CN114588107B - Ibuprofen lysine salt injection and preparation method thereof - Google Patents
Ibuprofen lysine salt injection and preparation method thereof Download PDFInfo
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- CN114588107B CN114588107B CN202210353999.2A CN202210353999A CN114588107B CN 114588107 B CN114588107 B CN 114588107B CN 202210353999 A CN202210353999 A CN 202210353999A CN 114588107 B CN114588107 B CN 114588107B
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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
- A61K9/08—Solutions
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- 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
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- 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, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
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- 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
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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
- A61K9/0012—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
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- 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]
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 dissolved out more quickly and takes effect more quickly, related preparations of the ibuprofen lysine salt are available on the market abroad, and only 2 companies are currently used as injections.
The ibuprofen lysine salt is a compound prepared from ibuprofen and lysine, and the ibuprofen and the lysine exist in the form of ibuprofen and lysine respectively in vivo after administration, so that the ibuprofen lysine salt has the same pharmacological action as the 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 per ml of ibuprofen lysine in water for injection USP (corresponding to 10mg (±) -ibuprofen). 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.
Wherein 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 of ibuprofen lysine salt, 2100mg of beta-cyclodextrin, and 7.0 pH per 100mL of injection solution.
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 prescription 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:
17.1g of ibuprofen lysine salt (calculated as ibuprofen, 10g, 0.0485mol)
Alpha-cyclodextrin 15.5g (0.0159 mol)
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 in a silica-plated 2ml colorless medium borosilicate film-covered penicillin bottle.
Prescription 1-2
17.1g of ibuprofen lysine salt (calculated as ibuprofen, 10g, 0.0485mol)
alpha-Cyclodextrin 13.5g (0.0139 mol)
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
17.1g of ibuprofen lysine salt (calculated as ibuprofen, 10g, 0.0485mol)
Alpha-cyclodextrin 11.5g (0.0118 mol)
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) Ibuprofen lysine salt in the prescribed amount 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, 10 g)
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 examined that the substances of example 1 increase significantly more than those of example 2, which shows that beta-cyclodextrin acts to protect the ibuprofen lysine salt, which is the active ingredient, better than alpha-cyclodextrin.
Example 4
Prescription 4:
ibuprofen lysine salt 17.1g (calculated as ibuprofen, 10 g)
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, 10 g)
Beta-cyclodextrin 21.0g
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) Ibuprofen lysine salt in the prescribed amount 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, 10 g)
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, 10 g)
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 ibuprofen lysine salt injection sold in the market, the increase of related substances of the ibuprofen lysine salt injection sold 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, the sodium chloride injection or the glucose injection may need to be intravenously dripped during use, and the stability of the ibuprofen lysine salt injection in the sodium chloride injection or the glucose injection needs to be examined.
2 ibuprofen lysine salt injection (example 5) (2ml, 0.2g, calculated as ibuprofen) are 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 after dilution respectively to investigate compatibility stability.
As a result: the ibuprofen lysine salt injection, 100ml 0.9% sodium chloride injection and 5% glucose injection are compatible, and within 8 hours, all indexes have no obvious change and are basically stable. The results are shown in tables 2 and 3.
Table 2 compatibility stability test results with 0.9% sodium chloride injection
TABLE 3 compatibility stability test results of 5% 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: 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 film-coated (silicon dioxide) penicillin bottle as the preparation inner packing material.
TABLE 4 comparison of sample stability behavior
Claims (2)
1. An ibuprofen lysine salt injection is prepared from ibuprofen lysine salt, beta-cyclodextrin and a pH regulator, and is characterized in that the pH value of the injection is 7.0, and each 100mL of the injection contains 1710mg of ibuprofen lysine salt and 2100mg of beta-cyclodextrin; the injection is prepared by 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 9.0-10.0 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 I, 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 filling amount to be 2.15ml +/-0.05 ml, filling nitrogen before and after filling, filling in a silica-plated 2ml colorless medium borosilicate bottle, wherein the rubber plug adopts a film-coated rubber plug.
2. The ibuprofen lysine salt injection is prepared from ibuprofen lysine salt, beta-cyclodextrin and a pH regulator, and is characterized in that each 1000mL of injection contains 17100mg of ibuprofen lysine salt and 21000mg of beta-cyclodextrin, the pH value of the injection is 7.0, and the injection is prepared by 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 I, 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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| US5866162A (en) * | 1993-08-10 | 1999-02-02 | Smithkline Beecham P.L.C. | Pharmaceutical composition containing a drug/β-cyclodextrin complex in combination with an acid-base couple |
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| CN102992997A (en) * | 2012-11-20 | 2013-03-27 | 北京阜康仁生物制药科技有限公司 | New medical salt of dexibuprofen |
| CN103893767A (en) * | 2013-09-17 | 2014-07-02 | 天津市嵩锐医药科技有限公司 | Ibuprofen medicine composition with stable quality |
| CN110693822A (en) * | 2019-09-29 | 2020-01-17 | 山东罗欣药业集团股份有限公司 | Ibuprofen injection and preparation method thereof |
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2022
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| Ján Kyselovič等人.A Randomized, Double-Blind, Placebo-Controlled Trial of Ibuprofen Lysinate in Comparison to Ibuprofen Acid for Acute Postoperative Dental Pain.《Pain Ther》.2020,第1卷249-259. * |
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