CN114557954A - Dissoluble microneedle containing active microalgae, microneedle patch, preparation method and application - Google Patents

Dissoluble microneedle containing active microalgae, microneedle patch, preparation method and application Download PDF

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CN114557954A
CN114557954A CN202210202045.1A CN202210202045A CN114557954A CN 114557954 A CN114557954 A CN 114557954A CN 202210202045 A CN202210202045 A CN 202210202045A CN 114557954 A CN114557954 A CN 114557954A
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microalgae
microneedle
microneedle patch
dissolvable
polymer
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王瑞兵
张庆文
王泽雨
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University of Macau
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    • 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
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    • 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
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    • 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
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Abstract

The invention discloses a dissolvable microneedle containing active microalgae, a microneedle patch, a preparation method and application, and belongs to the technical field of microneedle process technology and microalgae preparations. The dissolved microneedle patch based on the active microalgae can deliver the active microalgae to generate oxygen in the deep layer of the skin through photosynthesis so as to realize local treatment, and has high biocompatibility, painless minimally invasive property and good adaptability. The preparation method of the dissolvable microneedle patch containing the active microalgae, provided by the invention, has the advantages of simple and rapid preparation process, mild conditions and good universality, can ensure the long-term activity of the microalgae, is easy to store and transport, and is beneficial to commercialization.

Description

Dissoluble microneedle containing active microalgae, microneedle patch, preparation method and application
Technical Field
The invention relates to the technical field of active microalgae delivery, microneedle technology and microalgae preparations, in particular to a dissolvable microneedle containing active microalgae, a microneedle patch, a preparation method and application.
Background
Oxygen therapy has been widely used in a variety of clinical conditions such as tumor therapy, burn recovery, and the like. Recent research findings indicate that local dissolved oxygen delivery can reverse the tumor hypoxic environment to promote wound healing, stimulating collagen regeneration in the skin. However, the conventional local delivery method of dissolved oxygen at present has the problems of small delivery amount, difficult continuous delivery and insufficient delivery depth. And delivery of drugs by injection, oral administration, etc. suffers from poor patient compliance and first pass effects affecting drug absorption. Therefore, in response to the problem of local dissolved oxygen delivery, a new generation of delivery system capable of continuously and stably supplying oxygen and ensuring delivery efficiency and patient safety is still required to be developed.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a dissolvable microneedle containing active microalgae, a microneedle patch, a preparation method and application.
The invention is realized by the following steps:
the invention provides a dissolvable microneedle containing active microalgae, which is prepared from photosynthetic raw materialsThe concentration of the active microalgae with photosynthesis is 105-108The mass percent of the water-soluble polymer is 30-50% per milliliter.
The invention also provides a dissolvable microneedle patch containing the active microalgae, which comprises a backing and a microneedle array arranged on the backing, wherein the microneedle array is formed by the dissolvable microneedles.
The invention also provides a preparation method of the dissolving microneedle patch based on the active microalgae, which comprises the following steps: mixing active microalgae with photosynthesis, a water-soluble polymer material and sterile water, pouring the mixture into a micropore array mold, centrifuging to remove bubbles, adding the polymer material for preparing the backing, centrifuging for the second time and drying to prepare the dissolvable microneedle patch.
The invention also provides application of the soluble microneedle patch in preparing a medicament or a reagent for improving tumor hypoxia, promoting wound healing, recovering skin burn, treating dentistry or improving microenvironment of anemia.
The invention has the following beneficial effects:
the invention provides a dissolvable microneedle containing active microalgae, a microneedle patch, a preparation method and application, wherein the preparation raw materials of the dissolvable microneedle comprise active microalgae with photosynthesis, a water-soluble polymer and sterile water, and the concentration of the active microalgae with photosynthesis is 105-108The mass percentage of the water-soluble polymer is 30-50% per milliliter, the dissolved microneedle patch based on the active microalgae can generate oxygen in the deep layer of the skin through photosynthesis by delivering the active microalgae so as to realize local treatment, and the dissolved microneedle patch based on the polymer has high biocompatibility, is painless and minimally invasive and has good adaptability.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
Fig. 1 is a fluorescence imaging diagram of a dissolving microneedle patch based on active microalgae in example 1 of the present invention;
fig. 2 is a scanning electron microscope image of an active microalgae-based dissolving microneedle patch of example 1 of the present invention;
FIG. 3 shows 10 used in example 1 of the present invention7Time-to-oxygen production curve of chlorella per milliliter concentration in light over 60 minutes;
FIG. 4 is a scanning electron micrograph of a microneedle tip collapsed in comparative example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The invention aims to provide a dissolvable microneedle patch containing active microalgae, and a preparation method and application thereof.
In order to achieve the above object of the present invention, the following technical solutions are adopted.
In a first aspect, embodiments of the present invention provide a dissolvable microneedle containing active microalgae, which is prepared from active microalgae having photosynthesis, a water-soluble polymer and sterile water, and has a concentration of the active microalgae having photosynthesis of 105-108The mass percent of the water-soluble polymer is 30-50% per milliliter.
In an optional embodiment, the active microalgae having photosynthesis is any one or more of cyanophyta, rhodophyta, chlorophyta and chrysophyta;
preferably, the active microalgae with photosynthesis is any one or more of chlorella;
more preferably, the active photosynthetic microalgae are Chlorella species within the phylum Chlorophyceae.
In alternative embodiments, the water-soluble polymer is a dissolving polymer and/or a degrading polymer;
preferably, the water-soluble polymer comprises one or more of acrylic resin, epoxy resin, polyethylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polydimethylsiloxane, polyester polyurethane, polyvinylpyrrolidone, chitosan, maltose, dextran, chondroitin sulfate, gelatin, hyaluronic acid and albumin;
preferably, the water-soluble polymer has a molecular weight of 5-1000 kDa;
more preferably, the water-soluble polymer is hyaluronic acid.
In an alternative embodiment, the microneedle body has a length of 300-1700 μm.
In a second aspect, embodiments of the present invention further provide a dissolvable microneedle patch containing active microalgae, which includes a backing and a microneedle array arranged on the backing, wherein the microneedle array is a microneedle array formed according to the dissolvable microneedle described above.
In an alternative embodiment, the backing is made of the following polymeric materials: one or more of acrylic resin, epoxy resin, polyethylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polydimethylsiloxane, polyester polyurethane, polyvinylpyrrolidone, chitosan, maltose, dextran, chondroitin sulfate, gelatin, hyaluronic acid and albumin;
preferably, the backing is made of a mixture of polyvinyl pyrrolidone and polyvinyl alcohol.
In an alternative embodiment, the starting materials for preparing the microneedle body and the backing from which the microneedle patch can be dissolved further comprise one or more of a plasticizer and a preservative.
In a third aspect, an embodiment of the present invention further provides a method for preparing a dissolving microneedle patch based on active microalgae, including: mixing active microalgae with photosynthesis, a water-soluble polymer material and sterile water, pouring the mixture into a micropore array mould, centrifuging to remove bubbles, adding the polymer material for preparing the backing, centrifuging for the second time, and drying to prepare the dissolvable microneedle patch.
In an alternative embodiment, a method of making a dissolvable microneedle patch comprises the steps of: to a concentration of 105-108Mixing each milliliter of active microalgae with a water-soluble polymer solution with the concentration of 30-50 percent, pouring the final mixed solution into a polydimethylsiloxane micropore array mold, and centrifuging for 30-60 minutes at the speed of 3000-;
adding the polymer solution with the concentration of 10-70% for preparing the backing part into the centrifuged polydimethylsiloxane micropore array mold, then continuously centrifuging at the speed of 3000 plus 5000rpm for 30-60 minutes, and drying to prepare the soluble microneedle patch.
Preferably, the method of making the dissolvable microneedle patch comprises the steps of: the final concentration of active microalgae is 10 per ml7Mixing the microalgae with a water-soluble polymer with the concentration of 50%, pouring the final mixed solution into a polydimethylsiloxane micropore array mold, and centrifuging for 30 minutes at the speed of 4000 rpm;
and after the polymer solution for preparing the backing part is cast, carrying out secondary centrifugation for 30 minutes at the speed of 4000rpm, and drying to prepare the soluble microneedle patch.
In a fourth aspect, the embodiment of the present invention further provides an application of the soluble microneedle patch in preparing a drug or a reagent for improving tumor hypoxia, promoting wound healing, recovering from skin burn, and treating or improving anemia microenvironment in a dental treatment.
The features and properties of the present invention are described in further detail below with reference to examples.
An object of the present invention is to provide dissolvable microneedles containing active microalgae including active microalgae having photosynthesis (microalgae that can produce oxygen), and transdermal delivery of the active microalgae is achieved by using a dissolving microneedle patch of a polymer component.
Oxygen therapy is a popular research direction in recent years, and in clinical practice, oxygen has been applied to the treatment of severe patients, the repair of skin of burn patients, and the like. Conventional oxygen therapy typically employs hyperbaric oxygen chamber therapy or local injections of oxygen. The former treatment requires large capsule instruments, which is expensive and time consuming. The long-term local injection treatment is painful for patients, and the continuous supply of oxygen is difficult to realize by common chemical drugs, and even has the risk of toxic and side effects. Microalgae is a common unicellular photosynthetic organism, is widely present in oceans or freshwater lakes, is widely applied to foods and health care products, and has high safety. The microalgae has the capability of efficiently and continuously generating oxygen through photocatalysis, and can be used as a continuous supply source of dissolved oxygen to realize continuous local oxygen supply.
The inventor creatively provides a new local dissolved oxygen supply mode, which utilizes the photosynthesis of microalgae by using natural microalgae to generate dissolved oxygen for local treatment. The safety of the microalgae is high, and toxic and side effects caused by medicaments can be avoided. Meanwhile, the microalgae can continuously perform photosynthesis, so that the continuous supply of oxygen and the stable level of supplied oxygen can be ensured. Is beneficial to realizing the treatment of related diseases and ensuring the safety and the controllability of the oxygen level in the body.
Transdermal delivery systems are widely used in the clinic as a safe and effective way of administering drugs. However, due to the natural barrier action of the skin, many larger sized drugs are blocked by the stratum corneum of the skin, which affects further absorption. Therefore, the dissolving microneedle patch technology is adopted in the invention, so that the problem of poor absorption degree of microalgae transdermal delivery is solved. The dissolving microneedle patch is a safer and more efficient skin delivery mode, and can avoid touching abundant capillaries and nerve endings in a dermis layer by controlling the length of the microneedle, so that the pain generated in the using process is reduced or eliminated; in addition, the microneedle patch is convenient to use, can be applied by self, and does not need to be operated by a professional. When the micro-algae micro-needle is manufactured, the water-soluble polymer component is used, so that the micro-needle can be quickly dissolved in the skin and release the effective component, and the micro-algae can be efficiently delivered. Meanwhile, the solid plasticity of the micro-needle is more beneficial to storage and transportation, and the stability of the effective components can be kept for a long time.
In a preferred embodiment of the present invention, the oxygen-producing microalgae is all microalgae included in cyanophyta, rhodophyta, chlorophyta, and chrysophyta; preferably, the oxygen-producing microalgae is chlorella.
The algae are unicellular microalgae, the individual form is small, the delivery in vivo is facilitated, meanwhile, the microalgae contain a large amount of chlorophyll, the photosynthesis of efficient oxygen production can be realized, and the unicellular microalgae are widely applied to food and health-care products, so that the unicellular microalgae have small toxic and side effects and high safety.
In a preferred embodiment of the present invention, the dissolved microneedle head polymer component is a water-soluble polymer such as acrylic resin, epoxy resin, polyethylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polydimethylsiloxane, polyester, polyurethane, and polyvinylpyrrolidone; and saccharides such as chitosan, maltose, and dextran; and any one of chondroitin sulfate, gelatin, hyaluronic acid and albumin and a mixture of the chondroitin sulfate, the gelatin, the hyaluronic acid and the albumin in any proportion. Preferably, the dissolving microneedle needle polymer component is hyaluronic acid.
Different polymers can provide different functions for dissolving the microneedle patch system, for example, the polymer with better water solubility can realize quick drug delivery, and meanwhile, the polymer with lower water solubility can help realize slow release of drugs as a needle. Therefore, the polymer material can be selected according to the requirements of different diseases, and different polymers can be mixed and used in different proportions according to comprehensive requirements and algae characteristics. The dissolving microneedle patch system provided by the invention can select corresponding different polymers according to needs.
In a preferred embodiment of the present invention, the dissolved microneedle backing polymer component may be a water-soluble polymer such as acrylic resin, epoxy resin, polyethylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polydimethylsiloxane, polyester, polyurethane, and polyvinylpyrrolidone; and saccharides such as chitosan, maltose, and dextran; and any one of chondroitin sulfate, gelatin, hyaluronic acid and albumin and a mixture of the chondroitin sulfate, the gelatin, the hyaluronic acid and the albumin in any proportion. Preferably, the dissolving microneedle backing polymer component is polyvinylpyrrolidone and a polyvinyl alcohol blend.
The backing portion of the microneedle patch needs to have a certain mechanical strength and flexibility, so that polymers with different properties can be selected as the backing material of the microneedle patch according to specific applications. At the same time, the polymers can also be screened for adhesion properties and for complete absorption by the skin.
In one embodiment, polyvinylpyrrolidone and polyvinyl alcohol blends can be utilized to construct microneedle patch backings that are moderately tough and do not have adhesive and absorptive properties.
In another embodiment, hyaluronic acid can be used to construct microneedle patch backings that are mechanically strong and adhesive, and can be completely absorbed by the skin.
A preparation method of a dissolving microneedle patch based on active microalgae comprises the following steps: mixing the active microalgae with a polymer material, pouring the mixture into a polydimethylsiloxane micropore array mold, and centrifuging the mixture to remove bubbles. Adding the backing polymer material, centrifuging twice, mixing uniformly, and drying the polymer solution to obtain the dissolved microneedle patch.
The preparation method of the dissolving microneedle patch based on the active microalgae is simple and rapid in preparation process, mild in condition, universal and beneficial to subsequent product development and commercialization.
In a preferred embodiment of the present invention, the above-mentioned preparation method further comprises a step of firstly obtaining a concentration of 105-108Each milliliter of active microalgae was mixed with a needle polymer solution of a certain concentration (30% -50% (w/v)), and the final mixed solution was poured into a polydimethylsiloxane microwell array mold and centrifuged at 4000rpm for 30-60 minutes to remove air bubbles. Removing the excessive needle polymer solution in the mold, adding backing polymer material with certain concentration (10% -70% (w/v)), centrifuging at 4000rpm for 30-60 min, mixing thoroughly, and drying the polymer solution at 30-50 deg.CTo obtain a dissolved microneedle patch;
preferably, the active microalgae is present at a final concentration of 10 per ml7Mixing the microalgae with a polymer of 30% concentration and centrifuging at 4000rpm for 30 minutes;
preferably, a solution of backing polymer material with a concentration of 50% is cast and then centrifuged twice at 4000rpm for 30 minutes; preferably, the final drying temperature is 30 degrees celsius.
In other embodiments, the same material can be used directly to mix the microalgae and cast to fill the mold, such that the backing and tip portions are uniform, and dried directly after centrifugation.
The active microalgae dissolving microneedle patch provided by the invention can realize local high-efficiency delivery of microalgae, is beneficial to continuous supply of local dissolved oxygen, can keep the activity of the microalgae, and avoids the first-pass effect of a medicament and the influence of the digestion effect of gastrointestinal enzymes on the delivery concentration of the microalgae.
The microalgae can be Chlorella with high oxygen production efficiency and low toxicity, and can produce anti-inflammatory effect on local skin after transdermal delivery to help repair skin inflammation.
Example 1
In the embodiment, the microalgae is chlorella and is purchased from Shanghai plain biology technology company, the hyaluronic acid, the polyvinylpyrrolidone and the polyvinyl alcohol are purchased from Shanghai Aladdin Biotechnology GmbH, and the polydimethylsiloxane micropore array mold is purchased from Taizhou Microcore medicine technology company.
A hyaluronic acid solution (Mw 20kDa, 30% (w/v)), and a mixed solution (Mw 30kDa, 30% (w/v)) of polyvinylpyrrolidone (Mw 30kDa, 30% (w/v)) and polyvinyl alcohol (Mw 30kDa, 30% (w/v), 1:1(w/w)) were prepared and sufficiently evacuated of air bubbles by ultrasonic dissolution.
To a concentration of 107Centrifuging 3 ml of microalgae mother liquor per ml to remove the culture medium, adding 1 ml of hyaluronic acid solution, pouring the needle mixed liquor into a polydimethylsiloxane micropore array mould, centrifuging at the speed of 4000rpm for 30 minutes to fill the needle cavity, and separatingThe excess solution above the mold was removed after the heart.
The mixed solution of polyvinylpyrrolidone and polyvinyl alcohol (0.1 ml) was poured into the upper layer of the mold. Centrifuge again at 4000rpm for 40 minutes and dry at 30 degrees celsius for three hours. After completely drying, the mold is peeled off to obtain the microneedle patch.
Because the chlorella has red fluorescence, the prepared active microalgae dissolving microneedle patch is subjected to fluorescence imaging and scanning electron microscope imaging. Referring to fig. 1, it can be seen from fig. 1 that the needle head of the prepared microneedle patch is clear and uniform in size, red fluorescence emitted from chlorella is contained in the needle head, which proves that the chlorella has good activity after encapsulation, and referring to fig. 2, which is a scanning electron microscope image of the chlorella-containing dissolved microneedle patch, it can be seen from fig. 2 that the needle head of the obtained microneedle patch under the scanning electron microscope is uniform in size, the surface of the needle head is complete and smooth, 10 used in example 1 of the present invention is 107The time-oxygen production curve of each chlorella per milliliter concentration in 60 minutes of illumination is shown in figure 3, and the figure 3 shows that the chlorella has good oxygen production capability under the illumination condition and can realize stable and continuous oxygen supply.
Example 2
In the embodiment, the microalgae is spirulina and is purchased from Shanghai plain biology technology company, chitosan, polyvinylpyrrolidone and polyvinyl alcohol are purchased from Shanghai Aladdin Biotechnology GmbH, and the polydimethylsiloxane micropore array mold is purchased from Taizhou micro-core medicine technology company.
A chitosan solution (Mw 60kDa, 30% (w/v)), and a mixed solution of polyvinylpyrrolidone (Mw 30kDa, 30% (w/v)) and polyvinyl alcohol (Mw 30kDa, 30% (w/v), 1:1(w/w)) were prepared and sufficiently evacuated of air bubbles by ultrasonic dissolution.
To a concentration of 107Centrifuging 3 ml of microalgae mother liquor per ml to remove the culture medium, adding 1 ml of chitosan solution, pouring the needle mixed liquor into a polydimethylsiloxane micropore array mold, centrifuging at the speed of 4000rpm for 30 minutes to fillThe needle was hollow and centrifuged to remove excess solution above the mold.
The mixed solution of polyvinylpyrrolidone and polyvinyl alcohol (0.1 ml) was poured into the upper layer of the mold. The mixture was centrifuged again at 4000rpm for 40 minutes and naturally dried at room temperature. After complete drying, the mold was peeled off to obtain a microneedle patch.
Example 3
In the embodiment, the microalgae is chlamydomonas and is purchased from Shanghai plain biology technologies, chitosan and polyvinylpyrrolidone are purchased from Shanghai Aladdin Biotechnology, Inc., and the polydimethylsiloxane micropore array mold is purchased from Taizhou micro-core medicine technologies.
A chitosan solution (Mw 60kDa, 40% (w/v)) and polyvinylpyrrolidone (Mw 30kDa, 50% (w/v)) were prepared and sufficiently evacuated of air bubbles by ultrasonic dissolution.
To a concentration of 107Centrifuging 3 ml of microalgae mother liquor per ml to remove the culture medium, then adding 1 ml of chitosan solution, pouring the needle mixed liquor into a polydimethylsiloxane micropore array mould, centrifuging at the speed of 4000rpm for 30 minutes to fill a needle cavity, removing the redundant solution on the mould after centrifuging, and drying at the temperature of 30 ℃ for three hours.
0.1 ml of polyvinylpyrrolidone solution was poured into the upper layer of the mould after it had dried. The mixture was centrifuged again at 4000rpm for 30 minutes and dried at 30 ℃ overnight. After complete drying, the mold was peeled off to obtain a microneedle patch.
Example 4
In the embodiment, the microalgae is chlorella and is purchased from Shanghai plain biology technology company, the hyaluronic acid is purchased from Shanghai Aladdin Biotechnology, Inc., and the polydimethylsiloxane micro-pore array mold is purchased from Taizhou micro-core medicine technology company.
A hyaluronic acid solution (Mw 1000kDa, 30% (w/v)) was prepared and the air bubbles were sufficiently evacuated by ultrasonic dissolution.
To a concentration of 108Every 3 ml of microalgae mother liquor is centrifuged to remove the culture medium, then 1 ml of hyaluronic acid solution is added, the mixed solution is poured into a polydimethylsiloxane micropore array mold, and the mixed solution is centrifuged at 4000rpm for 50 minutes to fill all cavities. And (4) drying at 40 ℃ overnight, and after complete drying, stripping the mold to obtain the microneedle patch.
Example 5
In the embodiment, the microalgae is scenedesmus and is purchased from Shanghai plain biology technology company, the hyaluronic acid, the polyvinylpyrrolidone and the polyvinyl alcohol are purchased from Shanghai Aladdin Biotechnology, Inc., and the polydimethylsiloxane micropore array mold is purchased from Taizhou micro-core medicine technology company.
A hyaluronic acid solution (Mw 200kDa, 30% (w/v)), and a mixed solution (Mw 30kDa, 30% (w/v)) of polyvinylpyrrolidone (Mw 30kDa, 30% (w/v)) and polyvinyl alcohol (Mw 30kDa, 30% (w/v), 1:1(w/w)) were prepared and sufficiently evacuated of air bubbles by ultrasonic dissolution.
To a concentration of 107Centrifuging 3 ml of microalgae mother liquor per ml to remove the culture medium, then adding 1 ml of hyaluronic acid solution, pouring the needle mixed liquor into a polydimethylsiloxane micropore array mould, centrifuging at the speed of 4000rpm for 30 minutes to fill a needle cavity, and removing the redundant solution on the mould after centrifuging.
0.1 ml of mixed solution of polyvinylpyrrolidone and polyvinyl alcohol was poured into the upper layer of the mold. Centrifuge again at 4000rpm for 30 minutes and dry at 38 degrees celsius overnight. After complete drying, the mold was peeled off to obtain a microneedle patch.
Example 6
In the embodiment, the microalgae is fibroalgae and is purchased from Shanghai plain biology technology, hyaluronic acid and chitosan are purchased from Shanghai Aladdin Biotechnology, Inc., and the polydimethylsiloxane micropore array mold is purchased from Taizhou Microcore medicine technology.
Hyaluronic acid solutions (Mw 200kDa, 30% (w/v)) and chitosan solutions (Mw 60kDa, 50% (w/v)) were prepared and sufficiently evacuated of air bubbles by ultrasonic dissolution.
To a concentration of 108Centrifuging 3 ml of microalgae mother liquor per ml to remove the culture medium, then adding 1 ml of hyaluronic acid solution, pouring the needle mixed liquor into a polydimethylsiloxane micropore array mould, centrifuging at the speed of 4000rpm for 30 minutes to fill a needle cavity, and removing the redundant solution on the mould after centrifuging.
0.1 ml of chitosan solution was poured into the upper layer of the mold. Centrifuge again at 4000rpm for 30 minutes and dry at 40 degrees celsius overnight. After complete drying, the mold was peeled off to obtain a microneedle patch.
Comparative example 1
A hyaluronic acid solution (Mw 20kDa, 3% (w/v)), and a mixed solution (Mw 30kDa, 30% (w/v)) of polyvinylpyrrolidone (Mw 30kDa, 30% (w/v), 1:1(w/w)) and polyvinyl alcohol were prepared and sufficiently evacuated of air bubbles by ultrasonic dissolution.
To a concentration of 107Centrifuging 3 ml of microalgae mother liquor per ml to remove the culture medium, then adding 1 ml of hyaluronic acid solution, pouring the needle mixed liquor into a polydimethylsiloxane micropore array mould, centrifuging at the speed of 4000rpm for 30 minutes to fill a needle cavity, and removing the redundant solution on the mould after centrifuging.
The mixed solution of polyvinylpyrrolidone and polyvinyl alcohol (0.1 ml) was poured into the upper layer of the mold. Centrifuge again at 4000rpm for 40 minutes and dry at 30 degrees celsius for three hours. After complete drying, the mold was peeled off to obtain a microneedle patch.
The microneedle patch needle prepared by the method is too soft, lacks mechanical strength and cannot support, and the needle collapses after being applied to skin, so that the effect of inserting into the skin cannot be realized. A scanning electron microscope picture of the collapsed microneedle is shown in fig. 4.
Comparative example 2
A hyaluronic acid solution (Mw 2000kDa, 30% (w/v)), and a mixed solution (Mw 30kDa, 30% (w/v)) of polyvinylpyrrolidone (Mw 30kDa, 30% (w/v)) and polyvinyl alcohol (Mw 30kDa, 30% (w/v), 1:1(w/w)) were prepared and sufficiently evacuated of air bubbles by ultrasonic dissolution.
To a concentration of 107Centrifuging 3 ml of microalgae mother liquor per ml to remove the culture medium, then adding 1 ml of hyaluronic acid solution, pouring the needle mixed liquor into a polydimethylsiloxane micropore array mould, centrifuging at the speed of 4000rpm for 30 minutes to fill a needle cavity, and removing the redundant solution on the mould after centrifuging.
The mixed solution of polyvinylpyrrolidone and polyvinyl alcohol (0.1 ml) was poured into the upper layer of the mold. Centrifuge again at 4000rpm for 40 minutes and dry at 30 degrees celsius for three hours. After complete drying, the mold was peeled off to obtain a microneedle patch.
The microneedle patch needle prepared by the method has strong mechanical property, but has high brittleness and poor flexibility, can be broken when being applied to skin, and cannot be inserted into the skin and dissolved in the subcutaneous tissue.
Comparative example 3
A hyaluronic acid solution (Mw 20kDa, 30% (w/v)), and a mixed solution (Mw 30kDa, 30% (w/v)) of polyvinylpyrrolidone (Mw 30kDa, 30% (w/v)) and polyvinyl alcohol (Mw 30kDa, 30% (w/v), 1:1(w/w)) were prepared and sufficiently evacuated of air bubbles by ultrasonic dissolution.
To a concentration of 103Centrifuging 3 ml of microalgae mother liquor per ml to remove the culture medium, then adding 1 ml of hyaluronic acid solution, pouring the needle mixed liquor into a polydimethylsiloxane micropore array mould, centrifuging at the speed of 4000rpm for 30 minutes to fill a needle cavity, and removing the redundant solution on the mould after centrifuging.
The mixed solution of polyvinylpyrrolidone and polyvinyl alcohol (0.1 ml) was poured into the upper layer of the mold. Centrifuge again at 4000rpm for 40 minutes and dry at 30 degrees celsius for three hours. After complete drying, the mold was peeled off to obtain a microneedle patch.
The prepared active microalgae dissolving microneedle patch is subjected to fluorescence imaging, and the result shows that the prepared microneedle patch has a clear needle head and uniform size, but only weak chlorella fluorescence is observed in the needle head. To a concentration of 103Testing oxygen generation capacity of chlorella solution per milliliter under illumination, making an oxygen generation curve, and finding smallToo low a concentration of coccobacillus results in poor oxygen production efficiency.
Comparative example 4
A hyaluronic acid solution (Mw 20kDa, 30% (w/v)), and a mixed solution (Mw 30kDa, 30% (w/v)) of polyvinylpyrrolidone (Mw 30kDa, 30% (w/v)) and polyvinyl alcohol (Mw 30kDa, 30% (w/v), 1:1(w/w)) were prepared and sufficiently evacuated of air bubbles by ultrasonic dissolution.
To a concentration of 107Centrifuging 3 ml of microalgae mother liquor per ml to remove the culture medium, then adding 1 ml of hyaluronic acid solution, pouring the needle mixed liquor into a polydimethylsiloxane micropore array mould, centrifuging at the speed of 1000rpm for 30 minutes to fill a needle cavity, and removing the redundant solution on the mould after centrifuging.
The mixed solution of polyvinylpyrrolidone and polyvinyl alcohol (0.1 ml) was poured into the upper layer of the mold. Centrifuge again at 1000rpm for 40 minutes and dry at 30 degrees celsius for three hours. After complete drying, the mold was peeled off to obtain a microneedle patch.
The micro-needle patch prepared by the method is easy to break when being applied to skin due to uneven stress caused by the fact that a large amount of bubbles exist in the patch and the solution is not fully filled in a mould due to the fact that partial needle heads are found to be incomplete in demoulding and the centrifugal speed is too low.
Comparative example 5
A hyaluronic acid solution (Mw 20kDa, 30% (w/v)), and a mixed solution (Mw 30kDa, 30% (w/v)) of polyvinylpyrrolidone (Mw 30kDa, 30% (w/v)) and polyvinyl alcohol (Mw 30kDa, 30% (w/v), 1:1(w/w)) were prepared and sufficiently evacuated of air bubbles by ultrasonic dissolution.
To a concentration of 107Centrifuging 3 ml of microalgae mother liquor per ml to remove the culture medium, then adding 1 ml of hyaluronic acid solution, pouring the needle mixed liquor into a polydimethylsiloxane micropore array mould, centrifuging at the speed of 4000rpm for 20 minutes to fill a needle cavity, and removing the redundant solution on the mould after centrifuging.
The mixed solution of polyvinylpyrrolidone and polyvinyl alcohol (0.1 ml) was poured into the upper layer of the mold. Centrifuge again at 4000rpm for 40 minutes and dry at 70 degrees celsius for three hours. After complete drying, the mold was peeled off to obtain a microneedle patch.
The microneedle patch prepared by the method has extremely high brittleness due to overhigh drying temperature, and is very easy to break when being applied to the surface of the skin. Meanwhile, the patch is subjected to fluorescence imaging, and the fact that red fluorescence of chlorella does not exist, the chlorella is completely dead due to high temperature, and the oxygen production capacity is lost is found.
In summary, the embodiment of the invention provides a dissolvable microneedle based on active microalgae, a microneedle patch, a preparation method and an application. The dissolved microneedle patch based on the active microalgae can generate oxygen through photosynthesis in the deep layer of the skin by delivering the active microalgae so as to realize local treatment, and the dissolved microneedle patch based on the polymer has high biocompatibility, no pain and minimal invasion and good adaptability. The preparation method of the active microalgae dissolving microneedle patch provided by the invention has the advantages of simple and rapid preparation process, mild conditions and good universality, and the microneedle has good mechanical property and toughness, can ensure the long-term activity of microalgae, is easy to store and transport, and is beneficial to commercialization.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A dissolvable microneedle containing active microalgae is prepared from active microalgae with photosynthesis, water-soluble polymer and sterile water, wherein the concentration of the active microalgae with photosynthesis is 105-108The mass percent of the water-soluble polymer is 30-50% per milliliter.
2. The dissolvable microneedle according to claim 1, wherein said active microalgae is selected from the group consisting of cyanophyta, rhodophyta, chlorophyta and chrysophyta;
preferably, the active microalgae with photosynthesis is any one or more of chlorella;
more preferably, the active microalgae having photosynthesis is chlorella within the chlorella phylum.
3. The dissolvable microneedle containing active microalgae of claim 1, wherein said water soluble polymer is a dissolving polymer and/or a degrading polymer;
preferably, the water-soluble polymer comprises one or more of acrylic resin, epoxy resin, polyethylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polydimethylsiloxane, polyester polyurethane, polyvinylpyrrolidone, chitosan, maltose, dextran, chondroitin sulfate, gelatin, hyaluronic acid and albumin;
preferably, the water-soluble polymer has a molecular weight of 5-1000 kDa;
more preferably, the water-soluble polymer is selected from hyaluronic acid.
4. The soluble microneedle containing active microalgae according to claim 1, wherein the length of said microneedle body is 300-1700 μm.
5. A dissolvable microneedle patch containing active microalgae, comprising a backing and a microneedle array arranged on the backing, wherein the microneedle array is formed by dissolvable microneedles according to any one of claims 1-4.
6. The dissolvable microneedle patch according to claim 5, wherein a backing portion of said dissolvable microneedle patch is made of a polymer;
preferably, the polymer for preparing the microneedle backing portion comprises one or more of acrylic resin, epoxy resin, polyethylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polydimethylsiloxane, polyester polyurethane, polyvinylpyrrolidone, chitosan, maltose, dextran, chondroitin sulfate, gelatin, hyaluronic acid and albumin;
preferably, the polymer from which the microneedle backing portion is made is a blend of polyvinylpyrrolidone and polyvinyl alcohol.
7. The dissolvable microneedle patch according to claim 5, wherein said microneedle array and backing are prepared from materials further comprising one or more of plasticizers and preservatives.
8. A method of making a dissolvable microneedle patch according to any one of claims 5-7 comprising active microalgae, comprising: mixing active microalgae with photosynthesis, a water-soluble polymer material and sterile water, pouring the mixture into a micropore array mold, centrifuging to remove bubbles, adding the polymer material for preparing the backing, centrifuging for the second time and drying to prepare the dissolvable microneedle patch.
9. The method of manufacturing of claim 8, wherein the method of manufacturing the dissolvable microneedle patch comprises the steps of: to a concentration of 105-108Mixing active microalgae per milliliter with a water-soluble polymer solution with the concentration of 30-50 percent, pouring the final mixed solution into a polydimethylsiloxane micropore array mold, and centrifuging at the speed of 3000-5000rpm for 30-60 minutes;
adding the polymer solution with the concentration of 10% -70% for preparing the backing part into the centrifuged polydimethylsiloxane micropore array mold, then continuously centrifuging at the speed of 3000-;
preferably, the method of making the dissolvable microneedle patch comprises the steps of: the final concentration of the active microalgae is 10 per milliliter7Mixing microalgae with 50% water-soluble polymer, and pouring the final mixed solution into polydimethyl siliconA siloxane microwell array mold and centrifuged at 4000rpm for 30 minutes;
and after the polymer solution for preparing the backing part is cast, carrying out secondary centrifugation for 30 minutes at the speed of 4000rpm, and drying to prepare the soluble microneedle patch.
10. Use of the dissolvable microneedle according to any one of claims 1-4, or the dissolvable microneedle patch according to any one of claims 5-7, or the dissolvable microneedle patch prepared according to the method of any one of claims 8-9 for preparing a medicament or agent for improving tumor hypoxia, promoting wound healing, skin burn recovery, dental treatment or improving the microenvironment of anemia.
CN202210202045.1A 2022-03-03 2022-03-03 Dissoluble microneedle containing active microalgae, microneedle patch, preparation method and application Pending CN114557954A (en)

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