CN111218013B - Preparation method and application of crosslinked polymer - Google Patents
Preparation method and application of crosslinked polymer Download PDFInfo
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
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- 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
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- C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to a preparation method and application of a cross-linked polymer, wherein the preparation method comprises the following steps: stirring and dissolving sodium carboxymethylcellulose and galactose in water to obtain a mixture, then adding a cross-linking agent, stirring and dissolving, adjusting the system to the reaction temperature for polymerization reaction, and adjusting the pH of a reaction product to 1-5 to obtain a cross-linked polymer after the reaction is finished; the cross-linking agent used in the reaction is citric acid and derivatives thereof; the cross-linked polymer has good solubility and mechanical strength when used for preparing soluble microneedles. The maximum drug release of the drug-loaded soluble microneedle can reach 0.1033 mg. Compared with the prior art, the invention has the advantages of good moisture resistance, good solubility, simple and easy preparation method and high drug release amount during drug loading.
Description
Technical Field
The invention belongs to the technical field of microneedles, and particularly relates to a preparation method and application of a cross-linked polymer.
Background
Inspired by the fact that blood is obtained by being bitten by mosquitoes, if the transdermal drug delivery system can form a micro-channel on the skin layer through the micro-needle, the drug enters the blood circulation through the micro-channel, the problem that the drug penetrates through the barrier of the skin stratum corneum is solved, the bioavailability of the drug is greatly enhanced, and the drug effect is improved. Compared with the traditional syringe, the micro-needle is divided into two parts, one part is a needle tip part loaded with most of the medicine; a part of the base part mainly plays a supporting role. Polymeric microneedles are of interest due to their excellent biocompatibility, biodegradability, low toxicity, strength toughness, and low cost; the soluble micro-needle avoids the biocompatibility problems of silicon, metal and other non-soluble micro-needles, intracutaneous fracture, secondary damage of wastes and the like, does not have the strict requirements of the hollow micro-needle on preparation and matched equipment thereof, has the characteristics of convenient production and preparation, quick drug release, no secondary damage and the like, and is a micro-needle dosage form with extremely promising drug transdermal delivery. In the prior art, the preparation method of the drug-loaded soluble microneedle comprises two steps: firstly, dissolving a drug in a water-soluble raw material mixed solution, secondly, injecting the solution into a microneedle mould by adopting a centrifugal or vacuum method, drying and demoulding to obtain the drug-loaded soluble microneedle.
Researches show that the dissoluble micro-needle prepared from the biocompatible material has the defects that the hardness of the micro-needle is not enough to pierce the stratum corneum of the skin due to high hygroscopicity of the material, or the viscosity is too high to be beneficial to preparation and molding, and the like. The formation of a composite material from such biocompatible materials to improve its properties is one of the ways to solve the problem.
Puerarin has poor water solubility and fat solubility, the solubility in water is only 4.62mg/mL, oral administration is difficult to absorb, the bioavailability is only 3.799 percent, and only injection and eye drops are clinically used at present (2015 edition of Chinese pharmacopoeia). The injection administration needs special medical care personnel, and most of injection materials are disposable materials, which not only generate medical waste, but also have lower patient compliance; oral delivery methods require multiple administrations due to low bioavailability. Therefore, the development of a new puerarin preparation with high efficiency and environmental protection is of great significance.
Disclosure of Invention
The first object of the present invention is to provide a method for preparing a crosslinked polymer, which overcomes the above-mentioned disadvantage of the prior art that is not moisture-resistant;
the second purpose of the present invention is to provide a method for preparing soluble microneedles capable of improving water-insoluble drugs in order to overcome the defects of the prior art that puerarin drugs are not easy to use and have low bioavailability, so as to achieve the preparation of water-insoluble drug soluble microneedles, reduce drug waste, and improve the safety of microneedles.
The purpose of the invention can be realized by the following technical scheme:
a method of preparing a crosslinked polymer comprising the steps of: stirring and dissolving sodium carboxymethylcellulose and galactose in water to obtain a mixture, adding a cross-linking agent, stirring and dissolving, adjusting the system to the reaction temperature for polymerization, and adjusting the pH of a reaction product to 1-5 after the reaction is finished to obtain the cross-linked polymer; the cross-linking agent is citric acid and derivatives thereof.
The reaction temperature is 50-80 ℃; the reaction time of the polymerization reaction is 5-10 h.
The reaction temperature is 50 ℃, and the reaction time is 10 h.
The ratio of the sodium carboxymethylcellulose to the galactose is 1g: 1-3 g.
The addition amount of the citric acid is 10-20% of the mass of the mixture.
The invention also provides an application of the cross-linked polymer, wherein the cross-linked polymer is used for preparing the soluble microneedle, and the soluble microneedle comprises a base and a needlepoint; the preparation method comprises the following steps:
(1) preparation of the needle tip part: taking a microneedle mould, using a pipette to take a polymer solution to be spread on the surface of the microneedle mould, and carrying out first centrifugal treatment to obtain a needle tip part;
(2) preparation of the base part: taking out the microneedle mould, using a pipette to take a polymer solution to be flatly laid on the surface of the microneedle mould, and carrying out second centrifugal treatment to obtain the base part;
(3) preparation of soluble microneedles: and taking out the microneedle mould, and peeling the microneedle mould after drying treatment to obtain the soluble microneedle.
The centrifugal rotating speed of the first centrifugal treatment and the centrifugal rotating speed of the second centrifugal treatment are 3000-4500 rpm and 60-90 minutes, and preferably 3000 rpm and 60 minutes are selected as the centrifugal rotating speed.
The drying treatment is drying for 24-48 h at 40-45 ℃, preferably drying for 48h at 40 ℃.
In the step (1), the polymer solution is added with the water-insoluble drug, and the water-insoluble drug is dissolved and mixed uniformly to obtain a water-insoluble drug mixed solution, wherein the water-insoluble drug mixed solution is used for manufacturing a needle tip part.
In the step (1), the water-insoluble medicine is puerarin.
Furthermore, the concentration of the puerarin in the mixed liquid of the water-insoluble medicines is 20 mg/mL.
The double-layer microneedle is convenient for visual observation, and two coloring agents with different colors can be added into the polymer mixed liquid and respectively used for manufacturing the needle tip and the base part.
In the step (1), trypan blue is added into the polymer solution, and is dissolved and mixed uniformly to obtain a trypan blue mixed solution, wherein the trypan blue mixed solution is used for manufacturing a needle tip part.
In the step (2), rhodamine is firstly added into the polymer solution, and is dissolved and mixed uniformly to obtain rhodamine mixed solution, and the rhodamine mixed solution is used for manufacturing the needle tip part.
Furthermore, the concentration of trypan blue in the trypan blue mixed solution is 0.1mg/mL, and the concentration of rhodamine in the rhodamine mixed solution is 0.1 mg/mL.
Compared with the prior art, the invention has the following advantages:
(1) compared with the uncrosslinked simple polymer, the crosslinked polymer prepared by the invention has better humidity resistance and solubility which does not influence the release of the drug;
(2) galactose and sodium carboxymethylcellulose are adopted as main materials of the double-layer microneedle, so that the polymer composite material with good biocompatibility is simple and easy to obtain, the safety is high, and the solubility is good; the mechanical property is good, and the skin can be punctured;
(3) the preparation method of the double-layer microneedle is simple to operate, the microneedle part and the base part can be well bonded only at room temperature, the method is simple and easy to implement, special equipment and a manufacturing process are not needed, and the preparation method is suitable for popularization and use.
Drawings
Fig. 1 is a photograph of the soluble microneedle of example 1;
FIG. 2 is an infrared spectrum of the crosslinked polymer in example 2 and example 3;
FIG. 3 is the results of moisture absorption testing of the crosslinked polymer of example 2;
fig. 4 shows the dissolution of the soluble microneedles in example 2;
FIG. 5 shows the results of moisture absorption test of the crosslinked polymer in example 3;
fig. 6 shows the dissolution of the soluble microneedles in example 3;
FIG. 7 is a soluble microprobe of example 3 tested for ex vivo pigskin puncture performance;
fig. 8 shows the drug release of the puerarin-loaded microneedle in the soluble microneedle in example 4.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
Example 1
(1) Accurately weighing 1.0g of dextro-galactose and 1.0g of sodium carboxymethylcellulose, dissolving in 20mL of deionized water at room temperature, accurately weighing 20% of citric acid by mass fraction, stirring for dissolving, completely mixing, reacting for 10 hours under the condition of 50 ℃ water bath, and adjusting the pH value to 5 by using 50% NaOH to obtain the cross-linked polymer;
(2) the cross-linked polymer is further used for manufacturing the soluble micro-needle: measuring 2mL of the cross-linked polymer obtained in the step (1), adding trypan blue, and uniformly mixing to obtain 0.1mg/mL trypan blue mixed solution;
(3) weighing 2mL of the polymer obtained in the step (1), adding a rhodamine B coloring agent, and uniformly mixing to obtain 0.1mg/mL of rhodamine B mixed solution;
(4) placing the microneedle mould into a 5mL small centrifuge tube, transferring 300 mu L of the mixed solution obtained in the step (2) by using a liquid transferring gun, and paving the mixed solution on the surface of the mould; setting the centrifugal speed at 3000 rpm, centrifuging for 60 min for the first time, and taking out. And (4) transferring 500 mu L of the mixed solution obtained in the step (3) for the second time, and repeating the operation for the first time. And (3) taking out the mold, putting the mold into a 40 ℃ oven for drying for 48h, taking out the mold, and peeling the mold to obtain the microneedle as shown in figure 1.
As can be seen from fig. 1, the crosslinked polymer in this example was successfully prepared into the soluble microneedle having the shape of a needle tip and a base by two-time centrifugation and one-time oven drying at 40 ℃.
Example 2
(1) A cross-linked polymer is prepared by accurately weighing 1.0g of dextral galactose and 1.0g of sodium carboxymethylcellulose (CMC), dissolving in 20mL of deionized water at room temperature, accurately weighing 20% citric acid by mass fraction, stirring for dissolving, mixing completely, reacting in 50 deg.C water bath for 10h with pH of 1, and performing infrared test on cross-linking result as shown in figure 2, wherein the infrared spectrum of the product of example 2 is 1725.66cm -1 A new ester bond peak appears, indicating successful ester formation with citric acid. The cross-linked polymerization reaction of the sodium carboxymethylcellulose and the galactose is shown to be successfully prepared to obtain the cross-linked polymer.
(2) Drying the crosslinked polymer in the step (1) in an oven at 40 ℃ to form a film, weighing the mass of the film by using a precision balance, placing the film in a simulated constant humidity environment with the air temperature of 30 ℃ and a cup of 100mL water in a drying pan, placing the film in the simulated constant humidity environment for 5h, 10h, 15h, 20h and 25h, taking out the film, weighing the mass by using the precision balance, and calculating the moisture absorption rate of the polymer at different time points under the same humidity. As a comparative experiment, 1.0g galactose and 1.0g sodium carboxymethyl cellulose are accurately weighed, dissolved in 20mL deionized water, dissolved at room temperature, dried to form a film and placed under the same conditions to measure the moisture absorption rate of the uncrosslinked polymer, and as a result, as shown in FIG. 3, when the air temperature is 30 ℃, the moisture absorption rate of the uncrosslinked polymer is increased from 14.33% of the moisture absorption rate at 5h to 25.05% of the moisture absorption rate at 25h, and the moisture absorption rate of the crosslinked polymer is increased from 4.51% of the moisture absorption rate at 5h to 16.43% of the moisture absorption rate at 25h, and the moisture absorption rate of the uncrosslinked polymer is much higher than that of the crosslinked polymer with the increase of time, which shows that the moisture resistance of the uncrosslinked polymer is improved as compared with the moisture resistance of the crosslinked polymer chemically crosslinked by citric acid.
(3) And (3) testing the solubility: in order to observe the solubility of the microneedle prepared from the cross-linked polymer, the microneedle is pressed on the in-vitro pigskin for 1h, 3h, 7h, 10h, 12h and 24h, and then the change of the microneedle is observed as shown in fig. 4, as can be seen from fig. 4, the shape of the tip of the microneedle is observed by a microscope after the microneedle is inserted into the pigskin for a certain time, the volume of the microneedle is gradually reduced along with the extension of the staying time, and the microneedle prepared by the microneedle has good solubility.
Example 3
(1) A cross-linked polymer is prepared by accurately weighing 1.0g of dextro-galactose and 1.0g of sodium carboxymethylcellulose, dissolving in 20mL of deionized water, dissolving at room temperature, accurately weighing 20% by mass of citric acid, stirring for dissolving, completely mixing, reacting for 10 hours under the condition of 50 ℃ water bath, adjusting the pH value to 5 by using 50% NaOH, and performing a cross-linking result infrared test as shown in figure 2. As can be seen from figure 2, an infrared spectrogram of a product of example 3 is consistent with an infrared spectrogram of a CMC-galactose cross-linked polymer, which shows that the sodium carboxymethylcellulose and the galactose are subjected to a cross-linking polymerization reaction, and the cross-linked polymer is successfully prepared.
(2) Drying the polymer in the step (1) in an oven at 40 ℃ to form a film, weighing the mass of the film by using a precision balance, placing the film in a simulated constant humidity environment in a drying pot with the air temperature of 30 ℃ and a cup of 100mL water, placing in the container for 5h, 10h, 15h, 20h and 25h, taking out, weighing with a precision balance, calculating the moisture absorption rate of the polymer at different time points under the same humidity for comparison, accurately weighing 1.0g galactose and 1.0g sodium carboxymethylcellulose, dissolving in 20mL deionized water, the moisture absorption rate of the uncrosslinked polymer was measured under the same conditions after dissolving at room temperature and drying to form a film, and the results are shown in FIG. 5, as can be seen from FIG. 5, when the air temperature was 30 ℃, the moisture absorption rate of the uncrosslinked polymer was greater than that of the crosslinked polymer, indicating that the uncrosslinked polymer was inferior in moisture resistance.
(3) And (3) testing the solubility: in order to observe the solubility of the microneedle prepared from the cross-linked polymer, the microneedle is pressed on the in vitro pigskin for 5min, 7min, 9min and 15min, and the shape change of the microneedle is observed as shown in fig. 6, which shows that the volume of the microneedle is gradually reduced along with the extension of the staying time, and the prepared microneedle has good solubility.
(4) And (3) carrying out micro-needle puncture performance test on in vitro pigskin: the water remained on the surface of the skin of the in-vitro pigskin is removed by using filter paper before use, the corium side is placed downwards and fixed on a laboratory bench, a 1000N weight is used for pressing a microneedle patch to vertically administer the medicine, the microneedle patch is removed after 30s, the obvious pinhole array form is shown in figure 7, and as can be seen from figure 7, through the test of the puncture performance of the microneedle on the in-vitro pigskin, the result shows that the 1000N force is applied to the double-layer microneedle, the surface of the pigskin is obviously perforated, and the pigskin has good mechanical hardness.
Example 4
Preparation of puerarin-carried micro needle and drug release test thereof
(1) Accurately weighing 1.0g of dextro-galactose and 1.0g of sodium carboxymethylcellulose, dissolving in 20mL of deionized water at room temperature, accurately weighing 20% by mass of citric acid, stirring for dissolving, mixing completely, reacting for 10h under the condition of 50 ℃ water bath, and adjusting the pH value to be 5 by using 50% NaOH.
(2) And (2) measuring 4mL of the cross-linked polymer solution obtained in the step (1), accurately weighing puerarin, dissolving and uniformly mixing to obtain 20mg/mL puerarin mixed solution.
(3) Placing the microneedle mould into a 5mL small centrifuge tube, transferring the mixed solution obtained in the step (2) by using a liquid transfer gun, and paving the mixed solution on the surface of the mould; setting the centrifugal speed at 3000 rpm, centrifuging for 60 min for the first time, and taking out. And (5) carrying out second transfer of the mixed liquid obtained in the step (1), and repeating the first operation. And taking out the mold, putting the mold into a 40 ℃ oven to be dried for 48h, taking out the mold, and peeling the mold to obtain the puerarin-loaded microneedle.
(4) In order to study the drug release of the puerarin-loaded micro-needles in vitro, 100 micro-needles were completely dissolved in deionized water, and the total amount of puerarin in the micro-needles was measured by ultraviolet-visible spectrophotometry (UV-VIS). Inserting the microneedle prepared under the same conditions into the in-vitro pigskin, removing the microneedle from the pigskin after a certain time, completely dissolving the microneedle in deionized water, measuring the content of the remaining puerarin in the microneedle by using an ultraviolet-visible spectrophotometry (UV-VIS), and calculating the amount of the puerarin released into the pigskin as shown in FIG. 8. As can be seen from FIG. 8, the in vitro drug release amount of the 100-needle puerarin microneedle increased with time, and the maximum drug release amount was 0.1033 mg.
The result of the test on the puncture performance of the in vitro pigskin by the micro needle shows that the 1000N force is applied to the double-layer microneedle, the surface of the pigskin has obvious perforation, and the pigskin has good mechanical hardness. After the pig skin is inserted for a certain time, the shape of the needle point of the microneedle is observed by a microscope, and the volume of the microneedle is shown to be gradually reduced along with the extension of the staying, so that the prepared microneedle has good solubility. The humidity test result shows that the air temperature is 30 ℃, the humidity is 25.05%, and when the microneedle to be tested is placed for 25 hours, the moisture absorption rate of the crosslinked microneedle is reduced to 16.43%, and the shape of the microneedle is kept unchanged. Under the maximum drug-loading rate of the puerarin, the maximum drug release amount of 100 micro-needles obtained by the mould is 0.1033 mg. The therapeutic dose of the puerarin injection is 100 mg-200 mg, and the prepared 10 micro-needles can meet the requirement of administration, and the area of the micro-needles is equivalent to the area of a common plaster patch, namely 9cm by 12 cm; the invention provides a preparation method of a novel cross-linked polymer soluble microneedle patch, which is simple and easy to implement, does not need special equipment and a manufacturing process and is simple to operate.
Example 5
(1) Accurately weighing 1.0g of dextral galactose and 3.0g of sodium carboxymethylcellulose, dissolving in 20mL of deionized water at room temperature, accurately weighing 10% citric acid by mass fraction, stirring for dissolving, mixing completely, reacting for 5 hours under the condition of 80 ℃ water bath, and adjusting pH to 5 by using 50% NaOH to obtain the cross-linked polymer;
(2) the cross-linked polymer is further used for manufacturing the soluble micro-needle: measuring 2mL of the cross-linked polymer in the step (1), adding trypan blue, and uniformly mixing to obtain 0.1mg/mL trypan blue mixed solution;
(3) weighing 2mL of the polymer in the step (1), adding a rhodamine B coloring agent, and uniformly mixing to obtain 0.1mg/mL of rhodamine B mixed solution;
(4) placing the microneedle mould into a 5mL small centrifuge tube, transferring 300 mu L of the mixed solution obtained in the step (2) by using a liquid transferring gun, and paving the mixed solution on the surface of the mould; setting the centrifugal speed at 4500 rpm, centrifuging for 90 min for the first time, and taking out. And (4) transferring 500 mu L of the mixed solution obtained in the step (3) for the second time, and repeating the operation for the first time. And (3) taking out the mold, putting the mold into a 45 ℃ oven for drying for 24h, taking out the mold, and peeling the mold to obtain the microneedle as shown in figure 1.
As can be seen from fig. 1, the crosslinked polymer in this embodiment is successfully prepared into the soluble microneedle having the shape of a needle tip and a base by two times of centrifugation and one time of oven drying at 40 ℃.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes or modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.
Claims (5)
1. The application of a cross-linked polymer is characterized in that the cross-linked polymer is used for preparing a soluble microneedle, and the soluble microneedle comprises a base and a needle tip; the preparation method comprises the following steps:
(1) preparation of the needle tip part: taking a microneedle mould, using a pipette to take a cross-linked polymer solution to be flatly laid on the surface of the microneedle mould, and carrying out first centrifugal treatment to obtain the needle tip part;
(2) preparation of the base part: taking out the microneedle mould, using a pipette to take the cross-linked polymer solution to be flatly laid on the surface of the microneedle mould, and carrying out second centrifugal treatment to obtain the base part;
(3) preparation of soluble microneedles: taking out the microneedle mould, drying, and peeling off the microneedle mould to obtain the soluble microneedle;
the crosslinked polymer is prepared by the following method:
stirring and dissolving sodium carboxymethylcellulose and galactose in water to obtain a mixture, adding a cross-linking agent, stirring and dissolving, adjusting the system to the reaction temperature for polymerization, and adjusting the pH of a reaction product to 1-5 after the reaction is finished to obtain the cross-linked polymer; the cross-linking agent is citric acid and derivatives thereof;
the reaction temperature is 50-80 ℃; the reaction time of the polymerization reaction is 5-10 h;
the ratio of the sodium carboxymethylcellulose to the galactose is 1g: 1-3 g;
the addition amount of the citric acid is 10% -20% of the mass of the mixture.
2. The use of a crosslinked polymer according to claim 1, wherein the first and second centrifugation are performed at a centrifugation speed of 3000 to 4500 rpm for 60 to 90 minutes.
3. The use of a crosslinked polymer according to claim 2, wherein the drying treatment is drying at 40-45 ℃ for 24-48 h.
4. The use of a crosslinked polymer according to claim 1, wherein in step (1), the poorly water soluble drug is added to the crosslinked polymer solution, and the mixture is dissolved and mixed uniformly to obtain a poorly water soluble drug mixture, wherein the poorly water soluble drug mixture is used for manufacturing the needle tip portion.
5. The use of a crosslinked polymer according to claim 4, wherein in step (1), the poorly water-soluble drug is puerarin.
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| CN109364017A (en) * | 2018-09-03 | 2019-02-22 | 中山大学 | Quick separating type solubility micropin and preparation method thereof |
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