CN109200012A - A kind of layering dissolution micropin containing inorganic salts - Google Patents
A kind of layering dissolution micropin containing inorganic salts Download PDFInfo
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- CN109200012A CN109200012A CN201710546759.3A CN201710546759A CN109200012A CN 109200012 A CN109200012 A CN 109200012A CN 201710546759 A CN201710546759 A CN 201710546759A CN 109200012 A CN109200012 A CN 109200012A
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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
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—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
- A61K47/38—Cellulose; Derivatives thereof
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
Abstract
The present invention discloses a kind of layering dissolution micropin containing inorganic salts, including the needle point on the needle body and needle body in substrate, substrate；The needle point is mixed by inorganic salt solution, stabilizer, the water-soluble high-molecular material of film forming and bioactive ingredients；The needle body and substrate are made of the water-soluble high-molecular material of film forming or the water-soluble high-molecular material of film forming with stabilizer.The invention also discloses above-mentioned, and the preparation method of micropin is dissolved in the layering containing inorganic salts.The present invention effectively improves the formability of the micropin needle point containing inorganic salts, improves the stability of bioactive ingredients, is of great significance for the development of micropin technology.
Description
Technical field
The present invention relates to pharmaceutical technology fields.Micropin is dissolved more particularly, to a kind of layering containing inorganic salts.
Background technique
With the development of dissolution micropin technology, the macromoleculars such as biologically active polypeptide, albumen are contained in micropin,
It is transported to by micropin intradermal to reach the hot spot that therapeutic effect is increasingly becoming people's research.In protein medicaments such as vaccines
Manufacturing process in, in order to maintain the activity of large biological molecule, inorganic salts are added to adjust in microenvironment locating for molecule
Ionic strength and pH value make it keep stability, also have to these inorganic salts in the manufacturing process of micropin with biology point
Son contains in needle point together.But inorganic salts can be easy to be precipitated and influence the mechanical performance of micropin during micropin is dry,
Seriously, then it form needle point can not.
There is the macromolecule material for stablizing protein conformation using chondroitin sulfate, glucan, polyvinylpyrrolidone etc.
Material production micropin, since the brittleness of itself material influences the formability of micropin along with the presence of the inorganic salts in solution.
Accordingly, it is desirable to provide a kind of effectively solve the not easily molded production micropin needle point containing inorganic salt solution and polypeptide and egg
The micropin of the stability problem of white active component.
Summary of the invention
It is an object of the present invention to provide a kind of, and micropin is dissolved in the layering containing inorganic salts, which can improve containing nothing
The formability of the micropin needle point of machine salt and the stability for improving bioactive ingredients.
It is another object of the present invention to provide the preparation methods of above-mentioned layering dissolution micropin.
In order to achieve the above objectives, the present invention adopts the following technical solutions:
The present invention provides a kind of, and micropin is dissolved in the layering containing inorganic salts, including the needle body and needle body in substrate, substrate
On needle point, the needle point mixes by inorganic salt solution, stabilizer, the water-soluble high-molecular material of film forming and bioactive ingredients
Conjunction is made.Wherein, the length of the needle point is less than or equal to 2/3rds of micropin overall length (needle body on needle point and substrate).
In the preferred embodiment of the present invention, the stabilizer include small molecule active stabilizer, can for trehalose,
Mannitol, sucrose, arginine, mixture one or more of in Calcium Glucoheptonate.
In preferred embodiment of the invention, the stabilizer also includes high molecular reactive stabilizer, can be Portugal
Glycan, chondroitin sulfate (CS), mixture one or more of in polyvinylpyrrolidone (PVP).Wherein, the glucan
Molecular weight is 10,000 or more, and chondroitin sulfate molecular weight is 30,000-5 ten thousand, and polyvinylpyrrolidonemolecules molecules amount is 10,000-150 ten thousand.
In the preferred embodiment of the present invention, the quality of the small molecule active stabilizer and Large molecule active stabilizer
Than for 10:1-1:10.
In the present invention, small molecule active stabilizer is hydroaropic substance, has good moisture retention, energy and active constituent
Between under the action of intermolecular force, be looped around around active constituent, have the function of water lock moisturizing；And high molecular reactive
Stabilizer is hydrophilic material, can under the action of intermolecular force (such as hydrogen bond) with interact between active constituent,
The space structure of stabilizing active ingredient；And inorganic salts are used to adjust the ionic strength around active constituent, make the electricity of active constituent
Lotus keeps stablizing, to reach the active purpose of stabilizing active ingredient.
In the preferred embodiment of the present invention, the water-soluble high-molecular material of the film forming be cellulose derivative,
The water soluble polymers material such as chitosan derivatives, polyvinyl alcohol and its derivative, PVP-VA64, Sodium Hyaluronate, sodium alginate
The mixture of one or more of material.The cellulose derivative includes but is not limited to sodium carboxymethylcellulose, hydroxypropyl first
Base cellulose；The chitosan derivatives include but is not limited to carboxymethyl chitosan；The polyvinyl alcohol derivative includes but not
It is limited to polyvinyl alcohol-polyethylene glycol；
Wherein, sodium carboxymethylcellulose (CMC) molecular weight is 10,000-100 ten thousand and crosslinking CMC, hydroxypropyl methyl cellulose
(HPMC) molecular weight is 5000-100 ten thousand, and carboxymethyl chitosan molecular weight is 10,000-100 ten thousand, and polyvinyl alcohol (PVA) molecular weight is
5000 or more, polyvinyl alcohol-polyethylene glycol (PVA-PEG) molecular weight is 5000-10 ten thousand, and PVP-VA64 molecular weight is 10,000-100
Ten thousand, Sodium Hyaluronate (HA) molecular weight is 1-100 ten thousand, and sodium alginate molecular weight is 10,000-100 ten thousand.
In the preferred embodiment of the present invention, the water-soluble high-molecular material of the film forming and the mass ratio of stabilizer
It is related to the molecular weight of the two, it is furthermore preferred that the mass ratio of the water-soluble high-molecular material of the film forming and stabilizer is 10:
1-1:10.When the mass ratio of the water-soluble high-molecular material of the film forming and stabilizer is less than 10:1, the ratio of stabilizer
It is too small, it is unable to reach the active purpose of long-time stable active constituent；When the water-soluble high-molecular material of the film forming and steady
When determining the mass ratio of agent and being greater than 1:10, since needle point layer is mainly made of small molecule after drying, due to itself brittleness not
Yi Chengzhen, needle point can not be demoulded completely.
In the preferred embodiment of the present invention, the bioactive ingredients are protected including but not limited to treatment or reparation
Polypeptide drug, the protein medicaments, nucleic acid drug, vaccine of strong effect.Wherein, the polypeptide drug can be interference
Element, insulin, thymic activity pentapeptide, go parathormone, glucagon, growth factor, Lumbrokinase, Argireline, oxytocins,
What Leuprorelin, superoxide dismutase, calcitonin, recombination human brain benefit peptide etc. were synthesized or extracted has treatment, prevention and increasing
The polypeptide of strong immunization；The protein medicaments can be interleukins, erythropoietin(EPO), tumor necrosis factor, chain
Kinases, fibroblast growth factor, recombinant human epidermal growth factor, human growth hormone recombinant, monoclonal antibody, genetic engineering
The synthesis such as hepatitis B vaccine, recombination or the albumen with treatment, prevention and enhancing immunization extracted；The nucleic acid drug
Can be Fomivirsen (Fomivirsen), ATP, coacetylase, deoxynucleotide, CTP, UTP, nitrine adenosine, polyinosinic acid,
The synthesis such as arabinosy ladenosine, cytarabine, recombination or the nucleic acid with treatment, prevention and enhancing immunization extracted；It is described
It includes the albumen with treatment or defense reaction that vaccine, which can be influenza vaccines, rabies vaccine, hepatitis B vaccine, hepatitis C vaccine etc.,
The vaccine of class, inactivation of viruses class, DNA class.Further, adjuvant can be contained in the vaccine.
Preferably, the osmotic pressure of the inorganic salt solution is equal with human body fluid, is sodium chloride, potassium chloride, biphosphate
The mixture of one or more of the inorganic salt solutions such as sodium, disodium hydrogen phosphate, zinc chloride.Including but not limited to following several salt
Concentration: (1) 0.01mM PBS (pH 7.4): 8g NaCl, 0.2g KCl, 1.44g Na2HPO4With 0.24g KH2PO4It is dissolved in
It is formulated in 1000ml distilled water；(2) 0.01mM PBS (pH 7.2): 8.5g NaCl, 2.86g Na2HPO412H2O and
0.312g Na H2PO42H2O, which is dissolved in 1000ml distilled water, to be formulated；(3) 0.3mM NaCl solution: 18g NaCl is dissolved in
It is formulated in 1000ml distilled water；(4) 0.1mM NaCl solution: 6g NaCl, which is dissolved in 1000ml distilled water, to be formulated；
(5)0.022mM ZnCl2Solution: 3g ZnCl2It is dissolved in 1000ml distilled water and being formulated.
In the present invention, if between the bioactive ingredients and inorganic salt solution proportionate relationship satisfaction can generate it is uniform
The transparent inorganic salt solution containing bioactive ingredients；Inorganic salt solution and film forming containing bioactive ingredients
Proportionate relationship between water-soluble high-molecular material and stabilizer, as long as meeting the water-soluble high-molecular material of film forming and steady
Homogeneous and transparent solution can be dissolved into the inorganic salt solution containing bioactive ingredients by determining agent.
Further, the needle body and substrate are made using the water-soluble high-molecular material of film forming；Preferably, described
Needle body and substrate are made using the water-soluble high-molecular material of film forming with stabilizer；Wherein, described in needle body and substrate
The water-soluble high-molecular material of film forming and the mass ratio of stabilizer are 1:0-5.
Wherein, the water-soluble high-molecular material of the film forming can be cellulose derivative, chitosan derivatives, poly- second
One or more of the water-soluble high-molecular materials such as enol and its derivative, PVP-VA64, Sodium Hyaluronate, sodium alginate
Mixture, to keep the flexible of microneedle patch substrate.The cellulose derivative includes but is not limited to carboxymethyl cellulose
Sodium, hydroxypropyl methyl cellulose；The chitosan derivatives include but is not limited to carboxymethyl chitosan；The polyvinyl alcohol is derivative
Object includes but is not limited to polyvinyl alcohol-polyethylene glycol.The sodium carboxymethylcellulose molecular weight is 10,000-100 ten thousand and crosslinking
CMC, hydroxypropyl methyl cellulose molecular weight are 5000-100 ten thousand, and carboxymethyl chitosan molecular weight is 10,000-100 ten thousand, polyvinyl alcohol
Molecular weight is 5000 or more, and polyvinyl alcohol-polyethylene glycol molecular weight is 5000-10 ten thousand, and PVP-VA64 molecular weight is 10,000-100
Ten thousand, Sodium Hyaluronate molecular weight is 1-100 ten thousand, and sodium alginate molecular weight is 10,000-100 ten thousand.
In the preferred embodiment of the present invention, the stabilizer include small molecule active stabilizer, can for trehalose,
Mannitol, sucrose, arginine, mixture one or more of in Calcium Glucoheptonate.
In preferred embodiment of the invention, the stabilizer also includes high molecular reactive stabilizer, can be Portugal
Glycan, chondroitin sulfate, mixture one or more of in polyvinylpyrrolidone.The dextran molecule amount be 10,000 with
On, chondroitin sulfate molecular weight is 30,000-5 ten thousand, and polyvinylpyrrolidonemolecules molecules amount is 10,000-150 ten thousand.
In the preferred embodiment of the present invention, the quality of the small molecule active stabilizer and Large molecule active stabilizer
Than for 10:1-1:10.
Layering dissolution micropin of the present invention containing inorganic salts further includes subbasal backing.
The present invention also provides above-mentioned, and the preparation method of micropin is dissolved in the layering containing inorganic salts, comprising the following steps:
(1) preparation of needle point solution: bioactive ingredients are dissolved in inorganic salt solution, are prepared containing bioactivity
The inorganic salt solution of ingredient；Add water-soluble high-molecular material, the stabilizer to the nothing containing bioactive ingredients of film forming
Machine salting liquid, after dissolution, 0-4 DEG C of static 5-60min, degasification；
(2) preparation of needle body and substrate solution: the water-soluble high-molecular material of film forming is mixed with water, is added or is added without
Stabilizer, stirring, degasification after dissolution；
(3) micropin forms: needle point solution is added drop-wise on each micropin die unit, after mold bottom vacuumizes 5min,
It blows in and blows 10min, needle body and substrate solution are applied on each micropin die unit, mold bottom will after vacuumizing 10min
Redundance is blown off, after the dry 60min that blows in.
Beneficial effects of the present invention are as follows:
In the prior art, containing inorganic salt solution production, micropin needle point is not easily molded and polypeptide and albumen active component
There are problems for stability.The present invention by have to bioactive ingredients the small molecule active stabilizer such as trehalose of stabilization,
Mannitol, sucrose, arginine, Calcium Glucoheptonate etc. improve the stability of bioactive ingredients.It is steady by addition Large molecule active
Determine agent such as chondroitin sulfate, glucan, polyvinylpyrrolidone are main material, pass through the water-soluble of uniform mixed biologic compatibility
It is property film-forming high molecular material such as cellulose derivative, carboxymethyl chitosan, polyvinyl alcohol or polyvinyl alcohol-polyethylene glycol, transparent
Matter acid sodium etc. further improves the stability of bioactive ingredients and improves the formability of the micropin needle point containing inorganic salts.This
Outside, which compares merely with one or more filmogens such as cellulose derivative, carboxymethyl chitosan, polyvinyl alcohol
Or polyvinyl alcohol-polyethylene glycol, fibroin, Sodium Hyaluronate etc. are the micropin of micropin material production, are had intradermal faster
Dissolubility, general 3-10 minutes can dissolve, and can quickly separate with microneedle substrate, reduce microneedle patch attach on skin when
Between, using more convenient.
Detailed description of the invention
Specific embodiments of the present invention will be described in further detail with reference to the accompanying drawing.
Fig. 1 shows the schematic diagram of the layering dissolution micropin containing inorganic salts.
Fig. 2 shows Stereo microscopes to observe full wafer micropin form；A: embodiment 1, B: comparative example 3, C: comparative example 4.
Fig. 3 shows 45 micropin of embodiment in its fluorescence distribution situation of fluorescence microscopy microscopic observation.
Fig. 4 shows the skin penetrating ability of 45 micropin of embodiment.
Fig. 5 shows the metamorphosis before and after 2 micropin of embodiment effect rat；A: before pricking rat skin, B: rat skin is pricked
After 5min.
Specific embodiment
In order to illustrate more clearly of the present invention, the present invention is done further below with reference to preferred embodiments and drawings
It is bright.Similar component is indicated in attached drawing with identical appended drawing reference.It will be appreciated by those skilled in the art that institute is specific below
The content of description is illustrative and be not restrictive, and should not be limited the scope of the invention with this.
1 one kind of embodiment contains inorganic salts using filmogen sodium carboxymethylcellulose (CMC) as basic framework material
Layering dissolution micropin preparation method
1, needle point solution is prepared:
Weigh CMC (sodium carboxymethylcellulose, the ten thousand) 0.08g of molecular weight 10,000-10, chondroitin sulfate (CS, molecular weight 30,000-5
Ten thousand) influenza vaccines PBS (0.01M, pH 7.2) salting liquid containing 1mg/mL is added in 0.004g, trehalose 0.004g
0.912ml, after stirring and dissolving, 0 DEG C of standing 5min, centrifugation degasification is spare.
2, needle body and substrate solution:
Weighing PVA, (ultrapure water 7mL is added in polyvinyl alcohol, the ten thousand) 3g of molecular weight 10,000-5, and water-bath magnetic stirs under the conditions of 80 DEG C
It mixes, the degasification after it is completely dissolved, and it is spare to drop to room temperature.
3, micropin forms:
First needle point solution is added drop-wise on each micropin die unit, after PDMS mold bottom vacuumizes 5min, blows in and blows
After 10min.Needle body and substrate solution are applied on each micropin die unit again.After PDMS mold bottom vacuumizes 10min
Redundance is blown off, after the dry 60min that blows in, mold is placed on 6h in 20% humidity drying box, patch is by lining demoulding preparation
Enter and leave micropin shown in FIG. 1.
4, each parameter of micropin is detected
1) it detects vaccine activity in micropin: after a piece of micropin after shaping and demoulding is dissolved in corresponding inorganic salt solution, taking
200ul, which is added in 96 orifice plates, detects activity using Elisa kit, and is compared with the control group of same concentrations.
2) full wafer micropin form micropin aciculiform: is observed by Stereo microscope.
3) micropin Mechanics Performance Testing:
Using instrument: computer strength stroke testing machine (model:1220SB) sets the strength upper limit as 5N, is using probe
(2mm × 2mm), testing micropin number every time is 16.Micropin is fixed on objective table, upward, setting objective table moves needle point
Dynamic speed is 1.1mm/s.After the completion of test, the case where having seen whether needle point fracture using Stereo microscope.
Comparative example 1-5, embodiment 2-10
According to the method for embodiment 1, according to the substance weight percentage provided in table 1, comparative example 1-5, embodiment are prepared
The micropin of 2-10 simultaneously investigates the activity of its biomolecule, the integrality of micropin and mechanical property (being shown in Table 1 and Fig. 2).
From table 1 it follows that comparative example 1 is that needle point solution only uses the water-soluble high-molecular material containing film forming
CMC, the activity for the micropin active constituent produced only have the 25% of control group (the active constituent salting liquids of same concentrations), living
Property loss it is very much, but aciculiform is complete after its demoulding, without broken needle after single needle stress 0.32N；And its needle point of comparative example 2-5 composition is only
The activity for the micropin active constituent for having stabilizer (film forming is poor) to produce accounts for 80%-100% compared with control group, it was demonstrated that stablizes
Agent can make active constituent keep activity, but its demoulding after aciculiform it is imperfect, have after single needle stress 0.32N broken needle (Fig. 2 B,
2C)；Embodiment 1-10 uses the CMC containing good film-forming property and sodium alginate (content 1%-10% in aqueous solution) and steady simultaneously
Determine the one or more of agent (CS, glucan, PVP, trehalose, arginine, sucrose, Calcium Glucoheptonate), the results showed that it makes
The activity of micropin active constituent out accounts for 75%-95% compared with control group, and aciculiform is complete after demoulding, single needle stress 0.32N
Afterwards also without broken needle (Fig. 2A).
For table 1 using filmogen CMC as basic framework material, comparative example 1-5, embodiment 1-10 specifically match table
Embodiment 11 it is a kind of using filmogen hydroxypropyl methyl cellulose (HPMC) as basic framework material contain whether there is or not
The preparation method of the layering dissolution micropin of machine salt
1, needle point solution is prepared:
Weigh HPMC (hydroxypropyl methyl cellulose, molecular weight 10,000-10 ten thousand) 0.08g, CS 0.004g, trehalose
Hepatitis B DNA vaccine PBS (0.01M, pH 7.2) salting liquid 0.912ml containing 3mg/mL, after stirring and dissolving, 2 is added in 0.004g
DEG C stand 30min, centrifugation degasification it is spare.
2, needle body and substrate solution:
HPMC (molecular weight 10,000-10 ten thousand) 3.5g is weighed, ultrapure water 7.5mL is added, water-bath magnetic stirs under the conditions of 80 DEG C,
The degasification after it is completely dissolved, and it is spare to drop to room temperature.
3, micropin forms:
First needle point solution is added drop-wise on each micropin die unit, after PDMS mold bottom vacuumizes 5min, blows in and blows
After 10min.Needle body and substrate solution are applied on each micropin die unit again.After PDMS mold bottom vacuumizes 10min
Redundance is blown off, after the dry 60min that blows in, patch is demoulded by lining.
Comparative example 6, embodiment 12-21
Comparative example 6, embodiment are prepared according to the substance weight percentage provided in table 2 according to the method for embodiment 11
The micropin of 12-21 and according to embodiment the method investigate its biomolecule activity, the integrality of micropin and mechanical property (see
Table 2).
From Table 2, it can be seen that comparative example 6 is that needle point solution matrix only use the water soluble polymer material containing film forming
Expect HPMC, the activity for the micropin active constituent produced only has control group (the active constituent salting liquids of same concentrations)
25%, there are many loss of activity, but aciculiform is complete after its demoulding, without broken needle after single needle stress 0.32N；Embodiment 11-21 is simultaneously
Using the HPMC containing good film-forming property and PVP-VA64 (content 1%-10% in aqueous solution) and stabilizer (CS, glucan,
PVP, trehalose, arginine, sucrose, Calcium Glucoheptonate) one or more, the results showed that its micropin active constituent produced
Activity 75%-95% is accounted for compared with control group, aciculiform is complete after demoulding, also without broken needle after single needle stress 0.32N.
For table 2 using filmogen HPMC as basic framework material, comparative example 6, embodiment 11-21 specifically match table
A kind of point containing inorganic salts using filmogen Sodium Hyaluronate (HA) as basic framework material of embodiment 22
The preparation method of layer dissolution micropin
1, needle point solution is prepared:
Weighing HA, (Sodium Hyaluronate, ten thousand) 0.08g, CS 0.004g, trehalose 0.004g, addition contain molecular weight 40,000-6
Insulin PBS (0.01M, pH 7.2) salting liquid 0.912ml of 2mg/mL, after stirring and dissolving, 4 DEG C of standing 60min are centrifuged degasification
It is spare.
2, needle body and substrate solution:
It weighs CMC (molecular weight 10,000-10 ten thousand) 1g, PVA-PEG (molecular weight 5000-1 ten thousand) 2g and ultrapure water 7mL is added, 80
Water-bath magnetic stirs under the conditions of DEG C, the degasification after it is completely dissolved, and it is spare to drop to room temperature.
3, micropin forms:
First needle point solution is added drop-wise on each micropin die unit, after PDMS mold bottom vacuumizes 5min, blows in and blows
After 10min.Needle body and substrate solution are applied on each micropin die unit again.After PDMS mold bottom vacuumizes 10min
Redundance is blown off, after the dry 60min that blows in, patch is demoulded by lining.
Comparative example 7, embodiment 23-32,
Comparative example 7, embodiment are prepared according to the substance weight percentage provided in table 3 according to the method for embodiment 22
The micropin of 23-32 is simultaneously investigated the activity of its biomolecule, the integrality of micropin and mechanical property according to 1 method of embodiment and (is shown in Table
3)。
From table 3 it is observed that comparative example 7 is that needle point solution matrix only use the water soluble polymer material containing film forming
Expect HA, the activity for the micropin active constituent produced only has the 30% of control group (the active constituent salting liquids of same concentrations),
There are many loss of activity, but aciculiform is complete after its demoulding, without broken needle after single needle stress 0.32N；Embodiment 22-32 use simultaneously contains
There are the HA or HA of good film-forming property and the mixing (content 1%-10% in aqueous solution) of CMC, HPMC, PVP-VA64 and stabilizer
The one or more of (CS, glucan, PVP, trehalose, arginine, sucrose, Calcium Glucoheptonate), the results showed that it was produced
The activity of micropin active constituent accounts for 80%-95% compared with control group, and aciculiform is complete after demoulding, after single needle stress 0.32N
Without broken needle.
For table 3 using filmogen HA as basic framework material, comparative example 7, embodiment 22-32 specifically match table
A kind of layering containing inorganic salts using filmogen carboxymethyl chitosan as basic framework material of embodiment 40
Dissolve the preparation method of micropin
1, needle point solution is prepared:
Weigh carboxymethyl chitosan (molecular weight 20,000-25 ten thousand) 0.02g, CMC (molecular weight 10,000-10 ten thousand) 0.02g, PVP-
VA64 0.01g, CS 0.02g, trehalose 0.005g, sucrose 0.005g, arginine 0.005g, Calcium Glucoheptonate 0.005g are added
Fomivirsen NaCl (0.1mM) salting liquid 0.91ml containing 2mg/mL, after stirring and dissolving, 4 DEG C of standing 10min are centrifuged degasification
It is spare.
2, needle body and substrate solution:
PVA (molecular weight 100,000) 3g, CS0.2g, glucan 0.2g (100,000 or more molecular weight) is weighed, ultrapure water is added
6.1mL, water-bath magnetic stirs under the conditions of 80 DEG C, the degasification after it is completely dissolved, and it is spare to drop to room temperature.
3, micropin forms:
First needle point solution is added drop-wise on each micropin die unit, after PDMS mold bottom vacuumizes 5min, blows in and blows
After 10min.Needle body and substrate solution are applied on each micropin die unit again.After PDMS mold bottom vacuumizes 10min
Redundance is blown off, after the dry 60min that blows in, patch is demoulded by lining.
Comparative example 8, embodiment 33-39,41-43
Comparative example 8, embodiment are prepared according to the substance weight percentage provided in table 4 according to the method for embodiment 40
The micropin of 33-39,41-43 simultaneously investigate the activity of its biomolecule, the integrality of micropin and mechanical property (being shown in Table 4).
As can be seen from Table 4, comparative example 8 is that needle point solution matrix only use the water soluble polymer material containing film forming
Expect carboxymethyl chitosan, the activity for the micropin active constituent produced only has control group, and (the active constituent salt of same concentrations is molten
Liquid) 40%, there are many loss of activity, but its demoulding after aciculiform it is complete, without broken needle after single needle stress 0.32N；Embodiment 33-
39,41-43 is simultaneously using the mixed of the carboxymethyl chitosan containing good film-forming property or carboxymethyl chitosan and CMC, PVP-VA64
Close (content 0.5%-5% in aqueous solution) and stabilizer (CS, glucan, PVP, trehalose, arginine, sucrose, glucoheptonic acid
Calcium) one or more, the results showed that its micropin active constituent produced activity account for 80%-95% compared with control group,
Aciculiform is complete after demoulding, also without broken needle after single needle stress 0.32N.
Using filmogen carboxymethyl chitosan as basic framework material, comparative example 8, embodiment 33-43 are specifically matched table 4
Table
A kind of preparation method of the layering dissolution micropin containing inorganic salts of embodiment 44
1, needle point solution is prepared:
Weighing CS, (chondroitin sulfate, ten thousand) 0.1g, CMC (crosslinking CMC) 0.05g, trehalose 0.1g add molecular weight 30,000-5
Enter viral hepatitis type E vaccine (split vaccine contains aluminum hydroxide adjuvant) NaCl (0.3mM) salting liquid 0.835ml containing 3mg/mL, stirs
After mixing dissolution, it is spare to be centrifuged degasification by 4 DEG C of standing 10min.
2, needle body and substrate solution:
Carboxymethyl chitosan (average molecular weight 20,000 or so) 3g is weighed, ultrapure water 7mL is added, is stirred evenly to it completely
Degasification is centrifuged after dissolution, it is spare.
3, micropin forms:
First needle point solution is added drop-wise on each micropin die unit, after PDMS mold bottom vacuumizes 5min, blows in and blows
After 10min.Needle body and substrate solution are applied on each micropin die unit again.After PDMS mold bottom vacuumizes 10min
Redundance is blown off, after the dry 60min that blows in, patch is demoulded by lining.
A kind of micropin puncture detection of the layering dissolution micropin containing inorganic salts of embodiment 45
1, needle point solution is prepared:
PVP (molecular weight 10,000-2 ten thousand) 0.05g, HPMC (molecular weight 5000-1 ten thousand) 0.15g is weighed, trehalose 0.05g adds
Enter rhodamine NaCl (0.3mM) salting liquid 0.75ml containing 1mg/mL, after stirring and dissolving, 4 DEG C of standing 10min are centrifuged degasification
It is spare.
2, needle body and substrate solution:
CMC (molecular weight 100,000-100 ten thousand) 2g is weighed, ultrapure water 7mL is added in PVA-PEG 1g, stirs evenly to it completely
Decompression vacuum pumping degasification after dissolution, it is spare.
3, micropin forms:
First needle point solution is added drop-wise on each micropin die unit, after PDMS mold bottom vacuumizes 5min, blows in and blows
After 10min.Needle body and substrate solution are applied on each micropin die unit again.After PDMS mold bottom vacuumizes 10min
Redundance is blown off, after the dry 60min that blows in, patch is demoulded by lining.
4, micropin puncture:
The micropin being fabricated to is taken into fluorescence microscopy its fluorescence distribution situation under the microscope, as shown in figure 3, can be apparent
See that drug concentrates on tip portion.Pig skin surfaces are acted on using the power of 40N, and observe its skin using Trypan Blue
Skin puncture, as a result such as Fig. 4, micropin acts on the array pin hole of Trypan Blue after skin as can clearly see from the figure.
46 micropin of embodiment acts on the metamorphosis before and after rat abdomen skin
Optical microphotograph microscopic observation micropin form is taken after the micropin that embodiment 1-45 makes is demoulded, then by this micropin
It attaches on the rat abdomen skin after having shifted to an earlier date depilation in 24 hours, makes to press with finger 5min, micropin remainder is taken off
And it observes under an optical microscope.The result shows that by taking the layering micropin that embodiment 2 makes as an example (Fig. 5), after micropin demoulding, needle
Shape is complete (Fig. 5 A), and after acting on 5min on rat skin, about 2/3rds of needle point bottom have dissolved (Fig. 5 B), can recognize
It has been transported in skin for most of active medicine.
Obviously, the above embodiment of the present invention be only to clearly illustrate example of the present invention, and not be pair
The restriction of embodiments of the present invention may be used also on the basis of the above description for those of ordinary skill in the art
To make other variations or changes in different ways, all embodiments can not be exhaustive here, it is all to belong to this hair
The obvious changes or variations that bright technical solution is extended out are still in the scope of protection of the present invention.
Claims (10)
1. micropin is dissolved in a kind of layering containing inorganic salts, including the needle point on the needle body and needle body in substrate, substrate, feature
Be: the needle point is mixed by inorganic salt solution, stabilizer, the water-soluble high-molecular material of film forming and bioactive ingredients and is made
At.
2. micropin is dissolved in layering according to claim 1, it is characterised in that: the stabilizer is stablized comprising small molecule active
Agent, the small molecule active stabilizer is trehalose, mannitol, sucrose, arginine, one or more of mixed in Calcium Glucoheptonate
Close object.
3. micropin is dissolved in layering according to claim 2, it is characterised in that: the stabilizer also includes that Large molecule active is steady
Determine agent, the Large molecule active stabilizer is glucan, chondroitin sulfate, one or more of mixed in polyvinylpyrrolidone
Close object；The dextran molecule amount is 10,000 or more, and chondroitin sulfate molecular weight is 30,000-5 ten thousand, polyvinylpyrrolidonemolecules molecules amount
It is 10,000-150 ten thousand.
4. micropin is dissolved in layering according to claim 3, it is characterised in that: the small molecule active stabilizer and macromolecular
The mass ratio of active stabilizer is 10:1-1:10.
5. micropin is dissolved in layering according to claim 1, it is characterised in that: the water-soluble high-molecular material of the film forming
For sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, carboxymethyl chitosan, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol,
The mixture of one or more of PVP-VA64, Sodium Hyaluronate, sodium alginate；
Wherein, the sodium carboxymethylcellulose molecular weight is 10,000-100 ten thousand and crosslinking CMC, hydroxypropyl methyl cellulose molecule
Amount is 5000-100 ten thousand, and carboxymethyl chitosan molecular weight is 10,000-100 ten thousand, and polyvinyl alcohol molecule amount is 5000 or more, polyethylene
Alcohol-molecular weight polyethylene glycol is 5000-10 ten thousand, and PVP-VA64 molecular weight is 10,000-100 ten thousand, and Sodium Hyaluronate molecular weight is 1-
1000000, sodium alginate molecular weight is 10,000-100 ten thousand.
6. micropin is dissolved in layering according to claim 1, it is characterised in that: the osmotic pressure and human body of the inorganic salt solution
Body fluid pervious pressure is equal, and the inorganic salt solution is sodium chloride, potassium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, liquor zinci chloridi
One or more of mixture.
7. micropin is dissolved in layering according to claim 1, it is characterised in that: the water-soluble high-molecular material of the film forming
Mass ratio with stabilizer is 10:1-1:10.
8. micropin is dissolved in layering according to claim 1, it is characterised in that: the bioactive ingredients are polypeptide medicine
Object, protein medicaments, nucleic acid drug, vaccine.
9. micropin is dissolved in layering according to claim 1, it is characterised in that: the needle body and substrate are by the water-soluble of film forming
The water-soluble high-molecular material of property high molecular material or film forming is made with stabilizer；The water soluble polymer material of the film forming
The mass ratio of material and stabilizer is 1:0-5.
10. a kind of method for preparing any layering dissolution micropin of claim 1-9, comprising the following steps:
(1) preparation of needle point solution: bioactive ingredients are dissolved in inorganic salt solution, are prepared containing bioactive ingredients
Inorganic salt solution；Add water-soluble high-molecular material, the stabilizer to the inorganic salts containing bioactive ingredients of film forming
Solution, after dissolution, 0-4 DEG C of static 5-60min, degasification；
(2) preparation of needle body and substrate solution: the water-soluble high-molecular material of film forming is mixed with water, is added or is added without stabilization
Agent, stirring, degasification after dissolution；
(3) micropin forms: needle point solution being added drop-wise on each micropin die unit, after mold bottom vacuumizes 5min, is blown in
10min is blown, needle body and substrate solution are applied on each micropin die unit, mold bottom will be extra after vacuumizing 10min
Part is blown off, after the dry 60min that blows in.
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| CN201710546759.3A CN109200012A (en) | 2017-07-06 | 2017-07-06 | A kind of layering dissolution micropin containing inorganic salts |
| PCT/CN2018/094582 WO2019007380A1 (en) | 2017-07-06 | 2018-07-05 | Inorganic salt-containing layered dissolving micro-needle containing inorganic salt |
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| CN109884223A (en) * | 2019-02-23 | 2019-06-14 | 贵阳中医学院 | A kind of strychnia solubility micropin, preparation method and detection method and application |
| CN110339474A (en) * | 2019-07-19 | 2019-10-18 | 怡定兴科技股份有限公司 | For microneedle patch needle bottom composition and include its microneedle patch |
| CN111375124A (en) * | 2020-03-19 | 2020-07-07 | 上海缓释新材料科技有限公司 | Anti-aging slow-release soluble microneedle based on polylactic acid compound and preparation method thereof |
| CN111529920A (en) * | 2020-04-09 | 2020-08-14 | 四川大学 | Microneedle drug delivery device, manufacturing method thereof and skin disease treatment device |
| CN111617026A (en) * | 2020-06-09 | 2020-09-04 | 无锡元旭生物技术有限公司 | Sodium alginate swelling microneedle patch and preparation method thereof |
| CN113599501A (en) * | 2021-08-25 | 2021-11-05 | 北京三元基因药业股份有限公司 | Stable interferon microneedle preparation as well as preparation method and application thereof |
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| CN109884223A (en) * | 2019-02-23 | 2019-06-14 | 贵阳中医学院 | A kind of strychnia solubility micropin, preparation method and detection method and application |
| CN110339474A (en) * | 2019-07-19 | 2019-10-18 | 怡定兴科技股份有限公司 | For microneedle patch needle bottom composition and include its microneedle patch |
| TWI692499B (en) * | 2019-07-19 | 2020-05-01 | 怡定興科技股份有限公司 | Needle base composition for microneedle patch and microneedle patch containing same |
| US10793701B1 (en) | 2019-07-19 | 2020-10-06 | Win Coat Corporation | Base composition for microneedle patch and microneedle patch comprising the same |
| CN110339474B (en) * | 2019-07-19 | 2021-07-06 | 怡定兴科技股份有限公司 | Needle base composition for microneedle patch and microneedle patch comprising same |
| CN114728154A (en) * | 2019-10-09 | 2022-07-08 | 瓦克塞斯技术公司 | Silk fibroin-based microneedles and uses thereof |
| CN111375124A (en) * | 2020-03-19 | 2020-07-07 | 上海缓释新材料科技有限公司 | Anti-aging slow-release soluble microneedle based on polylactic acid compound and preparation method thereof |
| CN111529920A (en) * | 2020-04-09 | 2020-08-14 | 四川大学 | Microneedle drug delivery device, manufacturing method thereof and skin disease treatment device |
| CN111617026A (en) * | 2020-06-09 | 2020-09-04 | 无锡元旭生物技术有限公司 | Sodium alginate swelling microneedle patch and preparation method thereof |
| CN113599501A (en) * | 2021-08-25 | 2021-11-05 | 北京三元基因药业股份有限公司 | Stable interferon microneedle preparation as well as preparation method and application thereof |
| CN113599501B (en) * | 2021-08-25 | 2022-11-29 | 北京三元基因药业股份有限公司 | Stable interferon microneedle preparation as well as preparation method and application thereof |
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