CN113861330A - Method for synthesizing carbomer applied to animal vaccine adjuvant - Google Patents
Method for synthesizing carbomer applied to animal vaccine adjuvant Download PDFInfo
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
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- A61K2039/552—Veterinary vaccine
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
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Abstract
The invention discloses a method for synthesizing carbomer serving as an animal vaccine adjuvant, which is characterized in that allyl sucrose ether is used as a cross-linking agent, an applicable initiator is selected, supercritical carbon dioxide is used, an acrylic monomer is used for synthesizing carbomer polymer in a proper solvent system, the reaction temperature is selected to be 31.5-60 ℃, and the reaction pressure is selected to be 7.2-30 MPa. The method provided by the invention is simple and feasible, the system reaction is complete, the reaction is stable, the prepared carbomer is high in purity, uniform in polymerization degree distribution and good in safety, and the prepared carbomer has good adjuvant performance.
Description
Technical Field
The invention relates to a method for synthesizing carbomer for an animal vaccine adjuvant, in particular to a method for synthesizing carbomer polymer by a precipitation method under a supercritical carbon dioxide system.
Background
Carbomer is also called carbopol, and is also called carboxyvinyl copolymer, is a high molecular polymer obtained by chemically crosslinking an acrylic acid monomer and a crosslinking agent such as pentaerythritol allyl ether, sucrose allyl ether and the like, has the physical characteristics of white and loose powder and slightly special odor powder, has stronger hygroscopicity, is soluble in water, ethanol, glycerin and the like, has the characteristics of good gelling property, adhesiveness, thickening property, emulsifying property, suspending property, film forming property and the like, has stable and safe chemical properties, and has no irritation and allergy, and is widely used for thickening, stabilizing, slowly releasing or controlling release of daily chemical products and medicaments. The existing method for synthesizing carbomer is mainly obtained by polymerizing acrylic monomers and a cross-linking agent in a solution in the presence of an initiator. For example, in patent CN103755861A, an aqueous solution of tert-butanol is used as an aqueous phase reaction system, one of glucose acrylate, glycerol acrylate, 2, 9-decadiene or 2-hexadecenoic acid is used as a cross-linking agent, and one of persulfate or hydrogen peroxide is used as an initiator, and carbomer is synthesized under the condition of nitrogen protection and at a temperature of less than 65 ℃; in patent CN104761673A, sucrose diacrylate is used as a cross-linking agent, dodecanol acrylate monomer is added to copolymerize with acrylic acid, one of azobisisobutyronitrile, azobisisoheptonitrile and benzoyl peroxide is used as an initiator, and carbomer is prepared by polymerization at 45-70 ℃ under the protection of nitrogen.
The supercritical carbon dioxide is carbon dioxide with the critical temperature and pressure (Tc is 31.06 ℃, Pc is 7.39MPa) above, has the advantages of strong dissolving capacity, adjustable dissolving capacity, strong swelling capacity, diffusion capacity and permeability, high heat and mass transfer rate, capability of controlling the speed, reaction temperature and pressure of certain reactions, easy recycling, no solvent residue and the like. The polymerization reaction carried out in the supercritical carbon dioxide can overcome the defects of the conventional synthesis method to a certain extent, the proportion of reaction monomers can be regulated and controlled according to needs, the mixing at the molecular level is achieved, more excellent polymerization performance is exerted, less additives are added in the polymerization process, the product performance is not influenced, the product is directly separated from a medium phase in the reaction, the reaction temperature and the reaction pressure are moderate, the polymerization reaction process is simple, the product is easy to separate and purify, and the like, and the method has unique advantages of important practical application significance for the synthesis and production of polymers.
Disclosure of Invention
The invention aims to solve the technical problem of providing a high-efficiency vaccine adjuvant material which is prepared by using carbon dioxide as a gas medium in the synthesis of a carbomer polymer, particularly under the condition of supercritical carbon dioxide. The existing carbomer synthesis method adopts the condition of higher temperature for polymerization under the protection of nitrogen, the molecular weight of a product during the polymerization reaction is reduced along with the increase of the polymerization temperature and the reduction of the concentration of a monomer and an initiator, so that the carbomer with high uniformity and polymerization degree is difficult to obtain, and meanwhile, nitrogen is only used as a means for isolating oxygen and does not participate in the control of the polymerization reaction process. The carbomer polymerization reaction is carried out under the supercritical carbon dioxide condition, the carbon dioxide is not only a means of isolating oxygen, but also a control condition of the polymerization reaction, the initiator in the system can accelerate the decomposition, the reaction activation energy is reduced, a considerable amount of active free radicals can be quickly generated at low temperature, the reaction induction period is short, the polymerization reaction can be carried out at lower reaction temperature, meanwhile, the polymerization reaction can be stable and the conversion rate is improved by adjusting the reaction pressure and temperature of the system under the supercritical condition. The stability of a carbomer synthesis reaction system is enhanced, the controllability of the molecular weight distribution of the produced carbomer polymer is improved, the uniformity is better, and the carbomer polymer has higher adjuvant performance.
In order to achieve the technical aim, the method for preparing the carbomer comprises the steps of uniformly mixing a cross-linking agent of allyl sucrose ether, an acrylic acid monomer, an initiator and a solvent, and carrying out cross-linking polymerization reaction under the condition of supercritical carbon dioxide to obtain the carbomer polymer.
The method of the invention uses carbon dioxide as a reaction control factor and inert gas for isolating oxygen, selects a proper initiator at a lower temperature by using allyl sucrose ether and acrylic acid monomer above the critical temperature and pressure of the carbon dioxide, and adopts an environment-friendly ethyl acetate, cyclohexane and deionized water solvent system to react for cross-linking polymerization to obtain the carbomer polymer. The reaction process is controlled by utilizing the characteristic of the supercritical carbon dioxide to prepare a reaction product suitable for the vaccine adjuvant.
In the process of preparing the carbomer for the adjuvant, a byproduct safe initiator and solvent system is selected, so the invention also relates to the selection of the initiator and solvent system for synthesizing the carbomer for the adjuvant under the condition of supercritical carbon dioxide.
The initiators selected during the carbomer polymerization may be peroxides, azo and redox initiators.
The peroxide initiator may be organic peroxide, such as benzoyl peroxide, lauroyl peroxide, tert-butyl hydroperoxide, methyl ethyl ketone peroxide, tert-butyl peroxybenzoate, cyclohexanone peroxide sulfate, diisopropyl peroxydicarbonate, etc., or inorganic peroxide, such as one or more of hydrogen peroxide, potassium persulfate, sodium persulfate, and ammonium persulfate.
The azo initiator may be azobisisobutyronitrile, azobisisoheptonitrile, dimethyl azobisisobutyrate, azobisisobutylamidine hydrochloride, or the like. The initiation effect of the peroxide initiator and the azo initiator is generally applicable at a higher temperature, such as 50-90 ℃, and the application of the initiators in low-temperature polymerization is limited, but in a supercritical carbon dioxide system, the reaction activation energy is reduced, and active free radicals of the initiators can be generated in a considerable amount at a lower temperature, so that the polymerization can be carried out at a lower reaction temperature, and the applicable temperature range of the initiators is expanded.
The polymerization reaction can be carried out at a low temperature by using a redox initiator under supercritical carbon dioxide conditions (31.06 ℃ or higher). The oxidant which can be used as initiator of redox system can be hydrogen peroxide, hydroperoxide, persulfate, dialkyl peroxide, diacyl peroxide, etc., the reducer can be ferrous sulfate, sodium sulfite and amine, arylamine, oxalic acid, sugar, mercaptan, naphthenate, etc., and can be proportioned to make it into the invented product Benzoyl peroxide/ferrous pyrophosphate, persulfate/mercaptan, cumene hydroperoxide/ferrous chloride, potassium persulfate/ferrous chloride, hydroxydiisopropylbenzene peroxide (CHPO)/Tetraethylenepentamine (TEPA), and the like.
In the present invention, as the initiator, azobisisobutyronitrile among azo-based ones, azobisisobutylamidine hydrochloride, ammonium persulfate among peroxide-based ones, redox-based N, N-diethylhydroxylamine/sodium persulfate, iron persulfate/sodium bisulfite, ammonium persulfate/N, N-Diethylhydroxylamine (DEHA), potassium persulfate/potassium sulfite/thiourea dioxide, hydroxydiisopropylbenzene peroxide (CHPO) and/Tetraethylenepentamine (TEPA) are preferably used.
More preferably, the initiator is azobisisobutylamidine hydrochloride, ammonium persulfate/N, N-Diethylhydroxylamine (DEHA), N, N-diethylhydroxylamine/sodium persulfate, potassium persulfate/potassium sulfite/thiourea dioxide, iron persulfate/sodium bisulfite, hydroxydiisopropylbenzene peroxide (CHPO)/Tetraethylenepentamine (TEPA).
In the method for synthesizing carbomer, the solvent can be one or a combination of more of benzene, cyclohexane, ethyl acetate, deionized water and the like, and in the invention, the solvent is preferably one or more of ethyl acetate, deionized water and cyclohexane.
The technical scheme of the invention is as follows:
a method for synthesizing carbomer polymer for an animal vaccine adjuvant comprises the following steps:
adding the cross-linking agent allyl sucrose ether, an acrylic acid monomer, a solvent, an initiator and the like into a reaction kettle, sealing, introducing carbon dioxide to discharge air in the reaction kettle so as to ensure that the reaction is carried out in an oxygen-free environment, heating to a required reaction temperature, controlling the temperature in the reaction kettle and the pressure of the carbon dioxide within a supercritical range, controlling the stirring rate, controlling the reaction temperature, the pressure and the reaction time until the reaction is finished, and cooling the reaction kettle to room temperature after the reaction is finished; and opening an air outlet valve of the reaction kettle, reducing the pressure to normal pressure, taking out the product, filtering, washing, vacuum drying and storing.
In the method for synthesizing carbomer, the acrylic acid monomer accounts for 40-100% (excluding 100%) of the cross-linking agent allyl sucrose ether and the acrylic acid in terms of mole percentage of the two monomers. Preferably 60-100% (excluding 100%).
In the method for synthesizing carbomer, the initiator can be one or a combination of more of the azo compound, peroxide, persulfate, oxidation-reduction initiator and the like, and in the invention, initiators such as azodiisobutyl amidine hydrochloride, ammonium persulfate, N, N-Diethylhydroxylamine (DEHA)/sodium persulfate, sodium persulfate-sodium sulfite-formamidine (thiourea dioxide) and the like are preferably used, and the amount of the initiators is 0.5 to 15 percent of the weight of acrylic acid monomer.
In the method for synthesizing carbomer, the solvent can be one or a combination of benzene, cyclohexane, ethyl acetate, water and the like, in the invention, the combination of the solvents such as ethyl acetate, cyclohexane, deionized water and the like is preferably adopted, and the dosage is 100-800% of the weight of the acrylic monomer, preferably 400-700%.
According to the method for synthesizing carbomer, the pressure in the reaction kettle is 7.2-30 MPa.
According to the method for synthesizing carbomer, the reaction temperature is controlled to be 31.06-60 ℃.
The synthesis method of the carbomer has the reaction time of 1-24 hours.
The carbomer prepared by the method also belongs to the protection scope of the invention
Due to the adoption of the technical scheme, the invention has the advantages that: carbon dioxide is used for replacing nitrogen used in the existing method, the temperature and the pressure of the carbon dioxide are easy to reach the critical temperature and the critical pressure in industrial production, and meanwhile, the carbon dioxide has the advantages of incombustibility, no toxicity, good chemical stability, low price, easy obtainment and the like; in a supercritical carbon dioxide system, the reaction activation energy is reduced, and the active free radicals of the initiator can generate a considerable amount at a lower temperature, so that the polymerization reaction can be carried out at a lower reaction temperature; the polymerization process can be controlled by adjusting the system reaction pressure and temperature, so that the polymerization reaction is stable, the conversion rate is improved, the stability of a carbomer synthesis reaction system is enhanced, the synthesized carbomer has better uniformity and higher adjuvant performance; meanwhile, a byproduct safe initiator and an environment-friendly solvent system are selected in the preparation process, so that the preparation method is suitable for the production of the pharmaceutical grade carbomer.
The carbomer polymer provided by the invention is particularly suitable for poultry vaccines, livestock vaccines and pet vaccines.
The vaccine for poultry includes, but is not limited to, avian influenza vaccine, inactivated newcastle disease vaccine, infectious bursal disease vaccine, inactivated egg drop syndrome vaccine, infectious bronchitis vaccine, avian mycoplasmosis vaccine, and the like or combined vaccine of the vaccines.
The livestock vaccines include, but are not limited to, foot-and-mouth disease vaccines, pasteurella vaccines, streptococcus vaccines, brucella vaccines, peste des petits ruminants vaccines, porcine circovirus vaccines, porcine pseudorabies inactivated vaccines, swine fever vaccines, porcine reproductive and respiratory syndrome inactivated vaccines, porcine erysipelas vaccines, porcine parvovirus vaccines, porcine mycoplasmal pneumonia vaccines, porcine infectious atrophic rhinitis vaccines, bovine infectious pleuropneumonia vaccines, capripox vaccines and the like or vaccines of combination of the vaccines.
The pet vaccine includes but is not limited to rabies vaccine, canine distemper vaccine, canine infectious hepatitis vaccine, feline panleukopenia vaccine and the like or combined vaccine of the vaccines
The vaccine prepared based on the carbomer has the advantages of stability, safety and high efficiency.
Detailed Description
In order to make the present invention more easily understood, the present invention will be further described by combining examples and comparative examples, wherein the examples are implemented on the premise of the technical scheme of the present invention, and detailed implementation modes and specific operation processes are given, but the protection scope of the present invention is not limited by the following examples, and the corresponding proportions provided by the present invention can be achieved under the condition of the conventional production method. The starting materials used in the present invention may be obtained from commercial sources or conventional methods unless otherwise specified.
Example (b):
example 1 preparation of carbomer in supercritical carbon dioxide
In this example, the mole percentage of monomer acrylic acid in the total amount of the acrylic acid monomer in the cross-linking agent allyl sucrose ether and the acrylic acid monomer is 99.8% or more, the initiator is azobisisobutylamidine hydrochloride in an amount of 2% by weight of the acrylic acid monomer, the solvent is ethyl acetate and deionized water in a weight ratio of 2:3, and the solvent is 625% by weight of the acrylic acid monomer.
The method for preparing carbomer in supercritical carbon dioxide comprises the following steps:
40g (0.555mol) of monomer acrylic acid, 0.4g (0.001mol) of cross-linking agent allyl sucrose ether, 0.8g of initiator azobisisobutylamidine hydrochloride, 100g of solvent ethyl acetate and 150g of deionized water are respectively added into a reaction kettle and sealed. Introducing carbon dioxide for 10 minutes to discharge air in the reaction kettle, heating to the reaction temperature of 35 ℃, controlling the pressure of the carbon dioxide in the reaction kettle to reach 8MPa, starting the stirrer at the moment, and finishing the reaction after reacting for 12 hours. And cooling the reaction kettle to room temperature, opening an air outlet valve of the reaction kettle, reducing the pressure to normal pressure, and storing the obtained product which is a white product carbomer after filtering, washing and vacuum drying treatment.
The identification method for the synthetic product of carbomer comprises the following steps: dispersing 0.1g of the product in 10ml of water, stirring to dissolve it uniformly, dividing into two parts, adding 5 drops of thymol blue test solution (0.1 g of thymol blue is taken, 100ml of ethanol is added to dissolve it) into one part, and making the solution appear orange; and adding cresol red test solution (0.1 g of cresol red is put into a mortar, 26ml of 0.01mol/L sodium hydroxide solution is added into the mortar, and the mixture is ground and diluted to 250ml with water) into the other part, wherein 5 drops of the cresol red test solution are yellow.
The carbomer quality is determined according to potentiometric titration method in Chinese pharmacopoeia, and the carbomer has a carboxyl (-COOH) content of 62.3% and a pH value of 2.9.
Example 2 preparation of carbomer in supercritical carbon dioxide
In the embodiment, the mole percentage of monomer acrylic acid in the total amount of the acrylic monomer in the cross-linking agent allyl sucrose ether and the acrylic monomer is more than 99.8%, the initiator is ammonium persulfate, the amount of the initiator is 1.67% of the weight of the acrylic monomer, the solvent is ethyl acetate and deionized water, the weight ratio of the initiator to the acrylic monomer is 3:2, and the amount of the solvent is 416% of the weight of the acrylic monomer
The method for preparing carbomer in supercritical carbon dioxide comprises the following steps:
adding 40g (0.555mol) of monomer acrylic acid, 0.4g (0.001mol) of cross-linking agent allyl sucrose ether, 1.0g of initiator ammonium persulfate, 150g of solvent ethyl acetate and 100g of deionized water into a reaction kettle respectively, and sealing. And introducing carbon dioxide for 10 minutes to discharge air in the reaction kettle, heating to 60 ℃, controlling the pressure of the carbon dioxide in the reaction kettle to reach the required pressure of 10MPa, starting a stirrer at the moment, and finishing the reaction after reacting for 12 hours. Cooling the reaction kettle to room temperature, opening an air outlet valve of the reaction kettle, and reducing the pressure to normal pressure. The obtained product is a white product carbomer, and is stored after being filtered, washed, dried in vacuum.
The identification method for the synthetic product of carbomer comprises the following steps: dispersing 0.1g of the product in 10ml of water, stirring to dissolve it uniformly, dividing into two parts, adding 5 drops of thymol blue test solution (0.1 g of thymol blue is taken, 100ml of ethanol is added to dissolve it) into one part, and making the solution appear orange; and adding cresol red test solution (0.1 g of cresol red is put into a mortar, 26ml of 0.01mol/L sodium hydroxide solution is added into the mortar, and the mixture is ground and diluted to 250ml with water) into the other part, wherein 5 drops of the cresol red test solution are yellow.
The carbomer quality is determined according to potentiometric titration method in Chinese pharmacopoeia, the carboxyl (-COOH) content is determined to be 64.1%, and the pH value is 2.8.
Example 3 preparation of carbomer in supercritical carbon dioxide
In this example, the mole percentage of monomer acrylic acid in the total amount of the acrylic acid monomer in the cross-linking agent allyl sucrose ether and the acrylic acid monomer is 99.8% or more, the initiator is N, N-Diethylhydroxylamine (DEHA)/sodium persulfate in an amount of 1% by weight of the acrylic acid monomer, the solvent is ethyl acetate and deionized water in a weight ratio of 2:3, and the solvent is 625% by weight of the acrylic acid monomer
The method for preparing carbomer in supercritical carbon dioxide comprises the following steps:
adding 40g (0.555mol) of monomer acrylic acid, 0.4g (0.001mol) of cross-linking agent allyl sucrose ether, 0.4g of initiator N, N-Diethylhydroxylamine (DEHA)/sodium persulfate, 100g of solvent ethyl acetate and 150g of deionized water into a reaction kettle respectively, and sealing. And introducing carbon dioxide for 10 minutes to discharge air in the reaction kettle, heating to the reaction temperature of 40 ℃, controlling the pressure of the carbon dioxide in the reaction kettle to reach the required pressure of 8MPa, starting a stirrer at the moment, and finishing the reaction after reacting for 6 hours. Cooling the reaction kettle to room temperature, opening an air outlet valve of the reaction kettle, and reducing the pressure to normal pressure. The obtained product is a white product carbomer, and is stored after being filtered, washed, dried in vacuum.
The identification method for the synthetic product of carbomer comprises the following steps: dispersing 0.1g of the product in 10ml of water, stirring to dissolve it uniformly, dividing into two parts, adding 5 drops of thymol blue test solution (0.1 g of thymol blue is taken, 100ml of ethanol is added to dissolve it) into one part, and making the solution appear orange; and adding cresol red test solution (0.1 g of cresol red is put into a mortar, 26ml of 0.01mol/L sodium hydroxide solution is added into the mortar, and the mixture is ground and diluted to 250ml with water) into the other part, wherein 5 drops of the cresol red test solution are yellow.
The carbomer quality is determined according to potentiometric titration method in Chinese pharmacopoeia, and the carbomer has a carboxyl (-COOH) content of 62.9% and a pH value of 2.9.
Example 4 preparation of carbomer in supercritical carbon dioxide
In this example, the mole percentage of monomer acrylic acid in the total amount of the acrylic acid monomer in the cross-linking agent allyl sucrose ether and the acrylic acid monomer is more than 99.8%, the initiator is sodium sulfate-sodium sulfite-thiourea dioxide, the amount of the initiator is 1% of the weight of the acrylic acid monomer, the solvent is ethyl acetate and deionized water, the weight ratio of the initiator to the acrylic acid monomer is 2:3, and the amount of the solvent is 416% of the weight of the acrylic acid monomer
The method for preparing carbomer in supercritical carbon dioxide comprises the following steps:
adding 60g (0.833mol) of monomer acrylic acid, 0.4g (0.001mol) of cross-linking agent allyl sucrose ether, 0.6g of initiator sodium persulfate/sodium sulfite/thiourea dioxide (the weight ratio of the three is 1:1: 4), 100g of solvent ethyl acetate and 150g of deionized water into a reaction kettle respectively, and sealing. And introducing carbon dioxide for 10 minutes to discharge air in the reaction kettle, heating to the reaction temperature of 40 ℃, controlling the pressure of the carbon dioxide in the reaction kettle to reach the required pressure of 20MPa, starting a stirrer at the moment, and finishing the reaction after reacting for 6 hours. Cooling the reaction kettle to room temperature, opening an air outlet valve of the reaction kettle, and reducing the pressure to normal pressure. The obtained product is a white product carbomer, and is stored after being filtered, washed, dried in vacuum.
The identification method for the synthetic product of carbomer comprises the following steps: dispersing 0.1g of the product in 10ml of water, stirring to dissolve it uniformly, dividing into two parts, adding 5 drops of thymol blue test solution (0.1 g of thymol blue is taken, 100ml of ethanol is added to dissolve it) into one part, and making the solution appear orange; and adding cresol red test solution (0.1 g of cresol red is put into a mortar, 26ml of 0.01mol/L sodium hydroxide solution is added into the mortar, and the mixture is ground and diluted to 250ml with water) into the other part, wherein 5 drops of the cresol red test solution are yellow.
The carbomer quality is determined according to a potentiometric titration method in Chinese pharmacopoeia, and the carbomer has a carboxyl (-COOH) content of 65.7 percent and a pH value of 3.1.
Example 5 preparation of carbomer in supercritical carbon dioxide
In the embodiment, the mole percentage of monomer acrylic acid in the total amount of the acrylic monomer in the cross-linking agent allyl sucrose ether and the acrylic monomer is more than 99.8%, the initiator is azobisisobutylamidine hydrochloride, the amount of the initiator is 1% of the weight of the acrylic monomer, the solvent is ethyl acetate and deionized water, the weight ratio of the ethyl acetate to the deionized water is 2:3, and the amount of the solvent is 416% of the weight of the acrylic monomer
The method of preparing carbomer of this example comprises the steps of:
monomer acrylic acid 40g (0.555mol), cross-linking agent allyl sucrose ether 0.4g (0.001mol), initiator azobisisobutylamidine hydrochloride 0.8g, solvent ethyl acetate 65g, cyclohexane 195g are added into the reaction kettle respectively and sealed. And introducing carbon dioxide for 10 minutes to discharge air in the reaction kettle, heating to the reaction temperature of 35 ℃, controlling the pressure of the carbon dioxide in the reaction kettle to reach the required pressure of 20MPa, starting a stirrer at the moment, and finishing the reaction after reacting for 6 hours. Cooling the reaction kettle to room temperature, opening an air outlet valve of the reaction kettle, and reducing the pressure to normal pressure. The obtained product is a white product carbomer, and is stored after being filtered, washed, dried in vacuum.
The identification method for the synthetic product of carbomer comprises the following steps: dispersing 0.1g of the product in 10ml of water, stirring to dissolve it uniformly, dividing into two parts, adding 5 drops of thymol blue test solution (0.1 g of thymol blue is taken, 100ml of ethanol is added to dissolve it) into one part, and making the solution appear orange; and adding cresol red test solution (0.1 g of cresol red is put into a mortar, 26ml of 0.01mol/L sodium hydroxide solution is added into the mortar, and the mixture is ground and diluted to 250ml with water) into the other part, wherein 5 drops of the cresol red test solution are yellow.
The carbomer quality is determined according to potentiometric titration method in Chinese pharmacopoeia, and the carbomer has a carboxyl (-COOH) content of 62.7% and a pH value of 3.0.
Example 6 preparation of carbomer in supercritical carbon dioxide
In this example, the mole percentage of monomer acrylic acid in the total amount of the acrylic monomer in the cross-linking agent allyl sucrose ether and the acrylic monomer is 99.8% or more, the initiator is ferric persulfate/sodium bisulfite, the amount of the initiator is 15% of the weight of the acrylic monomer, the solvent is ethyl acetate and deionized water, the weight ratio of the initiator to the solvent is 3:2, and the amount of the solvent is 625% of the weight of the acrylic monomer.
The method of preparing carbomer of this example comprises the steps of:
40g (0.555mol) of monomer acrylic acid, 0.4g (0.001mol) of cross-linking agent allyl sucrose ether, 6g of initiator ferric persulfate/sodium bisulfite, 150g of solvent ethyl acetate and 100g of deionized water are respectively added into a reaction kettle and sealed. And introducing carbon dioxide for 10 minutes to discharge air in the reaction kettle, heating to 60 ℃, controlling the pressure of the carbon dioxide in the reaction kettle to reach the required pressure of 30MPa, starting a stirrer at the moment, and finishing the reaction after reacting for 1 hour. Cooling the reaction kettle to room temperature, opening an air outlet valve of the reaction kettle, and reducing the pressure to normal pressure. The obtained product is a white product carbomer, and is stored after being filtered, washed, dried in vacuum.
The identification method for the synthetic product of carbomer comprises the following steps: dispersing 0.1g of the product in 10ml of water, stirring to dissolve it uniformly, dividing into two parts, adding 5 drops of thymol blue test solution (0.1 g of thymol blue is taken, 100ml of ethanol is added to dissolve it) into one part, and making the solution appear orange; and adding cresol red test solution (0.1 g of cresol red is put into a mortar, 26ml of 0.01mol/L sodium hydroxide solution is added into the mortar, and the mixture is ground and diluted to 250ml with water) into the other part, wherein 5 drops of the cresol red test solution are yellow.
The carbomer quality is determined according to potentiometric titration method in Chinese pharmacopoeia, and the carbomer has a carboxyl (-COOH) content of 59.7% and a pH value of 2.8.
Example 7 preparation of carbomer in supercritical carbon dioxide
In this embodiment, the mole percentage of the monomer acrylic acid in the total amount of the acrylic acid monomer in the cross-linking agent allyl sucrose ether and the acrylic acid monomer is more than 40%, the initiator is dicumyl peroxide/tetraethylenepentamine, the amount of the initiator is 0.5% of the weight of the acrylic acid monomer, the solvent is deionized water, and the amount of the solvent is 100% of the weight of the acrylic acid monomer.
The method of preparing carbomer of this example comprises the steps of:
20g (0.277mol) of monomer acrylic acid, 160g (0.4mol) of cross-linking agent allyl sucrose ether, 0.1g of initiator azo-diisobutyl amidine hydrochloride and 10g of solvent deionized water are respectively added into a reaction kettle and sealed. And introducing carbon dioxide for 10 minutes to discharge air in the reaction kettle, heating to the reaction temperature of 50 ℃, controlling the pressure of the carbon dioxide in the reaction kettle to reach the required pressure of 10MPa, starting a stirrer at the moment, and finishing the reaction after reacting for 24 hours. Cooling the reaction kettle to room temperature, opening an air outlet valve of the reaction kettle, and reducing the pressure to normal pressure. The obtained product is a white product carbomer, and is stored after being filtered, washed, dried in vacuum.
The identification method for the synthetic product of carbomer comprises the following steps: dispersing 0.1g of the product in 10ml of water, stirring to dissolve it uniformly, dividing into two parts, adding 5 drops of thymol blue test solution (0.1 g of thymol blue is taken, 100ml of ethanol is added to dissolve it) into one part, and making the solution appear orange; and adding cresol red test solution (0.1 g of cresol red is put into a mortar, 26ml of 0.01mol/L sodium hydroxide solution is added into the mortar, and the mixture is ground and diluted to 250ml with water) into the other part, wherein 5 drops of the cresol red test solution are yellow.
The carbomer quality is determined according to potentiometric titration method in Chinese pharmacopoeia, and the carbomer has a carboxyl (-COOH) content of 57.1% and a pH value of 3.3.
Example 8 preparation of carbomer in supercritical carbon dioxide
In this example, the mole percentage of monomer acrylic acid in the total amount of the acrylic monomer in the cross-linking agent allyl sucrose ether and the acrylic monomer is 73% or more, the initiator is azobisisobutylamidine hydrochloride and ammonium persulfate, the amount of the initiator is 10% of the weight of the acrylic monomer, the solvent is ethyl acetate, deionized water and cyclohexane, the weight ratio of the three is 1:1:2, and the amount of the solvent is 400% of the weight of the acrylic monomer.
The method of preparing carbomer of this example comprises the steps of:
adding 40g (0.277mol) of monomer acrylic acid, 40g (0.1mol) of cross-linking agent allyl sucrose ether, 2g of initiator azobisisobutylamidine hydrochloride, 2g of ammonium persulfate, 40g of solvent ethyl acetate, 40g of deionized water and 80g of cyclohexane into a reaction kettle respectively, and sealing. And introducing carbon dioxide for 10 minutes to discharge air in the reaction kettle, heating to the reaction temperature of 50 ℃, controlling the pressure of the carbon dioxide in the reaction kettle to reach the required pressure of 7.2MPa, starting the stirrer at the moment, and finishing the reaction after reacting for 6 hours. Cooling the reaction kettle to room temperature, opening an air outlet valve of the reaction kettle, and reducing the pressure to normal pressure. The obtained product is a white product carbomer, and is stored after being filtered, washed, dried in vacuum.
The identification method for the synthetic product of carbomer comprises the following steps: dispersing 0.1g of the product in 10ml of water, stirring to dissolve it uniformly, dividing into two parts, adding 5 drops of thymol blue test solution (0.1 g of thymol blue is taken, 100ml of ethanol is added to dissolve it) into one part, and making the solution appear orange; and adding cresol red test solution (0.1 g of cresol red is put into a mortar, 26ml of 0.01mol/L sodium hydroxide solution is added into the mortar, and the mixture is ground and diluted to 250ml with water) into the other part, wherein 5 drops of the cresol red test solution are yellow.
The carbomer quality is determined according to a potentiometric titration method in Chinese pharmacopoeia, and the carbomer has a carboxyl (-COOH) content of 58.9 percent and a pH value of 3.2.
Example 9 preparation of carbomer in supercritical carbon dioxide
In the embodiment, the mole percentage of monomer acrylic acid in the total amount of the acrylic monomer in the cross-linking agent allyl sucrose ether and the acrylic monomer is more than 99.2%, the initiator is azobisisobutylamidine hydrochloride, the amount of the initiator is 10% of the weight of the acrylic monomer, the solvent is ethyl acetate and cyclohexane, the weight ratio of the ethyl acetate to the cyclohexane is 3:4, and the amount of the solvent is 700% of the weight of the acrylic monomer.
The method of preparing carbomer of this example comprises the steps of:
monomer acrylic acid 40g (0.277mol), cross-linking agent allyl sucrose ether 0.8g (0.002mol), initiator azobisisobutylamidine hydrochloride and N, N-diethylhydroxylamine/sodium persulfate 2g, solvent ethyl acetate 120g, cyclohexane 160g were added to the reaction kettle, and the kettle was sealed. And introducing carbon dioxide for 10 minutes to discharge air in the reaction kettle, heating to the reaction temperature of 31.06 ℃, controlling the pressure of the carbon dioxide in the reaction kettle to reach the required pressure of 7.2MPa, starting the stirrer at the moment, and reacting for 24 hours to finish the reaction. Cooling the reaction kettle to room temperature, opening an air outlet valve of the reaction kettle, and reducing the pressure to normal pressure. The obtained product is a white product carbomer, and is stored after being filtered, washed, dried in vacuum.
The identification method for the synthetic product of carbomer comprises the following steps: dispersing 0.1g of the product in 10ml of water, stirring to dissolve it uniformly, dividing into two parts, adding 5 drops of thymol blue test solution (0.1 g of thymol blue is taken, 100ml of ethanol is added to dissolve it) into one part, and making the solution appear orange; and adding cresol red test solution (0.1 g of cresol red is put into a mortar, 26ml of 0.01mol/L sodium hydroxide solution is added into the mortar, and the mixture is ground and diluted to 250ml with water) into the other part, wherein 5 drops of the cresol red test solution are yellow.
The carbomer quality is determined according to potentiometric titration method in Chinese pharmacopoeia, and the carbomer has a carboxyl (-COOH) content of 59.6% and a pH value of 3.1.
Comparative example: comparative example 1 this comparative example provides a method for preparing carbomer under nitrogen protection conditions comprising the steps of:
40g of monomer acrylic acid, 0.4g of cross-linking agent allyl sucrose ether, 0.8g of initiator azobisisobutyronitrile, 65g of solvent ethyl acetate and 195g of cyclohexane are respectively added into a reaction kettle and sealed. And introducing nitrogen for 10 minutes to discharge the air in the reaction kettle, heating to the reaction temperature of 60 ℃, controlling the pressure of the nitrogen in the reaction kettle to reach 1MPa, starting the stirrer at the moment, and finishing the reaction after reacting for 12 hours. And cooling the reaction kettle to room temperature, opening an air outlet valve of the reaction kettle, reducing the pressure to normal pressure, and storing the obtained product which is a white product carbomer after filtering, washing and vacuum drying treatment.
The identification method for the synthetic product of carbomer comprises the following steps: dispersing 0.1g of the product in 10ml of water, stirring to dissolve it uniformly, dividing into two parts, adding 5 drops of thymol blue test solution (0.1 g of thymol blue is taken, 100ml of ethanol is added to dissolve it) into one part, and making the solution appear orange; and adding cresol red test solution (0.1 g of cresol red is put into a mortar, 26ml of 0.01mol/L sodium hydroxide solution is added into the mortar, and the mixture is ground and diluted to 250ml with water) into the other part, wherein 5 drops of the cresol red test solution are yellow.
The carbomer quality is determined according to potentiometric titration method in Chinese pharmacopoeia, and the carbomer has a carboxyl (-COOH) content of 60.7% and a pH value of 2.9.
Comparative example 2 this comparative example provides a method for preparing carbomer under conventional pressure with carbon dioxide comprising the steps of:
40g of monomer acrylic acid, 0.4g of cross-linking agent allyl sucrose ether, 0.8g of initiator azobisisobutylamidine hydrochloride, 65g of solvent ethyl acetate and 195g of cyclohexane are respectively added into a reaction kettle and sealed. And introducing carbon dioxide for 10 minutes to discharge air in the reaction kettle, heating to the reaction temperature of 40 ℃, controlling the pressure of nitrogen in the reaction kettle to reach 1MPa, starting the stirrer at the moment, and finishing the reaction after reacting for 12 hours. And cooling the reaction kettle to room temperature, opening an air outlet valve of the reaction kettle, reducing the pressure to normal pressure, and storing the obtained product which is a white product carbomer after filtering, washing and vacuum drying treatment.
The identification method for the synthetic product of carbomer comprises the following steps: dispersing 0.1g of the product in 10ml of water, stirring to dissolve it uniformly, dividing into two parts, adding 5 drops of thymol blue test solution (0.1 g of thymol blue is taken, 100ml of ethanol is added to dissolve it) into one part, and making the solution appear orange; and adding cresol red test solution (0.1 g of cresol red is put into a mortar, 26ml of 0.01mol/L sodium hydroxide solution is added into the mortar, and the mixture is ground and diluted to 250ml with water) into the other part, wherein 5 drops of the cresol red test solution are yellow.
The carbomer quality is determined according to potentiometric titration method in Chinese pharmacopoeia, the carboxyl (-COOH) content is determined to be 60.1%, and the PH value is 2.9.
EXPERIMENTAL EXAMPLE 1 carbomer Polymer physical Property characterization experiment
Subject: the carbomer polymers prepared in examples 1 to 5, comparative example 1 and comparative example 2 provided by the present invention were characterized for physical properties.
1. Viscosity measurement
Under the condition of room temperature of 25 ℃, according to the requirements of pharmacopeia, 0.5 g of carbomer is uniformly dispersed in 98ml of water, after the carbomer is fully swelled and uniformly mixed, the pH value is adjusted to 7.3-7.8 by using 15% sodium hydroxide solution, water is added to 100ml of carbomer and uniformly mixed, the kinematic viscosity of carbomer is measured by using a rotational viscometer, and the data of each group are shown in the following table 1:
TABLE 1 viscosity of carbomer under different synthesis conditions
From the viscosity data, the carbomer polymer synthesized under the supercritical condition has higher kinematic viscosity, which is related to the uniform speed of free radicals generated in the reaction process, mild polymerization reaction and increased molecular weight under the supercritical low-temperature condition.
1.1 measurement of glass transition temperature
The glass transition temperature (Tg) of the polymer under different conditions, as measured by Differential Scanning Calorimetry (DSC) of the synthesized carbomer, is shown in Table 2 below:
TABLE 2 glass transition temperature (Tg) of carbomer under different synthesis conditions
| Grouping | Tg(℃) |
| Example 1 | 140.6 |
| Example 2 | 139.5 |
| Example 3 | 139.8 |
| Example 4 | 141.2 |
| Example 5 | 137.9 |
| Example 6 | 137.2 |
| Example 7 | 132.1 |
| Example 8 | 136.7 |
| Example 9 | 135.2 |
| Comparative example 1 | 131.4 |
| Comparative example 2 | 130.9 |
From the glass transition temperature, the glass transition temperature of the carbomer polymer synthesized under the supercritical condition is correspondingly improved, which shows that the polymerization reaction is stable under the condition and the crosslinking degree of a polymerization system is higher.
Experimental example 2 experiment of immunoadjuvant Performance of the synthetic carbomer Polymer
2.1 preparation of Polymer adjuvants and vaccines thereof
According to the preparation method of the production rule of the porcine circular inactivated vaccine, the carbomer synthesized in the examples 1 to 9 and the comparative examples 1 and 2 is prepared into the carbomer adjuvant by configuring the carbomer with the same proportion concentration, and the porcine circular inactivated vaccine is prepared by mixing the 11 adjuvants with the porcine circular inactivated antigen.
2.2 Security verification
2.2.1 cell safety assay
The in vitro cytotoxicity test is one of the most commonly used methods for evaluating the safety of biomedical materials, and the invention adopts a Cell Counting Kit-8(CCK-8) Kit to evaluate and determine the biological safety of carbomer polymers. Suspending cells by MARK145, wherein the number of the cells is 80000/ml, inoculating the cells into a 96-well plate, adding only culture medium to the outermost circle of the plate, adding 100 microliter of cell suspension to each well of an experimental well and a blank control well, adding 10 microliter of adjuvants in examples 1 to 9 and adjuvants in comparative examples 1 and 2 to each well, repeating 5 times for each sample, incubating for 48 hours at 37 ℃ in a carbon dioxide incubator, adding 10 microliter of CCK-8 to each well, reading the absorbance value of each well at a wavelength of 450nm by using a microplate reader after continuing incubation for 4 hours at 37 ℃ in the carbon dioxide incubator, and calculating the data according to the calculation formula of the cell viability as shown in the following Table 3:
TABLE 3 cell viability for different carbomer adjuvants prepared in Experimental example 2
The experimental results show that the cell survival rate of the adjuvant is obviously higher in examples 1 to 9 than in comparative examples 1 and 2, and the carbomer polymer provided by the invention has good cell safety, wherein the cell safety data of examples 1 and 2 are superior to those of other examples.
2.2.2 animal safety test
The carbomer polymers synthesized in the examples 1 to 9 and the comparative examples 1 and 2 of the invention are subjected to a comparative test of safety of animals with porcine circular vaccine adjuvant, 25 mice weighing 18-22 g are used, 0.5ml of vaccine is injected subcutaneously for each mouse, healthy susceptible pigs of the same variety, 4 months old and 40Kg weight are used, 17 pigs are used, and 4ml of vaccine is injected intramuscularly for each pig, and the observation is continued for 7 days one by one. No death or obvious local adverse reaction or systemic reaction caused by vaccine injection occurs, and the specific results are shown in the following table 4.
TABLE 4 vaccine safety test results of mice and pigs with adjuvant vaccines prepared under different synthesis conditions
2.3 vaccine stability test
The porcine circovirus vaccines of each group prepared in the experimental example 2 are placed at 2-8 ℃ for 24 months, and the physical properties of the porcine circovirus vaccines are observed, and the specific results are shown in the following table 5.
TABLE 5 vaccine stability test results
| Grouping | Stability of |
| Example 1 | Stable and non-layering for 24 months |
| Example 2 | Stable and non-layering for 24 months |
| Example 3 | Stable and non-layering for 24 months |
| Example 4 | Stable and non-layering for 24 months |
| Example 5 | Stable and non-layering for 24 months |
| Example 6 | Stable and non-layering for 24 months |
| Example 7 | Stable and non-layering for 24 months |
| Example 8 | Stable and non-layering for 24 months |
| Example 9 | 24Stable and non-layering in months |
| Comparative example 1 | Layered, the lower layer presents a foggy deposit |
| Comparative example 2 | Layered, the lower layer presents a foggy deposit |
2.4 porcine circovirus adjuvant potency assay
Animal immunization is carried out according to the requirements of the production regulation of the porcine circovirus vaccine: 5-6-week-old PCV 2ELISA antibody-negative healthy female clean-grade Balb/c mice (PCV 2ELISA antibody titer is not higher than 1:50) are used for respectively inoculating 5 mice each with the porcine circular-ring carbomer adjuvant vaccines of examples 1 to 9 and the vaccines of comparative examples 1 and 2 provided by the invention subcutaneously, each mouse is immunized with 0.2 ml, and a blank control group is arranged. Each group of mice was kept separately for observation. Blood was collected at 1 week, 2 weeks, 3 weeks, 4 weeks, and 5 weeks after immunization, and serum was separated and PCV 2ELISA antibody titer was measured by ELISA antibody detection. The results were averaged for each group and all controls were negative. The data show that the mean antibody titers of each of the examples 1-9 provided by the present invention are higher than the comparative example. Specific data are shown in table 6.
TABLE 6 results of animal immunization evaluation Ring antibody level test
The efficacy experiment shows that the circular vaccine using the carbomer adjuvant provided by the invention can reach the antibody level required by the regulation, and has better immune effect compared with the conventional synthetic carbomer.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A method for synthesizing a carbomer polymer is characterized in that a cross-linking agent of allyl sucrose ether, an acrylic acid monomer, an initiator and a solvent are uniformly mixed, and cross-linking polymerization reaction is carried out under the condition of supercritical carbon dioxide to obtain the carbomer polymer.
2. The synthesis method according to claim 1, wherein the initiator is a peroxide initiator, an azo initiator or an initiator redox initiator;
wherein, the peroxide initiator adopts organic peroxide or inorganic peroxide, the organic peroxide is selected from one or more than two of benzoyl peroxide, lauroyl peroxide, tert-butyl hydroperoxide, methyl ethyl ketone peroxide, tert-butyl peroxybenzoate, cyclohexanone peroxide sulfate and diisopropyl peroxydicarbonate, and the inorganic peroxide is selected from one or more than two of hydrogen peroxide, potassium persulfate, sodium persulfate and ammonium persulfate;
the azo initiator is selected from one or more of azodiisobutyronitrile, azodiisoheptonitrile, dimethyl azodiisobutyrate and azodiisobutyl amidine hydrochloride in any combination;
the oxidant in the redox system initiator is one or more than two of hydrogen peroxide, hydroperoxide, persulfate, dialkyl peroxide and diacyl peroxide in any combination, and the reducing agent is one or more than two of ferrous sulfate, sodium sulfite, amine, arylamine, oxalic acid, sugar, mercaptan and naphthenate in any combination;
the solvent can be one or a combination of more of benzene, cyclohexane, ethyl acetate, deionized water and the like.
3. The method of claim 2, wherein the redox initiator is selected from the group consisting of t-butyl hydroperoxide/sodium metabisulfite, benzoyl peroxide/sucrose, t-butyl hydroperoxide/sodium metabisulfite, benzoyl peroxide/N, N-dimethylaniline, ammonium persulfate/sodium bisulfite, potassium persulfate/sodium bisulfite, hydrogen peroxide/tartaric acid, ammonium persulfate/ferrous sulfate, hydrogen peroxide/ferrous chloride, persulfate/sodium bisulfite, persulfate/phosphorous acid, benzoyl peroxide/N, n-diethylaniline, benzoyl peroxide/ferrous pyrophosphate, persulfate/mercaptan, cumene hydroperoxide/ferrous chloride or potassium persulfate/ferrous chloride;
the azo initiator is selected from azobisisobutyronitrile or azobisisobutylamidine hydrochloride;
the peroxide initiator adopts ammonium persulfate;
preferably, the redox initiator is selected from N, N-diethylhydroxylamine/sodium persulfate, hydroxydiisopropylbenzene peroxide (CHPO)/tetraethylenepentamine, or potassium persulfate/potassium sulfite/thiourea dioxide.
4. The method according to claim 3, wherein the initiator is selected from one or more of azodiisobutyl amidine hydrochloride, ammonium persulfate, N, N-diethylhydroxylamine/sodium persulfate, ammonium persulfate/N, N-Diethylhydroxylamine (DEHA), potassium persulfate/potassium sulfite/thiourea dioxide, iron persulfate/sodium bisulfite, hydroxydiisopropylbenzene/tetraethylenepentamine peroxide;
the initiator is preferably selected from azobisisobutylamidine hydrochloride, ammonium persulfate, N, N-diethylhydroxylamine/sodium persulfate, potassium persulfate/potassium sulfite/thiourea dioxide;
the solvent is one or a combination of ethyl acetate, deionized water or cyclohexane.
5. The method according to any one of claims 1-4, wherein: the acrylic acid monomer accounts for 40-100% of the total amount of the cross-linking agent allyl sucrose ether and the acrylic acid monomer, but does not account for 100%.
6. The method according to any one of claims 1-4, wherein: the dosage of the initiator is 0.5 to 15 percent of the weight of the acrylic monomer.
7. The method according to any one of claims 1-4, wherein: the amount of the solvent is 100-700% of the weight of the acrylic monomer.
8. The method according to any one of claims 1-4, wherein: the pressure of the cross-linking polymerization reaction is 7.2-30 MPa; the temperature of the cross-linking polymerization reaction is controlled to be 31.06-60 ℃; the reaction time of the cross-linking polymerization reaction is 1-24 hours.
9. Carbomer prepared by the process of any one of claims 1 to 8.
10. Use of a method according to any one of claims 1 to 8 or carbomer prepared thereby in the preparation of a vaccine.
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