A pharmaceutical composition of ibuprofen injection and a preparation method thereof

Abstract

The application belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition of ibuprofen injection and a preparation method thereof. The pharmaceutical composition of ibuprofen injection comprises, in parts by weight, 5 parts of ibuprofen, 3-4 parts of aminotrizol, 5-6.5 parts of sodium chloride, 0.1-2 parts of sodium hydroxide, a pH regulator and water for injection. The pH of the pharmaceutical composition of ibuprofen injection is 7-8.5. The ibuprofen is added in a particle size state of D10 of 3-3.5 microns, D50 of 15-20 microns and D90 of 40-50 microns during the preparation of the pharmaceutical composition of ibuprofen injection. The injection pharmaceutical composition of the application can effectively promote the dissolution of ibuprofen and avoid the formation of insoluble substances or microparticles due to poor solubility of ibuprofen.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to an ibuprofen injection pharmaceutical composition and its preparation method. Background Technology

[0002] Patent ductus arteriosus (PDA) is a common circulatory complication in preterm infants. An unclosed ductus arteriosus can lead to serious consequences such as increased pulmonary blood flow, heart failure, and respiratory distress. Ibuprofen, as a cyclooxygenase (COX) inhibitor, can induce ductus arteriosus closure by inhibiting prostaglandin synthesis and promoting smooth muscle contraction. Ibuprofen is used to treat neonatal PDA, and intravenous administration of ibuprofen tromethorphan injection has become an important drug option for treating PDA in preterm infants, especially suitable for infants who are intolerant to or have contraindications to traditional therapies (such as indomethacin).

[0003] However, ibuprofen is a weakly acidic drug with extremely poor water solubility. But when treating patent ductus arteriosus in newborns, a higher concentration of ibuprofen is required, and high-concentration ibuprofen has even worse solubility during preparation. To address this, patent CN102892410 discloses that tromethamine helps increase the dissolution rate of ibuprofen in aqueous solvents.

[0004] However, patent CN105055389A points out that when the ibuprofen concentration is increased, if the tromethorphan concentration is not increased, the presence of excessive visible insoluble particles can easily occur, and crystals may even precipitate. To solve this problem, patent CN105055389A employs a cyclical process of multiple heating and cooling during solution preparation, utilizing temperature changes to promote ibuprofen dissolution. However, this repeated heating and cooling process is time-consuming, has low production efficiency, and is prone to drug oxidation or increased degradation risk, affecting the safety and stability of the formulation. Simultaneously, repeated temperature changes may lead to container material fatigue or impaired sealing, introducing other particles or impurities and compromising the sterility and safety of the formulation.

[0005] Therefore, there is a lack of efficient, stable, and industrially suitable technical solutions that can effectively address the formation of insoluble substances or insoluble particles due to poor solubility during the preparation of high-concentration ibuprofen injections, and further improvements are urgently needed. Summary of the Invention

[0006] To address the problems of existing ibuprofen injection solutions, this invention provides an ibuprofen injection pharmaceutical composition that effectively promotes ibuprofen dissolution and avoids the formation of insoluble matter or particles due to poor ibuprofen solubility.

[0007] This invention provides an ibuprofen injection pharmaceutical composition, which, by weight, comprises 5 parts ibuprofen, 3-4 parts tromethamine, 5-6.5 parts sodium chloride, 0.1-2 parts sodium hydroxide, a pH adjuster, and water for injection. The pH of the ibuprofen injection pharmaceutical composition is 7-8.5. The ibuprofen is added during the preparation of the ibuprofen injection pharmaceutical composition in a particle size distribution with a D10 of 3-3.5 μm, a D50 of 15-20 μm, and a D90 of 40-50 μm.

[0008] In some embodiments, the amount of tromethamine is 3.5 to 4 parts.

[0009] In some embodiments, the sodium chloride content is 5.5 to 6.5 parts.

[0010] In some embodiments, the sodium hydroxide is 0.5 to 1 part.

[0011] In some embodiments, the ibuprofen injection pharmaceutical composition comprises, by weight, 5 parts ibuprofen, 3.5-4 parts tromethorphan, 5.5-6.5 parts sodium chloride, 0.5-1 parts sodium hydroxide, a pH adjuster, and water for injection.

[0012] In some embodiments, the pH adjuster is hydrochloric acid.

[0013] In some embodiments, the pH of the ibuprofen injection pharmaceutical composition is 7 to 8.5.

[0014] In some embodiments, the pH of the ibuprofen injection pharmaceutical composition is 7.4 to 8.5.

[0015] In some embodiments, the pH of the ibuprofen injection pharmaceutical composition is 7.4 to 8.2.

[0016] In some embodiments, the pH of the ibuprofen injection pharmaceutical composition is 7.8 to 8.0.

[0017] In some embodiments, each ml of the ibuprofen injection pharmaceutical composition comprises 5 mg of ibuprofen, 3-4 mg of tromethorphan, 5-6.5 mg of sodium chloride, 0.1-2 mg of sodium hydroxide, a pH adjuster, and the remainder is water for injection.

[0018] In some embodiments, each ml of the ibuprofen injection pharmaceutical composition comprises 3.5 to 4 mg of tromethamine.

[0019] In some embodiments, each ml of the ibuprofen injection pharmaceutical composition comprises 5.5 to 6.5 mg of sodium chloride.

[0020] In some embodiments, each ml of the ibuprofen injection pharmaceutical composition includes 0.5 to 1 mg of sodium hydroxide.

[0021] In some embodiments, the ibuprofen has a D50 of 41-47 μm and a D90 of 16-19 μm.

[0022] In some embodiments, the ibuprofen D10 is 3~3.4 μm.

[0023] The present invention also provides a method for preparing the ibuprofen injection pharmaceutical composition described above, the preparation method comprising the following steps:

[0024] A. Add tromethorphan, sodium chloride, sodium hydroxide, and ibuprofen to water for injection at 40~80℃, stir to dissolve, and obtain solution I;

[0025] B. Add a pH adjuster to solution I to adjust the pH, thereby obtaining the ibuprofen injection drug composition.

[0026] In some implementations, step A includes:

[0027] A1. Add tromethorphan, sodium chloride, and sodium hydroxide to water for injection at 40~80℃, stir to dissolve, and obtain solution II;

[0028] A2. Add ibuprofen to solution II, stir to dissolve, and obtain solution I.

[0029] In some embodiments, the water for injection in step A is at a temperature of 50-80°C.

[0030] In some embodiments, the water for injection in step A is at a temperature of 50-60°C.

[0031] In some embodiments, the pH adjuster is hydrochloric acid, and step B includes:

[0032] Hydrochloric acid solution was added to solution I to adjust the pH, thus obtaining the ibuprofen injection drug composition.

[0033] In some embodiments, the hydrochloric acid solution is prepared by mixing hydrochloric acid and water for injection, and the concentration of the hydrochloric acid solution is 1~3 mol / L.

[0034] In some embodiments, the pH adjuster is hydrochloric acid, and step B includes:

[0035] B1. Add hydrochloric acid solution to solution I to adjust the pH;

[0036] B2. Filling and sealing, sterilizing at 110~130℃ for 15min~30min to obtain the ibuprofen injection drug composition.

[0037] In some embodiments, the ibuprofen injection drug composition is sterilized by autoclaving.

[0038] In some embodiments, the high-pressure sterilization conditions are sterilization at 110~130℃ for 15min~30min.

[0039] In some embodiments, the sterilization conditions are 121°C for 15 minutes.

[0040] In some embodiments, the ibuprofen added in step A has a D50 of 15-20 μm and a D90 of 40-50 μm.

[0041] In some embodiments, the ibuprofen added in step A has a D50 of 41-47 μm and a D90 of 16-19 μm.

[0042] In some embodiments, the ibuprofen D10 added in step A is 3~3.5 μm.

[0043] In some embodiments, the ibuprofen D10 added in step A is 3~3.4 μm.

[0044] This invention overcomes the limitations of existing technologies that use tromethamine to improve ibuprofen solubility. Instead, it proposes optimizing the sodium chloride content in the injection solution and controlling the particle size of the ibuprofen raw material added during the preparation of the ibuprofen injection solution to promote ibuprofen dissolution. This significantly improves the solubility of high-concentration ibuprofen in the injection solution, avoids the formation of insoluble particles, and also avoids the cumbersome steps of multiple heating and cooling during solution preparation. This improves the efficiency of the preparation process and ensures the stability and safety of the drug. Detailed Implementation

[0045] The present invention will be further described in detail below with reference to the embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in the art based on the disclosure of the present invention shall fall within the protection scope of the present invention.

[0046] In this application, the terms “comprising,” “including,” and “containing,” and their equivalents, shall be understood in an open, non-exclusive sense, meaning “including but not limited to,” implying that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be covered. In this document, unless the context clearly specifies otherwise, singular terms shall cover plural references, and vice versa.

[0047] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with the other components constituting a drug dosage form and physiologically compatible with the receptor, without excessive toxicity, irritation, allergic reactions or other problems or complications, and is commensurate with a reasonable benefit / risk ratio.

[0048] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms associated with the disease, including inhibiting the progression of the disease or condition and alleviating the disease or condition.

[0049] In this application, unless otherwise specified, ibuprofen in the pharmaceutical composition refers to the ibuprofen compound.

[0050] In this application, portions may be expressed in milligrams.

[0051] In this application, the pharmaceutical excipients or reagents involved may be derived from commercial sources.

[0052] In this application, unless otherwise specified, "%" in the embodiments of this application refers to the mass percentage.

[0053] In this application, the original drug listed in the National Medical Products Administration's generic drug reference preparation catalog (serial number 23-101) is used as the reference preparation (specification 10mg / 2ml), and its trade name is Pedea.

[0054] In this application, the method for detecting insoluble particulate matter is the first method (photoresistance method) in the 2020 edition of the Pharmacopoeia of the People's Republic of China, Part III, 0903.

[0055] Examples 1-3

[0056] The amounts of each raw material used in Examples 1-3 are shown in Table 1, and the preparation methods are as follows:

[0057] (1) Add tromethamine, sodium chloride and sodium hydroxide to water for injection at 60°C in one go, stir to dissolve, and obtain solution II;

[0058] (2) Add ibuprofen to solution II, stir to dissolve, and obtain solution I;

[0059] (3) Add 1 mol / L hydrochloric acid solution to solution I to adjust the pH, fill and seal, sterilize at 121℃ for 15 min to obtain ibuprofen injection drug composition. The hydrochloric acid solution is prepared by hydrochloric acid and water for injection.

[0060] Table 1. Prescription dosages for Examples 1-3

[0061]

[0062] Table 2 Comparison of visible foreign matter and insoluble particles (day 0)

[0063]

[0064] The sample specifications for Examples 1-3 were 10 mg / 2 ml; the particle sizes of the ibuprofen added in Examples 1-3 were D10 3.10 μm, D50 16.37 μm, and D90 41.58 μm. Table 2 shows that at day 0, the detection indicators for visible foreign matter and insoluble microparticles in the samples of Examples 1-3 were comparable to, or even superior to, the reference formulation. Furthermore, the osmolality of the samples in Examples 1-3 was all within the range of 0.285–0.310 mOsmol / kg, comparable to the reference formulation.

[0065] Table 3. Accelerated Test Stability Comparison (40℃±2℃, RH 75%±5%, June)

[0066]

[0067] “ / ” indicates that it was not detected.

[0068] Table 4. Stability Comparison in Long-Term Tests (30℃±2℃, RH 65%±5%, 18 Months)

[0069]

[0070] “ / ” indicates that it was not detected.

[0071] As can be seen from Tables 3 and 4, the samples of Examples 1 to 3 showed no significant changes in any of the detection indicators after being placed under accelerated conditions for 6 months and under long-term conditions for 18 months, indicating comparable stability.

[0072] Example 4, Comparative Examples 1-2: Screening of Sodium Chloride Dosage

[0073] Table 5 Screening of Sodium Chloride Dosage

[0074]

[0075] Example 4 and Comparative Examples 1 and 2 were prepared using the same method as in Example 1, with a specification of 10 mg / 2 ml. In Example 4 and Comparative Examples 1 and 2, the ibuprofen particles added had a particle size D10 of 3.10 μm, a D50 of 16.37 μm, and a D90 of 41.58 μm.

[0076] Table 6 Comparison of Osmotic Molar Concentration

[0077]

[0078] As can be seen from Table 6, the osmotic molar concentration of the sample in Example 4 is comparable to that of the reference preparation.

[0079] Table 7 Comparison of visible foreign matter and insoluble particles in the accelerated high-temperature (60℃) test.

[0080]

[0081] Table 8 Comparison of visible foreign matter and insoluble particles in the accelerated test under 4500 lx illumination.

[0082]

[0083] As shown in Tables 7 and 8, in the high-temperature and light-accelerated tests, the sample of Example 4 showed no significant changes in visible foreign matter and insoluble particles at days 0, 10, and 30, and the ibuprofen content remained essentially unchanged. Furthermore, the number of insoluble particles was significantly less than in the samples of Comparative Example 1 and Comparative Example 2. This indicates that the sodium chloride content has a significant impact on the solubility and stability of ibuprofen when preparing high-concentration ibuprofen injection, and excessively low sodium chloride content leads to lower osmotic pressure.

[0084] Meanwhile, in the preparation of high-concentration ibuprofen injection solution (such as comparative examples 2-4 of that patent), the sodium chloride content used is 7.7 mg / ml, which is higher than the sodium chloride content used in this invention. The resulting ibuprofen injection solution exhibits significant precipitation; in the influencing factor test, white precipitates appear after 5 days at 40℃ and 60℃. However, in the preparation of high-concentration ibuprofen injection solution, this invention, by controlling the sodium chloride content within the range of 5-6.5 mg / ml, effectively promotes ibuprofen dissolution, avoiding the formation of insoluble matter or particles due to poor ibuprofen solubility. Simultaneously, the ibuprofen exhibits high stability, with no precipitation and a essentially unchanged content.

[0085] Examples 5-8. pH Screening

[0086] Table 9. Stability Comparison in Accelerated High-Temperature Tests (60℃)

[0087]

[0088] The difference between Examples 5-8 and Example 4 is the pH value; the preparation method is the same as that in Example 1. " / " indicates not detected. The ibuprofen added in Examples 5-8 has a particle size of D10 of 3.10 μm, D50 of 16.37 μm, and D90 of 41.58 μm.

[0089] Table 10. Stability Comparison in Accelerated Testing under 4500 lx Illumination

[0090]

[0091] “ / ” indicates that it was not detected.

[0092] As shown in Tables 9 and 10: For the samples with pH values ​​of 6.6–8.2, there were no significant differences in other test indicators except for pH value. After being placed under high temperature conditions for 30 days, there were no significant differences in any test indicators for all samples. After being exposed to light for 30 days, the samples with pH values ​​of 6.6 and 7.0 showed a significant increase in the content of impurity I, impurity IV, and total unknown impurities. The samples with pH values ​​of 7.4–8.2 showed a slight increase in the content of impurity I and impurity IV, but this increase was not significant. The impurity content of the samples with pH values ​​of 7.4–8.2 was within the acceptable range, and there were no significant changes in other test indicators for all samples. In addition, the test indicators for visible foreign matter and insoluble particles in the samples of Examples 5–8 all met the requirements.

[0093] Examples 9-10 and Comparative Examples 3-4: Ibuprofen Particle Size Screening

[0094] Table 11 Ibuprofen Particle Size Screening

[0095]

[0096] The difference between Examples 9-10, Comparative Examples 3-4 and Example 4 lies in the different particle sizes of the ibuprofen raw materials (as shown in Table 11). The preparation method is the same as that of Example 1.

[0097] Table 12 Dissolution time and composition stability of ibuprofen raw materials with different particle sizes

[0098]

[0099] As shown in Table 12, when preparing high-concentration ibuprofen injection, controlling the particle size of the ibuprofen raw material to be 3-3.5 μm for D10, 15-20 μm for D50, and 40-50 μm for D90 results in faster ibuprofen dissolution and better stability. When the particle size of the ibuprofen raw material is larger, the dissolution rate slows down; when the particle size is smaller, the dissolution rate is faster, but the stability deteriorates. Furthermore, the visible foreign matter and insoluble particulate matter indicators of the samples in Examples 9-10 all met the requirements.

Claims

1. A pharmaceutical composition for ibuprofen injection, characterized in that, The ibuprofen injection drug composition comprises, by weight, 5 parts ibuprofen, 3-4 parts tromethamine, 5-6.5 parts sodium chloride, 0.1-2 parts sodium hydroxide, a pH adjuster, and water for injection. The pH of the ibuprofen injection drug composition is 7-8.

5. The ibuprofen is added during the preparation of the ibuprofen injection drug composition with a particle size of D10 of 3-3.5 μm, D50 of 15-20 μm, and D90 of 40-50 μm. Each ml of the ibuprofen injection drug composition comprises 5 mg ibuprofen, 3-4 mg tromethamine, 5-6.5 mg sodium chloride, 0.1-2 mg sodium hydroxide, a pH adjuster, and the remainder is water for injection.

2. The ibuprofen injection pharmaceutical composition according to claim 1, characterized in that, The ibuprofen injection pharmaceutical composition comprises, by weight, 5 parts ibuprofen, 3.5-4 parts tromethorphan, 5.5-6.5 parts sodium chloride, 0.5-1 parts sodium hydroxide, a pH adjuster, and water for injection.

3. The ibuprofen injection pharmaceutical composition according to claim 1, characterized in that, The pH of the ibuprofen injection drug composition is 7.4~8.

2.

4. A method for preparing an ibuprofen injection pharmaceutical composition as described in any one of claims 1 to 3, characterized in that, The preparation method includes the following steps: A. Add tromethorphan, sodium chloride, sodium hydroxide, and ibuprofen to water for injection at 40~80℃, stir to dissolve, and obtain solution I; B. Add a pH adjuster to solution I to adjust the pH, thereby obtaining the ibuprofen injection drug composition.

5. The preparation method according to claim 4, characterized in that, Step A includes: A1. Add tromethorphan, sodium chloride, and sodium hydroxide to water for injection at 40~80℃, stir to dissolve, and obtain solution II; A2. Add ibuprofen to solution II, stir to dissolve, and obtain solution I.

6. The preparation method according to claim 4, characterized in that, The pH adjuster is hydrochloric acid, and step B includes: Hydrochloric acid solution was added to solution I to adjust the pH, thereby obtaining the ibuprofen injection drug composition. The hydrochloric acid solution was prepared by mixing hydrochloric acid and water for injection, and the concentration of the hydrochloric acid solution was 1~3 mol / L.

7. The preparation method according to claim 4, characterized in that, The ibuprofen added in step A has a D10 of 3~3.5μm, a D50 of 15~20μm, and a D90 of 40~50μm.

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