CN1965850B - Roxithromycin injection and preparation process thereof - Google Patents

Abstract

The invention discloses a roxithromycin injection and a preparation method thereof. The invention has good solubility and is suitable for intravenous administration. In the present invention, roxithromycin and aspartic acid react at room temperature in the required amount of water to generate soluble salts, aspartic acid and roxithromycin react in equimolar numbers, and the injection contains 50-500 mg of roxithromycin Mycin, the obtained solution can be made into a solution injection or after adding an appropriate amount of proppant, it can be freeze-dried to obtain a powder injection. The preparation is convenient, and the process conditions are easy to control. It includes roxithromycin and aspartic acid. The invention dissolves in water, has fast drug release speed and good stability, and can rapidly exert curative effect.

Description

A kind of roxithromycin injection and preparation method thereof

technical field

The present invention relates to a kind of roxithromycin injection, more specifically, relate to the lyophilized powder injection of roxithromycin aspartate and the solution type injection, the present invention also provides roxithromycin aspartate freeze-dried Preparation method of powder injection and solution injection.

Background technique

Roxithromycin (RXM) is a new type of macrolide antibiotic that was put into clinical practice in the early 1990s. Its chemical name is (9E)-[O-[(2-methoxyethoxy)methyl]oxime Base] erythromycin, which introduces an oxime ether side chain at the 9-position of erythromycin, thus improving its acid resistance and stability. Its antibacterial spectrum is similar to that of erythromycin, and it has strong antibacterial effect on Gram-positive bacteria, and it also has good antibacterial effect on Gram-negative bacteria such as meningococcus, gonorrhoeae, influenza bacillus, pertussis bacillus, Brucella, etc. In addition, it also has inhibitory effect on some spirochetes, mycoplasma pneumoniae and rickettsia. Clinically, roxithromycin is mainly used for upper and lower respiratory tract infections, pneumonia caused by chlamydia and mycoplasma infections, skin and soft tissue infections, genitourinary tract infections, and ENT infections. In addition to its antibacterial effect, roxithromycin has also been clinically proven to improve immunity and anti-inflammation. In addition, it is also used in combination with proton pump inhibitors such as omeprazole and lansoprazole to treat gastric ulcers caused by Helicobacter pylori.

After oral administration of 150 mg of roxithromycin to healthy subjects, the maximum blood concentration is 6.6-7.9 mg/L, while the C _max of 500 mg erythromycin is only 1.78 mg/L; the peak time is 1.5-1.9 h ; The elimination half-life is about 12h. Roxithromycin non-specifically binds to albumin, the binding force is weak, and the binding rate is about 15.6-26.7%, but it specifically binds strongly to α ₁ -acid glycoprotein, and there is a phenomenon of saturation; it binds to lipoprotein The binding rate is 7-11%; it is rarely combined with red blood cells and globulin. Early pharmacokinetic studies found that after a single oral dose of [ ¹⁴ C]-roxithromycin to healthy subjects, a total of 74.2% of the dose was recovered, of which 7.4% were recovered in urine, 53.4% in feces, and 13.4% in respiratory excretion. %. Four metabolites were found in urine. The results of in vivo experiments in healthy volunteers showed that eating before taking the drug can reduce the bioavailability and peak plasma concentration of roxithromycin.

Roxithromycin has obvious first-pass elimination in the gastrointestinal tract. At 37°C in the artificial gastric juice of pH 1-3, two degradation pathways, deerythromycin and geometric isomerization conversion, can occur. Degradation speed and geometric isomerization conversion The degree is pH-dependent. Under the conditions of pH 5.0, 7.4, and 10, no degradation occurs when incubated at 37°C. According to literature reports, when roxithromycin is administered orally, the medicine absorbed through the gastrointestinal tract only accounts for 50% of the dosage, and the rest is all excreted, causing a lot of waste. It is not suitable for patients with abnormal drug or gastrointestinal absorption function, as well as some patients with serious conditions. Therefore it is clinically necessary to make it into an injection.

In 2003, CN1452975A disclosed a roxithromycin injection, and its water-soluble salts were roxithromycin hydrochloride, roxithromycin tartrate and roxithromycin lactobionate. However, this study found that the aspartate salt of roxithromycin has better solubility and is more suitable for making injection dosage forms.

Contents of the invention

The invention provides some injection forms of roxithromycin water-soluble salts with relatively convenient, economical and industrialized production methods and a preparation method thereof.

The present invention is realized in the following way: the roxithromycin and aspartic acid react with a molar ratio of 1:1 to form a salt, which can form a clear aqueous solution, which is suitable for making an injection form.

Injection of the present invention, active ingredient is roxithromycin aspartate, and the solubility in water can reach 75mg/mL in terms of roxithromycin, and the aqueous solution pH that it forms is moderate simultaneously, within the scope of 5.0-6.5, so both It is suitable for intravenous administration and can ensure that the roxithromycin is not destroyed; in addition, the formed salt is easy to release the roxithromycin in the aqueous solution, which can ensure that it can quickly and fully exert its drug effect.

The injection of the present invention can be a freeze-dried powder injection or a solution injection. Wherein the solution type injection can be water injection or infusion, and wherein water injection is made by sterilizing aqueous solution of roxithromycin aspartate; Wherein infusion is made by adding appropriate amount of osmotic pressure adjustment to aqueous solution of roxithromycin aspartate The agent is sterilized by hot pressing; the freeze-dried powder injection is made by adding an appropriate amount of proppant to an aqueous solution of roxithromycin aspartate and then freeze-dried.

The injection of the present invention may contain freeze-dried proppants and osmotic pressure regulators. The lyophilized proppant can be mannitol, dextran-20, dextran-40; the osmotic pressure regulator can be sodium chloride, glucose.

The injection of the present invention contains an effective amount of roxithromycin aspartate, which is equivalent to 50-500 mg of roxithromycin.

The preparation method of roxithromycin injection of the present invention is characterized in that: put roxithromycin and aspartic acid in a beaker at a molar ratio of 1:1, add water for injection, stir and dissolve at room temperature, add activated carbon for needles , stirred at 40°C for 20 minutes, filtered, the carbon cake was washed twice with the remaining water for injection, the original solution of the lotion was combined and filtered through a 0.22-0.45μm microporous membrane, and divided into ampoules according to the predetermined dose, at 100°C Circulating steam sterilization for 30 minutes to obtain roxithromycin aspartate injection; add 1/3 mannitol of the dose of roxithromycin to the water for injection, subpackage and freeze-dry to obtain the freeze-dried injection; add 6 times Measure the sodium chloride of roxithromycin and 10000ml of water for injection, which can be divided into 100 infusion bottles, and roxithromycin aspartate infusion can be obtained through autoclaving at 115°C for 30 minutes.

Compared with the prior art, the present invention has the advantages of: more convenient, economical, and easy to industrialized production; roxithromycin aspartate is dissolved in water, and can release roxithromycin quickly after being made into an injection for intravenous administration, The effective antibacterial concentration is achieved, the therapeutic effect is rapidly exerted, and the pH value is suitable, and the occurrence rate of intravenous administration of phlebitis and other adverse reactions is low; the injection of the present invention is investigated through a stability test, and the result is good stability. In view of the advantages of the present invention, it has good clinical application prospects and significance.

The present invention is better illustrated by the following examples. However, the present invention is not limited by the following examples.

Detailed ways

Embodiment 1: the preparation of roxithromycin aspartate for injection:

The composition of the prescription is: (based on 100 sticks)

Roxithromycin 15.0g

Aspartic Acid 2.4g

Mannitol 5.0g

Water for injection 200mL

Weigh the mannitol of the prescribed amount, add water for injection to make a solution with a concentration of about 15%, and set aside. Weigh the prescribed amount of roxithromycin and aspartic acid, put them in a 250mL beaker, add about 120mL of water for injection and the above-mentioned mannitol solution, stir at room temperature until completely dissolved, add 0.16g of activated carbon for needles, and Stir for 20 minutes, filter, wash the charcoal cake twice with the remaining water for injection, combine the original solution of the lotion, pass through a 0.22 μm microporous membrane filter for sterilization, pack aseptically according to the predetermined dose, and freeze-dry to obtain the product.

Embodiment 2: the preparation of roxithromycin aspartate injection:

The composition of the prescription is: (based on 100 sticks)

Roxithromycin 15.0g

Aspartic Acid 2.4g

Water for injection 200mL

Weigh the prescribed amount of roxithromycin and aspartic acid, place in a 250mL beaker, add about 160mL of water for injection, stir at room temperature until completely dissolved, add 0.16g of activated carbon for needles, stir at 40°C for 20 minutes, filter After that, the charcoal cake was washed twice with the remaining water for injection, and the stock solution of the lotion was combined and filtered through a 0.45 μm microporous membrane, divided into ampoules according to the predetermined dose, and sterilized by circulating steam at 100°C for 30 minutes.

Embodiment 3: the preparation of roxithromycin aspartate infusion:

The composition of the prescription is: (based on 100 sticks)

Roxithromycin 15.0g

Aspartic Acid 2.4g

Sodium chloride 90.0g

Water for injection 10000mL

Weigh the prescribed amount of roxithromycin, aspartic acid and sodium chloride, put them in a 10000mL beaker, add about 8000mL of water for injection, stir at room temperature until completely dissolved, add 80.0g of activated carbon for needles, and stir at 40°C After 20 minutes, filter, wash the charcoal cake twice with the remaining water for injection, combine the original washing solution and filter it through a 0.45 μm microporous membrane, pack it into infusion bottles according to the predetermined dose, and sterilize it by autoclaving at 115°C for 30 minutes. .

The following test data can illustrate the benefits of the present invention:

Test Example 1: Comparison of Solubility of Roxithromycin and Roxithromycin Aspartate

Table 1 Roxithromycin, roxithromycin aspartate solubility results (20 ℃)

Test example 2: Roxithromycin aspartate stability test result

Table 2 Experimental results of influencing factors

Note: "-" in Table 2 indicates that this test has not been carried out.

Table 3 accelerated experiment results

Table 4 Long-term retention sample test results

Test conclusion: Roxithromycin aspartate injection has good stability.

Test Example 3 Special Safety Test

It is used to test whether the intravenous administration of roxithromycin aspartate has irritation, allergy and hemolysis reaction, so as to determine whether the drug can be used for intravenous administration.

3.1 Vascular stimulation experiment

(1) Test drug: Roxithromycin aspartate injection related to the present invention.

(2) Test animals: rabbits, 1.8-2.5kg, both male and female.

(3) Test method: 6 rabbits weighing 1.8-2.5 kg were randomly divided into 2 groups with 3 rabbits in each group. Three rabbits were infused with roxithromycin aspartate 15 mg/kg (calculated as roxithromycin) through the ear vein, and the administration volume was 5 mL/kg. 3 rabbits were infused with equal volume of normal saline through ear veins once a day for three consecutive times. After administration, the reaction of blood vessels at the injection site and away from the injection site were observed with the naked eye. As a result, there was no abnormal reaction in blood vessels after administration. There was no significant difference in blood vessels. The vascular irritation was scored according to the criteria in Table 4, and the score was 0. 24 hours after the last administration, the rabbit was put to death, and a section of blood vessel was respectively taken at the injection site and about 5 cm away from the injection site, fixed in 10% formaldehyde solution, embedded in paraffin, stained with HE, and examined with a light microscope (40× 3.2), observe the histopathological changes. The results of histopathological examination showed that the roxithromycin aspartate injection was administered continuously for 3 days, and there were no obvious abnormal changes in the blood vessels at the injection site and the blood vessels away from the injection site in the rabbits, and there was no obvious abnormal change compared with the rabbit blood vessels in the normal saline control group. The difference is that there is no vascular irritation.

Table 4 Scoring criteria for visual inspection of vascular irritation

Result judgment standard: ≤0.5 non-irritating, ≤2.5 slightly irritating, ≤4.5 moderately irritating, ≤6.0 heavily irritating

3.2 Allergy test

Male guinea pigs, weighing 250-350 g, were randomly divided into 3 groups, 6 guinea pigs per group. The experimental group was intraperitoneally injected with roxithromycin aspartate injection 11.6mg/kg (calculated as roxithromycin), 0.5mL/piece, once every other day, a total of 3 times, and the positive control group was injected with the same volume of 1% fresh Egg white, and the blank control group were injected with the same volume of normal saline in the same way. Fourteen days after the first administration, 3 rats were taken from each group, and 1.0 mL/dog of aspartic acid injection was intravenously injected. Observe whether the animals have allergic reactions such as sneezing, scratching the nose, retching or coughing, piloerection, convulsions, dyspnea, incontinence, shock and death, and observe for 1 hour. The results are shown in Table 5. In the roxithromycin aspartate injection and normal saline groups, there was no allergic symptom, and 100% of the egg white positive control group went into shock. The remaining 3 were treated in the same way after 21 days, and the same indicators were observed, and the results were the same as before.

Allergy test of table 5 roxithromycin aspartate injection

Note: (-) no allergic reaction; (+) allergic reaction

3.3 In vitro hemolysis test

Blood was collected from the central artery of the rabbit ear. According to the method in the literature, the glass beads were stirred to remove fibrin, washed with normal saline and centrifuged (1000rpm, 15min), repeated several times until the supernatant had no red color, and then mixed with normal saline according to the volume ratio to 2.0 % red blood cell suspension for testing.

Take 7 test tubes for each group, add different volumes of roxithromycin aspartate injection and red blood cell suspension to each tube as shown in Table 4, 5, and 6, and add normal saline to tube 6 for blank. For control, distilled water was added to tube 7 as a complete hemolysis control. After shaking gently, each tube was placed in a 37°C water bath for 3 hours, 15min and 30min respectively. 45min, 1.0h, 2.0h, 3.0h each recorded once, a total of 6 times. According to the literature standard, visually observe whether there is hemolysis. After the last observation, fully shake each test tube to observe whether there is precipitation and agglutination. The results are shown in Tables 6-9. No hemolysis and hemagglutination were found in the in vitro hemolysis test of roxithromycin aspartate injection, and there was no significant difference compared with normal saline. The distilled water group was completely hemolyzed, producing a red transparent solution. Microscopic examination of erythrocytes by conventional methods showed no rupture and abnormal morphology of erythrocytes.

The in vitro hemolysis test of table 6 roxithromycin aspartate injection (5mg/mL) (calculated as roxithromycin)

Judgment: (-) means no hemolysis, no agglutination, no precipitation reaction; (+) means complete hemolysis.

Table 7 In vitro hemolysis test of roxithromycin aspartate injection (1.5mg/mL) (calculated as roxithromycin)

Judgment: (-) means no hemolysis, no agglutination, no precipitation reaction; (+) means complete hemolysis.

The in vitro hemolysis test of table 8 roxithromycin aspartate (injection 0.6mg/mL) (calculated as roxithromycin)

Judgment: (-) means no hemolysis, no agglutination, no precipitation reaction; (+) means complete hemolysis.

Table 9 Judgment criteria for hemolysis and agglutination of red blood cells

Experimental results:

This drug has no hemolysis, no vascular irritation, and no allergic reaction.

Claims (11)

1. a roxithromycin injection, is characterized in that: it comprises the roxithromycin aspartic acid salt that roxithromycin and aspartic acid react with molar ratio 1: 1, contains equivalent to in the injection 50-500 mg roxithromycin, the pH of which is 5.0-6.5. 2. the roxithromycin injection according to claim 1 is characterized in that: the injection contains the roxithromycin aspartate equivalent to the roxithromycin of 150mg. 3. Roxithromycin injection according to claim 1, is characterized in that: described injection is the lyophilized powder injection of roxithromycin aspartate or solution type injection. 4. The roxithromycin injection according to claim 1, characterized in that: the lyophilized powder injection is formed by adding an appropriate amount of proppant to an aqueous solution of roxithromycin aspartate, followed by freeze-drying. 5. Roxithromycin injection according to claim 4, is characterized in that: wherein proppant is selected from mannitol, dextran-20 or dextran-40. 6. Roxithromycin injection according to claim 3, is characterized in that: described solution type injection is aqueous injection or transfusion. 7. The roxithromycin injection according to claim 6; it is characterized in that: the aqueous injection of roxithromycin injection is formed by sterilizing an aqueous solution of roxithromycin aspartate. 8. The roxithromycin injection according to claim 6, characterized in that: the infusion is sterilized by adding an appropriate amount of osmotic pressure regulator to an aqueous solution of roxithromycin aspartate. 9. Roxithromycin injection according to claim 8, is characterized in that: described osmotic pressure regulator is sodium chloride or glucose. 10. a preparation method of roxithromycin injection as claimed in claim 1 is characterized in that: roxithromycin and aspartic acid are made by reacting in a mol ratio of 1:1. 11. the preparation method of roxithromycin injection according to claim 10, wherein roxithromycin and aspartic acid are placed in beaker and add water for injection, stir and dissolve at room temperature, add gac for needle, at 40 Stir at ℃ for 20 minutes, filter, wash the charcoal cake twice with the remaining water for injection, combine the original solution of the lotion and filter it through a 0.22-0.45 μm microporous membrane, pack it into ampoules according to the predetermined dose, and circulate steam at 100 °C Sterilize for 30 minutes to get roxithromycin aspartate injection; add 1/3 roxithromycin dose of mannitol to the water for injection, subpackage and freeze dry to get freeze-dried injection; add 6 times the amount The sodium chloride of roxithromycin and 10000ml of water for injection can be divided into 100 infusion bottles, and roxithromycin aspartate infusion can be obtained after autoclaving at 115°C for 30 minutes.