CN105078880A - Macromolecular soluble microneedle used for cutaneous penetration of polypeptide and protein medicines and preparation method of macromolecular soluble microneedle - Google Patents
Macromolecular soluble microneedle used for cutaneous penetration of polypeptide and protein medicines and preparation method of macromolecular soluble microneedle Download PDFInfo
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- CN105078880A CN105078880A CN201510580635.8A CN201510580635A CN105078880A CN 105078880 A CN105078880 A CN 105078880A CN 201510580635 A CN201510580635 A CN 201510580635A CN 105078880 A CN105078880 A CN 105078880A
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Abstract
The invention discloses a macromolecular soluble microneedle used for polypeptide and protein medicines. The macromolecular soluble microneedle comprises a base as well as a needle body on the base and a needle point on the needle body, wherein the base and the needle body are made of a mixture of a high polymer material and a stabilizer; and solid active peptide or protein medicines are embedded into the needle point. The concentration degree of the medicines embedded in the needle point of the macromolecular soluble microneedle is relatively high, and nearly no residual medicines exist on the bottom of the needle body, so that the administration efficiency and the administration accuracy are greatly improved; in addition, the part entering the subcutaneous tissue of the needle body can rapidly dissolve, and further degrade to be completely absorbed by the tissues without toxic or side effects, so that the possible needle breaking risk existing in the microneedle made of other materials such as metal, glass and silicon is avoided. The preparation method of the macromolecular soluble microneedle is carried out under simple technological conditions, is low in price, and suitable for volume production, and the macromolecular soluble microneedle can be widely applied to the field of cutaneous penetration of macromolecular medicines.
Description
Technical field
The invention belongs to micropin preparing technical field, specifically, relate to solvable micropin of a kind of macromolecule for Peptides and proteins transdermal administration and preparation method thereof.
Background technology
The molecular weight of polypeptide and protein is often thousands of to hundreds of thousands, and granular size, between l ~ 100nm, generally can not enter subcutaneous tissue by diffuse transmission keratodermatitis as small-molecule drug.Due to the inside and outside unstability of peptide and protein medicine, clinical main dosage form is solution type injection agent and freeze-dried powder, pharmaceutical grade protein in vivo and in vitro environment may stand the chemical degradation of Various Complex and physical change and inactivation, the destruction of easy receptor endoenzyme and antibacterial and body fluid, non-injection administration bioavailability is low.Peptides and proteins administering mode mainly contains drug administration by injection and non-injection administration, and non-injection administration comprises nasal-cavity administration, pulmonary administration, oral administration, transdermal administration etc.Conventional injection drug-delivery preparation generally comprises prerequisite medicaments injection, microball preparation, liposome, vaccine controlled release preparation etc., polypeptide and the hypodermic bioavailability of protein drug high, but this type of administering mode can produce very large pain, patient compliance is poor, there is infection risk, also can produce medical waste and pollute.
In recent years, non-injection administration mode develops comparatively rapid.Fat-soluble medicine comparatively easily absorbs after entering nasal cavity and directly enters systemic blood circulation, cross from liver and gastrointestinal head and destroy, polypeptide and protein drug generally all adopt spray delivery to go deep into nasal cavity, adopt absorption enhancer and enzyme inhibitor etc. can improve polypeptide and pharmaceutical grade protein nasal absorption, administration volume is little, and medicament contg is high, is beneficial to drug substance stable, but prolonged application can damage nasal mucosa and cilium, the medicine relative bioavailability of nasal-cavity administration is lower; The general first-selected low dose of powder spray system of intake system of pulmonary administration, micronization technology can ensure that medicine is not detained at trachea or bronchus, enter lung tissue smoothly, as the pulmonary inhalation of insulin medicament, can control patient blood glucose by the mode of pulmonary administration, quite, the relative bioavailability of pulmonary administration medicine is very high for curative effect and injection, but effective repeatability of the drug absorption rate of pulmonary administration and research is poor, and long term administration also may have side effects to pulmonary; For polypeptide and protein drug oral administration, general interpolation permeation enhancers and the protease inhibitor etc. of passing through promotes that medicine absorbs in gastrointestinal tract, but the administration environment of gastrointestinal tract complexity makes the activity of polypeptide and protein medicaments very easily destroy, and administering effect is poor; In addition, transdermal administration for macromolecular drug is studied, someone attempted iontophoresis, utilize the mechanism such as conductance, electric osmose and solvent traction to make macromolecular drug enter skin by the passage such as pore, sweat gland, agent permeates therethrough horny layer infiltrates subcutaneous tissue directly can enter the blood circulation such as blood of human body, lymph participation metabolism.
For polypeptide and protein-based macromolecular drug administration, respectively there are pluses and minuses with upper type.For improving administering mode further, microneedle cutaneous research makes great progress.It is the firm and horny layer of densification of epidermis that macromolecular drug enters subcutaneous maximum obstacle, and micropin can pierce through horny layer creates some micron levels passage at epidermis, makes macromolecular drug enter subcutaneous tissue.Generally, micropin length 500 μm ~ 1500 μm, dry needle point pierces through horny layer and enters and subcutaneously to contact with sensory nerve ending, but can not destroy deep layer neurocyte, and thus administration process is without obvious pain.The making material of micropin has monocrystal silicon, metal, polysaccharide and polymer etc., and according to different administration mechanism, micropin is divided into the Four types such as coating micropin, solid micropin, hollow microneedles and solvable micropin.For solvable medicine carrying micropin, coating micropin drug loading is less, and medication coat is wayward; Solid micropin and hollow microneedles can increase dosage, coordinate the methods such as electron ion infiltration, phonophoresis, electrophoresis, can promote operational efficiency, but there is broken needle risk, cause irreversible injury to skin.Solvable medicine carrying micropin adopts easy molten Biodegradable polymer material, good biocompatibility, select suitable processing technology comparatively accurately can also control drug loading, and process conditions are gentle, the biological activity of the macromolecular drug such as polypeptide and protein can not be destroyed, be suitable for the transdermal administration of macromolecular drug.
Macromolecule solvable microneedle cutaneous be a kind of emerging administering mode; by needle point embedding polypeptide and protein-based active macromolecules medicine; pharmaceutically active can be protected not to be damaged; dry needle point can pierce through keratodermatitis easily simultaneously; directly polypeptide and protein-based active macromolecules medicine are delivered to subcutaneous, enter human recycle system after being absorbed by histolysis and play drug effect.Micropin administration is once daily, wound is minimum, without wound infection risk, and the administration without the need to complexity easy and simple to handle is trained, micropin makes formula and is made up of all kinds of degradable high polymer material with good biocompatibility, dissolve in and subcutaneously to be had no side effect by tissue Absorption And Metabolism, safety and environmental protection; In addition, different classes of macromolecule dissolution performance is different, and thus embedding medicinal rate of release also has speed, can design different macromolecule needle body accordingly and fill solution formula, for the Co ntrolled release of polypeptide and protein-based active macromolecules medicine.
Summary of the invention
The object of the invention is the many deficiencies improving polypeptide and protein-based active macromolecules medicine conventional subcutaneous injection existence, as injection pain, easy infection, the pollution of generation medical waste etc., solvable micropin is utilized to realize the painless transdermal administration of polypeptide and protein-based active macromolecules medicine, and pass through to control the drug loading of polypeptide and protein-based active macromolecules medicine and subcutaneous rate of release, realize medicine controlled releasing, the therapeutic effect that the Co ntrolled release as insulin can promote diabetics is experienced with treatment.
The solvable micropin of a kind of macromolecule for Peptides and proteins of the present invention, the solvable micropin of described macromolecule comprises pedestal and is positioned at the needle body on pedestal and the needle point on needle body; Described pedestal and needle body are made up of the mixture of macromolecular material and stabilizing agent; Embedding solid active polypeptide or protein drug in described needle point.
The solvable micropin of a kind of macromolecule for Peptides and proteins of the present invention, the solvable micropin of described macromolecule conically or class conical, whole height is 200-2000 μm, and needle point bottom diameter is 5-30 μm, and needle body bottom diameter is 200-800 μm; Described length of needlepoint is 50-400 μm.
Described macromolecular material is selected from polyvinyl alcohol, poly-carboxymethyl cellulose, chondroitin sulfate, PLGA, fibroin, dextrin, hyaluronic acid or gelatin.
The solvable micropin of a kind of macromolecule for Peptides and proteins of the present invention, described stabilizing agent is selected from sucrose, glucose, trehalose or chitosan.
The solvable micropin of a kind of macromolecule for Peptides and proteins of the present invention, described solid active polypeptide or protein drug are selected from insulin, interferon, collagen protein, heparin, superoxide dismutase or tissue growth factor.
The length of side of the solvable micropin of described macromolecule or diameter are 1-20mm, and it is positioned on pedestal by the needle point integrated array on needle body and needle body, and array specification is 1 × 1-20 × 20, and needle tip spacing is 500-5000 μm.
The preparation method of the solvable micropin of a kind of macromolecule for Peptides and proteins of the present invention, described preparation method concrete steps are: 1) under room temperature, solid active polypeptide or protein-based drug solution is dripped at the polydimethylsiloxane microneedles template die cavity top position pipettor of clean surface, ensure that drug solution covers die cavity completely, application of vacuum 10-30min, fill up after die cavity until solution, remove cavity surface extra medicinal solution, continue moisture evaporation in evacuation 20-30min to die cavity and completely, guarantee that medicine concentrates on needle point position; 2), under room temperature, the die cavity top position pipettor after above-mentioned pastille drips the mixed solution of macromolecular material and stabilizing agent, and solution to be mixed covers die cavity, application of vacuum 1-2h; 3) microneedles template is placed in ventilation natural air drying, the demoulding, the micropin sheet after the demoulding is placed in vacuum drying oven inner drying 4-10h, and dried finished product low temperature seal saves backup.
The preparation method of the solvable micropin of a kind of macromolecule for Peptides and proteins of the present invention, described step 1) in the viscosity of mixed solution of macromolecular material and stabilizing agent be 90-150MPas.
The preparation method of the solvable micropin of a kind of macromolecule for Peptides and proteins of the present invention, repeats step 1) be operated to required drug loading, then continue subsequent step.
Compared with prior art, the intensity of the needle point embedding medicinal of the solvable micropin of the macromolecule for Peptides and proteins of the present invention is higher, almost noresidue medicine bottom needle body, thus substantially increases operational efficiency and precision in drug administration; In addition, needle body enters hypodermic part and can to dissolve rapidly and degradable subsequently, is absorbed, has no side effect, avoid the broken needle risk that other material micropins such as metal, glass, silicon may exist by tissue digestion.Therefore, micropin preparation process condition of the present invention is simple, cheap, is applicable to producing in enormous quantities, can be widely used in macromolecular drug transdermal administration field.
Accompanying drawing explanation
Fig. 1: macromolecule solvable micropin preparation flow figure; Fig. 2: macromolecule solvable micropin light field figure; Fig. 3: macromolecule solvable micropin fluorescence microscopy figure; Fig. 4: macromolecule solvable micropin drying time and Relationship between Mechanical figure; Fig. 5: design sketch tested by the different solvable micropin mechanical property of macromolecule drying time and Corii Sus domestica; Fig. 6: the solvable micropin of macromolecule in time of staying of Intradermal on the impact of solute effect; Fig. 7: the solvable micropin of macromolecule external Corii Sus domestica test design sketch.
Detailed description of the invention
Below in conjunction with specific embodiment, the solvable micropin of the macromolecule for Peptides and proteins of the present invention is described further, but protection scope of the present invention is not limited to this.
Embodiment 1
1) preparation of polydimethylsiloxane micropin mould
By liquid polydimethylsiloxane prepolymer thing and firming agent in mass ratio 10:1 mix, stir rear evacuation and remove bubble, inject in special container and leave standstill, 8h is heated under 60 DEG C of conditions, crosslinkable obtains the uniform polydimethylsiloxaneelastomer elastomer thin slice of the better thickness of toughness, and recycling laser micro/nano rice processing technique carrys out the polydimethylsiloxane micropin mould that carve has specific dimensions.
2) preparation of mixed solution
Polyvinyl alcohol and sucrose all can be used as food additive, are used for making micropin and have no side effect, safety and environmental protection.The mass ratio of polyvinyl alcohol, sucrose, deionized water is 8:6:15, polyvinyl alcohol crystal powder is added in ultra-pure water, heated and stirred 4h under 90 DEG C of conditions, dissolve completely and form clear transparent solutions, add sucrose mealy crystal continuation stirring 30min again and obtain macromolecule mixed solution, be placed in cooling evacuation removing micro-bubble in glass container and obtain needle body filling liquid, under room temperature, mixed solution viscosity is about 130MPas.
3) preparation of the solvable micropin of macromolecule
Above the polydimethylsiloxane micropin mould cavity of clean surface, the marked by fluorescein isothiocyanate insulin protein drug solution of 100 μ L concentration 0.1g/mL is dripped with the pipettor of 10-100 μ L range, the volume of solution can be dripped according to drug loading adjustment, need ensure that drop covers die cavity completely.Application of vacuum 15min fills up after die cavity until drug solution and removes excess surface drug solution, continues evacuation 20min and moisture in die cavity is evaporated completely, and this process can drip drug solution number of times according to drug loading adjustment and be respectively 1 time, 2 times, 3 times, 5 times.In die cavity top position uniform application step 2) mixed solution prepared, application of vacuum 2h treats that it fills up die cavity, natural draft drying one is late, then the demoulding after the micropin of drying being adhered to the suitable PMMA of size or cardboard pad, the dry 8h of ambient temperature in vacuum, can obtain the insulin micropin meeting instructions for use, low temperature lower seal is preserved, as shown in Figure 1, the light field of the overall appearance of micropin and local micropin and fluorescence microscope images are as shown in Figures 2 and 3 for preparation flow.
The solvable micropin of macromolecule of above-mentioned preparation comprises pedestal and is positioned at the needle body on pedestal and the needle point on needle body; Described pedestal and needle body are made up of the mixture of polyvinyl alcohol and sucrose; Embedding insulin in described needle point.Conically, whole height is 1000 μm to the solvable micropin of described macromolecule, and needle point bottom diameter is 10 μm, and needle body bottom diameter is 300 μm; Described length of needlepoint is 200 μm.The length of side 10mm of the solvable micropin of described macromolecule, it is positioned on pedestal by the needle point integrated array on needle body and needle body, and array specification is 10 × 10.
Performance test
1) the solvable micropin Mechanics Performance Testing of macromolecule and determining drying time
Adopt the insulin micropin of preparation in embodiment 1, under room temperature, the micropin getting some firm demouldings divides 6 groups, be placed in vacuum drying oven, one group of micropin is taken out every 2h from 0h, detect micropin mechanical property with ergometer, and detect its saturating horny layer effect of thorn after demoulding under different dry time conditions by penetrating Corii Sus domestica, utilize microscopic examination to compare.Result shows that at least vacuum drying 6h guarantee micropin all can sting transdermal, mechanical curves rises and represents that micropin compressive property is better sooner, drying time, longer mechanical property was better, and Corii Sus domestica administration test experiments corresponding to the micropin of different drying time as shown in Figures 4 and 5.
2) macromolecule solvable medicine carrying micropin transdermal test in vitro administration experiment
Adopt the insulin micropin of preparation in embodiment 1, under room temperature, get some bone dry micropins and divide 8 groups, after penetrating Corii Sus domestica, dissolution time is respectively 0s, 5s, 10s, 30s, 1min, 2min, 5min, 10min, observe respectively under microscope micropin most advanced and sophisticated dissolve completely base extract Corii Sus domestica after pattern and medicine in Corii Sus domestica enter and distribution situation, the medicament contg before and after utilizing microplate reader to detect to dissolve completely in micropin sheet.Result shows, microneedle patch slowly dissolves the most advanced and sophisticated medicine of release at Intradermal absorptive tissue moisture, the most advanced and sophisticated fluorescence of micropin slowly weakens, and the fluorescence intensity of intradermal drug strengthens gradually, after penetrating Corii Sus domestica 2min, micropin tip is dissolved in subcutaneous tissue completely, without obvious fluorescence bottom micropin, medicine is almost all delivered in body, and administering effect corresponding to the different Intradermal time of staying as shown in Figure 6; Micropin is dissolved in subcutaneous completely, different drug loading micropin, and its transdermal administration efficiency can reach more than 95%, as shown in Figure 7.
Claims (9)
1. for the solvable micropin of macromolecule of Peptides and proteins transdermal administration, it is characterized in that, the solvable micropin of described macromolecule comprises pedestal and is positioned at the needle body on pedestal and the needle point on needle body; Described pedestal and needle body are made up of the mixture of macromolecular material and stabilizing agent; Embedding solid active polypeptide or protein drug in described needle point.
2. the solvable micropin of a kind of macromolecule for Peptides and proteins transdermal administration according to claim 1, it is characterized in that, the solvable micropin of described macromolecule conically or class conical, whole height is 200-2000 μm, needle point bottom diameter is 5-30 μm, and needle body bottom diameter is 200-800 μm; Described length of needlepoint is 50-400 μm.
3. the solvable micropin of a kind of macromolecule for Peptides and proteins transdermal administration according to claim 1, it is characterized in that, described macromolecular material is selected from polyvinyl alcohol, poly-carboxymethyl cellulose, chondroitin sulfate, PLGA, fibroin, dextrin, hyaluronic acid or gelatin.
4. the solvable micropin of a kind of macromolecule for Peptides and proteins transdermal administration according to claim 1, it is characterized in that, described stabilizing agent is selected from sucrose, glucose, trehalose or chitosan.
5. the solvable micropin of a kind of macromolecule for Peptides and proteins transdermal administration according to claim 1, it is characterized in that, described solid active polypeptide or protein drug are selected from insulin, interferon, collagen protein, heparin, superoxide dismutase or tissue growth factor.
6. the solvable micropin of a kind of macromolecule for Peptides and proteins transdermal administration according to claim 1, it is characterized in that, the length of side of the solvable micropin of described macromolecule or diameter are 1-20mm, it is positioned on pedestal by the needle point integrated array on needle body and needle body, array specification is 1 × 1-20 × 20, and needle tip spacing is 500-5000 μm.
7. the preparation method of the solvable micropin of a kind of macromolecule for Peptides and proteins transdermal administration according to claim 1, it is characterized in that, described preparation method concrete steps are: 1) under room temperature, solid active polypeptide or protein-based drug solution is dripped at the polydimethylsiloxane microneedles template die cavity top position pipettor of clean surface, ensure that drug solution covers die cavity completely, application of vacuum 10-30min, fill up after die cavity until solution, remove cavity surface extra medicinal solution, continue evacuation 20-30min complete to the evaporation of die cavity internal solvent, guarantee that medicine concentrates on needle point position, 2), under room temperature, the die cavity top position pipettor after above-mentioned pastille drips the mixed solution of macromolecular material and stabilizing agent, and solution to be mixed covers die cavity, application of vacuum 1-2h, 3) microneedles template is placed in ventilation natural air drying, the demoulding, the micropin after the demoulding is placed in vacuum drying oven inner drying 4-10h, and dried finished product low temperature seal saves backup.
8. the preparation method of the solvable micropin of a kind of macromolecule for Peptides and proteins transdermal administration according to claim 7, is characterized in that, described step 1) in the viscosity of mixed solution of macromolecular material and stabilizing agent be 90-150MPas.
9. the preparation method of the solvable micropin of a kind of macromolecule for Peptides and proteins transdermal administration according to claim 7, is characterized in that, repeats step 1) be operated to required drug loading, then continue subsequent step.
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