CN112641932A - Preparation method of parathyroid hormone microneedle - Google Patents

Preparation method of parathyroid hormone microneedle Download PDF

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CN112641932A
CN112641932A CN202011519526.2A CN202011519526A CN112641932A CN 112641932 A CN112641932 A CN 112641932A CN 202011519526 A CN202011519526 A CN 202011519526A CN 112641932 A CN112641932 A CN 112641932A
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microneedle
pth
mold
patch according
microneedle patch
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石磊
金拓
吴飞
于如月
张宇桐
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Shanghai Jiaotong University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • 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
    • 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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

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  • General Chemical & Material Sciences (AREA)
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Abstract

The invention discloses a preparation method of parathyroid hormone micro-needle, which comprises the steps of pouring a polymer material aqueous solution containing PTH on a mold with a micropore matrix, filling the polymer solution into all micropores, performing freeze-thaw cycle on the mold poured with the PTH solution, and finally performing membrane uncovering and drying. The preparation process is simple, the processing conditions are mild, and the whole process is not contacted with an organic solvent. Drug release is achieved by loading PTH in a polymeric material that swells upon contact with body fluids. PTH, as a macromolecular protein drug, is not stable, and the administration route is still limited to injection, and the frequent administration causes great inconvenience. PTH microneedles can greatly reduce such pain due to injection, and at the same time, exhibit great advantages in many aspects such as safety and cost, and can provide a better route of administration for PTH.

Description

Preparation method of parathyroid hormone microneedle
Technical Field
The invention belongs to the technical field of transdermal drug delivery systems, and relates to a preparation method of parathyroid hormone (PTH) microneedles, which is a preparation method of PTH microneedles for delivering drugs into a body in a mode of transdermal attachment of the microneedles.
Background
PTH has the primary function of regulating calcium and phosphorus metabolism in vertebrates, and contributes to elevated blood calcium levels and reduced blood phosphorus levels. At present, PTH is used as a macromolecular protein drug, and the stability is poor, so that the administration route is only limited to injection administration, and the administration frequency is frequent, which causes great inconvenience. PTH microneedles can greatly reduce such pain due to injection, and at the same time, exhibit great advantages in many aspects such as safety and cost, and can provide a better route of administration for PTH.
The micro-needle is a small needle dot matrix with the length less than 1mm, and the micro-needle can only pierce the horny layer of the skin without touching the dermis, so that pain sensation can not be generated, and skin injury can not be caused. The research on the soluble microneedle, the hydrogel microneedle and the responsive microneedle is numerous, but the soluble microneedle can cause the deposition of microneedle materials in the skin and is not suitable for frequent administration, the responsive microneedle needs a large amount of oxidase and has low bioavailability, and the hydrogel microneedle can cause drug inactivation by adopting a chemical crosslinking method to cause low bioavailability, so that the bioavailability is remarkably improved by adopting a hydrogel freezing, thawing and physical crosslinking method. Materials for preparing microneedles include metals, single crystalline silicon, polymers, ceramics, etc., wherein the polymeric polysaccharide is selected from alcohols, sodium carboxymethyl cellulose, dextran, hyaluronic acid, chitosan, polyethylene glycol, etc.
It was found through a search of the prior patent literature that the inventive patent application of CN108135837 discloses a zinc composition for coating a microneedle array; wherein the zinc compound is selected from the group consisting of zinc, pharmaceutically acceptable zinc salts, and mixtures thereof, the composition comprising a therapeutically active amount of an active agent; at least a portion of the composition is present as a coating on at least a portion of the microneedles; and said active agent is selected from the group consisting of hGH, TPA, CGRP, LHRH analogs, gonadorelin and nafarelin, pro-tocols, hMG, hGG, vasopressin, desmopressin, insulin, ACTH and its analogs, calcitonin, PTH antagonists, PTHrP, oxytocin, and the like. However, coated microneedles are low in drug loading and are not able to control and sustain release of the drug.
CN103889497 patent application discloses a microneedle fusion method which provides a microneedle array in which a drug is held only at the tip of a microneedle, and in the preparation, a) a microneedle array 2 is prepared using a water-soluble polymer as a material, b) a drug solution 1 to be fused to the tip of the microneedle array 2 is prepared, and c) the tip of the microneedle array 2 is brought into contact with the drug solution 1 for a short time. The main component of the water-soluble polymer in the drug solution is the same as the main component of the water-soluble polymer that is the material of the microneedle array. However, the drug can only be loaded on the surface of the micro-needle in this way, and the controlled release and the sustained release of the drug cannot be realized.
Disclosure of Invention
The invention aims to provide a preparation method of parathyroid hormone microneedle, aiming at the problems of inconvenience, safety, cost and the like caused by frequent injection of PTH. The present invention provides another administration mode of PTH (transdermal administration of PTH), which is a microneedle patch that can deliver PTH into the body by transdermal attachment.
The purpose of the invention is realized by the following technical scheme:
the present invention relates to a microneedle patch,
a) contains a PTH which is a component of a high-density polyethylene,
b) polyvinyl alcohol is used as a main micro-needle forming material,
c) polyvinyl alcohol is used as a backing film forming material for supporting the microneedle array.
As an embodiment of the present invention, the microneedle constituent material further includes other hydrophilic polymer materials.
The other hydrophilic polymer material is selected from alcohol, sodium carboxymethylcellulose, dextran, hyaluronic acid, chitosan, and polyethylene glycol.
As one embodiment of the present invention, the mass fraction of PTH in the microneedle constituent material is between 0.5% and 1.2%. The mass fraction range of polyvinyl alcohol in the microneedle component material is 20-70%, dextran is 5-10%, sodium carboxymethylcellulose is 1-20%, and the balance is water.
The invention also relates to a preparation method of the microneedle patch, which comprises the following steps:
a) preparing a polymer solution containing PTH as a microneedle constituent material;
b) casting the PTH-containing polymer solution onto a mold having an array of micro-holes;
c) coating a polyvinyl alcohol adhesion layer on the mould;
d) attaching a prefabricated backing layer to the back of the cast microneedle;
e) removing the mold after freezing and thawing;
f) the microneedle patch was dried.
As an embodiment of the present invention, in step b), the mold with the micro pore array is a hydrophobic polymer mold having a micro pore structure that is air-permeable and water-impermeable.
As an embodiment of the present invention, in step b), the casting includes placing the mold on a vacuum tank and sucking the polymer solution into micro-pin holes.
As an embodiment of the invention, in step d), the backing layer is prepared by casting the polymer solution onto a horizontal plate, freezing and thawing at least once and then curing.
As an embodiment of the invention, in the step e), the freezing temperature is-20 to-80 ℃ for 2 to 96 hours, the thawing temperature is 0 to 40 ℃ for 1 to 30 hours; the drying temperature in the step f) is-2-50 ℃, and the drying time is 1-96 hours.
As an embodiment of the present invention, in step f), the length of the microneedle after drying is 100-.
Compared with the prior art, the invention has the following beneficial effects:
1) the back lining layer is prepared by adopting the polymer solution which is the same as the needle point, and the polyvinyl alcohol is used as the back lining film forming material for supporting the micro-needle lattice, so that the back lining layer is tightly combined with the needle point of the micro-needle, the back lining film and the needle point can be consistently separated from the mould when the film is uncovered, and the problem of needle breakage can not occur in the process;
2) the hyaluronic acid is selected, so that the swelling capacity of the prescription is improved, and the drug release rate and the transdermal absorption efficiency of the drug are improved;
drawings
Other features, objects and advantages of the invention will become more apparent upon reading of the detailed description of non-limiting embodiments with reference to the following drawings:
fig. 1 is a flow chart of PTH microneedle preparation;
fig. 2 is a mold picture of PTH microneedles;
fig. 3 is a film uncovering picture of PTH microneedles;
fig. 4 is a photomicrograph of PTH microneedles after drying;
fig. 5 is a cumulative release profile of PTH microneedles;
fig. 6 is the drug loading uniformity of PTH microneedles.
Detailed Description
The present invention will be described in detail with reference to examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that it would be apparent to those skilled in the art that several modifications and improvements can be made without departing from the inventive concept. All falling within the scope of the present invention.
1. Polymeric materials for microneedles
The PVA polymer material adopted by the invention has wide application in the field of pharmacy and good skin compatibility. The PVA aqueous solution can be solidified into gel after freezing-unfreezing circulation, and the more the circulation times, the higher the crosslinking degree of the gel.
2. Principle and material requirement for filling micropores
The filling micropores utilize the principle of pressure difference, and can adopt vacuum-pumping or centrifugal operation.
The mold material is a hydrophobic polymer mold with a micropore array and has a gas-permeable and water-impermeable micropore structure. Due to air permeability, the polymer solution can be filled in the micropores only when the vacuum pumping is carried out; secondly, the mold material should be hydrophobic to avoid the microneedles from sticking to the mold and damaging the needle shape when separating the microneedles from the mold. In the present invention we use a polytetrafluoroethylene mold material.
In the invention, in order to better separate the microneedles from the mold, the backing layer is prepared by polyvinyl alcohol solution (10-35%), and polyvinyl alcohol is used as a backing film forming material for supporting the microneedle array, so that the backing layer is tightly combined with the tips of the microneedles, the backing film and the tips of the microneedles can be uniformly separated from the mold when the film is uncovered, and the problem of broken needles cannot occur in the process.
Pictures of PTH microneedles, approximately 900 μm in length, are disclosed in the present invention, see figure 4.
3. Microneedle strength
The dried micro-needle has stronger hardness and can penetrate through the stratum corneum of the skin, and after contacting and absorbing body fluid, the micro-needle material can swell and not dissolve, thereby forming a diffusion channel of the medicament and realizing the release of PTH.
In the invention, the drug loading of PTH microneedles is measured, and the difference of the drug loading of the microneedles is within an allowable range.
Specific examples are shown in the following examples:
example 1 preparation of PTH microneedles Using PVA, CMC-Na and Dextran as materials
Fig. 1 discloses a process for preparing PTH microneedles, which comprises pouring a polymer solution onto a mold having a pore array, filling the pores with the polymer solution, thawing the polymer solution by freezing, removing the film, and drying to obtain PTH microneedles. The method comprises the following specific steps:
first, a mixed aqueous solution of a PVA aqueous solution (10 to 30%, w/w, 15% in this example) and CMC-Na (3 to 10%, w/w sodium carboxymethylcellulose, 5% in this example) and Dextran (3 to 10%, w/w, 7% in this example) was prepared, and PTH and the two solutions were thoroughly mixed in a certain ratio (mass ratio 1/6/3 of the PTH, PVA aqueous solution, Dextran and sodium carboxymethylcellulose mixed aqueous solution). Then pouring the prepared liquid medicine on a polytetrafluoroethylene mold (as shown in figure 2) with a micropore array (which can be array diameter of 600-800um, microneedle height of 1.0-3.0mm, and spacing between needle point and needle point of 900um-5 mm; as an example, array diameter of 660um, microneedle height of 1.2mm, and spacing between needle point and needle point of 950um in this embodiment), vacuumizing the back of the mold to fill the liquid medicine into micropores, taking a little PVA solution, thinly coating the PVA solution on the surface of the mold which is fully absorbed with the needle point layer solution, then paving a backing layer (thickness of 500um-10mm, in this embodiment, 600um) prepared by PVA polymer solution (concentration of 12% -30%, in this embodiment, 18%), freezing and thawing the mold and the backing layer together (thickness of 600um, freezing for 8 hours), thawing at 4 ℃ for 5 hours), and varying the number of cycles (e.g., 1-5), the degree of crosslinking of the PVA can be adjusted. After the freezing and unfreezing, the micro-needle with the back lining layer is separated from the mold, and finally the micro-needle is dried. The microneedle after uncovering the membrane is shown in figure 3; as can be seen from fig. 3, the microneedles are needle-shaped intact and have no broken needles.
Comparative example 1 preparation of PTH microneedles Using PVA, HA and Dextran as materials
First, a PVA aqueous solution (16%, w/w) and a mixed aqueous solution of HA (3%) and Dextran (2.5%, w/w) were prepared, and PTH and the two solutions were thoroughly mixed in a certain ratio (mass ratio of the PTH, PVA aqueous solution, Dextran and HA mixed aqueous solution was 0.8/6.5/2.5). Then pouring the prepared liquid medicine on a polytetrafluoroethylene mould with a micropore array (the array diameter is 660um, the height of a microneedle is 1.2mm, and the distance between a needle point and the needle point is 950um), vacuumizing the back of the mould to fill the liquid medicine into the micropore, taking a small amount of PVA solution, thinly coating the PVA solution on the surface of the mould which is fully absorbed with the needle point layer solution, then paving a back lining layer (the thickness is 600um) prepared by PVA polymer solution (the concentration is 18%), and then carrying out freezing and unfreezing on the mould carrying the liquid medicine and the back lining layer together for (-20 ℃, freezing for 8 hours, unfreezing at 4 ℃, 5 hours) and different circulation times (such as 2 times) to adjust the crosslinking degree of the PVA. After the freezing and unfreezing, the micro-needle with the back lining layer is separated from the mold, and finally the micro-needle is dried. The microneedle after uncovering the membrane has incomplete needle shape and broken needles.
Comparative example 2 preparation of PTH microneedles Using PVA and HA as materials
Firstly, preparing a PVA aqueous solution (16 percent, w/w) and hyaluronic acid (2 percent), and fully and uniformly mixing PTH and the two solutions according to a certain proportion (the mass ratio of the PTH to the PVA to the HA aqueous solution is 1.5/7.5/2.5). Then pouring the prepared liquid medicine on a polytetrafluoroethylene mold with a micropore array (the array diameter is 660um, the height of a microneedle is 1.2mm, and the distance between a needle point and the needle point is 950um), vacuumizing the back of the mold to fill the liquid medicine into the micropore, taking a small amount of PVA solution, thinly coating the PVA solution on the surface of the mold which is fully absorbed with the needle point layer solution, then paving a back lining layer (the thickness is 500um-10mm, in the embodiment, 600um is selected) prepared by adopting PVA polymer solution (the concentration is 18%), then freezing and unfreezing the mold and the back lining layer which are loaded with the liquid medicine together for (-20 ℃, freezing for 8 hours, unfreezing at 4 ℃, 5 hours), and carrying out 2 times of circulation, so that the crosslinking degree of the PVA can be adjusted. After the freezing and unfreezing, the micro-needle with the back lining layer is separated from the mold, and finally the micro-needle is dried. The microneedle after uncovering the membrane has incomplete needle shape and broken needles.
Comparative example 3 preparation of PTH microneedle made of PVA and chitosan
Firstly, preparing a PVA aqueous solution (16 percent, w/w) and chitosan (2 percent), and fully and uniformly mixing PTH and the two solutions according to a certain proportion (the mass ratio of the PTH to the PVA to the chitosan is 1.5/7.5/2.5). Then pouring the prepared liquid medicine on a polytetrafluoroethylene mold with a micropore array (the array diameter is 660um, the height of a microneedle is 1.2mm, and the distance between a needle point and the needle point is 950um), vacuumizing the back of the mold to fill the liquid medicine into the micropore, taking a small amount of PVA solution, thinly coating the PVA solution on the surface of the mold which is fully absorbed with the needle point layer solution, then paving a back lining layer (the thickness is 500um-10mm, in the embodiment, 600um is selected) prepared by adopting PVA polymer solution (the concentration is 18%), then freezing and unfreezing the mold and the back lining layer which are loaded with the liquid medicine together for (-20 ℃, freezing for 8 hours, unfreezing at 4 ℃, 5 hours), and 3 times of circulation, so that the crosslinking degree of the PVA can be adjusted. After the freezing and unfreezing, the micro-needle with the back lining layer is separated from the mold, and finally the micro-needle is dried. The microneedle after uncovering the membrane has incomplete needle shape and broken needles.
Example 2 release kinetics of PTH microneedles
To examine the release of PTH, the microneedles prepared above were placed in a Franz diffusion cell apparatus in PBS at pH 7.4, stirred at 37 ℃ at 100rpm, the tips of the microneedles were covered with a plastic film, sampled periodically, and the PTH concentration was measured using a PTH-ELISA kit. Through calculation, a PTH cumulative release curve is obtained, and the result is shown in FIG. 5; as can be seen in figure 5, the release process is smooth.
Example 3 drug Loading uniformity test of PTH microneedles
PTH microneedles PTH were loaded in polymer solution and we examined the uniformity of drug loading of the microneedles in order to verify the uniformity of PTH dispersion in the solution. Placing three microneedles in PBS buffer solution with pH of 7.4, respectively, placing in 37 → water bath shaker for 3h, shaking uniformly, collecting leachate, and measuring the leachate of the microneedles by using PTH-ELISA kit to obtain results shown in FIG. 6; as can be seen from fig. 6, the uniformity of the drug loading was good.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.

Claims (10)

1. A microneedle patch characterized by comprising a microneedle array sheet,
a) contains a PTH which is a component of a high-density polyethylene,
b) polyvinyl alcohol is used as a main micro-needle forming material,
c) polyvinyl alcohol is used as a backing film forming material for supporting the microneedle array.
2. The microneedle patch according to claim 1, wherein said microneedle constituent material further comprises another hydrophilic polymer material.
3. The microneedle patch according to claim 2, wherein said other hydrophilic polymer material is selected from the group consisting of alcohol, sodium carboxymethyl cellulose, dextran, hyaluronic acid, chitosan, polyethylene glycol.
4. The microneedle patch according to claim 1, wherein a mass fraction of PTH in said microneedle constituent material is between 0.5% and 1.2%.
5. A method of manufacturing a microneedle patch according to any one of claims 1 to 4, comprising the steps of:
a) preparing a polymer solution containing PTH as a microneedle constituent material;
b) casting the PTH-containing polymer solution onto a mold having an array of micro-holes;
c) coating a polyvinyl alcohol adhesion layer on the mould;
d) attaching a prefabricated backing layer to the back of the cast microneedle;
e) removing the mold after freezing and thawing;
f) the microneedle patch was dried.
6. The method for preparing a microneedle patch according to claim 5, wherein in step b), the mold having the micropore array is a hydrophobic polymer mold having a pore structure that is air-permeable and water-impermeable.
7. The method of preparing a microneedle patch according to claim 5, wherein the casting in step b) comprises placing a mold on a vacuum tank and sucking the polymer solution into a pinhole.
8. The method for preparing a microneedle patch according to claim 5, wherein the backing layer is prepared by casting the polymer solution onto a horizontal plate, freezing and thawing at least once, and then solidifying in step d).
9. The method for preparing a microneedle patch according to claim 5, wherein in step e), the freezing temperature is-20 to-80 ℃ for 2 to 96 hours, the thawing temperature is 0 to 40 ℃ for 1 to 30 hours; the drying temperature in the step f) is-2-50 ℃, and the drying time is 1-96 hours.
10. The method for preparing a microneedle patch according to claim 5, wherein the length of the dried microneedle in step f) is 100-1000 μm.
CN202011519526.2A 2020-12-21 2020-12-21 Preparation method of parathyroid hormone microneedle Pending CN112641932A (en)

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Publication number Priority date Publication date Assignee Title
CN109010258A (en) * 2018-08-30 2018-12-18 上海交通大学 A kind of preparation method of epiphysin micropin patch
CN110270007A (en) * 2019-07-15 2019-09-24 上海交通大学 One kind supporting biomolecule micropin and preparation method thereof

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* Cited by examiner, † Cited by third party
Title
朱嗣文等: "艾塞那肽相转化微针的制备及处方优化", 《中国医药工业杂志》 *

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