CN116236437A - Micro-needle patch taking osmotic pressure as power and preparation method thereof - Google Patents

Micro-needle patch taking osmotic pressure as power and preparation method thereof Download PDF

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Publication number
CN116236437A
CN116236437A CN202211448633.XA CN202211448633A CN116236437A CN 116236437 A CN116236437 A CN 116236437A CN 202211448633 A CN202211448633 A CN 202211448633A CN 116236437 A CN116236437 A CN 116236437A
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osmotic pressure
powered
microneedle
drug
osmotic
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顾臻
俞计成
张宇琪
赵升
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Zhejiang University ZJU
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Zhejiang University ZJU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K38/38—Albumins
    • A61K38/385—Serum albumin
    • 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
    • A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
    • 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
    • A61M2037/0023—Drug applicators using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

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  • Health & Medical Sciences (AREA)
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  • Dermatology (AREA)
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  • Pharmacology & Pharmacy (AREA)
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Abstract

The invention discloses a micro-needle patch with osmotic pressure as power and a preparation method thereof, wherein the micro-needle patch with osmotic pressure as power can be carried and used, and the micro-needle patch with osmotic pressure as power comprises: an osmotic pressure pharmacokinetic unit, a liquid compartment, and a microneedle array. The osmotic pressure medicine power unit comprises an osmotic pressure regulating tablet core and a semipermeable membrane, wherein the osmotic pressure regulating tablet core is in direct contact with the semipermeable membrane; the liquid chamber is communicated with the osmotic pressure medicine power unit and can convey liquid to the osmotic pressure medicine power unit; the microneedle array is communicated with the osmotic pressure medicine power unit and comprises a plurality of hollow microneedles, and the hollow microneedles are provided with a plurality of microperforations on the top end and/or the side wall. The invention can make the administration mode more accurate, efficient, lower in frequency and more comfortable, thereby meeting the requirements of people on the accurate, low-frequency and comfortable subcutaneous administration mode.

Description

Micro-needle patch taking osmotic pressure as power and preparation method thereof
The present application claims priority from chinese patent application 2021114863641, whose filing date is 2021, 12, 07. The present application refers to the entirety of this chinese patent application.
Technical Field
The invention relates to the field of medical instruments, in particular to a microneedle patch taking osmotic pressure as power and a preparation method thereof.
Background
With the development of society and the improvement of medical level, people's attention to health is unprecedented. The traditional modes of intravenous, subcutaneous, intramuscular and the like which need multiple long-term administration cannot meet the requirements of patients on improving the drug effect, having few side effects and high-efficiency treatment and high-quality life. Although there are various modes of administration in the prior art, such as conventional injections, pre-flush injections, needleless injections, and automatic first-aid injection needles. These modes of administration are effective in certain situations, but still do not meet the needs of people for accurate, efficient, low frequency, comfortable modes of administration.
Disclosure of Invention
The invention aims to overcome the defect that the drug delivery mode in the prior art cannot meet the requirements of people on accuracy, high efficiency, low frequency and comfort, and provides a microneedle patch taking osmotic pressure as power and a preparation method thereof.
The invention solves the technical problems by the following technical scheme:
an osmotic pressure powered microneedle patch that can be carried around for use, the osmotic pressure powered microneedle patch comprising: an osmotic pressure pharmacokinetic unit, a liquid compartment, and a microneedle array. The osmotic pressure medicine power unit comprises an osmotic pressure regulating tablet core and a semipermeable membrane, and the osmotic pressure regulating tablet core is in direct contact with the semipermeable membrane; the liquid chamber is communicated with the osmotic pressure medicine power unit, and can convey liquid to the osmotic pressure medicine power unit; the micro-needle array is communicated with the osmotic pressure medicine power unit and comprises a plurality of hollow micro-needles, and a plurality of micro-needle holes are formed in the top end and/or the side wall of each hollow micro-needle.
In this scheme, adopt above-mentioned structural style, can make osmotic pressure be miniaturized, convenient practicality of microneedle paster of power, a plurality of microperforations holes of seting up on hollow microneedle's the lateral wall can very big regulation and control medicine release rate and position, reduce the gathering of local medicine, realize the long-term uniform release of medicine, do benefit to subcutaneous absorption, make the mode of dosing more accurate, high-efficient, the frequency is lower, more comfortable to can satisfy people to accurate, low frequency, comfortable subcutaneous mode of dosing's demand.
Preferably, the inner diameter of the hollow microneedle is tapered in a direction away from the osmotic pressure pharmacokinetic unit.
In this scheme, adopt above-mentioned structural style, can provide the maintenance of whole osmotic pressure for osmotic pressure dynamic microneedle paster to and can provide mechanical strength in order to pierce the skin with the microneedle smoothly for the microneedle.
Preferably, the microperforations are uniformly distributed along the axial direction of the hollow microneedle.
In the scheme, the structure is adopted, so that aggregation of local medicines can be further reduced, long-acting and uniform release of the medicines is realized, and subcutaneous absorption is facilitated.
Preferably, the osmotic pressure powered microneedle patch further comprises a filtration unit disposed between the osmotic pressure pharmacokinetic unit and the microneedle array.
In the scheme, the liquid entering the microneedle array can be filtered by adopting the structure, so that large particles in the osmotic pressure medicament power unit can be prevented from jamming the hollow microneedles, and normal release of medicaments is ensured.
Preferably, the osmotic pressure powered microneedle patch further comprises a rapid response channel, the rapid response channel is arranged in the osmotic pressure regulating tablet core, the rapid response channel is filled with an osmotic agent, and the rapid response channel is arranged below the semipermeable membrane and is communicated with the microneedle array above the filter unit.
In the scheme, the reaction time of the medicine and the liquid can be shortened by adopting the structural form, so that the medicine can enter the microneedle array from the osmotic pressure medicine power unit more quickly, and the waiting time is reduced.
Preferably, the semipermeable membrane is arranged above and/or around the osmotic drug power unit, an osmotic pressure difference is generated across the semipermeable membrane, the semipermeable membrane allowing the liquid in the liquid chamber to flow into the osmotic drug power unit but not allowing the substance in the osmotic drug power unit to flow back into the liquid chamber.
In the scheme, the structure is adopted, so that the liquid can only flow from the liquid chamber to the osmotic pressure medicine power unit but cannot flow reversely, and subcutaneous medicine administration can be successfully completed.
Preferably, the osmotic pressure pharmacokinetic unit comprises: the medicine layer is capable of containing small molecule medicines, polypeptides, proteins, gene medicines and/or cells, viruses and bacteria; the elastic membrane is arranged at the upper end of the medicine layer, and can push out medicine of the medicine layer through the hollow micro-needle; the boosting layer is arranged at the upper end of the elastic membrane and is communicated with the liquid chamber, and the boosting layer can absorb thrust generated by water expansion to push the elastic membrane.
In the scheme, the liquid in the medicine layer can be pushed out of the osmotic pressure medicine power unit more quickly by adopting the structural form, so that the waiting time is reduced.
Preferably, the semipermeable membrane is arranged around the osmotic pressure drug power unit, an osmotic pressure difference is generated on two sides of the semipermeable membrane, and the semipermeable membrane allows the liquid in the liquid chamber to flow into the osmotic pressure drug power unit, but does not allow the substance of the osmotic pressure drug power unit to flow into the liquid chamber reversely.
In this scheme, adopt above-mentioned structural style, can accelerate the rate that liquid in the liquid room is to osmotic pressure medicine power unit infiltration, can also guarantee simultaneously that liquid can only flow from the liquid room to osmotic pressure medicine power unit, but can not reverse flow to make subcutaneous administration can accomplish smoothly.
Preferably, the hollow microneedles have an inner diameter of 100 nm to 400 microns, an outer diameter of 10 microns to 600 microns, and a length of 100 microns to 2000 microns.
In this scheme, adopt above-mentioned structural style, can reduce the thickness of whole osmotic pressure as the microneedle paster of power, do benefit to the laminating of actual skin, improve comfort and reliability.
Preferably, the osmotic pressure powered microneedle patch further comprises a liquid feeding system, wherein the liquid feeding system is communicated with the liquid chamber, the liquid feeding system can supply liquid to the liquid chamber, and an osmotic pressure regulating solution of the liquid feeding system is a gradient solution.
In the scheme, the structure is adopted, so that various liquids required by the micro-needle patch work with osmotic pressure as power can be supplemented to the liquid chamber through the liquid feeding system outside, and the applicability of the micro-needle patch with osmotic pressure as power is improved.
Preferably, the liquid chamber comprises an anti-reflux device capable of preventing liquid from flowing back from the liquid chamber to the liquid supply system.
In the scheme, by adopting the structure, the anti-reflux device can prevent liquid from flowing back to the liquid feeding system from the liquid chamber, so that the drug feeding process can be smoothly completed.
A method of preparing an osmotically powered microneedle patch for use in the manufacture of an osmotically powered microneedle patch as described above, the method comprising:
step 1: preparing the microneedle array and the osmotic pressure pharmacokinetic unit;
step 2: the microneedle array is communicated and spliced with the osmotic pressure drug power unit;
step 3: and the liquid chamber is communicated and spliced with the osmotic pressure medicine power unit.
In the scheme, the whole preparation process is simple and has strong operability.
Preferably, in step 1, a step of preparing a drug layer is further included, and a step of disposing the drug layer inside or below the osmotic pressure pharmacokinetic unit.
Preferably, step 1 further comprises the step of preparing a filtration unit and the step of disposing the filtration unit between the osmotic drug power unit and the microneedle array.
The invention has the positive progress effects that: the micro-needle patch taking osmotic pressure as power is small in size, convenient and practical, the drug release rate and the position can be greatly regulated and controlled by a plurality of micro-needle holes formed in the side wall of the hollow micro-needle, the aggregation of local drugs is reduced, the long-acting uniform release of the drugs is realized, subcutaneous absorption is facilitated, the drug delivery mode is more accurate, efficient, lower in frequency and more comfortable, and accordingly the requirements of people on the accurate, low-frequency and comfortable subcutaneous drug delivery mode can be met.
Drawings
Fig. 1 is a full cross-sectional view of an osmotically powered microneedle patch according to an embodiment of the present invention.
Fig. 2 is a full cross-sectional view of a hollow microneedle of an osmotically powered microneedle patch according to an embodiment of the present invention.
Fig. 3 is a top view of an osmotically powered microneedle patch according to an embodiment of the present invention.
Fig. 4 is a bottom view of an osmotically powered microneedle patch according to an embodiment of the present invention.
Fig. 5 is a full cross-sectional view of an osmotically powered microneedle patch according to an embodiment of the present invention.
Fig. 6 is a full cross-sectional view of a two-osmotically powered microneedle patch according to an embodiment of the present invention.
Fig. 7 is a schematic diagram of the structure and assembly of a four-class osmotically powered microneedle patch according to an embodiment of the present invention.
Fig. 8 is a photograph of a microneedle structure of a four-category osmotic pressure powered microneedle patch according to an embodiment of the present invention.
Figure 9 is a schematic illustration of a four-osmotically powered microneedle patch semipermeable membrane according to an embodiment of the present invention.
Fig. 10 shows the release profile of a four-loaded simulated drug (food coloring brilliant blue, P) osmotically powered microneedle patch according to an embodiment of the present invention.
Fig. 11 shows the release profile of a four-loaded simulated drug (food coloring brilliant blue, P) osmotically powered microneedle patch according to example four of the present invention.
Fig. 12 shows the release profile of a four-loaded simulated drug (food coloring brilliant blue, P) osmotically powered microneedle patch according to example four of the present invention.
Fig. 13 is a graph showing the release profile of an osmotically powered microneedle patch loaded with drug (cytarabine) according to example four of the present invention.
Figure 14 is a graph showing the release profile of an osmotically powered microneedle patch loaded with drug (cytarabine) according to example four of the present invention.
FIG. 15 is a graph showing the release profile of an osmotically powered microneedle patch loaded with Bovine Serum Albumin (BSA) according to example four of the present invention.
FIG. 16 shows drug release performance of a drug-loaded (cytarabine) osmotically-powered microneedle patch according to example four of the present invention in rats.
Reference numerals illustrate:
liquid chamber 1
Semipermeable membrane 2
Osmotic pressure drug power unit 3
Hollow microneedle 4
Liquid supply system 5
Side wall 6
Micropin holes 7
Top cover 8
Fast response channel 10
Microneedle array 11
Boosting layer 12
Elastic membrane 13
Drug layer 14
Detailed Description
The invention is further illustrated by means of examples which follow, without thereby restricting the scope of the invention thereto.
Example 1
As shown in fig. 1-5, the present embodiment provides a microneedle patch with osmotic pressure as power, which uses osmotic pressure as power, and has a smaller volume, and adopts a miniaturized and light-weight design, so that the microneedle patch can be carried and used with a user, and comprises an osmotic pressure drug power unit 3, a liquid chamber 1 and a microneedle array 11. The osmotic pressure medicine power unit 3 comprises an osmotic pressure regulating tablet core and a semipermeable membrane 2, the semipermeable membrane 2 has selective water permeability and rigidity, the osmotic pressure regulating tablet core is in direct contact with the semipermeable membrane 2, and a cavity inside the osmotic pressure regulating tablet core can contain medicines or other substances; the liquid chamber 1 is communicated with the osmotic pressure medicine power unit 3, and the liquid chamber 1 can convey liquid to the osmotic pressure medicine power unit 3; the microneedle array 11 is in communication with the osmotic pressure drug power unit 3, the microneedle array 11 can generate micropores to release drugs and enhance drug delivery, the microneedle array 11 comprises a plurality of hollow microneedles 4, and a plurality of microperforations 7 are formed in the side walls 6 of the hollow microneedles 4, and of course, those skilled in the art will understand that the microperforations 7 can also be provided at the tips of the microneedles.
In this embodiment, a plurality of microperforations 7 formed on the side wall 6 of the hollow microneedle 4 can greatly regulate and control the drug release rate and position, reduce the aggregation of local drugs, realize the long-acting uniform release of the drugs, facilitate the subcutaneous absorption, make the subcutaneous administration mode more accurate, the frequency lower, more comfortable, thereby can satisfy the needs of people for accurate, low-frequency and comfortable subcutaneous administration modes.
As shown in fig. 1-2, the inner diameter of the hollow microneedles 4 gradually decreases in a direction away from the osmotic pressure pharmacokinetic unit 3, and in other embodiments, the hollow microneedles 4 may be cylindrical in shape.
In this embodiment, the hollow microneedle 4 is generally tapered with a hollow interior, the sidewall 6 of the tapered space can provide maintenance of the entire osmotic pressure for the microneedle patch powered by the osmotic pressure, and the tapered spike can provide mechanical strength for the microneedle, so that the microneedle can be successfully penetrated into the skin.
As shown in fig. 1-2, micropins 7 are uniformly distributed along the axial direction of hollow microneedle 4, e.g., micropins 7 are uniformly spread in parallel over the sidewall 6 of the tapered microneedle.
In this embodiment, the micro needle holes 7 uniformly distributed on the side wall 6 of the taper needle can further reduce a certain part of the medicine in the aggregation micro needle, which is more beneficial to realizing long-acting uniform release of the medicine and subcutaneous absorption.
As shown in fig. 1-2, the osmotic pressure powered microneedle patch further comprises a filter unit disposed between the osmotic pressure drug power unit 3 and the microneedle array 11.
In this embodiment, the filtration unit can filter the liquid entering the microneedle array 11, so that large particles in the osmotic pressure drug power unit 3 can be prevented from jamming the hollow microneedles 4, and normal release of the drug can be ensured.
As shown in fig. 1-5, the micro-needle patch with osmotic pressure as power further comprises a fast response channel 10 with a hollow structure, wherein the fast response channel 10 is arranged in the osmotic pressure regulating tablet core, the fast response channel 10 is filled with an osmotic agent which absorbs water rapidly and dissolves, and the fast response channel 10 is arranged above the micro-needle array 11 and is communicated with the micro-needle array 11.
In this embodiment, the rapid response channel 10 and the osmotic agent are configured to accelerate the reaction time between the drug and the liquid, so that the drug can enter the microneedle array 11 from the osmotic pressure drug power unit 3 more quickly, and the waiting time is reduced.
As shown in fig. 1-5, the microneedle patch with osmotic pressure as power further comprises a semipermeable membrane 2 made of cellulose acetate, wherein the semipermeable membrane 2 is arranged above the osmotic pressure drug power unit 3, and in other embodiments, the semipermeable membrane 2 can also be arranged around the osmotic pressure drug power unit 3, and an osmotic pressure difference is generated on two sides of the semipermeable membrane 2, so that the semipermeable membrane 2 allows the liquid in the liquid chamber 1 to flow into the osmotic pressure drug power unit 3, but does not allow the substance in the osmotic pressure drug power unit 3 to flow reversely into the liquid chamber 1.
In the present embodiment, the semipermeable membrane 2 allowing only one-way permeation can ensure that the liquid can only flow from the liquid chamber 1 to the osmotic pressure drug power unit 3, but cannot flow in the reverse direction, thereby enabling the subcutaneous administration to be smoothly completed.
As shown in fig. 1 to 5, the inner diameter of the hollow microneedle 4 is 100 nm to 400 μm, the outer diameter of the hollow microneedle 4 is 10 μm to 600 μm, and the length of the hollow microneedle 4 is 100 μm to 2000 μm.
In this embodiment, the size of the hollow microneedle 4 is limited to the above range, so that the thickness of the microneedle patch using osmotic pressure as power can be reduced, the actual skin fitting can be facilitated, and the comfort and reliability can be improved.
As shown in fig. 1-5, the osmotic pressure powered microneedle patch further comprises a top cover 8 and a fluid supply system 5, the fluid supply system 5 being disposed on the top cover 8 and in communication with the fluid chamber 1, the fluid supply system 5 being capable of supplying fluid to the fluid chamber 1.
In this embodiment, the design of the liquid supply system 5 can supplement various liquids required for the operation of the osmotic pressure powered microneedle patch to the liquid chamber 1 through the liquid supply system 5 from the outside, and improve the applicability of the osmotic pressure powered microneedle patch.
As shown in fig. 1-5, the liquid chamber 1 includes an anti-reflux device that prevents liquid from flowing back from the liquid chamber 1 to the liquid supply system 5.
In the present embodiment, the backflow preventing device can prevent the backflow of the liquid from the liquid chamber 1 back to the liquid feeding system 5, so that the administration process can be smoothly completed.
Example 2
The present embodiment also provides an osmotic pressure powered microneedle patch, which has a structure substantially the same as that of the osmotic pressure powered microneedle patch of embodiment 1, except that: as shown in fig. 6, the osmotic pressure drug power unit 3 includes a drug layer 14, the drug layer 14 changes the poorly soluble drug into suspension mainly by the inhalation of moisture, the dispersibility and fluidity of the drug are improved, and the drug layer 14 can also accommodate the drug itself in gel form, such as cells, viruses, bacteria, etc.; and an elastic membrane 13 provided at an upper end of the medicine layer 14 and capable of pushing out the medicine of the medicine layer 14 through the hollow microneedles 4. And the boosting layer 12 is arranged at the upper end of the elastic membrane 13 and is communicated with the liquid chamber 1, and the boosting layer 12 can push the elastic membrane 13 by the thrust generated by water absorption expansion.
In this embodiment, the addition of the boosting layer 12 and the elastic membrane 13 can push the drug in the drug layer 14 out of the microperforated holes 7 through the elastic membrane 13 by means of the thrust generated by the water absorption expansion of the boosting layer 12, so that the drug can be pushed out of the osmotic drug power unit 3 more quickly, and the waiting time is reduced.
As shown in fig. 1-5, the microneedle patch using osmotic pressure as power further comprises a semipermeable membrane 2 made of cellulose acetate, wherein the semipermeable membrane 2 is arranged around the osmotic pressure drug power unit 3, and an osmotic pressure difference is generated on two sides of the semipermeable membrane 2, so that the semipermeable membrane 2 allows the liquid in the liquid chamber 1 to flow into the osmotic pressure drug power unit 3, but does not allow the substances in the osmotic pressure drug power unit 3 to flow into the liquid chamber 1 reversely.
In this embodiment, the above-mentioned structural form is adopted, so that the rate of permeation of the liquid in the liquid chamber 1 to the osmotic pressure drug power unit 3 can be increased, and meanwhile, the liquid can be ensured to flow from the liquid chamber 1 to the osmotic pressure drug power unit 3 only, but not to flow reversely, so that subcutaneous drug administration can be successfully completed.
Example 3
The embodiment provides a method for preparing a microneedle patch using osmotic pressure as power, which is used for preparing the microneedle patch using osmotic pressure as power, and comprises the following steps:
step 1: preparing a microneedle array 11 and an osmotic pressure drug power unit 3;
step 2: the microneedle array 11 is communicated and spliced with the osmotic pressure drug power unit 3;
step 3: the liquid chamber 1 is connected with the osmotic pressure medicine power unit 3 in a communicating way.
In this embodiment, a microneedle substrate is first prepared, and the microneedle substrate includes a microneedle array 11 and an osmotic pressure drug power unit 3, and is manufactured by a hollow microneedle 4 mold; subsequently, preparing the drug and osmotic agent tablets with or without inner ring channels, or directly adding compaction in situ (and may be drug-loaded gel); secondly, spraying a cellulose acetate film in situ, or paving a prefabricated semipermeable membrane 2; finally, the water feeding chamber and the water supply system are arranged, and the microneedle patch taking osmotic pressure of the osmotic pump as power is obtained. Meanwhile, in step 1, a step of preparing a drug layer and a step of disposing the drug layer inside or below the osmotic pressure drug power unit 3 are further included. And a step of preparing a filtration unit, and a step of disposing the filtration unit between the osmotic pressure drug power unit 3 and the microneedle array 11. The whole assembly process is simple, the operability is strong, the patch is thin, and comfortable, convenient and stable use is realized.
Example 4
This example uses the preparation method of example 3.
A process flow diagram of one type of method for preparing a microneedle patch with osmotic pressure as a motive force is shown in fig. 7. FIG. 7a is a schematic diagram of an assembled structure, divided into (1) a microneedle base, showing the microneedles as a 3-needle array; (2) the permeation and medicine carrying center adopts a hollow structure to improve the water transmission effect; (3) a semipermeable membrane, a prefabricated semipermeable membrane is paved; (4) the sealing ring adopts a semi-permeable membrane up-down symmetrical sealing design; (5) the cover Chu Shuishi is designed as a water injection cavity structure with a deformable top end film. FIG. 7 is a specific assembly process, wherein FIG. 7a is a schematic illustration of the fitting; fig. 7b is an assembled schematic view.
The micro-needle patch with osmotic pressure as power designed in fig. 7 is subjected to electron scanning microscope characterization, as shown in fig. 8, wherein fig. 8a and 8b show the shape and size of a micro-needle base 3-needle array stainless steel micro-needle, the length of the micro-needle is 1238+/-38 mu m, and the needle point is in an oblique angle structure; FIGS. 8c and 8d show the inside structure of the microneedle base with a needle pitch of 2mm, a pinhole inner diameter of 100 μm and a wall thickness of 50. Mu.m. Wherein the scale of the 8a graph is 300 μm; the scale bar of FIG. 8b is 300 μm; the scale of the 8c chart is 500 μm; the scale of the 8d plot is 30 μm.
The semipermeable membrane (3) used for the osmotically powered microneedle patch of fig. 7 is a preformed semipermeable membrane. As shown in fig. 9, fig. 9a is a schematic diagram of an acetic acid semipermeable membrane prepared in advance by a spray process, and fig. 9b is a physical diagram of the semipermeable membrane prepared in fig. 9 a. The semipermeable membrane preparation liquid selected by optimization is as follows: by adjusting the technical parameters of the spraying process, 310g of acetone, 9g of cellulose acetate, 5g of water and 0.75g of PEG-400, semipermeable membranes with adjustable surface roughness and membrane thickness can be obtained, and as shown in figures 9c and 9d, 100mL (i, low dose), 200mL (ii, medium dose) and 300mL (iii, high dose) of semipermeable membrane preparation solutions with different dosages are respectively utilized to obtain semipermeable membranes with different thicknesses, wherein the thicknesses of the semipermeable membranes are 13.99 mu m,42.81 mu m and 56.95 mu m respectively; in the patch assembly process, the process is optimized, so that the surface with larger roughness faces upwards to the water chamber, and the rough surface can improve the surface area of the surface to improve the water penetration efficiency. Wherein, FIG. 9a is a schematic diagram of a semipermeable membrane prepared by a spray method; FIG. 9b is a photograph of a semipermeable membrane prepared at a medium dose (200 mL of semipermeable membrane preparation); FIG. 9c is a scanning electron microscope picture of semipermeable membranes prepared at different doses; the scale of fig. 9c is: the graph i-iii is 20 μm; iv plot 25 μm; fig. 9d is a plot of the thickness statistics (n=6) of the semipermeable membranes obtained from different doses of the preparation.
One of the most important features of the osmotic pressure-powered patch is to control the release of the drug by using the osmotic pressure as the power, and after the osmotic pressure-powered patch shown in fig. 7 is assembled, the release performance of the osmotic pressure-powered patch is examined and optimized, as shown in fig. 10-15. In fig. 10, the in vitro release performance of the patch using the food color brilliant blue simulated drug (P), glucose+peg-4000+p (simulated drug 10%) as the permeation+drug center, and the semipermeable membrane ii (medium dose) were combined for monitoring, and it was found that the patch using osmotic pressure as the power can maintain the linear release effect for 24 hours, and the main release mode within 24 hours was determined to be zero-order release by combining the structural characteristics of the patch using osmotic pressure as the power. Wherein fig. 10 is a 200 milliliter release system, release was monitored at 630nm, and the thick solid line in fig. 10 is a linear fit line (n=5).
In addition, osmotic+drug center of the osmotically powered patch was adjusted. As shown in fig. 11 and 12, osmotic + drug centers were adjusted to either glucose + P (simulated drug 10%) or sodium chloride + P (simulated drug 10%), and osmotic pressure-powered patches exhibited zero order release for 24 hours, which was faster than glucose patches (fig. 12) due to sodium chloride bi-ionization (fig. 11). Wherein, fig. 11 is the release performance of the osmotic pressure-powered microneedle patch loaded with a simulated drug (food color brilliant blue, P), glucose+p (simulated drug 10%), semipermeable membrane ii (medium dose), 200ml release system, 630nm monitoring release, and the thick solid line in fig. 11 is a linear fit line (n=5); fig. 12 is the release performance of an osmotically powered microneedle patch loaded with a simulated drug (food color brilliant blue, P), sodium chloride+p (simulated drug 10%), semi-permeable membrane ii (medium dose), 200ml release system, 630nm monitoring release, and the thick solid line in fig. 12 is a linear fit line (n=5).
Osmotic pressure-powered patch permeation + drug center drug type and content changes are also one of the means of adjusting its release properties. As shown in fig. 13 and 14, the release performance of cytarabine (hydrochloride) drug is controlled by the type of osmotic agent and the drug loading rate of cytarabine, and the zero-order release time of the whole patch is increased along with the increase of the drug loading rate, wherein the zero-order release time of sodium chloride+cytarabine (20%) is 12 hours. Wherein, fig. 13 is the release performance of a drug-loaded (cytarabine) -osmotic-pressure-powered microneedle patch, sodium chloride+cytarabine (5% or 20%), semipermeable membrane is ii (medium dose), 200ml release system, 276nm monitored release, and the thick solid line in fig. 13 is a linear fit line (n=6); fig. 14 is the release profile of an osmotically powered microneedle patch loaded with drug (cytarabine), glucose+cytarabine (5% or 20%), semipermeable membrane ii (medium dose), 200ml release system, 276nm monitored release, and the thick solid line in fig. 14 is a linear fit line (n=6).
Unlike small molecule drugs, which have multiple effects on dissolution and diffusion behavior, the osmotic pressure-powered patch of fig. 7 also exhibits zero-order controlled release of the protein drug, as shown in fig. 15, the osmotic pressure-powered microneedle patch loaded with Bovine Serum Albumin (BSA) exhibits stable zero-order release performance throughout the release (14 hours) at a release rate different from that of the small molecule drug. Wherein figure 15 is glucose+bsa (20%), semipermeable membrane ii (medium dose), 100ml release system, 280nm monitored release. The thick solid line in the figure is a linear fit line (n=4).
The osmotically powered microneedle patch of fig. 7 was assembled by optimizing the choice of sodium chloride or glucose loading + cytarabine (10%) as the osmotic + drug center, combined with a semipermeable membrane for ii (medium dose). The performance of osmotic pressure-powered patches for drug release of cytarabine in rats was then monitored. As shown in fig. 16, both osmotically powered patches exhibited sustained and controlled release for up to 24 hours compared to subcutaneous injections, with the area under the curve of the sodium chloride + cytarabine patch being greater than the glucose + cytarabine microneedle patch. Compared with the oral osmotic tablet medicine, the patch with osmotic pressure as power shows similar blood concentration curve, so that the acting time and bioavailability of the medicine can be greatly improved. Wherein fig. 16 shows that the semipermeable membrane is ii (medium dose), the equivalent amount of cytarabine is subcutaneously injected as a control group, and the rat body weight in the experiment is 250-300 g, and the blood concentration (n=5) of the rat is monitored by high performance liquid chromatography (276 nm).
While specific embodiments of the invention have been described above, it will be appreciated by those skilled in the art that this is by way of example only, and the scope of the invention is defined by the appended claims. Various changes and modifications to these embodiments may be made by those skilled in the art without departing from the principles and spirit of the invention, but such changes and modifications fall within the scope of the invention.

Claims (14)

1. The utility model provides a osmotic pressure is microneedle paster of power, its characterized in that, osmotic pressure is microneedle paster of power can hand-carry the use, osmotic pressure is microneedle paster of power includes:
the osmotic pressure medicine power unit comprises an osmotic pressure regulating tablet core and a semipermeable membrane, wherein the osmotic pressure regulating tablet core is in direct contact with the semipermeable membrane;
a fluid chamber in communication with the osmotic pressure pharmacokinetic unit, the fluid chamber capable of delivering fluid to the osmotic pressure pharmacokinetic unit;
the micro-needle array is communicated with the osmotic pressure medicine power unit and comprises a plurality of hollow micro-needles, and a plurality of micro-needle holes are formed in the top end and/or the side wall of each hollow micro-needle.
2. The osmotically-powered microneedle patch of claim 1, wherein the inner diameter of the hollow microneedles tapers in a direction away from the osmotic pharmacokinetic unit.
3. The osmotically-powered microneedle patch of claim 2, wherein the microperforations are uniformly distributed along the axial direction of the hollow microneedles.
4. The osmotically-powered microneedle patch of claim 1, further comprising a filtration unit disposed between the osmotically-powered unit and the microneedle array.
5. The osmotic pressure powered microneedle patch of claim 4, further comprising a fast response channel disposed within the osmotic pressure regulating patch core, the fast response channel filled with an osmotic agent, the fast response channel disposed below the semipermeable membrane and in communication with the microneedle array above the filtration unit.
6. The osmotically-powered microneedle patch of claim 5, wherein the semipermeable membrane is disposed over and/or around the osmotic drug power unit, creating an osmotic pressure differential across the semipermeable membrane that allows liquid in the liquid chamber to flow into the osmotic drug power unit but does not allow material within the osmotic drug power unit to flow back into the liquid chamber.
7. The osmotically-powered microneedle patch of claim 1, wherein the osmotically-powered unit comprises:
a drug layer capable of containing small molecule drugs, polypeptides, proteins, genetic drugs and/or cells, viruses, bacteria;
an elastic membrane disposed at an upper end of the medicine layer, the elastic membrane being capable of pushing out medicine of the medicine layer through the hollow microneedles;
the boosting layer is arranged at the upper end of the elastic membrane and is communicated with the liquid chamber, and the boosting layer can absorb thrust generated by water expansion to push the elastic membrane.
8. The osmotically-powered microneedle patch of claim 7, wherein the semipermeable membrane is disposed around the osmotic drug power unit and an osmotic pressure differential is created across the semipermeable membrane, the semipermeable membrane allowing fluid in the fluid chamber to flow into the osmotic drug power unit but not allowing material of the osmotic drug power unit to flow back into the fluid chamber.
9. The osmotically-powered microneedle patch of claim 1, wherein the hollow microneedles have an inner diameter of 100 nm-400 microns, an outer diameter of 10-600 microns, and a length of 100-2000 microns.
10. The osmotically-powered microneedle patch of claim 1, further comprising a fluid delivery system in communication with the fluid chamber, the fluid delivery system being capable of supplying a fluid to the fluid chamber, the osmolarity adjusting solution of the fluid delivery system being a gradient solution.
11. The osmotically-powered microneedle patch of claim 10, wherein the liquid chamber comprises an anti-reflux device capable of preventing liquid from flowing back from the liquid chamber to the liquid supply system.
12. A method of preparing an osmotically powered microneedle patch, wherein the method of preparing is used to manufacture an osmotically powered microneedle patch according to any one of claims 1-11, the method of preparing comprising:
step 1: preparing the microneedle array and the osmotic pressure pharmacokinetic unit;
step 2: the microneedle array is communicated and spliced with the osmotic pressure drug power unit;
step 3: and the liquid chamber is communicated and spliced with the osmotic pressure medicine power unit.
13. The method of claim 12, further comprising the step of preparing a drug layer in step 1, and the step of disposing the drug layer within or below the osmotic pharmacokinetic unit.
14. The method of claim 12, further comprising the step of preparing a filtration unit in step 1, and the step of disposing the filtration unit between the osmotic pharmacokinetic unit and the microneedle array.
CN202211448633.XA 2021-12-07 2022-11-18 Micro-needle patch taking osmotic pressure as power and preparation method thereof Pending CN116236437A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116585606A (en) * 2023-06-15 2023-08-15 徕兄健康科技(威海)有限责任公司 Self-adjustable microneedle patch for local anesthesia

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116585606A (en) * 2023-06-15 2023-08-15 徕兄健康科技(威海)有限责任公司 Self-adjustable microneedle patch for local anesthesia

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