CN111588689B - Cornea minimally invasive soluble microneedle patch and preparation method and application thereof - Google Patents

Cornea minimally invasive soluble microneedle patch and preparation method and application thereof Download PDF

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CN111588689B
CN111588689B CN202010569210.8A CN202010569210A CN111588689B CN 111588689 B CN111588689 B CN 111588689B CN 202010569210 A CN202010569210 A CN 202010569210A CN 111588689 B CN111588689 B CN 111588689B
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minimally invasive
microneedle patch
cornea
polylactic acid
pla
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CN111588689A (en
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李星熠
林德青
师帅
陈浩
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Wenzhou Medical University
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Wenzhou Medical University
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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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • A61M2037/0053—Methods for producing microneedles

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  • Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Ophthalmology & Optometry (AREA)
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Abstract

The cornea minimally invasive soluble microneedle patch is obtained by a casting method in one step, has the advantages of simplicity and rapidness in operation, good reproducibility and the like, can effectively break through a cornea epithelial barrier after being applied to an ocular surface, realizes effective enrichment of a medicament in a cornea stroma layer, improves the bioavailability of the medicament, and has the advantages of simplicity and convenience in administration mode, minimally invasive administration and the like.

Description

Cornea minimally invasive soluble microneedle patch and preparation method and application thereof
Technical Field
The invention relates to the technical field of microneedle patches, in particular to a cornea minimally invasive soluble microneedle patch and a preparation method and application thereof.
Background
Fungal keratitis is a type of infectious cornea disease with a very high blindness rate, which is inferior to cataract especially in developing countries. Up to now, it has been found that over 100 fungi can cause corneal infection, with major pathogenic bacteria including fusarium, aspergillus, candida, campylobacter, and the like. Because of strong fungus penetrability, severe complications such as suppurative corneal ulcer, corneal perforation, endophthalmitis and the like are extremely easy to cause if clinical treatment cannot be carried out timely and effectively.
For fungal keratitis, two strategies, namely antifungal drug treatment and surgical treatment, are generally adopted clinically. The antifungal medicine (polyene medicine: amphotericin B and the like, azole antifungal medicine: fluconazole and the like) has the advantages of economy, simple and convenient administration, good patient compliance and the like, and has good application prospect in clinical medicine treatment. Due to the existence of the cornea barrier, the medicine is difficult to break through the cornea epithelial layer to reach the cornea stroma layer after ocular surface administration, so that the bioavailability of the medicine is extremely low. In order to overcome the shortcomings of the conventional ocular surface preparations, researchers have attempted to develop various novel drug delivery systems (e.g., hydrogels, liposome polymer nanoparticles, microneedles, etc.), and to significantly improve the bioavailability of the drug by prolonging the retention of the drug on the ocular surface or improving the ability of the drug to penetrate the corneal epithelium.
Disclosure of Invention
In order to solve the requirements of clinical drug treatment of fungal keratitis, the invention provides a cornea minimally invasive soluble microneedle patch, a preparation method and application thereof, which can realize effective puncture of a cornea epithelial layer, improve the entry of drug molecules into a cornea stroma layer and effectively enhance the bioavailability and curative effect of the drug.
The technical scheme adopted by the invention is as follows: the cornea minimally invasive soluble microneedle patch consists of a matrix material and an active ingredient, wherein the matrix material is a compound of sodium Hyaluronate (HA) and polylactic acid (PLA), and the active ingredient is a hydrophobic antifungal drug.
The mass content of polylactic acid (PLA) in the matrix material is 10-30%.
The mass content of polylactic acid (PLA) in the matrix material is 30%.
The hydrophobic antifungal drug is fluconazole.
A preparation method of a cornea minimally invasive soluble microneedle patch, which comprises the following steps: and dissolving polylactic acid and drug molecules in acetone, then adding the mixture into sodium hyaluronate aqueous solution, stirring and uniformly mixing the mixture, pouring the mixture into a PDMS mold, placing the PDMS mold into a precise blast drying oven, volatilizing the mixture at 45 ℃ overnight, and stripping the mixture to obtain the microneedle patch.
The mass ratio of the polylactic acid to the sodium hyaluronate is 1:9-3:7.
Application of a corneal minimally invasive soluble microneedle patch in preparing a medicament for treating fungal keratitis is provided.
The beneficial effects of the invention are as follows: the invention provides a cornea minimally invasive soluble micro-needle patch, a preparation method and application thereof, wherein the minimally invasive soluble micro-needle patch is obtained by a casting method in one step, and the preparation method has the advantages of simplicity and rapidness in operation, good reproducibility and the like, can effectively break through the barrier of the cornea epithelial layer after being applied to the ocular surface, realizes the effective enrichment of a medicament in the cornea stroma layer, improves the bioavailability of the medicament, and has the advantages of simplicity and convenience in administration mode, minimally invasive administration and the like.
Drawings
Fig. 1 shows the morphology of microneedle patches with different PLA content.
Fig. 2 is a scanning electron microscope image of microneedle patches of different PLA content.
Figure 3 shows cornea retention after application of the microneedle ocular surface with different PLA content.
Fig. 4 shows corneal epithelial penetration after application of the microneedle ocular surface with varying PLA content.
Fig. 5 is a graph of corneal OCT after application of different PLA content microneedle ocular surfaces.
Fig. 6 is a schematic diagram of a method for preparing a corneal minimally invasive soluble microneedle patch according to the present invention.
Detailed Description
The invention will be better illustrated with reference to the drawings and some specific embodiments.
Example 1
Preparation of 0% PLA minimally invasive soluble microneedle patch by using double distilled water and acetone as solvents
Accurately weighing 0.05g of fluconazole, dissolving in 1 mL acetone together, then adding into 10 mL sodium hyaluronate aqueous solution (10 mg/mL), stirring, pouring into PDMS mould, volatilizing at 45 ℃ overnight in a precise blast drying oven, and stripping the microneedle patch.
Example 2
Preparation of 10% PLA minimally invasive soluble microneedle patch by using double distilled water and acetone as solvents
Accurately weighing 0.01g of polylactic acid (PLA) and 0.05g of fluconazole, dissolving in 1 mL acetone together, then adding into 10 mL sodium hyaluronate aqueous solution (9 mg/mL), stirring and mixing uniformly, pouring into a PDMS mould, placing into a precise blast drying oven, volatilizing at 45 ℃ overnight, and stripping the microneedle patch.
Example 3
Preparation of 30% PLA minimally invasive soluble microneedle patch by using double distilled water and acetone as solvents
Accurately weighing 0.03g of polylactic acid (PLA) and 0.05g of fluconazole, dissolving in 1 mL acetone together, then adding into 10 mL sodium hyaluronate aqueous solution (7 mg/mL), stirring and mixing uniformly, pouring into a PDMS mould, placing into a precise blast drying oven for volatilizing overnight at 45 ℃, and stripping the microneedle patch.
Example 4
Ocular surface residence time of minimally invasive soluble microneedle patches with different PLA contents
The prepared minimally invasive soluble microneedle patches with different PLA contents and equivalent fluorescein sodium content are placed on the ocular surface of New Zealand white rabbits, and the residence time of the microneedle patches on the ocular surface is observed at different time points. The results are shown in fig. 3, and as the PLA content increases, the retention time of the microneedle patch on the ocular surface increases accordingly. When the mass content of polylactic acid (PLA) is 10-30%, the retention time of the microneedle patch on the ocular surface can reach about 2 hours.
Example 5
Corneal epithelial penetration capability of minimally invasive soluble microneedle patches of different PLA content
The prepared minimally invasive soluble microneedle patches with different PLA contents are placed on the eye surfaces of New Zealand white rabbits, and the capability of the microneedle patches to penetrate through the corneal epithelium layer is observed 5 minutes after the pressure is applied. As shown in fig. 4 and 5, the microneedle patch was able to penetrate the corneal epithelium layer with increasing PLA content; the 30% pla microneedle patch had the best penetration of the corneal epithelium.
From the morphology graph of the microneedle patches with different PLA contents in FIG. 1 and the scanning electron microscope graph of the microneedle patches with different PLA contents in FIG. 2, it can be seen that when the PLA content is greater than 30%, the polylactic acid (PLA) and the hyaluronic acid gel structure of the basal phase are separated, so as to influence the corneal epithelium penetration effect. And when the PLA content is more than 30%, too high a PLA content will cause discomfort to the eyes of the patient because the PLA is a poorly soluble phase.
The minimally invasive soluble microneedle patch is applied to the ocular surface to improve the bioavailability of the drug, and the operation method is as follows: the minimally invasive soluble microneedle patch is placed on the ocular surface, and the effective puncture of the corneal epithelium layer is realized by slightly pressing the patch with the thumb, so that the entry of drug molecules into the corneal stroma layer is improved, and the bioavailability and the curative effect of the drug are effectively enhanced.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above examples, and all technical solutions belonging to the concept of the present invention belong to the protection scope of the present invention. It should be noted that modifications and adaptations to the present invention may occur to one skilled in the art without departing from the principles of the present invention and are intended to be within the scope of the present invention.

Claims (3)

1. The cornea minimally invasive soluble microneedle patch is characterized by comprising a matrix material and an active ingredient, wherein the matrix material is a compound of sodium hyaluronate and polylactic acid (PLA), the active ingredient is a hydrophobic antifungal drug, the mass content of the polylactic acid (PLA) in the matrix material is 30%, the soluble microneedle patch is prepared by dissolving polylactic acid and drug molecules in acetone, then adding the dissolved polylactic acid and drug molecules into sodium hyaluronate aqueous solution, stirring and uniformly mixing the dissolved polylactic acid and drug molecules, pouring the mixture into a PDMS (polydimethylsiloxane) mould, placing the PDMS mould in a precise air drying oven for volatilizing overnight at 45 ℃, and stripping the polylactic acid and the drug molecules to obtain the microneedle patch.
2. The corneal minimally invasive soluble microneedle patch of claim 1, wherein the hydrophobic antifungal agent is fluconazole.
3. Use of the corneal minimally invasive soluble microneedle patch of claim 1 in the preparation of a medicament for treating fungal keratitis.
CN202010569210.8A 2020-06-20 2020-06-20 Cornea minimally invasive soluble microneedle patch and preparation method and application thereof Active CN111588689B (en)

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Publication number Priority date Publication date Assignee Title
WO2008011625A2 (en) * 2006-07-21 2008-01-24 Georgia Tech Researh Corporation Microneedle devices and methods of drug delivery or fluid withdrawal
CN103260693A (en) * 2010-10-19 2013-08-21 塔夫茨大学信托人 Silk fibroin-based microneedles and methods of making the same
CN106422045A (en) * 2016-09-05 2017-02-22 中国科学院理化技术研究所 Flexible slow-release micro-needle patch and preparation method thereof
CN107349175A (en) * 2017-06-06 2017-11-17 浙江理工大学 A kind of microneedle patch for loading fatty brown stain agent and preparation method thereof
JP2018193300A (en) * 2015-09-11 2018-12-06 株式会社バイオセレンタック Sustained-release multi-layer micro needle that can be cut off from base or sheet
KR20180134744A (en) * 2017-06-09 2018-12-19 주식회사 스몰랩 Micro needle elastic structure
KR20190060516A (en) * 2017-11-24 2019-06-03 주식회사 스몰랩 Micro needle and method of fabricating the same
CN110917176A (en) * 2018-08-31 2020-03-27 中科微针（北京）科技有限公司 Implantable sustained-release microneedle patch and preparation method thereof

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EP2338557A1 (en) * 2009-12-23 2011-06-29 Debiotech S.A. Soluble microneedle
GB201317005D0 (en) * 2013-09-25 2013-11-06 Blueberry Therapeutics Ltd Composition and methods of treatment

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WO2008011625A2 (en) * 2006-07-21 2008-01-24 Georgia Tech Researh Corporation Microneedle devices and methods of drug delivery or fluid withdrawal
CN103260693A (en) * 2010-10-19 2013-08-21 塔夫茨大学信托人 Silk fibroin-based microneedles and methods of making the same
JP2018193300A (en) * 2015-09-11 2018-12-06 株式会社バイオセレンタック Sustained-release multi-layer micro needle that can be cut off from base or sheet
CN106422045A (en) * 2016-09-05 2017-02-22 中国科学院理化技术研究所 Flexible slow-release micro-needle patch and preparation method thereof
CN107349175A (en) * 2017-06-06 2017-11-17 浙江理工大学 A kind of microneedle patch for loading fatty brown stain agent and preparation method thereof
KR20180134744A (en) * 2017-06-09 2018-12-19 주식회사 스몰랩 Micro needle elastic structure
KR20190060516A (en) * 2017-11-24 2019-06-03 주식회사 스몰랩 Micro needle and method of fabricating the same
CN110917176A (en) * 2018-08-31 2020-03-27 中科微针（北京）科技有限公司 Implantable sustained-release microneedle patch and preparation method thereof

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Title
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