Liquid composition for injection containing dextrofenprofen

Abstract

The present invention relates to a liquid injection composition containing a poorly soluble drug, i.e., dexibuprofen, as an effective ingredient, and more particularly, a liquid injection composition containing dexibuprofen, which is composed of, relative to 100 parts by weight of dexibuprofen, 70 to 100 parts by weight of lysine as a solvent, 1 to 10 parts by weight of diethanolamine as a stabilizer, 15 to 100 parts by weight of benzyl alcohol as an analgesic agent, and 600 to 830 parts by weight of water for injection.

Description

Technical Field

[0001] This invention relates to an injectable liquid composition containing a poorly soluble drug, namely dextrorotatory ibuprofen, as an active ingredient. Specifically, the injectable liquid composition contains dextrorotatory ibuprofen and comprises, relative to 100 parts by weight of dextrorotatory ibuprofen, 70-100 parts by weight of lysine as a solvent, 1-10 parts by weight of diethanolamine as a stabilizer, 15-100 parts by weight of benzyl alcohol as a pain reliever, and 600-830 parts by weight of water for injection. Background Technology

[0002] Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that reduces pain, fever, and inflammation. Its chemical name is 2-(4-isobutylphenyl)propionic acid, with a molecular weight of 206.28. It is currently marketed under brand names such as Motrin, Advil, and Nuprin.

[0003] Ibuprofen has two optical isomers, (R)-ibuprofen and (S)-ibuprofen, of which (S)-ibuprofen exhibits pharmacological activity. In ibuprofen formulations containing a racemic mixture as the active ingredient, (R)-ibuprofen is substantially converted to (S)-ibuprofen in vivo, after which it exhibits activity. The (S)-ibuprofen is specifically referred to as dexibuprofen.

[0004] While ibuprofen and dextro-ibuprofen offer many advantages over other analgesics such as aspirin or acetaminophen, their poor water solubility, classifying them as poorly soluble drugs, presents significant limitations in their formulation. Therefore, numerous attempts and efforts are still being made to develop pharmaceutically stable liquid compositions by improving their water solubility.

[0005] First, Korean Patent No. 10-0851679 (August 5, 2008) discloses a liquid composition comprising an aqueous solution of arginine and ibuprofen, wherein the molar ratio of arginine is less than 1 mole compared to 1 mole of ibuprofen. This ibuprofen liquid composition is currently marketed under the trade name "Caldolor Injection" and is used as an adjunct therapy to anesthetic analgesics for pain relief.

[0006] The aforementioned caldocorlate injection contains 100 mg of ibuprofen per 1 mL. When used for intravenous injection, the ibuprofen concentration is diluted to approximately 4 mg / mL using an infusion set before being administered to the body. However, the problem with this caldocorlate injection is that when the ibuprofen concentration is diluted below 20 mg / mL, ibuprofen precipitates out, forming insoluble precipitates. These precipitates can clog the injection needle of the infusion set used for intravenous injection, ultimately hindering drug delivery.

[0007] To address these issues, Patent No. 10-2019-141871 (December 26, 2019) discloses a pharmaceutical composition for use as an injectable concentrate for dilution when infused into the human body, characterized in that the molar ratio of arginine to 1 mole of ibuprofen is 1 to 1.28, and the pH is 7.5 to 8.0.

[0008] According to the description, these pharmaceutical compositions do not produce precipitates even when ibuprofen is diluted to approximately 4 mg / mL. However, while arginine, used as an additive in the patent, is a pharmaceutically safe substance, reports indicate that intravenous injection may cause side effects such as changes in blood pressure. Therefore, when using arginine as an additive in injectable preparations, it is important to note that it is contraindicated for patients with myocardial infarction or a history of myocardial infarction.

[0009] In addition to the aforementioned patent, Patent No. 10-0425900 (March 23, 2004) discloses a transparent liquid ibuprofen solution comprising ibuprofen, a surfactant, and an amine. The surfactant is selected from one or more of octylhexanoyl glycerol, polyethylene glycol sorbitan fatty acid ester, or polyoxyethylene 40 cured castor oil, and the amine is selected from one or more of ethylenediamine, monoethanolamine, diethanolamine, or triethanolamine.

[0010] Furthermore, Patent No. 10-2004-0106915 (December 20, 2004) discloses a dissolution method that completely dissolves ibuprofen in a mixture of polyethylene glycol, polyvinylpyrrolidone, sodium dodecyl sulfate, diethanolamine, and basic amino acids, thereby significantly improving the dissolution rate. Patent No. 10-1236528 (February 18, 2013) discloses a liquid composition of dextrorotatory ibuprofen containing dextrorotatory ibuprofen and diethylene glycol monoethyl ether, polyethylene glycol, polysorbate, KOH, or NaOH.

[0011] However, ibuprofen liquid compositions produced using the existing dissolution methods described above are all developed for the manufacture of capsules or syrups as oral formulations, and therefore have limitations as they are unsuitable for use as injectable solutions. Because injectable drugs differ from oral formulations, even trace amounts of precipitates or sediments formed in the solution can cause needle blockage and reduced pharmacological efficacy during human injection.

[0012] [Prior Technology Documents]

[0013] [Patent Literature]

[0014] Korean Patent No. 10-0425900 (issued March 23, 2004);

[0015] Korean Patent Publication No. 10-2004-0106915 (December 20, 2004);

[0016] Korean Patent No. 10-0851679 (August 5, 2008);

[0017] Korean Patent No. 10-1236528 (February 18, 2013);

[0018] Korean Patent Publication No. 10-2019-141871 (December 26, 2019). Summary of the Invention

[0019] Technical issues

[0020] Therefore, the purpose of this invention is to provide a liquid composition for injection containing dextrorotatory ibuprofen, which does not produce precipitates or sediments even when the concentration of dextrorotatory ibuprofen is diluted to about 4 mg / mL, thus allowing for intravenous infusion of the original injectable solution containing dextrorotatory ibuprofen.

[0021] Another objective of this invention is to provide an injectable liquid composition containing dextro ibuprofen, which can be used for intramuscular or intravenous injection as needed, without causing changes in blood pressure in the human body, and can be safely administered to patients with myocardial infarction.

[0022] Technical solution

[0023] The injectable liquid composition containing dextrorotatory ibuprofen according to the present invention preferably comprises, relative to 100 parts by weight of dextrorotatory ibuprofen, 70-100 parts by weight of lysine, 1-10 parts by weight of diethanolamine, 15-100 parts by weight of benzyl alcohol, and 600-830 parts by weight of water for injection.

[0024] Preferably, the injectable liquid composition further includes 5 to 80 parts by weight of dilute hydrochloric acid at a concentration of 10% as a pH adjuster.

[0025] Preferably, the injectable liquid composition has a concentration of 50-110 mg of dextrorotatory ibuprofen as the active ingredient in 1 mL of solution, and a pH of 7.5-8.0.

[0026] Preferably, the injectable liquid composition containing dextro-ibuprofen according to the first embodiment of the present invention comprises, relative to 100 parts by weight of dextro-ibuprofen, 74 parts by weight of lysine, 1 part by weight of diethanolamine, 15 parts by weight of benzyl alcohol, and 810 parts by weight of water for injection, wherein the concentration of dextro-ibuprofen is 100 mg per 1 mL of solution and the pH is 7.7.

[0027] Preferably, the injectable liquid composition containing dextro-ibuprofen according to the second embodiment of the present invention comprises, relative to 100 parts by weight of dextro-ibuprofen, 80 parts by weight of lysine, 1 part by weight of diethanolamine, 15 parts by weight of benzyl alcohol, 10 parts by weight of 10% dilute hydrochloric acid, and 794 parts by weight of water for injection, wherein the concentration of dextro-ibuprofen is 100 mg per 1 mL of solution and the pH is 7.7.

[0028] Beneficial effects

[0029] The beneficial effect of the liquid composition for injection containing dextrorotatory ibuprofen according to the present invention is that no precipitates or sediments are produced in the solution, whether in the form of the injectable concentrate or when the concentration of ibuprofen is diluted to about 4 mg / mL, so it can be safely used for intramuscular or intravenous injection.

[0030] It exhibits excellent stability of the active ingredients, and there is no need to worry about it causing changes in blood pressure in the human body, thus it can be safely infused for patients with myocardial infarction. Attached Figure Description

[0031] Figures 1 to 3 The chromatograms are those showing whether or not a soft substance is produced after the injectable liquid compositions manufactured according to Examples 1, 2 and Comparative Example 1 of the present invention are stored under harsh conditions (60°C) for 2 weeks. Detailed Implementation

[0032] The present invention will now be described in detail. However, even components necessary for carrying out the present invention that have already been described in the prior art or that can be easily implemented by those skilled in the art based on known techniques will not be specifically described.

[0033] The injectable liquid composition containing dextrobuprofen of the present invention comprises dextrobuprofen as an active ingredient, lysine, diethanolamine, benzyl alcohol, and water for injection, and may also include dilute hydrochloric acid as a pH adjuster.

[0034] Lysine is an essential amino acid, chemically named 2,6-diaminohexanoic acid, with a molecular weight of 146. This lysine cannot be synthesized in the human body; it is synthesized from aspartic acid in microorganisms and from acetyl-CoA (coenzyme) and α-ketoglutarate in yeast.

[0035] The industrial method for mass production of lysine involves fermenting sugarcane with Corynebacterium glutamicum, or synthesizing the precursor racemic aminocaprolactam from caprolactam as a starting material, followed by photolysis of L-pyrrolidone carboxylic acid to obtain L-lysine.

[0036] Lysine plays a vital role in the production of muscle protein, calcium absorption, hormones, enzymes and antibody production, postoperative recovery, and the recovery period after herpes simplex infection. Conversely, a deficiency of lysine can lead to loss of appetite, weight loss, anemia, fatigue, poor concentration, enzyme abnormalities, and stunted growth.

[0037] In this invention, lysine acts as a solvent, dissolving the poorly soluble drug dextro-ibuprofen. The solubility of dextro-ibuprofen increases in alkaline solutions with high pH due to the ionization of its carboxyl group (-COOH). Lysine, like arginine, is a basic amino acid, and a 10% aqueous solution of lysine has a pH of approximately 9-10. Therefore, lysine can increase the solubility of dextro-ibuprofen.

[0038] The lysine content is 70-100 parts by weight relative to 100 parts by weight of dextro-ibuprofen. If the lysine content is less than 70 parts by weight, the solubility of dextro-ibuprofen decreases, potentially leading to precipitation. Conversely, if it exceeds 100 parts by weight, the amount of hydrochloric acid used as a pH adjuster increases, raising safety concerns for the injectable formulation. For reference, a suitable pH for ensuring the safety of the injectable formulation is 7.5-8.0, and the amount of hydrochloric acid used for pH adjustment should not exceed 1% by weight.

[0039] The diethanolamine is a colorless liquid or white solid crystal with a molecular weight of 105. It has a slightly rotten fish or shellfish odor or an ammonia smell and a density higher than water. It is readily soluble in ethanol and water, but poorly soluble in ether and benzene, and is a strongly alkaline substance. Industrially, it is mainly used as a raw material in cosmetics, and is commonly used in the synthesis of surfactants such as laurylamide or cocoamide.

[0040] The diethanolamine described in this invention acts as a stabilizer, improving the solubility of dextro-ibuprofen and further inhibiting the formation of decomposition products. The content of diethanolamine is 1 to 10 parts by weight relative to 100 parts by weight of dextro-ibuprofen. If the content of diethanolamine is less than 1 part by weight, the stability of the injection solution may decrease over time due to the formation of dextro-ibuprofen decomposition products. Conversely, if the content exceeds 10 parts by weight, excessive foaming may occur during the filtration process in the injection solution manufacturing process, causing manufacturing difficulties.

[0041] For reference, when the content of diethanolamine exceeds 15 parts by weight, safety issues may arise due to toxicity and other problems. Therefore, the US FDA limits the amount of diethanolamine used in injectable solutions to below 1.5% by weight, citing safety concerns such as toxicity.

[0042] Then, benzyl alcohol is a colorless and transparent liquid among aromatic alcohols, which can be used as a solvent and extractant, anti-volatile agent, anti-foaming agent, preservative, defoamer, and viscosity reducer. Its molecular weight is 108, and its density is slightly higher than that of water.

[0043] The benzyl alcohol described in this invention is a pain-relieving agent that can reduce pain when the undiluted injection solution is injected intramuscularly. The filtration process during the manufacturing of the injection solution can also inhibit the formation of foam.

[0044] The content of benzyl alcohol is 15 to 100 parts by weight relative to 100 parts by weight of dextro-ibuprofen. If the content of benzyl alcohol is less than 15 parts by weight, a large amount of foam may occur during the filtration process in the manufacturing of the injection, which may cause manufacturing difficulties. Conversely, if it exceeds 100 parts by weight, safety issues may occur due to toxicity and other problems.

[0045] Finally, the water for injection functions as both a solvent and a carrier, stably dissolving dextro ibuprofen, lysine, and diethanolamine before delivering them into the body. It may contain 600-830 parts by weight relative to 100 parts by weight of dextro ibuprofen. The water for injection is similar to that used in ordinary injectable preparations; preferably, it is water for injection manufactured through distillation or ultrafiltration.

[0046] In addition to the aforementioned components, the injectable liquid composition containing dextro-ibuprofen according to the present invention may, as needed, include dilute hydrochloric acid, preferably a 10% concentration. The dilute hydrochloric acid serves as a pH adjuster; if a 10% concentration is used, it comprises 5 to 80 parts by weight relative to 100 parts by weight of dextro-ibuprofen. The amount of dilute hydrochloric acid used is sufficient to adjust the pH of the liquid composition of the present invention to 7.5 to 8.0, preferably to pH 7.7.

[0047] For reference, the pH of blood in the body is approximately 7.3 to 7.7. If the pH of the injection solution exceeds this range, reaching above 8.5, pain may occur during injection, and it may also be a cause of phlebitis. Furthermore, if the pH of the injection solution drops below 6.5, the solubility of dextromethorphan decreases, and precipitation may occur.

[0048] The concentration of the dextrorotatory ibuprofen, which is the active ingredient in this invention, is 50-110 mg per 1 mL of solution, preferably 100 mg. Depending on the patient's symptoms or treatment purpose, 50-3200 mg of dextrorotatory ibuprofen can be injected once a day or in two or more divided injections.

[0049] The liquid composition for injection containing dextromethorphan of the present invention can be used for both intramuscular and intravenous injection. For intramuscular injection, the undiluted solution of the liquid composition is directly injected intramuscularly. For intravenous injection, the undiluted solution is diluted to a concentration of approximately 4 mg / mL of dextromethorphan before intravenous injection.

[0050] When using the injection stock solution for intravenous injection, the diluent can be intravenous infusion water, such as physiological saline, glucose injection, or Ringer's solution with added lactose.

[0051] The features and effects of the present invention will be described below with reference to embodiments and comparative examples.

[0052] [Example 1]

[0053] 10g of dextro-ibuprofen and 7.4g of lysine were poured into a beaker, and 60mL of water for injection was added, followed by thorough stirring. Then, 0.1g of diethanolamine and 1.5g of benzyl alcohol were added, and water for injection was added until the final volume reached 100mL. The resulting liquid composition for injection has a dextro-ibuprofen concentration of 100mg / mL and a pH of 7.7.

[0054] [Examples 2-6]

[0055] The procedure was carried out in the same manner as in Example 1, but the contents of each component were changed as shown in Table 1 below. 1 mL of 10% dilute hydrochloric acid was added to adjust the pH to 7.7. The resulting injectable liquid composition contained 100 mg / mL of dextromethorphan at a pH of 7.7. The amounts (mg) of each component used in Table 1 below are calculated based on the content in 1 mL of solution.

[0056] [Table 1] (Unit: mg)

[0057] Dextrorotatory ibuprofen 100 100 100 100 100 100 Lysine 74 80 100 74 100 100 diethanolamine 1 1 1 5 5 10 dilute hydrochloric acid - 10 30 5 30 80 benzyl alcohol 15 15 15 60 60 100 Water for Injection 810 794 754 756 705 610 Total (unit: mg) 1,000 1,000 1,000 1,000 1,000 1,000

[0058] [Comparative Example 1]

[0059] 10g of dextro-ibuprofen and 6g of lysine were poured into a beaker, followed by 1.5g of benzyl alcohol and 60mL of water for injection. The mixture was stirred thoroughly, and then the water for injection was added until the final volume reached 100mL. The resulting liquid composition for injection had a dextro-ibuprofen concentration of 100mg / mL and a pH of 6.9.

[0060] [Comparative Examples 2-4]

[0061] The procedure was carried out in the same manner as Comparative Example 1, but the contents of each component were changed as shown in Table 2 below. The concentration of dextrorotatory ibuprofen in the prepared injectable liquid composition was 100 mg / mL, and the pH was as shown in Table 2. The dosage (mg) of each component in Table 2 below is the result of conversion based on the content in 1 mL of solution.

[0062] [Table 2] (Unit: mg)

[0063] Dextrorotatory ibuprofen 100 100 100 100 Lysine 60 74 80 100 benzyl alcohol 15 15 15 15 Water for Injection 825 811 805 785 Total (unit: mg) 1,000 1,000 1,000 1,000 pH 6.9 7.7 8.4 9.0

[0064] [Experimental Example]

[0065] (1) Stability test of the diluted solution at room temperature

[0066] The injectable liquid compositions prepared according to the embodiments and comparative examples were diluted with appropriate amounts of physiological saline until the concentration of dextro ibuprofen reached 4 mg / mL. Each diluted solution was stored at room temperature for 48 hours, and the change in the content (%) of the active ingredient, dextro ibuprofen, was measured according to the time period. The results were then recorded in Tables 3 and 4 below.

[0067] [Table 3]

[0068] initial 99.8 99.4 99.8 99.7 99.5 99.7 12 hours later 99.1 99.2 99.7 98.9 99.2 99.8 24 hours later 98.7 98.9 99.8 99.3 98.7 99.4 48 hours later 99.6 99.5 99.1 98.7 98.4 99.6 pH of the diluted solution 6.7 7.3 7.4 7.5 7.4 7.0

[0069] [Table 4]

[0070]

[0071]

[0072] (2) Visually inspect the changes in the properties of the diluted solution.

[0073] The injectable liquid compositions prepared according to the embodiments and comparative examples were diluted with an appropriate amount of physiological saline to achieve a concentration of dextroprofen of 4 mg / mL. Each diluted solution was stored at room temperature for 48 hours, and the changes in the properties of each solution were observed visually at the initial, 12-hour, and 24-hour intervals.

[0074] The test results showed that in the liquid compositions of Examples 1 to 6, all test compositions remained transparent and pale yellow after 48 hours. However, the liquid compositions of the comparative examples showed the results shown in Table 5 below.

[0075] [Table 5]

[0076] initial Formation of suspended matter transparent pale yellow transparent pale yellow transparent pale yellow 12 hours later Precipitate formed transparent pale yellow transparent pale yellow transparent pale yellow 24 hours later Precipitate formed transparent pale yellow transparent pale yellow transparent pale yellow 48 hours later Precipitate formed Precipitate formed transparent pale yellow transparent pale yellow

[0077] (3) Testing of the injectable concentrate under harsh conditions

[0078] The injectable liquid compositions manufactured according to the embodiments and comparative examples were stored in a cavity at a temperature of 60°C for 2 weeks in their original state, and the amount of dextrorotatory ibuprofen softening substance produced was determined by HPLC at time points after 3 days, 1 week, and 2 weeks.

[0079] The test results showed that no soft substances were detected in any of the liquid compositions in Examples 1 to 6 after two weeks. However, the liquid compositions of the comparative examples showed the results shown in Table 6 below.

[0080] [Table 6]

[0081] initial Not detected Not detected Not detected Not detected Three days later 0.16％ Not detected Not detected Not detected One week later 0.22％ 0.14％ 0.11％ 0.17％ Two weeks later 0.36％ 0.21％ 0.19％ 0.15％

[0082] Appendix Figure 1 and Figure 2 The chromatograms are of the injectable liquid compositions prepared according to Examples 1 and 2 of the present invention, after being stored under harsh conditions (60°C) for 2 weeks to observe whether a softening substance occurs. Figure 3 This is a chromatogram taken under the same conditions of the liquid composition for injection prepared according to Comparative Example 1 described above.

[0083] from Figure 1 and Figure 2 As can be seen from the data, no soft substances were detected except for dextrorotatory ibuprofen, but from... Figure 3It can be seen that two types of soft substances are produced at positions 27.845 min and 47.451 min respectively.

[0084] [Evaluate]

[0085] As shown in the test results, in Comparative Examples 1 and 2, which did not use the stabilizer diethanolamine, when the concentration of dextromethorphan was diluted to 4 mg / mL, precipitation occurred over time at room temperature. In particular, when the injectable solution was stored under harsh conditions at 60°C, all comparative examples began to produce a soft substance after one week, and 0.15% to 0.36% of the soft substance was produced after two weeks.

[0086] However, the injectable liquid composition manufactured according to embodiments of the present invention not only maintains the original injectable solution state, but also exhibits excellent stability of all active ingredients under harsh conditions of up to 60°C and at room temperature when the concentration of dextrorotatory ibuprofen is diluted to 4 mg / mL. Furthermore, no soft substances or precipitates were observed to form.

Claims

1. An injectable liquid composition containing dextrorotatory ibuprofen, characterized in that, Its composition is as follows, relative to 100 parts by weight of dextrorotatory ibuprofen, it contains 70-100 parts by weight of lysine, 1-10 parts by weight of diethanolamine, 15-100 parts by weight of benzyl alcohol, and 600-830 parts by weight of water for injection; the pH is 7.5-8.0, and even if the concentration of said dextrorotatory ibuprofen is diluted to 4 mg / mL, no precipitate or sediment is produced.

2. The injectable liquid composition containing dextrorotatory ibuprofen according to claim 1, characterized in that, The liquid composition also includes 5-80 parts by weight of dilute hydrochloric acid with a concentration of 10%.

3. The injectable liquid composition containing dextrorotatory ibuprofen according to claim 1 or claim 2, characterized in that, The concentration of the dextrorotatory ibuprofen is 50-110 mg per 1 mL of solution.

Images