A cloxacillin sodium composition and preparation method thereof

Abstract

Cloxacillin Sodium is an organic compound with the molecular formula C 19 H 18 Cl2N3NaO6S. It is a white powder or crystalline powder; slightly smelly and bitter; hygroscopic. Cloxacillin sodium is prepared into an injection for administration, which is mainly used to treat penicillinase-producing Staphylococcus aureus infections, including sepsis, endocarditis, pneumonia, and skin and soft tissue infections. Because it has multiple easily hydrolyzed groups, such as β-lactam rings and amide bonds, it has poor stability and is easily hydrolyzed. In order to improve the stability of cloxacillin sodium, the present invention uses Bicine (N,N-bis(hydroxyethyl)glycine) as a buffer salt and CMC / AA / AM as a hygroscopic agent (carboxymethyl cellulose (CMC) connected to acrylic acid (AA) connected to acrylamide (AM)), and adopts a sterile packaging process to obtain a highly stable cloxacillin sodium preparation.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a cloxacillin sodium composition and a preparation method thereof, and in particular relates to a cloxacillin sodium powder injection and a preparation method thereof. Background Art

[0002] Cloxacillin Sodium is an organic compound with the molecular formula C 19 H 18 Cl2N3NaO6S. This product is a white or crystalline powder with a slight odor and bitter taste. It is hygroscopic. It is readily soluble in water, soluble in ethanol, and almost insoluble in ethyl acetate. Cloxacillin sodium is formulated for administration as an injection and is primarily used to treat penicillinase-producing Staphylococcus aureus infections, including sepsis, endocarditis, pneumonia, and skin and soft tissue infections. It can also be used for mixed infections caused by Streptococcus pyogenes or Streptococcus pneumoniae and penicillin-resistant Staphylococci.

[0003] Cloxacillin sodium is a semi-synthetic penicillin that is acid-resistant and penicillinase-resistant. It has antibacterial activity against Gram-positive cocci and Neisseria. Its antibacterial activity against enzyme-producing strains of Staphylococcus (including Staphylococcus aureus and coagulase-negative Staphylococci) is stronger than that of oxacillin. However, its antibacterial effect against penicillin-sensitive Staphylococci and various streptococci is weaker than that of penicillin, and it is ineffective against methicillin-resistant Staphylococci.

[0004] The structure of cloxacillin sodium, shown in Formula A, contains multiple readily hydrolyzable groups, such as a β-lactam ring and an amide bond. This results in poor stability and easy hydrolysis. References to relevant literature indicate that the major impurities in cloxacillin sodium for injection are the following structures (A) to (F), as shown in Table 1.

[0005]

[0006] Table 1 Main impurities of cloxacillin sodium for injection

[0007]

[0008] Currently, most cloxacillin sodium for injection available on the market are single-powder preparations prepared using aseptic packaging. This preparation method places high demands on the API, requiring strict control of its sterility and ensuring that the pH after dissolution with physiological saline is within the specified range. Because the cloxacillin sodium API is hygroscopic, the preparation process must control the risk of moisture absorption caused by moisture in the vial. Furthermore, the safety, effectiveness, and quality control of cloxacillin sodium powder injection are closely related to the cleanliness of the operating environment, the sterilization and drying process, the removal of carbon dioxide gas during the filling process, the amount of pH adjuster, and the amount of excipients added. Therefore, it is necessary to optimize the existing formulation and process to improve product stability.

[0009] The following are the specific names of the various codes involved in the full text:

[0010] Table 2 Names or structural formulas corresponding to the abbreviations mentioned in the text

[0011] Summary of the Invention

[0012] In order to solve the stability problem of cloxacillin sodium medicament, the present invention optimizes the cloxacillin sodium prescription.

[0013] The invention provides a cloxacillin sodium composition, comprising the following components in a mass ratio: 40-60 parts of a cloxacillin sodium raw material, 1.0-2.5 parts of a buffer salt, and 10.0-20.0 parts of a moisture absorbent.

[0014] Furthermore, the mass ratio of cloxacillin sodium raw material: buffer salt: desiccant is 50:1.5-2.0:13.0-15.0.

[0015] Furthermore, the mass ratio of cloxacillin sodium raw material: buffer salt: desiccant is 50:2.0:13.0.

[0016] In the technical solution of the present invention, the buffer salt is one or more of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), N,N-bis(hydroxyethyl)glycine (Bicine), (2-aminoethyl)trimethylammonium chloride (cholaminechloride), and N-acetylglycine (Acetamido-glycine);

[0017] Furthermore, in a specific technical solution of the present invention, the buffer salt is N,N-bicine (Bicine).

[0018] The ChP2020 version stipulates that the pH value of the raw material drug cloxacillin sodium is 5-7. The aqueous solution of cloxacillin sodium is unstable under strong acidic conditions and is prone to hydrolysis. The impurities of penicillic acid and penicillaldehyde produced by hydrolysis will cause the pH to further decrease and the hydrolysis rate to accelerate. The buffer salt Bicine has a certain pH stabilizing effect, preventing the pH from deviating from the normal range. As a buffer, it can slow down the pH fluctuation of the aqueous solution of cloxacillin sodium and reduce the degradation of the drug solution after clinical reconstitution. This reduces the risk of rapid hydrolysis and ineffectiveness of the aqueous solution of penicillin sodium at room temperature and a sharp increase in allergic impurities, ensuring the safety and effectiveness of clinical medication.

[0019] In the technical solution of the present invention, the desiccant is one or more of CMC-g-AA, CMC-g-AM, CMC / AA / AM, and CMC / AA / AMPS.

[0020] Furthermore, the present invention uses CMC / AA / AM as a moisture absorbent.

[0021] Furthermore, the mass ratio of carboxymethyl cellulose, acrylic acid and acrylamide in the desiccant CMC / AA / AM is 1:3:3.

[0022] In the technical solution of the present invention, CMC / AA / AM is an organic polymer desiccant with good hygroscopicity, which can absorb water competitively with cloxacillin sodium, thereby preventing the hydrolysis of cloxacillin sodium.

[0023] The above-mentioned cloxacillin sodium composition may further be added with a pharmaceutically acceptable carrier or excipient. Preferably, the composition is in the form of granules, capsules, tablets, dispersible tablets, or powder injections.

[0024] Furthermore, the dosage form of the cloxacillin sodium composition of the present invention is powder injection.

[0025] The present invention also provides a method for preparing the above-mentioned cloxacillin sodium composition powder injection, comprising the following steps: uniformly mixing a cloxacillin sodium raw material, a buffer salt, and a hygroscopic agent, and filling with sterile nitrogen before and after powder filling, wherein the nitrogen pressure before powder filling is 0.05 to 0.2 MPa and the time is 0.05 to 2 seconds; and the nitrogen pressure after powder filling is 0.05 to 0.2 MPa and the time is 0.05 to 1 second.

[0026] Furthermore, the nitrogen pressure before powder filling is 0.1 MPa and the time is 1 s; the nitrogen pressure after powder filling is 0.1 MPa and the time is 0.05 s.

[0027] As a further improvement of cloxacillin sodium for injection, this powder injection is directly packaged with sterile powder, and sterile nitrogen is injected before and after the powder is filled, thereby avoiding direct contact between cloxacillin sodium and water.

[0028] The beneficial effects of the present invention are as follows: a cloxacillin sodium powder injection formulation prepared using the formulation and process of the present invention and supplemented with the buffer salt Bicine and the hygroscopic agent CMC / AA / AM exhibits significantly better stability during storage than a product obtained by directly packaging cloxacillin sodium powder alone. This excellent stability prevents the increased risk of allergies caused by the accumulation of impurities following hydrolysis of cloxacillin sodium, thereby ensuring clinical drug safety. Furthermore, the addition of nitrogen effectively prevents oxidation and hydrolysis of cloxacillin sodium, ensuring both clinical safety and efficacy. DETAILED DESCRIPTION

[0029] The present invention is further explained below with reference to specific examples, but the examples do not limit the present invention in any form.

[0030] Example 1 Effect of different buffer salts on product quality

[0031] Cloxacillin sodium powder injection is clinically administered by intramuscular injection after dissolving in water for injection. For intravenous infusion, it should be diluted with 5% glucose injection or sodium chloride injection. Therefore, maintaining a constant hydrogen ion concentration in the cloxacillin sodium powder injection system is crucial.

[0032] An ideal buffer should have the following characteristics: high solubility in water; a dissociation constant that is minimally affected by temperature and the composition of the ionic medium; stability, resistance to enzymatic degradation; poor permeability through biological membranes; minimal salt effect, and minimal influence of concentration, temperature, and ions in the medium on the dissociation constant. Currently, some common buffers lack significant advantages. Therefore, the present invention considers the use of novel buffers that are zwitterions.

[0033] The present invention selects the following four solid novel buffers Bicine, HEPES, cholamine chloride, and Acetamido-glycine for investigation, investigates their effects on product quality through specific experiments, and screens out the best buffer.

[0034] Experiment 1

[0035] Prescription composition:

[0036]

[0037] The specific steps are:

[0038] (A) Accurately weigh 50.00g of cloxacillin sodium;

[0039] (B) Fill the vial with sterile nitrogen (pressure: 0.1 MPa, time: 1 s), aseptically dispense the powder into dry vials at a rate of 0.5 g / vial, and then fill with sterile nitrogen (pressure: 0.01 MPa, time: 0.05 s). Immediately add the stopper and cap to obtain 100 vials of the finished product, cloxacillin sodium for injection.

[0040] Experiment 2

[0041] Prescription composition:

[0042]

[0043] The specific steps are:

[0044] (A) Accurately weigh 50.00g of cloxacillin sodium and 2.00g of HEPES, add equal amounts incrementally and mix thoroughly;

[0045] (B) Fill the vial with sterile nitrogen (pressure: 0.1 MPa, time: 1 s), aseptically dispense the powder into dry vials at a rate of 0.5 g / vial, and then fill with sterile nitrogen (pressure: 0.01 MPa, time: 0.05 s). Immediately add the stopper and cap to obtain 100 vials of the finished product, cloxacillin sodium for injection.

[0046] Experiment 3

[0047] Prescription composition:

[0048]

[0049] The specific steps are:

[0050] (A) Accurately weigh 50.00g of cloxacillin sodium and 2.00g of bicine, add equal amounts and mix thoroughly;

[0051] (B) Fill the vial with sterile nitrogen (pressure: 0.1 MPa, time: 1 s), aseptically dispense the powder into dry vials at a rate of 0.5 g / vial, and then fill with sterile nitrogen (pressure: 0.01 MPa, time: 0.05 s). Immediately add the stopper and cap to obtain 100 vials of the finished product, cloxacillin sodium for injection.

[0052] Experiment 4

[0053] Prescription composition:

[0054]

[0055] The specific steps are:

[0056] (A) Accurately weigh 50.00g of cloxacillin sodium and 2.00g of cholamine chloride, add equal amounts and mix thoroughly;

[0057] (B) Fill the vial with sterile nitrogen (pressure: 0.1 MPa, time: 1 s), aseptically dispense the powder into dry vials at a rate of 0.5 g / vial, and then fill with sterile nitrogen (pressure: 0.01 MPa, time: 0.05 s). Immediately add the stopper and cap to obtain 100 vials of the finished product, cloxacillin sodium for injection.

[0058] Experiment 5

[0059] Prescription composition:

[0060]

[0061] The specific steps are:

[0062] (A) Accurately weigh 50.00 g of cloxacillin sodium and 2.00 g of acetamido-glycine, and dilute and mix in equal amounts.

[0063] (B) Sterile nitrogen gas was introduced into the vial (pressure: 0.1 MPa, time: 1 s), and the powder was aseptically dispensed into the dry vial at a rate of 0.5 g / vial. The vial was then filled with sterile nitrogen gas (pressure: 0.01 MPa, time: 0.05 s), and the vial was immediately stoppered and capped to obtain 100 vials of the finished product, cloxacillin sodium for injection.

[0064] According to the guidelines for drug stability testing, the samples in experiments 1 to 5 were accelerated at 60°C and 75% RH for 10 days and 30 days. The test results are shown in Table 3:

[0065] Table 3 Effects of different buffer salts on product quality

[0066]

[0067]

[0068] Note: Y1~Y4 represent yellow standard colorimetric solutions No. 1~4

[0069] The above data show that in Experiment 1, when no buffer salt was added, the pH value changed significantly, with some increase in related substances. By day 30, the solution color approached Y2, and the content decreased to 81.5%. In Experiment 2, after adding HEPES, impurities increased somewhat, with impurity A increasing significantly, while its content decreased. In Experiment 4, after adding cholamine chloride, the solution color approached Y3 by day 30, and the impurities increased significantly, while the content decreased to 86.6%. In Experiment 5, after adding acetamido-glycine, the content decreased to 88.2% by day 30, showing a significant increase in impurities. At the accelerated test temperature (60°C), the decomposition of cloxacillin sodium is affected by pH. Therefore, the addition of a buffer improves the stability of cloxacillin sodium injection by raising and stabilizing its pH during storage.

[0070] The pH value in Experiment 3 was stable and unchanged; there was no significant increase in related substances A, B, or E. The API content was higher than in the groups containing other buffer salts, and all quality indicators were significantly superior to those in Experiments 1, 2, 4, and 5. Bicine, as a buffer, offers advantages, effectively maintaining a constant solution pH. Its basic chemical properties are stable, it is readily soluble in water, and its storage conditions are consistent with those of cloxacillin sodium. This suggests that bicine is a more suitable buffer for cloxacillin sodium injection.

[0071] Example 2 Effect of different hygroscopic agents on product quality

[0072] We selected four organic polymer materials as hygroscopic agents for cloxacillin sodium compositions, namely: CMC-g-AA, CMC-g-AM, CMC / AA / AM, and CMC / AA / AMPS.

[0073] Experiment 6

[0074] The following are the preparation methods of CMC-g-AA, CMC-g-AM, CMC / AA / AM, and CMC / AA / AMPS:

[0075] Conditions for the preparation of organic polymer desiccant:

[0076]

[0077] Preparation process:

[0078] Preparation of CMC-g-AA:

[0079] In a nitrogen atmosphere, 1g of CMC was dissolved in water in a three-necked flask. The mixture was stirred at 50°C for 30 minutes to gelatinize and then cooled to room temperature. 50ml of 0.05g / ml NaOH solution was added, followed by 0.08g of initiator APS, 0.006g of crosslinker NMBA, and 6g of AA. The temperature was immediately raised to 60°C for reaction. The reaction was continued for 3 hours before completion and cooling to room temperature. The mixture was precipitated with ethanol, washed, and vacuum-dried to obtain a CMC-g-AA solid powder desiccant.

[0080] Preparation of CMC-g-AM:

[0081] In a nitrogen atmosphere, 1g of CMC and 0.02g of the initiator APS-NaHSO3 (n(NaHSO3):n(APS)=1:1) were added to a three-necked flask. The mixture was then stirred with 50mL of distilled water until dissolved. 4g of AM was added and the temperature was raised to 40°C. Stirring was continued, and 0.004g of the crosslinker NMBA was added. The reaction was allowed to proceed for 20 minutes. Finally, 50ml of a 0.02g / ml NaOH solution was added and the reaction was continued for 3 hours before the reaction was terminated. The CMC-g-AM solid powder desiccant was obtained by ethanol precipitation, washing, and vacuum drying.

[0082] CMC / AA / AM preparation:

[0083] Under a nitrogen atmosphere, 1g of CMC and 0.02g of the initiator APS-NaHSO₃ (n(NaHSO₃):n(APS)=1:1) were added to a three-necked flask. The mixture was dissolved in 150ml of purified water and heated to 40°C, stirring continuously until completely dissolved. After adding 50ml of a 0.07g / ml NaOH solution, 3g of AA and 3g of AM were added, along with 0.04g of the crosslinker NMBA. The mixture was allowed to react at 40°C for 2h before completion. The CMC / AA / AM solid powder desiccant was obtained by precipitating with ethanol, washing, and vacuum drying.

[0084] Preparation of CMC / AA / AMPS:

[0085] In a nitrogen atmosphere, 1g of CMC and 0.15g of initiator APS were added to a three-necked flask and dissolved in 150ml of purified water. Once the CMC was completely dissolved, 50ml of 0.08g / ml NaOH solution was added, followed immediately by 6g of AA and 3.5g of AMPS. Then, 0.02g of the crosslinker NMBA was added simultaneously. The reaction was allowed to proceed at 50°C for 2h before completion. The CMC / AA / AMPS solid powder desiccant was precipitated, washed with ethanol, and then vacuum-dried.

[0086] Formula composition Under the selected buffer conditions, the effect of adding hygroscopic agent on product quality was investigated:

[0087] Experiment 7

[0088] Prescription composition:

[0089]

[0090] The specific steps are:

[0091] (A) Accurately weigh 50.00g of cloxacillin sodium and 2.00g of bicine, add equal amounts and mix thoroughly;

[0092] (B) Accurately weigh 50.00g of cloxacillin sodium and 15.00g of CMC-g-AA, and add equal amounts gradually and mix thoroughly;

[0093] (C) Fill the vial with sterile nitrogen (pressure: 0.1 MPa, time: 1 s), aseptically dispense the powder into dry vials at a rate of 0.5 g / vial, and then fill with sterile nitrogen (pressure: 0.01 MPa, time: 0.05 s). Immediately add the stopper and cap to obtain 100 vials of the finished product, cloxacillin sodium for injection.

[0094] Experiment 8

[0095] Prescription composition:

[0096]

[0097] The specific steps are:

[0098] (A) Accurately weigh 50.00g of cloxacillin sodium and 2.00g of bicine, add equal amounts and mix thoroughly;

[0099] (B) Accurately weigh 50.00g of cloxacillin sodium and 15.00g of CMC-g-AM, and add equal amounts gradually and mix thoroughly;

[0100] (C) Fill the vial with sterile nitrogen (pressure: 0.1 MPa, time: 1 s), aseptically dispense the powder into dry vials at a rate of 0.5 g / vial, and then fill with sterile nitrogen (pressure: 0.01 MPa, time: 0.05 s). Immediately add the stopper and cap to obtain 100 vials of the finished product, cloxacillin sodium for injection.

[0101] Experiment 9

[0102] Prescription composition:

[0103]

[0104] The specific steps are:

[0105] (A) Accurately weigh 50.00g of cloxacillin sodium and 2.00g of bicine, add equal amounts and mix thoroughly;

[0106] (B) Accurately weigh 50.00g of cloxacillin sodium and 15.00g of CMC / AA / AM, and add equal amounts gradually and mix thoroughly;

[0107] (C) Fill the vial with sterile nitrogen (pressure: 0.1 MPa, time: 1 s), aseptically dispense the powder into dry vials at a rate of 0.5 g / vial, and then fill with sterile nitrogen (pressure: 0.01 MPa, time: 0.05 s). Immediately add the stopper and cap to obtain 100 vials of the finished product, cloxacillin sodium for injection.

[0108] Experiment 10

[0109] Prescription composition:

[0110]

[0111] The specific steps are:

[0112] (A) Accurately weigh 50.00g of cloxacillin sodium and 2.00g of bicine, add equal amounts and mix thoroughly;

[0113] (B) Accurately weigh 50.00g of cloxacillin sodium and 15.00g of CMC / AA / AMPS, and add equal amounts gradually and mix thoroughly;

[0114] (C) Fill the vial with sterile nitrogen (pressure: 0.1 MPa, time: 1 s), aseptically dispense the powder into dry vials at a rate of 0.5 g / vial, and then fill with sterile nitrogen (pressure: 0.01 MPa, time: 0.05 s). Immediately add the stopper and cap to obtain 100 vials of the finished product, cloxacillin sodium for injection.

[0115] According to the guidelines for drug stability testing, the samples in experiments 3, 7 to 10 were accelerated at 40 ± 2°C and 75 ± 5% RH for 30 days. The test results are shown in Table 4:

[0116] Table 4 Effect of different desiccant on product quality

[0117]

[0118]

[0119] Note: Y1~Y4 represent yellow standard colorimetric solutions No. 1~4

[0120] A comparative study was conducted in Experimental Groups 7, 8, 9, and 10, each containing different hygroscopic agents, in addition to the selected buffering agent Bicine. The results showed that Experiment 9 (with CMC / AA / AM added to the formulation) showed a smaller increase in impurities A, B, E, and total impurities, as well as higher API content, compared to Experiment 3 (with only Bicine added). Furthermore, Experimental Group 9 (with CMC / AA / AM added to the formulation) exhibited superior performance in various indicators, including content, impurities, and pH stability, compared to the hygroscopic agents CMC-g-AA, CMC-g-AM, and CMC / AA / AMPS. This demonstrates that using CMC / AA / AM as a hygroscopic agent can effectively reduce the hydrolysis of cloxacillin sodium during shelf storage.

[0121] Example 3 Orthogonal Design Method for Prescription Selection (Determining the Dosage of Bicine, CMC / AA / AM)

[0122] After multiple experiments, we determined that bicine was the buffer salt and CMC / AA / AM was the hygroscopic agent. Based on their conventional dosage range, a two-factor, four-level orthogonal experiment was established using cloxacillin sodium content, total impurity content, and pH after 10 days as indicators. The factor levels are shown in Table 5, and the orthogonal experiment results are shown in Table 6.

[0123] Prescription composition:

[0124]

[0125] Table 5 Factor levels

[0126]

[0127] Table 6 Prescription orthogonal test results (n=3)

[0128]

[0129]

[0130] Experimental results show that when the dosage of 50g of cloxacillin sodium (the API dosage is fixed at 50g), 2.0g of bicine, and 13g of CMC / AA / AM is used, the total impurity content is lowest, the pH value is most stable, and the cloxacillin sodium content meets the requirements. The results also indicate that when the dosage of bicine is between 1.5g and 2.0g, and the dosage of CMC / AA / AM is between 13.0g and 15.0g, the impurity content is low and the pH value is stable. The addition of the buffer salt bicine and the desiccant CMC / AA / AM within this dosage range exhibits a synergistic effect, improving the stability of the drug.

[0131] In summary, the cloxacillin sodium powder for injection prepared using the formulation and process of the present invention, with the addition of the buffer salt Bicine and the hygroscopic agent CMC / AA / AM, exhibits significantly better stability during storage than a product obtained by directly packaging cloxacillin sodium powder alone. This excellent stability can prevent the increased risk of allergies caused by the accumulation of impurities after cloxacillin sodium hydrolysis, thereby ensuring clinical drug safety.

Claims

1. A cloxacillin sodium composition, comprising the following components in the following mass ratios: Cloxacillin sodium raw material 50: buffer salt 1.5-2.0: desiccant 13.0-15.0; The buffer salt is N,N-bicine; The desiccant is carboxymethyl cellulose connected with acrylic acid and acrylamide; the mass ratio of carboxymethyl cellulose, acrylic acid and acrylamide in the desiccant is 1:3:3; The dosage form of the composition is powder injection.

2. The composition according to claim 1, wherein The preparation method is composed of the following components in the following mass ratios: 50% cloxacillin sodium raw material: 2.0% buffer salt: 13.0% desiccant.

3. A method for preparing a powder injection using the cloxacillin sodium composition according to any one of claims 1 to 2, comprising the following steps: uniformly mixing the cloxacillin sodium raw material, a buffer salt, and a hygroscopic agent, and filling the powder with sterile nitrogen before and after filling, wherein: The nitrogen pressure before powder filling is 0.05~0.2MPa, and the time is 0.05~2s; the nitrogen pressure after powder filling is 0.05~0.2MPa, and the time is 0.05~1s.

4. The preparation method according to claim 3, comprising the following steps: the nitrogen pressure before powder filling is 0.1 MPa and the time is 1 s; the nitrogen pressure after powder filling is 0.1 MPa and the time is 0.05 s.

Images