.22 μm filter membrane, controlling the filling amount to be 2.15ml +/-0.05 ml, filling nitrogen before and after filling, and filling in 2ml colorless medium borosilicate film-coated penicillin bottles coated with silicon dioxide.
Example 6
Prescription 6:
ibuprofen lysine salt 17.1g (calculated as ibuprofen, 10g)
Beta-cyclodextrin 23.0g
Adding water for injection to 1000ml
(1) Adding beta-cyclodextrin of a prescription amount into 100ml of water for injection, stirring and dissolving, adjusting the pH value to 9.5 by using 1mol/L sodium hydroxide solution, heating the solution to 45 ℃, and stirring for about 1 hour to obtain a solution I.
(2) The prescribed amount of ibuprofen lysine salt was added to 900ml of water for injection, and stirred at room temperature for 5 minutes to obtain solution II.
(3) Adding the solution II into the solution 1, continuing stirring for 30 minutes, and adjusting the pH value to 7.3 by using 1mol/L hydrochloric acid to obtain a solution III.
(4) Filtering the solution III with 0.45 μm and 0.22 μm filter membrane, controlling the filling amount to be 2.15ml +/-0.05 ml, filling nitrogen before and after filling, and filling in 2ml colorless medium borosilicate film-coated penicillin bottles coated with silicon dioxide.
Example 7
Prescription 7:
ibuprofen lysine salt 17.1g (calculated as ibuprofen, 10g)
Beta-cyclodextrin 25.0g
Adding water for injection to 1000ml
(1) Adding the beta-cyclodextrin of the prescription amount into 100ml of water for injection, stirring and dissolving, adjusting the pH value to 9.5 by using 1mol/L sodium hydroxide solution, heating the solution to 45 ℃, and stirring for about 1 hour to obtain a solution I.
(2) The prescribed amount of ibuprofen lysine salt was added to 900ml of water for injection, and stirred at room temperature for 5 minutes to obtain solution II.
(3) Solution II was added to solution 1, stirring was continued for 30 minutes, and the pH was adjusted to 7.5 with 1mol/L hydrochloric acid to give solution III.
(4) Filtering the solution III with 0.45 μm and 0.22 μm filter membrane, controlling the loading amount to be 2.15ml +/-0.05 ml, and filling into 2ml colorless medium borosilicate film-coated penicillin bottles coated with silicon dioxide.
Example 8
The ibuprofen lysine salt injection which is not adopted in the technical scheme of the invention and is marketed in the United states is taken as a comparative example, and the stability test is carried out on the ibuprofen lysine salt injection prepared in the example shown in the table 1 under the conditions of 40 ℃ and 75% of relative humidity for 3 months and 25 ℃ and 60% of relative humidity. The test results are shown in Table 1.
TABLE 1 stability test results
The data for the prepared sample day 0 were very slightly different and the data are not listed. The invention is superior to the products sold on the market, the product of example 5 has the best stability, the properties are basically not changed, and the products of other examples accelerate the observation that the color of the medicine is slightly yellow at the final stage of 3 months. The ibuprofen lysine salt injection adopting the technical scheme of the invention still has good stability under long-term storage conditions. Moreover, the results of the products of the examples are not very different when the products are placed upside down and rightly, which shows that the products have better compatibility with the rubber plug.
Compared with the commercially available ibuprofen lysine salt injection, the increase of related substances of the commercially available ibuprofen lysine salt injection in stability investigation is obviously larger than that of the implementation example of the invention, and the beta-cyclodextrin plays a role in protecting the ibuprofen lysine salt serving as an active ingredient.
Example 9
Because the ibuprofen lysine salt injection is a small-volume injection, intravenous drip of the sodium chloride injection or the glucose injection is possibly needed when the ibuprofen lysine salt injection is used, and the stability of the ibuprofen lysine salt injection in the sodium chloride injection or the glucose injection needs to be studied.
2 ibuprofen lysine salt injection (example 5) (2ml:0.2g, calculated by ibuprofen) is taken and added into 100ml of 0.9% sodium chloride injection and 5% glucose injection respectively, and indexes are detected before (0 hour) dilution and after 1, 2, 4 and 8 hours of dilution respectively, and compatibility stability is inspected.
As a result: after the ibuprofen lysine salt injection is matched with 100ml of 0.9% sodium chloride injection and 5% glucose injection, within 8 hours, all indexes have no obvious change and are basically stable. The results are shown in tables 2 and 3.
TABLE 2 results of compatibility stability test with 0.9% sodium chloride injection
TABLE 35% stability test results for the formulation of glucose injection
| Time/h | Appearance character | pH value | The related substances are all mixed |
| 0 | Colorless clear liquid | 7.0 | 0.02 |
| 1 | Colorless clear liquid | 7.0 | 0.02 |
| 2 | Colorless clear liquid | 7.0 | 0.03 |
| 4 | Colorless clear liquid | 7.0 | 0.03 |
| 8 | Colorless clear liquid | 7.0 | 0.03 |
Example 10
We repeated the formulation and process of example 5 with the best stability and examined the effect of 2 inner wrappers on product stability: the inner packing materials are respectively as follows: a common borosilicate bottle adopts a coated (silicon dioxide) penicillin bottle. The results show that: the sample adopting the common packing material is turbid after being placed at room temperature for about 2 months, which indicates that the inner packing material needs to adopt a coated (silicon dioxide) penicillin bottle as the preparation inner packing material.
TABLE 4 comparison of sample stability behavior
Claims (10)
1. An ibuprofen lysine salt injection contains ibuprofen lysine salt, beta-cyclodextrin and pH regulator.
2. The ibuprofen lysine salt injection as claimed in claim 1, wherein the molar ratio of ibuprofen lysine salt and β -cyclodextrin in said injection is 3.30: 1-2.20: 1.
3. the ibuprofen lysine salt injection as claimed in claim 2, wherein the molar ratio of ibuprofen lysine salt to β -cyclodextrin in said injection is 2.80: 1, or 2.76: 1, or 2.62: 1.
4. The ibuprofen lysine salt injection according to claim 1, wherein the pH value of the injection is 6.5-7.5, preferably 7.0.
5. The ibuprofen lysine salt injection according to claim 4, wherein the pH of said injection is 7.0.
6. The ibuprofen lysine salt injection as claimed in claim 1, wherein each 100mL of the injection contains 1710mg of ibuprofen lysine salt and 1800 mg-2500 mg of beta-cyclodextrin.
7. The ibuprofen lysine salt injection according to claim 1, wherein the injection comprises 1710mg of ibuprofen lysine salt, 2100mg of beta-cyclodextrin and 7.0 of injection p H in each 100mL of injection.
8. A process for the preparation of ibuprofen lysine salt injection as claimed in any of claims 1-7, comprising the steps of:
(1) dissolving beta-cyclodextrin in sodium hydroxide solution;
(2) adding ibuprofen lysine salt into water for injection to form an ibuprofen lysine salt aqueous solution;
(3) adding the ibuprofen lysine salt aqueous solution into the beta-cyclodextrin aqueous solution to form an ibuprofen lysine salt-beta-cyclodextrin complex solution.
9. A process for the preparation of ibuprofen lysine salt injection as claimed in any of claims 1-7, comprising the steps of:
(1) adding beta-cyclodextrin of a formula amount into 100ml of water for injection, stirring and dissolving, adjusting the pH value to 9.0-10.0 by using 1mol/L sodium hydroxide solution, heating the solution to 40-50 ℃, and stirring for about 1 hour to obtain a solution I;
(2) adding ibuprofen lysine salt with the prescription amount into 900ml of water for injection, and stirring for 5 minutes at room temperature to obtain a solution II;
(3) adding the solution II into the solution 1, continuously stirring for 30 minutes to ensure that the beta-cyclodextrin fully includes ibuprofen lysine salt, and then adjusting the pH value to 6.8-7.2 by using 1mol/L hydrochloric acid to obtain a solution III;
(4) filtering the solution III with 0.45 μm and 0.22 μm filter membrane, controlling the loading amount to be 2.15ml +/-0.05 ml, filling nitrogen before and after filling, filling into 2ml colorless medium borosilicate vials coated with silicon dioxide, wherein the rubber plug adopts a coated rubber plug.
10. The ibuprofen lysine salt injection is characterized by comprising ibuprofen lysine salt, beta-cyclodextrin and a pH regulator, wherein each 1000mL of injection contains 17100mg of the ibuprofen lysine salt and 21000mg of the beta-cyclodextrin, the pH value of the injection is about 7.0, and the injection is prepared by the following method, wherein the preparation method comprises the following steps: (1) adding beta-cyclodextrin of a prescription amount into 100ml of water for injection, stirring and dissolving, adjusting the pH value to 9.5 by using 1mol/L sodium hydroxide solution, heating the solution to 45 ℃, and stirring for about 1 hour to obtain a solution I; (2) adding ibuprofen lysine salt with the prescription amount into 900ml of water for injection, and stirring for 5 minutes at room temperature to obtain a solution II; (3) adding the solution II into the solution 1, continuously stirring for 30 minutes to ensure that the beta-cyclodextrin fully includes ibuprofen lysine salt, and then adjusting the pH value to 7.0 by using 1mol/L hydrochloric acid to obtain a solution III; (4) filtering the solution III with 0.45 μm and 0.22 μm filter membrane, controlling the loading amount to be 2.15ml +/-0.05 ml, filling nitrogen before and after filling, filling into 2ml colorless medium borosilicate vials coated with silicon dioxide, wherein the rubber plug adopts a coated rubber plug.
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