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CN106038516A - Compound drug loading tissue pasting membrane and preparation method thereof - Google Patents

Compound drug loading tissue pasting membrane and preparation method thereof Download PDF

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Publication number
CN106038516A
CN106038516A CN201610377528.XA CN201610377528A CN106038516A CN 106038516 A CN106038516 A CN 106038516A CN 201610377528 A CN201610377528 A CN 201610377528A CN 106038516 A CN106038516 A CN 106038516A
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CN
China
Prior art keywords
medicine
layer
liquid
band
adhesive film
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201610377528.XA
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Chinese (zh)
Inventor
刘光万
吴昌琳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suzhou Bo Chuang Kang Pharmaceutical Technology Co., Ltd.
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Suzhou Bochuang Kangyuan Biotechnology Co Ltd
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Publication of CN106038516A publication Critical patent/CN106038516A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1808—Epidermal growth factor [EGF] urogastrone
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1858—Platelet-derived growth factor [PDGF]
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
    • A—HUMAN NECESSITIES
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    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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Abstract

The invention relates to the field of biological medicine, in particular to a compound drug loading tissue pasting membrane and a preparation method thereof. The drug loading tissue pasting membrane comprises cationic layers and anionic layers which are overlapped alternatively, at least one of the cationic layers and the anionic layers is a drug layer, at least one of the cationic layers and the anionic layers contains a charged drug, and the drug is a compound drug. The drug loading tissue pasting membrane has good tissue adhesion, good biocompatibility and biodegradable absorbability and good stability, and the physical and chemical properties of the drug loading tissue pasting membrane can be adjusted by adjusting composition of the materials.

Description

A kind of compound medicine medicine carrying tissue adhesive film and preparation method thereof
Technical field
The present invention relates to biomedicine field, particularly relate to a kind of compound medicine medicine carrying tissue adhesive film and preparation thereof Method, this medicine carrying tissue adhesive film can carry out local directly sustained-release and controlled release administration by surgical operation implantation sufferer tissue site and control Treat various disease.
Background technology
Along with developing rapidly of science and technology, the medicine of a large amount of New raxa is constantly found, but stops a lot of novel drugs at present The biggest obstacle of Clinical practice is just a lack of effective medicine-feeding technology.In prior art, exist cannot real pin for a lot of medicine-feeding technologies To focus, slow release is difficult to the problems such as effective control, and these problems can cause that Formulations for systemic administration, dosage are big, side effect is big, targeting Property poor, enter cell interior drug dose few, do not reach clinical therapeutic efficacy.So for most medicines, the most such as Compound medicine, the most all there is the problem that various similar needs improve in it in terms of carrier, so for drug-supplying system, especially It is that the research in terms of carrier increasingly comes into one's own.
Summary of the invention
The shortcoming of prior art in view of the above, it is an object of the invention to provide a kind of compound medicine medicine carrying tissue Adhesive film and its production and use, this medicine carrying tissue adhesive film can be implanted sufferer tissue site by surgical operation, carry out The local directly various disease of sustained-release and controlled release drug treatment, is used for solving the problems of the prior art.
For achieving the above object and other relevant purposes, first aspect present invention provides a kind of medicine carrying tissue adhesive film, more Be specially compound medicine medicine carrying tissue adhesive film, described medicine carrying tissue adhesive film include alternately superposition cationic layer and cloudy from Sublayer, at least one of which in described cationic layer and anion layer is in medicine layer or described cationic layer and anion layer At least one of which contains charged medicine, and described medicine is compound medicine.
Concrete, described cationic layer is shown generally as positive charge, and described anion layer is shown generally as negative charge.
When at least one of which in described cationic layer and anion layer is medicine layer, as the cationic layer of medicine layer And/or anion layer is charged medicine, the cationic layer not as medicine layer can be containing the carrier material of band cation group Material, the anion layer not as medicine layer can be containing the carrier material of band anionic group.
When at least one of which in described cationic layer and anion layer contains charged medicine, cationic layer can contain With the carrier material of cation group, anion layer can be containing the carrier material of band anionic group.
In medicine carrying tissue adhesive film provided by the present invention, the carrier material of described band cation group be per se with Positive charge or be dissolved in after solvent ionizes the material with positive charge, can be dissolved in water in an embodiment of the present invention After ionizing, with the material of positive charge.
The carrier material of described band cation group preferably can the biocompatible materials of vivo degradation.
Concrete, the optional organic polymer polymerization carrying cation group of the carrier material of described band cation group Thing, the polysaccharide of band cation group, the polypeptide of band cation group, the albumen of band cation group and cation lipid The combination of one or more in body etc..
Described organic high molecular polymer refers specifically to construction unit (a kind of construction unit or the various structures identical by many Unit) high-molecular weight compounds that is formed by connecting is repeated by covalent bond, in an embodiment of the present invention, the most available Organic high molecular polymer with cation group includes but not limited to: polymine, tree-like daiamid macromolecule, sun from In sub-polyester (object lesson such as cation poly phosphate, poly-phosphoramide, polymethacrylates etc.), polyvinylpyridine etc. The combination of one or more.
Described polysaccharide refers specifically to generate multiple monosaccharide, more specifically more than ten monosaccharide during a part hydrolysis Sugar, the polysaccharide of described band cation group can be the polysaccharide of band cation group own, it is also possible to be to be obtained by modification The polysaccharide with cation group obtained.Polysaccharide is modified so that it is this area with the technology of cation group Prior art, can be specifically the method such as grafted amino group on side chain.In an embodiment of the present invention, the most available Polysaccharide with cation group includes but not limited to: Chitosan-phospholipid complex (object lesson such as chitosan quaternary ammonium salt, low takes For degree carboxymethyl chitosan, N-trimethyl chitosan TMC, containing imidazole radicals chitosan, Chitosan-Thiolated Polymers etc.), cationic starch and derivative One in thing (object lesson such as the cyclodextrin etc. with cation group) and other polysaccharides with cation group Or multiple combination.
The polypeptide of described band cation group or albumen can be the polypeptide per se with cation group or albumen, it is possible to To be the polypeptide with cation group or albumen obtained by modification.In an embodiment of the present invention, specifically can be selected for The polypeptide of band cation group or albumen include but not limited to: polylysine or poly arginine and their derivant are (concrete The example of derivant is such as: introduce PEG, galactose, lactose, folic acid, transferrins etc. on polypeptide), collagen, gelatin, serum white The combination of one or more in albumen etc..Due to some albumen (such as collagen, gelatin, serum albumin etc.) at various ph values Both it had been possibly shown as positively charged, it is also possible to be shown as electronegative (with positive charge under the pH value less than isoelectric point, IP, at height With negative charge under the pH value of isoelectric point, IP), so this type of material can not only be used for cationic layer, it is possible to as anion layer.
Described cationic-liposome can be selected for the various cationic-liposome in this area, concrete available example include but not It is limited to: with the cationic-liposome that DOTMA is similar to body, prepared by DOTAP, spennidine cholesterol.
In medicine carrying tissue adhesive film provided by the present invention, the carrier material of described band anionic group be per se with Negative charge or be dissolved in after solvent ionizes the material with negative charge, can be dissolved in water in an embodiment of the present invention After ionizing, with the material of negative charge.
The carrier material of described band anionic group preferably can the biocompatible materials of vivo degradation.
Concrete, the optional organic polymer polymerization carrying anionic group of the carrier material of described band anionic group Thing, the polysaccharide of band anionic group, the polypeptide of band anionic group, the albumen of band anionic group and anion lipid The combination of one or more in body etc..
In an embodiment of the present invention, the organic high molecular polymer of concrete available band anionic group include but It is not limited to: such as the anion being made up of dicarboxylic acids be given in CN1524184A.
The polysaccharide of described band anionic group can be the polysaccharide of band anionic group own, it is also possible to be by changing Property obtain the polysaccharide with anionic group.Polysaccharide is modified so that its with anionic group technology for this The prior art in field, is specially such as (more specifically example such as carboxymethyl starches etc.) such as anionic starch.Real in the present invention one Executing in mode, the polysaccharide of concrete available band anionic group includes but not limited to: carboxymethyl cellulose, carboxymethyl chitosan Sugar, hyaluronic acid, alginic acid, carboxymethyl starch, chondroitin sulfate, heparin and their derivant and other with the moon from The combination of one or more in the polysaccharide of subbase group etc..
The polypeptide of described band anionic group can be the polypeptide per se with anionic group, it is also possible to be by modification The polypeptide with anionic group obtained.In an embodiment of the present invention, concrete available band anionic group is many Peptide includes but not limited to: the group of one or more in polyglutamic acid or poly-aspartate and derivant, collagen, gelatin etc. Close.
Described anionic liposome can be selected for the various anionic liposome in this area, concrete available example include but not It is limited to: AS-ODNs anionic liposome, DOPG/DOPE anionic liposome etc..
In medicine carrying tissue adhesive film provided by the present invention, described charged medicine can be specifically positively charged Medicine and/or electronegative medicine, as long as it is with electric charge, can be used to as medicine layer or be contained in described medicine carrying group Knitting in adhesive film, its amount comprised is generally effective therapeutic dose.Therapeutically effective amount, corresponding to the purpose for the treatment of indication, refers specifically to One consumption is after during suitable administration, it is possible to reach to treat the effect of indication.Treatment specifically includes pharmacy and/or life Preventative, the curative or retentivity of reason effect is disposed.This effect be preferably meant that medically can reduce indication one or Multiple symptom or indication is completely eliminated, or retardance, postpone the generation of indication and/or reduce indication development or deteriorate Risk.
Concrete, when at least one of which in described cationic layer and anion layer is medicine layer, described medicine layer is concrete Can be selected for charged medicine, specifically, when cationic layer is medicine layer, it can include positively charged medicine, and works as When anion layer is medicine layer, it can include electronegative medicine.
More specifically, for positively charged medicine, when at least one of which of cationic layer is medicine layer, positively charged The medicine of lotus can form electrostatic interaction as medicine layer with the anion layer closed on；When it is contained in cationic layer as pharmaceutical pack And/or time in anion layer, it can be located at and forms electrostatic interaction in cationic layer with the anion layer that closes on, thus stably by It is contained in described medicine carrying tissue adhesive film, or can be located in anion layer, positively charged medicine and band anionic group After carrier material effect, this layer still appears as negative charge on the whole, forms electrostatic interaction with the carrier material of band cation group, Thus be stably contained in described medicine carrying tissue adhesive film.And for electronegative medicine, when anion layer When at least one of which is medicine layer, electronegative medicine can form electrostatic interaction as medicine layer with the cationic layer closed on；When When it is contained in cationic layer and/or anion layer as pharmaceutical pack, its cationic layer that can be located in anion layer and close on Form electrostatic interaction, thus be stably contained in described medicine carrying tissue adhesive film, or can be located at band cation group material Rushing in layer, after the carrier material effect of electronegative medicine and band cation group, this layer still appears as positive charge on the whole, Form electrostatic interaction with the carrier material of band anionic group, thus be stably contained in described medicine carrying tissue adhesive film.
Described charged medicine, the most charged compound medicine, can be some itself i.e. with electric charge Compound medicine, it is also possible to be that some compound medicines are through being combined with electrically charged (positive charge or negative charge) material or material or wrap Wrap up in the drug composite with electric charge of formation.Medicine is combined with electrically charged (positive charge or negative charge) material or material or wraps The method of the drug composite with electric charge wrapping up in formation is the state of the art, concrete drug composite include but not It is limited to polymer, medicine and cation group material that medicinal liposome, medicine phospholipid, medicine and anionic group material are formed The polymer etc. formed.The form of drug composite can be microsphere, microcapsule, microgranule, micelle, micelle etc..
Concrete, described medicine is compound medicine.
Described compound medicine refers generally to the compound with single structure, more specifically micromolecular compound medicine, its Molecular weight is generally no greater than 20000, and the most generally no greater than 15000, the most generally no greater than 10000, the most typically No more than 8000, the most generally no greater than 6000, the most generally no greater than 4000, the most generally no greater than 3000, more Concrete generally no greater than 2000, the most generally no greater than 1500, the most concrete generally no greater than 1000.Described compound medicine Thing can be to pass through chemosynthesis, it is also possible to is the compound of separation and Extraction from plant, animal, microorganism.Specifically include but It is not limited to: such as fluorouracil, Sutent, Sorafenib, camptothecine, paclitaxel, rapamycin, etoposide, also include resisting Give birth to element class medicine (such as: colistin, ofloxacin, amoxicillin, clarithromycin, cefazolin etc.), antiviral drugs (replace by grace Card Wei, vidarabine, Didansine, polyinosini, azidothymidine AZT, acyclovir, amantadine, bromine Australia alkene uridnine) etc., chemical combination The object lesson of the drug composite with electric charge that thing medicine is formed such as the Sorafenib microsphere etc. with sodium alginate parcel.
In medicine carrying tissue adhesive film provided by the present invention, cationic layer and anion layer replace superposition, and can pass through Electrostatic attraction combines, and is formed for the tissue adhesive film of medicine carrying, and described cationic layer is shown generally as positive charge, described the moon from Sublayer is shown generally as negative charge.Can be specifically cationic layer material and band anion layer material is entered by electrostatic attraction The method of row alternating deposit, such as polyelectrolyte self-assembly method layer by layer etc..It replaces superposition for cationic layer and anion layer Number of times is not particularly limited, and those skilled in the art can glue by (e.g., drug loading, degradation time etc.) adjustment tissue according to actual needs The gross thickness of pad pasting, the gross thickness of described tissue adhesive film can≤1000 μm, more specifically can≤600 μm, the most permissible ≤ 400 μm, more specifically can≤200 μm, be specifically as follows 0.05 μm-1000 μm further.For each layer of cationic layer and/ Or for anion layer, those skilled in the art can be according to the kind of material and be actually needed (e.g., drug loading, degradation time etc.) Adjust the thickness of each cationic layer and/or anion layer, it is possible to further determine that medicine, the carrier material of band cation group With the usage amount of the carrier material of band anionic group, its thickness can be 0.0005 μm--100 μm, more specifically can be with 0.001 μ M--50 μm, can be more specifically Nano grade, and time prepared by cationic layer and anion layer, the usage amount of material is 1: 0.005--200。
Second aspect present invention provides the preparation method of described medicine carrying tissue adhesive film, comprises the steps: on substrate Alternating deposit cationic layer and anion layer, prepare tissue adhesive film.
Medicine carrying tissue adhesive film provided by the present invention can intactly be taken off from substrate after preparation completes, and can be independent Stably exist in other attachment material (such as substrate, backing etc.).
Concrete, when at least one of which in described cationic layer and anion layer is medicine layer, and described preparation method is permissible It is polyelectrolyte self-assembly method layer by layer, specifically may include steps of:
Alternating deposit cationic layer and anion layer on substrate, prepare tissue adhesive film, is being deposited as medicine Layer material layer time, use charged medicine to deposit.
Concrete, on substrate, alternating deposit cationic layer and anion layer method specifically include following steps: in deposition During non-drug layer, the solution of the carrier material of substrate alternate immersion or spraying band cation group and the carrier of band anionic group The solution of material, when deposition of medicament layer, then soaks or sprays the solution of charged medicine, washs (concrete after deposition every time Can be to wash with water), be dried, take off film after completing alternating deposit, obtain described tissue adhesive film.
More specifically, the solution of described band cation group material, the solution of band anionic group material, charged medicine The solution of thing can be all aqueous solution, it is possible to adds suitable salt ion in aqueous and stretches situation with the space changing molecule, The kind of the salt ion being particularly used in the space stretching, extension situation changing molecule is well known in the prior art, as added in the solution Add NaCl, KCl etc..
The concentration of solution of used material when those skilled in the art can adjust deposition according to the kind of material, pH value, Salt ionic concentration etc., in an embodiment of the present invention, in the solution used during deposition, salt ionic concentration is specifically as follows≤ 10mol/L, can be more specifically 0.05-10mol/L, and pH value can be 3-11.
When at least one of which in described cationic layer and anion layer contains charged medicine, described preparation method can To be polyelectrolyte self-assembly method layer by layer, specifically may include steps of:
Alternating deposit cationic layer and anion layer on substrate, prepare tissue adhesive film；And it is viscous at preparation tissue During pad pasting, medicine is implanted in described tissue adhesive film.
Concrete, on substrate, alternating deposit cationic layer and anion layer method specifically include following steps: substrate is handed over Solution for immersion or the carrier material of the solution of the carrier material of spraying band cation group and band anionic group (is depositing During including the material layer of medicine, in the solution depositing this material layer, then may further include medicine), wash after deposition every time Wash (be specifically as follows and wash with water), be dried, take off film after completing alternating deposit, obtain described tissue adhesive film.
Those skilled in the art can be selected for suitable method, is implanted by medicine in described tissue adhesive film, specifically may is that When deposition contains the cationic layer of charged medicine, the carrier material of medicine with band cation group is mixed and deposits (can be specifically carrier material and the mixed solution of medicine soaking or spraying band cation group)；In deposition containing electrically charged The anion layer of medicine time, the carrier material of medicine with band anionic group is mixed that to carry out depositing (can be specifically to soak Or spray carrier material and the mixed solution of medicine of band anionic group)；In addition it is also possible to preparing tissue adhesive film After, re-use the solution that the instantaneous spraying of high pressure contains medicine, and carry out further washing, being dried.
Third aspect present invention provides a kind of tissue adhesive film purposes in preparing drug carrier material.
Described medicine is specially charged medicine, charged compound medicine the most as above.
Concrete, described tissue adhesive film includes cationic layer and the anion layer of alternately superposition.
More specifically, at least one of which in described cationic layer and anion layer be medicine layer or described cationic layer and At least one of which in anion layer is used for comprising charged medicine.
Medicine carrying tissue adhesive film provided by the present invention has good tissue adhesion, good biocompatibility and can Degraded and absorbed, good stability, its physics, chemical property can be regulated by the composition of regulation material.Additionally, described load Medicine tissue adhesive membrane preparation method is simple, and drug loading can be measured as required and be adjusted, and carrier material can protect the medicine being carried Thing (such as makes RNA avoid being degraded), and can be transported to expeditiously in target cell by the medicine being carried, the most such as: described Medicine carrying tissue adhesive film directly can be pasted onto lesions position by surgical operation and (i.e. pass through surgical operation by medicine carrying tissue adhesive film Implanted sustained-release administration treats various diseases), it is administered directly, targeting is good, and medicine local concentration height therapeutic effect is good, side effect Little, low to the genotoxic potential of organism, there is the highest biological safety.
Accompanying drawing explanation
Fig. 1 is shown as the gel electrophoresis experiment schematic diagram of embodiment 29siRNA.
Fig. 2 is shown as embodiment 30 cell transfection assay schematic diagram.
Fig. 3 is shown as embodiment 30 relative intensity of fluorescence schematic diagram.
Detailed description of the invention
Below by way of specific instantiation, embodiments of the present invention being described, those skilled in the art can be by this specification Disclosed content understands other advantages and effect of the present invention easily.The present invention can also be by the most different concrete realities The mode of executing is carried out or applies, the every details in this specification can also based on different viewpoints and application, without departing from Various modification or change is carried out under the spirit of the present invention.
Before further describing the specific embodiment of the invention, it should be appreciated that protection scope of the present invention is not limited to down State specific specific embodiments；It is also understood that the term used in the embodiment of the present invention is specific concrete in order to describe Embodiment rather than in order to limit the scope of the invention；In description of the invention and claims, unless in literary composition Additionally explicitly pointing out, singulative " ", " one " and " this " include plural form.
When embodiment provides numerical range, it should be appreciated that unless the present invention is otherwise noted, two ends of each numerical range Between point and two end points, any one numerical value all can be selected for.Unless otherwise defined, in the present invention use all technology and The same meaning that scientific terminology and those skilled in the art of the present technique are generally understood that.Except in embodiment use concrete grammar, equipment, Outside material, according to those skilled in the art's grasp to prior art and the record of the present invention, it is also possible to use and this Any method, equipment and the material of the prior art that the method described in inventive embodiments, equipment, material are similar or equivalent comes real The existing present invention.
Unless otherwise indicated, the experimental technique that disclosed in this invention, detection method, preparation method all use this technology to lead Conventional molecular biology, biochemistry, chromatin Structure and the analysis in territory, analytical chemistry, cell are cultivated, recombinant DNA technology and The routine techniques of association area.These technology have improved explanation in existing document, specifically can be found in Sambrook etc. MOLECULAR CLONING:A LABORATORY MANUAL, Second edition, Cold Spring Harbor Laboratory Press, 1989and Third edition, 2001；Ausubel etc., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley&Sons, New York, 1987and periodic updates；the Series METHODS IN ENZYMOLOGY, Academic Press, San Diego；Wolffe, CHROMATIN STRUCTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998；METHODS IN ENZYMOLOGY, Vol.304, Chromatin (P.M.Wassarman and A.P.Wolffe, eds.), Academic Press, San Diego, 1999；With METHODS IN MOLECULAR BIOLOGY, Vol.119, Chromatin Protocols (P.B.Becker, ed.) Humana Press, Totowa, 1999 etc..
Embodiment 1
In aseptic working platform, preparation one 12 cm diameter culture dishs, a built-in same diameter silicon chip film (scrubbed, Sterilizing and depyrogenation process), it is dried；Prepare solution A (1mg/ml chitosan, the 0.1mol/L of band cation group material respectively Acetic acid, 0.2mol/L NaCl, pH=4) and B liquid (1mg/ml carboxymethyl chitosan, the 0.15mol/L of band anionic group material NaCl, pH=6)；Take part B liquid add small RNA medicine (eGFP-siRNA (sense:5 '- GGCACAAGCUGGAGUACAAUU-3’；Antisense:5 '-UUGUACUCCAGCUUGUGCCUU-3 ', 20ug/mL) and cell Targeting factor (hyaluronic acid, molecular weight is less than 20,000 dalton, 10ug/mL) and target polypeptide (1 × 10-4Mg/ml) it is configured to C Liquid, target polypeptide amino acid sequence is: valine-glycine-val-ala-proline-glycine；Above-mentioned solution It is filled to respectively in the instantaneous spraying equipment of high pressure, first toward culture dish inner high voltage instantaneous spraying C liquid, drying and forming-film；Then high pressure Instantaneous spraying A liquid, rinses with water for injection；Then high pressure instantaneous spraying B liquid, rinses with water for injection, such alternating spray A Liquid, B liquid, flushing, repetitive operation；High pressure instantaneous spraying A liquid, rinses with water for injection the most again；Last high pressure instantaneous spraying C Liquid, rinses with water for injection, is dried, takes off film, and veneer water for injection rinses, and dried must carry small RNA medicine and implant Formula tissue adhesive film.
Embodiment 2
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short with the B liquid (alginic acid of 2mg/ml, 6 to 8 ten thousand molecular weight, 0.15mol/L NaCl, pH=6) of band anionic group material B liquid；B liquid adds small RNA medicine (with embodiment 1,20ug/mL) and the cell-targeting factor (hyaluronic acid, molecule Amount is less than 20,000 dalton, 10ug/mL), A liquid adds target polypeptide (1 × 10-4Mg/ml), target polypeptide amino acid sequence For: Isoleucine-lysine-valine-alanine-valine；Flat board is submerged initially in solution A 20 minutes, takes out into cleaning Liquid washing is dried；Again flat board is immersed in B solution 30 minutes, take out and be dried into cleanout fluid washing, the most alternately 160 times, Finally rinse with water for injection, be dried, take off film, small RNA medicine implanted tissue adhesive film must be carried.
Embodiment 3
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short B liquid with the B liquid (hyaluronic acid of 2mg/ml, 0.15mol/L NaCl, pH=6) of band anionic group material；In A liquid again (cation lipid preparation method is with reference to " anionic liposome-cationic-liposome is multiple to add small RNA cationic-liposome The gene transfection of compound mediation ", pharmacy practice magazine, 2011 (29): 4, small RNA is with embodiment 1, small RNA sun Cationic liposomal addition is 0.5mg/ml, small nucleic acids drug loading 21.7%) stir and target polypeptide (1 × 10-4mg/ Ml), target polypeptide amino acid sequence is: arginine-glycine-aspartic acid；Flat board is submerged initially in solution A 20 minutes, takes The cleanout fluid washing that comes in and goes out is dried；Again flat board is immersed in B solution 30 minutes, takes out and be dried into cleanout fluid washing, so replace into Row 180 times, finally rinses with water for injection, is dried, takes off film, must carry small RNA medicine implanted tissue adhesive film.
Embodiment 4
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short B liquid with the B liquid (hyaluronic acid of 2mg/ml, 0.15mol/L NaCl, pH=6) of band anionic group material；In B liquid again (preparation method is with reference to " anionic liposome-cationic liposome complex mediation to add small RNA anionic liposome Gene transfects ", pharmacy practice magazine, 2011 (29): 4, small RNA is with embodiment 1, small RNA anionic liposome Addition is 0.5mg/ml, small nucleic acids drug loading 12.4%) stir and target polypeptide (1 × 10-4Mg/ml), target polypeptide Amino acid sequence is: valine-glycine-val-ala-proline-glycine, and flat board is submerged initially in solution A 20 Minute, take out and be dried into cleanout fluid washing；Again flat board is immersed in B solution 30 minutes, take out and be dried, so into cleanout fluid washing Alternately 180 times, finally rinse with water for injection, be dried, take off film, small RNA medicine implanted tissue adhesive must be carried Film.
Embodiment 5
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；A liquid adds small RNA cationic-liposome (preparation method such as embodiment 3, dense Degree is 0.5mg/ml) and target polypeptide (1 × 10-4Mg/ml) stirring, target polypeptide amino acid sequence is: arginine-sweet ammonia Acid-aspartic acid；Above-mentioned solution is filled in the instantaneous spraying equipment of high pressure respectively, first toward the instantaneous spraying of culture dish inner high voltage A liquid, is dried, then high pressure instantaneous spraying B liquid, rinses with water for injection, such alternating spray A liquid, B liquid, flushing, repetitive operation 200 times；Last high pressure instantaneous spraying A liquid again, rinses with water for injection, is dried, takes off film, and veneer water for injection rinses, and is dried Process to carry small RNA medicine implanted tissue adhesive film.
Embodiment 6
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short with the B liquid (alginic acid of 2mg/ml, 6 to 8 ten thousand molecular weight, 0.15mol/L NaCl, pH=6) of band anionic group material B liquid；(concentration 1.5mg/ml, microsphere diameter 10 μm is to 16 μm to add Sorafenib hyaluronate microspheres in B liquid；Drug loading 7.58%), A liquid adds target polypeptide (1 × 10-4Mg/ml), target polypeptide amino acid sequence is: isoleucine-rely ammonia Acid-valine-alanine-valine；Flat board is submerged initially in solution A 20 minutes, takes out and be dried into cleanout fluid washing；Again will be flat Plate immerses in B solution 30 minutes, takes out and is dried into cleanout fluid washing, the most alternately 30 times, finally rinses with water for injection, It is dried, takes off film, Sorafenib medicine implanted tissue adhesive film must be carried.
Embodiment 7
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；B liquid adds Sutent sodium alginate micro ball (concentration 1.0mg/ml, microsphere diameter 10 μm is to 15 μm；Drug loading 6.28%), A liquid adds target polypeptide (1 × 10-4Mg/ml) stir, target polypeptide amino Acid order is: arginine-glycine-aspartic acid；Above-mentioned solution is filled in the instantaneous spraying equipment of high pressure respectively, the most past Culture dish inner high voltage instantaneous spraying A liquid, is dried, then high pressure instantaneous spraying B liquid, rinses with water for injection, such alternating spray A Liquid, B liquid, flushing, repetitive operation 50 times；Last high pressure instantaneous spraying A liquid again, rinses with water for injection, is dried, takes off film, veneer Rinsing with water for injection, dried must carry Sutent medicine implanted tissue adhesive film.
Embodiment 8
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short B liquid with the B liquid (hyaluronic acid of 2mg/ml, 0.15mol/L NaCl, pH=6) of band anionic group material；In B liquid again (concentration 1.0mg/ml, microsphere diameter 0.15 μm is to 0.26 μm to add ganglioside sodium alginate micro ball；Drug loading 7.3%) stir Mix uniform and target polypeptide (1 × 10-4Mg/ml), target polypeptide amino acid sequence is: valine-glycine-valine the-the third ammonia Acid-proline-glycine, is submerged initially in flat board in solution A 20 minutes, takes out and is dried into cleanout fluid washing；Again flat board is immersed B In solution 30 minutes, take out and be dried into cleanout fluid washing, the most alternately 30 times, finally rinse with water for injection, be dried, take off Film, must carry ganglioside medicine implanted tissue adhesive film.
Embodiment 9
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；B liquid adds antibacterial peptide (1.5mg/ml)；Above-mentioned solution is filled to high pressure wink respectively Time spraying equipment in, first toward culture dish inner high voltage instantaneous spraying A liquid, be dried, then high pressure instantaneous spraying B liquid, uses injection Water rinses, such alternating spray A liquid, B liquid, flushing, repetitive operation 80 times；Last high pressure instantaneous spraying A liquid again, uses water for injection Rinsing, be dried, take off film, veneer water for injection rinses, and dried obtains antimicrobial peptide medicine implanted tissue adhesive film.
Embodiment 10
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；B liquid adds interleukin-2 (0.5mg/ml)；Above-mentioned solution is filled to high pressure respectively In instantaneous spraying equipment, first toward culture dish inner high voltage instantaneous spraying A liquid, being dried, then high pressure instantaneous spraying B liquid, with injection Rinse with water, such alternating spray A liquid, B liquid, flushing, repetitive operation 50 times；Last high pressure instantaneous spraying A liquid again, uses injection Water rinses, and is dried, takes off film, and veneer water for injection rinses, and dried must carry interleukin-2 medicine implanted tissue adhesive film.
Embodiment 11
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；(concentration is to add Afatinib (Afatinib) cation PEG nanoparticle in A liquid 0.5mg/ml) with target polypeptide (1 × 10-4Mg/ml) stirring, target polypeptide amino acid sequence is: arginine-glycine- Aspartic acid；Above-mentioned solution is filled in the instantaneous spraying equipment of high pressure respectively, first toward culture dish inner high voltage instantaneous spraying A Liquid, is dried, then high pressure instantaneous spraying B liquid, rinses with water for injection, such alternating spray A liquid, B liquid, flushing, repetitive operation 200 times；Last high pressure instantaneous spraying A liquid again, rinses with water for injection, is dried, takes off film, and veneer water for injection rinses, and is dried Process to carry Afatinib (Afatinib) medicine implanted tissue adhesive film.
Embodiment 12
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；(concentration is to add imatinib (Imatinib) cation PEG nanoparticle in A liquid 0.8mg/ml) with target polypeptide (1 × 10-4Mg/ml) stirring, target polypeptide amino acid sequence is: arginine-glycine- Aspartic acid；Above-mentioned solution is filled in the instantaneous spraying equipment of high pressure respectively, first toward culture dish inner high voltage instantaneous spraying A Liquid, is dried, then high pressure instantaneous spraying B liquid, rinses with water for injection, such alternating spray A liquid, B liquid, flushing, repetitive operation 200 times；Last high pressure instantaneous spraying A liquid again, rinses with water for injection, is dried, takes off film, and veneer water for injection rinses, and is dried Process to carry imatinib (Imatinib) medicine implanted tissue adhesive film.
Embodiment 13
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；(concentration is to add Axitinib (Axitinib) anion PEG nanoparticle in B liquid 0.8mg/ml) with target polypeptide (1 × 10-4Mg/ml) stirring, target polypeptide amino acid sequence is: arginine-glycine- Aspartic acid；Above-mentioned solution is filled in the instantaneous spraying equipment of high pressure respectively, first toward culture dish inner high voltage instantaneous spraying A Liquid, is dried, then high pressure instantaneous spraying B liquid, rinses with water for injection, such alternating spray A liquid, B liquid, flushing, repetitive operation 200 times；Last high pressure instantaneous spraying A liquid again, rinses with water for injection, is dried, takes off film, and veneer water for injection rinses, and is dried Process to carry Axitinib (Axitinib) medicine implanted tissue adhesive film.
Embodiment 14
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；A liquid adds Ceritinib cation PEG nanoparticle (concentration is 0.8mg/ml) with Target polypeptide (1 × 10-4Mg/ml) stirring, target polypeptide amino acid sequence is: arginine-glycine-aspartic acid；? Above-mentioned solution is filled in the instantaneous spraying equipment of high pressure respectively, first toward culture dish inner high voltage instantaneous spraying A liquid, is dried, then High pressure instantaneous spraying B liquid, rinses with water for injection, such alternating spray A liquid, B liquid, flushing, repetitive operation 200 times；The most again High pressure instantaneous spraying A liquid, rinses with water for injection, is dried, takes off film, and veneer water for injection rinses, and it is auspicious that dried must carry color For Buddhist nun's medicine implanted tissue adhesive film.
Embodiment 15
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；B liquid adds fluorouracil (1.0mg/ml)；Above-mentioned solution is filled to high pressure respectively In instantaneous spraying equipment, first toward culture dish inner high voltage instantaneous spraying A liquid, being dried, then high pressure instantaneous spraying B liquid, with injection Rinse with water, such alternating spray A liquid, B liquid, flushing, repetitive operation 100 times；Last high pressure instantaneous spraying A liquid again, with injection Rinsing with water, be dried, take off film, veneer water for injection rinses, and dried must carry fluorouracil medicine implanted tissue adhesive Film.
Embodiment 16
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short with the B liquid (alginic acid of 2mg/ml, 6 to 8 ten thousand molecular weight, 0.15mol/L NaCl, pH=6) of band anionic group material B liquid；B liquid adds handkerchief trastuzumab (Pertuzumab) medicine (20ug/mL), flat board is submerged initially in solution A 20 minutes, Take out and be dried into cleanout fluid washing；Again flat board is immersed in B solution 30 minutes, take out and be dried into cleanout fluid washing, so replace Carry out 100 times, finally rinse with water for injection, be dried, take off film, handkerchief trastuzumab (Pertuzumab) medicine implanted group must be carried Knit adhesive film.
Embodiment 17
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；B liquid adds handkerchief trastuzumab (Pertuzumab) medicine (20ug/mL)；Above-mentioned molten Liquid is filled in the instantaneous spraying equipment of high pressure respectively, first toward culture dish inner high voltage instantaneous spraying A liquid, is dried, then high pressure wink Time spraying B liquid, with water for injection rinse, such alternating spray A liquid, B liquid, flushing, repetitive operation 100 times；Last high pressure wink again Time spraying A liquid, with water for injection rinse, be dried, take off film, veneer with water for injection rinse, dried must carry handkerchief trastuzumab (Pertuzumab) medicine implanted tissue adhesive film.
Embodiment 18
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；B liquid adds Lidamycin LDM (0.5mg/ml, high molecular weight protein class antitumor antibiotics)； Above-mentioned solution is filled in the instantaneous spraying equipment of high pressure respectively, first toward culture dish inner high voltage instantaneous spraying A liquid, is dried, connects High pressure instantaneous spraying B liquid, rinse with water for injection, such alternating spray A liquid, B liquid, flushing, repetitive operation 80 times；The most again High pressure instantaneous spraying A liquid, rinses with water for injection, is dried, takes off film, and veneer water for injection rinses, and dried must carry power and reach Mycin medicine implanted tissue adhesive film.
Embodiment 19
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short B liquid with the B liquid (hyaluronic acid of 2mg/ml, 0.15mol/L NaCl, pH=6) of band anionic group material；In B liquid again Add VEGF (VEGF) (0.5mg/ml), stir and target polypeptide (1 × 10-4Mg/ml), target polypeptide Amino acid sequence is: valine-glycine-val-ala-proline-glycine, and flat board is submerged initially in solution A 20 Minute, take out and be dried into cleanout fluid washing；Again flat board is immersed in B solution 30 minutes, take out and be dried, so into cleanout fluid washing Alternately 80 times, finally rinse with water for injection, be dried, take off film, VEGF (VEGF) drug entities must be carried Adhesive film.
Embodiment 20
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short B liquid with the B liquid (hyaluronic acid of 2mg/ml, 0.15mol/L NaCl, pH=6) of band anionic group material；In B liquid again Add epidermal growth factor (EGF) (0.5mg/ml), stir, flat board is submerged initially in solution A 20 minutes, takes out into cleaning Liquid washing is dried；Again flat board is immersed in B solution 30 minutes, take out and be dried into cleanout fluid washing, the most alternately 100 times, Finally rinse with water for injection, be dried, take off film, epidermal growth factor (EGF) drug entities adhesive film must be carried.
Embodiment 21
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；B liquid adds nerve growth factor (NGF) (0.5mg/ml)；Above-mentioned solution is filled respectively Install in the instantaneous spraying equipment of high pressure, first toward culture dish inner high voltage instantaneous spraying A liquid, be dried, then high pressure instantaneous spraying B Liquid, rinses with water for injection, such alternating spray A liquid, B liquid, flushing, repetitive operation 50 times；Last high pressure instantaneous spraying A again Liquid, rinses with water for injection, is dried, takes off film, and veneer water for injection rinses, and dried must carry nerve growth factor (NGF) Medicine implanted tissue adhesive film.
Embodiment 22
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；B liquid adds fibroblast growth factor (FGF) (0.5mg/ml)；Above-mentioned solution Being filled to respectively in the instantaneous spraying equipment of high pressure, first toward culture dish inner high voltage instantaneous spraying A liquid, be dried, then high pressure is instantaneous Spraying B liquid, rinses with water for injection, such alternating spray A liquid, B liquid, flushing, repetitive operation 80 times；The last instantaneous spray of high pressure again Being coated with A liquid, rinse with water for injection, be dried, take off film, veneer water for injection rinses, and dried obtains Desmocyte growth factor Son (FGF) drug entities adhesive film.
Embodiment 23
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short with the B liquid (alginic acid of 2mg/ml, 6 to 8 ten thousand molecular weight, 0.15mol/L NaCl, pH=6) of band anionic group material B liquid；B liquid adds heparin medicine (1.5mg/mL), flat board is submerged initially in solution A 20 minutes, take out and wash into cleanout fluid It is dried；Again flat board is immersed in B solution 30 minutes, take out and be dried into cleanout fluid washing, the most alternately 100 times, finally use Water for injection rinses, and is dried, takes off film, must carry heparin drug entities adhesive film.
Embodiment 24
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；B liquid adds lycium barbarum polysaccharide medicine (1.0mg/mL)；Above-mentioned solution is filled to respectively In the instantaneous spraying equipment of high pressure, first toward culture dish inner high voltage instantaneous spraying A liquid, it is dried, then high pressure instantaneous spraying B liquid, uses Water for injection rinses, such alternating spray A liquid, B liquid, flushing, repetitive operation 100 times；Last high pressure instantaneous spraying A liquid again, uses Water for injection rinses, and is dried, takes off film, and veneer water for injection rinses, and dried must carry lycium barbarum polysaccharide drug entities adhesive film.
Embodiment 25
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；B liquid adds lentinan (0.5mg/ml)；Above-mentioned solution is filled to high pressure respectively In instantaneous spraying equipment, first toward culture dish inner high voltage instantaneous spraying A liquid, being dried, then high pressure instantaneous spraying B liquid, with injection Rinse with water, such alternating spray A liquid, B liquid, flushing, repetitive operation 80 times；Last high pressure instantaneous spraying A liquid again, uses injection Water rinses, and is dried, takes off film, and veneer water for injection rinses, and dried must carry lentinan medicine implanted tissue adhesive film.
Embodiment 26
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short B liquid with the B liquid (hyaluronic acid of 2mg/ml, 0.15mol/L NaCl, pH=6) of band anionic group material；In B liquid again Add pachyman (0.5mg/ml), stir and target polypeptide (1 × 10-4Mg/ml), target polypeptide amino acid sequence is: Valine-glycine-val-ala-proline-glycine, is submerged initially in flat board in solution A 20 minutes, takes out into clear Wash liquid is dried；Again flat board is immersed in B solution 30 minutes, take out and be dried into cleanout fluid washing, the most alternately 80 times, Finally rinse with water for injection, be dried, take off film, pachyman drug entities adhesive film must be carried.
Embodiment 27
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short B liquid with the B liquid (hyaluronic acid of 2mg/ml, 0.15mol/L NaCl, pH=6) of band anionic group material；In B liquid again Add polyporusum bellatus (0.5mg/ml), stir, flat board is submerged initially in solution A 20 minutes, take out into cleanout fluid washing dry Dry；Again flat board is immersed in B solution 30 minutes, take out and be dried into cleanout fluid washing, the most alternately 100 times, finally with note Penetrate and rinse with water, be dried, take off film, polyporusum bellatus drug entities adhesive film must be carried.
Embodiment 28
Medicine carrying tissue adhesive membrane drug delivery system embodiment 1-27 prepared carries out evaluation of its biocompatibility detection, tool Standby excellent biocompatibility, specific as follows:
1. cell toxicity test:
Reference/technical standard: GB/T 16886.5-2003
Cell strain: L-929 cell (l cell)
Culture fluid: containing the DMEM of 10% (V/V) calf serum
Blank: with batch cell culture fluid
Negative control: high density polyethylene (HDPE) (see GB/T16886 cell toxicity test standard)
Positive control: 5g/L phenol solution
Extraction medium: with criticizing the DMEM without calf serum
Extraction time: 24 hours
Test sample extraction ratio: 1g/5ml
Test method: lixiviating solution test (mtt assay)
At 27 DEG C, 5%CO2Blank, negative control, positive control contact adherent growth with test sample lixiviating solution Cell, after cultivating 72h, adds MTT liquid, hatches 4h.After absorption, add DMSO, by spectrophotometer under wavelength 630nm right Each group carries out absorbance measurement, and calculates the relative rate of increase of cell.
Result: the cytotoxicity of test sample: 0 grade
Conclusion: with reference to GB/T 16886.5-2003, this test sample no cytotoxicity.
2. picosecond laser pulse
Reference/technical standard: GB/T 16886.10-2005
Experimental animal: healthy new zealand rabbit
Extraction medium: 0.9% sodium chloride injection
Test sample: material lixiviating solution
Negative control: with batch extraction medium
Route of exposure: intradermal injection
Judging quota: observe 24h, 48h, 72h erythema, the edema extent of reaction
Result: after injection, 24h, 48h, 72h injection site and surrounding skin tissue are all without erythema, edema reaction, test side Dermoreaction is not more than control sides dermoreaction.
Conclusion: with reference to GB/T 16886.10-2005, this test sample is without Intradermal irritant reaction.
3. acute systemic toxicity
Reference/technical standard: GB/T 16886.11-1997/ASTM F 750
Experimental animal: healthy mice
Extraction medium: 0.9% sodium chloride injection
Test sample: material lixiviating solution
Negative control: with batch extraction medium
Route of exposure: tail vein injection
Judging quota: observe 4h, 24h, 48h, 72h animal general state, toxicity performance and dead animal number.
Result: in the 72h observation period, the reaction of test sample treated animal is not more than negative control treated animal.
Conclusion: with reference to GB/T 16886.11-1997/ASTM F 750, this test sample acute systemic toxicity result accords with Close requirement.
4. hemolytic test
Reference/technical standard: GB/T 16886.4-2003/GB/T 16175-1996
Experimental animal: healthy new zealand rabbit
Prepared by dilution anticoagulant Sanguis Leporis seu oryctolagi: fresh anticoagulant Sanguis Leporis seu oryctolagi+0.9% sodium chloride injection
Negative control: 0.9% sodium chloride injection
Positive control: distilled water
Route of exposure: tail vein injection
Test method: test sample is immersed by a certain percentage in 0.9% sodium chloride injection, 37 DEG C of water bath heat preservation 30min After, add 0.2ml and dilute fresh anticoagulant Sanguis Leporis seu oryctolagi, 37 DEG C of water bath heat preservation 60min.2500rpm takes supernatant after being centrifuged 5min, with purple Outer spectrophotometer measures its absorbance at 545nm, calculates hemolysis rate.
Result: the hemolysis rate of this test sample is 0.2%.
Conclusion: with reference to GB/T 16886.4-2003, the hemolytic test result of this test sample meets the requirement of medical material.
Embodiment 29
Stability and integrity test:
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short B liquid with the B liquid (hyaluronic acid of 2mg/ml, 0.15mol/L NaCl, pH=6) of band anionic group material；Take part B Liquid adds small RNA medicine (such as embodiment 1,10ug/mL) and is configured to C liquid, above-mentioned solution is filled to high pressure respectively instantaneous In spraying equipment, first toward culture dish inner high voltage instantaneous spraying A liquid, drying and forming-film；Then high pressure instantaneous spray coating liquor B, with injection Rinse with water；Then high pressure instantaneous spray coating liquor A, rinses with water for injection, such alternating spray A liquid, B liquid, flushing, repetitive operation 4 times altogether；High pressure instantaneous spraying A liquid, rinses with water for injection the most again；High pressure instantaneous spraying C liquid, rushes with water for injection again Washing, be dried, such alternating spray A liquid, C liquid, flushing, repetitive operation 7 times altogether, take off film, veneer water for injection rinses, and is dried Process to carry small RNA medicine implanted tissue adhesive film.
The above-mentioned plural layers prepared are placed in 1M NaCl solution, hatch certain time, by the sustained-release liquid of gained First pass through the ultra-filtration centrifuge tube filtration treatment that molecular cut off is 30KDa, remove macromolecular substances.It is then passed through molecular cut off Ultra-filtration centrifuge tube for 3KDa refilters process, removes the salt ion in sustained-release liquid, i.e. desalting processing.Finally slow processed Release liquid, run glue as sample liquid at electrophoresis tank and process.Use polyacrylamide gel electrophoresis method (PAGE) herein, verify multilamellar The genomic integrity of thin film release siRNA and Dependent Stability experiment.
The stability of the gel electrophoresis experimental verification slow release siRNA sequence of Fig. 1 and integrity.Carry the tissue adhesive of siRNA Film is hatched in 1M NaCl solution, and film gradually ruptures dissolving, after 6 days, has been difficult to observe by article shaped.Real from Fig. 1 gel electrophoresis In testing, it can be seen that, not it is observed that the siRNA dissociated after lysate desalination in 6 days, and can be clear after lysate desalination in 10 days The siRNA dissociated is seen on ground, thus it is presumed that, film is gradually rupturing in course of dissolution, leachable be siRNA with yin, yang from Subbase unity is fit, and along with the degraded of anions and canons group, siRNA gradually dissociates out, and maintains the steady of siRNA sequence Qualitative and integrity.
Embodiment 30
Cell transfection assays:
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short B liquid with the B liquid (hyaluronic acid of 2mg/ml, 0.15mol/L NaCl, pH=6) of band anionic group material；Take part B Liquid adds small RNA medicine (such as embodiment 1,10ug/mL) and is configured to C liquid, above-mentioned solution is filled to high pressure respectively instantaneous In spraying equipment, first toward culture dish inner high voltage instantaneous spraying A liquid, drying and forming-film；Then high pressure instantaneous spray coating liquor B, with injection Rinse with water；Then high pressure instantaneous spray coating liquor A, rinses with water for injection, such alternating spray A liquid, B liquid, flushing, repetitive operation 4 times altogether；High pressure instantaneous spraying A liquid, rinses with water for injection the most again；High pressure instantaneous spraying C liquid, rushes with water for injection again Washing, be dried, such alternating spray A liquid, C liquid, flushing, repetitive operation 2 times altogether, take off film, veneer water for injection rinses, and is dried Process to carry small RNA medicine implanted tissue adhesive film.
Using the above-mentioned tissue adhesive film prepared as experimental group, i.e. experimental group is for being loaded with the most poly-electricity of eGFP-siRNA Solving the film of qualitative response 2 times, negative control group is to be loaded with common siRNA to replace polyelectrolyte and react the film of 2 times (preparation method is with real Testing group, only eGFP-siRNA replaces with common siRNA).Experimental group and negative control group are placed in 6 orifice plates respectively, respectively will EGFP-HEK 293T cell be inoculated in 6 orifice plates thereon (additionally using do not place adhesive film hole direct inoculation cell as sky White matched group), observe its fluorescence intensity change situation respectively at 1 day, 2 days and 3 days, result shows Fig. 2.In Fig. 3, list reality Test group, negative control group and the relative intensity of fluorescence of blank group, it can be seen that blank group and negative control group fluorescence in 3 days Intensity has almost no change, and experimental group increased fluorescence intensity in 3 days over time and significantly reduces.It is loaded with eGFP by secondary checking The tissue adhesive film of siRNA can make the fluorescence intensity of eGFP-HEK 293T cell weaken, and illustrates that eGFP siRNA transfects into cell Reticent induction of target gene.
Embodiment 31
Stability and integrity test:
In aseptic working platform, prepare one 12 cm diameter culture dishs, a built-in same diameter polymer material film (warp Washing and sterilizing depyrogenation process), water for injection rinses and is dried；Prepare A liquid (the 1mg/ml glue of band cation group material respectively Former, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=3.5) and band anionic group material B liquid (1mg/ml hyaluronic acid, 0.15mol/L NaCl, pH=6)；(concentration is to add Afatinib (Afatinib) cation PEG nanoparticle in A liquid 0.5mg/ml) with target polypeptide (1 × 10-4Mg/ml) stirring, target polypeptide amino acid sequence is: arginine-glycine- Aspartic acid；Above-mentioned solution is filled in the instantaneous spraying equipment of high pressure respectively, first toward culture dish inner high voltage instantaneous spraying A Liquid, is dried, then high pressure instantaneous spraying B liquid, rinses with water for injection, such alternating spray A liquid, B liquid, flushing, repetitive operation 200 times；Last high pressure instantaneous spraying A liquid again, rinses with water for injection, is dried, takes off film, and veneer water for injection rinses, and is dried Process to carry Afatinib (Afatinib) medicine implanted tissue adhesive film.
The above-mentioned plural layers prepared are placed in 1M NaCl solution, hatch certain time, by the sustained-release liquid of gained Purification, can separate acquisition Afatinib, separates the amount of the Afatinib obtained compared to the Afatinib of addition during preparation Amount is not decreased obviously.Visible, stability and the integrity of medicine are kept.
Embodiment 32
Cell transfection assays:
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short B liquid with the B liquid (hyaluronic acid of 2mg/ml, 0.15mol/L NaCl, pH=6) of band anionic group material；In B liquid again Add VEGF (VEGF) (0.5mg/ml), stir and target polypeptide (1 × 10-4Mg/ml), target polypeptide Amino acid sequence is: valine-glycine-val-ala-proline-glycine, and flat board is submerged initially in solution A 20 Minute, take out and be dried into cleanout fluid washing；Again flat board is immersed in B solution 30 minutes, take out and be dried, so into cleanout fluid washing Alternately 80 times, finally rinse with water for injection, be dried, take off film, VEGF (VEGF) drug entities must be carried Adhesive film.
The above-mentioned plural layers prepared are placed in 1M NaCl solution, hatch certain time, by the sustained-release liquid of gained Purification, can separate acquisition VEGF, is detected by VEGF detection kit, separates the amount phase of the VEGF obtained The amount of the VEGF added during compared with preparation is not decreased obviously.Visible, stability and the integrity of medicine are kept.
Embodiment 33
In aseptic working platform, prepare a macromolecular material flat board (scrubbed, sterilizing and depyrogenation process), be dried；Point Pei Zhi the solution A (2mg/ml chitosan, 0.1mol/L acetic acid, 0.2mol/L NaCl, pH=4) of band cation group material It is called for short B liquid with the B liquid (hyaluronic acid of 2mg/ml, 0.15mol/L NaCl, pH=6) of band anionic group material；In B liquid again Add polyporusum bellatus (0.5mg/ml), stir, flat board is submerged initially in solution A 20 minutes, take out into cleanout fluid washing dry Dry；Again flat board is immersed in B solution 30 minutes, take out and be dried into cleanout fluid washing, the most alternately 100 times, finally with note Penetrate and rinse with water, be dried, take off film, polyporusum bellatus drug entities adhesive film must be carried.
The above-mentioned plural layers prepared are placed in 1M NaCl solution, hatch certain time, it is thus achieved that sustained-release liquid.Survey Polysaccharide component in amount sustained-release liquid, it appeared that the amount of polysaccharide is compared to the polysaccharide of addition during preparation in the sustained-release liquid of separation acquisition Amount be not decreased obviously.Visible, stability and the integrity of medicine are kept.
In sum, present invention effect overcomes various shortcoming of the prior art and has high industrial utilization.
The principle of above-described embodiment only illustrative present invention and effect thereof, not for limiting the present invention.Any ripe Above-described embodiment all can be modified under the spirit and the scope of the present invention or change by the personage knowing this technology.Cause This, have usually intellectual such as complete with institute under technological thought without departing from disclosed spirit in art All equivalences become are modified or change, and must be contained by the claim of the present invention.

Claims (10)

1. a medicine carrying tissue adhesive film, described medicine carrying tissue adhesive film includes cationic layer and the anion layer of alternately superposition, At least one of which in described cationic layer and anion layer is at least in medicine layer or described cationic layer and anion layer Layer is containing charged medicine, and described medicine is compound medicine.
2. a kind of medicine carrying tissue adhesive film as claimed in claim 1, it is characterised in that when described cationic layer and anion layer In at least one of which when being medicine layer, cationic layer and/or anion layer as medicine layer are charged medicine, not as The cationic layer of medicine layer contains the carrier material of band cation group, and the anion layer not as medicine layer contains band anion The carrier material of group；When at least one of which in described cationic layer and anion layer contains charged medicine, cation The layer carrier material containing band cation group, anion layer contains the carrier material of band anionic group.
3. a kind of medicine carrying tissue adhesive film as claimed in claim 2, it is characterised in that the carrier material of described band cation group Material selected from the organic high molecular polymer of band cation group, the polysaccharide of band cation group, the polypeptide of band cation group, The combination of one or more in albumen with cation group and cationic-liposome.
4. a kind of medicine carrying tissue adhesive film as claimed in claim 2, it is characterised in that the carrier material of described band anionic group Material selected from the organic high molecular polymer of band anionic group, the polysaccharide of band anionic group, the polypeptide of band anionic group, The combination of one or more in albumen with anionic group and anionic liposome.
5. a kind of medicine carrying tissue adhesive film as claimed in claim 2, it is characterised in that the carrier material of described band cation group The carrier material of material and band anionic group selects biocompatible materials.
6. a kind of medicine carrying tissue adhesive film as claimed in claim 1, it is characterised in that described cationic layer is shown generally as Positive charge, described anion layer is shown generally as negative charge.
7. a kind of medicine carrying tissue adhesive film as claimed in claim 1, it is characterised in that described charged medicine is that medicine is multiple Fit.
8. the preparation method of the medicine carrying tissue adhesive film as described in claim 1-7 any claim, comprises the steps: Alternating deposit cationic layer and anion layer on substrate, prepare tissue adhesive film.
9. tissue adhesive film purposes in preparing drug carrier material, described tissue adhesive film include the sun of alternately superposition from Sublayer and anion layer.
10. purposes as claimed in claim 9, it is characterised in that at least one of which in described cationic layer and anion layer is At least one of which in medicine layer or described cationic layer and anion layer is used for comprising charged medicine.
CN201610377528.XA 2016-03-14 2016-05-31 Compound drug loading tissue pasting membrane and preparation method thereof Pending CN106038516A (en)

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