WO2021047628A1 - 一种缓释微针贴片及其制备方法 - Google Patents

一种缓释微针贴片及其制备方法 Download PDF

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WO2021047628A1
WO2021047628A1 PCT/CN2020/114743 CN2020114743W WO2021047628A1 WO 2021047628 A1 WO2021047628 A1 WO 2021047628A1 CN 2020114743 W CN2020114743 W CN 2020114743W WO 2021047628 A1 WO2021047628 A1 WO 2021047628A1
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microneedle
glycerophosphate
sustained
release
needle tip
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PCT/CN2020/114743
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English (en)
French (fr)
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邢梦真
江林
高云华
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中科微针（北京）科技有限公司
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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
    • 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
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • 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

Definitions

  • the invention relates to the field of medical technology. More specifically, it relates to a sustained-release microneedle patch and a preparation method thereof.
  • Sustained-release microneedles are a new type of transdermal drug formulation that can achieve sustained and smooth drug delivery after acting intradermally. It is suitable for the use of drugs that require long-term administration and a narrow therapeutic window. It can reduce the number of administrations and improve patient medication. The advantages of safety and convenience have greatly improved the patient's medication compliance, and occupies an important position in the research of new microneedle drug delivery formulations.
  • Existing sustained-release microneedles are mainly based on (1) sustained-release systems such as microspheres, liposomes, and solid dispersions; (2) degradable polymer materials such as polylactic acid-glycolic acid copolymer and chitosan; (3) Sol-gel phase transition materials are designed.
  • phase change microneedles including: cross-linked polyvinyl alcohol, polylactic acid-glycolic acid copolymer-polyethylene glycol-polylactic acid-glycolic acid copolymer (PLGA-PEG-PLGA) triblock Copolymer, carbomer, poloxamer, etc.
  • Chinese patent CN102202720A discloses a method for preparing phase-inversion polymer microneedles using cross-linked polyvinyl alcohol. Through repeated operations of freezing at -20°C and thawing at 4°C, water-soluble polyvinyl alcohol is formed by microcrystalline construction in an aqueous solution. Gel, so as to achieve sustained-release drug delivery, but the preparation process is cumbersome and time-consuming, and is not suitable for mass industrial production of sustained-release microneedles; while phase change microneedles made of PLGA-PEG-PLGA triblock copolymer The synthesis process of raw materials is complex and the water solubility of the materials is poor. Organic reagents need to be introduced.
  • the drug-loaded carbomer or poloxamer solution is applied to the surface of the skin treated by the microneedle.
  • a sol-gel phase occurs. Change the process to form a drug reservoir and realize the slow release of the drug.
  • sol-gel phase transition materials that have sufficient mechanical strength to pierce the stratum corneum of human skin, and the microneedles can be converted from liquid sol to solid gel during the manufacturing process.
  • the porous skeleton microneedle that is conducive to the penetration of the drug is prepared, which has important research significance for promoting the sustained and gentle release of the drug in the skin.
  • An object of the present invention is to provide a sustained-release microneedle patch with good skin piercing effect.
  • Another object of the present invention is to provide a method for preparing a sustained-release microneedle patch.
  • a sustained-release microneedle patch includes a needle body and a needle tip on the needle body, and the needle tip includes a glycerophosphate compound and a non-ionic cellulose ether compound.
  • At least the needle tip portion includes a part prepared by a needle tip preparation solution that can achieve gelation during the drying process of the microneedle patch;
  • the solute of the needle tip preparation solution includes glycerophosphate compounds and non-ionic cellulose ether compounds.
  • the glycerophosphate compound is selected from any one or more of sodium glycerophosphate, potassium glycerophosphate, magnesium glycerophosphate, and calcium glycerophosphate.
  • the non-ionic cellulose ether compound is one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, and hydroxybutyl methyl cellulose, or A mixture of several.
  • the non-ionic cellulose ether compound accounts for 2%-40% of the total mass of the preparation liquid.
  • the solid content ratio of the non-ionic cellulose ether compound and the glycerophosphate compound is 1:1-100:1, more preferably 5:1-50:1.
  • the solute of the needle tip preparation solution further includes a porogen, and the porogen accounts for 2%-20% of the total mass of the needle tip preparation solution.
  • the porogen is one or more of trehalose, calcium hydrogen phosphate or sodium hydrogen carbonate.
  • the solute of the needle tip preparation solution further includes at least one active ingredient.
  • the active ingredient is one or more of polypeptide drugs, protein drugs, chemical drugs, skin care active ingredients, health care active ingredients, and plant extract ingredients.
  • the microneedle is an integrated microneedle, a layered microneedle, a coated microneedle or a bubble type microneedle.
  • a preparation method of sustained-release microneedle patch includes at least the following steps:
  • the glycerophosphate compound is selected from any one or more of sodium glycerophosphate, potassium glycerophosphate, magnesium glycerophosphate, and calcium glycerophosphate;
  • the non-ionic cellulose ether compound is hydroxypropyl One or a mixture of cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, and hydroxybutyl methyl cellulose.
  • the sustained-release microneedle patch provided by the present invention includes a nonionic cellulose ether compound and a glycerol phosphate compound additive in the needle tip preparation solution.
  • the glycerol phosphate can compete with the cellulose ether compound for water molecules.
  • the cellulose ether compound is dehydrated and precipitated when the temperature is lower than the normal cloud point, so that the cloud point is changed to make the microneedle gel in the drying process, and the gel microneedle with good skin puncture effect is prepared, and the package is realized.
  • the drug-laden body is released slowly.
  • the prescription of the microneedle tip of the cellulose ether compound containing glycerol phosphate additives has a good skin puncture effect, the tip is sharp and full, and the substrate is flexible. It is suitable for integrated microneedles, layered microneedles, and coated microneedles. , Preparation of bubble microneedle.
  • FIG. 1 shows the sol-gel phase transition process diagram of the microneedle preparation process in Example 1.
  • Figure 2 shows the topography of the microneedle prepared in Example 1 of the present invention.
  • Fig. 3 shows a diagram of the puncture effect of the microneedle prepared in Example 1 of the present invention.
  • FIG. 4 shows the effect diagram of the skin effect of the microneedles prepared in Comparative Example 1 and Example 1 of the present invention.
  • Figure 5 shows a process diagram of the layered microneedle intradermal sustained-release drug delivery process prepared in Example 10 of the present invention.
  • Figure 6 shows a schematic diagram of the structure of a coated microneedle prepared in Example 11 of the present invention.
  • FIG. 7 shows a schematic diagram of the structure of a bubble-type microneedle prepared in Example 12 of the present invention.
  • Figure 8 shows the in vitro percutaneous penetration curves of diclofenac sodium microneedles in Examples 34-37 of the present invention.
  • Figure 9 shows the in vitro permeation curves of the sustained-release layered microneedles containing different contents of porogen in Examples 38-40 of the present invention.
  • the present invention first provides a sustained-release microneedle patch with a good skin puncture effect, including a needle body and a needle tip on the needle body, at least the needle tip
  • the part includes a part prepared from a needle tip preparation solution that can achieve gelation during the drying process of the microneedle patch; the solute of the needle tip preparation solution includes glycerophosphate compounds and non-ionic cellulose ether compounds.
  • the needle tip preparation solution can form the needle tip portion or the entire needle body of the sustained-release microneedle, or form a coating on the surface of the needle tip, that is, the present invention is suitable for integrated microneedles, layered microneedles, Preparation of coated microneedles and bubble microneedles.
  • Non-ionic cellulose ether derivatives are the products after the hydrogen of the hydroxyl group in the cellulose polymer is replaced by the hydrocarbon group.
  • the etherification process makes the cellulose that is insoluble in water have good water-soluble properties, in addition, it is also chemically inert. , Biocompatibility, biodegradability and other excellent properties, so that it is widely used in the field of pharmaceutical preparations, and the material itself has good mechanical properties and film-forming properties, suitable for the prescription research and application of microneedle preparations.
  • phase transition temperature is called the cloud point, and its gelation characteristics
  • the principle is: in an aqueous solution, there are three interactions between cellulose molecules and water molecules: (1) the hydrogen bonding between and within the cellulose molecular chain; (2) the hydrogen between the cellulose molecules and the water molecules. Bonding; (3) The hydrophobic interaction between the hydrocarbon groups of cellulose molecules. When the ambient temperature of the solution is low, the hydrogen bond interaction between cellulose molecules and water molecules dominates, and cellulose exhibits good water solubility.
  • the gelation temperature of cellulose ether is not only affected by the molecular weight, degree of substitution, and concentration of the material itself, but also changes due to the use of certain additives, such as salting-out electrolytes (such as phosphate and chloride), polyols (such as glycerin) , Polyethylene glycol), polyol esters (such as glycerol phosphate compounds) and so on.
  • salting-out electrolytes such as phosphate and chloride
  • polyols such as glycerin
  • Polyethylene glycol Polyethylene glycol
  • polyol esters such as glycerol phosphate compounds
  • glycerophosphate compounds have both phosphate ions and polyol hydroxyl groups, which makes them more advantageous in the process of adjusting the cloud point of cellulose ether.
  • a small amount of addition can greatly reduce the turbidity of cellulose ether materials. Point temperature.
  • the technical principle of the needle tip preparation solution provided by the present invention is: in an aqueous solution, glycerol phosphate compounds can compete with cellulose ether compounds for water molecules, so that cellulose ether compounds are dehydrated and precipitated when the temperature is lower than the normal cloud point, thereby changing their Gelation temperature.
  • the microneedle prescription of the cellulose ether compound containing glycerol phosphate has good skin puncture effect, the needle tip is sharp and plump, and the base has good flexibility.
  • the glycerophosphate compound includes any one of sodium glycerophosphate, potassium glycerophosphate, magnesium glycerophosphate, and calcium glycerophosphate.
  • the non-ionic cellulose ether compound is any one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, and hydroxybutyl methyl cellulose Or a mixture of several.
  • the non-ionic cellulose ether compound accounts for 2%-40% of the total mass of the preparation liquid.
  • the solid content ratio of the non-ionic cellulose ether compound and the glycerophosphate compound is 1:1-100:1.
  • the solid content ratio of the non-ionic cellulose ether compound and the glycerophosphate compound is 5:1-50:1.
  • the solute of the needle tip preparation solution further includes a porogen, and the porogen accounts for 2%-20% of the total mass of the needle tip preparation solution.
  • the porogen is one of trehalose, calcium hydrogen phosphate or sodium bicarbonate. These three porogens have significant pore-forming effects in the sustained-release microneedle patch provided by the present invention.
  • the cumulative penetration of the drug is over 80%, and the bioavailability of the drug is improved.
  • the solute of the needle tip preparation solution also includes at least one active ingredient; preferably, the active ingredient is polypeptide drugs, protein drugs, chemical drugs, skin care active ingredients, health care active ingredients, and plant extracts.
  • the active ingredient is polypeptide drugs, protein drugs, chemical drugs, skin care active ingredients, health care active ingredients, and plant extracts.
  • the ingredients specifically diclofenac sodium, interferon, captopril, hexapeptide, etc.
  • the microneedle is an integrated microneedle, a layered microneedle, a coated microneedle or a bubble type microneedle.
  • a preparation method of sustained-release microneedle patch includes at least the following steps:
  • microneedle to be prepared can perform the subsequent corresponding preparation steps according to the type of microneedle to be prepared, such as preparation of supporting microneedles, mold forming, etc., and can refer to the following specific examples.
  • the glycerophosphate compound is any one of sodium glycerophosphate, calcium glycerophosphate, potassium glycerophosphate, and magnesium glycerophosphate;
  • the nonionic cellulose ether compound is hydroxypropyl cellulose, hydroxypropyl cellulose, and hydroxypropyl cellulose. Any one or a mixture of propyl methyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, and hydroxybutyl methyl cellulose.
  • the solid content ratio of the nonionic cellulose ether compound and the glycerophosphate compound is 1:1-100:1; further preferably, the nonionic cellulose ether compound and the glycerophosphate compound have a solid content ratio of 1:1 to 100:1; The solid content ratio of the compound is 5:1-50:1.
  • the microneedle is an integrated microneedle, a layered microneedle, a coated microneedle or a bubble type microneedle.
  • Example 1 According to the prescription of Example 1 in Table 1, use a pipette to pipette 5.525 mL of ultrapure water into a centrifuge tube, use an electronic balance to accurately weigh 0.075 g of sodium glycerophosphate into the centrifuge tube to dissolve, and then weigh 2.4 Add g hydroxypropyl cellulose to the centrifuge tube, stir, after the solution is completely dissolved, use the centrifugal method to remove the bubbles in the solution to obtain the microneedle preparation solution;
  • the sustained-release microneedle patch was prepared by the preparation method of Example 1. The difference is that the prescription of the microneedle preparation solution is the formula of Example 2 in Table 1, namely: ultrapure water 5.48mL, sodium glycerophosphate 0.12g, Hydroxypropyl cellulose 2.4g.
  • the sustained-release microneedle patch was prepared by the preparation method of Example 1. The difference is that the prescription of the microneedle preparation liquid is the formula of Example 3 in Table 1, namely: ultrapure water 5.44mL, sodium glycerophosphate 0.16g, Hydroxypropyl cellulose 2.4g.
  • the sustained-release microneedle patch was prepared by the preparation method of Example 1. The difference is that the prescription of the microneedle preparation solution is the formula of Example 4 in Table 1, namely: ultrapure water 5.145mL, sodium glycerophosphate 0.185g, Hydroxypropyl cellulose 2.4g.
  • the sustained-release microneedle patch was prepared by the preparation method of Example 1. The difference is that the prescription of the microneedle preparation solution is the formula of Example 5 in Table 1, namely: 5.36 mL of ultrapure water, 0.24 g of sodium glycerophosphate, Hydroxypropyl cellulose 2.4g.
  • the sustained-release microneedle patch was prepared by the preparation method of Example 1. The difference is that the prescription of the microneedle preparation solution is the formula of Example 6 in Table 1, namely: ultrapure water 5.12mL, sodium glycerophosphate 0.12g, Hydroxypropyl cellulose 2.4g.
  • the 7 tubes of microneedle preparation solution prepared in step (1) in Examples 1-6 and Comparative Example 1 were successively placed in a constant temperature stability box set at different temperatures, and the set temperatures included: 37°C, 35°C. °C, 33°C, 31°C, 29°C, 26°C, 23°C, 20°C, 4°C. Place it in a constant temperature stability box for 2 hours to stabilize the temperature of the solution, and then take it out to observe the condition of the solution.
  • Table 2 The results are summarized in Table 2.
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Example 6 37°C Clear and transparent Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish 33°C Clear and transparent Clear and transparent Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish 31°C Clear and transparent Clear and transparent Clear and transparent Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloudy and whitish 29°C Clear and transparent Clear and transparent Clear and transparent Clear and transparent Clear and transparent Clear and transparent Cloudy and whitish Cloudy and whitish Cloudy and whitish Cloud
  • Fig. 1(a) is the sol state after sample loading
  • Fig. 1(b) is the gel state during the drying process.
  • the microneedles were prepared by the mold method at room temperature (25°C). At this time, the cloud point of the microneedle solution of Example 1 was higher than the room temperature, and the solution was in a clear and transparent sol state; during the drying process, as the water volatilized, sodium glycerophosphate The gradual increase in concentration makes the cloud point of the microneedle solution gradually decrease. When the temperature is lower than room temperature, the solution flocculates and becomes a turbid and whitish gel state.
  • Example 1 of the present invention The morphology of the microneedle prepared in Example 1 of the present invention is shown in FIG. 2, and the puncture effect of the microneedle prepared in Example 1 is shown in FIG. 3.
  • the substrate After the microneedle patch prepared by this method is completely dried, the substrate is flat, has good flexibility, and the needle tip is sharp and full.
  • a pig ear skin puncture experiment was carried out. After trypan blue staining, a complete array of microneedle pinholes remained on the skin, which proved that the microneedle patch made by this method had a good skin puncture effect.
  • Comparative Example 1 The microneedle state of the microneedle after 8 hours of treatment on the skin is shown as mark a, and the skin state is shown as mark 1. It can be seen that the needle tip has completely dissolved in the skin after 8 hours of treatment on the skin, and the substrate is peeled off , There is no solution residue on the skin;
  • Example 1 The microneedle state of the microneedle after being applied to the skin for 8 hours is shown as mark b-1, and the skin state is shown as mark 2.
  • the b-1 microneedle is due to the addition of sodium glycerophosphate. , which makes the microneedle exhibit swelling properties, the needle tip absorbs water, swells, and becomes soft in the skin to form a gel. When the substrate is removed, there is a white gel residue on the skin, indicating that the microneedle has a certain slow-release effect;
  • Example 1 The microneedle state of the microneedle after 72 hours of acting on the skin is shown as mark b-2, and the skin state is shown as mark 3, it can be seen that the microneedle has further swelled, but after 72 hours, there is no gel residue on the skin, indicating that, After about 72 hours of decomposition and release, the skin has completely absorbed the microneedles.
  • the sustained-release microneedle patch was prepared by the preparation method of Example 1. The difference is that the prescription of the microneedle preparation solution is the formula of Example 7 in Table 3, namely: 5.3 mL of ultrapure water, 0.3 g of sodium glycerophosphate, Hypromellose 2.4g.
  • the sustained-release microneedle patch was prepared by the preparation method of Example 1. The difference is that the prescription of the microneedle preparation solution is the formula of Example 8 in Table 3, namely: 5.2 mL of ultrapure water, 0.4 g of sodium glycerophosphate, Hypromellose 2.4g.
  • the sustained-release microneedle patch was prepared by the preparation method of Example 1. The difference is that the prescription of the microneedle preparation solution is the formula of Example 8 in Table 3, namely: ultrapure water 5mL, sodium glycerophosphate 0.6g, hydroxyl Propyl methyl cellulose 2.4g.
  • the cloud point temperature of the microneedle preparation solution in Examples 7-9 measured according to the method in Test Example 1 is shown in Table 4 below.
  • microneedle tip preparation solution was prepared.
  • Figure 5 shows the process of sustained-release intradermal drug delivery with layered microneedles.
  • the stratified microneedle design enables the microneedle to use the phase change of the needle tip to achieve the slow release of the drug after the microneedle is applied to the skin, and the substrate can be dissolved after a period of action, so as to realize the subcutaneous embedding of the drug-loaded needle tip.
  • the backing layer can be removed from the skin to avoid skin irritation and inconvenience caused by long-term application to patients, and further improve the medication compliance and safety of patients.
  • Preparation of coating solution use a pipette to weigh 6.2mL of ultrapure water into a centrifuge tube, use an electronic balance to accurately weigh 0.2g of sodium glycerophosphate, add it to the centrifuge tube, and after dissolving, weigh 1.6g The hydroxypropyl cellulose is added to the centrifuge tube and stirred to dissolve to obtain the microneedle coating solution.
  • the sustained-release microneedle patch was prepared by the preparation method of Example 1, except that, according to the ingredients shown in the following table, a porogen was also added to the needle tip preparation solution.
  • the obtained microneedle patch also has a good sustained-release effect, and the presence of the porogen can promote the release of the drug to a certain extent, thereby controlling the sustained-release time.
  • the sustained-release microneedle patch was prepared by the preparation method of Example 1, except that, according to the ingredients shown in the following table, the needle tip preparation solution also added active ingredients.
  • the obtained microneedle patch also has a better sustained-release effect, and the active ingredient can exert its active effect very well.
  • the sustained-release microneedle patch was prepared by the preparation method of Example 1, except that, according to the ingredients shown in the following table, the needle tip preparation solution also added active ingredients.
  • the obtained microneedle patch also has a better sustained-release effect, and the active ingredient can exert its active effect very well.
  • the sustained-release microneedle patch was prepared by the preparation method of Example 1, except that, according to the ingredients shown in the following table, the needle tip preparation solution also added active ingredients.
  • the obtained microneedle patch also has a better sustained-release effect, and the active ingredient can exert its active effect very well.
  • Table 8 The prescription design table of sustained-release microneedles containing skin care drugs
  • Example 34-37 The in vitro transdermal drug release effect of the sustained-release integrated microneedle containing diclofenac sodium
  • microneedle solution Preparation of microneedle solution: According to Table 9, 8 mL of microneedle solutions containing 75 mg/mL diclofenac sodium and different porogens were prepared according to the design in Table 9. According to the preparation method of Example 1, dry and shaped microneedles were obtained.
  • the results show that the sustained-release microneedle patch containing about 2.1 mg of diclofenac sodium per tablet can achieve a stable drug release lasting 72 hours after administration, and the addition of the porogen makes the microneedle
  • the amount of drug released by needles has been significantly increased.
  • the pore-forming effect of the trehalose porogen and calcium hydrogen phosphate porogen is more significant, and the cumulative penetration of the drug can reach more than 85%, which improves the bioavailability of the drug.
  • Example 38-40 In vitro transdermal drug release effect of sustained-release stratified microneedles coated with tranexamic acid
  • microneedle tip solution prepare 8mL of microneedle solution containing 50mg/mL tranexamic acid and different contents of trehalose. According to the preparation method of Example 10, the substrate can be quickly dissolved and drug-loaded tip is obtained. Layered microneedles embedded in the skin to achieve slow drug release.
  • An automatic transdermal instrument was used for in vitro transdermal penetration experiments.
  • Sampling The method is to take all, and automatically add the same volume of receiving liquid after each sampling.
  • the sampling time is 0h, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 36h, 48h, 72h.
  • the in vitro permeation curves of the sustained-release layered microneedles containing different contents of porogen are shown in FIG. 9.
  • the results show that each piece of sustained-release layered microneedle patch containing about 0.4 mg of tranexamic acid, one hour after the administration, the backing layer is removed and the patch is embedded in the skin
  • the drug-loaded needle tip can achieve a stable drug release that lasts for 72 hours, and the microneedle drug release speed is significantly increased with the increase of the porogen trehalose, thereby achieving a controlled release of the drug.

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Abstract

一种缓释微针贴片及其制备方法，涉及医药技术领域。所述微针贴片包括针体和针体上的针尖，所述针尖中包括甘油磷酸盐类化合物和非离子型纤维素醚类化合物。甘油磷酸盐可与纤维素醚类化合物竞争水分子，从而改变其浊点，使微针在干燥过程中发生凝胶化，制得具有良好皮肤穿刺效果的凝胶微针，实现包载药物的体内缓慢释放。

Description

一种缓释微针贴片及其制备方法 技术领域
本发明涉及医药技术领域。更具体地，涉及一种缓释微针贴片及其制备方法。
背景技术
缓释微针是一种作用皮内后，可实现药物持续、平缓递送的新型透皮给药制剂，适用于需长期给药，治疗窗窄药物的使用，具有减少给药次数，提高患者用药安全性和便利性等优点，极大地提高了患者的用药依从性，在新型微针给药制剂研究中占有重要地位。现有缓释微针主要基于(1)微球、脂质体、固体分散体等缓释体系；(2)聚乳酸-羟基乙酸共聚物、壳聚糖等可降解聚合物材料；(3)溶胶-凝胶相转换材料进行设计。其中，缓释体系的引入使得制备过程更为繁琐，且载药量会降低；可降解聚合物材料因水溶性差，常需使用有机试剂作溶剂，不可避免地造成有机溶剂残留，引起安全问题。
当前，有关相变微针的研究不多，包括：交联聚乙烯醇、聚乳酸-羟基乙酸共聚物-聚乙二醇-聚乳酸-羟基乙酸共聚物(PLGA-PEG-PLGA)三嵌段共聚物、卡波姆、泊洛沙姆等。
中国专利CN102202720A公开了一种利用交联聚乙烯醇制备相转化聚合物微针的方法，通过-20℃冷冻，4℃解冻的反复操作，使得水溶性聚乙烯醇在水溶液中通过微晶构建形成凝胶，从而实现药物的缓释递送，但该制备工艺流程繁琐，耗时长，不适于缓释微针的大批量工业化生产；而PLGA-PEG-PLGA三嵌段共聚物制作的相变微针，原材料合成工艺复杂，且材料水溶性差，需引入有机试剂，存在安全隐患(Marc Pearton，Chris Allender，Keith Brain，et al.Gene Delivery to the Epidermal Cells of Human Skin Explants Using Microfabricated Microneedles and Hydrogel Formulations.Pharmaceutical Research.2008,25(2)：407-416.)；卡波姆和泊洛沙姆凝胶均因具有良好的温敏特点，在制药行业被广泛用作局部治疗药物的载体，作用于粘膜或皮肤等患处时，可实现药物的持续释放，但这两种材料机械强度极差，无法制成具有皮肤穿刺性的微针，现有研究均是先使用有足够机械强度的金属微针或聚合物微针预处理皮肤，待微通道打开，再将载药的卡波姆或泊洛沙姆溶液涂覆于微针处理过的皮肤表面，利用其温敏特性，发生溶胶-凝胶的相变过程，形成药物储库，实现药物的缓慢释放。
针对上述问题，寻找适用的溶胶-凝胶相转换材料，使其具备足够的机械强度可以刺穿人体皮肤角质层，且使微针在制作过程中即可实现由液态溶胶转变成固态凝胶的过程，制得有利于药物透过的多孔骨架微针，对促进药物皮内持续、平缓释放，具有重要的研究意义。
发明内容
本发明的一个目的在于提供一种具有良好的皮肤穿刺效果的缓释微针贴片。
本发明的另一个目的在于提供一种缓释微针贴片的制备方法。
为达到上述目的，本发明采用下述技术方案：
一种缓释微针贴片，包括针体和针体上的针尖，所述针尖中包括甘油磷酸盐类化合物和非离子型纤维素醚类化合物。
优选地，至少所述针尖部位包括在微针贴片干燥过程中可实现凝胶化的针尖制备液制备而成的部分；
所述针尖制备液的溶质包括甘油磷酸盐类化合物和非离子型纤维素醚类化合物。
优选地，所述甘油磷酸盐类化合物选自甘油磷酸钠、甘油磷酸钾、甘油磷酸镁、甘油磷酸钙中的任意一种或多种。
优选地，所述非离子型纤维素醚类化合物为羟丙基纤维素、羟丙甲基纤维素、甲基纤维素、羟乙基甲基纤维素、羟丁基甲基纤维素中的一种或几种的混合物。
优选地，所述非离子型纤维素醚类化合物占制备液总质量的2％-40％。
优选地，所述非离子型纤维素醚类化合物和甘油磷酸盐类化合物的固含量比为1:1-100:1，更优选为5:1-50:1。
优选地，所述针尖制备液的溶质还包括致孔剂，所述致孔剂占针尖制备液总质量的2％-20％。
优选地，所述致孔剂为海藻糖、磷酸氢钙或碳酸氢钠中的一种或几种。
优选地，所述针尖制备液的溶质还包括至少一种活性成分。
优选地，所述活性成分为多肽类药物、蛋白类药物、化学类药物、护肤活性成分、保健类活性成分、植物提取物成分中的一种或几种。
优选地，所述微针为一体式微针、分层式微针、涂层式微针或气泡式微针。
一种缓释微针贴片的制备方法，至少包括以下步骤：
称取甘油磷酸盐类化合物加入到超纯水中溶解，得到甘油磷酸盐水溶液；
称取非离子型纤维素醚类化合物加入到甘油磷酸盐水溶液中，加入或不加入致孔剂，加入或不加入活性成分，搅拌溶解后脱除气泡，得到针尖制备液。
优选地，所述甘油磷酸盐类化合物选自甘油磷酸钠、甘油磷酸钾、甘油磷酸镁、甘油磷酸钙中的任意一种或多种；所述非离子型纤维素醚类化合物为羟丙基纤维素、羟丙甲基纤维素、甲基纤维素、羟乙基甲基纤维素、羟丁基甲基纤维素中的一种或几种的混合物。
本发明的有益效果如下：
本发明提供的缓释微针贴片，其针尖制备液中包括非离子型纤维素醚类化合物和甘油磷酸盐化合物添加剂，在水溶液中，甘油磷酸盐可与纤维素醚类化合物竞争水分子，使得纤维素醚类化合物在低于正常浊点温度时便脱水析出，从而改变其浊点使微针在干燥过程中发生凝胶化，制得具有良好皮肤穿刺效果的凝胶微针，实现包载药物的体内缓慢释放。含有甘油磷酸盐类添加剂的纤维素醚化合物的微针针尖的处方，具有良好的皮肤穿刺效果，针尖尖锐、饱满，基底柔韧性好，适用于一体式微针、分层式微针、涂层式微针、气泡式微针的制备。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细的说明。
图1示出实施例1中微针制备过程的溶胶-凝胶相变过程图。
图2示出本发明实施例1所制备的微针形貌图。
图3示出本发明实施例1所制备的微针穿刺效果图。
图4示出本发明对比例1与实施例1所制备的微针皮肤作用效果图。
图5示出本发明实施例10制备的分层微针皮内缓释递药过程图。
图6示出本发明实施例11制备的涂层微针的结构示意图。
图7示出本发明实施例12制备的气泡式微针结构示意图。
图8示出本发明实施例34-37中双氯芬酸钠的微针体外经皮渗透曲线。
图9示出本发明实施例38-40含有不同含量致孔剂的缓释分层微针的体外经皮渗透曲线。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例和附图对本发明做进一步的说明。附图中相似的部件以相同的附图标记进行表示。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
针对背景技术中提到的现有技术中存在的技术问题，本发明首先提供一种具有良好的皮肤穿刺效果的缓释微针贴片，包括针体和针体上的针尖，至少所述针尖部位包括在微针贴片干燥过程中可实现凝胶化的针尖制备液制备而成的部分；所述针尖制备液的溶质包括甘油磷酸盐类化合物和非离子型纤维素醚类化合物。本领域技术人员可以理解的是，针尖制备液可以形成缓释微针的针尖部位或者整个针体，也可以在针尖表面形成涂层等，即本发明适用于一体式微针、分层式微针、涂层式微针、气泡式微针的制备。
非离子型纤维素醚类衍生物是纤维素高分子中羟基的氢被烃基取代后的生成物，醚化过程使得原本水不溶解的纤维素具备了良好的水溶性质，此外，还具有化学惰性、生物相容性和可生物降解等优良性能，使其在医药制剂领域被广泛应用，且材料本身具有良好的机械性能和成膜性，适用于微针制剂的处方研究和应用。
部分非离子型纤维素醚化合物的水溶液在进行升温处理时，会出现聚合物絮凝现象，发生由溶胶向凝胶的相变过程，该相变温度点被称为浊点，其凝胶化特性的原理是：水溶液中，纤维素分子与水分子之间存在三种相互作用：(1)纤维素分子链间、链内的氢键作用；(2)纤维素分子与水分子之间的氢键作用；(3)纤维素分子烃基间的疏水作用。当溶液所处环境温度较低时，纤维素分子与水分子间的氢键相互作用力占主导，纤维素表现出良好的水溶性，当温度升高到浊点温度时，纤维素与水分子间的氢键断裂，使得纤维素分子间的疏水性相互作用更具优势，表现为纤维素从水中絮凝，形成水不溶性的凝胶。
纤维素醚的凝胶化温度除受材料本身分子量、取代度、浓度影响，还因某些添加剂的使用而改变，如：盐析型电解质(如磷酸盐、氯化物)，多元醇(如甘油、聚乙二醇)，多元醇酯(如甘油磷酸盐类化合物)等。其中，甘油磷酸盐类化合物因同时兼具磷酸根离子和多元醇羟基，使其在对纤维素醚浊点的调节过程中更具优势，少量的添加即可极大降低纤维素醚材料的浊点温度。
本发明提供的针尖制备液技术原理为：在水溶液中，甘油磷酸盐类化合物可与纤维素醚化合物竞争水分子，使得纤维素醚化合物在低于正常浊点温度时便脱水析出，从而改变 其凝胶化温度。含有甘油磷酸盐的纤维素醚化合物的微针处方具有良好的皮肤穿刺效果，针尖尖锐、饱满，基底柔韧性好。
优选地，所述甘油磷酸盐类化合物，包括：甘油磷酸钠、甘油磷酸钾、甘油磷酸镁、甘油磷酸钙中的任意一种。
优选地，所述非离子型纤维素醚类化合物为羟丙基纤维素、羟丙甲基纤维素、甲基纤维素、羟乙基甲基纤维素、羟丁基甲基纤维素中的任意一种或几种的混合物。
优选地，所述非离子型纤维素醚类化合物占制备液总质量的2％-40％。
优选地，所述非离子型纤维素醚类化合物和甘油磷酸盐类化合物的固含量比为1:1-100:1。
进一步优选地，所述非离子型纤维素醚类化合物和甘油磷酸盐类化合物的固含量比为5:1-50:1。
优选地，所述针尖制备液的溶质还包括致孔剂，所述致孔剂占针尖制备液总质量的2％-20％。
优选地，所述致孔剂为海藻糖、磷酸氢钙或碳酸氢钠中的一种，这三种致孔剂在本发明提供的缓释微针贴片中的致孔效果较为显著，可实现药物累积渗透量80％以上，提高药物的生物利用度。
优选地，所述针尖制备液的溶质还包括至少一种活性成分；优选地，所述活性成分为多肽类药物、蛋白类药物、化学类药物、护肤类活性成分、保健类活性成分、植物提取物成分中的一种或几种，具体地可以为双氯芬酸钠、干扰素、卡托普利、六胜肽等。
优选地，所述微针为一体式微针、分层式微针、涂层式微针或气泡式微针。
一种缓释微针贴片的制备方法，至少包括以下步骤：
称取甘油磷酸盐类化合物化加入到超纯水中溶解，得到甘油磷酸盐水溶液；
称取非离子型纤维素醚类化合物加入到甘油磷酸盐溶液中，加入或不加入致孔剂，加入或不加入活性成分，搅拌溶解后脱除气泡，得到针尖制备液。
本领域技术人员可以根据所要制备的微针类型，进行后续相应的制备步骤，例如制备支撑微针、模具成型等，可以参考下面的具体实施例。
优选地，所述甘油磷酸盐类化合物为甘油磷酸钠、甘油磷酸钙、甘油磷酸钾、甘油磷酸镁中的任意一种；所述非离子型纤维素醚类化合物为羟丙基纤维素、羟丙甲基纤维素、甲基纤维素、羟乙基甲基纤维素、羟丁基甲基纤维素中的任意一种或几种的混合物。
优选地，所述非离子型纤维素醚类化合物和甘油磷酸盐类化合物的固含量比为1:1-100:1；进一步优选地，所述非离子型纤维素醚类化合物和甘油磷酸盐类化合物的固含量比为5:1-50:1。
优选地，所述微针为一体式微针、分层式微针、涂层式微针或气泡式微针。
为了更清楚地说明本发明，下面结合优选实施例和附图对本发明做进一步的说明。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
实施例1
按照以下步骤制备缓释微针贴片：
(1)按照表1中实施例1的处方，使用移液枪移取5.525mL超纯水加入离心管中， 使用电子天平精密称取0.075g甘油磷酸钠加入离心管中溶解，然后称取2.4g羟丙基纤维素加入离心管中，搅拌，待溶液溶解完全后，使用离心法脱除溶液中的气泡，得到微针制备液；
(2)使用所制的微针制备液，采用PDMS模具法制备微针，并通过气泵对微针模具进行负压抽真空处理，保证溶液完全进入针孔中，完成后打开通风设备，加速微针干燥成型。
表1对比例1、实施例1-6的微针制备液处方
  超纯水(mL) 甘油磷酸钠(g) 羟丙基纤维素(g)
对比例1 5.6 0 2.4
实施例1 5.525 0.075 2.4
实施例2 5.48 0.12 2.4
实施例3 5.44 0.16 2.4
实施例4 5.145 0.185 2.4
实施例5 5.36 0.24 2.4
实施例6 5.12 0.48 2.4
实施例2
采用实施例1的制备方法制备缓释微针贴片，不同之处在于，微针制备液的处方选用表1中实施例2的处方，即：超纯水5.48mL，甘油磷酸钠0.12g，羟丙基纤维素2.4g。
实施例3
采用实施例1的制备方法制备缓释微针贴片，不同之处在于，微针制备液的处方选用表1中实施例3的处方，即：超纯水5.44mL，甘油磷酸钠0.16g，羟丙基纤维素2.4g。
实施例4
采用实施例1的制备方法制备缓释微针贴片，不同之处在于，微针制备液的处方选用表1中实施例4的处方，即：超纯水5.145mL，甘油磷酸钠0.185g，羟丙基纤维素2.4g。
实施例5
采用实施例1的制备方法制备缓释微针贴片，不同之处在于，微针制备液的处方选用表1中实施例5的处方，即：超纯水5.36mL，甘油磷酸钠0.24g，羟丙基纤维素2.4g。
实施例6
采用实施例1的制备方法制备缓释微针贴片，不同之处在于，微针制备液的处方选用表1中实施例6的处方，即：超纯水5.12mL，甘油磷酸钠0.12g，羟丙基纤维素2.4g。
对比例1
按照以下步骤制备缓释微针贴片：
(1)按照表1中对比例1的处方，使用移液枪移取5.6mL超纯水加入离心管中，称取2.4g羟丙基纤维素加入离心管中，搅拌，待溶液溶解完全后，使用离心法脱除溶液中的气泡，得到微针制备液；
(2)使用所制的微针制备液，采用PDMS模具法制备微针，并通过气泵对微针模具进行负压抽真空处理，保证溶液完全进入针孔中，完成后打开通风设备，加速微针干燥成型。
试验例1性能观察
(1)不同配方微针制备液的浊点温度：
将实施例1-6以及对比例1中第(1)步配制得到的7管微针制备液先后置于设定了不同温度的恒温稳定性箱中，设定的温度包括：37℃，35℃，33℃，31℃，29℃，26℃，23℃，20℃，4℃。在恒温稳定性箱中放置2小时，使溶液温度稳定，然后取出观察溶液情况，结果汇总如表2所示。
表2不同温度条件下放置2小时后的对比例1及实施例1-6的溶液状态
存放温度 比较例1 实施例1 实施例2 实施例3 实施例4 实施例5 实施例6
37℃ 澄清透明 浑浊发白 浑浊发白 浑浊发白 浑浊发白 浑浊发白 浑浊发白
35℃ 澄清透明 浑浊发白 浑浊发白 浑浊发白 浑浊发白 浑浊发白 浑浊发白
33℃ 澄清透明 澄清透明 浑浊发白 浑浊发白 浑浊发白 浑浊发白 浑浊发白
31℃ 澄清透明 澄清透明 澄清透明 浑浊发白 浑浊发白 浑浊发白 浑浊发白
29℃ 澄清透明 澄清透明 澄清透明 澄清透明 浑浊发白 浑浊发白 浑浊发白
26℃ 澄清透明 澄清透明 澄清透明 澄清透明 澄清透明 浑浊发白 浑浊发白
23℃ 澄清透明 澄清透明 澄清透明 澄清透明 澄清透明 浑浊发白 浑浊发白
20℃ 澄清透明 澄清透明 澄清透明 澄清透明 澄清透明 澄清透明 浑浊发白
4℃ 澄清透明 澄清透明 澄清透明 澄清透明 澄清透明 澄清透明 澄清透明
通过实验及文献记载，得到实施例1-6以及对比例1中含有不同量甘油磷酸钠的羟丙基纤维素微针制备液的浊点温度情况，如下表3所示。
表3实施例1-6及对比例1中微针制备液的浊点温度
  溶液浊点
对比例1 约40℃(文献记载)
实施例1 33-35℃
实施例2 31-33℃
实施例3 29-31℃
实施例4 26-29℃
实施例5 20-23℃
实施例6 低于20℃
以上结果表明，通过添加不同剂量的甘油磷酸钠添加剂，可显著改变羟丙基纤维素的浊点。
(2)微针制备过程的溶胶-凝胶相变过程
如附图1所示，图1(a)为加样后的溶胶状态，图1(b)为干燥过程中的凝胶状态。室温(25℃)条件下通过模具法制备微针，此时实施例1的微针溶液浊点高于室温温度，溶液为澄清透明的溶胶状态；干燥过程中，随着水分挥发，甘油磷酸钠浓度逐渐提高，使得微针溶液浊点逐渐降低，当低于室温温度时，溶液发生絮凝，呈浑浊发白的凝胶状态。
(3)所制微针形貌及皮肤穿刺效果
本发明实施例1制备得到的微针形貌如图2所示，实施例1制备得到的微针穿刺效果如图3所示。通过该方法制得的微针贴片在干燥完全后，基底平整、具有良好柔韧性， 针尖尖锐、饱满。进行了猪耳皮肤穿刺实验，台盼蓝染色后，皮肤上留有完整的微针针孔阵列，证明了该方法所制的微针贴片具有良好的皮肤穿刺效果。
(4)微针作用皮肤后效果
对比例1和实施例1制备得到的微针作用皮肤8小时以及实施例1制备得到的微针作用皮肤72小时后效果如图4所示。对比例1微针在作用皮肤8小时后的微针状态如标记a所示，皮肤状态如标记1所示，可知当其作用皮肤8小时后，针尖在皮内已溶解完全，揭去基底时，皮肤上无溶液残留；实施例1微针在作用皮肤8小时后的微针状态如标记b-1所示，皮肤状态如标记2所示，其中b-1微针因甘油磷酸钠的加入，使得微针呈溶胀性能，针尖在皮内吸水、溶胀、变软，形成凝胶，揭去基底时，皮肤上有白色凝胶残留，说明该微针有一定的缓释效果；实施例1微针在作用皮肤72小时后的微针状态如标记b-2所示，皮肤状态如标记3所示，可知微针有了进一步溶胀，但72小时后，皮肤上无凝胶残留，说明，经72小时左右的分解、释放，皮肤已经完全吸收了该微针。
实施例7
采用实施例1的制备方法制备缓释微针贴片，不同之处在于，微针制备液的处方选用表3中实施例7的处方，即：超纯水5.3mL，甘油磷酸钠0.3g，羟丙甲基纤维素2.4g。
实施例8
采用实施例1的制备方法制备缓释微针贴片，不同之处在于，微针制备液的处方选用表3中实施例8的处方，即：超纯水5.2mL，甘油磷酸钠0.4g，羟丙甲基纤维素2.4g。
实施例9
采用实施例1的制备方法制备缓释微针贴片，不同之处在于，微针制备液的处方选用表3中实施例8的处方，即：超纯水5mL，甘油磷酸钠0.6g，羟丙甲基纤维素2.4g。
试验例2
按照试验例1中的方法测得实施例7-9中微针制备液的浊点温度如下表4所示。
表4实施例7-9微针制备液处方及其微针溶液的浊点温度
  超纯水(mL) 甘油磷酸钠(g) 羟丙甲基纤维素(g) 溶液浊点
实施例7 5.3 0.3 2.4 30-32℃
实施例8 5.2 0.4 2.4 25-27℃
实施例9 5 0.6 2.4 20-22℃
实施例10
按照以下步骤制备分层微针：
(1)制备微针针尖：按照实施例1的配制方法和处方制备微针的针尖制备溶液。
(2)使用可溶性材料作为微针基底：按照对比例1的配制方法和处方制备微针基底溶液。
(3)先使用针尖溶液，在PDMS模具上加样，待溶液干燥成膜后，添加基底溶液，吹风至整片微针完全干透成型。
分层微针皮内缓释递药过程图如图5所示。分层微针的设计，可使微针作用于皮肤后，利用针尖的相变实现药物的缓慢释放，而基底可在作用一段时间后发生溶断，从而实现载药针尖的皮下包埋，微针背衬层可从皮肤上取下，避免长期贴敷给患者带来的皮 肤刺激性和不便性，进一步提高了患者的用药顺应性和安全性。
实施例11
涂层微针的制备
(1)涂层溶液的制备：使用移液枪称取6.2mL超纯水加入离心管中，使用电子天平精密称取甘油磷酸钠0.2g，加入离心管中，溶解后，再称取1.6g羟丙基纤维素加入离心管中，搅拌溶解，即得微针涂层溶液。
(2)支撑微针的制备：使用移液枪移取6.92mL超纯水加入离心管中，使用电子天平精密称取0.08g六水合氯化镁加入离心管中溶解，然后称取3g聚乙烯醇加入离心管中，搅拌后于80℃的条件下加热溶解，使用离心法脱除溶液中的气泡，得到微针制备液，使用模具法制得成型微针作为支撑微针。
3.使用涂层溶液对干燥完全的聚乙烯醇可溶性微针进行涂层操作，得到聚乙烯醇涂层微针。所述涂层微针的结构示意图如图6所示。所得微针贴片具有好的缓释效果。
实施例12气泡式微针的制备
(1)针尖溶液的制备：使用移液枪称取6.2mL超纯水加入离心管中，使用电子天平精密称取甘油磷酸钾0.2g，加入离心管中，溶解后，再称取1.6g羟丙基纤维素加入离心管中，搅拌溶解，即得针尖溶液。
(2)速溶型基底溶液的制备：使用移液枪移取15.6mL超纯水加入离心管中，使用电子天平精密称取0.4g聚乙烯吡咯烷酮K120 0.4g加入离心管中溶解，然后称取4g羟乙基纤维素加入离心管中，搅拌溶解后，使用离心法脱除溶液中的气泡，得到微针基底溶液。
(3)在PDMS模具上，先加入低浓度的针尖溶液，待其干透成膜后，再添加速溶型基底溶液，吹风干燥至微针完全成型即可。得到的气泡式微针结构示意图如图7所示。所得微针贴片具有好的缓释效果。
实施例13-15含有致孔剂的缓释微针的制备
采用实施例1的制备方法制备缓释微针贴片，不同之处在于，按照下表所示的成分，针尖制备液中还加入了致孔剂。得到的微针贴片同样具有较好的缓释效果，且致孔剂的存在能够在一定程度上促进药物的释放，从而起到控制缓释时间的作用。
表5含有不同种类致孔剂的缓释微针处方设计表
Figure PCTCN2020114743-appb-000001
实施例16-21包载多肽、蛋白类药物的缓释微针的制备
采用实施例1的制备方法制备缓释微针贴片，不同之处在于，按照下表所示的成分，针尖制备液中还加入了活性成分。得到的微针贴片同样具有较好的缓释效果，且活性成分能够很好的发挥其活性效果。
表6包载多肽、蛋白类药物的缓释微针处方设计表
Figure PCTCN2020114743-appb-000002
实施例22-27包载化学类药物的缓释微针的制备
采用实施例1的制备方法制备缓释微针贴片，不同之处在于，按照下表所示的成分，针尖制备液中还加入了活性成分。得到的微针贴片同样具有较好的缓释效果，且活性成分能够很好的发挥其活性效果。
表7包载化学类药物的缓释微针处方设计表
Figure PCTCN2020114743-appb-000003
实施例28-33包载护肤类药物的缓释微针的制备
采用实施例1的制备方法制备缓释微针贴片，不同之处在于，按照下表所示的成分，针尖制备液中还加入了活性成分。得到的微针贴片同样具有较好的缓释效果，且活性成分能够很好的发挥其活性效果。
表8包载护肤类药物的缓释微针处方设计表
Figure PCTCN2020114743-appb-000004
实施例34-37包载双氯芬酸钠的缓释一体微针的体外经皮释药效果
(1)微针溶液配制：按照表9设计配制含有75mg/mL双氯芬酸钠以及不同致孔剂的 的微针溶液各8mL，按照实施例1的制备方法，获得干燥、成型的微针。
(2)含有不同添加剂的微针的体外经皮缓释效果评价
使用全自动透皮仪进行体外经皮渗透实验，使用植皮后的猪耳朵皮肤为透皮材料，温度控制在37±0.5℃，接收液为0.01M的磷酸盐缓冲溶液(pH＝7.4)，取样方式为全取，每次取样后自动补加相同体积的接收液，取样时间为0h、1h、2h、4h、6h、8h、12h、16h、24h、36h、48h、72h。含有不同添加剂的缓释微针的体外经皮渗透曲线如图8所示。
参照本发明附图8，结果表明，每片包载约2.1mg双氯芬酸钠的缓释微针贴片，在给药后，可实现持续72小时的平稳释药，且致孔剂的添加使得微针释药量明显提高，其中，以海藻糖致孔剂和磷酸氢钙致孔剂的致孔效果更为显著，实现药物累积渗透量达到85％以上，提高了药物的生物利用度。
表9包载双氯芬酸钠的缓释微针处方设计表
Figure PCTCN2020114743-appb-000005
实施例38-40包载氨甲环酸的缓释分层微针的体外经皮释药效果
(1)微针针尖溶液配制：按照表10设计配制含有50mg/mL氨甲环酸以及不同含量海藻糖的微针溶液8mL，按照实施例10的制备方法，获得基底可快速溶断、载药针尖埋植于皮内实现缓慢释药的分层微针。
(2)含有不同含量致孔剂的分层微针的体外经皮缓释效果评价
使用全自动透皮仪进行体外经皮渗透实验，使用植皮后的猪耳朵皮肤为透皮材料，温度控制在37±0.5℃，接收液为0.01M的磷酸盐缓冲溶液(pH＝7.4)，取样方式为全取，每次取样后自动补加相同体积的接收液，取样时间为0h、1h、2h、4h、6h、8h、12h、16h、24h、36h、48h、72h。含有不同含量致孔剂的缓释分层微针的体外经皮渗透曲线如图9所示。
参照本发明附图9，结果表明，每片包载约0.4mg氨甲环酸的缓释分层微针贴片，在给药1小时后，揭去背衬层，包埋在皮内的载药针尖可实现持续72小时的平稳释药，且随着致孔剂海藻糖添加量的提高微针释药速度明显加快，从而实现药物的可控释放。
表10包载氨甲环酸的缓释分层微针处方设计表
Figure PCTCN2020114743-appb-000006
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本 发明的实施方式的限定，对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动，这里无法对所有的实施方式予以穷举，凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。

Claims (11)

  1. 一种缓释微针贴片，包括针体和针体上的针尖，其特征在于，所述针尖中包括甘油磷酸盐类化合物和非离子型纤维素醚类化合物。
  2. 根据权利要求1所述的缓释微针贴片，其特征在于，至少所述针尖部位包括在微针贴片干燥过程中可实现凝胶化的针尖制备液制备而成的部分；
    所述针尖制备液的溶质包括甘油磷酸盐类化合物和非离子型纤维素醚类化合物。
  3. 根据权利要求1所述的缓释微针贴片，其特征在于，所述甘油磷酸盐类化合物选自甘油磷酸钠、甘油磷酸钾、甘油磷酸镁、甘油磷酸钙中的任意一种或多种。
  4. 根据权利要求1所述的缓释微针贴片，其特征在于，所述非离子型纤维素醚类化合物为羟丙基纤维素、羟丙甲基纤维素、甲基纤维素、羟乙基甲基纤维素、羟丁基甲基纤维素中的一种或几种的混合物；优选地，所述非离子型纤维素醚类化合物占制备液总质量的2％-40％。
  5. 根据权利要求1所述的缓释微针贴片，其特征在于，所述非离子型纤维素醚类化合物和甘油磷酸盐类化合物的固含量比为1:1-100:1，更优选为5:1-50:1。
  6. 根据权利要求1所述的缓释微针贴片，其特征在于，所述针尖制备液的溶质还包括致孔剂，所述致孔剂占针尖制备液总质量的2％-20％。
  7. 根据权利要求6所述的缓释微针贴片，其特征在于，所述致孔剂为海藻糖、磷酸氢钙或碳酸氢钠中的一种或几种。
  8. 根据权利要求1所述的缓释微针贴片，其特征在于，所述针尖制备液的溶质还包括至少一种活性成分；优选地，所述活性成分为多肽类药物、蛋白类药物、化学类药物、护肤类活性成分、保健类活性成分、植物提取物成分中的一种或几种。
  9. 根据权利要求1所述的缓释微针贴片，其特征在于，所述微针为一体式微针、分层式微针、涂层式微针或气泡式微针。
  10. 一种缓释微针贴片的制备方法，其特征在于，至少包括以下步骤：
    称取甘油磷酸盐类化合物加入到超纯水中溶解，得到甘油磷酸盐水溶液；
    称取非离子型纤维素醚类化合物加入到甘油磷酸盐水溶液中，加入或不加入致孔剂，加入或不加入活性成分，搅拌溶解后脱除气泡，得到针尖制备液。
  11. 根据权利要求10所述的制备方法，其特征在于，所述甘油磷酸盐类化合物选自甘油磷酸钠、甘油磷酸钾、甘油磷酸镁、甘油磷酸钙中的任意一种或多种；所述非离子型纤维素醚类化合物为羟丙基纤维素、羟丙甲基纤维素、甲基纤维素、羟乙基甲基纤维素、羟丁基甲基纤维素中的一种或几种的混合物。
PCT/CN2020/114743 2019-09-12 2020-09-11 一种缓释微针贴片及其制备方法 WO2021047628A1 (zh)

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