CN110200913B - Preparation method of embedded sulbactam amoxicillin amide compound - Google Patents
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Abstract
The invention discloses a preparation method of an embedded sulbactam amoxicillin amide compound, which comprises the following steps of firstly, carrying out covalent reaction on a protein compound in duck egg white and glucan in water to obtain a graft, namely a water phase; dissolving the sulbactam amoxicillin amide compound in the soybean oil to obtain an oil phase; and then mixing the water phase and the oil phase through high-pressure homogenization to prepare the embedded nano emulsion of the sulbactam amoxicillin amide compound medicine. The nano emulsion has a stable oil-water interfacial film and good water solubility, and brings possibility for the preparation production of the compound; the embedding effect is good, no agglomeration or aggregation phenomenon exists within 12 months, the particles are uniform and stable, the particle size is small, and the particles can be well absorbed by a human body. The raw materials are simple and easy to obtain, the method is safe, the cost is low, the preparation process is simple, the method is easy to apply to industrial production, a new idea is provided for the production of water-insoluble pharmaceutical preparations, and meanwhile, the comprehensive development and utilization of high-value-added components in the egg industry can be promoted, and the economic value is improved.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of an embedded sulbactam amoxicillin amide compound.
Background
Sulbactam is an artificially synthesized irreversible competitive beta-lactamase inhibitor, has weak antibacterial activity and slightly stronger antibacterial activity than clavulanic acid, has bactericidal action only on gonococcus and acinetobacter when used singly, and has strong inhibitory action on most beta-lactamase produced by gram-positive bacteria and gram-negative bacteria. The amoxicillin has wide antibacterial spectrum, strong bactericidal power and quick action, and can be widely used in clinic because the amoxicillin can be orally taken; can be used for treating typhoid fever, other salmonella infection, cold carrier infection, and urinary tract, ear, nose, throat, respiratory tract and soft tissue infection. WHO recommends the beta-lactam oral antibiotics as the first choice and becomes one of the most attractive and fastest-developing varieties of antibiotics. However, as the beta-lactam structure in the amoxicillin molecule is easy to open and unstable, easy to degrade and poor in water solubility, the sodium salt is frequently used in the injection. Sulbactam also has a certain instability problem, is influenced by factors such as pH, temperature, oxidation and the like, and the beta-lactam structure of sulbactam is also easy to open the ring, so that the whole molecule is damaged, the content is reduced, and related substances are increased.
Among the chemical structure modifications of organic drugs, salt formation, ester formation and amide modification are a common method. The utilization of two different drug molecules with synergistic functions, which are modified by these methods, to combine the structures of the two drugs in one molecule or to make the pharmacophores of the two drugs compatible in one molecule, is one of the current research interests of pharmaceutical workers. In earlier research (CN201210290947.1), the inventor utilizes modification technology to form a sulbactam amoxicillin amide compound by amidating amoxicillin and sulbactam ester, and realizes the synthesis of the sulbactam amoxicillin amide compound with a novel structure, wherein the structural formula is as follows:
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of an embedded sulbactam amoxicillin amide compound, which solves the problems that the sulbactam amoxicillin amide compound has poor water solubility, is difficult to prepare a water-soluble preparation and has poor stability of a beta-lactam structure in the compound structure.
In order to solve the technical problems, the invention adopts the following technical scheme: a preparation method of an embedded sulbactam amoxicillin amide compound comprises the following steps:
1) dissolving duck egg white in water, adding glucan to obtain a mixed solution, adjusting the pH of the mixed solution to 4-8, stirring at room temperature for 1-2 h until the mixed solution is completely dissolved, placing the mixed solution in a water bath at 50 ℃ for reaction for 1-6 h, cooling to room temperature after the reaction is finished, centrifuging to obtain a supernatant, and dialyzing to obtain a graft, namely a water phase;
2) dissolving the sulbactam amoxicillin amide compound in the soybean oil, and fully stirring to obtain an oil phase;
3) mixing the water phase obtained in the step 1) and the oil phase obtained in the step 2), and carrying out high-pressure homogenization to obtain the nanoemulsion embedded with the sulbactam amoxicillin amide compound.
The duck egg white is transparent colloid and mainly comprises protein, fat, carbohydrate, calcium, phosphorus, iron, riboflavin, nicotinic acid, vitamin A and C. Wherein, the solid accounts for 13 percent, about 90 percent of the solid is protein, and the solid is mainly egg albumin (75 percent), the egg albumin mostly exists in the form of hydrophilic protein, most hydrophobic amino acids are in the molecule, the structure is easy to unfold under the action of high-pressure homogenization and calcium, phosphorus, iron and other groups, and the protein compound interacts with the ovomucoid (15 percent), the ovomucoid (7 percent) and the companion albumin (3 percent), thereby endowing stronger hydrophobic interaction and disulfide bond crosslinking among the molecules, having the capability of fast absorbing to the interface, being capable of fast extending and orienting after reaching the interface and forming a film with strong cohesive force and viscoelasticity after reaching the interface and interacting with adjacent molecules, and forming a protein surfactant of a specific category; and the emulsification effect of the protein compound is further improved under the synergistic effect of the protein compound and the ovotransferrin and lysozyme in the egg white. The components of the duck egg white are different from other egg white in protein types, trace elements, other nutrients and the like, and the difference of the components can cause the duck egg white to be suitable for embedding the sulbactam amoxicillin amide compound medicine.
Under the action of strong shearing, impacting and cavitation generated under high pressure, egg white forms a protein compound with a protein surfactant, a hydrophilic group of the protein compound is combined with a water phase, and a lipophilic group is combined with an oil phase, so that the compound protein can be bound on the surface of emulsion droplets to form an oil-water interface film, oil droplets are fixed, efficient loading and embedding of sulbactam amoxicillin amide compound medicines are completed, and numerous micro or even micron or nano-scale emulsions are formed. The micro jet flow generated by cavitation effect is utilized to uniformly mix the oil phase and the water phase, so that the liquid substance is superfine. Meanwhile, glucan grafted and connected to egg albumin stretches on the surface of the emulsion drop due to the hydrophilicity of the glucan, so that the emulsion drop stably exists in water for a long time, and precipitation and aggregation of the emulsion drop are avoided.
Preferably, the mass of the duck egg white, the water and the glucan is 1: 2-10: 0.05 to 0.2.
Preferably, the molecular weight of the glucan is 5000-50000.
Preferably, the concentration of the sulbactam amoxicillin amide compound dissolved in the soybean oil in the step 2) is 5-100 mg/ml.
Preferably, the mixing volume ratio of the water phase to the oil phase is 1: 5-20.
Preferably, the pressure range of the high-pressure homogenization is 300-500 bar, and the time range of the high-pressure homogenization is 10-30 min.
Preferably, the centrifugal speed is 4000-6000 rpm, and the centrifugal time is 10-20 min.
Preferably, the molecular weight of the dialysis membrane in dialysis is 10. + -. 0.2 kDa.
Compared with the prior art, the invention has the following beneficial effects:
1. the sulbactam amoxicillin amide compound medicine-protein compound-glucan embedded type nano emulsion provided by the invention takes an oil phase containing the sulbactam amoxicillin amide compound medicine as an inner core, a protein compound in duck egg white as an oil-water interface film, and glucan grafted on the protein compound is positioned on the outer layer of the nano emulsion. The nano emulsion has a stable oil-water interface film, extends on the surface of emulsion droplets due to the hydrophilicity of glucan, avoids the aggregation of the emulsion droplets, has good water solubility, and brings possibility for the preparation production of the compound; the embedding effect is good, the stability of the compound is improved, no agglomeration or aggregation phenomenon exists within 12 months, the effective storage period of the sulbactam amoxicillin amide compound medicine is prolonged, and the compound medicine has good application prospect.
2. The nano emulsion particles prepared by the invention are uniform and stable, have small particle size and can be well absorbed by human bodies. When in use, the sulbactam amoxicillin amide compound medicine is released along with the degradation of glucan and protein under the action of digestive enzyme of a human body, and the corresponding efficacy is exerted; the glucose and the protein peptide obtained by simultaneous decomposition also provide nutrient substances for human bodies.
3. The invention takes glucan and duck egg white as raw materials, belongs to conventional food, is non-toxic, easy to degrade, safe, low in cost, simple in preparation process and short in production period, is easy to apply in industrial production, provides a new idea for the production of water-insoluble pharmaceutical preparations, and can promote the comprehensive development and utilization of high value-added components in the egg product industry and improve the economic value.
Drawings
Figure 1 is a nanoparticle size distribution diagram of the sulbactam amoxicillin amide complex drug-protein complex-dextran nanoemulsion after being embedded, which is prepared in example 1 of the invention.
Detailed Description
The present invention will be described in further detail with reference to examples.
Example 1
1) Dissolving duck egg white in distilled water with the volume 2 times that of the duck egg white in a reaction bottle, adding glucan with the molecular weight of 25000 to enable the addition amount of the glucan to be 0.05 times of the mass of the duck egg white, adjusting the pH value of the solution to 4.0 by using a phosphate buffer solution, stirring the solution at room temperature for 2 hours until the glucan is completely dissolved, placing the solution in a water bath with the temperature of 40 ℃ for reaction for 1 hour, cooling the solution to the room temperature after the reaction is finished, centrifuging the solution at 4000rpm for 15 minutes to remove insoluble substances, and dialyzing supernatant liquid at the temperature of 4 ℃ for 24 hours (the dialysis molecular weight is 10 +/-0.2 kDa) to obtain a graft;
2) dissolving the sulbactam amoxicillin amide compound in the soybean oil, and fully stirring to ensure that the concentration of the sulbactam amoxicillin amide compound is 5mg/ml, thereby obtaining an oil phase;
3) mixing the water phase obtained in the step 1) and the oil phase obtained in the step 2) according to a volume ratio of 5:1, and performing high-pressure homogenization to obtain the embedded sulbactam amoxicillin amide compound drug-protein compound-glucan nano emulsion, wherein the pressure of the high-pressure homogenization is 500bar, and the time of the high-pressure homogenization is 10 min.
Example 2
1) Dissolving duck egg white in distilled water with the volume 10 times that of the duck egg white in a reaction bottle, adding dextran with the molecular weight of 50000 to enable the addition amount of the dextran to be 0.2 time of the mass of the duck egg white, adjusting the pH value of the solution to 8.0 by using a phosphate buffer solution, stirring for 2 hours at room temperature until the dextran is completely dissolved, placing the solution in a water bath with the temperature of 40 ℃ for reaction for 6 hours, cooling to room temperature after the reaction is finished, centrifuging at 6000rpm for 10 minutes to remove insoluble substances, taking supernatant, and dialyzing for 24 hours (the dialysis molecular weight is 10 +/-0.2 kDa) at the temperature of 4 ℃ to obtain a graft, namely a water phase;
2) dissolving the sulbactam amoxicillin amide compound in the soybean oil, and fully stirring to ensure that the concentration of the sulbactam amoxicillin amide compound is 100mg/ml, thereby obtaining an oil phase;
3) mixing the water phase obtained in the step 1) and the oil phase obtained in the step 2) according to a volume ratio of 20:1, and performing high-pressure homogenization to obtain the embedded sulbactam amoxicillin amide compound drug-protein compound-glucan nano emulsion, wherein the pressure of the high-pressure homogenization is 400bar, and the high-pressure homogenization time is 30 min.
Example 3
1) Dissolving duck egg white in distilled water with the volume 5 times that of the duck egg white in a reaction bottle, adding glucan with the molecular weight of 5000 into the reaction bottle to enable the addition amount of the glucan to be 0.1 time of the mass of the duck egg white, adjusting the pH value of the solution to 5.0 by using a phosphate buffer solution, stirring the solution at room temperature for 2 hours until the glucan is completely dissolved, placing the solution in a water bath with the temperature of 40 ℃ for reaction for 2 hours, cooling the solution to the room temperature after the reaction is finished, centrifuging the solution at 5000rpm for 20 minutes to remove insoluble substances, and dialyzing supernatant at the temperature of 4 ℃ for 24 hours (the dialysis molecular weight is 10 +/-0.2 kDa) to;
2) dissolving the sulbactam amoxicillin amide compound in the soybean oil, and fully stirring to ensure that the concentration of the sulbactam amoxicillin amide compound is 50mg/ml, thereby obtaining an oil phase;
3) mixing the water phase obtained in the step 1) and the oil phase obtained in the step 2) according to a volume ratio of 10:1, and performing high-pressure homogenization to obtain the embedded sulbactam amoxicillin amide compound drug-protein compound-glucan nano emulsion, wherein the pressure of the high-pressure homogenization is 300bar, and the time of the high-pressure homogenization is 20 min.
Example 4
1) Dissolving duck egg white in distilled water with the volume 5 times that of the duck egg white in a reaction bottle, adding glucan with the molecular weight of 30000 to enable the addition amount of the glucan to be 0.15 times of the mass of the duck egg white, adjusting the pH value of the solution to 7.0 by using a phosphate buffer solution, stirring the solution at room temperature for 2 hours until the glucan is completely dissolved, placing the solution in a water bath with the temperature of 40 ℃ for reaction for 1 hour, cooling the solution to the room temperature after the reaction is finished, centrifuging the solution at 4000rpm for 20 minutes to remove insoluble substances, and dialyzing supernatant liquid at the temperature of 4 ℃ for 24 hours (the dialysis molecular weight is 10 +/-0.2 kDa) to obtain a graft;
2) dissolving the sulbactam amoxicillin amide compound in the soybean oil, and fully stirring to ensure that the concentration of the sulbactam amoxicillin amide compound is 20mg/ml, thereby obtaining an oil phase;
3) mixing the water phase obtained in the step 1) and the oil phase obtained in the step 2) according to a volume ratio of 10:1, and performing high-pressure homogenization to obtain the embedded sulbactam amoxicillin amide compound drug-protein compound-glucan nano emulsion, wherein the pressure of the high-pressure homogenization is 400bar, and the time of the high-pressure homogenization is 15 min.
Example 5
1) Dissolving duck egg white in distilled water with the volume 5 times that of the duck egg white in a reaction bottle, adding glucan with the molecular weight of 40000 to enable the addition amount of the glucan to be 0.2 times of the mass of the duck egg white, adjusting the pH value of the solution to 6.0 by using a phosphate buffer solution, stirring for 2 hours at room temperature until the glucan is completely dissolved, placing the solution in a water bath with the temperature of 40 ℃ for reaction for 1 hour, cooling to the room temperature after the reaction is finished, centrifuging for 15 minutes at 4000rpm to remove insoluble substances, and dialyzing supernatant for 24 hours (the dialysis molecular weight is 10 +/-0.2 kDa) at the temperature of 4 ℃ to obtain a graft, namely a water phase;
2) dissolving the sulbactam amoxicillin amide compound in the soybean oil, and fully stirring to ensure that the concentration of the sulbactam amoxicillin amide compound is 50mg/ml, thereby obtaining an oil phase;
3) mixing the water phase obtained in the step 1) and the oil phase obtained in the step 2) according to a volume ratio of 15:1, and performing high-pressure homogenization to obtain the embedded sulbactam amoxicillin amide compound drug-protein compound-glucan nano emulsion, wherein the pressure of the high-pressure homogenization is 500bar, and the time of the high-pressure homogenization is 10 min.
Example 6
1) Dissolving duck egg white in distilled water with the volume 10 times that of the duck egg white in a reaction bottle, adding glucan with the molecular weight of 6000 to enable the addition amount of the glucan to be 0.05 times of the mass of the duck egg white, adjusting the pH value of the solution to 4.0 by using a phosphate buffer solution, stirring for 2 hours at room temperature until the glucan is completely dissolved, placing the solution in a water bath with the temperature of 40 ℃ for reaction for 2.5 hours, cooling to room temperature after the reaction is finished, centrifuging at 6000rpm for 10min to remove insoluble substances, taking supernatant, and dialyzing for 24 hours (the dialysis molecular weight is 10 +/-0.2 kDa) at the temperature of 4 ℃ to obtain a graft, namely a water phase;
2) dissolving the sulbactam amoxicillin amide compound in the soybean oil, and fully stirring to ensure that the concentration of the sulbactam amoxicillin amide compound is 50mg/ml, thereby obtaining an oil phase;
3) mixing the water phase obtained in the step 1) and the oil phase obtained in the step 2) according to a volume ratio of 10:1, and performing high-pressure homogenization to obtain the embedded sulbactam amoxicillin amide compound drug-protein compound-glucan nano emulsion, wherein the pressure of the high-pressure homogenization is 300bar, and the time of the high-pressure homogenization is 20 min.
Example 7
1) Dissolving duck egg white in distilled water with the volume 2 times that of the duck egg white in a reaction bottle, adding glucan with the molecular weight of 10000 to enable the addition amount of the glucan to be 0.2 time of the mass of the duck egg white, adjusting the pH of the solution to 4.0 by using a phosphate buffer solution, stirring the solution at room temperature for 2 hours until the glucan is completely dissolved, placing the solution in a water bath with the temperature of 40 ℃ for reaction for 5 hours, cooling the solution to the room temperature after the reaction is finished, centrifuging the solution at 6000rpm for 20 minutes to remove insoluble substances, and dialyzing supernatant at the temperature of 4 ℃ for 24 hours (the dialysis molecular weight is 10 +/-0.2 kDa) to obtain a graft, namely;
2) dissolving the sulbactam amoxicillin amide compound in the soybean oil, and fully stirring to ensure that the concentration of the sulbactam amoxicillin amide compound is 50mg/ml, thereby obtaining an oil phase;
3) mixing the water phase obtained in the step 1) and the oil phase obtained in the step 2) according to a volume ratio of 10:1, and performing high-pressure homogenization to obtain the embedded sulbactam amoxicillin amide compound drug-protein compound-glucan nano emulsion, wherein the pressure of the high-pressure homogenization is 300bar, and the time of the high-pressure homogenization is 20 min.
Example 8
1) Dissolving duck egg white in distilled water with the volume 5 times that of the duck egg white in a reaction bottle, adding glucan with the molecular weight of 25000 to enable the addition amount of the glucan to be 0.2 times of the mass of the duck egg white, adjusting the pH value of the solution to 5.0 by using a phosphate buffer solution, stirring the solution at room temperature for 2 hours until the glucan is completely dissolved, placing the solution in a water bath with the temperature of 40 ℃ for reaction for 5 hours, cooling the solution to the room temperature after the reaction is finished, centrifuging the solution at 4000rpm for 20 minutes to remove insoluble substances, and dialyzing supernatant liquid at the temperature of 4 ℃ for 24 hours (the dialysis molecular weight is 10 +/-0.2 kDa) to obtain a graft;
2) dissolving the sulbactam amoxicillin amide compound in the soybean oil, and fully stirring to ensure that the concentration of the sulbactam amoxicillin amide compound is 50mg/ml, thereby obtaining an oil phase;
3) mixing the water phase obtained in the step 1) and the oil phase obtained in the step 2) according to a volume ratio of 5:1, and performing high-pressure homogenization to obtain the embedded sulbactam amoxicillin amide compound drug-protein compound-glucan nano emulsion, wherein the pressure of the high-pressure homogenization is 300bar, and the time of the high-pressure homogenization is 30 min.
Example 9
1) Dissolving duck egg white in distilled water with the volume 2 times that of the duck egg white in a reaction bottle, adding glucan with the molecular weight of 10000 to enable the addition amount of the glucan to be 0.2 time of the mass of the duck egg white, adjusting the pH of the solution to 7.0 by using a phosphate buffer solution, stirring the solution at room temperature for 2 hours until the glucan is completely dissolved, placing the solution in a water bath with the temperature of 40 ℃ for reaction for 5 hours, cooling the solution to the room temperature after the reaction is finished, centrifuging the solution at 4000rpm for 15 minutes to remove insoluble substances, and dialyzing supernatant at the temperature of 4 ℃ for 24 hours (the dialysis molecular weight is 10 +/-0.2 kDa) to obtain a graft, namely;
2) dissolving the sulbactam amoxicillin amide compound in the soybean oil, and fully stirring to ensure that the concentration of the sulbactam amoxicillin amide compound is 50mg/ml, thereby obtaining an oil phase;
3) mixing the water phase obtained in the step 1) and the oil phase obtained in the step 2) according to a volume ratio of 10:1, and performing high-pressure homogenization to obtain the embedded sulbactam amoxicillin amide compound drug-protein compound-glucan nano emulsion, wherein the pressure of the high-pressure homogenization is 500bar, and the time of the high-pressure homogenization is 20 min.
The particle size of the sulbactam amoxicillin amide compound drug-protein compound-glucan nanometer aqueous emulsion prepared in example 1 is detected by a laser particle sizer, and the result is shown in figure 1. As can be seen from the figure, the particle size of the sulbactam amoxicillin amide compound drug-protein compound-glucan nano-water emulsion prepared by the invention is about 237.7 +/-9.31 nm, and the emulsion can achieve the purpose of sterilization through a 450nm filter membrane.
The particle size and drug loading rate of the sulbactam amoxicillin amide complex drug-protein complex-glucan nano-water emulsion prepared in example 1-9 are measured at different time periods, and the results are shown in table 1.
TABLE 1
As can be seen from the table 1, the drug-loading rate of the nano emulsion prepared by the method has no significant change to the sulbactam amoxicillin amide compound drug in different time periods, which shows that the nano emulsion has good embedding effect, no agglomeration or aggregation phenomenon in 12 months, and good stability; the particles are uniform and stable, and do not agglomerate in aqueous solution, which shows that the prepared nano emulsion has good water solubility, smaller particle size and easy absorption.
The above description is only exemplary of the present invention and should not be taken as limiting, and any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. A preparation method of an embedded sulbactam amoxicillin amide compound is characterized by comprising the following steps:
1) dissolving duck egg white in water, adding glucan to obtain a mixed solution, adjusting the pH of the mixed solution to 4-8, stirring at room temperature for 1-2 h until the mixed solution is completely dissolved, placing the mixed solution in a water bath at 50 ℃ for reaction for 1-6 h, cooling to room temperature after the reaction is finished, centrifuging to obtain a supernatant, and dialyzing to obtain a water phase; the duck egg white, water and glucan are 1: 2-10: 0.05 to 0.2;
2) dissolving the sulbactam amoxicillin amide compound in the soybean oil, and fully stirring to obtain an oil phase;
3) mixing the water phase obtained in the step 1) and the oil phase obtained in the step 2), and carrying out high-pressure homogenization to obtain the sulbactam amoxicillin amide compound embedded nano emulsion.
2. The method for preparing the embedded sulbactam amoxicillin amide compound as claimed in claim 1, wherein the molecular weight of the glucan is 5000-50000.
3. The method for preparing the embedded sulbactam amoxicillin amide compound as claimed in claim 1, wherein the concentration of the sulbactam amoxicillin amide compound in the step 2) dissolved in the soybean oil is 5-100 mg/ml.
4. The preparation method of the embedded sulbactam amoxicillin amide compound as claimed in claim 1, wherein the mixing volume ratio of the water phase and the oil phase is 1: 5-20.
5. The method for preparing the embedded sulbactam amoxicillin amide compound as claimed in claim 1, wherein the high pressure homogenization pressure is 300-500 bar, and the high pressure homogenization time is 10-30 min.
6. The method for preparing the embedded sulbactam amoxicillin amide compound as claimed in claim 1, wherein the centrifugation speed is 4000-6000 rpm, and the centrifugation time is 10-20 min.
7. The method for preparing the embedded sulbactam amoxicillin amide complex as claimed in claim 1, wherein the dialyzed molecular weight is 10 ± 0.2 kDa.
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| JPH08104620A (en) * | 1994-10-05 | 1996-04-23 | Green Cross Corp:The | Fat emulsion containing medicine |
| GB0503684D0 (en) * | 2005-02-23 | 2005-03-30 | Ici Plc | Emulsifiers and emulsions |
| CN102302450B (en) * | 2011-09-06 | 2013-02-27 | 复旦大学 | Hydrophobic drug-albumin-glucan nano emulsion, as well as preparation method and application thereof |
| CN102786536B (en) * | 2012-08-16 | 2014-08-20 | 重庆大学 | Sulbactam amoxicillin amide complex for treatment of acute bacterial infection of pig and synthesis method |
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2019
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