CN115721607A

CN115721607A - Levofloxacin lactate injection and preparation method thereof

Info

Publication number: CN115721607A
Application number: CN202211450332.0A
Authority: CN
Inventors: 李飞
Original assignee: Huaxiashengsheng Pharmaceutical Beijing Co ltd
Current assignee: Huaxiashengsheng Pharmaceutical Beijing Co ltd
Priority date: 2022-11-19
Filing date: 2022-11-19
Publication date: 2023-03-03
Anticipated expiration: 2042-11-19
Also published as: CN115721607B

Abstract

The application relates to the technical field of medicines, and particularly discloses a levofloxacin lactate injection and a preparation method thereof. The levofloxacin lactate injection comprises the following raw materials: the levofloxacin lactate technical material, hydroxylated lecithin, oleic acid, a cosolvent, a glucose aqueous solution, cytidine disodium triphosphate and lidocaine carbonate aqueous solution, and the preparation method comprises the following steps: s1, mixing the raw material medicine with oleic acid, and stirring until the raw material medicine is completely dissolved; s2, adding a glucose aqueous solution and hydroxylated lecithin, and performing high-shear treatment by using a high-shear emulsifier; s3, adding the cosolvent, the cytidine disodium triphosphate and the lidocaine carbonate aqueous solution, and then continuously stirring and mixing for 5-15min; s4: carrying out ultrahigh pressure nano homogenization treatment for 2-4 times. The levofloxacin lactate injection prepared in the application has mild, quick and effective action, and is suitable for people who need to treat weak bodies of infectious diseases or have high drug sensitivity.

Description

Levofloxacin lactate injection and preparation method thereof

Technical Field

The application relates to the technical field of medicines, in particular to levofloxacin lactate injection and a preparation method thereof.

Background

Levofloxacin lactate can be used for treating systemic infections such as urogenital system infection, respiratory tract infection, gastrointestinal tract infection, typhoid, bone and joint infection, skin soft tissue infection, septicemia and the like caused by sensitive bacteria, has the characteristics of wide antibacterial spectrum and strong antibacterial action, and is widely used at present, but levofloxacin lactate belongs to the field of fluoroquinolone antibiotics, once the levofloxacin lactate is taken by mistake or allergic reaction is caused, irreversible damage to organs is possibly caused, along with the increase of the application range of the levofloxacin lactate, reports about a plurality of side effects of the levofloxacin lactate are increased day by day, including hepatotoxicity, central nerve and peripheral nerve abnormity and blood sugar change abnormity which are unrelated to allergic reaction, and serious discomfort can be caused by injection under the condition that the organism has high sensitivity to the levofloxacin lactate, so that the prevention and reduction of adverse reaction generation of the levofloxacin lactate become an important problem to be solved in clinical treatment.

Disclosure of Invention

In order to reduce the possibility that the lactic acid levofloxacin generates adverse reactions to stimulate human bodies and reduce the side effects of medicines, the application provides the lactic acid levofloxacin injection and the preparation method thereof.

In a first aspect, the application provides a levofloxacin lactate injection, which adopts the following technical scheme:

the levofloxacin lactate injection comprises the following raw materials in parts by weight: 0.4-0.6 part of levofloxacin lactate raw drug, 5-8 parts of hydroxylated lecithin, 10-12 parts of oleic acid, 2-5 parts of cosolvent, 25-35 parts of glucose aqueous solution, 0.4-0.8 part of cytidine disodium triphosphate and 0.1-0.3 part of lidocaine aqueous solution.

By adopting the technical scheme, the slightly soluble drug levofloxacin lactate can be completely dissolved in the oil phase, so that the drug can be fully dissolved in oleic acid, and then the oil-in-water emulsion is formed by adopting hydroxylated lecithin and adding a glucose aqueous solution capable of controlling the osmotic pressure of the injection; the oil-in-water type emulsion has good drug loading capacity of hydrophobic drugs, has strong capability of penetrating blood brain barriers, has targeting affinity to lymphatic system, ensures that the drugs have higher bioavailability, minimizes the stimulation possibly to other cells of a body, controls the release of a great amount of drugs in blood, slows down the increase of blood concentration, avoids the phenomenon of violent rise, has good fluidity of the oil-in-water type, has no obvious pain, and can be quickly mixed and dissolved with a glucose aqueous solution; the possibility of some neurotoxic side effects of people with drug-sensitive constitution is reduced by adding the cytidine disodium triphosphate, the brain and the nervous system are nourished, the immunity and the restoring force of the brain and the nervous system are improved, the stimulation of the drug to the nervous system is further reduced, and the drug risk is reduced; the injection adopts the lidocaine carbonate aqueous solution, pain of sensitive people can be relieved by lidocaine medicines when the emulsion is injected, stimulation to skin is relieved, and the lidocaine medicines can expand blood vessels and combine with targeting effect to enable the injection to go to a lymphatic system more quickly to exert drug effect, and reduce lymphadenectasis caused by infection.

Preferably, the HLB value of the hydroxylated lecithin is 10 to 12.

By adopting the technical scheme, the hydroxylated lecithin injected into a human body can play a role in protecting the heart, regulating the activation degree of brain cells, emulsifying and removing blood fat and the like, and the hydroxylated lecithin with the HLB value within the range of 10-12 is adopted, and the characteristic of good hydrophilic property of the hydroxylated lecithin is utilized to form the oil-in-water emulsion injection with good fluidity.

Preferably, the cosolvent comprises polyethylene glycol and ethanol in a weight ratio of 1.

Preferably, the lidocaine aqueous solution is a lidocaine carbonate aqueous solution prepared by mixing lidocaine hydrochloride and a sodium bicarbonate solution under the condition of carbon dioxide saturation.

By adopting the technical scheme, the ph of lidocaine hydrochloride is adjusted through the reaction with alkaline sodium bicarbonate, so that the ph of injection reaches the corresponding standard, and the neutralization acidity ensures that the environment of an injection system is the same as that of a weakly alkaline blood system, so that the injection is mild and not irritated.

Preferably, the concentration of glucose in the aqueous glucose solution is 5 to 8wt%.

By adopting the technical scheme, the osmotic pressure of the injection system can be regulated and controlled by adding glucose, so that the balance of the concentration and the osmotic pressure index in blood is maintained; and when abnormal blood sugar changes occur in quinolone injection, blood sugar is normally abnormally reduced three days before injection, and glucose in the injection can play a compensation role, so that severe hypoglycemia is avoided.

In a second aspect, the application provides a preparation method of levofloxacin lactate injection, which adopts the following technical scheme:

a preparation method of levofloxacin lactate injection comprises the following steps:

s1, mixing the raw material medicine with oleic acid, and stirring until the raw material medicine is completely dissolved to obtain an oil phase;

s2, adding a glucose aqueous solution and hydroxylated lecithin into the oil phase, and performing high-shear treatment by using a high-shear emulsifier to obtain levofloxacin lactate colostrum;

and S3, adding the cosolvent, the cytidine disodium triphosphate and the lidocaine carbonate aqueous solution, and then continuously stirring and mixing for 5-15min to obtain the levofloxacin lactate injection.

Preferably, the high shear operation in step S2 is performed at a rotation speed of 24000 to 26000 rpm.

Through adopting above-mentioned technical scheme, through high shear treatment, smash the oil phase shearing into the invisible tiny oil droplet of naked eye, compare in traditional mixed shearing, the oil droplet is smashed more tiny, and shearing effect is good to a large amount of mixed shearing time has been practiced thrift.

Preferably, the preparation method of the levofloxacin lactate injection further comprises the step S4: and carrying out ultrahigh-pressure nano homogenization treatment on the obtained levofloxacin lactate injection for 2-4 times.

By adopting the technical scheme, the homogenization is carried out, so that the sizes and the volumes of oil drops are close, and the phenomenon that the blood concentration after injection is unstable due to uneven drug release amount caused by different sizes of the oil drops is avoided.

In summary, the present application has the following beneficial effects:

1. the oil-in-water emulsion injection prepared by the method has good hydrophobic drug loading capacity, good fluidity of the injection, no obvious pain in the injection process, small damage to other cells of a human body due to target affinity of a lymphatic system, less drug release amount in blood of the emulsion injection, and less stimulation to visceral organs due to the fact that only a few drugs participate in liver and intestine circulation.

2. The preferable characteristics of the lidocaine carbonate aqueous solution and the oil-in-water emulsion injection are matched, the lidocaine components can be more quickly permeated through the blood brain barrier of a human body by the emulsion injection, the blood vessel can be expanded, the circulation and the dispersion of the medicine can be accelerated, the dosage form can effectively reduce the medicine amount participating in the liver and intestine circulation of the human body, and the metabolic burden of viscera can be relieved, so that the levofloxacin lactate injection prepared in the application has mild and quick effect, and is suitable for people who need to treat the weak body of the infection diseases or people who have high sensitivity to the medicine.

3. According to the method, the cytidine disodium triphosphate is matched with the lecithin, so that the resistance and the restoring force of a cerebral nervous system can be improved by nourishing brain cells and nerve cells, the stimulation of a medicine to neurons is reduced, and the method is milder for a human body.

Detailed Description

The present application is further described in detail with reference to the following examples, which are specifically illustrated by the following: the following examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer, and the starting materials used in the following examples are available from ordinary commercial sources unless otherwise specified.

The lidocaine carbonate aqueous solution described in the present application is a nai-le product sold by Jiangsu Jichuan pharmaceutical Co.

Examples

Example 1

The levofloxacin lactate injection comprises the following raw materials: 0.4g of levofloxacin lactate technical drug, 5g of hydroxylated lecithin, 10g of oleic acid, 1g of polyethylene glycol, 1g of ethanol, 25g of 5wt% glucose aqueous solution, 0.4g of cytidine disodium triphosphate and 0.1g of lidocaine carbonate aqueous solution.

s1, mixing a levofloxacin lactate raw drug and oleic acid, and stirring until the levofloxacin lactate raw drug and the oleic acid are completely dissolved to obtain an oil phase;

s2, adding a glucose aqueous solution and hydroxylated lecithin into the oil phase, and performing high-shear treatment on the mixed water phase, oil phase and hydroxylated lecithin components for 10S at the rotating speed of 24000rpm by using a high-shear emulsifying machine to obtain levofloxacin lactate colostrum;

s3, adding polyethylene glycol, ethanol, cytidine disodium triphosphate and lidocaine carbonate aqueous solution, and continuously stirring and mixing for 5min to obtain levofloxacin lactate injection;

and S4, treating the levofloxacin lactate injection for 2 times by using an ultrahigh pressure nano homogenizer, wherein the pressure is 1400bar.

Example 2

The levofloxacin lactate injection comprises the following raw materials: 0.5g of levofloxacin lactate raw drug, 6.5g of hydroxylated lecithin, 11g of oleic acid, 2g of polyethylene glycol, 1.5g of ethanol, 30g of 6.5wt% glucose aqueous solution, 0.6g of cytidine disodium triphosphate and 0.2g of lidocaine carbonate aqueous solution.

s2, adding 6.5wt% of glucose aqueous solution and hydroxylated lecithin into the oil phase, and performing high-shear treatment on the mixed water phase and the oil phase for 12.5 seconds at 25000rpm by using a high-shear emulsifying machine to obtain levofloxacin lactate colostrum;

s3, adding polyethylene glycol, ethanol, cytidine disodium triphosphate and lidocaine carbonate aqueous solution, and then continuously stirring and mixing for 10min to obtain levofloxacin lactate injection;

and S4, treating for 3 times by using an ultrahigh pressure nano homogenizer, wherein the pressure is 1500bar.

Example 3

The levofloxacin lactate injection comprises the following raw materials: 0.6g of levofloxacin lactate raw drug, 8g of hydroxylated lecithin, 12g of oleic acid, 3g of polyethylene glycol, 2g of ethanol, 35g of glucose aqueous solution, 0.8g of cytidine disodium triphosphate and 0.3g of lidocaine carbonate aqueous solution.

s1, mixing the raw material medicines with oleic acid, and stirring until the raw material medicines are completely dissolved to obtain an oil phase;

s2, adding a glucose aqueous solution and hydroxylated lecithin into the oil phase, and performing high-shear treatment on the mixed aqueous phase and the mixed oil phase for 15S by using a high-shear emulsifying machine at the rotation speed of 26000rpm to obtain levofloxacin lactate colostrum;

s3, adding a cosolvent, cytidine disodium triphosphate and lidocaine carbonate aqueous solution, and then continuously stirring and mixing for 15min to obtain levofloxacin lactate injection;

and S4, treating for 4 times by using an ultrahigh pressure nano homogenizer, wherein the pressure is 1600bar.

Example 4

A levofloxacin lactate injection solution, which is prepared according to the method of example 1, except that the lidocaine hydrochloride aqueous solution is equally replaced with the lidocaine carbonate aqueous solution in step S3.

Example 5

A levofloxacin lactate injection solution according to the method of example 1, except that high shearing is not used in step S2, low normal shearing at 8000rpm is used and the shearing time is extended to 15min.

Example 6

A levofloxacin lactate injection, produced according to the method of example 1, except that the homogenization step S4 was not performed for 3 homogenization treatments.

Comparative example

Comparative example 1

A levofloxacin lactate injection, carried out according to the method of example 1, except that: the aqueous solution of glucose in the raw material was replaced with pure water in equal amounts.

Comparative example 2

A levofloxacin lactate injection, carried out according to the method of example 1, except that: no raw material of cytidine disodium triphosphate is added, namely, no cytidine disodium triphosphate is added in the step S3.

Comparative example 3

A levofloxacin lactate injection, carried out according to the method of example 1, except that: no lidocaine carbonate aqueous solution was added to the raw materials.

Comparative example 4

An injection of levofloxacin lactate prepared according to the method of example 1, except that: soybean oil is used as an oil phase.

Performance test

1. Blood concentration changes

2. Adverse reaction test

pH detection

Detection method/test method

1. Blood concentration change: after a healthy white mouse is placed into a test box and fed for 3 days, 50 microliters of levofloxacin lactate injection prepared in the application is injected into the mouse, and the blood concentration of the levofloxacin lactate injection is detected after 0.5h, 1h, 4h, 12h, 24h and 48h of injection respectively.

2. Adverse reaction experiment: after 10 healthy mice were placed in a test box and fed with the same amount of food for 3 days, 50 microliters of levofloxacin lactate injection prepared in the present application was injected into each mouse, the reaction of the mice was observed, and the blood glucose content was measured once a day, with the results shown in table 1.

And 3, pH detection: the PH values of the levofloxacin lactate injections prepared in the examples and comparative examples were measured by using a PH meter, and the results are shown in table 2.

The levofloxacin lactate injection prepared in example 1 was injected into mice at the following blood concentrations: 3.07. Mu.g/ml at 0.5h, 1.83. Mu.g/ml at 1h, 0.66. Mu.g/ml at 4h, 0.55. Mu.g/ml at 12h, 0.52. Mu.g/ml at 24h, 0.33. Mu.g/ml at 48 h.

The levofloxacin lactate injection prepared in example 2 was injected into mice at the following blood concentrations: 3.08. Mu.g/ml at 0.5h, 1.85. Mu.g/ml at 1h, 0.68. Mu.g/ml at 4h, 0.53. Mu.g/ml at 12h, 0.51. Mu.g/ml at 24h and 0.35. Mu.g/ml at 48 h.

The levofloxacin lactate injection prepared in example 3 was injected into mice at the following blood concentrations: 3.06. Mu.g/ml at 0.5h, 1.79. Mu.g/ml at 1h, 0.67. Mu.g/ml at 4h, 0.54. Mu.g/ml at 12h, 0.52. Mu.g/ml at 24h and 0.34. Mu.g/ml at 48 h.

The levofloxacin lactate injection prepared in example 4 was injected into mice at blood concentrations of: 3.12. Mu.g/ml at 0.5h, 1.88. Mu.g/ml at 1h, 0.63. Mu.g/ml at 4h, 0.56. Mu.g/ml at 12h, 0.53. Mu.g/ml at 24h and 0.37. Mu.g/ml at 48 h.

The levofloxacin lactate injection prepared in example 5 was injected into mice at blood concentrations of: 4.62. Mu.g/ml at 0.5h, 1.83. Mu.g/ml at 1h, 0.78. Mu.g/ml at 4h, 0.53. Mu.g/ml at 12h, 0.52. Mu.g/ml at 24h, 0.33. Mu.g/ml at 48 h.

The levofloxacin lactate injection prepared in example 6 was injected into mice at the following blood concentrations: 3.32. Mu.g/ml at 0.5h, 0.89. Mu.g/ml at 1h, 0.66. Mu.g/ml at 4h, 0.55. Mu.g/ml at 12h, 0.50. Mu.g/ml at 24h and 0.35. Mu.g/ml at 48 h.

The levofloxacin lactate injection prepared in comparative example 1 was injected into mice at blood concentrations of: 3.03. Mu.g/ml at 0.5h, 1.78. Mu.g/ml at 1h, 0.65. Mu.g/ml at 4h, 0.52. Mu.g/ml at 12h, 0.50. Mu.g/ml at 24h and 48h0.31. Mu.g/ml.

The levofloxacin lactate injection prepared in the comparative example 2 was injected into mice, and the blood concentration thereof was: 3.09. Mu.g/ml at 0.5h, 1.87. Mu.g/ml at 1h, 0.65. Mu.g/ml at 4h, 0.53. Mu.g/ml at 12h, 0.51. Mu.g/ml at 24h and 0.33. Mu.g/ml at 48 h.

The levofloxacin lactate injection prepared in the comparative example 3 was injected into mice, and the blood concentration thereof was: 2.65. Mu.g/ml at 0.5h, 3.00. Mu.g/ml at 1h, 0.97. Mu.g/ml at 4h, 0.55. Mu.g/ml at 12h, 0.52. Mu.g/ml at 24h, 48h0.33. Mu.g/ml.

The levofloxacin lactate injection prepared in comparative example 4 was injected into mice at blood concentrations of: 3.02. Mu.g/ml at 0.5h, 1.83. Mu.g/ml at 1h, 0.65. Mu.g/ml at 4h, 0.54. Mu.g/ml at 12h, 0.50. Mu.g/ml at 24h and 48h0.32. Mu.g/ml.

Table 1:

and (3) detection result of the pH value:

combining the detection results of the example 1 and the example 4 with the detection results of the ph value, it can be seen that when the lidocaine hydrochloride aqueous solution is used, the ph value detected by the ph meter does not meet the injection requirement, and the ph value after the sodium bicarbonate reaction is closer to the blood ph and milder.

It can be seen from the performance test results of example 1 and example 5 that, by using a common mixing and shearing method, the obtained emulsion injection can see tiny oil droplets under naked eyes, and presents as inclusions with uneven sizes under a microscope, while the inclusion in example 1 has similar volume and size, can be uniformly distributed in a water phase, is beneficial to maintaining the stability of blood concentration, controls the blood concentration between the minimum toxic concentration and the minimum effective concentration, and reduces abnormal fluctuation.

As can be seen from the results of the performance test combining example 1 and comparative example 1, 2 mice in the comparative example were not resistant to the pharmaceutical preparation and exhibited a phenomenon of hypoglycemia on the first and second days of injection, but only 1 mouse in example 1 exhibited a slight decrease in blood glucose on the third day and had little effect on the daily activities of the mice.

As can be seen from the results of the performance tests combining example 1 and comparative example 2, 3 mice were hyperexcitable and only 1 mouse was twitch occasionally without the cytidine disodium triphosphate, and in example one, only 1 mouse was hyperexcitable, which indicates that the injection of the present application for the mice was able to reduce the degree and possibility of twitch.

The performance test results of example 1 and comparative example 3 show that the blood concentration increases slowly for about 0.5-1h without adding the drug, and the utilization speed is accelerated after adding the drug.

Combining the performance test results of example 1 and comparative example 4, it can be seen that the emulsion fluidity of the injection prepared by using other oil phase matrixes such as soybean oil and fat is inferior to that of the injection prepared by using oleic acid as a matrix, which causes the blood of the mouse to become sticky after injection, and the mouse gradually becomes tired and moves slowly after the injection.

The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.

Claims

1. The levofloxacin lactate injection is characterized by comprising the following raw materials in parts by weight: 0.4-0.6 part of levofloxacin lactate raw drug, 5-8 parts of hydroxylated lecithin, 10-12 parts of oleic acid, 2-5 parts of cosolvent, 25-35 parts of glucose aqueous solution, 0.4-0.8 part of cytidine disodium triphosphate and 0.1-0.3 part of lidocaine aqueous solution.

2. The levofloxacin lactate injection according to claim 1, wherein the levofloxacin lactate injection comprises: the HLB value of the hydroxylated lecithin is 10-12.

3. The levofloxacin lactate injection according to claim 1, wherein the levofloxacin lactate injection comprises:

the cosolvent comprises polyethylene glycol and ethanol in a weight ratio of 1.

4. The levofloxacin lactate injection according to claim 1, wherein the levofloxacin lactate injection comprises: the lidocaine aqueous solution is a lidocaine carbonate aqueous solution prepared from lidocaine hydrochloride and sodium bicarbonate solution under the condition of carbon dioxide saturation.

5. The levofloxacin lactate injection according to claim 1, wherein the levofloxacin lactate injection comprises: the concentration of glucose in the glucose aqueous solution is 5-8wt%.

6. The process for preparing levofloxacin lactate injection according to any one of claims 1 to 5, comprising the steps of:

7. The process for preparing levofloxacin lactate injection according to claim 6, wherein the ratio of the total amount of levofloxacin lactate in the injection is as follows: the high shear operation in the S2 step is carried out at a rotation speed of 24000 to 26000 rpm.

8. The method for preparing levofloxacin lactate injection according to claim 6, wherein the preparation method comprises the following steps: the preparation method of the levofloxacin lactate injection further comprises the step S4: and carrying out ultrahigh pressure nano homogenization treatment on the obtained levofloxacin lactate injection for 2-4 times.