CN106422045A - Flexible slow-release microneedle patch and preparation method thereof - Google Patents
Flexible slow-release microneedle patch and preparation method thereof Download PDFInfo
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- CN106422045A CN106422045A CN201610803643.9A CN201610803643A CN106422045A CN 106422045 A CN106422045 A CN 106422045A CN 201610803643 A CN201610803643 A CN 201610803643A CN 106422045 A CN106422045 A CN 106422045A
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- micropin
- medicine
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Classifications
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- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
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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
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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- 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
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- 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
- A61M2207/00—Methods of manufacture, assembly or production
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medical Informatics (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a flexible sustained-release microneedle patch and a preparation method thereof, the microneedle patch comprises microneedles, a substrate and a lining, the microneedles and the substrate form a microneedle array, a matrix material of the microneedles or the matrix material of the microneedle array contains a crystal form drug, and the solubility of the crystal form drug in water is less than 100 mu g/ml. The microneedle patch has the characteristics of simple process, high preparation safety, low process cost, high drug-loading rate and the like.
Description
Technical field
The invention belongs to pharmaceutical technology field, more particularly, to a kind of flexibility slow release microneedle patch and its preparation side
Method.
Background technology
Transdermal delivery system is a kind of dosage form that medicine passes through percutaneous drug delivery, and this dosage form has and surmounts oral and injection etc.
The particular advantages of general form of administration.Micropin is one of physical enhancement method of percutaneous dosing.Micropin can change the logical of skin
Permeability, it can create the passage of micron-scale on skin, thus allowing drug molecule to pass through.Solubility micropin is by medicine
Thing and soluble matrix material are blended, after micropin pierces skin, dissolving or degraded with host material and discharge medicine, with
When, it is dissolved in after skin after needle point, microneedle patch can peel, needs to stick for a long time without as conventional patch, be a kind of
Painless, safe, autonomous administering mode.
In recent years, insoluble drug delivery system is always one of emphasis and difficult point of galenic pharmacy research.For microneedle patch
Piece, dissolubility in water for the insoluble drug is relatively low, in order to meet suitable dosage, needs of a relatively high micropin to carry medicine
Amount, medicine usual consideration organic solvent dissolves, and needs the macromolecule material selecting to be dissolved in organic solvent in preparation optimization
Material, and the micropin patch for Intradermal dissolving, simultaneously need to considering the water solublity of macromolecular material, selectable macromolecular material
Scope is narrower, and the residual of organic solvent also can reduce the safety of preparation simultaneously.Additionally for micropin slow releasing preparation, existing skill
Art is first medicine to be loaded in the microgranules such as microsphere, liposome, then medicine carrying microgranule is loaded into micropin host material.Microsphere, liposome
Preparation technology is loaded down with trivial details, envelop rate and drug loading low it is impossible to meet suitable micropin dosage；Need in microspheres simultaneously
Consider the residual of organic solvent.Above several respects all limit slightly solubility in terms of preparation security, technological operation, process costs
Development in terms of micropin drug-delivery preparation for the medicine.
A kind of fibroin albumen slow release micropin is disclosed, described fibroin albumen slow release in Chinese patent CN 105079953A
Micropin includes substrate layer and the medicine storing bag of long capsule shape.The present invention utilizes the drug storage containing capillary drug storage chamber that fibroin albumen manufactures
Capsule memory action medicine, medicine is slowly discharged capillary drug storage chamber and is beneficial to skin absorption.But the micropin of this patent prepares work
Skill is sufficiently complex, is not suitable for the production in enormous quantities of pharmaceutical preparation.
A kind of nanoparticle transdermal drug delivery system is disclosed, in this patent, micropin is sky in Chinese patent CN 204158882U
Heart micropin, medicine is in the drug-reservoir layer being stored in micropin upper strata in the form of liposome, solid lipid nanoparticle or microemulsion.
Pharmaceutical preparation discharges in bank, the empty road being formed on skin by micropin, reaches percdation administration.But used by this patent
Micropin be water-insoluble micropin, safety is high；Medicine needs to be prepared into the preparations such as liposome, microemulsion, complex production process,
With high costs.
Document (Ke C J, Lin Y J, Hu Y C, et al.Multidrug release based on
microneedle arrays filled with pH-responsive PLGA hollow microspheres[J]
.Biomaterials,2012,33(20):A kind of system of the solubility micropin being loaded with PLGA microsphere is provided in 5156-5165.)
Preparation Method.The method is that again prepared by the PLGA micro-ball load of the pH preparing response micropin in soluble high-molecular material,
After micropin acts on skin, needle point is dissolved in Intradermal and the slow releasing preparation of medicine is imported Intradermal.The benefit of the method is institute
The PLGA of preparation is pH response, can discharge medicine according to the pH of skin epidermis.But the method is loaded down with trivial details in technological operation, micro-
Organic solvent residual may be led in ball processing technology, affect safety, the micropin drug loading that this method makes simultaneously is low, no
The preparation that method meets heavy dose of medicine produces.
Present invention aim to address the deficiency of existing slow release microneedle patch, provide a kind of process is simple, with low cost, peace
Quan Xinggao and the preparation method of the big soluble slow release microneedle patch of drug loading.Insoluble drug can be passed through water solublity by the method
The micropin of macromolecular material imports Intradermal, reaches minimally invasive administering mode steady in a long-term.
Content of the invention
The invention solves the problems that first technical problem be to overcome the shortcomings of existing slow release microneedle patch preparation, provide one
Plant the slow release microneedle patch of the solvable insoluble drug of Intradermal, thus realizing convenience, efficient, safe administration purpose.
The invention solves the problems that second technical problem be a kind of solvable insoluble drug of Intradermal slow release microneedle patch
Preparation method.
For solving above-mentioned technical problem, the present invention adopts following technical proposals：
A kind of flexibility slow release microneedle patch, including micropin, substrate with served as a contrast, micropin and substrate composition microneedle array, its
Crystal habit medicine is contained, described crystal habit medicine is in water in the host material of the host material of middle micropin or microneedle array
Dissolubility is less than 100 μ g/ml；Preferably, described crystal habit medicine dissolubility in the aqueous solution in the range of pH4-9 is less than
100μg/ml.
Described microneedle patch is divided into two kinds, and that is, one kind contains crystal habit medicine for only micropin needle body, and another is
Microneedle array contains crystal habit medicine, and that is, micropin and substrate all contain crystal habit medicine.
In the present invention, in the aqueous solution in the range of pH4-9, dissolubility is difficult less than the crystal habit medicine of 100 μ g/ml
It is dissolved in the medicine of water, described medicine includes but is not limited to：Etonogestrel, ethinylestradiol, levonorgestrel, norgestrel, Progesterone,
Estradiol, estradiol valerate, ethinylestradiol, norethindrone, artemisinin derivatives, enoxolone, vinpocetine, Triptolide,
Ketoprofen, paclitaxel, Docetaxel, Cephalomannine, camptothecine, Sorafenib, oxaprozin, rutin, Herba Apii graveolentis
Element, Hesperidin or lignocaine, haloperidol, thiothixene, clozapine, olanzapine, pimozide, Ziprasidone, stable, chlorine
Fluorine Zhuo ethyl ester, alprazolam, Sertraline, donepezil, selegiline, pergolide, artane, bromocriptine, benzene support
Product, nordazepam, etizolam, clotiazepam, cetrorelix, Itraconazole, posaconazole, indomethacin, Alprostadil, he
Ke Mosi, chlorambucil, Anastrozole, Raltitrexed, epirubicin, letrozole, mefloquine, primaquine, oxibutynin, support
Special Luoding, allylestrenol, lovastatin, simvastatin, atorvastatin and/or raloxifene.
Preferably, the host material of the host material of micropin or microneedle array and the mass ratio of crystal habit medicine are 3: 1-
1000∶1.
Preferably, the host material of described micropin is selected from carboxymethyl cellulose, hydroxypropyl cellulose, hydroxy ethyl fiber
Element, polyvidon (PVP), hyaluronate sodium, chondroitin sulfate, shitosan, carboxymethyl chitosan, carboxymethyl chitin,
One or more of polyvinyl alcohol, water-soluble fibroin albumen, collagen protein and gelatin.
Preferably, the host material of described substrate be selected from carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,
Polyvidon (PVP), hyaluronate sodium, chondroitin sulfate, shitosan, carboxymethyl chitosan, carboxymethyl chitin, poly- second
One or more of enol, water-soluble fibroin albumen, collagen protein and gelatin.
The host material of the host material of described micropin or described substrate can be straight chain type can also be cross-linking type high score
Sub- material.
Preferably, described carboxymethyl cellulose molecular weight is 10-2000kDa；Described hydroxypropyl cellulose molecular weight is 10-
2000kDa；Described hydroxyethyl cellulose molecular weight is 10-2000kDa；Described polyvinylpyrrolidonemolecules molecules amount is 30-
2000KDa；Described hyaluronate sodium molecular weight is 10-2000KDa；Described chondroitin sulfate molecular weight is 50-1000kDa；Institute
Stating chitosan molecule amount is 20-2000KDa；Described carboxymethyl chitosan molecular weight is 10-800KDa；Described carboxymethyl chitin
Molecular weight is 10-2000KDa；Described polyvinyl alcohol molecule amount is 10-1000KDa；Described water-soluble fibroin molecular weight of albumen is
10-500KDa；Described collagen molecules amount is 10-200KDa；And/or described gelatine molecular weight is 10-1000KDa.
Preferably, the micropin length of described intradermal administration microneedle patch is 0.1mm-1mm.
Preferably, described lining is served as a contrast for pressure sensitive adhesive.
The present invention provides a kind of preparation method of flexibility slow release microneedle patch.
The preparation of this microneedle patch comprises the steps：
Prepare micropin host material aqueous solution：Crystal habit medicaments uniformity is scattered in host material aqueous solution, is formed
Emulsion, as micropin injection molding liquid；
Preparation base substrate material aqueous solution, as substrate injection molding liquid；
Described micropin injection molding liquid is injected in micropin mould and prepares micropin, by described micropin injection molding liquid or substrate injection molding liquid note
Substrate is prepared in a subtle way in needle mould tool；
It is dried, stick and served as a contrast；And
The micropin demoulding.
As can be seen that the microneedle patch of preparation is divided into two kinds, one kind is to carry medicine one microneedle patch, and another kind is to carry medicine to divide
Layer microneedle patch.Carry the substrate of medicine one microneedle patch and micropin needle body all adopts micropin note film liquid preparation.Carry medicine layering pin micro-
The micropin needle body of pin paster adopts micropin note film liquid preparation, and substrate adopts substrate note film liquid preparation.
The particle diameter of crystal habit medicine is relevant with slow release effect.It is appreciated that the slow release of different crystal form medicine is to grain
Footpath requires difference, can select the grain of corresponding crystal habit medicine according to the requirement to crystal habit slow release speed of medicine
Footpath.The particle diameter of preferably described crystal habit medicine is less than 30 μm, and the particle diameter of more preferably described crystal habit medicine is less than 20 μm,
Enough amounts can be had to inject in the pin hole of micropin mould, obtain the micropin with the crystal habit medicine of desired concn.
When crude drug crystal particle diameter is more than 30 μm, the grinding of crystal habit medicine, grinding and sieving can be obtained the crystalline substance of uniform particle sizes
Volume morphing medicine.
Preferably, described micropin host material and the mass ratio of crystal habit medicine are 3: 1-1000: 1, on the one hand select
, to ensure micropin mechanical strength and skin-piercing, another aspect those skilled in the art can be according to adaptation for suitable mass ratio
Disease and clinical administration amount etc. require, and select the mass ratio of suitable host material and crystal habit medicine.
The weight of host material aqueous solution can be selected according to the viscosity of the host material of micropin and the host material of substrate
Concentration, to obtain the host material aqueous solution having good fluidity and being accurately controlled liquid volume added.Preferably, described micropin
The mass concentration of host material aqueous solution is 1-40wt%；The mass concentration of described base substrate material aqueous solution is 1-
40wt%.
Preferably, micropin injection molding liquid is made to be added in mould micropore with pressurization or vacuumizing method, thus in avoiding making
In micropin, the generation of bubble is it is ensured that the puncture ability of micropin.According to applying stressed method it is preferable that pressure applied
For 0.2-0.6MPa, applying pressure time is 1min-20min.Method according to evacuation is it is preferable that vacuum will reach
0.05-0.1MPa, the time of evacuation is 3min-2h.
When micropin and substrate all contain medicine, micropin injection molding liquid can be made to be added to mould with pressurization or vacuumizing method micro-
Kong Zhong, once prepares and completes micropin and substrate, obtains microneedle array.
Beneficial effects of the present invention are as follows：
In prior art, medicine is to be molecularly dispersed in micropin substrate.Because medicine is insoluble in water, work as medicine dissolution
When adding water-soluble high-molecular material composition micropin host material in organic solvent, medicine is in water-soluble high-molecular material
It is also easy to produce precipitation, and the presence of organic solvent is also possible to lead to the precipitation of water-soluble high-molecular material it is not easy to disperse, no
Method forms micropin preparation.Microneedle patch according to the present invention and preparation method thereof, directly will be micro- with crystal for the medicine being insoluble in water
Particle shape formula is dispersed in water-soluble high-molecular material, prepares Intradermal soluble microneedle patch preparation, brilliant in microneedle patch
The dissolubility of the drug particles of volume morphing is easily controlled, and is conducive to dispersion and the slow release of medicine, by skin controlled-release function with
And medicament slow release purpose can be reached by providing the medicine crystal meeting Particle size requirements.In addition, in present invention process condition only
Use water as dispersion solvent, mild condition, it is to avoid organic solvent using residual, preparation security improves；Micropin prepares work
Also avoid in skill and medicine is wrapped in the medium loaded down with trivial details technique of micro-liposome, process is simple, cost reduces, and substantially increases
The drug loading of microneedle patch.
Brief description
Below in conjunction with the accompanying drawings the specific embodiment of the present invention is described in further detail.
Fig. 1 illustrates the structure of microneedle patch, and wherein 1a is the structure of microneedle patch each several part；1b is integrated load medicine microneedle patch
The structure of piece；1c is the structure that layering carries medicine microneedle patch.
Fig. 2 illustrates photo under stereomicroscope for the microneedle patch.
Fig. 3 illustrates microneedle patch side view under the microscope.
Fig. 4 illustrates the skin penetrating ability of microneedle patch.
Fig. 5 illustrates the cumulative release percentage curves of microneedle patch release in vitro.
Specific embodiment
In order to be illustrated more clearly that the present invention, with reference to preferred embodiments and drawings, the present invention is done further
Bright.In accompanying drawing, similar part is indicated with identical reference.It will be appreciated by those skilled in the art that institute is concrete below
The content of description is illustrative and be not restrictive, and should not be limited the scope of the invention with this.
Embodiment 1：The preparation of intradermal administration slow release microneedle patch
1) weigh the carboxymethyl cellulose 0.5g of molecular weight 200KDa, add 4.5ml water, preparing mass fraction is 10%
Carboxymethyl cellulose aqueous solution.
2) sieve after the crystal habit crude drug of paclitaxel being ground, obtain the medicine crystal that particle diameter is 10 μm about.Weigh
The medicine crystal 100mg being sieved adds in above-mentioned carboxymethyl cellulose aqueous solution, magnetic agitation (1500rpm, 12h), prepared base
Material and drug quality are than for 5:1 micropin emulsion (i.e. micropin injection molding liquid).
3) the micropin emulsion of 80 μ l is added in micropin mould, by way of evacuation, so that micropin emulsion is entered in a subtle way
In pin pin hole.
4) the micropin mould of above-mentioned plus good micropin emulsion is placed in 25 DEG C, is dried 4 hours under 20% damp condition, be obtained
Microneedle array.
5) backside of substrate of microneedle array after the drying sticks pressure sensitive adhesive and is served as a contrast.
6) demoulding.
As shown in Figure 1 b, in described microneedle patch, the density of micropin is 400 pins/square centimeter to obtained microneedle patch,
Micropin length 0.65mm.
Embodiment 2：The preparation of intradermal administration slow release microneedle patch
1) weigh PVP K30 2g, add 4ml water, prepare the polyvidon aqueous solution that mass fraction is 33%.
2) sieve after the crystal habit crude drug of etonogestrel being ground, obtain the medicine crystal that particle diameter is 15 μm about.Claim
The medicine crystal 100mg being sieved is taken to add in the aqueous solution of above-mentioned PVP K30, magnetic agitation (2000rpm, 6h), prepared substrate
Material and drug quality are than for 20:1 micropin emulsion (micropin injection molding liquid).
3) the micropin emulsion of 150 μ l is added in micropin mould, by way of pressurization, makes micropin emulsion enter micropin
In pin hole.Microneedle patch 100 pins/square centimeter, pin length 0.50mm.
4) the micropin mould of above-mentioned plus good micropin emulsion is placed in 25 DEG C, is dried 6 hours under 30% damp condition.
5) the microneedle substrate back side after the drying is sticked pressure sensitive adhesive and is served as a contrast.
6) demoulding.
Obtained microneedle patch as shown in Figure 1 b, microneedle patch 400 pins/square centimeter, pin length 0.30mm.
Embodiment 3：The preparation of intradermal administration slow release microneedle patch
1) weigh the hyaluronate sodium 0.5g that molecular weight is 1500KDa, add 9.5ml water, preparing mass fraction is 5%
Aqueous solution of sodium hyaluronate.
2) sieve after the crystal habit crude drug of Artemether being ground, obtain the crystal habit medicine that particle diameter is 20 μm.Weigh
The crystal habit medicine 50mg being sieved adds in hyalomitome aqueous acid, magnetic agitation (1000rpm, 12h), prepared substrate material
Material and drug quality ratio are for 10:1 micropin emulsion.
3) the micropin emulsion of 100 μ l is added in micropin mould, by way of evacuation, so that micropin emulsion is entered in a subtle way
In pin pin hole.Microneedle patch 169 pins/square centimeter, pin length 0.85mm.
4) the micropin mould of above-mentioned plus good micropin emulsion is placed in 15 DEG C, is dried 4 hours under 20% damp condition.
5) the microneedle substrate back side after the drying is sticked pressure sensitive adhesive and is served as a contrast.
6) demoulding.
Obtained microneedle patch as shown in Figure 1 b, microneedle patch 400 pins/square centimeter, pin length 0.30mm.
Embodiment 4：The preparation of intradermal administration slow release microneedle patch
1) weigh the carboxymethyl cellulose 0.5g that molecular weight is 200KDa, add 4.5ml water, preparing mass fraction is 10%
Carboxymethyl cellulose aqueous solution.
2) sieve after the crystal habit crude drug of levonorgestrel being ground, obtain the crystal habit medicine that particle diameter is 5 μm.Claim
The crystal habit medicine 100mg being sieved is taken to add in above-mentioned carboxymethyl cellulose aqueous solution, magnetic agitation (1500rpm, 12h),
Prepared host material and drug quality are than for 5:1 micropin emulsion, as pastille micropin injection molding liquid.
3) the pastille micropin injection molding liquid of 85 μ l is added in micropin mould, by way of evacuation, makes micropin emulsion
Enter in micropin pin hole.
4) weigh carboxymethyl cellulose 0.1g, add 0.9ml water, prepare the carboxymethyl cellulose water that mass fraction is 10%
Solution, as substrate injection molding liquid.
5) above-mentioned substrate injection molding liquid 50 μ l is added to the above-mentioned micropin mould having been added to pastille micropin injection molding liquid further
In tool, and evacuation, it is to avoid the generation of bubble.
6) the micropin mould of above-mentioned plus good micropin emulsion is placed in 25 DEG C, is dried 6 hours under 30% damp condition.
7) the microneedle substrate back side after the drying is sticked pressure sensitive adhesive and is served as a contrast.
8) demoulding.
Obtained microneedle patch as illustrated in figure 1 c, microneedle patch 400 pins/square centimeter, pin length 0.30mm.
Embodiment 5：The preparation of intradermal administration slow release microneedle patch
1) weigh the carboxymethyl cellulose 0.5g that molecular weight is 200KDa, add 4.5ml water, preparing mass fraction is 10%
Carboxymethyl cellulose aqueous solution.
2) sieve after the crystal habit crude drug of levonorgestrel being ground, obtain the crystal habit medicine that particle diameter is 15 μm.
Weigh the crystal habit medicine 25mg being sieved and add in the aqueous solution of above-mentioned carboxymethyl cellulose, magnetic agitation (2000rpm,
6h), prepared host material and drug quality are than for 20:1 micropin emulsion.
3) the micropin emulsion of 40 μ l is added in micropin mould, by way of evacuation, so that micropin emulsion is entered in a subtle way
In pin pin hole.
4) weigh carboxymethyl cellulose 0.1g, add 0.9ml water, prepare the carboxymethyl cellulose water that mass fraction is 10%
Solution, as substrate injection molding liquid.
5) above-mentioned microneedle substrate injection molding liquid 80 μ l is added to further and above-mentioned has been added to the micro- of pastille micropin injection molding liquid
In needle mould tool, and evacuation, it is to avoid the generation of bubble.
6) the micropin mould of above-mentioned plus good micropin emulsion is placed in 25 DEG C, is dried 6 hours under 30% damp condition.
7) the microneedle substrate back side after the drying is sticked pressure sensitive adhesive and is served as a contrast.
8) demoulding.
Obtained microneedle patch as illustrated in figure 1 c, microneedle patch 400 pins/square centimeter, pin length 0.65mm.
Embodiment 6：The skin-piercing experiment of slow release microneedle patch
The microneedle patch that will make in embodiment 1, acts on fresh porcine skin, presses with finger 1min, dense using 1%
The Trypan Blue 20min of degree, wipes unnecessary trypan blue away using cotton swab, and whether then observe has pin hole, as Fig. 3 institute on skin
It is shown as the photo of Trypan Blue Corii Sus domestica, can significantly see micropin pin hole.
Embodiment 7：Slow release microneedle patch extracorporeal releasing experiment
The microneedle patch made in embodiment 2 is as experimental group microneedle patch.
Prepare the scattered microneedle patch of molecular state with solvent dissolution method, as a control group.Preparation technology is as follows：Weigh support
Pregnene 100mg, plus the dissolving of 4ml ethanol.Separately take PVP K30 2g, be added in said medicine solution, stirring and dissolving, as micropin
Injection molding liquid.Take above-mentioned micropin injection molding liquid 100 μ l to be added in same experimental group identical micropin mould, made by the method for pressurization micro-
Pin injection molding liquid enters in micropin pin hole.The micropin mould of above-mentioned plus good micropin injection molding liquid is placed in 25 DEG C, 30% humidity bar
It is dried 6 hours under part.
Extracorporeal releasing experiment：Experimental group and matched group microneedle patch are placed in bag filter, add for maintaining in balance, bag filter
1ml volume fraction is 30% PEG400-PBS reception liquid (volume fraction in PEG400 with PBS solution for the PEG400), by this
Bag filter is placed in beaker, with 50ml volume fraction be 30% PEG400-PBS solution for receive medium.Experiment condition is,
37 ± 0.5 DEG C of waters bath with thermostatic control, magnetic agitation 600rpm.Respectively at predetermined time point 2h, 4h, 6h, 12h, 24h, 48h, 72h,
(each time point takes out reception liquid 50ml, and supplements equivalent immediately for 96h, 120h, 144h, 168h, 192h, 216h, 240h sampling
The fresh reception liquid of isothermal).The sample taking out is through 0.45 μm of membrane filtration.Sample is measured contained by high performance liquid chromatograph
The concentration of etonogestrel.Liquid phase chromatogram condition：40 DEG C of column temperature, flow velocity 1ml/min, Detection wavelength 205nm, sample size 10 μ l, stream
Dynamic is mutually acetonitrile：Water=55:45.The cumulative release percentage curves of two groups of microneedle patch release in vitro are shown in Fig. 5.
In preparation process, etonogestrel is dissolved in ethanol the microneedle patch of matched group, and medicine is added with molecular forms
In micropin substrate, due to molecule precipitation and assemble, the aggregate particle size of drug molecule wayward so that slow releasing function not
It is easily controlled.Different from matched group, according to the microneedle patch of the present invention, the microgranule of crystal habit medicine is dispersed in micropin base
In matter, it is to avoid the problems referred to above, medicine can be played with good dispersion and slow releasing function.Release in vitro by two groups of microneedle patch
Cumulative release curve can be seen that (see Fig. 5), medicine with crystal form be dispersed in microneedle patch in micropin substrate compared to
The microneedle patch being molecularly dispersed in micropin substrate has obvious slow release effect.According to the microneedle patch of the present invention, medicine
It is dispersed in the aqueous solution of micropin host material with crystal form, the microneedle patch thus prepared also avoid the residual of organic solvent
Stay, safety improves.
Embodiment 8-16：
The preparation method of embodiment 8-16 such as embodiment 1, the design parameter of a component and micropin wherein in embodiment 8-16
Paster becomes pin situation to see as table 1.
Table 1：The each component parameter of embodiment 8-16
By the external slow release experiment of embodiment 8-14, the microneedle patch of 16 preparations, experimental technique is with embodiment 7, test knot
Fruit shows, embodiment 8-14, the microneedle patch of 16 preparations all have good slow release effect.
Obviously, the above embodiment of the present invention is only intended to clearly illustrate example of the present invention, and is not right
The restriction of embodiments of the present invention, for those of ordinary skill in the field, also may be used on the basis of the above description
To make other changes in different forms, all of embodiment cannot be exhaustive here, every belong to this
Obvious change that bright technical scheme is extended out or change the row still in protection scope of the present invention.
Claims (11)
1. a kind of flexibility slow release microneedle patch, including micropin, substrate with served as a contrast, micropin and substrate composition microneedle array, it is special
Levy and be, in the host material of micropin or the host material of microneedle array, contain crystal habit medicine, described crystal habit medicine
In water, dissolubility is less than 100 μ g/ml.
2. microneedle patch according to claim 1 is it is characterised in that described crystal habit medicine is in the range of pH4-9
In aqueous solution, dissolubility is less than 100 μ g/ml；Preferably, crystal is determined according to the requirement to crystal habit slow release speed of medicine
The particle diameter of form medicine, it is highly preferred that the particle diameter of described crystal habit medicine is less than 30 μm, most preferably, described crystal shape
The particle diameter of state medicine is less than 20 μm.
3. microneedle patch according to claim 1 is it is characterised in that the described host material of micropin or described substrate
Host material is respectively selected from carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvidon, hyaluronic acid
Sodium, chondroitin sulfate, shitosan, carboxymethyl chitosan, carboxymethyl chitin, polyvinyl alcohol, water-soluble fibroin albumen, collagen egg
One or more of white and gelatin.
4. microneedle patch according to claim 3 is it is characterised in that carboxymethyl cellulose molecular weight is 10-2000kDa；
Hydroxypropyl cellulose molecular weight is 10-2000kDa；Hydroxyethyl cellulose molecular weight is 10-2000kDa；Polyvinylpyrrolidone
Molecular weight is 30-2000KDa；Hyaluronate sodium molecular weight is 10-2000KDa；Chondroitin sulfate molecular weight is 50-1000kDa；
Chitosan molecule amount is 20-2000KDa；Carboxymethyl chitosan molecular weight is 10-800KDa；Carboxymethyl chitin molecular weight is
10-2000KDa；Polyvinyl alcohol molecule amount is 10-1000KDa；Water-soluble fibroin molecular weight of albumen is 10-500KDa；Collagen egg
White molecular weight is 10-200KDa；And/or gelatine molecular weight is 10-1000KDa.
5. microneedle patch according to claim 1 is it is characterised in that the quality of described host material and crystal habit medicine
Than for 3: 1-1000: 1.
6. microneedle patch according to claim 1 is it is characterised in that described lining is served as a contrast for pressure sensitive adhesive.
7. microneedle patch according to claim 1 is it is characterised in that described medicine is selected from：Etonogestrel, ethinylestradiol, a left side
Norgestrel, norgestrel, Progesterone, estradiol, estradiol valerate, ethinylestradiol, norethindrone, artemisinin derivatives, Radix Glycyrrhizae
Subacid, vinpocetine, Triptolide, ketoprofen, paclitaxel, Docetaxel, Cephalomannine, camptothecine, rope
La Feini, oxaprozin, rutin, apigenin, Hesperidin or lignocaine, haloperidol, thiothixene, clozapine, olanzapine,
Pimozide, Ziprasidone, stable, ethyl loflazepate, alprazolam, Sertraline, donepezil, selegiline, pergolide,
Artane, bromocriptine, benzetropine, nordazepam, etizolam, clotiazepam, cetrorelix, Itraconazole, pool are husky
Health azoles, indomethacin, Alprostadil, tacrolimuss, chlorambucil, Anastrozole, Raltitrexed, epirubicin, letrozole,
Mefloquine, primaquine, oxibutynin, tolterodine, allylestrenol, lovastatin, simvastatin, atorvastatin and/or thunder
Lip river former times is fragrant.
8. microneedle patch according to claim 1 is it is characterised in that described micropin length is 0.1mm -1mm.
9. the preparation method of flexibility slow release microneedle patch as claimed in claim 1 is it is characterised in that the system of this microneedle patch
Standby comprise the steps：
Prepare micropin host material aqueous solution；Crystal habit medicaments uniformity is scattered in micropin host material aqueous solution, is formed
Emulsion, as micropin injection molding liquid；
Preparation base substrate material aqueous solution, as substrate injection molding liquid；
Described micropin injection molding liquid is injected in micropin mould and prepares micropin, described micropin injection molding liquid or substrate injection molding liquid are injected micro-
Substrate is prepared in needle mould tool；
It is dried, stick and served as a contrast；And
The micropin demoulding.
10. preparation method according to claim 9 is it is characterised in that the quality of described micropin host material aqueous solution is dense
Spend for 1-40wt%；The mass concentration of described base substrate material aqueous solution is 1-40wt%.
11. preparation methoies according to claim 9 are it is characterised in that the matter of described host material and crystal habit medicine
Amount ratio is 3: 1-1000: 1.
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Cited By (23)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107233297A (en) * | 2017-06-16 | 2017-10-10 | 广州新济薇娜生物科技有限公司 | Soluble micropin containing slightly solubility contraceptive and preparation method thereof |
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