CN116407646A - Preparation method and application of dual-carrier dual-drug temperature response type drug delivery system - Google Patents
Preparation method and application of dual-carrier dual-drug temperature response type drug delivery system Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 92
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000002775 capsule Substances 0.000 claims abstract description 136
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims abstract description 17
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- 239000004695 Polyether sulfone Substances 0.000 claims description 64
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- 239000001257 hydrogen Substances 0.000 claims description 13
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- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
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- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
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- 108010059993 Vancomycin Proteins 0.000 abstract description 13
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- LCTORFDMHNKUSG-XTTLPDOESA-N vancomycin monohydrochloride Chemical compound Cl.O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 LCTORFDMHNKUSG-XTTLPDOESA-N 0.000 abstract description 11
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- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 2
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- ZIUHHBKFKCYYJD-UHFFFAOYSA-N n,n'-methylenebisacrylamide Chemical compound C=CC(=O)NCNC(=O)C=C ZIUHHBKFKCYYJD-UHFFFAOYSA-N 0.000 description 2
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- 229960003165 vancomycin Drugs 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 2
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 2
- 239000011715 vitamin B12 Substances 0.000 description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
- A61K47/6911—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
- A61K47/6915—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome the form being a liposome with polymerisable or polymerized bilayer-forming substances, e.g. polymersomes
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P10/00—Shaping or working of foodstuffs characterised by the products
- A23P10/30—Encapsulation of particles, e.g. foodstuff additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention belongs to the technical field of preparation of drug carriers, and particularly relates to a preparation method and application of a dual-carrier dual-drug temperature response type drug delivery system. The preparation method of the dual-carrier dual-drug temperature response type drug delivery system comprises the following steps: firstly preparing finger-hole-shaped PES capsules by a phase transition method; at the same time, for better grafting of the polymer, byN，N-Dimethylacetamide (DMAC) to erode PES capsule surface; finally, the PAAC/PAAM polymer is respectively grafted on PES capsules with the corroded surfaces by a chemical grafting method. Through a drug release experiment of VB12 and vancomycin hydrochloride, the relation between different grafting ratio combinations and temperature response is explored. Experimental findings when PES-g-PAAC and PES-g-PAAMThe temperature response of the drug delivery system is best when the graft ratio is close to 1:1. Because of the unique double-carrier model, the novel drug delivery system can conveniently remove and replace drugs, a certain convenience is improved for drug replacement by combined administration, and meanwhile, the data provides precious guidance for improving the feasibility of the multi-drug delivery system.
Description
Technical Field
The invention belongs to the technical field of preparation of drug carriers, and particularly relates to a preparation method and application of a dual-carrier dual-drug temperature response type drug delivery system.
Background
Stimulus-responsive drug delivery systems have received attention for their ability to control release of drugs, to increase bioavailability of drugs, and to reduce toxicity. Drug delivery systems for various external stimuli (e.g., light, temperature, pH, and electricity) have been systematically studied. With the mechanistic studies of some diseases, single drug therapy approaches have failed to meet the clinical dosing requirements. As an example of drug combination therapy, H.pylori infection is typically treated with a combination of antibiotics and cancer is typically treated with a combination of multiple chemotherapeutic agents. Thus, the advantages of combining a stimulus-responsive drug delivery system with multi-drug therapy have been the focus of current research.
Drug delivery systems for simultaneous loading of multiple drugs reported to date are generally based on the division of a single carrier cavity, followed by loading different drugs into their respective closed compartments, e.g. in a layer-by-layer configuration [1,2] Dual or multi-lumen structure [3-5] And polymeric micelles [6,7] . However, continuous separation of the multi-chamber system chamber units of these single carriers has not been possible, which makes such single carrier drug delivery systems less flexible.
Disclosure of Invention
In order to overcome the defects and shortcomings of the existing single-carrier multi-drug delivery system, the invention aims to provide a preparation method and application of a dual-carrier dual-drug temperature response type drug delivery system.
The conception of the invention: the carrier of the drug delivery system of the non-IPN (interpenetrating polymer network) structure is prepared based on a high molecular material of Polyacrylamide (PAAM) and polyacrylic acid (PAAC) which has the temperature-sensitive characteristic of UCST (upper critical co-solvent temperature). Different medicines are loaded into different carriers, and when the external temperature is lower than UCST, the carriers generate hydrogen bonds with the carriers due to carboxylic acid groups and amide groups on the surfaces of the carriers, so that the medicines are prevented from being released from the carriers; when the external temperature is higher than the USCT, the hydrogen bond between the carriers is broken, so that the drug molecules are easy to release from the carriers, and the temperature-responsive drug release behavior is generated.
Compared with the response temperature range of the traditional IPN-structured drug delivery system, the dual-carrier dual-drug temperature response drug delivery system can respond to temperature and rapidly release drugs in a smaller temperature range (25-30 ℃). Such multi-drug delivery systems overcome the irreversibility and inflexibility of conventional multi-drug delivery systems. In the present invention, one carrier is damaged during transportation or storage, and can be replaced with a new unit of the same carrier, similar to maintenance of a machine. Different medicines can be replaced at any time to perform combined treatment, so that clinical medication is more convenient.
In order to achieve the above purpose, the present invention provides the following technical solutions:
a dual carrier dual drug temperature responsive drug delivery system comprising a PES-g-PAAC capsule and a PES-g-PAAM capsule, both of which are loaded with a small molecular drug, preferably a hydrophilic small molecular drug such as vitamin B12, vancomycin hydrochloride, etc., the drug-loaded PES-g-PAAC capsule and the drug-loaded PES-g-PAAM capsule surface being connected by intermolecular hydrogen bonds that inhibit release of the drug from the PES capsule when the aqueous solution temperature is lower than UCST of the PAAM-PAAC pair of materials; when the temperature of the aqueous solution is higher than that of UCST (PAAM-PAAC) which is a pair of materials, hydrogen bonds between the PES-g-PAAC capsule carrying the medicine and the PES-g-PAAM capsule carrying the medicine are mutually separated due to fracture, so that the medicine can be more easily released from PES capsules, and the response of the medicine release to the temperature is achieved.
The preparation method of the dual-carrier dual-drug temperature response type drug delivery system comprises the following steps:
(1) Preparation of finger-hole PES capsule: dissolving a certain amount of polyether sulfone (PES) in N, N-Dimethylacetamide (DMAC) by adopting a sol-gel phase inversion method, adding LiCl, PEG400 and polyvinylpyrrolidone (PVP) into the solution, stirring to obtain a solution, exhausting, dripping the obtained solution into water at 30 ℃ through a syringe, and curing the solution for 30min to obtain the finger-hole-shaped PES capsule;
further, in step (1): PES, liCl, PEG400, PVP and DMAC are used in the amount relationship of (3.4-3.8) g: (0.2-0.3) g: (5-6) g:6g: (22-26) mL, preferably 3.69g:0.275g:5.63g:6g:25mL.
Further, the weight average molecular weight of the polyethersulfone is 40000-80000.
(2) Surface erosion of finger hole PES capsule: soaking the PES bag in the DMAC solvent for 40s, taking out, washing with kerosene for several times, solidifying in water at 37 ℃ for more than 4d, washing with water for 2-3 times each day until the water becomes clear, and finally drying at 40 ℃ for later use;
(3) Surface grafting of PES capsules: by ceric amine nitrate and over 98wt% of concentrated H 2 SO 4 The preparation method comprises the steps of forming an initiating system, adding a proper amount of distilled water into N, N' -methylenebisacrylamide (BIS) serving as a cross-linking agent, pre-oxidizing in air, adding a finger-hole-shaped PES (polyether sulfone) capsule with the corroded surface after 20v/v% formic acid is soaked for 12-24 hours into the system under the protection of inert gas after pre-oxidizing, adding acrylic acid or acrylamide, stirring in a water bath at 60 ℃ until the solution in the system becomes clear, taking out, washing with water, and drying to obtain PES-g-PAAM capsules or PES-g-PAAC capsules with different grafting rates.
Further, in step (3): PES, cerinamine nitrate, dense H 2 SO 4 The relation between the amount of BIS and the amount of BIS is (0.09-0.11) g: (1.8-2.1) g: (7.36-9.2) g: (1.0-1.3) g, preferably 0.1g:2g:8g:1.2g.
The grafting ratio is calculated according to the following formula:
wherein G% represents the grafting ratio; m is m 0 And m g Representing the mass of PES capsules before and after grafting respectively;
(4) Combination drug delivery of PES-g-PAAC vesicles and PES-g-PAAM vesicles: PES-g-PAAM capsules and PES-g-PAAC capsules of different grafting ratios in (3) are combined. When loading one drug in combination, VB12 was chosen as the simulated drug and PES-g-PAAC capsules were placed together in 20mLVB12 solution (50. Mu.g/mL) and soaked at 20℃for 24h. When two medicaments are jointly loaded, VB12 and vancomycin hydrochloride are selected as simulated medicaments, PES-g-PAAM capsules are placed in 20mLVB12 solution (50 mu g/mL) for soaking for 24 hours at the temperature of 20 ℃, and PES-g-PAAC capsules are placed in 20mL vancomycin hydrochloride solution (50 mu g/mL) for soaking for 24 hours;
(5) Release of the dual carrier drug: when the combination is loaded with a drug for release, 20mL of distilled water at the same temperature as the 20mL of the solution of LVB12 immersed in (4) is added at 5 ℃, 10 ℃,15 ℃,20 ℃, 25 ℃ and 30 ℃. And sucking 1mL of the aliquoting solution in different time intervals, measuring the absorbance of the aliquoting solution, pouring the aliquoting solution back after the measurement, and calculating the corresponding concentration of VB12 according to the measured absorbance. When the two drugs are jointly loaded for release, the two solutions in (4) are mixed at 5 ℃, 10 ℃,15 ℃,20 ℃, 25 ℃ and 30 ℃ after soaking. And sucking 1mL of the aliquoting solution in different time intervals, measuring the absorbance of the aliquoting solution, pouring the aliquoting solution back after the measurement, and respectively calculating the concentrations of VB12 and vancomycin hydrochloride according to the measured absorbance.
The single drug in vitro release experiment shows that: when the grafting ratio of PES-g-PAAM capsule to PES-g-PAAC capsule is 0.68-1.33, the drug release quantity is maximum, and the hydrogen bond switching effect of PAAM and PAAC is most obvious.
The in vitro release experiment of the double drugs can be known: when the grafting ratio of the PES-g-PAAM capsule to the PES-g-PAAC capsule is 0.8-1.2, the release of both drugs can show a certain temperature response.
The dual-carrier dual-drug temperature response type drug delivery system is mainly researched for application of a dual-carrier dual-drug delivery system at present, and response materials are required to be changed for actual human body application so as to reach the response temperature of a human body. However, the dual-carrier temperature-responsive drug delivery system has potential application scenarios, such as easy deterioration of food at 25-30 ℃, and the system can be loaded with two different preservatives, and release the preservatives when the food is at deterioration temperature, so as to achieve the combined preservative effect.
Compared with the prior art, the invention has the advantages that:
(1) The non-IPN system has a narrower response temperature range than the traditional IPN structured drug delivery system, which has a greater potential for accurate drug delivery.
(2) Compared with the traditional drug delivery system with a saccular structure, the PES capsule of the drug delivery system is provided with the finger-hole-shaped channel, so that the influence of bending factors can be reduced, and the drug release speed is greatly improved.
(3) Compared with a single-carrier double-drug delivery system, the double-carrier drug delivery system can simultaneously release two drugs, and can overcome the problem that the drugs can only be released layer by layer due to the hydrophilic and hydrophobic structure of the single carrier.
Drawings
FIG. 1 is an infrared absorption spectrum of ungrafted PES capsules and grafted PES capsules.
FIG. 2 is a scanning electron microscope image of ungrafted PES capsules (unetched, corroded) and grafted PES capsules.
FIG. 3 is a state diagram of ungrafted PES capsules and grafted PES capsules after immersion in DMAC.
FIG. 4 is a graph showing the release of PES-g-PAAC capsules and PES-g-PAAM capsules combined with carriers of different grafting ratios for VB12 at different temperatures.
FIG. 5 is a graph showing the release of VB12 (left) and vancomycin hydrochloride (right) at different temperatures for a PES-g-PAAC capsule and PES-g-PAAM capsule combined carrier at different grafting rates at different temperatures.
FIG. 6 is a graph showing the release of VB12 (left) and vancomycin hydrochloride (right) at different temperatures for a PES-g-PAAC capsule and PES-g-PAAM capsule combined carrier at different grafting rates at different temperatures.
Detailed Description
The technical scheme of the invention is further described below with reference to the embodiment and the attached drawings.
Example 1: preparation of the Dual Carriers
(1) Preparation of finger-hole-shaped PES (polyether sulfone) capsules
Finger-hole PES capsules were prepared by a "sol-gel" phase inversion method, i.e., 3.69g polyethersulfone (PES, MW40000, vingida advanced materials limited) was dissolved in 25mL of N, N-Dimethylacetamide (DMAC) with stirring, then 0.275g licl, 5.63g peg400 and 6g polyvinylpyrrolidone (PVP, MW 30000) were added and stirred until completely dissolved. The solution was left at 3 ℃ for a period of time until bubbles in the solution disappeared. The solution was then dropped into water by syringe at a curing temperature of 30 ℃ to cure it. After a curing time of 30min, a finger-hole shaped PES capsule was obtained, as shown in FIG. 2 (a-b), the surface morphology (scale bar 1 μm) of which is shown in FIG. 2a, and the cross-sectional morphology (scale bar 50 μm) of which is shown in FIG. 2b.
(2) Surface erosion of finger hole PES bladder
In order to make the polymer PAAC/PAAM grafted onto the surface of PES capsules more easily, the surface of the prepared PES capsules was corroded with DMAC solvent, the PES capsules were soaked in DMAC solvent for 40s, taken out, washed 2 times with kerosene, soaked in 37 ℃ water for 4d, washed 2-3 times per day with water until the water became clear. Finally, the PES bag with the corroded surface is dried in an oven at 40 ℃ and placed for standby. The surface morphology of the PES capsule after etching (scale bar 5 μm) is shown in fig. 2c, and the cross-sectional morphology (scale bar 50 μm) is shown in fig. 2d.
(3) Surface grafting of PES capsules
0.1000g PES bag is weighed and put into 20v/v% formic acid solution for soaking for 24 hours for standby, and taken out when in use. In a three-necked flask, 150mL of distilled water, 2g of cerinamine nitrate, 4.36mL of 98wt% concentrated H were added 2 SO 4 And 1.2g of N, N' -methylenebisacrylamide (BIS). Ceric amine nitrate and concentrated H 2 SO 4 An initiation system, BIS as a crosslinking agent, was composed. The whole system is placed in air for pre-oxidation for 1h, and after the pre-oxidation is finished, N is introduced 2 After 5min, 0.1g PES bag soaked with formic acid was added to a three-necked addition bottle followed by the addition of a quantity of acrylic acid AAC/acrylamide AAM monomer. The reaction mixture was under N 2 The environment was stirred in a water bath at 60℃for 24h at a speed of 100rpm until the solution became clear. Taking out the bag after reaction, soaking in distilled water for 2-3d, changing water 2 times per day to remove surface residueThe remaining reactants, namely PES-g-PAAC capsules and PES-g-PAAM capsules, were obtained respectively.
When the acrylic acid AAC of the added monomer is 6g, the grafting rate of the obtained PES-g-PAAC capsule is 25%;
when the monomer acrylamide AAM added was 5g, the grafting ratio of the PES-g-PAAM capsules obtained was 17%.
The infrared absorption spectra of PES-g-PAAC capsules and PES-g-PAAM capsules are shown in FIG. 1. The cross-sectional morphology of the PES-g-PAAC capsule (scale bar 10 μm) is shown in FIG. 2e, and the cross-sectional morphology of the PES-g-PAAM capsule (scale bar 10 μm) is shown in FIG. 2f.
The PES-g-PAAC capsules and PES-g-PAAM capsules with different grafting rates are finally obtained by adjusting the dosage of the acrylic acid AAC/acrylamide AAM.
Calculation of PES capsule grafting
The above grafted PES capsules were immersed in pure water for 48 hours (water was changed 2 to 3 times per day) and dried at 40℃until the quality remained unchanged, and the grafting ratio was calculated according to the following formula.
Wherein G% represents the grafting ratio; m is m 0 And m g Representing the mass of PES capsules before and after grafting, respectively.
Infrared characterization of PES capsules
To characterize whether the polymer PAAC/PAAM was successfully attached to PES capsules, a certain amount of PES-g-PAAC grafted capsules and PES-g-PAAM grafted capsules and ungrafted (non-corroded surface) PES capsules were taken, respectively, and the tablets were ground against potassium bromide (300:1 mass ratio to capsules) and tested under infrared, as shown in FIG. 1.
From FIG. 1 we can see that the presence of PES-g-PAAM and PES-g-PAAC, respectively, belongs to-CONH 2 1670cm of (F) -1 1716cm of carbonyl stretching vibration peak and-COOH -1 Carbonyl stretching vibration peaks, while no characteristic peak of carbonyl was observed on blank PES capsules.
Characterization of surface topography of PES capsules
The cross-section and the surface morphology of the PES capsules after drying, which were not subjected to corrosion treatment, the PES capsules after corrosion, the PES-g-PAAC capsules and the PES-g-PAAM capsules were observed under a Scanning Electron Microscope (SEM), as shown in FIG. 2.
Fig. 2 shows Scanning Electron Microscope (SEM) images of different types of PES capsules. The surface of the ungrafted PES capsule is relatively smooth, tight, clean, and the cross-section shows tight finger pores and a solid surface, which would be detrimental to grafting, while also potentially affecting drug release. The PES capsule after corrosion with N, N-Dimethylacetamide (DMAC) had a relatively rough surface, was uneven, and many finger-hole-like pores were maintained, but the surface was thin, indicating corrosion. The surfaces of the PES-g-PAAC capsule and the PES-g-PAAM capsule are adhered with a porous, uneven and irregular surface, and have similar straight holes, which are quite different from the surfaces.
Corrosion resistance test of PES-g-PAAC, PES-g-PAAM capsules
The grafted dried capsules and ungrafted capsules were simultaneously soaked in DMAC solvent for different times for photographic comparison as shown in fig. 3. Wherein a is a PES capsule which is ungrafted (and the surface is not corroded), b is a PES-g-PAAC capsule, and c is a PES-g-PAAM capsule.
From fig. 3 it was found that the ungrafted PES capsules were completely dissolved in DMAC solvent for one minute, whereas the grafted PES capsules took a long time (24 h) in DMAC solvent to slowly dissolve away PES, leaving a transparent globular structure, leaving only the polymer grafted on the capsules.
Example 2: in vitro drug-loading experiments with double carriers
(1) In vitro Release test
(1) Single drug Release test
And respectively calculating the grafting rates of the PES-g-PAAC capsules and the PES-g-PAAM capsules, and combining the PES-g-PAAM capsules with different grafting rates and the PES-g-PAAC capsules with different grafting rates to obtain eight groups of capsules with different grafting rates. For each combination, 5 PES-g-PAAC capsules and 5 PES-g-PAAM capsules were placed together in 20mLVB12 solution (50. Mu.g/mL) and soaked at 20℃for 24 hours, then 20mL of distilled water of the same temperature was added at 5 ℃, 10 ℃,15 ℃,20 ℃, 25 ℃ and 30 ℃. 1mL aliquots of the solution were aspirated at different time intervals and their absorbance was measured at 361 nm; after measurement, an aliquot of the solution was poured back. The concentration of VB12 was calculated from the measured absorbance and a concentration-time plot was drawn, as shown in FIG. 4, wherein: a1, 12% -9%; a2, 12% -15%; a3, 12% -21%; a4, 12-25%; a5, 13% -14%; a6, 17% -9%; a7, 17% -21%; a8, 17-25%. And (3) injection: the numbers before and after "-" in A1-A8 refer to the grafting rates of PES-g-PAAM capsules and PES-g-PAAC capsules, respectively.
(2) Double drug release experiments
To further investigate the switching effect of the drug delivery system when two different drugs were loaded separately, 12% grafting PES-g-PAAM capsules were combined with 10%,15%,20% and 24% grafting PES-g-PAAC capsules, respectively, and 17% grafting PES-g-PAAM capsules were combined with 10%,15%,20% and 24% grafting PES-g-PAAC capsules, respectively, to obtain eight sets of different grafting capsules and combinations of capsules. At a temperature of 20deg.C, 5 PES-g-PAAM capsules in each combination were immersed in 20mLVB12 solution (50. Mu.g/mL) for 24 hours, while 5 PES-g-PAAC capsules were immersed in 20mL vancomycin hydrochloride solution (50. Mu.g/mL) for 24 hours. Soaking, and mixing the two solutions at 5deg.C, 10deg.C, 15deg.C, 20deg.C, 25deg.C and 30deg.C. 1mL aliquots of the solution were aspirated over different time intervals and their absorbance was measured at 361nm and 281 nm; after measurement, an aliquot of the solution was poured back. The concentrations of VB12 and vancomycin hydrochloride were calculated from the measured absorbance, respectively, and concentration-time charts were drawn, as shown in FIGS. 5-6, in which: b1, 12% -10%;
12% -15% of B2%; b3 is 12% -20% B4:12% -24%; 17% -10% of C1:; 17% -15% C3:17% -20% C2:17%; 17% -24% of C4. And (3) injection: the numbers before and after "-" in B1-B4 and C1-C4 refer to the grafting rate of PES-g-PAAM capsules and PES-g-PAAC capsules respectively.
(2) Drug release profile
(1) Single drug release
To explore the switching effect of this drug delivery system, we combined PES-g-PAAM with different grafting rates with PES-g-PAAC, selected single drug vitamin B12 (VB 12) as model drug, and carried out the drug at different temperatures (5 ℃, 10 ℃,15 ℃,20 ℃, 25 ℃ and 30 ℃)Release experiments. As shown in fig. 4, the cumulative drug concentration in groups A1, A2, A5 is lower when the temperature is lower than 25 ℃, and the cumulative drug concentration is significantly higher when the temperature is higher than 25 ℃. Interestingly, the cumulative drug concentration of groups A7 and A8 was also significantly higher at 25 ℃. This means that when the temperature is lower than UCST (upper critical co-dissolution temperature), interaction occurs between PES-g-PAAC and PES-g-PAAM capsules through intermolecular hydrogen bonds, preventing release of the drug, whereas when the temperature is higher than UCST, hydrogen bonds generated between carriers are broken, the interacted parts are separated, and drug molecules easily pass through the surface of PES capsules. In contrast, groups A3, A4, A6 were found to have no such temperature responsiveness. Through the statistical comparison of the grafting rates of different groups, the drug release amount is maximum when the grafting rate ratio of the PES-g-PAAM capsule to the PES-g-PAAC capsule is 0.68-1.33, and the hydrogen bond switching effect of the PAAM and the PAAC is most obvious. This is because when the contact area of the two carriers is the same, and the-CONH on PES capsules 2 When the amount is relatively close to the-COOH amount, intermolecular hydrogen bonds and hydrogen bond effects are best at the capsule-to-capsule contact site. However, when the grafting ratio of PES-g-PAAC and PES-g-PAAM is too large, incomplete or lack of hydrogen bonding at the contact site does not produce a switching effect of drug release.
(2) Double drug release
VB12 and vancomycin hydrochloride were chosen as model drugs and loaded into PES-g-PAAM and PES-g-PAAC carriers, respectively. Drug release experiments were performed at different temperatures (5 ℃, 10 ℃,15 ℃,20 ℃, 25 ℃ and 30 ℃). From fig. 5 we find that groups B1 and B2 also exhibit the same temperature responsive phenomenon as when a single drug is released. At temperatures below 25 ℃, the cumulative release concentrations of VB12 and vancomycin hydrochloride are both relatively low, but at 25 ℃, the cumulative release concentrations of VB12 and vancomycin are significantly greater than the drug release concentrations at other temperatures. However, as the difference in grafting ratio becomes larger, the temperature responsiveness exhibited by the group becomes less pronounced even when the drug release profile of the 12% PES-g-PAAM and 24% PES-g-PAAC combination is such that no relationship between any temperature and drug release concentration is exhibited. Also, in FIG. 6 we found that the response of drug release to temperature was not evident in the 17% PES-g-PAAM and 10% PES-g-PAAC combinations and 17% PES-g-PAAM and 24% PES-g-PAAC combinations, which were significantly different in grafting rate; in contrast, in the groups C2 and C3 where the grafting ratio was relatively close, but when the temperature reached 25 ℃, the cumulative drug concentrations of VB12 and vancomycin increased significantly, and also exhibited good temperature responsiveness. Through this experiment we found that even in both drug models, a certain temperature responsiveness can be exhibited when the ratio of grafting ratio of PES-g-PAAM capsule to PES-g-PAAC capsule is 0.8-1.2.
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Claims (9)
1. The dual-carrier dual-drug temperature response type drug delivery system is characterized by comprising a PES-g-PAAC (polyether sulfone-polyamide) capsule and a PES-g-PAAM capsule, wherein a small molecular drug m is loaded in the PES-g-PAAC capsule, a small molecular drug n is loaded in the PES-g-PAAM capsule, and the small molecular drug m is the same as or different from n;
when the temperature of the aqueous solution of the double-carrier double-drug is lower than that of UCST of the PAAM-PAAC material, the PES-g-PAAC bag carrying the drug is connected with the surface of the PES-g-PAAM bag carrying the drug through intermolecular hydrogen bonds, and the double-drug is hardly released;
when the temperature of the aqueous solution of the double-carrier double-medicine is higher than that of UCST of the PAAM-PAAC pair material, hydrogen bonds between the PES-g-PAAC bag carrying medicine and the PES-g-PAAM bag carrying medicine are mutually separated due to fracture, and the double-medicine is released from the bags;
the grafting ratio of the PES-g-PAAM capsule to the PES-g-PAAC capsule is 0.68-1.33;
the grafting ratio of the PES-g-PAAM capsule to the PES-g-PAAC capsule is 0.8-1.2;
wherein, the grafting ratio G% is calculated according to the following formula:
m 0 and m g Representing the mass of PES capsules before and after grafting, respectively.
2. The dual carrier dual drug temperature responsive drug delivery system of claim 1, wherein the PES-g-PAAC capsule or PES-g-PAAM capsule preparation method comprises the steps of:
(1) Preparation of finger-hole PES capsule: dissolving polyethersulfone in N, N-dimethylacetamide, adding LiCl, PEG400 and polyvinylpyrrolidone, stirring to obtain a solution, exhausting, dripping the obtained solution into water at 30 ℃, and curing for 30min to obtain a finger-hole-shaped PES bag;
(2) Surface erosion of finger hole PES capsule: soaking the finger-hole-shaped PES bag obtained in the step (1) in N, N-dimethylacetamide for 40s, taking out, cleaning with kerosene, then placing in 37 ℃ water for curing for more than 4d, taking out, and then drying at 40 ℃ for later use;
(3) Surface grafting of PES capsules: by ceric amine nitrate and98wt% of concentrated H 2 SO 4 The preparation method comprises the steps of forming an initiating system, adding an appropriate amount of distilled water serving as a cross-linking agent, pre-oxidizing in air, adding a finger-hole-shaped PES (polyether sulfone) capsule with the corroded surface after 20v/v% formic acid is soaked for 12-24 hours into the system under the protection of inert gas after pre-oxidizing, adding acrylic acid or acrylamide, stirring in a water bath at 60 ℃ until the solution in the system becomes clear, taking out, washing with water, and drying to obtain PES-g-PAAM capsules or PES-g-PAAC capsules with different grafting rates.
3. The dual carrier dual drug temperature responsive drug delivery system of claim 2, wherein in step (1): PES, liCl, PEG400, PVP and DMAC are used in the amount relationship of (3.4-3.8) g: (0.2-0.3) g: (5-6) g:6g: (22-26) mL.
4. The dual carrier dual drug temperature responsive drug delivery system of claim 2, wherein in step (3): PES, cerinamine nitrate, dense H 2 SO 4 The relation between the amount of BIS and the amount of BIS is (0.09-0.11) g: (1.8-2.1) g: (7.36-9.2) g: (1.0-1.3) g.
5. The dual carrier dual drug temperature responsive drug delivery system of claim 2, wherein the polyethersulfone has a weight average molecular weight of 40000-80000.
6. The dual carrier dual drug temperature responsive drug delivery system of claim 1, wherein the PES-g-PAAC capsule, PES-g-PAAM capsule loading small molecule drug steps are: the PES-g-PAAC capsule and the PES-g-PAAM capsule are respectively soaked in an aqueous solution containing small molecules of the drug for more than 24 hours, and then the two solutions are mixed.
7. Use of a dual carrier dual drug temperature responsive drug delivery system as claimed in any one of claims 1 to 6 in combination.
8. The use according to claim 7, wherein the temperature of the environment of administration is 25 ℃ to 30 ℃.
9. The use according to claim 7, wherein the dual carrier is loaded with two different preservatives.
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