Dexibuprofen solution as well as preparation method and application thereof

Abstract

The invention relates to a dexibuprofen true solution as well as a preparation method and application thereof. Specifically, the invention relates to a dexibuprofen true solution oral drop, which is prepared from 5 mg to 400 mg / ml of dexibuprofen and a cosolvent, the weight ratio of the dexibuprofen to the cosolvent is about 1.5: 1. Optionally, the dexibuprofen solution is subpackaged in a single-dose or multi-dose package. The prescription is the optimal prescription determined on the basis of a large number of optimized prescriptions, the design is reasonable, and the process is suitable for industrial production. The product is controllable in quality and stable in performance.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of a true solution of dexibuprofen. BACKGROUND

[0002] Ibuprofen has a long history since it was launched in the UK in 1966, and has gradually become one of the most common non-steroidal anti-inflammatory drugs in clinical use, and is ranked as one of the three mainstay drugs for antipyretic and analgesic, together with aspirin and acetaminophen. The structure of ibuprofen is not complex, but has one chiral center, thus having two enantiomers, i.e. levobuprofen and dexibuprofen. At present, the racemic mixture of ibuprofen is sold and used in clinical use, and the proportion of levobuprofen and dexibuprofen is 1:1, but in fact, the main active ingredient is dexibuprofen.

[0003] Dexibuprofen was first successfully developed and launched by Gebro-Broscheh GMbH company in Austria in 1994, and then was launched in many countries. In China, the drug was developed and launched by Hubei Baike Hengdi Pharmaceutical Company in 2001. The enantiomer of dexibuprofen is the active ingredient in the racemic mixture of ibuprofen, which plays an anti-inflammatory role by inhibiting cyclooxygenase (COX) and reducing the synthesis of prostaglandin, thus exerting pharmacological and therapeutic effects. At the same time, dexibuprofen does not need to be converted after entering the body, and can easily and rapidly achieve a high blood drug concentration, thus showing the characteristics of fast onset and strong effect. In addition, dexibuprofen also has the characteristics of not interfering with the biosynthesis of adipose tissue in the body, not participating in the lipid metabolism pathway, and eliminating the possibility of high sensitivity habit reaction. Therefore, dexibuprofen is more thoroughly cleared from the body than the racemic mixture of ibuprofen, further reducing the probability of adverse reactions caused by drug accumulation in the body.

[0004] The racemic mixture of ibuprofen is inactive in vitro and needs to be converted into dexibuprofen to show pharmacological effects. The individual differences in this chiral conversion process make racemic ibuprofen have complex pharmacokinetic and pharmacodynamic properties, and the dosage is difficult to accurately determine. S-ibuprofen has little activity on COX-2, while R-ibuprofen has a definite inhibitory effect on COX. The activity of R-ibuprofen is 160 times that of S-ibuprofen and 1.6 times that of the racemate. Therefore, R-ibuprofen has higher efficacy and can achieve therapeutic effects at a small dose. Clinical studies have shown that, compared with ibuprofen, R-ibuprofen at half the dose of ibuprofen can achieve the same or even better clinical efficacy, and reduce the incidence of adverse reactions. Since S-ibuprofen is involved in the lipid metabolism pathway and is incorporated into triglycerides together with endogenous fatty acids, it interferes with lipid metabolism and produces toxicity. R-ibuprofen does not participate in this metabolic pathway, so it has less toxicity. Based on the above results, the potential advantages of R-ibuprofen are fast absorption, small dose, strong effect, less toxicity, and fast onset (Yoon, J.S., et al., The effects and safety of dexibuprofen compared with ibuprofen in febrile children caused by upper respiratory tract infection. Br J Clin Pharmacol, 2008. 66(6): p. 854-60).

[0005] At present, the ibuprofen dosage forms on the market at home and abroad include ordinary tablets, capsules, suppositories, creams, suspensions, sustained-release tablets, emulsions, etc. However, due to the low bioavailability of traditional preparations, a large dose is often used, which may cause adverse reactions. The most commonly used dosage form in clinical practice is ibuprofen suspension. However, during use, it is found that it has the disadvantages of slow onset, small antipyretic amplitude, and short duration. Therefore, frequent and large doses are required to achieve satisfactory therapeutic effects. The increase in single dose and the increase in the number of doses increase the incidence of drug side effects and adverse reactions, and may even cause serious complications such as severe drug eruption, gastrointestinal bleeding, acute renal failure, central nervous system symptoms, thrombocytopenia, and granulocytopenia.

[0006] Although clinical practice shows that dextro ibuprofen is a drug with good efficacy and high safety, there are still some problems to be solved, such as poor solubility, low bioavailability, strong nephrotoxicity, gastrointestinal discomfort, and lack of sustained-release dosage forms. New research focuses on the study of its structure-activity relationship, using it as a lead compound to screen derivatives with higher selectivity, fewer adverse reactions, and stronger efficacy, or using nanotechnology and materials to develop new dosage forms of dextro ibuprofen, improve bioavailability, and improve drug administration routes (see Zhang Enjing, Research Progress of Dextro Ibuprofen. Drug Biotechnology. 2018. 25(03): p. 281-282).

[0007] In the inventor's previous patent application CN109381426A, a dextro ibuprofen oral spray is provided, but the spray is a liquid atomized by a spray pump under the condition of gas power. Due to the increase of the solubility of dextro ibuprofen to 40% under the action of the cosolvent, the specific gravity of the solution increases, and the ordinary atomizing pump cannot be atomized, so a special spray pump is needed to realize it. Even so, due to the air flow of the spray after atomization, the water in the drug solution evaporates to form a powder, which is inhaled into the lungs, which may pose a safety risk for pediatric medication. In addition, the spray needs to be packaged with multiple measurements, and preservatives need to be added to ensure its quality.

[0008] In view of the above technical problems in the prior art, the present application provides a new dextro ibuprofen preparation, which has the significant characteristics of fast absorption, rapid onset, stronger effect, and no serious adverse reactions. SUMMARY

[0009] In a first aspect, the present application provides a true solution of dextro ibuprofen, comprising:

[0010] 5-400 mg / ml, preferably 20-250 mg / ml, more preferably 20 mg / ml to 100 mg / ml, even more preferably 20-50 mg / ml, even more preferably 20-40 mg / ml of dextro ibuprofen, and a cosolvent;

[0011] The weight ratio of the dextro ibuprofen to the cosolvent is 0.5:1 to 2.5:1, preferably 1:1 to 2:1; preferably about 1.5:1;

[0012] Preferably, the cosolvent is selected from one or more of L-arginine, L-lysine, and L-histidine.

[0013] In the context of the present application, the term "true solution" refers to a solution in which the solute (such as a drug) is uniformly dispersed in a solvent in a molecular or ionic state, transparent and stable, as opposed to the terms "suspension", "emulsion", etc.

[0014] True Solution is a homogeneous, stable mixture in which the solute is completely dissolved in the solvent in the form of molecules or ions, forming a single phase system.

[0015] Generally, True Solution has the following basic characteristics:

[0016] 1. Homogeneity: The solute is uniformly dispersed. The composition and properties of each part are exactly the same.

[0017] 2. Stability: Without external conditions change (such as evaporation, temperature change), the solution will not spontaneously precipitate or separate.

[0018] 3. Transparency: Generally transparent, but no visible particles to the naked eye.

[0019] 4. Particle size: The particle size of the solute is less than 1 nanometer, belonging to the molecular or ionic level, which can pass through filter paper and semi-permeable membrane.

[0020] The differences between True Solution, colloid and suspension are shown in Table 1:

[0021] Table 1

[0022] Properties True solution Colloid Suspension Particle size Less than nanometer 1-100 nanometer 100 nanometer Stability Very high Relatively stable Heterogeneous, visible particles Tyndall effect No Yes Obvious (under strong light) Filterability Pass through filter paper Pass through filter paper Cannot pass through filter paper

[0023] The term "co-solvent" appearing in the context of the present application means an auxiliary material capable of forming a soluble intermolecular complex, association or complex salt, etc. with a poorly soluble drug in a solvent to increase the solubility of the poorly soluble drug in the solvent, such as a basic substance capable of forming a salt with an acidic poorly soluble substance, an acidic substance capable of forming a salt with a basic poorly soluble substance, a substance capable of forming a complex or association through a heteroatom, etc.

[0024] The term "about" as used herein generally means close to the numerical value within an error range generally acceptable to those skilled in the art. If not specifically limited, it is generally in the range of ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or even ±1%.

[0025] In a specific embodiment, the true solution of dexibuprofen of the present application further comprises 2%-20% (v / v) of a taste masking agent selected from at least one of glycerol, lactic acid, tartaric acid, preferably glycerol. Glycerol is miscible with water and can produce a significant solubilization effect on buprofen, aiming to increase the solubility of the main drug in water, avoiding the precipitation of the main drug due to its low solubility, and causing the phenomenon of crystallization.

[0026] In a specific embodiment, the true solution of dexibuprofen of the present application comprises 2%-20% of glycerol.

[0027] In a specific embodiment, the true solution of dexibuprofen of the present application further comprises 0.01-100 mg / ml of a flavoring agent; the "flavoring agent" refers to an auxiliary ingredient capable of improving the tolerance of the patient to the bad taste of the drug, so that the patient is less likely to feel unpleasant, including natural flavoring agents (such as sucrose, glucose syrup, fructose syrup, honey, stevioside, sodium chloride, potassium chloride, etc.) and synthetic flavoring agents (sucralose, aspartame, sodium saccharin, cyclamate, acesulfame potassium, etc.).

[0028] In a specific embodiment, the true solution of dexibuprofen of the present application comprises 0.1-1 mg / ml of sucralose. In a specific embodiment, the true solution of dexibuprofen of the present application comprises 40-80 mg / ml of sucrose.

[0029] In a specific embodiment, the true solution of dexibuprofen of the present application further comprises 0.01-10 mg / ml, preferably 0.1-5 mg / ml of an odorant, the "odorant" refers to an auxiliary ingredient capable of improving the tolerance of the patient to the bad smell of the drug, so that the patient is less likely to feel unpleasant, including volatile terpenes (such as menthol, borneol, camphor, etc.), fruit flavors (such as apple flavor, orange flavor, strawberry flavor, banana flavor, etc.) and sugars (such as glucose, fructose, etc.).

[0030] In a specific embodiment, the true solution of dexibuprofen of the present application further comprises 0.1-10 mg / / ml, preferably 0.2-1.0 mg / / ml of a preservative, the "preservative" refers to an auxiliary ingredient used to inhibit or kill the growth of microorganisms (such as bacteria, mold, yeast) to prevent the drug from being contaminated or deteriorated during storage and use, including but not limited to the following types: parabens, such as methyl paraben, ethyl paraben, propyl paraben; alcohols, such as benzalkonium chloride; phenylethyl alcohol; organic mercury, such as thiomersal; acids / esters, such as benzoic acid, sodium benzoate; sorbic acid; potassium sorbate.

[0031] In a specific embodiment, the true solution of dexibuprofen of the present application comprises 0.2-1.0 mg / / ml of ethyl paraben.

[0032] In a specific embodiment, the true solution of dexibuprofen of the present application is dissolved in water.

[0033] In a specific embodiment, the true solution of dexibuprofen of the present application is packaged in a disposable sterile container.

[0034] In a specific embodiment, the true solution of dexibuprofen of the present application is used orally.

[0035] In another aspect, the present application provides use of a true solution of dextro ibuprofen according to the present application for the manufacture of an antipyretic analgesic medicament.

[0036] In another aspect, the present application provides a method of preparing a true solution of dextro ibuprofen, said method comprising the steps of:

[0037] 1) mixing dextro ibuprofen and a co-solvent, wherein the weight ratio of dextro ibuprofen to co-solvent is from 0.5:1 to 2.5:1, preferably from 1:1 to 2:1; preferably about 1.5:1;

[0038] 2) dissolving the mixture of dextro ibuprofen and co-solvent of step 1) in purified water;

[0039] 3) further adding purified water, stirring to homogeneity, and

[0040] 4) sterilizing the solution obtained in step 3) and dispensing in sterile containers.

[0041] In a particular embodiment, the present application provides a method of preparing a true solution of dextro ibuprofen, said method comprising the steps of:

[0042] 1) mixing 5-400 g, preferably 20 g of dextro ibuprofen and L-arginine, wherein the weight ratio of dextro ibuprofen to L-arginine is about 1.5:1;

[0043] 2) adding 0.2-1.0 g of ethyl parahydroxybenzoate and 20 ml of glycerol to 100 ml of purified water to clear dissolution;

[0044] 3) adding the mixture of dextro ibuprofen and L-arginine prepared in step 1) to the aqueous solution prepared in step 2) under stirring conditions, making up to 1000 ml, and stirring until complete dissolution.

[0045] In a particular embodiment, the present application provides a 2% true solution of dextro ibuprofen comprising:

[0046] about 20 mg / ml of dextro ibuprofen;

[0047] about 13.3 mg / ml of L-arginine;

[0048] about 20 ml of glycerol;

[0049] 40-80 mg / ml of sucrose; and

[0050] 0.2-1.0 mg / ml of ethyl parahydroxybenzoate.

[0051] In a particular embodiment, the present application provides a 4% true solution of dextro ibuprofen comprising:

[0052] about 40 mg / ml dextropropoxyphene;

[0053] about 26.6 mg / ml L-arginine;

[0054] about 20 ml glycerol;

[0055] 40-80 mg / ml sucrose; and

[0056] 0.2-1.0 mg / ml ethylparaben.

[0057] The test results of the embodiments of the present application prove that the 2% and 4% dextropropoxyphene true solution provided by the present application has rapid absorption, fast onset of antipyretic effect, good bioavailability, accurate dosage, reduced side effects, and becomes the first true solution multi-dose package of 2% and 4% specifications in the dextropropoxyphene series of children's preparations so far. In addition, it is the only new dosage form of true solution single-dose package with the smallest administration volume (1 ml per person).

[0058] In specific embodiments, the volume of the dextropropoxyphene drops of the present application is 0.5-1.5 ml, specifically, the volume of the dextropropoxyphene drops of the present application is 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml, 1.0 ml, 1.1 ml, 1.2 ml, 1.3 ml, 1.4 ml, 1.5 ml, or within a range between any two of the above.

[0059] The dextropropoxyphene true solution provided by the present application has multiple significant advantages compared to traditional suspensions or other dosage forms, especially in the scenarios of children's medication, oral liquid preparations, etc. The following are its main advantages:

[0060] 1) Higher dosage accuracy: completely dissolved, uniform concentration, avoiding dosage errors caused by insufficient shaking of suspensions, especially suitable for accurate dosing of children;

[0061] 2). Faster onset: faster absorption speed, dissolved drugs can be absorbed faster through the gastrointestinal tract, with shorter onset time than suspensions;

[0062] 3). Easier to take: better taste, no granular feeling, clear and transparent solution, no foreign body sensation, higher acceptance by children;

[0063] 4). Better stability: less likely to precipitate, stratify, high stability in solution state, no need to shake before each use;

[0064] 5). Lower administration volume: high concentration, concentrated dosage, some new dosage forms (such as 2% true solution) can only need 1 mL per time to achieve the therapeutic dose, especially suitable for younger children;

[0065] 6) More conducive to aseptic / conservation management: can be used for single dose packaging. BRIEF DESCRIPTION OF DRAWINGS

[0066] Figure 1 Chromatogram of the related substances test of the dextropropoxyphene true solution batch no. (230806-1, 20 mg / ml) long-term sample left for 24 months is shown;

[0067] Figure 2 Chromatogram of the related substances test of the dextropropoxyphene true solution batch no. (230806-2, 20 mg / ml) long-term sample left for 24 months is shown;

[0068] Figure 3 Chromatogram of the related substances test of the dextropropoxyphene true solution batch no. (230806-3, 20 mg / ml) long-term sample left for 24 months is shown. DETAILED DESCRIPTION

[0069] The present disclosure will be further illustrated by the following non-limiting examples. It is well known to those skilled in the art that many modifications can be made to the present disclosure without departing from the spirit thereof, and that such modifications are to be included within the scope of the present disclosure. Unless otherwise specified, the experimental materials used are available from commercial companies.

[0070] Example 1. Preparation of dextropropoxyphene true solution

[0071] The specific preparation process is as follows:

[0072] 1) Mix the prescribed amount of dextropropoxyphene and L-arginine, and reserve;

[0073] 2) Measure an appropriate amount of purified water (about 90-100 ml), and add the prescribed amount of menthol and sucralose to it, and stir until completely dissolved;

[0074] 3) Under stirring conditions, add the mixture of dextropropoxyphene and L-arginine prepared in step 1) to the aqueous solution prepared in step 2), and stir until completely dissolved;

[0075] 4) Add the prescribed amount of glycerol to the mixed solution prepared in step 3), and make up to 1000 ml with water, and stir until uniform, and the product is obtained.

[0076] 5) Sterile filter the clear semi-finished product obtained in 4), and fill the filtrate into one-time formed 1 ml or 0.8 ml polyethylene plastic bottles, and seal, and the product is obtained.

[0077] The formula composition of the dextropropoxyphene true solution is as shown in Table 2 below:

[0078] Table 2

[0079]

[0080] Example 2. Preparation of 2% dextrophenylalanine true solution

[0081] The specific preparation process is as follows:

[0082] 1) Mix the prescribed amount of dextrophenylalanine and L-arginine, and reserve;

[0083] 2) Measure an appropriate amount of purified water (about 90-100 ml), add the prescribed amount of dextrophenylalanine and L-arginine mixture in 1) to it, stir to dissolve. Add the prescribed amount of sucrose, and stir until completely dissolved;

[0084] 3) Weigh the prescribed amount of p-hydroxybenzoic acid ethyl ester (pass through a 60-mesh sieve), add it to the prescribed amount of glycerol, stir to dissolve, add 100 ml of purified water to dissolve, transfer to 2), add purified water to 1000 ml scale, stir until completely dissolved, and you get it;

[0085] 4) Filter the semi-finished solution in 3) through a sterile filter, and continue to filter the filtrate into 30 ml glass bottles, seal the caps, and you get it.

[0086] The formulation composition of 2% dextrophenylalanine true solution is shown in Table 3 below:

[0087] Table 3

[0088]

[0089] Example 3. Preparation of 4% dextrophenylalanine true solution

[0090] The composition of 4% dextrophenylalanine true solution is shown in the table below:

[0091]

[0092] The specific preparation process is as follows:

[0093] 1) Mix the prescribed amount of dextrophenylalanine and L-arginine, and reserve;

[0094] 2) Measure an appropriate amount of purified water (about 90-100 ml), add the prescribed amount of dextrophenylalanine and L-arginine mixture in 1) to it, stir to dissolve. Add the prescribed amount of sucrose, and stir until completely dissolved;

[0095] 3) Weigh the prescribed amount of p-hydroxybenzoic acid ethyl ester (pass through a 60-mesh sieve), add it to the prescribed amount of glycerol, stir to dissolve, add 100 ml of purified water to dissolve, transfer to 2), add purified water to 1000 ml scale, stir until completely dissolved, and you get it;

[0096] 4) Filter the semi-finished solution in 3) through a sterile filter, and continue to filter the filtrate into 15 ml glass bottles, seal the caps, and you get it.

[0097] Example 4: Comparison of 2% dexibuprofen true solution of the present application with 2% dexibuprofen suspension in terms of therapeutic efficacy and safety

[0098] 1. Subjects and Methods

[0099] 1.1. Subjects

[0100] 1.1.1. Patient Inclusion Criteria

[0101] ① Age 17-65 years, and the degree of pain is mainly moderate.

[0102] ② Patients with fever caused by upper respiratory tract infection, body temperature above 38.5℃.

[0103] 1.1.2. Exclusion Criteria, Except for the following cases, patients meeting the above conditions can be enrolled

[0104] ① Active or recurrent peptic ulcer;

[0105] ② Decompensated heart failure or severe hypertension patients;

[0106] ③ Diabetes or other metabolic diseases;

[0107] ④ Liver, kidney, and blood system diseases;

[0108] ⑤ History of drug allergy;

[0109] ⑥ Patients who have received immunosuppressive agents, D-penicillamine, chloroquine, and local or systemic treatment of adrenal cortex hormones within 3 weeks before the trial;

[0110] ⑦ Pregnant women and lactating women;

[0111] ⑧ Patients undergoing anticoagulant therapy.

[0112] 1.1.3. Exclusion Criteria

[0113] ① Patients who have not completed the required medication time and have exited the trial.

[0114] ② Patients who discontinued medication due to severe adverse reactions were not counted for efficacy, but adverse reactions were included in statistical analysis.

[0115] 1.2. Experimental Group Patients meeting the inclusion criteria were randomly divided into two groups according to disease duration, disease stage, disease condition, age, and gender, and a randomized double-blind trial was conducted.

[0116] 1.3. Administration Method

[0117] 2% Dexibuprofen True Solution Group (Prescription 8): According to the volume of individualized calculated dose of 10 mg / kg, take it all at once, twice a day, for 3 consecutive days.

[0118] 2% dexibuprofen suspension control group: according to the volume of individualized dose of 10 mg / kg, taken orally, twice a day, for 3 days.

[0119] Two groups of test period were not used other NSAIDs, analgesics and hormones.

[0120] 1.4 observation index pain classification using visual scale method, under the guidance of doctors, by patients fill in. 1, no pain or no pain (scale 0~1); 2, mild pain, but can live and work, sleep is not disturbed (scale 2~4); 3, moderate pain, that is, there are obvious symptoms of pain, normal life, work and sleep are disturbed (scale 4~7); 4, severe pain, there are severe pain symptoms, normal life, work and sleep are severely disturbed (scale 8~10). The change of body temperature of patients with fever at each time point after medication.

[0121] 1.5 efficacy evaluation of patients with pain, pain intensity difference (PID), total pain intensity difference (SPID) and pain relief degree (PAR) were used for comprehensive evaluation. PID is the difference value of pain intensity measured before and after medication; SPID is the sum of the value of each PID divided by the corresponding observation time. PAR is divided into 5 levels; 0 is no relief, 1 is relief, pain relief about 25%; 2 is moderate relief, symptoms are obviously improved, the relief rate is greater than 50%; 3 is obvious relief, greater than 75%; 4 is complete relief, pain relief more than 90%, 0 is invalid, 1, 2 is effective, 3, 4 is obvious. The effective rate (effective + obvious) and the obvious rate were calculated, and the moderate relief degree was also calculated. According to the daily body temperature change, the antipyretic effect of patients with fever was judged.

[0122] 1.6 adverse reaction self tolerance record patients before and after medication, the self-conscious discomfort reaction. Compare the blood routine, liver function and fecal occult blood before and after medication, and statistically analyze the adverse reactions related to drugs according to 5 levels (related, possibly related, unrelated, possibly unrelated and unable to judge). If there is serious reaction, stop medication in time.

[0123] 1.7 statistical processing of measurement data was compared by t test, count data was compared by x 2 test, and the total effective rate was compared by Ridit analysis.

[0124] 2 results

[0125] 2.1 analgesic effect of dexibuprofen true solution

[0126] 2.1.1 patient's general condition The pain intensity of two groups was mainly moderate, and the patients were distributed in postoperative analgesia in hospital. There was no significant difference in age, sex and pain intensity between the two groups (P>0.05) (see table 4).

[0127] Table 4: Age, gender and pain intensity distribution between two groups

[0128] Group n Age (years) Male / female Pain intensity Moderate pain (%) True solution group 68 36.91±10.12 37 / 31 7.52±0.97 71 Suspension group 65 36.42±11.08 35 / 30 7.21±0.88 73

[0129] 2.1.2 Analgesic effect The PID of the dextropropoxyphene true solution group was higher than that of the dextropropoxyphene suspension group (P<0.05~0.01) within the first 4 hours after administration, and the SPID value was also higher than that of the dextropropoxyphene suspension group (P<0.05). Within 24~72 hours after administration, the indicators of the dextropropoxyphene true solution group were still higher than those of the dextropropoxyphene suspension group, but the difference was not statistically significant (P>0.05). Within the first 4 hours after administration, the PAR of the dextropropoxyphene true solution group was higher than that of the dextropropoxyphene suspension group (P<0.05~0.01) (see Table 5).

[0130] Table 5: PID and PAR at each time point after administration

[0131]

[0132] *P<0.05, true solution group SPID vs. suspension group SPID; P1 is the comparison of PID between two groups, and P2 is the comparison of PAR between two groups.

[0133] Table 6: Comparison of therapeutic effect between two groups (%)

[0134]

[0135] The difference in therapeutic effect between two groups was not statistically significant (P>0.05) (see Table 6).

[0136] 2.1.3 Adverse reactions No adverse reactions such as bloody stool, constipation and diarrhea were found in patients of both groups,

[0137] Peripheral blood and liver function were normal.

[0138] 2.2 Antipyretic effect of true solution and suspension

[0139] 2.2.1 General condition of patients All patients were inpatients with fever due to respiratory tract infection, and the age, gender and body temperature of patients in two groups were not statistically significant (P>0.05) (see Table 7)

[0140] Table 7: Age and body temperature of two groups

[0141] Table 7: Age and body temperature of two groups

[0142]

[0143] 2.2.2 Antipyretic effect Both the true solution of dexibuprofen and the suspension of buprofen have antipyretic effect, but the body temperature of the true solution of dexibuprofen is lower than that of the suspension within 2 hours after administration, and the temperature decreasing amplitude of the true solution is greater than that of the suspension within 4 hours after administration (P<0.05-0.01) (see Table 8).

[0144] Table 8: Temperature change and temperature decreasing amplitude of two groups after administration

[0145]

[0146] P1 is the comparison of temperature change of two groups, and P2 is the comparison of temperature decreasing amplitude of two groups.

[0147] 3 Conclusion

[0148] In the clinical observation of postoperative pain cases, the PIA of the true solution of dexibuprofen is higher than that of the suspension of buprofen within 4 hours after administration, the SPID is also higher than that of the suspension, the PID of the true solution group is greater than 4 within 1-2 hours after administration, and the PID of the suspension group is within 4 hours after administration; the PAR of the true solution group is obviously higher than that of the suspension group, which indicates that the analgesic intensity of the true solution of dexibuprofen is greater than that of the suspension of dexibuprofen, so the analgesic effect of the true solution of dexibuprofen is faster and stronger than that of the suspension of dexibuprofen. In the clinical observation of fever cases, the temperature decreasing amplitude of the true solution of dexibuprofen is greater than that of the suspension of dexibuprofen within 4 hours after administration, which indicates that the temperature decreasing effect of the true solution of dexibuprofen is stronger than that of the suspension of dexibuprofen, and the effect is fast.

[0149] In summary, the true solution of dexibuprofen has definite analgesic and antipyretic effect, is absorbed faster than the suspension of dexibuprofen, has stronger effect, has no serious adverse reactions, and is safe to use, which is the outstanding clinical value of the present application, and has obvious advantages compared with the suspension of dexibuprofen.

[0150] Example 5. Comparative study of the antipyretic effect of 4% true solution of dexibuprofen and suspension of buprofen on children

[0151] The suspension of buprofen is a commonly used antipyretic and analgesic drug for children. The true solution of dexibuprofen and the suspension of buprofen are respectively applied to children with high fever for clinical observation, aiming to observe the antipyretic effect of the present application and the suspension of buprofen, and the results are reported as follows.

[0152] 1. Subjects and methods

[0153] 1.1 Subjects 238 children with acute upper respiratory tract infection with fever were observed in our hospital from September 2020 to April 2022, including 126 males and 112 females, aged 6 months to 12 years, with a disease course of 6-24 hours. There were 84 cases with a body temperature (axillary temperature) of 38.5-39.0℃, 126 cases with a body temperature of 39.1-40.0℃, and 28 cases with a body temperature of >40.0℃. They were randomly divided into dexibuprofen group and buprofen group: 122 cases in the dexibuprofen group, including 64 males and 58 females, aged (3.24±2.5) years, with a body temperature of (39.32±0.33)℃; 116 cases in the buprofen group, including 62 males and 54 females, aged (3.51±2.3) years, with a body temperature of (39.41±0.39)℃. There was no statistically significant difference in gender, age, body temperature, and disease course between the two groups (P>0.05), and they were comparable.

[0154] 1.2 Methods

[0155] 1.2.1 Administration method

[0156] Dexibuprofen true solution group: oral drop; prescription 11 in Example 3;

[0157] Buprofen suspension group: oral administration, using a randomized double-blind method, administered by nurses, 10 mg / kg each time, twice a day.

[0158] 1.2.2 Efficacy observation indicators and evaluation methods The body temperature was detected before and after medication at 0.75, 1.0, 1.5, 4.0, and 6.0 hours, and the body temperature drop was calculated. The body temperature detection method used the axillary temperature method, and the nurses helped the children to wipe the axillary fossa. The mercury of the thermometer was shaken below 35℃ and then placed in the middle of the axillary fossa. After 5 minutes, the nurses read the readings. The overall antipyretic efficacy evaluation: comparison of the body temperature drop at different times, the number of cases (%) with a body temperature drop of 1.5℃ in each group, and the number of cases (%) with a body temperature drop to 36.0-37.5℃.

[0159] 1.2.3 Adverse reaction evaluation Observation of children after medication for rash, sweating, low body temperature (body temperature below 36.0℃), nausea, vomiting, diarrhea, gastrointestinal bleeding, etc.

[0160] 1.2.4 Statistical processing SPSS 16.0 statistical software was used. Measurement data was represented by , independent sample t test was used for comparison between groups; χ2 test was used for comparison of count data. P<0.05 was considered statistically significant.

[0161] 2 Results

[0162] 2.1 Two groups of different time after administration of body temperature drop amplitude Comparison of two groups of 0.75, 1.0, 6.0h after administration of body temperature drop amplitude of dextropropoxyphene true solution group was significantly higher than that of propoxyphene suspension group (P<0.05), see Table 9.

[0163] Table 9: Two groups of different time after administration of body temperature drop amplitude

[0164]

[0165] 2.2 Two groups of body temperature drop number comparison Two groups of body temperature drop 1.5 There was a significant difference (P<0.05), and the number of body temperature drop to 36.0-37.5℃ had no significant difference (P>0.05), see Table 10.

[0166] Table 10: Two groups of different time after administration of body temperature drop amplitude (n, %)

[0167]

[0168] 2.3 Adverse reactions The incidence of adverse reactions in two groups was low. There were 1 case of rash, 1 case of excessive sweating, 1 case of low body temperature, 1 case of nausea, and 2 cases of vomiting in the dextropropoxyphene true solution group; there were 2 cases of rash, 1 case of excessive sweating, 1 case of nausea, and 1 case of vomiting in the propoxyphene suspension group. There were no adverse reactions such as diarrhea, gastrointestinal bleeding, allergy, and granulocytopenia in both groups, and the adverse reactions were improved after 6h of administration. There was no significant difference in the total incidence of adverse reactions between the two groups (χ2=0.05, P>0.05).

[0169] 3 CONCLUSION

[0170] The clinical study of the present application found that the dextropropoxyphene true solution was accurate in dosage, easy to use, and had good compliance, while the propoxyphene suspension was not accurate in dosage, had a large volume to take, and had poor compliance. Both had good antipyretic effect and good safety, and no serious adverse reactions occurred. However, the comparison of the antipyretic amplitude after administration of the two drugs at different times found that the dextropropoxyphene true solution could better reduce the body temperature of the children after 0.75, 1.0, and 6.0h of administration, which proved that dextropropoxyphene had a faster and more lasting antipyretic effect.

[0171] Example 6. Study on the analgesic effect of the dextropropoxyphene true solution of the present application on mice at different administration doses

[0172] 40 four-week-old Kunming mice, with an average weight of 20g, half male and half female, were randomly divided into four groups, 10 mice in each group, namely a blank control group, a low-dose group, a medium-dose group, and a high-dose group. After modeling by hot radiation tail-flick test, the mice in the low-, medium-, and high-dose groups were administered with 50, 75, and 100mg·kg -1The low dose of the oral administration of the true solution of the dextropropoxyphene of the present application (the prescription 8 in Example 2) was compared with the high dose of the suspension of the dextropropoxyphene.

[0173] The results showed that:

[0174] The low dose (50 mg·kg-1) was ineffective, while the middle dose (75 mg·kg-1) and the high dose (100 mg·kg-1) were effective. The PMPA of the high dose group was 38.7%, and the PMPA of the middle dose group was 28.3%, indicating that the analgesic effect of the high dose was stronger than that of the middle dose. The PMPA of the suspension of the dextropropoxyphene was 11.1% at the same dose (100 mg·kg-1), and the PMPA of the true solution of the dextropropoxyphene of the present application was 38.7%, indicating that the analgesic effect of the true solution was stronger than that of the suspension. Meanwhile, the Tmax of the true solution was 30 min, and the Tmax of the suspension was 2 h, indicating that the true solution had a faster onset of action than the suspension.

[0175] The time-effect relationship of the analgesic effect of the true solution of the dextropropoxyphene of the present application and the suspension of the dextropropoxyphene on mice showed that the analgesic effect of the true solution on mice was enhanced with the increase of the dose.

[0176] Example 7. Pharmacokinetic study of the true solution of the dextropropoxyphene of the present application in beagle dogs

[0177] Ten beagle dogs, 8 months old, with an average weight of 9.5 kg, half male and half female, were randomly divided into two groups, 4 dogs in each group. The dogs in the two groups were respectively given the true solution of the dextropropoxyphene of prescription 8 (200 mg / dog in terms of the content of the main drug) and the suspension of the dextropropoxyphene (200 mg / dog in terms of the content of the main drug) prepared in Example 2. Blood samples were collected from the lateral small hidden veins of the hind limbs at 30 min, 1 h, 2 h, 4 h, 8 h, 16 h and 24 h after administration. After plasma pretreatment, the blood drug concentration after administration was determined by HPLC analysis method, and the pharmacokinetic parameters were calculated.

[0178] The results show that the main pharmacokinetic parameters AUC0-24h, T1 / 2, Tmax, Cmax of the oral true solution are 29994.05±9409.14 mg·L-1·min, 324.79±129.37 min, 52.5±15 min, 78.74±17.26 mg·L-1 respectively; the main pharmacokinetic parameters AUC0-24h, T1 / 2, Tmax, Cmax of the suspension are 27560.78±7370.69 mg·L-1·min, 230.29±111.01 min, 120±42.43 min, 67.46±10.33 mg·L-1 respectively. The relative bioavailability of the dextrophenoxylamine oral true solution relative to the suspension is (109.55±19.59)%. The pharmacokinetic parameters of the two groups are statistically processed, and by variance analysis, AUC0-24h, MRT0-24h, T1 / 2, CLz / F and Cmax have no significant difference between the oral true solution and the suspension (P>0.05); Tmax has significant difference between the oral true solution and the suspension (P<0.05), Tmax of the oral true solution is significantly smaller than that of the suspension, and the peak time is about 1h-1.5h earlier than that of the suspension. The dextrophenoxylamine oral true solution is bioequivalent to the dextrophenoxylamine suspension, but it has more rapid onset and is more suitable for the needs of clinical children for antipyretic and analgesic treatment.

[0179] The dextrophenoxylamine oral true solution of the present application provides a new convenient, high compliance, stable performance, rapid antipyretic, reliable efficacy and promising pediatric dextrophenoxylamine dosage form for antipyretic and analgesic treatment of children.

[0180] Comparing the dextrophenoxylamine true solution with other dosage forms, the traditional antipyretic and analgesic drug ibuprofen has been used in the medical market for many years, and has reliable efficacy and good safety. There are tablets, capsules, true suspensions, oral suspensions, sustained-release dosage forms, injection solutions and the like. These dosage forms can be selected by different people for medication, and play an active role in the clinical application of the drug. However, due to the pharmacology and physicochemical properties of dextrophenoxylamine, the dosage is large, the water solubility is poor, and oral administration, especially for children, is more difficult. Based on the above reasons, the dextrophenoxylamine true solution is invented, and the dosage form characteristics compared with the existing dosage forms are as follows:

[0181] 1. The suspension, the quantitative accuracy of pediatric administration is not accurate, the suspension is settled, there are problems of uniformity, taste and the like, the compliance of children for oral administration is poor, and there is still certain difficulty, which affects the efficacy.

[0182] 2. The oral suspension, the volume of administration is large, the quantitative accuracy of administration by a syringe is poor, especially the accuracy of the dosage of children of different ages, and there is a compliance problem of children in use.

[0183] 3. The oral true solution of the present application is a new dosage form, and the liquid medicine is a true solution. The biggest feature of this dosage form is convenient for children to take medicine. This dosage form is a true solution, does not contain any bacteriostatic agent, tastes suitable for children, and the cooperation of children is better when taking medicine. The liquid medicine is quickly dropped into the mouth, has large dispersity, and is accurately quantified.

[0184] 4. The true solution can be packaged in single dose, which not only facilitates children to take medicine scientifically, but also avoids cross infection or waste caused by repeated use of multi-dose suspension packaging.

[0185] 5. The oral true solution is quickly absorbed. The pharmacokinetic study of beagle dogs proves that the Tmax of the true solution of the present application is about 30 min, and the Tmax of the suspension is about 2 h, which is about 4 times faster than the absorption of the suspension. This is an advantage that cannot be ignored for children to take medicine.

[0186] 6. The pharmacokinetic study of beagle dogs proves that the true solution of dextropropoxyphene of the present application is bioequivalent to the dextropropoxyphene suspension.

[0187] 7. The PMPA of mice of the true solution of dextropropoxyphene of the present application is 38.7%, while the PMPA of the control dextropropoxyphene suspension is 11.1%, which shows that the analgesic effect of the true solution of dextropropoxyphene of the present application is stronger than that of the suspension.

[0188] 8. The oral true solution of dextropropoxyphene of the present application belongs to the variety in the list of encouraging research and development of children's medicine issued by the National Health Commission and other three departments. Its outstanding features are small volume, accurate quantification, convenient use for children (2-14 years old), fast absorption, reliable drug efficacy, stable performance, suitable for industrialized production transformation, and excellent prospects for children's medicine. The double advantages of market intellectual property and price setting, the potential huge market space of clinical, and the social and economic benefits are obvious.

[0189] Example 8. The control study of antipyretic effect of the true solution of dextropropoxyphene of the present application and the suspension of ibuprofen in children aged 6 months to 6 years

[0190] Acute Upper Respiratory Infection (AURI) refers to the acute infection of the upper respiratory tract caused by various pathogens, commonly known as "cold", which is a common disease in children, mainly involving the nose, nasopharynx and pharynx, more than 90% of which is caused by viruses, and bacterial infection is often secondary to viral infection. Acute upper respiratory tract infection is the first common and frequently-occurring disease in children (6 months to 6 years old), and fever is one of the most common symptoms of acute upper respiratory tract infection in children. Ibuprofen is one of the commonly used antipyretics for children and is also recommended by WHO. Dextro-ibuprofen, as the pure spatial counterpart of ibuprofen, is a new antipyretic, which is recently used for the treatment of high fever in children. The dextro-ibuprofen oral true solution of the present application and the ibuprofen suspension were compared for the treatment of 6-month to 6-year-old children with high fever, and the antipyretic effects of the two drugs were observed, and the research results are reported as follows:

[0191] 1. Data and methods

[0192] 1.1 Case selection

[0193] From January to May 2021, 148 children with acute upper respiratory tract infection with fever were admitted to the emergency department of a hospital in Beijing, including 85 males and 63 females, aged 6 months to 6 years, with a disease course of 6-24 hours, and a body temperature of 38.5-39.0℃ in 49 cases, 39.1-40.0℃ in 53 cases, and >40.0℃ in 24 cases. Moreover, none of the children in the group had used any antipyretic drugs within 6 hours before admission.

[0194] 1.2 Grouping and administration method

[0195] 148 children with high fever aged 6 months to 6 years were randomly divided into two groups, 74 cases in each group. The observation group took dextro-ibuprofen true solution (prescription 8 in the embodiment 2) 7mg / kg, and the control group took ibuprofen suspension 10mg / kg. The dextro-ibuprofen true solution was dropped into the oral cavity, and the ibuprofen suspension was administered orally.

[0196] 1.3 Efficacy observation index and evaluation method

[0197] The body temperature before and 1h, 2h after administration was detected respectively, and the body temperature drop amplitude was calculated. The body temperature was detected by axillary temperature method, and the sterilized thermometer was placed in the axillary fossa. The reading was taken after 5 minutes of upper arm compression under the axillary fossa. The antipyretic effect was evaluated by comparing the body temperature drop amplitude at different times after administration, the number of cases (%) of each group with 1℃ body temperature drop, and the number of cases (%) with body temperature drop to 36.0-37.5℃

[0198] 1.4 Adverse reaction evaluation

[0199] The observation of children after administration was carried out to observe whether there were nausea, vomiting, diarrhea, gastrointestinal bleeding, etc.

[0200] 1.5 Statistical treatment

[0201] SPSS 16.0 statistical software was used. Measurement data was expressed as (T±s), two independent sample t test was used for comparison between groups, x 2 test was used for count data. P<0.05 was considered statistically significant.

[0202] 2 Results

[0203] 2.1 General data

[0204] There was no statistically significant difference in gender, age, body temperature, and disease duration between the two groups (P>0.05), and they were comparable, as shown in Table 11.

[0205] Table 11: Comparison of general data

[0206]

[0207] 2.2 Efficacy evaluation

[0208] The temperature drop amplitude in the dextrophenyl ibuprofen true solution group and the ibuprofen suspension group at 1h and 2h after medication was significantly different (P>0.05), as shown in Table 12.

[0209] Table 12: Temperature drop amplitude in the two groups at 1h and 2h after medication

[0210]

[0211] The number of cases of temperature drop in the two groups was compared. The number of cases of temperature drop 1℃ and temperature drop to 36.0℃-37.5℃ in the dextrophenyl ibuprofen true solution group and the ibuprofen suspension group was significantly different (P<0.05), as shown in Table 13.

[0212] Table 13: Comparison of temperature drop in the two groups after medication (cases, %)

[0213]

[0214] 2.3 Adverse reactions

[0215] The incidence of adverse reactions in the dextrophenyl ibuprofen true solution group and the ibuprofen suspension group was low. There was 1 case of hypothermia and 1 case of nausea and vomiting in the dextrophenyl ibuprofen group, 2 cases of rash, 2 cases of excessive sweating, and 2 cases of nausea and vomiting in the ibuprofen group. There were no adverse reactions such as granulocytopenia in both groups, and the mild adverse reactions that had occurred improved spontaneously after 8h. There was no statistically significant difference in the total incidence of adverse reactions between the two groups (x 2 =0.05, P>0.05).

[0216] 3 Conclusion

[0217] Ibuprofen has been used in clinic for more than 30 years as an anti-inflammatory and analgesic drug. It is considered as the most effective non-steroidal anti-inflammatory drug and is the only non-steroidal anti-inflammatory drug recommended by FDA for clinical use. Its antipyretic effect is stronger than that of acetaminophen and lasts longer. Oral administration is the most common, convenient and relatively safe administration method. Ibuprofen, as a cyclooxygenase inhibitor, exerts antipyretic effect by inhibiting the synthesis of prostaglandin in hypothalamus, stimulating vasopressin and melanocyte-stimulating hormone of posterior pituitary gland, increasing the heat-dissipating process, and lowering the control point of body temperature center, thereby achieving antipyretic effect. The antipyretic effect lasts for a long time and has low toxicity. Ibuprofen is a suspension composed of equal amounts of dextro-ibuprofen and levo-ibuprofen. Dextro-ibuprofen is a pure spatial enantiomer of ibuprofen and is the effective active ingredient of ibuprofen. Dextro-ibuprofen has the effect of inhibiting cyclooxygenase at an effective dose, while levo-ibuprofen does not have this effect. The metabolic characteristics of dextro-ibuprofen and levo-ibuprofen are also different. Levo-ibuprofen is related to the fatty acid metabolism pathway and is combined with endogenous fatty acids on triolein, while dextro-ibuprofen is not related to these special metabolic reactions. Therefore, dextro-ibuprofen is more completely cleared from the body than ibuprofen suspension and is less likely to accumulate and cause poisoning.

[0218] Studies have found that the bioavailability of dextro-ibuprofen is equivalent to 0.66 of that of ibuprofen suspension. After ibuprofen suspension enters the human body, 50% to 60% of levo-ibuprofen becomes dextro-ibuprofen through "metabolic inversion". Therefore, in order to achieve the same clinical efficacy of ibuprofen suspension at a safe therapeutic dose, the present application determines that dextro-ibuprofen true solution is orally administered at 7 mg / kg, and the control group is administered with ibuprofen suspension at 10 mg / kg.

[0219] The clinical evaluation results of the present application show that in children aged 6 months to 6 years, there is no statistically significant difference in antipyretic effect between oral administration of 7 mg / kg of dextro-ibuprofen suspension and oral administration of 10 mg / kg of ibuprofen suspension (P>0.05). However, it is found that the body temperature is recorded at 1 h and 2 h after oral administration, and the study results show that there is a statistically significant difference in the body temperature drop amplitude between the two groups at 1 h and 2 h after administration (P<0.05), which proves that the dextro-ibuprofen true solution of the present application at a dose of 7 mg / kg is smaller than the dose of 10 mg / kg of ibuprofen suspension in the control group, and not only has the characteristics of fast absorption and rapid cooling, but also has the clinical value characteristics of low toxicity and side effects.

[0220] Example 9. Stability test results of 2% dextro-ibuprofen true solution of the present application

[0221] The purpose of this example is to study the stability of 2% dextro-ibuprofen true solution prepared according to the formula of Example 1 under the conditions of the proposed market packaging, so as to provide necessary basis for formulating the shelf life.

[0222] Test Conditions

[0223] 1) Accelerated test: The proposed marketing package was placed at a temperature of 40°C and a relative humidity of 75% for 6 months.

[0224] 2) Long-term test: The proposed marketing package sample was placed in a dark environment for natural storage.

[0225] Investigation Indexes

[0226] The investigation indexes included appearance, pH value, content, related substances, and reconstitution test.

[0227] Sample Source and Batch Number

[0228] The 2% dexibuprofen true solution was continuously produced in three batches using prescription 8 and process, with batch numbers 230806-1, 230806-2, and 230806-3, respectively, and was self-made.

[0229] Test Results:

[0230] 1) Accelerated test results

[0231] The dexibuprofen true solution was placed in a 40°C oven, and samples were taken at the 1st, 2nd, 3rd, and 6th months for stability test and detection of each investigation index, with the results shown in Tables 14 and 15.

[0232] Table 14: Accelerated test results of 2% dexibuprofen true solution

[0233]

[0234]

[0235] Table 15: Accelerated test results of 2% dexibuprofen true solution

[0236]

[0237] The accelerated test results showed that the three batches of samples had no changes in appearance, pH value, main drug content, and related substance inspection after being placed at 40°C and RH 75% for 6 months, proving that the invented dexibuprofen true solution was stable in performance at a concentration of 20 mg / ml / branch under the condition of accelerated test for 6 months.

[0238] 2) Long-term stability test results

[0239] The three batches of granisetron hydrochloride nasal spray were placed in a room temperature environment, and samples were taken at the 3rd, 6th, 9th, 12th, 18th, 24th, and 36th months for stability test and detection of each investigation index, with the results shown in Tables 16 and 17, and the chromatogram shown in Figures 1 to 3 .

[0240] Table 16: Results of 2% dexibuprofen true solution at room temperature long-term sample retention experiment

[0241]

[0242] Table 17: Results of 2% dexibuprofen true solution at room temperature long-term sample retention experiment

[0243]

[0244]

[0245] Conclusion

[0246] The results of 2% dexibuprofen true solution 6-month accelerated test and 24-month long-term stability test show that the dexibuprofen true solution of the present application has good stability.

[0247] Example 10. Stability test of dexibuprofen true solution of the present application

[0248] The present inventors tested the stability of each concentration of buprofen true solution prepared in Example 1 using the same analysis method as Example 8, and the results showed that at concentrations of 5 mg / ml, 40 mg / ml, 100 mg / ml, 200 mg / ml, 300 mg / ml and 400 mg / ml, all had similar stability. At room temperature, all were colorless and clear solutions, and the results of 6-month accelerated test and 24-month long-term stability test showed that all had good stability.

[0249] The prescription of the present application is the best prescription determined on the basis of a large number of optimized prescriptions, and is reasonable in design and suitable for industrial production. The product quality is controllable and the performance is stable. The results of clinical trials of the examples prove that the absorption is rapid, the antipyretic effect is fast, the bioavailability is good, the dosing is accurate, the toxic and side effects are reduced, and the present application becomes the first true solution multi-dose package of 2% and 4% specifications in the buprofen series of children's preparations so far; in addition, it is the only true solution single-dose package of the smallest volume (1 ml / person) new dosage form.

Claims

1. A true solution of dexibuprofen comprising: 5-400 mg / ml, preferably about 20 to about 250 mg / ml, more preferably about 20 to about 100 mg / ml, even more preferably about 20 to about 50 mg / ml, even more preferably about 20 to about 40 mg / ml dexibuprofen, and a co-solvent; the weight ratio of the dexibuprofen to the co-solvent is 0.5:1 to 2.5:1, preferably 1:1 to 2:1; preferably about 1.5:1; preferably, the true solution of dexibuprofen is a dexibuprofen oral drop.

2. The true solution of dexibuprofen according to claim 1, wherein the co-solvent is selected from one or more of L-arginine, L-lysine and L-histidine.

3. The true solution of dexibuprofen according to claim 1 or 2, wherein the true solution of dexibuprofen further comprises 2% to 20% (v / v) of a taste-masking agent selected from at least one of glycerol, lactic acid and tartaric acid, preferably glycerol.

4. The true solution of dexibuprofen according to any one of claims 1 to 3, wherein the true solution of dexibuprofen further comprises 0.01 to 100 mg / ml of a flavoring agent; preferably, the flavoring agent is selected from sucrose, glucose syrup, fructose syrup, honey, stevioside, sodium chloride, potassium chloride, chloro sucrose, aspartame, sodium saccharin, cyclamate, acesulfame and advantame.

5. The true solution of dexibuprofen according to any one of claims 1 to 4, wherein the true solution of dexibuprofen further comprises 0.01 to 10 mg / ml, preferably 0.1 to 5 mg / ml of an odorant agent selected from menthol, borneol, camphor, apple essence, orange essence, strawberry essence, banana essence, dextrose and fructose.

6. The true solution of dexibuprofen according to any one of claims 1 to 4, wherein the true solution of dexibuprofen further comprises 0.1 to 10 mg / ml, preferably 0.2 to 1.0 mg / ml of a preservative agent selected from methyl paraben, ethyl paraben, propyl paraben, benzalkonium chloride, phenylethyl alcohol, benzoic acid, sodium benzoate, sorbic acid and potassium sorbate.

7. A 2% true solution of dexibuprofen comprising: about 20 mg / ml dexibuprofen; about 13.3 mg / ml L-arginine; about 20 ml glycerol; 40 to 80 mg / ml sucrose; and 0.2 to 1.0 mg / ml ethyl paraben.

8. A 4% true solution of dexibuprofen comprising: about 40 mg / ml dexibuprofen; about 26.6 mg / ml L-arginine; about 20 ml glycerol; 40 to 80 mg / ml sucrose; and 0.2 to 1.0 mg / ml ethyl paraben.

9. The dextrophenylalanine true solution of dextrophenylalanine according to claim 7 or 8, wherein the dextrophenylalanine true solution is divided in single use containers, preferably the volume of the dextrophenylalanine true solution is 0.5-1.5 ml, optionally the volume of the dextrophenylalanine true solution is 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml, 1.0 ml, 1.1 ml, 1.2 ml, 1.3 ml, 1.4 ml, 1.5 ml, or in a range between any two of the aforementioned.

10. The dextrophenylalanine true solution of dextrophenylalanine according to any one of claims 1-9, wherein the dextrophenylalanine true solution is dissolved in water.

11. Use of the dextrophenylalanine true solution of dextrophenylalanine according to any one of claims 1-10 for the manufacture of an antipyretic analgesic medicament; preferably the dextrophenylalanine true solution is for oral administration.

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