Preparation method of compound sulfanilamide pharmaceutical preparation

Abstract

The invention provides a preparation method of a compound sulfonamide medicinal preparation. The compound sulfonamide medicinal preparation contains a premix prepared from sulfadiazine, sulfamethoxazole, trimethoprim, sodium bicarbonate and a slow-release coating medium. Compared with sulfadiazine, sulfamethoxazole and trimethoprim preparations, the sodium bicarbonate coated compound is high in bioavailability, and after the sodium bicarbonate coated compound is added, caking in urine can be remarkably reduced, and the stability of the preparation is not affected.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drugs in the biopharmaceutical field, and relates to a method for preparing a compound sulfonamide drug preparation, specifically a sulfamethoxazole premix. Background Technology

[0002] Combination preparations of sulfadiazine (SD), sulfamethoxazole (SMZ), and trimethoprim (TMP) are widely used in veterinary medicine.

[0003] Sulfadiazine (SD) is a white or off-white crystalline powder; odorless and tasteless, its color gradually darkens upon exposure to light. SD is slightly soluble in ethanol or acetone, practically insoluble in water; readily soluble in sodium hydroxide or ammonia solution, and soluble in dilute hydrochloric acid. SD is readily absorbed orally, reaching peak plasma concentration in 3–4 hours. Cerebrospinal fluid concentrations can reach 70% of plasma concentrations, with approximately 45% protein binding in blood. Its half-life is 8–13 hours, and after 24 hours, 30%–40% is excreted unchanged and 15%–30% is excreted in the urine as acetylated forms. SD is readily absorbed from the gastrointestinal tract after oral administration, with approximately 70% or more of the administered dose absorbed, but absorption is relatively slow. Peak plasma concentration is reached 3–6 hours after administration, and the peak free plasma concentration after a single oral dose of 2g is approximately 30–60 mg / L. The drug has low urinary solubility and is prone to crystalluria.

[0004] Sulfamethoxazole (SMZ) is a white crystalline powder; odorless. SMZ is practically insoluble in water; readily soluble in dilute hydrochloric acid, sodium hydroxide solution, or ammonia solution. Its antibacterial spectrum is similar to SD, but its antibacterial activity is stronger. The acetylated metabolites of sulfonamides have low solubility in the body and easily crystallize in the urethra, leading to crystalluria, hematuria, and anuria. When used in high doses, it is advisable to take it concurrently with sodium bicarbonate. When used in combination with the potentiator TMP, its antibacterial efficacy is significantly enhanced, increasing several to dozens of times. Clinically, it is used for tonsillitis, acute bronchitis, lung infections, urinary tract infections, purulent skin infections, bacillary dysentery, and typhoid fever.

[0005] Trimethoprim (TMP) is a white or off-white crystalline powder; odorless. TMP is slightly soluble in chloroform, sparingly soluble in ethanol or acetone, and practically insoluble in water; it is readily soluble in glacial acetic acid. Its antibacterial spectrum is similar to that of sulfonamides. When used in combination with sulfonamides, it can enhance their efficacy several to dozens of times. It is suitable for respiratory infections, chronic bronchitis in the elderly, bacillary dysentery, urinary tract infections, enteritis, typhoid fever, malaria, etc. As a feed additive, it has a significant synergistic effect when used in combination with sulfonamides and antibiotics, increasing the effect ten to dozens of times. It is not used alone, but is generally used in a 1:5 ratio to treat septicemia, pullorum disease, fowl typhoid, cholera, and secondary bacterial infections of the respiratory system caused by Escherichia coli in poultry and livestock. It can also be used for the prevention and treatment of coccidiosis.

[0006] Sulfamethoxazole / trimethoprim belongs to the sulfonamide class of antibacterial drugs and has good antibacterial activity against most Gram-positive and Gram-negative bacteria. It is also effective against coccidia and Toxoplasma gondii. Both SMZ and SD compete with para-aminobenzoic acid for dihydrofolate synthase, inhibiting dihydrofolate production and thus exerting an antibacterial effect; their combined effect is additive. TMP inhibits bacterial dihydrofolate reductase, preventing the reduction of dihydrofolate to tetrahydrofolate. The combined use of these three drugs provides a dual blocking effect on the bacterial synthesis of tetrahydrofolate, significantly enhancing their antibacterial activity. During medication, it is important to drink plenty of water to reduce the risk of kidney damage from crystal formation in the urine.

[0007] Characteristics of sulfonamide drugs: Sulfonamide drugs have low solubility in urine and easily form crystals that can damage the kidneys. During medication, it is advisable to drink plenty of water and take sodium bicarbonate to alkalize the urine and reduce crystal formation. Excessive dosage will increase toxic side effects, while insufficient dosage will not only fail to treat the condition but may also lead to drug resistance in pathogens. Generally speaking, the initial dose of sulfonamide drugs should be doubled, and after the acute phase, medication should be continued for 3-4 days before discontinuation. Sulfadiazine and sulfamethoxazole have a half-life of 10-24 hours and are classified as intermediate-acting drugs.

[0008] Sulfonamides have low solubility in urine and are prone to crystallizing, which can damage the kidneys. During treatment, patients should drink plenty of water and take sodium bicarbonate to alkalize the urine and reduce crystal formation. To better suit clinical applications, a sulfamethoxazole premix has been developed that facilitates clinical administration, reduces the frequency of dosing, and minimizes post-administration damage to animals. Summary of the Invention

[0009] The technical problem solved by this invention is to overcome the cumbersome administration process and the nephrotoxicity of sulfonamides in animals after administration of existing sulfonamide premixes. The sulfonamide premix is ​​convenient for mixing with feed or for direct administration. Furthermore, this invention provides a simple method for preparing the sulfonamide premix, with a wide range of excipient choices, suitable for large-scale industrial production.

[0010] The present invention provides a method for preparing a sulfamethoxazole-trimethoprim premix, characterized in that the sulfamethoxazole-trimethoprim premix comprises sulfadiazine, sulfamethoxazole, and trimethoprim; wherein the content of sulfadiazine is 30 w / w%-40 w / w%, the content of sulfamethoxazole is 30 w / w%-40 w / w%, and the content of trimethoprim is 12 w / w%-16 w / w.

[0011] The sulfamethoxazole premix of the present invention has high stability. Under high temperature (40℃±2℃) and high humidity (75%±5% relative humidity) conditions, the content of the active ingredient did not decrease after 6 months of storage, showing good stability.

[0012] As one embodiment of the present invention, the sulfamethoxazole premix further comprises a sodium bicarbonate coating, wherein the sodium bicarbonate coating is formed by coating sodium bicarbonate with a sustained-release coating material selected from ethyl cellulose and / or acrylic resin; the content of the sodium bicarbonate coating material is 3w / w%-4w / w.

[0013] This invention, by further adding sodium bicarbonate coating, not only does not reduce the stability of sulfamethoxazole premix, but also significantly reduces crystallization caused by the low solubility of sulfonamide drugs in urine.

[0014] In one embodiment of the present invention, the sulfamethoxazole premix further comprises a diluent, wherein the diluent is starch, glucose, or β-dextrin.

[0015] This invention provides a method for preparing a sulfamethoxazole-trimethoprim premix, characterized by using a fluidized bed drying method to prepare a sodium bicarbonate coating, and mixing sulfadiazine, sulfamethoxazole, trimethoprim, and a diluent uniformly to prepare the sulfamethoxazole-trimethoprim premix.

[0016] This invention provides a method for preparing a sulfamethoxazole premix, characterized in that the method includes: step (1) preparing the sodium bicarbonate coating by placing sodium bicarbonate in a fluidized bed, wherein the ratio of ethyl cellulose to sodium bicarbonate is 0.5:1 to 1:1, dissolving ethyl cellulose in ethanol to prepare a slurry, wherein the ratio of ethyl cellulose to ethanol is 0.1:1 to 0.2:1, and spray-drying the mixture of ethyl cellulose and sodium bicarbonate and the ethyl cellulose slurry in a fluidized bed to obtain the sodium bicarbonate coating.

[0017] Step (2) Mix sulfadiazine, sulfamethoxazole, trimethoprim, the sodium bicarbonate coating prepared in step (1) with a diluent to obtain the sulfamethoprim premix.

[0018] In one embodiment of the present invention, the sulfadiazine coating content is 30 w / w%-40 w / w%.

[0019] The sulfamethoxazole coating content is 30w / w%-40w / w, the trimethoprim coating content is 12w / w%-16w / w, the sodium bicarbonate coating content is 3w / w%-4w / w, and the balance is diluent. Attached Figure Description

[0020] Figure 1 This is a concentration-time curve of sulfadiazine.

[0021] Figure 2 This is a concentration-time curve of sulfamethoxazole.

[0022] Figure 3 This is a concentration-time curve of trimethoprim. Detailed Implementation

[0023] The present invention will be further described below with reference to specific embodiments, and the advantages and features of the present invention will become clearer with the description. However, these embodiments are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions can be made to the details and form of the technical solutions of the present invention without departing from the spirit and scope of the present invention, but such modifications and substitutions all fall within the protection scope of the present invention. The chemical reagents used in the present invention are all analytical grade and purchased from Sinopharm Group. Unless otherwise specified, the experimental methods described in the present invention are conventional methods; the biological materials described, unless otherwise specified, can be obtained commercially.

[0024] According to the sulfamethoxazole-trimethoprim premix proposed in this invention, the mass ratio of its components is 30%-40% sulfadiazine, 30%-40% sulfamethoxazole, and 12%-16% trimethoprim. Other components include 3%-4% sodium bicarbonate coating and a diluent. The diluent is one or more of starch, β-dextrin, glucose, etc.

[0025] Raw material preparation: The sulfadiazine (content 99.6%), sulfamethoxazole (content 99.7%), trimethoprim (content 99.7%), sodium bicarbonate, and starch used in the following examples are all from the same manufacturer and the same batch.

[0026] Preparation Example 1

[0027] 1.1 Raw materials and content of each component

[0028] The premix of sulfamethoxazole and trimethoprim has the following mass ratio: sulfadiazine 30%, sulfamethoxazole 30%, trimethoprim 12%, sodium bicarbonate coating 3%, and diluent 25%.

[0029] The diluent mentioned above is starch.

[0030] 1.2 Preparation steps

[0031] 1.2.1 Preparation of sodium bicarbonate coating

[0032] The fluidized bed drying method for preparing sodium bicarbonate coating specifically includes the following steps:

[0033] 1. After the ethyl cellulose and sodium bicarbonate are mixed evenly, they are placed in a fluidized bed, and the ratio of ethyl cellulose to sodium bicarbonate is 0.5:1.

[0034] 2. Ethyl cellulose is dissolved in ethanol to prepare a slurry with adhesive properties. The ratio of ethyl cellulose to ethanol is 0.1:1 to 0.2:1.

[0035] 3. The above mixture and slurry are subjected to fluidized bed spray drying to obtain sodium bicarbonate coated material.

[0036] The above-mentioned sulfadiazine, sulfamethoxazole, trimethoprim, sodium bicarbonate coating and starch are mixed evenly according to the weight parts to obtain a sulfamethoprim premix.

[0037] Preparation Example 2

[0038] 2.1 Raw materials and content of each component

[0039] The premix of sulfamethoxazole and trimethoprim has the following mass ratios: sulfadiazine 35%, sulfamethoxazole 35%, trimethoprim 14%, sodium bicarbonate coating 3.5%, and diluent 12.5%.

[0040] The diluent mentioned above is starch.

[0041] 2.2 Preparation steps

[0042] 2.2.1 Preparation of sodium bicarbonate coating

[0043] The fluidized bed drying method for preparing sodium bicarbonate coating specifically includes the following steps: 1. After uniformly mixing the ethyl cellulose and sodium bicarbonate, place them in a fluidized bed, wherein the ratio of ethyl cellulose to sodium bicarbonate is 0.75:1.

[0044] 2. Ethyl cellulose is dissolved in ethanol to prepare a slurry with adhesive properties. The ratio of ethyl cellulose to ethanol is 0.1:1 to 0.2:1.

[0045] 3. The above mixture and slurry are subjected to fluidized bed spray drying to obtain sodium bicarbonate coated material.

[0046] The above-mentioned sulfadiazine, sulfamethoxazole, trimethoprim, sodium bicarbonate coating and starch are mixed evenly according to the weight parts to obtain a sulfamethoprim premix.

[0047] Preparation Example 3

[0048] 3.1 Raw materials and content of each component

[0049] The premix of sulfamethoxazole and trimethoprim has the following mass ratios: sulfadiazine 38%, sulfamethoxazole 38%, trimethoprim 16%, sodium bicarbonate coating 4%, and diluent 4%.

[0050] The diluent mentioned above is starch.

[0051] 3.2 Preparation steps

[0052] 3.2.1 Preparation of sodium bicarbonate coating

[0053] The fluidized bed drying method for preparing sodium bicarbonate coating specifically includes the following steps:

[0054] 1. After uniformly mixing the ethyl cellulose and sodium bicarbonate, place the mixture in a fluidized bed. The ethyl cellulose and...

[0055] The ratio of sodium bicarbonate is 1:1;

[0056] 2. Ethyl cellulose is dissolved in ethanol to prepare a slurry with adhesive properties. The ratio of ethyl cellulose to ethanol is 0.1:1 to 0.2:1.

[0057] 3. The above mixture and slurry are subjected to fluidized bed spray drying to obtain sodium bicarbonate coated material.

[0058] The above-mentioned sulfadiazine, sulfamethoxazole, trimethoprim, sodium bicarbonate coating and starch are mixed evenly according to the weight parts to obtain a sulfamethoprim premix.

[0059] Preparation Example 4

[0060] Except for the absence of sodium bicarbonate coating, the raw materials and component contents of Example 3, as well as the preparation...

[0061] The sulfamethoxazole-trimethoprim premix prepared by this method has the following mass ratio of components: sulfadiazine 40%, sulfamethoxazole 40%, trimethoprim 16%, and diluent 4%.

[0062] Two additional control samples were established.

[0063] Comparative Example 1

[0064] Preparation of reference standard 1

[0065] A sulfamethoxazole-trimethoprim premix, wherein the mass ratio of its components is 20% sulfadiazine, 20% sulfamethoxazole, 8% trimethoprim, and 52% starch.

[0066] The above components are mixed evenly to obtain the final product.

[0067] Comparative Example 2

[0068] Preparation of reference standard 2

[0069] A sulfamethoxazole-trimethoprim premix, wherein the mass ratio of its components is 20% sulfadiazine, 20% sulfamethoxazole, 8% trimethoprim, 2% sodium bicarbonate, and 50% starch.

[0070] The above components are mixed evenly to obtain the final product.

[0071] Example 5: Changes in serum drug concentration after administration of the sulfamethoxazole premix of the present invention and comparison with the control.

[0072] 5.1 Reagents and Animals

[0073] Healthy pigs weighing 100kg-105kg were randomly divided into 5 groups of 20 each: Sample 1, Sample 2, Sample 3, Control 1, and Control 2. The samples prepared in Examples 1-3 were administered to each group.

[0074] Samples 1, 2, 3, and control samples 1 and 2 prepared in Examples 1 and 2 were acclimatized to the environment for one week. The dosages of Samples 1, 2, 3, Control Samples 1, and Control Samples 2 in the examples were calculated based on 0.6g of sulfadiazine raw material, 0.6g of sulfamethoxazole raw material, and 0.24g of trimethoprim raw material. These were then mixed into feed and fed to the corresponding Sample 1 group, Sample 2 group, Sample 3 group, Control Sample 1 group, and Control Sample 2 group in sequence. Peripheral venous blood was collected from the same site at 0h, 0.5h, 1.0h, 1.5h, 3.0h, 5h, 8h, and 12h after feeding and placed in anticoagulant tubes for later use.

[0075] 5.2 Sample Preparation

[0076] Take 5 ml of the collected blood, centrifuge at 3500 r / min for 5 min, and inject 20 μL of serum for analysis.

[0077] 5.3 Detection Methods

[0078] Chromatographic conditions and system suitability test: Octadecylsilane-bonded silica gel was used as the stationary phase, and acetylene-water-triethylamine (200:799:1) (pH adjusted to 5.9 with sodium hydroxide solution or glacial acetic acid) was used as the mobile phase; the detection wavelength was 240 nm. The theoretical plate number, calculated based on the trimethoprim peak, should not be less than 4000, and the resolution of the sulfadiazine, sulfamethoxazole, and trimethoprim peaks should meet the requirements.

[0079] Separately weigh appropriate amounts of sulfadiazine, sulfamethoxazole, and trimethoprim reference standards, and add 0.1 mol / L;

[0080] The solution was dissolved and quantitatively diluted with hydrochloric acid to prepare a solution containing approximately 0.2 mg of sulfadiazine and 0.2 mg of sulfamethoxazole per 1 ml.

[0081] Mix with a solution of 80 μg of trimethoprim, shake well, and determine using the same method. Calculate the result based on the peak area using the external standard method.

[0082] Test instrument: Shimadzu LC-20 high performance liquid chromatograph.

[0083] For the statistical analysis of experimental data, 20 data points were obtained from the blood concentrations of sulfadiazine, sulfamethoxazole, and trimethoprim in each group. The maximum and minimum values ​​were removed, and the average of the remaining 18 data points was used for statistical analysis. The statistical results are shown in Table 1-3.

[0084] Table 1. Sulfadiazine Concentration - Timeline

[0085]

[0086]

[0087] Table 2. Sulfamethoxazole Concentration - Timeline

[0088]

[0089] Table 3. Trimethoprim Concentration - Timeline

[0090]

[0091] For Tables 1, 2, and 3, Figure 1 , Figure 2 , Figure 3 Analysis of the results showed that with the increase of drug use time, sulfadiazine, sulfamethoxazole, and trimethoprim all had high peak blood concentrations and high bioavailability within the same time period.

[0092] Example 6. Clinical treatment trial of the sulfamethoxazole-trimethoprim premix of the present invention.

[0093] Clinical trial, grouping of sick pigs: 200 sick pigs from a pig farm in Luoyang were randomly selected. The clinical manifestations were lethargy, loss of appetite, fever (some up to 40℃), and excretion of yellow or gray loose feces. The feces often contained blood clots. In severe cases, the pigs excreted black or red watery feces, which contained mucus and had a fishy odor. The diagnosis was swine dysentery, and sulfamethoxazole and trimethoprim were used as the treatment.

[0094] 240 diseased pigs were randomly divided into 6 groups of 40 each. Samples 1-3 from the examples and control samples 1-2 were taken from each group and fed with 1000g of the sample per 1000kg of feed, three times a day (morning, noon, and evening) for 5 consecutive days. After stopping the medication, the pigs were observed for another 2 days. The control group was fed normally without medication. The pigs were observed once a day, and the recovery status was recorded.

[0095] Judgment criteria:

[0096] Cured – Body temperature returns to normal, dysentery disappears, and normal food intake resumes.

[0097] Uncured – fever, dysentery, loss of appetite.

[0098] The cure rate is expressed as a percentage.

[0099] The total number of pigs exhibiting crystallized urine was also counted, expressed as a number.

[0100] Judgment criteria:

[0101] Crystalluria – The urine is cloudy, and a white, lime-like substance can be seen at the urination site.

[0102] Non-crystallized urine – The urine is clear, and no white, lime-like residue is visible at the urination site.

[0103] The statistical results are shown in Tables 4 and 5.

[0104] Table 4 Cure Rate

[0105]

[0106] Table 5 Total number of heads showing crystalluria

[0107]

[0108] Analysis of the results in Tables 4 and 5 shows that with the increase of medication time, the sulfamethoxazole-trimethoprim premix has a high cure rate and can effectively reduce the occurrence of some crystalluria symptoms, which can well meet the formulation requirements. Moreover, it can reduce the possibility of crystalluria compared with the control product 2, which also contains sodium bicarbonate.

Claims

1. A compound sulfonamide drug formulation, characterized in that, It is prepared from the following raw materials in the stated parts by weight: sulfadiazine, sulfamethoxazole, trimethoprim, diluent, sodium bicarbonate, coating material, and the remainder being excipients.

2. The compound sulfonamide drug preparation according to claim 1, characterized in that, The sulfamethoxazole premix contains a sodium bicarbonate coating, which is formed by coating sodium bicarbonate with a sustained-release coating material selected from ethyl cellulose and / or acrylic resin; the sodium bicarbonate coating material content is 3w / w%-4w / w.

3. A compound sulfonamide drug preparation according to any one of claims 1 to 2, characterized in that, The sulfamethoxazole premix also includes a diluent, which is starch, glucose, or β-dextrin.

4. A method for preparing a compound sulfonamide drug formulation according to claim 1, characterized in that, The method includes: Step (1) Prepare the sodium bicarbonate coating. Sodium bicarbonate is placed in a fluidized bed, and the ratio of ethyl cellulose to sodium bicarbonate is 0.5:1 to 1:

1. Ethyl cellulose is dissolved in ethanol to prepare a slurry, and the ratio of ethyl cellulose to ethanol is 0.1:1 to 0.2:

1. The mixture of ethyl cellulose and sodium bicarbonate and the ethyl cellulose slurry are spray-dried in a fluidized bed to obtain the sodium bicarbonate coating. Step (2) involves preparing the compound sulfonamide drug formulation. The compound sulfonamide drug preparation is obtained by mixing sulfadiazine, sulfamethoxazole, trimethoprim, sodium bicarbonate coating prepared in step (1) with a diluent.

5. The method according to claim 4, characterized in that, The sulfadiazine content is 30w / w%-40w / w, the sulfamethoxazole content is 30w / w%-40w / w, the trimethoprim content is 12w / w%-16w / w, the sodium bicarbonate coating content is 3w / w%-4w / w, and the balance is diluent.

6. The use of the compound sulfonamide drug preparation according to any one of claims 1 to 3 in the preparation of anti-inflammatory drugs.

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