CN114099764B - Preparation method of W/O/W type temperature-sensitive embolic agent - Google Patents
Preparation method of W/O/W type temperature-sensitive embolic agent Download PDFInfo
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- CN114099764B CN114099764B CN202111432164.8A CN202111432164A CN114099764B CN 114099764 B CN114099764 B CN 114099764B CN 202111432164 A CN202111432164 A CN 202111432164A CN 114099764 B CN114099764 B CN 114099764B
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- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 claims description 18
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
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- 229960004528 vincristine Drugs 0.000 description 1
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- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0031—Hydrogels or hydrocolloids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices
Abstract
The invention provides a preparation method of a W/O/W type temperature-sensitive embolic agent, which comprises the following steps: dispersing the temperature-sensitive nano gel and a first aqueous developer in water to obtain an external water phase; mixing the internal water phase with the oil phase dispersed with the oily developer, and carrying out first emulsification to obtain a W/O emulsion; and mixing the W/O emulsion with external water, and carrying out second emulsification under an ice bath condition, wherein the second emulsification is intermittent emulsification to obtain the W/O/W type temperature-sensitive embolic agent. The preparation method ensures the stability of the prepared emulsion by carrying out intermittent emulsification under the ice bath condition, developers are dispersed in the external water phase and the oil phase of the W/O/W type temperature-sensitive embolic agent, the developing capability of the embolic agent is ensured by adjusting the dosage of the developers, and the embolization effect of the temperature-sensitive embolic agent is effectively ensured because the dosage of the developers in the external water phase is adjustable.
Description
Technical Field
The invention relates to the technical field of embolism, in particular to a preparation method of a W/O/W type temperature-sensitive embolic agent.
Background
Transcatheter Arterial Embolization chemotherapy (TACE) is one of the most important current treatments for middle and advanced liver cancer, in which Embolization agents play a very important role. The liquid embolic agent represented by the iodine oil emulsion is the liver tumor vascular embolization material which is most widely applied at present, and the traditional chemoembolization based on the iodine oil emulsion is called C-TACE (Convention-TACE). Although the iodized oil emulsion has good fluidity and can smoothly pass through a microcatheter to realize tumor peripheral vascular embolization, the iodized oil emulsion has poor embolization performance and is easily scoured and metabolized by blood to cause recanalization, under the condition, solid embolization agents such as gelatin Sponge (gelatin Sponge) and PVA (polyvinyl alcohol) are often needed to be matched for secondary embolization treatment, the operation of the secondary embolization treatment is complicated, the cost is increased, and embolization complications can be caused sometimes.
The poly-N-isopropylacrylamide temperature-sensitive nanogel has low viscosity in a sol state, can be converted into a non-flowable gel state from a good flowing state in a human body temperature environment, has good fluidity and embolization, can overcome the contradiction between the fluidity and the embolization of the traditional embolization agent, has drug-carrying slow-release performance, and is expected to become a new generation of embolization agent for interventional therapy. The temperature-sensitive gel does not have a developing function, and needs to be blended with a developer for realizing visualization in the operation. In the actual operation process, the developing capacity is often improved by selectively increasing the using amount of the developing agent; however, an excessive amount of the developer increases the viscosity of the gel and lowers the fluidity, and also decreases the gel strength and becomes soft, thereby impairing the embolization effect.
Disclosure of Invention
In view of the above, the present invention is directed to a method for preparing a W/O/W type temperature-sensitive embolization agent to coordinate the developability and embolization effect of the temperature-sensitive embolization agent.
The invention provides a preparation method of a W/O/W type temperature-sensitive embolic agent, which comprises the following steps:
providing temperature-sensitive nanogel, wherein the temperature-sensitive nanogel is a poly N-isopropyl acrylamide polymer with a three-dimensional network structure, and dispersing the temperature-sensitive nanogel and a first aqueous developer in water to obtain an external water phase;
providing an oil phase having dispersed therein an oily developer;
providing an internal water phase, mixing the internal water phase and the oil phase, and carrying out first emulsification to obtain a W/O emulsion;
and mixing the W/O emulsion with the external water, and carrying out secondary emulsification under an ice bath condition, wherein the secondary emulsification is intermittent emulsification to obtain the W/O/W type temperature-sensitive embolic agent.
Preferably, the second emulsification comprises: circularly carrying out shearing emulsification and pause at the rotating speed of 6000 r/min-10000 r/min, wherein the circulating frequency is at least 1, the shearing emulsification is carried out for 30 s-60 s every time, and the pause is carried out for 30 s-60 s every time;
the total shearing time of the second emulsification is 1-10 min.
Preferably, said first emulsification comprises: shearing and emulsifying at the rotating speed of 6000 r/min-10000 r/min for 1 min-10 min.
Preferably, the N-isopropylacrylamide-based polymer having a three-dimensional network structure is N-isopropylacrylamide or a crosslinked polymer of N-isopropylacrylamide and a comonomer selected from one or more of acrylic acid, N-propylacrylamide, methacrylic acid, hydroxyethyl methacrylate, hydroxyethyl acrylate, and acrylamide.
Preferably, the weight of the temperature-sensitive nanogel is 1 to 8g per 100ml of the external water phase; and/or
The mass ratio of the temperature-sensitive nanogel to the first aqueous developer is (1-6) to (0.5-50).
Preferably, the solvent of the oil phase is iodized oil and/or vegetable oil for injection.
Preferably, the solvent of the oily developer and the oil phase is iodized oil, and the mass ratio of the iodized oil to the first aqueous developer is (10-40): (0.5-50).
Preferably, the volume ratio of the internal aqueous phase to the oil phase is 1: (1-8); and/or
The total mass of the W/O/W type temperature-sensitive embolic agent is 100 parts, and the mass of the temperature-sensitive nanogel is 1-6 parts.
Preferably, in the step of dispersing the temperature-sensitive nanogel and the first aqueous developer in water, an aqueous chemotherapeutic agent is also added; the mass ratio of the water-based chemotherapeutic drug to the temperature-sensitive nano gel is (0.1-5) to (1-6); and/or
In the step of mixing the internal water phase and the oil phase, a surfactant is also added; the mass ratio of the surfactant to the oil phase is (0.01-2) to (10-40).
Preferably, the oil phase also has dispersed therein: oily chemotherapeutic drugs; the mass ratio of the oily chemotherapeutic drug to the oil phase is (0.05-1.5) to (10-40); and/or
The internal aqueous phase further comprises: an aqueous chemotherapeutic agent and/or a second aqueous imaging agent.
The invention provides a preparation method of a W/O/W type temperature-sensitive embolic agent, which comprises the following steps: dispersing the temperature-sensitive nano gel and a first aqueous developer in water to obtain an external water phase; providing an oil phase in which an oily developer is dispersed; mixing the inner water phase and the oil phase through the inner water phase, and carrying out first emulsification to obtain a W/O emulsion; and mixing the W/O emulsion with external water, and carrying out second emulsification under an ice bath condition, wherein the second emulsification is intermittent emulsification to obtain the W/O/W type temperature-sensitive embolic agent. Compared with the prior art, on one hand, the invention ensures that the emulsification process is carried out below the lower critical transition temperature (LCST) by carrying out intermittent emulsification under the ice bath condition, avoids the temperature-sensitive nanogel from losing the effect of the surfactant caused by overhigh shearing and temperature rise, and avoids the emulsion breaking and layering caused by the gel phase change of the temperature-sensitive nanogel, thereby preparing the emulsion with stable performance; on the other hand, through adopting specific steps, the better interaction of the whole body is realized, developers can be added into the external water phase and the oil phase of the obtained W/O/W type temperature-sensitive embolic agent in different degrees, the purpose of improving the developing capability of the embolic agent can be realized by adjusting the using amount of the developers in the external water phase and the oil phase, and meanwhile, the problems of reduced flowability and weakened embolism effect of the temperature-sensitive nanogel caused by overhigh using amount of the developers in the external water phase can be effectively avoided while the requirements on developing performance are met due to the adjustable using amount of the developers in the external water phase. In addition, the oily developer is dispersed in the oil phase, and the aqueous developer is dispersed in the external water phase, so that the developers with different polarities can stably exist in the same preparation form, and the stability of the embolic agent is favorably improved.
In addition, the preparation method provided by the invention has the advantages of simple process and stronger adjustability, can fully dissolve and disperse chemotherapeutic drugs with different solubilities (water solubility and oil solubility), and has broad-spectrum drug-loading property; meanwhile, the W/O/W type temperature-sensitive embolic agent prepared by the preparation method provided by the invention is liquid at normal temperature due to temperature sensitivity, and is converted into solid after injection, so that the contradiction between fluidity and embolization in the prior embolic agent can be effectively solved, and the W/O/W type temperature-sensitive embolic agent has a wide application prospect.
Drawings
FIG. 1 is a process flow diagram of a preparation method of a W/O/W type temperature-sensitive embolic agent provided by an embodiment of the invention;
FIG. 2 is a comparative graph of X-ray photographs taken of the temperature-sensitive embolic agent provided in example 1 and comparative examples 1-2.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below with reference to embodiments of the present invention, and it should be apparent that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The embodiment of the invention provides a preparation method of a W/O/W type temperature-sensitive embolic agent, which comprises the following steps:
a) Providing a temperature-sensitive nanogel, wherein the temperature-sensitive nanogel is a poly N-isopropylacrylamide polymer with a three-dimensional network structure, and dispersing the temperature-sensitive nanogel and a first aqueous developer in water to obtain an external water phase;
b) Providing an oil phase in which an oily developer is dispersed;
c) Providing an internal water phase, mixing the internal water phase and the oil phase, and carrying out first emulsification to obtain a W/O emulsion;
d) And mixing the W/O emulsion with external water, and carrying out second emulsification under an ice bath condition, wherein the second emulsification is intermittent emulsification to obtain the W/O/W type temperature-sensitive embolic agent.
It is understood that the above a), b), c), d) do not limit the order of the steps of the methods according to the embodiments of the present invention, and the order of the steps can be flexibly adjusted according to the actual production conditions, for example, the step a) can be performed after the steps b) and c) are completed.
Referring to fig. 1, fig. 1 is a process flow chart of a method for preparing a W/O/W type temperature-sensitive embolic agent according to an embodiment of the present invention.
The invention firstly disperses temperature sensitive nano-gel and a first aqueous developer in water to obtain an external water phase.
In the embodiment of the invention, the temperature-sensitive nanogel is a poly N-isopropylacrylamide polymer with a three-dimensional network structure, preferably N-isopropylacrylamide or a cross-linked polymer of N-isopropylacrylamide and a comonomer, and more preferably a cross-linked polymer of N-isopropylacrylamide and a comonomer; the polymer is different from a conventional linear poly N-isopropyl acrylamide polymer, has a three-dimensional network structure, and is marked as poly N-isopropyl acrylamide temperature-sensitive nanogel.
In the present embodiment, the comonomer is preferably selected from one or more of Acrylic Acid (AA), N-propyl acrylamide (NNP), methacrylic acid (MAA), hydroxyethyl methacrylate (HEMA), hydroxyethyl acrylate (HEA), and acrylamide (AAm); correspondingly, crosslinked polymers of N-isopropylacrylamide and a comonomer include crosslinker-crosslinked poly (N-isopropylacrylamide), crosslinker-crosslinked poly (NIP-co-AA), crosslinker-crosslinked poly (NIP-co-NNP), crosslinker-crosslinked poly (NIP-co-MMA), crosslinker-crosslinked poly (NIP-co-HEMA), crosslinker-crosslinked poly (NIP-co-HEA), and crosslinker-crosslinked poly (NIP-co-AAm); the crosslinking agent used for crosslinking is preferably one or more selected from the group consisting of N, N ' -methylenebisacrylamide, N ' -ethylenebisacrylamide, 1, 3-propylenediacrylamide, ethylene diacrylate, diethylene glycol diacrylate, triethylene glycol diacrylate, trimethylolpropane triacrylate, pentaerythritol triacrylate, and more preferably N, N ' -methylenebisacrylamide. In some embodiments, the crosslinker is N, N' -methylenebisacrylamide (hereinafter referred to as MBA).
The sources of the temperature-sensitive nanogel, the comonomer and the crosslinking agent are not particularly limited in the invention, and the temperature-sensitive nanogel, the comonomer and the crosslinking agent can be commercially available products well known to those skilled in the art, and can also be prepared into obtained products by adopting the conventional technical means in the art.
Taking MBA cross-linked poly (NIP-co-AA) as an example, the preparation method is preferably as follows:
adding N-isopropyl acrylamide, sodium dodecyl sulfate and MBA into a three-necked bottle provided with a reflux condenser tube and an air guide device, dissolving the N-isopropyl acrylamide, the sodium dodecyl sulfate and the MBA by using ultrapure water under magnetic stirring, introducing high-purity nitrogen into the reaction system for 20-40 min, heating the reaction system to 65-75 ℃, adding an initiator potassium persulfate, and adding N into the mixture 2 Reacting for 0.5-1h at 65-75 ℃ in the atmosphere, adding acrylic acid, continuing to react for 4-5 h to obtain a white turbid suspension, dialyzing and purifying the suspension in ultrapure water, and freeze-drying to obtain the freeze-dried powder, namely the poly (NIP-co-AA).
In the present embodiment, the first aqueous developer is preferably selected from one or more of iohexol, iopamidol, iodixanol and ioflurol, and more preferably iohexol, iopamidol, iodixanol or ioflurol. The source of the aqueous developer in the present invention is not particularly limited, and commercially available products known to those skilled in the art may be used.
In the step a), the operation of dispersing the temperature-sensitive nanogel and the first aqueous developer in water may refer to the conventional operation of a person skilled in the art, so that the temperature-sensitive nanogel and the first aqueous developer are completely dissolved in water, for example, a mechanical stirring method may be adopted.
In the step of dispersing the temperature-sensitive nanogel and the first aqueous developer in water, adjusting the addition amount of the temperature-sensitive nanogel to ensure that the mass of the temperature-sensitive nanogel in each 100mL of external aqueous phase is 1-8 g; in addition, the addition amount of the first aqueous developer is adjusted, so that the mass ratio of the temperature-sensitive nano gel to the first aqueous developer is (1-6): (0.5-50), thus ensuring the normal running of the phase transition behavior of the gel, avoiding the negative influence caused by the excessive or insufficient addition amount of the first aqueous developer, and when the addition amount of the first aqueous developer is less than the lower limit value of the addition amount, the developing capability of the suppository cannot be effectively improved; when the amount of the first aqueous developer added is larger than the upper limit value of the above amount, the plugging effect of the plugging agent is reduced.
In the embodiment of the invention, the mass of the temperature-sensitive nanogel is 1-6 parts, more preferably 2.8-5.9 parts, based on 100 parts of the total mass of the W/O/W type temperature-sensitive embolic agent; on the basis, the embolic agent has good fluidity while ensuring good embolization effect.
In the embodiment of the present invention, the mass of the first aqueous developer is 0.5 to 50 parts, more preferably 1.12 to 30 parts, based on 100 parts of the total mass of the W/O/W type temperature-sensitive plugging agent.
In the embodiment of the present invention, preferably, in the step of dispersing the temperature-sensitive nanogel and the first aqueous developer in water, an aqueous chemotherapeutic agent is further added; the mass ratio of the water-based chemotherapeutic drug to the temperature-sensitive nano gel is (0.1-5) to (1-6). More preferably, the mass ratio of the aqueous chemotherapeutic drug to the temperature-sensitive nanogel is (0.5-3) to (1-6).
The embodiment of the invention has no special limitation on the specific types and sources of the water-based chemotherapeutic drugs, and the drugs are mainly selected from purchased drugs.
According to the invention, the external water phase with the specific content is adopted, and the specific aqueous developer is dispersed in the external water phase, so that on one hand, the purpose of increasing the development capability of the preparation can be achieved by cooperating with the oily developer in the oil phase part, and on the other hand, the dosage of the aqueous developer in the external water phase can be adjusted, the influence on the fluidity of the suppository and the gel phase change behavior of the suppository due to the overhigh dosage of the aqueous developer in the external water phase can be avoided, and the embolism effect of the temperature-sensitive suppository can be ensured. It is worth noting that the excellent embolization effect and the excellent developability of the preparation can be ensured by adjusting the dosage of the temperature-sensitive nanogel and the developer in the temperature-sensitive embolization agent within the above range.
In step b), providing an oil phase in which an oily developer is dispersed.
In the embodiment of the invention, the solvent of the oil phase is an oil-soluble solvent, and the oily developer is dispersed in the oil-soluble solvent, so that the compatibility is good and the stability is high. The preparation method of the oil phase can refer to the conventional technology in the field, for example, the oil developer is added into the oil-soluble solvent and stirred uniformly to obtain the oil phase.
In some embodiments, the solvent of the oil phase is iodized oil and/or vegetable oil for injection. Preferably, the solvent of the oily developer and the oil phase is iodized oil, and the mass ratio of the iodized oil to the first aqueous developer is (10-40): 0.5-50. The iodized oil is used as an oil phase matrix and a developer, so that the dosage of the oily developer in the embolic agent can be maximized; in addition, by forming a W/O/W type, the water-soluble poly N-isopropyl acrylamide temperature-sensitive nano gel can stably coexist with the iodized oil, so that the stability of the preparation is remarkably improved while the embolization effect is improved. In addition, the addition amount of the iodized oil is adjusted to ensure that the mass ratio of the iodized oil to the first aqueous developer is (10-40): (0.5-50), more preferably (20-34): (0.5-50), so as to ensure the stability of the preparation and prevent demulsification caused by excessive iodized oil.
In some embodiments, the oily chemotherapeutic drug is dispersed in the oil phase, and the mass ratio of the oily chemotherapeutic drug to the iodized oil is (0.05-1.5): 10-40. Oily chemotherapeutic drugs are added into the oil phase, so that the oily chemotherapeutic drugs and the iodized oil are jointly used as the oil phase; meanwhile, the oily chemotherapeutic medicament is adjusted to ensure that the mass ratio of the oily chemotherapeutic medicament to the iodized oil is (0.05-1.5) to (10-40), preferably (0.07-1) to (10-40).
The specific types and sources of the oily chemotherapeutic drugs are not particularly limited in the embodiment of the invention, and the oily chemotherapeutic drugs are mainly purchased drugs.
In the step c), providing an internal water phase, mixing the internal water phase and the oil phase, and carrying out first emulsification to obtain the W/O emulsion.
The mixing method is not limited in any way, and the step of mixing the internal water phase and the oil phase can be performed by adopting a technical scheme of manual stirring or mechanical stirring which is well known to those skilled in the art, so that the internal water phase and the oil phase are uniformly mixed.
In some embodiments, the internal aqueous phase comprises: an aqueous chemotherapeutic agent and/or a second aqueous imaging agent. The concentration of the second aqueous developer dispersed in the internal aqueous phase in the embodiments of the present invention is not particularly limited, and may be a concentration in a range of 0 to a saturation concentration, which is well known to those skilled in the art. The embodiment of the invention disperses the second aqueous developer in the internal aqueous phase, which is beneficial to improving the amount of the developer in the temperature-sensitive suppository, thereby further improving the X-ray developing capability.
In embodiments of the present invention, the second aqueous developer is preferably selected from one or more of iohexol, iopamidol, iodixanol and iofluranol, more preferably iohexol, iopamidol, iodixanol or iofluranol. The source of the second aqueous developer in the present invention is not particularly limited, and commercially available products known to those skilled in the art may be used.
In some embodiments, the second aqueous developer has a mass of 0.1 to 5 parts, more preferably 0.5 to 2 parts, based on 100 parts of the total mass of the W/O/W type temperature-sensitive embolizing agent.
In the embodiment of the present invention, the specific types and sources of the aqueous chemotherapeutic agent are the same as those in the above technical solution, and are not described herein again.
In the embodiment of the invention, the mass of the aqueous chemotherapeutic drug in the internal water phase is 0.05-3 parts by total mass of the W/O/W type temperature-sensitive embolic agent as 100 parts.
In the present embodiment, the volume ratio of the internal aqueous phase and the oil phase is preferably 1: (1 to 8), more preferably 1: (2-3).
In an embodiment of the invention, the first emulsification comprises: shearing and emulsifying at the rotating speed of 6000 r/min-10000 r/min for 1 min-10 min.
In the embodiment of the invention, in the step of mixing the internal water phase and the oil phase, a surfactant is also added; the mass ratio of the surfactant to the iodized oil is (0.01-2) to (10-40). On the basis, the first emulsification process is preferably specifically as follows: mixing the inner water phase, the oil phase and the surfactant, and shearing and emulsifying at the rotating speed of 6000-10000 r/min for 1-10 min to obtain the W/O emulsion.
In the present embodiment, the surfactant is preferably polyglycerol polyricinoleate or tween. The source of the surfactant in the present invention is not particularly limited, and commercially available products known to those skilled in the art may be used.
In the embodiment of the present invention, the mass of the surfactant is 0.01 to 2 parts, more preferably 0.67 to 1.14 parts, based on 100 parts of the total mass of the W/O/W type temperature-sensitive plugging agent.
In the step d), mixing the W/O emulsion with external water, and carrying out second emulsification under the ice bath condition, wherein the second emulsification is batch emulsification, so as to obtain the W/O/W type temperature-sensitive embolic agent.
In the embodiment of the invention, after the W/O emulsion is obtained, the obtained W/O emulsion is mixed with the external water phase to carry out the second emulsification. The external aqueous phase is the same as that in the above technical scheme, and is not described herein again. Similarly, the mixing manner in the embodiments of the present invention is not particularly limited, and the technical solutions of manual stirring or mechanical stirring known to those skilled in the art can be adopted, so as to achieve uniform mixing.
In an embodiment of the invention, the volume ratio of the sum of the internal aqueous phase and the oil phase to the external aqueous phase is preferably 1: (1 to 5), more preferably 1: (1-2).
In the embodiment of the invention, the mixture of the W/O emulsion and the external water phase is emulsified for the second time under the ice bath condition, and the second emulsification is intermittent emulsification. The intermittent emulsification means that a pause exists in the emulsification process, and the emulsification step is continued after the pause step is finished. By carrying out intermittent emulsification under the ice bath condition, the emulsification process is ensured to be carried out below the lower critical transition temperature (LCST), the condition that the temperature-sensitive nanogel loses the function of a surfactant due to overhigh shearing and temperature rise is avoided, and the condition that emulsion breaking and layering are caused by gel phase change of the temperature-sensitive nanogel is avoided, so that the emulsion with stable performance is prepared.
In some embodiments, the second emulsification comprises: circularly shearing, emulsifying and pausing at the rotating speed of 6000 r/min-10000 r/min, wherein the circulating frequency is at least 1, the shearing and emulsifying are carried out for 30 s-60 s every time, and the pausing is carried out for 30 s-60 s every time; the total shearing time of the second emulsification is 2 min-10 min. The emulsification condition is adopted for emulsification to form W/O/W emulsion, emulsion breaking and layering caused by overhigh emulsification shearing strength are avoided, and meanwhile, too long process time caused by overlow emulsification shearing strength is avoided, and labor cost is increased.
In a specific embodiment, after the W/O emulsion and the external water are mixed, shearing and emulsifying are carried out for 30s under the ice bath condition at the rotating speed of 6000r/min, the time is stopped for 30s, then the shearing and emulsifying are carried out for 30s, the time is stopped for 4 times, the total shearing time is 3min, and the W/O/W type temperature-sensitive embolic agent is obtained.
In the embodiment of the invention, the poly-N-isopropylacrylamide temperature-sensitive nanogel is in a sol state below the lower critical transition temperature (LCST), and becomes hydrophobic and condensed to be in a solid state when the temperature is higher than or equal to the LCST, so that the original hydrophilic-lipophilic balance of the emulsion is destroyed, the phenomena of instability such as emulsion breaking, layering and the like of the emulsion are caused, and the temperature-sensitive nanogel loses the effect of a surfactant. On the basis, the embodiment of the invention can ensure that the emulsification process is carried out below the lower critical transition temperature (LCST) by carrying out intermittent emulsification under the ice bath condition, avoid the temperature-sensitive nanogel from losing the effect of the surfactant due to overhigh shearing and temperature rise, and avoid emulsion breaking and layering of the emulsion due to gel phase change of the temperature-sensitive nanogel, thereby preparing the emulsion with stable performance.
The preparation method provided by the invention has the advantages of simple process and stronger adjustability, can fully dissolve and disperse chemotherapeutic drugs with different solubilities (water solubility and oil solubility), and has broad-spectrum drug-loading property; meanwhile, the W/O/W type temperature-sensitive embolic agent prepared by the preparation method provided by the invention is liquid at normal temperature due to temperature sensitivity, and is converted into solid after injection, so that the contradiction between fluidity and embolization of the conventional embolic agent can be effectively solved, and the W/O/W type temperature-sensitive embolic agent has a wide application prospect.
It is understood that the aqueous chemotherapeutic drug and the oily chemotherapeutic drug mentioned in the above preparation method are added for improving the chemotherapeutic effect, and may be omitted, without affecting the preparation of the above composite emulsion, and the above drugs include, but are not limited to, doxorubicin hydrochloride, paclitaxel, cisplatin, carboplatin, oxaliplatin, docetaxel, gemcitabine, mitomycin, vincristine, and tinib antineoplastic drugs.
In summary, the preparation method of the W/O/W type temperature-sensitive embolic agent provided by the embodiment of the present invention comprises the following steps: dispersing the temperature-sensitive nano gel and a first aqueous developer in water to obtain an external water phase; providing an oil phase in which an oily developer is dispersed; mixing the internal water phase and the oil phase through the internal water phase, and carrying out first emulsification to obtain a W/O emulsion; and mixing the W/O emulsion with external water, and carrying out second emulsification under an ice bath condition, wherein the second emulsification is intermittent emulsification to obtain the W/O/W type temperature-sensitive embolic agent. Compared with the prior art, on one hand, the invention ensures that the emulsification process is carried out below the lower critical transition temperature (LCST) by carrying out intermittent emulsification under the ice bath condition, avoids the temperature-sensitive nanogel from losing the effect of the surfactant caused by overhigh shearing temperature rise, and avoids the emulsion breaking and layering caused by the gel phase change of the temperature-sensitive nanogel, thereby preparing the emulsion with stable performance; on the other hand, through adopting specific steps, the better interaction of the whole body is realized, developers can be added into the external water phase and the oil phase of the obtained W/O/W type temperature-sensitive embolic agent in different degrees, the purpose of improving the developing capability of the embolic agent can be realized by adjusting the using amount of the developers in the external water phase and the oil phase, and meanwhile, the problems of reduced flowability and weakened embolism effect of the temperature-sensitive nanogel caused by overhigh using amount of the developers in the external water phase can be effectively avoided while the requirements on developing performance are met due to the adjustable using amount of the developers in the external water phase. In addition, the oily developer is dispersed in the oil phase, and the aqueous developer is dispersed in the external water phase, so that the developers with different polarities can stably exist in the same preparation form, and the stability of the embolic agent is favorably improved.
In addition, the preparation method provided by the invention has the advantages of simple process and stronger adjustability, can fully dissolve and disperse the chemotherapeutic drugs with different solubilities (water solubility and oil solubility), and has broad-spectrum drug-loading property; meanwhile, the W/O/W type temperature-sensitive embolic agent prepared by the preparation method provided by the invention is liquid at normal temperature due to temperature sensitivity, and is converted into solid after injection, so that the contradiction between fluidity and embolization of the conventional embolic agent can be effectively solved, and the W/O/W type temperature-sensitive embolic agent has a wide application prospect.
In order to further illustrate the present invention, the following examples are provided for illustrative purposes. The starting materials used in the following examples of the invention are all commercially available, with the polyglycerol polyricinoleate being indicated as PGPR.
Example 1
In the embodiment 1 of the invention, a temperature-sensitive embolic agent is prepared according to the formula in table 1, and the temperature-sensitive nanogel is MBA cross-linked PNIP, and the specific preparation method comprises the following steps:
(1) The temperature-sensitive nanogel is poly (N-isopropyl acrylamide) crosslinked by N, N' -methylene bisacrylamide, and the preparation method comprises the following steps:
adding 2.263g of N-isopropylacrylamide, 0.032g of sodium dodecyl sulfate and 0.032g of MBA into a 250ml three-necked bottle provided with a reflux condenser tube and an air guide device, dissolving the mixture by using 170ml of ultrapure water under magnetic stirring, introducing high-purity nitrogen into the reaction system for 30min, heating the reaction system to 70 ℃, adding 0.095g of initiator potassium persulfate, and adding N into the mixture 2 Reacting at 70 + -1 deg.C for 4.5h under atmosphere to obtain white turbid suspension, and dialyzing and purifying the suspension in ultrapure waterAnd freeze-drying, and collecting the freeze-dried powder to obtain the medicine.
(2) Dissolving doxorubicin hydrochloride in water to a concentration of 5mg/ml, and using the solution as an internal aqueous phase;
dissolving paclitaxel in iodized oil to make its concentration be 3mg/ml, and using the solution as oil phase;
mixing the internal water phase and the oil phase according to the mass ratio in the table 1, wherein the volume ratio is 3:7, adding a surfactant of polyglycerol polyricinoleate (PGPR) to account for 2 percent of the total system by mass; after fully stirring and mixing, shearing and emulsifying for 5min at the rotating speed of 8000r/min to obtain W/O emulsion as a dispersion phase.
(3) Preparing an external water phase as a continuous phase according to the mass ratio in the table 1;
mixing and stirring the dispersed phase and the continuous phase according to the mass ratio in the table 1, wherein the volume ratio is 4:6; and under the ice bath condition, shearing and emulsifying at the rotating speed of 6000r/min for 30s, stopping for 30s, shearing and emulsifying again for 30s, stopping for 30s, recycling, shearing and emulsifying again and stopping for 4 times, and enabling the total shearing time to be 8min to obtain the temperature-sensitive embolic agent capable of developing and carrying the medicine.
TABLE 1
Example 2
In the embodiment 2 of the invention, a temperature-sensitive embolic agent is prepared according to the formula shown in table 2, and the temperature-sensitive nanogel is N, N' -methylene bisacrylamide crosslinked poly (NIP-co-AA), and the specific preparation method comprises the following steps:
(1) The temperature-sensitive nanogel is N, N' -methylene bisacrylamide cross-linked poly (NIP-co-AA), and the preparation method comprises the following steps:
adding 2.263g of N-isopropyl acrylamide, 0.032g of sodium dodecyl sulfate and 0.032g of N, N '-methylene bisacrylamide into a 250ml three-necked bottle provided with a reflux condenser tube and an air guide device, dissolving the N, N' -methylene bisacrylamide with 170ml of ultrapure water under magnetic stirring, introducing high-purity nitrogen into the reaction system for 30min, heating the reaction system to 70 ℃, adding an initiator for sulfurization0.095g of potassium in N 2 Reacting for 0.5h at 70 +/-1 ℃ in the atmosphere, adding 0.27g of acrylic acid, continuing to react for 4h to obtain a white turbid suspension, dialyzing and purifying the suspension in ultrapure water, freeze-drying, and collecting freeze-dried powder to obtain the compound.
(2) Dissolving Guitar decitabine in water to a concentration of 5mg/ml, and using the solution as an inner water phase;
dissolving paclitaxel in iodized oil to 3mg/ml, and using the solution as oil phase;
mixing the internal water phase and the oil phase according to the mass ratio in the table 2, wherein the volume ratio is 3:7, adding a surfactant of polyglycerol polyricinoleate (PGPR) to account for 2 percent of the total system by mass; after fully stirring and mixing, shearing and emulsifying for 8min at the rotating speed of 6000r/min to obtain W/O emulsion as a dispersion phase.
(3) Preparing an external water phase as a continuous phase according to the mass ratio in the table 2;
mixing and stirring the dispersed phase and the continuous phase according to the mass ratio in the table 2, wherein the volume ratio is 4:6; and under the ice bath condition, shearing and emulsifying for 30s at the rotating speed of 7000r/min, stopping for 30s, shearing and emulsifying for 30s again, stopping for 30s, and recycling, shearing and emulsifying and stopping for 6 times to ensure that the total shearing time is 4min, thus obtaining the temperature-sensitive embolic agent capable of developing and carrying the medicine.
TABLE 2
Example 3
In the embodiment 3 of the invention, a temperature-sensitive embolic agent is prepared according to the formula in table 3, and the temperature-sensitive nanogel is N, N' -methylenebisacrylamide-crosslinked poly (NIP-co-MMA), and the specific preparation method comprises the following steps:
(1) Weighing the temperature-sensitive nanogel according to the formula shown in Table 3.
(2) Preparing an internal water phase and an oil phase according to the formula shown in the table 3, mixing the internal water phase and the oil phase according to the proportion, adding a surfactant, fully stirring and mixing, and shearing and emulsifying at the rotating speed of 9000r/min for 9min to obtain a water-in-oil emulsion as a dispersed phase.
(3) Preparing an external water phase as a continuous phase according to a formula shown in a table 3; and (3) mixing the dispersed phase and the continuous phase prepared in the step (2) in proportion, shearing and emulsifying for 30s at the rotating speed of 9000r/min under the ice bath condition, stopping for 30s, shearing and emulsifying for 30s again, stopping for 30s, and circularly shearing, emulsifying and stopping for 2 times to ensure that the total shearing time is 2min to obtain the composite.
TABLE 3
Example 4
In the embodiment 4 of the invention, a temperature-sensitive embolic agent is prepared according to the formula in table 4, and the temperature-sensitive nanogel is N, N' -methylene bisacrylamide crosslinked poly (NIP-co-AAm), and the specific preparation method comprises the following steps:
(1) Weighing the temperature-sensitive nanogel according to the formula in the table 4.
(2) Preparing an internal water phase and an oil phase according to the formula of the formula shown in the table 4, mixing the internal water phase and the oil phase according to the proportion, adding a surfactant, fully stirring and mixing, and shearing and emulsifying at the rotating speed of 7000r/min for 10min to obtain a water-in-oil emulsion as a dispersed phase.
(3) Preparing an external water phase as a continuous phase according to a formula in a table 4; and (3) mixing the dispersed phase and the continuous phase prepared in the step (2) in proportion, shearing and emulsifying for 30s at the rotating speed of 8000r/min under the ice bath condition, stopping for 30s, shearing and emulsifying for 30s again, stopping for 30s, and circularly shearing, emulsifying and stopping for 12 times to ensure that the total shearing time is 7min to obtain the composite.
TABLE 4
Comparative example 1
The temperature-sensitive embolic agent is prepared by the preparation method provided by the embodiment 1; the difference lies in that: the iodized oil was replaced with soybean oil for injection.
Comparative example 2
The temperature-sensitive embolic agent is prepared by the preparation method provided by the embodiment 1; the difference lies in that: the external water phase does not contain aqueous developer, and the amount of the aqueous developer is supplemented to water, so that the water in the external water phase accounts for 52.41 percent of the total amount of the temperature-sensitive embolic agent.
Test example
1. When the temperature-sensitive embolizing agents provided in example 1 and comparative examples 1-2 were taken and subjected to radiography, as shown in fig. 1, the X-ray contrast ability of example 1 was significantly better than that of comparative examples 1-2.
2. The temperature-sensitive embolic agents of the embodiments 1 to 4 are stored for 14 days at 37 ℃, and the fact that the phase change of the external water phase part of each temperature-sensitive embolic agent occurs at 37 ℃, the external water phase part is changed into solid from liquid, and the appearance is uniform and does not break milk after being stored for 14 days is found, which indicates that the temperature-sensitive embolic agent provided by the invention has good stability, and can ensure the stable embolic effect for a long time after being injected into human bodies.
3. The temperature-sensitive embolic agents of the embodiments 1 to 4 are stored for 7 days at the temperature of minus 5 ℃, and after storage, the temperature-sensitive embolic agents are found to have uniform appearance, no demulsification, no excessive thickening and good fluidity, thereby indicating that the temperature-sensitive embolic agents provided by the invention have qualified cold storage stability.
4. Each performance test was performed on the temperature-sensitive embolic agents provided in examples 1 to 4, and the test results are shown in Table 5. The temperature-sensitive nanogel of example 2 was used in an amount of 2.80% and the aqueous developer was used in an amount of 8.63%, and the amount of the aqueous developer was higher than that of example 1, thereby causing a decrease in modulus and a decrease in embolization effect, but the modulus and dissipation rate were still within acceptable ranges.
TABLE 5 Performance data for temperature sensitive embolic agents provided in examples 1-4
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (9)
1. A preparation method of a W/O/W type temperature-sensitive embolic agent comprises the following steps:
providing temperature-sensitive nanogel, wherein the temperature-sensitive nanogel is a poly N-isopropyl acrylamide polymer with a three-dimensional network structure, and dispersing the temperature-sensitive nanogel and a first aqueous developer in water to obtain an external water phase;
providing an oil phase having dispersed therein an oily developer;
providing an internal water phase, mixing the internal water phase and the oil phase, and carrying out first emulsification to obtain a W/O emulsion;
mixing the W/O emulsion with the external water, and carrying out secondary emulsification under an ice bath condition, wherein the secondary emulsification is intermittent emulsification, so that the emulsification process is carried out below a low critical transition temperature, and a W/O/W type temperature-sensitive embolic agent is obtained; wherein, the weight of the temperature-sensitive nanogel is 1-8 g per 100ml of the external aqueous phase, and the mass ratio of the temperature-sensitive nanogel to the first aqueous developer is (1-6) to (0.5-50).
2. The method of claim 1, wherein the second emulsifying comprises: circularly shearing, emulsifying and pausing at the rotating speed of 6000 r/min-10000 r/min, wherein the circulating frequency is at least 1, the shearing and emulsifying are carried out for 30 s-60 s every time, and the pausing is carried out for 30 s-60 s every time;
the total shearing time of the second emulsification is 1-10 min.
3. The method of manufacturing according to claim 1, wherein the first emulsification comprises: shearing and emulsifying at the rotating speed of 6000 r/min-10000 r/min for 1 min-10 min.
4. The method according to claim 1, wherein the N-isopropylacrylamide-based polymer having a three-dimensional network structure is N-isopropylacrylamide or a crosslinked polymer of N-isopropylacrylamide and a comonomer selected from one or more of acrylic acid, N-N-propylacrylamide, methacrylic acid, hydroxyethyl methacrylate, hydroxyethyl acrylate and acrylamide.
5. The process according to any one of claims 1 to 4, wherein the solvent of the oil phase is iodized oil and/or vegetable oil for injection.
6. The production method according to claim 5, characterized in that the solvent of the oily developer and the oil phase is iodized oil, and the mass ratio of the iodized oil to the first aqueous developer is (10-40) to (0.5-50).
7. The method according to any one of claims 1 to 4, wherein the volume ratio of the internal aqueous phase to the oil phase is 1: (1-8); and/or
The total mass of the W/O/W type temperature-sensitive embolic agent is 100 parts, and the mass of the temperature-sensitive nanogel is 1-6 parts.
8. The method according to any one of claims 1 to 4, wherein in the step of dispersing the temperature-sensitive nanogel and the first aqueous developer in water, an aqueous chemotherapeutic agent is further added; the mass ratio of the water-based chemotherapeutic drug to the temperature-sensitive nano gel is (0.1-5) to (1-6); and/or
In the step of mixing the internal water phase and the oil phase, a surfactant is also added; the mass ratio of the surfactant to the oil phase is (0.01-2) to (10-40).
9. The production method according to any one of claims 1 to 4, wherein the oil phase further has dispersed therein: oily chemotherapeutic drugs; the mass ratio of the oily chemotherapeutic drug to the oil phase is (0.05-1.5) to (10-40); and/or
The internal aqueous phase comprises: an aqueous chemotherapeutic agent and/or a second aqueous imaging agent.
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