CN113855810A - Pharmaceutic adjuvant sodium polystyrene sulfonate microsphere and preparation method thereof - Google Patents
Pharmaceutic adjuvant sodium polystyrene sulfonate microsphere and preparation method thereof Download PDFInfo
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- 239000004005 microsphere Substances 0.000 title claims abstract description 211
- 229920001467 poly(styrenesulfonates) Polymers 0.000 title claims abstract description 150
- 229940006186 sodium polystyrene sulfonate Drugs 0.000 title claims abstract description 135
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 239000000546 pharmaceutical excipient Substances 0.000 title claims abstract description 25
- 238000004945 emulsification Methods 0.000 claims abstract description 38
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 31
- 230000009466 transformation Effects 0.000 claims abstract description 9
- 238000006277 sulfonation reaction Methods 0.000 claims abstract description 8
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 56
- 238000003756 stirring Methods 0.000 claims description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 239000004793 Polystyrene Substances 0.000 claims description 41
- 229920002223 polystyrene Polymers 0.000 claims description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- 239000003995 emulsifying agent Substances 0.000 claims description 29
- 238000005406 washing Methods 0.000 claims description 26
- 238000010438 heat treatment Methods 0.000 claims description 25
- 239000000839 emulsion Substances 0.000 claims description 24
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
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- 238000000746 purification Methods 0.000 claims description 9
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- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 8
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 8
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- 238000002156 mixing Methods 0.000 claims description 8
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 8
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 6
- FRIBMENBGGCKPD-UHFFFAOYSA-N 3-(2,3-dimethoxyphenyl)prop-2-enal Chemical compound COC1=CC=CC(C=CC=O)=C1OC FRIBMENBGGCKPD-UHFFFAOYSA-N 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 3
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- 229920000159 gelatin Polymers 0.000 claims description 3
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- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 239000007790 solid phase Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 107
- 229940079593 drug Drugs 0.000 abstract description 106
- 238000011068 loading method Methods 0.000 abstract description 49
- 239000002245 particle Substances 0.000 abstract description 44
- 238000000034 method Methods 0.000 abstract description 24
- 238000009826 distribution Methods 0.000 abstract description 15
- 239000011347 resin Substances 0.000 abstract description 2
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- 239000000463 material Substances 0.000 abstract 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
- 238000004140 cleaning Methods 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- YQSHYGCCYVPRDI-UHFFFAOYSA-N (4-propan-2-ylphenyl)methanamine Chemical compound CC(C)C1=CC=C(CN)C=C1 YQSHYGCCYVPRDI-UHFFFAOYSA-N 0.000 description 7
- 229960003782 dextromethorphan hydrobromide Drugs 0.000 description 7
- 239000012071 phase Substances 0.000 description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 6
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 description 5
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
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- 229960000907 methylthioninium chloride Drugs 0.000 description 5
- 238000009827 uniform distribution Methods 0.000 description 5
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
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- 238000005516 engineering process Methods 0.000 description 4
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- 239000007789 gas Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000008384 inner phase Substances 0.000 description 3
- 239000008385 outer phase Substances 0.000 description 3
- 229920000172 poly(styrenesulfonic acid) Polymers 0.000 description 3
- 229940005642 polystyrene sulfonic acid Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
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- 238000004626 scanning electron microscopy Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
- CDOUZKKFHVEKRI-UHFFFAOYSA-N 3-bromo-n-[(prop-2-enoylamino)methyl]propanamide Chemical compound BrCCC(=O)NCNC(=O)C=C CDOUZKKFHVEKRI-UHFFFAOYSA-N 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 238000012644 addition polymerization Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
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- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
Abstract
The application relates to the technical field of preparation of medicinal resin microspheres, and particularly discloses a medicinal auxiliary material sodium polystyrene sulfonate microsphere and a preparation method thereof. The preparation method of the pharmaceutic adjuvant sodium polystyrene sulfonate microspheres comprises the following steps of: s1, emulsification; s2, polymerization; s3, sulfonation; and S4, transformation. The sodium polystyrene sulfonate microspheres prepared by the method have the average particle size of about 42 micrometers, the particle size distribution range of the prepared sodium polystyrene sulfonate microspheres is narrow, and the sodium polystyrene sulfonate microspheres do not need to be crushed again in the using process, so that the structure of the sodium polystyrene sulfonate microspheres is not damaged, the sodium polystyrene sulfonate microspheres with proper particle sizes are easier to disperse uniformly in the preparation process, and the sodium polystyrene sulfonate microspheres have better drug loading capacity and drug release stability.
Description
Technical Field
The application relates to the technical field of preparation of medicinal resin microspheres, in particular to a medicinal adjuvant sodium polystyrene sulfonate microsphere and a preparation method thereof.
Background
The sodium polystyrene sulfonate is a light liquid, has no odor, and is easily soluble in water. The sodium polystyrene sulfonate solution is a water-soluble polymer with unique effect, is widely applied to the field of medicine and pharmacy, and can reduce the pain of patients and the economic burden of the patients by means of the auxiliary treatment of the sodium polystyrene sulfonate.
The method for preparing the sodium polystyrene sulfonate microspheres in the related technology is mainly to prepare the sodium polystyrene sulfonate microspheres through suspension polymerization, the prepared sodium polystyrene sulfonate microspheres have too large particles and need to be ground for use, and the grinding operation can damage the internal structure of the sodium polystyrene sulfonate microspheres, so that the sodium polystyrene sulfonate microspheres are unstable in drug loading and release, and the dosage of the drugs can be influenced; the prepared sodium polystyrene sulfonate microspheres have uneven particle size distribution, are not easy to disperse and precipitate in the process of preparing the sodium polystyrene sulfonate microsphere preparation with uneven particle size, are not easy to redisperse after precipitation, and also reduce the drug-loading capacity and drug-release stability of the sodium polystyrene sulfonate.
Aiming at the related technologies, the inventor believes that the preparation method in the related technologies has the defects of poor drug loading capacity and poor drug release stability of the prepared sodium polystyrene sulfonate microspheres.
Disclosure of Invention
In order to improve the drug loading performance and the drug release stability of the sodium polystyrene sulfonate microspheres, the application provides the sodium polystyrene sulfonate microspheres as the pharmaceutic adjuvant and a preparation method thereof.
In a first aspect, the application provides a preparation method of sodium polystyrene sulfonate microspheres as a pharmaceutical adjuvant, which adopts the following technical scheme:
a preparation method of a pharmaceutic adjuvant sodium polystyrene sulfonate microsphere comprises the following steps:
s1, emulsification: mixing styrene, divinyl benzene and an initiator, adding the mixture into an emulsifier for emulsification, and obtaining an emulsion after the emulsification is finished; the emulsifier is selected from any one of polyvinyl alcohol solution, gelatin solution and methyl cellulose solution;
s2, polymerization: heating the emulsion, stirring to 65-75 ℃, keeping for 2-4h, continuing to heat to 80-85 ℃, keeping for 2-4h, heating to 90-98 ℃, keeping for 1-2h, finishing the reaction, washing, centrifuging and drying to obtain polystyrene microspheres;
s3, sulfonation: sulfonating the polystyrene microspheres prepared in the step S2 to obtain sulfonated polystyrene microspheres;
s4, transformation: and (3) adding a sodium hydroxide solution into the sulfonated polystyrene microspheres prepared in the step S3, stirring, reacting to obtain a product solution, and purifying and drying the product solution to obtain the sodium polystyrene sulfonate microspheres.
By adopting the technical scheme, the emulsifier can improve the surface tension between the styrene, the divinylbenzene and the initiator in the emulsification process, so that the styrene, the divinylbenzene and the initiator are used as inner phases, and the emulsifier is used as an outer phase to wrap the inner phases, so that an oil-in-water uniform and stable emulsion is formed in a mixed system, the diameters of liquid beads of dispersed phases in the emulsion are tiny and uniform, and the later-stage polymerization reaction is favorably and fully performed, so that the prepared polystyrene microspheres have small particle sizes and uniform distribution, and the drug loading capacity and the drug release stability of the sodium polystyrene sulfonate microspheres in later-stage use are improved.
In the polymerization process, the addition polymerization reaction of the styrene and the divinylbenzene is carried out by initiating after the initiator forms free radicals, if the temperature is directly raised to a higher reaction temperature, the initiator can rapidly generate the free radicals, so that the polymerization reaction of the styrene and the divinylbenzene can be rapidly carried out, and the stable forming of the microspheres is not facilitated; in addition, the initiator which is caused by directly heating to a higher reaction temperature quickly generates free radicals, so that the structure formed inside the microsphere is compact, and the structure outside the microsphere is loose, which is not beneficial to maintaining the stability of drug release of the microsphere; the adoption of the three-step temperature rising mode is beneficial to the initiator to continuously and uniformly release free radicals, so that the polymerization reaction of the styrene and the divinyl benzene is relatively carried out at a constant speed, the formation of the polystyrene microspheres with small particle size and uniform distribution is further facilitated in the polymerization process, the formed polystyrene microspheres are uniform and stable in structure, and the drug loading capacity and the drug release stability of the sodium polystyrene sulfonate microspheres in later use can be finally improved.
Optionally, the stirring speed of the emulsification in the S1 is 7000-9000 r/min; the emulsifying time is 4-10 min.
By adopting the technical scheme, in the emulsification reaction process, the stirring speed has great influence on the emulsification effect, if the stirring speed is too low, the aim of fully mixing can not be achieved obviously, and the inner phase can not be uniformly dispersed in the outer phase and coated by the outer phase, so that the particle size of the polystyrene microspheres formed in the subsequent polymerization reaction is not uniform, and the stability of drug-loaded drug release kept by the sodium polystyrene sulfonate microspheres is not facilitated; if the stirring speed is too high, a large amount of bubbles are brought into an emulsion system, so that the emulsion becomes a three-phase system, and the existence of the gas can make the emulsion very unstable, thereby being not beneficial to the smooth proceeding of the subsequent polymerization reaction; therefore, the emulsion can be fully and uniformly stirred by selecting the stirring speed within the range, and the introduction of gas can be reduced as much as possible, so that a stable and uniform two-phase emulsion system is formed, the formation of the polystyrene microspheres with smaller particle size and uniform distribution in the subsequent polymerization reaction is facilitated, and the drug loading capacity and the drug release stability of the sodium polystyrene sulfonate microspheres in later use are improved. Secondly, the emulsification time is the key for determining the emulsification effect, and the emulsification time in the range is selected according to the viscosity and the proportion of the two-phase raw materials and the stirring speed during emulsification, so that the system can be fully emulsified, the particle size of the prepared polystyrene microsphere is smaller and is uniformly distributed, and the drug loading capacity and the drug release stability of the sodium polystyrene sulfonate microsphere during later use are improved.
Optionally, in step S1,
the weight ratio of the styrene to the divinylbenzene is (5-10): 1;
the initiator is 0.5-1% of the weight of the styrene;
the mass concentration of the emulsifier is 2.5-5%;
the weight ratio of the styrene to the emulsifier is 1: (2-6).
By adopting the technical scheme, when the mixture ratio of various raw materials is selected to be appropriate, the polymerization degree of the prepared sodium polystyrene sulfonate microsphere is appropriate, the raw material mixture ratio in the range enables the prepared polystyrene microsphere to have more excellent performances in all aspects, and further the drug loading capacity and the drug release stability of the sodium polystyrene sulfonate microsphere can be improved.
Optionally, the stirring speed when the emulsion is stirred at the increased temperature in the step S2 is 500 r/min.
By adopting the technical scheme, the stirring speed in the polymerization operation of preparing the sodium polystyrene sulfonate microspheres in the related technology is about 800-; in the application, the pre-emulsification step is adopted, so that the polymerization reaction can be stably, continuously and fully carried out by controlling the stirring speed of the polymerization at 500r/min in the polymerization process, a harsher stirring condition is not required to be controlled, the operation steps in the polymerization process are effectively simplified, the energy consumption required in the polymerization stirring process is reduced, the stirring speed can obviously reduce the generation of bubbles in the stirring process, the stable operation of the polymerization reaction is facilitated, and the drug loading capacity and the drug release stability of the sodium polystyrene sulfonate microspheres are further facilitated to be improved.
Optionally, the purification treatment in S4 includes the following steps:
I. washing the product solution with water until the pH value is neutral, then filtering, and taking a solid phase for drying;
II. Condensing, refluxing and cooking the dried sodium polystyrene sulfonate microspheres by using ethanol at the temperature of 80-90 ℃ for 2-3h, washing the cooked sodium polystyrene sulfonate microspheres by using water, and cooking the sodium polystyrene sulfonate microspheres by using water again for 2-3 h;
III, repeating the operation II.
By adopting the technical scheme, the product solution generated during transformation is filtered and dried and then is boiled by ethanol, the residual styrene on the sodium polystyrene sulfonate microspheres can be dissolved in the ethanol in the boiling process, then the styrene is condensed along with the ethanol in the condensation process, then the residual styrene on the microspheres is washed by water, and then the microspheres are boiled by water, so that the residual ethanol on the sodium polystyrene sulfonate microspheres is boiled, and then the purity of the final product can be improved by repeating the operation, the residual impurities on the sodium polystyrene sulfonate microspheres are reduced, and the sodium polystyrene sulfonate microspheres are favorable for keeping better drug loading capacity and drug release stability.
Optionally, the initiator in S1 is any one of azobisisobutyronitrile, cumene hydroperoxide, or benzoyl peroxide.
By adopting the technical scheme, the azodiisobutyronitrile, the cumene hydroperoxide and the benzoyl peroxide have moderate activity, the free radicals are generated in a homolytic way, the number of the free radicals generated in homolytic way is moderate, and the collision probability of the generated free radicals and raw materials of polymerization reaction is approximate, so that the polymerization reaction is promoted efficiently, the reaction degree of styrene and divinylbenzene is proper, the polystyrene microspheres with uniform particle size are generated, and the drug loading capacity and the drug release stability of the sodium polystyrene sulfonate microspheres are improved.
Optionally, the S3 includes the following steps: and (3) adding the polystyrene microspheres obtained in the step (S2) into a swelling reagent, swelling for 28-40min, adding concentrated sulfuric acid, stirring, reacting at the reaction temperature of 80-95 ℃ for 4-6h, and washing to be neutral after the reaction is finished to obtain the sulfonated polystyrene microspheres.
By adopting the technical scheme, the polystyrene microsphere formed by the polymerization reaction is swelled by using the swelling reagent, so that micropores on the surface of the microsphere are enlarged, the inner surface of the micropores is enlarged, and more sulfonate groups can be fully connected in the pores of the microsphere in the process of adding concentrated sulfuric acid for sulfonation. The proper swelling time is favorable for enabling the particle size of the microsphere to be uniform, and the microsphere with uniform particle size is favorable for enabling the sulfonate radical to be uniformly distributed in each hole of the microsphere, thereby being favorable for improving the drug release stability of the sodium polystyrene sulfonate microsphere.
Optionally, the swelling agent in S3 is dichloromethane, and the mass ratio of the swelling agent to the polystyrene microspheres to be swelled is (3-5): 1.
by adopting the technical scheme, compared with the traditional swelling solvent dichloroethane, the dichloromethane has lower toxicity, and the swelling reagent in the proportion range is selected, so that the swelling effect on the polystyrene microsphere is better, the uniform particle size and the uniform distribution of micropores on the whole microsphere of the sodium polystyrene sulfonate microsphere are facilitated, the microsphere shape of the sodium polystyrene sulfonate is favorably regular, and the drug-loading capacity and the drug release stability of the sodium polystyrene sulfonate microsphere are further improved.
Optionally, the mass concentration of the sodium hydroxide solution is 8-12%.
By adopting the technical scheme, the concentration of the sodium hydroxide is selected in the range in the transformation process, so that the sodium in the sodium hydroxide solution and the hydrogen atoms on the polystyrene sulfonic acid can be stably balanced, the sodium can be uniformly distributed on the polystyrene sulfonic acid microspheres, and the polystyrene sulfonic acid microspheres can keep the stability of the drug release performance in the later period.
In a second aspect, the application provides a pharmaceutical adjuvant sodium polystyrene sulfonate microsphere, which is prepared by the preparation method provided by the application.
By adopting the technical scheme, the prepared sodium polystyrene sulfonate microspheres have proper particle size and uniform particle size distribution, can be directly used without grinding in the follow-up process, and are easy to disperse uniformly and not easy to precipitate in the preparation process, so that the prepared sodium polystyrene sulfonate microspheres have strong drug loading capacity and drug release stability.
In summary, the present application has the following beneficial effects:
1. according to the method, emulsification operation is carried out before polymerization reaction, so that the raw materials for reaction form an oil-in-water uniform and stable emulsion, the later-stage polymerization reaction is favorably carried out fully, the particle size of the prepared polystyrene microspheres is small and is distributed uniformly, the average particle size of the sodium polystyrene sulfonate microspheres prepared by the method is 40-50, and the drug loading capacity and the drug release stability of the sodium polystyrene sulfonate microspheres in later use are improved.
2. According to the method, the emulsion can be fully and uniformly stirred by controlling the stirring speed and the stirring time during emulsification, and the introduction of gas can be reduced as much as possible, so that a stable and uniform two-phase emulsification system is formed, the formation of the polystyrene microspheres with smaller particle size and uniform distribution during the subsequent polymerization reaction is facilitated, and the drug loading capacity and the drug release stability of the sodium polystyrene sulfonate microspheres during later use are improved. By controlling proper stirring speed and stirring time, the average particle size of the prepared sodium polystyrene sulfonate microspheres is about 42 mu m, the drug loading rate reaches more than 30%, and the drug release rate of the sodium polystyrene sulfonate microspheres in 1h, 3h and 5h is gradually and stably reduced, so that the sodium polystyrene sulfonate microspheres have better drug release stability.
3. According to the method, the proportion of the raw materials is regulated, so that the sodium polystyrene sulfonate microspheres can reach a proper polymerization degree, and the prepared polystyrene microspheres have more excellent performances in all aspects, better drug loading capacity and better drug release stability.
4. According to the method, the prepared sodium polystyrene sulfonate microspheres are purified by ethanol cooking, so that residual organic impurities on the sodium polystyrene sulfonate microspheres can be reduced, and the organic residue in a final product is less than 1ppm, so that the high-purity sodium polystyrene sulfonate microspheres with light yellow appearance are prepared, and the sodium polystyrene sulfonate microspheres are favorable for keeping better drug-loading capacity and drug release stability.
Drawings
FIG. 1 is an SEM image of sodium polystyrene sulfonate microspheres prepared in comparative example 1 of the present application;
FIG. 2 is an SEM photograph of sodium polystyrene sulfonate microspheres prepared in example 1 of the present application;
FIG. 3 is a distribution diagram of the particle size of sodium polystyrene sulfonate microspheres prepared in example 1 of the present application.
Detailed Description
The present application will be described in further detail with reference to examples.
The molecular weight of the polyvinyl alcohol in the following examples and comparative examples was 1788.
Examples
Example 1
A pharmaceutical adjuvant polystyrene sodium sulfonate microsphere adopts the following preparation method:
s1, emulsification:
(1) an emulsifier was prepared by adding 7g of polyvinyl alcohol to 260g of water, then adding 2 drops of methylene blue reagent dropwise, and dissolving at 90 ℃. And cooling to be within 30 ℃ after dissolving to obtain the emulsifier.
(2) And (3) performing unblocking treatment on the raw material, namely loading 50g of alkaline alumina into a glass column, then adding styrene and divinyl benzene respectively to perform unblocking, and storing at the temperature of below 30 ℃.
(3) Emulsifying, namely mixing 44.5g of styrene, 7.5g of divinylbenzene and 0.4g of benzoyl peroxide, adding the mixture into the emulsifier in the step (1), and then emulsifying and stirring the mixture in an emulsifying machine; the stirring speed of emulsification is 8000 r/min; the emulsifying time is 8 min; and obtaining an emulsion after emulsification.
S2, polymerization: and (4) adding the emulsion prepared in the step (3) into a three-necked bottle, heating to 70 ℃ within 30min at a stirring speed of 400r/min, keeping for 3h, heating to 84 ℃ within 10min, keeping for 3h, heating to 95 ℃ within 10min, keeping for 1h, and finishing the reaction to obtain a reaction solution. And then adding hot water with the volume of 4 times of that of the reaction solution and the temperature of 90 ℃ into the reaction solution for washing, centrifuging, and drying at the temperature of 110 ℃ for 5 hours to obtain the polystyrene microsphere.
S3, sulfonation: weighing 20g of polystyrene microspheres in S2, adding the polystyrene microspheres into 100g of dichloromethane, swelling for 30min at room temperature, adding 100g of concentrated sulfuric acid (the mass concentration is 98%), heating to 82 ℃ within 30min at a stirring speed of 200r/min, keeping for 4h, heating to 95 ℃ within 10min, keeping for 2h, adding the mixed solution into 1000ml of deionized water after the reaction is finished, filtering in a quartz sand funnel after the reaction is fully stirred, and washing with a large amount of deionized water until the solution is neutral to obtain the sulfonated polystyrene microspheres.
S4, transformation: adding a sodium hydroxide solution with the mass concentration of 8% into the sulfonated polystyrene microspheres obtained in S3 to stabilize the pH value between 10 and 12, stirring for 120min, then finishing the reaction to obtain a product solution, and then purifying the product solution, wherein the purification treatment comprises the following steps:
I. washing the product solution with a large amount of deionized water until the pH value is neutral, then filtering, and drying the filtered solid;
II. Adding ethanol with the volume 4 times that of the dried solid into the dried solid, performing condensation reflux cooking for 2 hours at 85 ℃, cleaning the solid with deionized water after cooking, and cooking the solid with deionized water with the volume equal to that of the ethanol after cleaning for 2 hours;
III, repeating the operation II once, then washing the microspheres with a large amount of deionized water until the pH is neutral, and drying the microspheres at 105 ℃ for 12 hours to obtain the sodium polystyrene sulfonate microspheres.
Example 2
A pharmaceutical adjuvant polystyrene sodium sulfonate microsphere adopts the following preparation method:
s1, emulsification:
(1) an emulsifier was prepared by adding 6g of gelatin to 144g of water, then adding 2 drops of methylene blue reagent dropwise, and dissolving at 90 ℃. And cooling to be within 30 ℃ after dissolving to obtain the emulsifier.
(2) And (3) performing unblocking treatment on the raw material, namely loading 50g of alkaline alumina into a glass column, then adding styrene and divinyl benzene respectively to perform unblocking, and storing at the temperature of below 30 ℃.
(3) Emulsifying, namely mixing 37.5g of styrene, 7.5g of divinylbenzene and 0.2g of azobisisobutyronitrile, adding the mixture into the emulsifier in the step (1), and then emulsifying and stirring the mixture in an emulsifying machine; the stirring speed of emulsification is 7000 r/min; emulsifying for 10 min; and obtaining an emulsion after emulsification.
S2, polymerization: and (4) adding the emulsion prepared in the step (3) into a three-necked bottle, heating to 65 ℃ within 30min at a stirring speed of 500r/min, keeping for 4h, heating to 80 ℃ within 10min, keeping for 4h, heating to 90 ℃ within 10min, keeping for 2h, and finishing the reaction to obtain a reaction solution. And then adding hot water with the volume of 4 times of that of the reaction solution and the temperature of 90 ℃ into the reaction solution for washing, centrifuging, and drying at the temperature of 110 ℃ for 5 hours to obtain the polystyrene microsphere.
S3, sulfonation: weighing 20g of polystyrene microspheres in S2, adding the polystyrene microspheres into 80g of dichloromethane, swelling at room temperature for 35min, adding 100g of concentrated sulfuric acid (the mass concentration is 98%), heating to 80 ℃ within 30min at a stirring speed of 200r/min, keeping for 2h, heating to 95 ℃ within 10min, keeping for 2h, adding the mixed solution into 1000ml of deionized water after the reaction is finished, filtering in a quartz sand funnel after the reaction is fully stirred, and washing with a large amount of deionized water until the solution is neutral to obtain the sulfonated polystyrene microspheres.
S4, transformation: adding a sodium hydroxide solution with the mass concentration of 10% into the sulfonated polystyrene microspheres obtained in S3 to stabilize the pH value between 10 and 12, stirring for 150min, then finishing the reaction to obtain a product solution, and then purifying the product solution, wherein the purification treatment comprises the following steps:
I. washing the product solution with a large amount of deionized water until the pH value is neutral, then filtering, and drying the filtered solid;
II. Adding ethanol with the volume 4 times that of the dried solid into the dried solid, performing condensation reflux cooking for 2.5 hours at the temperature of 80 ℃, cleaning the solid by using deionized water after cooking, and cooking the solid by using the deionized water with the volume equal to that of the ethanol after cleaning, wherein the cooking time is 2.5 hours;
III, repeating the operation II once, then washing the microspheres with a large amount of deionized water until the pH value is neutral, and drying the microspheres at 110 ℃ for 5 hours to obtain the sodium polystyrene sulfonate microspheres.
Example 3
A pharmaceutical adjuvant polystyrene sodium sulfonate microsphere adopts the following preparation method:
s1, emulsification:
(1) an emulsifier was prepared by adding 7.5g of methylcellulose to 260g of water, then 2 drops of methylene blue reagent were added dropwise and dissolved at 90 ℃. And cooling to be within 30 ℃ after dissolving to obtain the emulsifier.
(2) And (3) performing unblocking treatment on the raw material, namely loading 50g of alkaline alumina into a glass column, then adding styrene and divinyl benzene respectively to perform unblocking, and storing at the temperature of below 30 ℃.
(3) Emulsifying, namely mixing 75g of styrene, 7.5g of divinylbenzene and 0.75g of cumene hydroperoxide, adding the mixture into the emulsifier in the step (1), and then emulsifying and stirring the mixture in an emulsifying machine; the stirring speed of emulsification is 9000 r/min; the emulsifying time is 4 min; and obtaining an emulsion after emulsification.
S2, polymerization: and (3) adding the emulsion prepared in the step (3) into a three-mouth bottle, heating to 75 ℃ within 30min at a stirring speed of 300r/min, keeping for 2h, then heating to 85 ℃ within 10min, keeping for 2h, heating to 98 ℃ within 10min, keeping for 1.5h, and then finishing the reaction to obtain a reaction solution. And then adding hot water with the volume of 4 times of that of the reaction solution and the temperature of 90 ℃ into the reaction solution for washing, centrifuging, and drying at the temperature of 110 ℃ for 5 hours to obtain the polystyrene microsphere.
S3, sulfonation: weighing 20g of polystyrene microspheres in S2, adding the polystyrene microspheres into 60g of dichloromethane, swelling for 40min at room temperature, adding 100g of concentrated sulfuric acid (the mass concentration is 98%), heating to 85 ℃ within 30min at a stirring speed of 200r/min, keeping for 3h, heating to 95 ℃ within 10min, keeping for 2h, adding the mixed solution into 1000ml of deionized water after the reaction is finished, filtering in a quartz sand funnel after the reaction is fully stirred, and washing with a large amount of deionized water until the solution is neutral to obtain the sulfonated polystyrene microspheres.
S4, transformation: adding a sodium hydroxide solution with the mass concentration of 12% into the sulfonated polystyrene microspheres obtained in S3 to stabilize the pH value between 10 and 12, stirring for 150min, then finishing the reaction to obtain a product solution, and then purifying the product solution, wherein the purification treatment comprises the following steps:
I. washing the product solution with a large amount of deionized water until the pH value is neutral, then filtering, and drying the filtered solid;
II. Adding ethanol with the volume 4 times that of the dried solid into the dried solid, performing condensation reflux cooking for 2.5 hours at the temperature of 80 ℃, cleaning the solid by using deionized water after cooking, and cooking the solid by using the deionized water with the volume equal to that of the ethanol after cleaning, wherein the cooking time is 2.5 hours;
III, repeating the operation II once, then washing the microspheres with a large amount of deionized water until the pH value is neutral, and drying the microspheres at 108 ℃ for 8 hours to obtain the sodium polystyrene sulfonate microspheres.
Example 4
A preparation method of a pharmaceutic adjuvant sodium polystyrene sulfonate microsphere comprises the following steps:
the difference from example 1 is that: and the stirring speed of emulsification in the S1 is 3000r/min, and the emulsification time is 2 min. Specifically, the operation of S1 is:
(1) an emulsifier was prepared by adding 7g of polyvinyl alcohol to 260g of water, then adding 2 drops of methylene blue reagent dropwise, and dissolving at 90 ℃. And cooling to be within 30 ℃ after dissolving to obtain the emulsifier.
(2) And (3) performing unblocking treatment on the raw material, namely loading 50g of alkaline alumina into a glass column, then adding styrene and divinyl benzene respectively to perform unblocking, and storing at the temperature of below 30 ℃.
(3) Emulsifying, namely mixing 44.5g of styrene, 7.5g of divinylbenzene and 0.4g of benzoyl peroxide, adding the mixture into the emulsifier in the step (1), and then emulsifying and stirring the mixture in an emulsifying machine; the stirring speed of emulsification is 3000 r/min; the emulsifying time is 2 min; and obtaining an emulsion after emulsification.
The other steps are exactly the same as in example 1.
Example 5
A preparation method of a pharmaceutic adjuvant sodium polystyrene sulfonate microsphere comprises the following steps:
the difference from example 1 is that: in S1, 2.4g of polyvinyl alcohol was added to 40g of water to prepare an emulsifier. Specifically, the operation of S1 is:
(1) an emulsifier was prepared by adding 2.4g of polyvinyl alcohol to 40g of water, then adding 2 drops of methylene blue reagent dropwise, and dissolving at 90 ℃. And cooling to be within 30 ℃ after dissolving to obtain the emulsifier.
(2) And (3) performing unblocking treatment on the raw material, namely loading 50g of alkaline alumina into a glass column, then adding styrene and divinyl benzene respectively to perform unblocking, and storing at the temperature of below 30 ℃.
(3) Emulsifying, namely mixing 44.5g of styrene, 7.5g of divinylbenzene and 0.4g of benzoyl peroxide, adding the mixture into the emulsifier in the step (1), and then emulsifying and stirring the mixture in an emulsifying machine; the stirring speed of emulsification is 8000 r/min; the emulsifying time is 8 min; and obtaining an emulsion after emulsification.
The other steps are exactly the same as in example 1.
Comparative example
Comparative example 1
A preparation method of a pharmaceutic adjuvant sodium polystyrene sulfonate microsphere comprises the following steps:
the difference from example 1 is that: the method comprises the following steps of not carrying out emulsification:
s1, polymerization: adding 44.5g of styrene, 7.5g of divinylbenzene, 0.4g of benzoyl peroxide and 267g of polyvinyl alcohol solution into a three-necked bottle, heating to 70 ℃ within 30min at a stirring speed of 900r/min, keeping for 3h, heating to 84 ℃ within 10min, keeping for 3h, heating to 95 ℃ within 10min, keeping for 1h, and then finishing the reaction to obtain a reaction solution. And then adding hot water with the volume of 4 times of that of the reaction solution and the temperature of 90 ℃ into the reaction solution for washing, centrifuging, and drying at the temperature of 110 ℃ for 5 hours to obtain the polystyrene microsphere.
S2, sulfonation: weighing 20g of polystyrene microspheres in S2, adding the polystyrene microspheres into 100g of dichloromethane, swelling for 30min at room temperature, adding 100g of concentrated sulfuric acid (the mass concentration is 98%), heating to 82 ℃ within 30min at a stirring speed of 200r/min, keeping for 4h, heating to 95 ℃ within 10min, keeping for 2h, adding the mixed solution into 1000ml of deionized water after the reaction is finished, filtering in a quartz sand funnel after the reaction is fully stirred, and washing with a large amount of deionized water until the solution is neutral to obtain the sulfonated polystyrene microspheres.
S3, transformation: adding a sodium hydroxide solution with the mass concentration of 8% into the sulfonated polystyrene microspheres obtained in S2 to stabilize the pH value between 10 and 12, stirring for 120min, then finishing the reaction to obtain a product solution, and then purifying the product solution, wherein the purification treatment comprises the following steps:
I. washing the product solution with a large amount of deionized water until the pH value is neutral, then filtering, and drying the filtered solid;
II. Adding ethanol with the volume 4 times that of the dried solid into the dried solid, performing condensation reflux cooking for 2 hours at 85 ℃, cleaning the solid with deionized water after cooking, and cooking the solid with deionized water with the volume equal to that of the ethanol after cleaning for 2 hours;
III, repeating the operation II once, then washing the microspheres with a large amount of deionized water until the pH is neutral, and drying the microspheres at 105 ℃ for 12 hours to obtain the sodium polystyrene sulfonate microspheres.
Comparative example 2
A preparation method of a pharmaceutic adjuvant sodium polystyrene sulfonate microsphere comprises the following steps:
the difference from example 1 is that: the temperature raising method in S2 is: the temperature is raised to 80 ℃ within 30min and kept for 3h, then the temperature is raised to 90 ℃ within 3h and kept for 5h, and then the reaction is finished.
Comparative example 3
A preparation method of a pharmaceutic adjuvant sodium polystyrene sulfonate microsphere comprises the following steps:
the difference from example 1 is that: s4 is not subjected to purification treatment. Specifically, the operation of S4 is:
adding a sodium hydroxide solution with the mass concentration of 8% into the sulfonated polystyrene microspheres obtained in S4 to stabilize the pH value to 10-12, stirring for 120min, then finishing the reaction to obtain a product solution, then washing the product solution with a large amount of deionized water until the pH value is neutral, then filtering, and drying the filtered solid at 105 ℃ for 12h to obtain the sodium polystyrene sulfonate microspheres.
Performance test
First, apparent Performance detection
The sodium polystyrene sulfonate microspheres prepared in examples 1 to 5 and comparative examples 1 to 3 were analyzed by scanning electron microscopy according to the method of the general rules of scanning electron microscopy for measuring micron-scale length of the Chinese national standard GB/T16594-2008, and the obtained particle size range data and average particle size data are shown in Table 1.
The SEM picture of the sodium polystyrene sulfonate microspheres prepared in example 1 is shown in fig. 1, the particle size distribution diagram of the sodium polystyrene sulfonate microspheres prepared in example 1 is shown in fig. 2, and the particle size distribution data is shown in table 3.
Secondly, detecting drug loading and drug release
1. Drug loading rate detection method
Weighing 1.5000g of the sodium polystyrene sulfonate microspheres in the examples 1-5 and the comparative examples 1-3, adding the sodium polystyrene sulfonate microspheres into 100mL of 10g/L dextromethorphan hydrobromide solution, stirring for 6h at the temperature of 60 ℃ and the stirring speed of 160r/min, then washing with water, and drying for 12h at the temperature of 60 ℃ to obtain the drug-loaded sodium polystyrene sulfonate. The drug loading amount of the sodium polystyrene sulfonate is calculated according to the concentration change of the dextromethorphan hydrobromide solution of the solution before and after drug loading, and the calculation result is shown in table 2 as follows:
Z＝[V×(C1-C0)/(m×1000×1000+V×(C1-C0))]x 100%, wherein:
z: the drug loading capacity (%) of the polystyrene sodium sulfonate microspheres;
v: dextromethorphan hydrobromide addition volume (mL);
C0: concentration (mg/L) of dextromethorphan hydrobromide solution before drug loading;
C1: concentration (mg/L) of dextromethorphan hydrobromide solution after drug loading;
the preferable reference range of the drug loading of the sodium polystyrene sulfonate microspheres is 30-35%.
2. The detection method of the drug release amount (simulating the intestinal fluid environment of a human body to carry out in-vitro drug release test) comprises the following steps:
preparing a phosphoric acid buffer solution with pH of 6.8 to simulate a human intestinal fluid environment solution, adding 800.0mL of phosphate buffer solution into a drug dissolution instrument, setting the temperature at 37 ℃, stirring at 100r/min, adding 0.3000g of drug-loaded polystyrene sodium sulfonate microspheres when the temperature of the system is stabilized to 37 ℃, sampling for 1h, 3h and 5h respectively, and calculating the drug release amount of each stage (the drug release amount of each time period is the accumulated drug release amount of the time period) by testing the content of dextromethorphan in the solution in the following calculation mode, wherein the calculation results are shown in Table 2:
s ═ C × V/(m × Z × 1000 × 1000) ] × 100%, where:
s: the release amount (%) of the sodium polystyrene sulfonate microspheres;
c: dextromethorphan hydrobromide solution concentration (mg/L);
v: volume of phosphate solution added (mL);
m: weight (g) of the drug-loaded sodium polystyrene sulfonate microspheres;
z: the drug loading capacity (%) of the polystyrene sodium sulfonate microspheres.
Wherein the concentration of the dextromethorphan hydrobromide solution is detected by gas chromatography. Chromatographic conditions are as follows: a chromatographic column: diamonsil C18 column (200 mm. times.4.6 mm,. phi.5. mu.m); mobile phase: using acetonitrile-water (70:30) solution (pH is adjusted to 3.4 by glacial acetic acid) containing 0.007mol/L dioctyl sodium sulfosuccinate and 0.007mol/L ammonium nitrate; flow rate: 1.0 ml/min; detection wavelength: 278 nm; sample introduction amount: 20 μ l.
Table 1 shows the reference range of the stable drug release amount of the sodium polystyrene sulfonate microspheres at different times
TABLE 1 sodium polystyrene sulfonate microsphere drug release reference range
| Time | 1h | 3h | 5h |
| Range of drug release amount | 42-58％ | 57-68％ | ≥67％ |
Table 2: tables of Property data of sodium polystyrene sulfonate microspheres prepared in examples 1-5 and examples 1-3
TABLE 3 table of particle size distribution of sodium polystyrene sulfonate microspheres prepared in example 1
| Particle size (. mu.m) | Percentage (%) |
| 30 | 7.12 |
| 35 | 14.54 |
| 40 | 30.53 |
| 45 | 25.13 |
| 50 | 16.62 |
| 55 | 6.06 |
As can be seen from Table 2 in combination with examples 1-3 and comparative example 1, the sodium polystyrene sulfonate microspheres prepared by the preparation method of the application have an average particle size significantly smaller than that of comparative example 1, the average particle size is substantially about 42 μm, and the distribution range of the particle size is smaller than that of comparative example 1, so that the sodium polystyrene sulfonate microspheres do not need to be crushed again in the later use process, the structure of the sodium polystyrene sulfonate microspheres is not damaged, and the sodium polystyrene sulfonate microspheres with proper particle sizes are easier to disperse uniformly in the preparation process, so that the sodium polystyrene sulfonate microspheres have better drug loading capacity and drug release stability.
The drug loading of the sodium polystyrene sulfonate microspheres of examples 1-3 is 30-35%, which is obviously higher than 18.2% of that of comparative example 1, and the drug loading of the sodium polystyrene sulfonate microspheres prepared by the method is larger, so that the sodium polystyrene sulfonate microspheres have better drug loading capacity; the release amounts of the sodium polystyrene sulfonate microspheres of examples 1 to 3 in 1h, 3h and 5h are all in the reference range of the release amount of the sodium polystyrene sulfonate microspheres of Table 1, the release amount in 1 to 3h is about 15%, the release amount in 3 to 5h is about 7%, and the release amount gradually decreases with the time, so that the sodium polystyrene sulfonate microspheres have better release stability. The sodium polystyrene sulfonate microspheres of comparative example 1 have drug release amounts within the range of Table 1 within 1h, 3h and 5h, and have drug release amount of only 5% within 1-3h, and drug release amount up to 27.1% within 3-5h, so that the drug release is extremely unstable and the using effect is poor.
It can be seen from table 2 in combination with examples 1 and 4 that the particle size of the sodium polystyrene sulfonate microspheres of example 4 is larger than that of example 1, and the distribution range of the particle size is wider than that of example 1. From the aspects of drug loading and drug release, the drug loading of example 4 is 28.3 percent and is also lower than 30.4 percent of that of example 1; the sodium polystyrene sulfonate microspheres in example 4 release 6% in 1-3h and 15.8% in 3-5h, and the release of the drug is almost less in 1-3h, and the release amount in 3-5h is suddenly increased, so the stability of the drug release is poor. Probably, the stirring speed and the stirring time during the emulsification operation do not meet the requirements, so that the emulsification process cannot be fully performed, and the drug loading capacity and the drug release stability of the sodium polystyrene sulfonate microspheres in example 4 are reduced.
As can be seen from Table 2 in combination with examples 1 and 5, the particle size of the sodium polystyrene sulfonate microsphere of example 5 is larger than that of example 1, and the particle size distribution is wider than that of example 1. The drug loading of the microsphere in example 5 is 27.5%, which is obviously lower than 30.4 of the microsphere in example 1, the drug release amount of the microsphere in example 5 in 1-3h is 23.3%, the drug release amount in 3-5h is 1%, and the drug is almost completely released in 1-3h, and the drug release amount in the subsequent process is insufficient, and the drug release is slow, so the drug release is unstable. Probably, the mass concentration of the emulsifier and the addition amount of the emulsifier are not in the ranges provided by the application, so that reactants cannot form uniform emulsion in the emulsifier, and the prepared sodium polystyrene sulfonate microspheres have large and nonuniform particle sizes, thereby influencing the drug loading rate and the drug release stability of the sodium polystyrene sulfonate microspheres.
As can be seen from Table 2 by combining example 1 and comparative example 2, the sum of the average particle sizes of the sodium polystyrene sulfonate microspheres of comparative example 2 is significantly larger than that of comparative example 1, the particle size distribution range is also significantly wider than that of example 1, the drug loading of comparative example 2 is 22.8%, which is lower than that of example 1 by 30.4, and the drug release amounts of the sodium polystyrene sulfonate microspheres of comparative example 2 in 1h, 3h and 5h are not in the reference ranges provided in Table 1; the sodium polystyrene sulfonate microspheres of the comparative example 2 have the drug release amount of 24.8 percent in 1-3h and the drug release amount of 3.1 percent in 3-5h, the drugs are almost completely released in 1-3h, and the drug release amount is rapidly reduced in 3-5h, so the sodium polystyrene sulfonate microspheres of the comparative example 2 have poor drug loading performance and drug release stability, probably because the two-step stepped temperature rise is adopted, the speed of the benzoyl peroxide for releasing free radicals is too high, the internal structure of the sodium polystyrene sulfonate microspheres formed in the polymerization process is compact, the external structure is loose, the particle size is large, the distribution is uneven, the drug loading amount and the drug release stability are poor, and the later-stage use is not facilitated.
As can be seen from table 2 in combination with example 1 and comparative example 3, although the particle size and the distribution range of the particle size of comparative example 3 are almost the same as those of the sodium polystyrene sulfonate microspheres of example 1, the drug loading is still significantly lower than that of example 1, probably because the polystyrene is remained on the sodium polystyrene sulfonate microspheres without purification treatment, and therefore the drug is not easy to attach to the sodium polystyrene sulfonate microspheres, and thus the drug loading of the sodium polystyrene sulfonate microspheres of comparative example 3 is reduced. The release amount of the sodium polystyrene sulfonate microspheres of comparative example 3 in 1h, 3h and 5h is not in the reference range provided in table 1, which indicates that the sodium polystyrene sulfonate microspheres without purification treatment have poor release stability, and may be caused by interference or obstruction to the release of the drug due to impurities remained on the polystyrene microspheres.
As can be seen from examples 1-3 in combination with tables 2 and 3, when the selected ratio of the raw materials is within the range provided by the present application, the sodium polystyrene sulfonate microspheres with narrow particle size distribution range, the distribution range of 30-55 μm and the average particle size of about 42 μm can be prepared by the preparation method of the present application, and the prepared sodium polystyrene sulfonate microspheres have good drug loading capacity and drug release stability.
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 (10)
1. A preparation method of a pharmaceutic adjuvant sodium polystyrene sulfonate microsphere is characterized by comprising the following steps:
s1, emulsification: mixing styrene, divinyl benzene and an initiator, adding the mixture into an emulsifier for emulsification, and obtaining an emulsion after the emulsification is finished; the emulsifier is selected from any one of polyvinyl alcohol solution, gelatin solution and methyl cellulose solution;
s2, polymerization: heating the emulsion, stirring to 65-75 ℃, keeping for 2-4h, continuing to heat to 80-85 ℃, keeping for 2-4h, heating to 90-98 ℃, keeping for 1-2h, finishing the reaction, washing, centrifuging and drying to obtain polystyrene microspheres;
s3, sulfonation: sulfonating the polystyrene microspheres prepared in the step S2 to obtain sulfonated polystyrene microspheres;
s4, transformation: and (3) adding a sodium hydroxide solution into the sulfonated polystyrene microspheres prepared in the step S3, stirring, reacting to obtain a product solution, and purifying and drying the product solution to obtain the sodium polystyrene sulfonate microspheres.
2. The preparation method of the sodium polystyrene sulfonate microsphere as the pharmaceutic adjuvant according to claim 1, which is characterized by comprising the following steps of: the stirring speed of the emulsification in the S1 is 7000-9000 r/min; the emulsifying time is 4-10 min.
3. The preparation method of the sodium polystyrene sulfonate microsphere as the pharmaceutic adjuvant according to claim 1, which is characterized by comprising the following steps of: in the step S1, in the step S,
the weight ratio of the styrene to the divinylbenzene is (5-10): 1;
the initiator is 0.5-1% of the weight of the styrene;
the mass concentration of the emulsifier is 2.5-5%;
the weight ratio of the styrene to the emulsifier is 1: (2-6).
4. The preparation method of the sodium polystyrene sulfonate microsphere as the pharmaceutic adjuvant according to claim 1, which is characterized by comprising the following steps of: in the step S2, the stirring speed when the emulsion is stirred at the increased temperature is 300-500 r/min.
5. The preparation method of the sodium polystyrene sulfonate microsphere as the pharmaceutic adjuvant according to claim 1, which is characterized by comprising the following steps of: the purification treatment in the S4 comprises the following steps:
I. washing the product solution with water until the pH value is neutral, then filtering, and taking a solid phase for drying;
II. Condensing, refluxing and cooking the dried sodium polystyrene sulfonate microspheres by using ethanol at the temperature of 80-90 ℃ for 2-3h, washing the cooked sodium polystyrene sulfonate microspheres by using water, and cooking the sodium polystyrene sulfonate microspheres by using water again for 2-3 h;
III, repeating the operation II.
6. The preparation method of the sodium polystyrene sulfonate microsphere as the pharmaceutic adjuvant according to claim 1, which is characterized by comprising the following steps of: the initiator in S1 is any one of azobisisobutyronitrile, cumene hydroperoxide or benzoyl peroxide.
7. The preparation method of the sodium polystyrene sulfonate microsphere as the pharmaceutic adjuvant according to claim 1, which is characterized by comprising the following steps of: the S3 includes the steps of: and (3) adding the polystyrene microspheres obtained in the step (S2) into a swelling reagent, swelling for 28-40min, adding concentrated sulfuric acid, stirring, reacting at the reaction temperature of 80-95 ℃ for 4-6h, and washing to be neutral after the reaction is finished to obtain the sulfonated polystyrene microspheres.
8. The preparation method of the pharmaceutic adjuvant sodium polystyrene sulfonate microsphere of claim 7, which is characterized in that: the swelling reagent in S3 is dichloromethane, and the mass ratio of the swelling reagent to the polystyrene microspheres to be swelled is (3-5): 1.
9. the preparation method of the sodium polystyrene sulfonate microsphere as the pharmaceutic adjuvant according to claim 1, which is characterized by comprising the following steps of: the mass concentration of the sodium hydroxide solution is 8-12%.
10. A pharmaceutic adjuvant sodium polystyrene sulfonate microsphere is characterized in that: prepared by the preparation method of any one of claims 1 to 9.
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