CN111920942A - Polymer microneedle for rapidly dissolving tophus and preparation method and application - Google Patents
Polymer microneedle for rapidly dissolving tophus and preparation method and application Download PDFInfo
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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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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4415—Pyridoxine, i.e. Vitamin B6
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
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- 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
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- 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
- A61K47/38—Cellulose; Derivatives thereof
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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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y107/00—Oxidoreductases acting on other nitrogenous compounds as donors (1.7)
- C12Y107/03—Oxidoreductases acting on other nitrogenous compounds as donors (1.7) with oxygen as acceptor (1.7.3)
- C12Y107/03003—Factor-independent urate hydroxylase (1.7.3.3), i.e. uricase
Abstract
The application discloses a polymer microneedle for rapidly dissolving tophus as well as a preparation method and application of the polymer microneedle. According to the polymer microneedle, the needle tip is embedded with the uric acid reducing pharmaceutical composition wrapped by the nano material; the pharmaceutical composition contains 0.005-0.05 weight parts of urate oxidase, 0.05-0.15 weight parts of sodium carbonate, 0.05-0.30 weight parts of sodium bicarbonate, 0.15-0.5 weight parts of magnesium chloride, and 1-2% of vitamin B6 by weight of urate oxidase. The polymer microneedle is directly attached to the disease sign part, the use is simple and convenient, the drug directly acts on the tophus to dissolve crystals, and the treatment effect is better; the drug can fully act with the urate crystal by being wrapped by the nano material, so that the fixed-point crystal dissolving effect is better, and the utilization rate of the drug is higher; almost has no toxic and side effect, and provides a more efficient and safe treatment scheme for clinically treating various diseases caused by high uric acid or high uric acid crystal deposition.
Description
Technical Field
The application relates to the technical field of tophus treatment, in particular to a polymer microneedle for quickly dissolving tophus as well as a preparation method and application of the polymer microneedle.
Background
Tophus, also known as gout nodule, is a crystal formed by deposition of uric acid in the joint capsule, synovial capsule, cartilage, bone or other tissues, and is commonly seen in patients with hyperuricemia and gout. Gout is common in the metatarsophalangeal joint of the big toe and may also occur in other larger joints, especially the ankle and foot joints. Due to repeated attack and tophus compression, not only tissue damage is caused, but also erosion of joint ends of sclerotin and deposition of tophus cause the joints to be in chronic inflammation, joint deformity or functional disorder, finally, joint cartilage degeneration, destruction and hyperosteogeny have extremely high disability rate, and daily life is seriously influenced. Superficial pain whetstone is easily broken to form skin ulcer, the wound is difficult to heal and the infection risk is increased. Therefore, the medicine can dissolve the tophus safely, quickly and effectively in clinic, and is a problem which needs to be solved urgently by patients with the gouty arthritis.
Uric acid is the final product of purine metabolism, and uric acid produced by oxidation of various purines is excreted with urine. Normally, uric acid in a human body is about 1200mg, about 600mg is newly generated every day, and about 600mg is metabolized and excreted; therefore, the production and excretion rates of uric acid in normal human bodies are almost constant and in an equilibrium state. However, if uric acid is produced too much to be excreted, or the excretion mechanism of uric acid is degraded, uric acid is retained in the body; in the past, symptoms such as gout were further caused. Therefore, the change of uric acid content in body fluid can reflect the conditions of metabolism, immunity and other functions in human body.
Clinically, the normal value of male uric acid is 149-416 mu mol/L, and the normal value of female uric acid is 89-357 mu mol 1/L; if the above index is exceeded, it is judged to be hyperuricemia. Hyperuricemia appears differently in different stages and can be classified into asymptomatic hyperuricemia and acute hyperuricemic arthritis. The asymptomatic hyperuricemia means that the blood uric acid concentration is increased in a blood drawing test, but no clinical symptoms of any related diseases appear. Although the duration of asymptomatic hyperuricemia can be long, there is still a major risk. Thus, both asymptomatic hyperuricemia and acute hyperuricemic arthritis; it is necessary to reduce uric acid to a standard level by dietary or pharmaceutical intervention.
The western medicine mainly has two schemes aiming at critical hyperuricemia, hyperuricemia and gout: firstly, through a chemical synthesis inhibitor, the activity of uricase group generation in the liver is inhibited, thereby reducing the production amount of uric acid; secondly, the reabsorption of uric acid by renal tubules is inhibited through a chemically synthesized inhibitor, so that the excretion of uric acid is increased; or the two schemes are mixed for use. The effect of dissolving and depositing urate crystals at joints and other parts is achieved by reducing hyperuricemia in vivo to cause the concentration gradient difference of urate. However, both of these proposals cause damage to the kidney and even chronic toxic reactions in the liver, spleen, heart, pancreas and bone marrow. Patients who have repeated gout with tophus deposits that cannot be dissolved by systemic uric acid reduction often require surgical invasive surgery to remove the stones. Wounds after surgical stone removal are difficult to heal, the risk of infection is obviously increased, and the adverse factors further aggravate local joint destruction damage and seriously affect the life quality of gout patients.
In the aspect of domestic clinical application, organic alkaloid extracted from plants or inorganic alkali existing in the nature is mainly adopted to have neutralization reaction with uric acid, so that the content of uric acid is reduced. However, the practical effect of clinical application is low, local crystallization is slow, and the use requirement is difficult to meet. In addition, the use of alkaline elements in large doses is also prone to cause alkalosis.
The micro-needle administration technology is a novel minimally invasive administration technology, and micro-needles with the diameter of more than 50 microns, such as 500 microns, are adopted to pierce the stratum corneum of a human body to form a channel which is favorable for drug delivery and promote the transdermal absorption of drugs. The microneedle can penetrate the stratum corneum of the skin to reach the deep layer of the skin, does not produce pain, and has the characteristics of high efficiency, no first-pass effect, convenient administration and the like. The array microneedles may be classified into inorganic microneedles, metallic microneedles, and polymer microneedles, depending on the composition of the material. The polymer microneedle is prepared from a polymer material with good biocompatibility, and the adverse effect on skin is not worried even if the microneedle is broken; therefore, the polymer microneedle has the characteristic of safe administration. In addition, the polymer microneedle has low cost of raw materials and easy processing, and is the microneedle with the most prospect at present.
The existing medicines for reducing uric acid or treating hyperuricemia and gouty arthritis are generally taken orally, and related researches and reports of micro-needle administration are few.
Disclosure of Invention
The purpose of the present application is to provide a novel polymer microneedle for rapidly dissolving tophus, and a preparation method and application thereof.
The following technical scheme is adopted in the application:
one aspect of the application discloses a polymer microneedle for rapidly dissolving tophus, wherein a needle tip of the polymer microneedle is embedded with a pharmaceutical composition for reducing uric acid, and the pharmaceutical composition is wrapped by a nano material; the pharmaceutical composition contains 0.005-0.05 weight parts of urate oxidase, 0.05-0.15 weight parts of sodium carbonate, 0.05-0.30 weight parts of sodium bicarbonate, 0.15-0.5 weight parts of magnesium chloride and 1-2% of vitamin B6 by weight of urate oxidase. The urate oxidase adopted by the application is natural uricase, human recombinant uricase or polyethylene glycol modified uricase.
The invention creatively provides a mode of micro-needle administration for dissolving the tophus to treat diseases such as gout arthritis and the like caused by uric acid crystallization, and develops a pharmaceutical composition suitable for micro-needle administration and a dosage form thereof; the polymer microneedle is attached to the disease symptom part, so that uric acid crystals can be conveniently and effectively reduced, and related diseases caused by high uric acid, especially gout arthritis, can be treated; moreover, the poisoning phenomenon can be reduced to the maximum extent by microneedle administration, and the damage to the kidney, the liver, the spleen, the heart, the pancreas, the bone marrow and the like can be reduced. It can be understood that the polymer microneedle of the application directly acts on a disease symptom part, directly acts on a tophus and degrades uric acid crystals; compared with the existing mode of dissolving uric acid crystals by reducing uric acid in blood and utilizing the difference of uric acid concentration, the polymer microneedle has better treatment effect.
It should be further noted that, in terms of controlled release of the drug, the polymer microneedle of the present application uses a biodegradable nanomaterial to encapsulate the drug composition to achieve the effect of controlled release. The urate oxidase is coated by biodegradable nano materials, and after the medicine enters a human body, the nano particles can be degraded and release the medicine after a certain time, so that the medicine can fully act with urate crystals at a focus part (such as a gout joint), and the urate oxidase has better fixed-point and targeted crystal dissolving effects and higher biological absorption rate and utilization rate. Generally speaking, the polymer microneedle combines the nanoparticles and the microneedle patch for controlled drug release, and has the advantages of painless minimally invasive property, convenience, easiness in use, high drug utilization rate and the like.
Preferably, the microneedle pharmaceutical composition further comprises a trace element, wherein the trace element is at least one of organic germanium, manganese, copper, selenium, zinc and potassium elements.
The trace elements can activate oxidase groups in vivo, and can be matched with the pharmaceutical composition of the application to improve the uric acid reducing effect of urate oxidase, and particularly have a better crystal dissolving effect on gouty arthritis.
Preferably, the amount of each element in the trace elements is 0.1-0.5% by weight of urate oxidase.
Preferably, the nanomaterial is a polylactic acid-glycolic acid copolymer.
Preferably, the polymeric microneedles are made from sodium carboxymethylcellulose.
The application also discloses application of the polymer microneedle in preparing a medicine for treating critical hyperuricemia, hyperuricemia or gouty arthritis. The traditional Chinese medicine composition for treating gouty arthritis is mainly capable of quickly and effectively dissolving uric acid crystals deposited on gouty joint parts, and avoiding pain of traditional surgical traumatic stone removal.
It can be understood that the polymer microneedle of the present application has a good effect of dissolving uric acid crystals, and thus can be used for treating various diseases caused by hyperuricemia, including critical hyperuricemia, gouty arthritis, and the like.
Yet another aspect of the present application discloses a method of preparing a polymer microneedle of the present application, comprising the steps of:
preparing a pharmaceutical composition, which comprises mixing urate oxidase and phosphoric acid buffer pair according to a ratio, adding polylactic acid-glycolic acid copolymer solution, dispersing uniformly, and preparing first nanoparticles by a spray dryer; mixing sodium carbonate, sodium bicarbonate, magnesium chloride, vitamin B6 and trace elements, adding polylactic acid-glycolic acid copolymer solution, dispersing uniformly, and preparing into second nanoparticles by a spray dryer; uniformly mixing the first nanoparticles and the second nanoparticles in proportion to obtain a pharmaceutical composition;
a step of coating the pharmaceutical composition, which comprises dissolving the polylactic acid-glycolic acid copolymer in an organic solvent to prepare a coating material solution; uniformly dispersing the prepared nano particles of the pharmaceutical composition into the prepared wrapping material solution, and adding a vitamin E polyethylene glycol succinate solution to form nano particles, so as to obtain the pharmaceutical composition wrapped by the nano material;
preparing polymer microneedles, namely adding the pharmaceutical composition wrapped by the nanomaterials into a sodium carboxymethylcellulose solution according to the dosage of each polymer microneedle to prepare a mixed solution, pouring the mixed solution into a microneedle patch mould, and then carrying out centrifugal treatment in a centrifugal machine to ensure that the mixed solution enters a pinhole cavity of the microneedle patch mould and most of the pharmaceutical composition wrapped by the nanomaterials is deposited at a needle point; and then curing, forming and demolding to obtain the polymer microneedle of the application.
The demolding can refer to the existing polymer microneedle preparation method, for example, a substrate of a polymer microneedle patch is adopted and fixed on the substrate through adhesive bonding to perform demolding; or adopting sodium carboxymethyl cellulose solution without the drug composition coated by the nano material, and demoulding after solidification. The method is not particularly limited, and is specifically determined according to product design or production conditions.
Preferably, in the preparation method of the present application, the organic solvent used in the step of coating the pharmaceutical composition is ethyl acetate.
Preferably, in the preparation method of the present application, the nanoparticles are specifically prepared at a temperature of about 0 ℃ and about 3 ℃.
Preferably, in the preparation method of the present application, the centrifugal treatment conditions for the preparation of the polymer microneedles are 5000-6000rpm for 3-6 min.
The polymer microneedle is prepared by centrifugal treatment, and on one hand, the mixed solution can be filled into a pinhole cavity of a microneedle patch die by centrifugal force; on the other hand, most of the medicinal composition wrapped by the nano material can be deposited on the needle point, and the use efficiency of the polymer microneedle is improved.
The beneficial effect of this application lies in:
the polymer microneedle for reducing uric acid crystals and treating gout arthritis directly sticks the polymer microneedle patch to a disease symptom part, and is simple and convenient to use; the drug can be fully reacted with urate crystal by being wrapped by the nano material, so that the drug has better fixed-point and targeted crystal dissolving effects and higher drug utilization rate; and has almost no toxic and side effects. The polymer microneedle directly acts on tophus to directly dissolve uric acid crystals, and provides a more efficient and safe treatment scheme for clinically treating various diseases caused by high uric acid or deposition of high uric acid crystals.
Drawings
FIG. 1 is a graph of the results of HPLC analysis of a nanomaterial-encapsulated pharmaceutical composition in the examples of the present application;
fig. 2 is a schematic view of a polymer microneedle patch in use in an embodiment of the present application;
fig. 3 is a schematic view of a polymer microneedle patch of an embodiment of the present application releasing a drug after application to the skin;
FIG. 4 is a confocal fluorescence microscope observation of polymer microneedles in an example of the present application;
fig. 5 is a graph showing the results of HPLC analysis of urate oxidase after the polymer microneedle patch prepared in the example of the present application was left at room temperature for 20 hours;
fig. 6 is a graph showing the results of the urate oxidase HPLC analysis after the polymer microneedle patch prepared in the example of the present application was left at room temperature for 96 hours;
fig. 7 is a graph showing the results of the urate oxidase HPLC analysis after the polymer microneedle patch prepared in the example of the present application was left at room temperature for 5 days;
FIG. 8 shows the experimental results of the in vitro transdermal delivery of polymer microneedles in the examples of the present application;
FIG. 9 shows the uricase release test results of polymer micro-needle of poly (lactic-co-glycolic acid) -coated pharmaceutical composition in the examples of the present application;
FIG. 10 shows the results of uricase release test on polymeric microneedles of sodium carboxymethylcellulose-encapsulated pharmaceutical compositions according to examples of the present application;
FIG. 11 shows the results of the assay of uricase in vitro degrading high concentrations of uric acid in polymer microneedles in the examples of the present application.
Detailed Description
The present application will be described in detail with reference to specific examples. The following examples are intended to be illustrative of the present application and should not be construed as limiting the present application.
Examples
Preparation of pharmaceutical composition
The pharmaceutical composition of the embodiment comprises 0.005-0.05 weight parts of urate oxidase, 0.05-0.15 weight parts of sodium carbonate, 0.05-0.30 weight parts of sodium bicarbonate, 0.15-0.5 weight parts of magnesium chloride, and vitamin B6 accounting for 1-2% of urate oxidase; in addition, the composition also contains organic germanium, manganese, copper, selenium, zinc and potassium elements, the dosage of each element is 0.1-0.5% of the weight of the urate oxidase, wherein the organic germanium can be added to 1% of the weight of the urate oxidase according to the requirement. In this example, the pharmaceutical composition was prepared into nanoparticles and then used for subsequent experiments, and the specific preparation method is as follows:
weighing 0.05g of urate oxidase, dispersing in a phosphate buffer pair consisting of sodium dihydrogen phosphate and disodium hydrogen phosphate and having a pH value of 7.1-9.0, adding a small amount of polylactic acid-glycolic acid copolymer solution, wherein the amount of polylactic acid-glycolic acid copolymer is about 20% -70% of the urate oxidase, and preparing into first nanoparticles by using a spray dryer.
Weighing 0.15g of sodium carbonate, 0.30g of sodium bicarbonate, 0.5g of magnesium chloride, 2% of vitamin B6 by weight of urate oxidase, 0.5% of organic manganese by weight of urate oxidase, 0.5% of organic copper by weight of urate oxidase, 0.5% of organic selenium by weight of urate oxidase, 0.5% of organic zinc by weight of urate oxidase, 0.5% of organic potassium by weight of urate oxidase and 1% of organic germanium by weight of urate oxidase, uniformly mixing, adding into a polylactic acid-glycolic acid copolymer solution, uniformly dispersing, wherein the dosage of the polylactic acid-glycolic acid copolymer is about 20% -70% of the weight of urate oxidase, and preparing into second nanoparticles by adopting a spray dryer.
The first nanoparticles and the second nanoparticles are mixed uniformly to obtain the pharmaceutical composition of the present example.
Second, nano-encapsulation and detection of pharmaceutical composition
1. Nanoparticle preparation
In this example, polylactic-co-glycolic acid (abbreviated as PLGA) was used as the coating material, and the specific coating method was as follows:
(1) weighing 6g of PLGA, and dissolving the PLGA in 60mL of organic solvent ethyl acetate to prepare a wrapping material solution;
(2) preparing 2.7L vitamin E polyethylene glycol succinate solution with concentration of 0.3% w/v for later use;
(3) adding the medicinal composition obtained by the step one and the step one of medicinal composition preparation into the wrapping material solution, and uniformly dispersing; then, dripping the packaging material solution containing the pharmaceutical composition into a vitamin E polyethylene glycol succinate solution with twice volume by using a Pasteur pipette, and carrying out high-speed oscillation while dripping until the addition is finished, and then continuing to oscillate for 15s to obtain an emulsion; transferring the emulsion into an ultrasonic generator, keeping the container immersed in ice water, and carrying out ultrasonic treatment for four times, 8s each time, wherein an ultrasonic instrument of 800W is adopted in the embodiment, the amplitude is 35%, the size of the probe tip is 1/8, the ultrasonic treatment is suspended between 8s each time to cool the solution, and then the probe is moved up and down to ensure uniform ultrasonic treatment;
(4) transferring all the products subjected to ultrasonic treatment in the step (3) into the rest vitamin E polyethylene glycol succinate solution, and continuously stirring for three hours to harden the nanoparticles to obtain the pharmaceutical composition wrapped by the nanomaterial;
(5) and (3) averagely dividing the product obtained in the step (4) into two centrifuge tubes, centrifuging for 30min at 17000 g, removing supernatant, adding 30mL of deionized water into each centrifuge tube, washing at least twice, and finally re-suspending by adopting 10mL of deionized water to obtain suspension, namely the nano material-coated pharmaceutical composition (nanoparticles), which can be used for subsequent experiments.
2. Wrap rate detection
Accurately weighing 5mg of the prepared pharmaceutical composition wrapped by the nano material, and dissolving the pharmaceutical composition in 4mL of acetonitrile to obtain a detection solution; the detection solution was filtered through a 0.22 μm teflon syringe filter and then analyzed by High Pressure Liquid Chromatography (HPLC).
This example uses a Waters 2695Separation Module system (Waters Corp., Milford, MA, USA), TSKgel UP-SW Columns (4.6X 30cm), and is kept at room temperature; the detection wavelength is 220nm, and the flow rate is 1 mL/min; the mobile phase is a mixture of methanol 70 and water 30; the injection amount is 20 mL; the amount of urate oxidase per injection was calculated using the calibration line.
The measurement results are shown in fig. 1, and the results show that almost all the drug in the nanomaterial-encapsulated pharmaceutical composition prepared in this example is encapsulated in the PLGA nanoparticles, and the encapsulation rate reaches over 90%.
3. Nanomaterial-encapsulated pharmaceutical composition release rate measurement
20mg of the prepared nanomaterial-encapsulated pharmaceutical composition was added to a 10mL capped glass vial and added to 6mL of a 20mM PBS solution at pH 7.4. Wherein, the PBS solution contains 20% methanol by volume, and the effect of the methanol is to accelerate the drug release. The vial was shaken in a shaker at 50rpm and the temperature was set at 37 ℃. At each preset interval, the vial was removed from the shaker and allowed to stand for several minutes to allow the microspheres to settle to the bottom. Then, 1mL of the supernatant was removed and an equal amount of fresh methanol-containing PBS was added. The vial was placed back in the shaker. The removed solution samples were analyzed using an HPLC system and the methods described above.
The measurement result shows that the slow release time of the drug composition wrapped by the nano material is about 5 days; in addition, the release speed of the drug can be controlled by controlling the dosage of the polylactic acid-glycolic acid copolymer, so that the sustained release effect is achieved, and the release time of the drug can be controlled to realize a better drug utilization effect.
4. Stability testing of nanomaterial-encapsulated pharmaceutical compositions
The degradation degree of the nanoparticles is judged by detecting the molecular weight change of the polylactic acid-glycolic acid copolymer serving as the coating material of the nanoparticles, so as to represent the stability of the nanoparticles of the pharmaceutical composition coated by the nanoparticles.
Specifically, this example tests the degree of molecular weight decrease of the polylactic acid-glycolic acid copolymer after the nanoparticles are left at room temperature (about 25 ℃) for 1 day, 2 days, 5 days, 10 days, and 15 days, respectively. The method for measuring the molecular weight comprises the following steps: determining the molecular weight of the original and degraded polymer samples by gel permeation chromatography; wherein the gel permeation color system consists of a Waters HPLC pump and a differential refraction detector; two gel permeation chromatography columns of polystyrene type cross-linked copolymer were connected together to cover a wider range of molecular weights, maintaining the temperature at 35 ℃; connecting a polystyrene type cross-linked copolymer protective column before two gel permeation chromatographic columns; chloroform was used as a mobile phase at a flow rate of 1mL/min and an injection volume of 100. mu.L; polystyrene standards were used to establish molecular weight calibration lines.
The measurement results show that the molecular weight of the nanoparticles hardly decreases within 1 day in the nanomaterial-encapsulated pharmaceutical composition of this example, the molecular weight decreases by only about 10% within 5 days, and the time for 50% decrease in molecular weight is longer than 10 days, indicating that the nanoparticles of this example have good stability.
Preparation and detection of polymer microneedle
1. Polymer microneedle preparation
Dissolving the pharmaceutical composition wrapped by the nano material prepared in the embodiment in a 10% sodium carboxymethyl cellulose solution to prepare a mixed solution; wherein, the amount of the pharmaceutical composition is 5 percent to 20 percent (W/W) of the sodium carboxymethyl cellulose, and the embodiment is 20 percent (W/W). Adding 75 mu L of the mixed solution into a microneedle patch mould, placing the mould in a centrifuge and centrifuging at 6000rpm for 4min to ensure that the mixed solution fully enters a pinhole cavity on the mould and most of the medicinal composition wrapped by the nanomaterial is deposited on a needle point. After centrifugation, the mixed solution was removed from the cavity and allowed to air dry overnight to allow the mixed solution to solidify. Then, 300. mu.L of a 10% sodium carboxymethylcellulose solution was added to the mold, and the mixture was centrifuged at 4000rpm for 1 min. After centrifugation, the mold was allowed to stand and air dried overnight to form microneedle patches. After the patch was formed, the patch was peeled off from the mold, and the polymer microneedle patch of this example was obtained. The polymer microneedle patch of this example had a base area of 1.5cm by 1.5cm, a microneedle density of 100 needles per square centimeter, and a microneedle height of about 500 μm to 1 mm. It will be appreciated that the footprint of the patch and the density of microneedles are both dependent on the mould; the height of the microneedles depends on the mold on the one hand and on whether the mixed solution effectively enters the pinhole cavity of the mold on the other hand; although the mixed solution is fully introduced into the pinhole cavity by centrifugation, the mixed solution still cannot completely fill the pinhole cavity, so that the height of the microneedle is 500-1 mm, and the height range can meet the use requirement.
Wherein, after 50 mul of mixed solution is added into a microneedle patch mould, the centrifugation speed can be 5000-6000rpm, the centrifugation time is generally 3-6min, under the condition, the mixed solution can fully enter a pinhole cavity of the mould, and most of the medicinal composition wrapped by the nano material can be deposited at the tip of a microneedle, thereby facilitating the release of the medicament.
When the microneedle patch of the present embodiment is used, as shown in fig. 2, the microneedle patch 01 is directly applied to the affected part; the microneedles of the microneedle patch 01 penetrate the epidermis 11 and dermis 12, and the tips of the needles slightly contact the subcutaneous tissue 13, releasing the drugs directly to the urate crystallization sites. In fig. 2, a is a schematic view of the microneedle patch applied to an affected part; b is a schematic diagram of the drug composition wrapped by the nano-material in the micro-needle, wherein 02 represents urate oxidase drug composition nano-particles; panel C is a schematic diagram of the diseased part of the patient, and 14 in panels A and C represents urate crystals. The polymer microneedle is shown in fig. 3, the bottom of the polymer microneedle is a water-soluble sodium hydroxymethyl cellulose base 31, and the needle tip part contains a large amount of urate oxidase drug composition 32 coated by aqueous polylactic acid-glycolic acid copolymer; after the microneedle is inserted into the skin, its action process is shown in fig. 3, including penetration 33, implantation 34, rapid release 35, and sustained release 36; after the needle is penetrated 33, the needle point part stays in the skin, the medicine composition wrapped by the nanometer material is planted at the affected part, the medicine composition wrapped by the nanometer material is quickly released from the needle point part of the microneedle, and the medicine is continuously released in the biodegradation process of the nanometer wrapping material; the medicinal composition wrapped by the nano material is gradually released by controlling the biodegradation of the micro needle; the degradation of the nano-coating material is controlled, and the drug composition is slowly released, so that the drug composition can be applied to the disease symptom part for a long time, the utilization rate and the action period of the drug composition are improved, and the effect of effectively degrading the tophus is achieved.
2. Polymer microneedle drug distribution testing
In order to observe the distribution of the drugs in the polymer microneedle, the present example adds the fluorescent dye sulforhodamine B into the wrapping material of the drug composition nano-microsphere, namely the polylactic acid-glycolic acid copolymer, and adds the fluorescent dye coumalin 314 into the sodium carboxymethylcellulose for preparing the polymer microneedle; preparing polymer microneedles according to the foregoing method; then observing the distribution of fluorescent molecules by using a confocal fluorescent microscope; and judging the distribution of the drug composition nano-microspheres in the polymer microneedles according to the distribution conditions of the fluorescent dye sulforhodamine B and the fluorescent dye kumalin 314.
The results are shown in fig. 4, (1) is an observation result diagram of the fluorescent dye coumalin 314, (2) is an observation result diagram of the fluorescent dye sulforhodamine B, and (3) is a superimposed view of two fluorescence channels of the coumalin 314 and the sulforhodamine B. The results in fig. 4 show that most of the fluorescent dye is distributed at the tip of the microneedle, consistent with the expected results.
3. Drug stability testing of polymeric microneedles
The effective amount of urate oxidase in freshly prepared polymer microneedle patches was tested in this example; then testing the effective amount of urate oxidase after the polymer microneedle patch is placed at the storage temperature of 4 ℃ for 10 days; and the effective amount of urate oxidase after a freshly prepared polymer microneedle patch was left at 95 ℃ for 1 hour was tested as a negative control. Wherein the effective amount is the ratio of the content of the active urate oxidase measured by the microneedle patch to the content of the active urate oxidase originally added in the microneedle patch; the content of active urate oxidase originally added in the microneedle patch is a theoretical value determined according to product design and formula. By detecting the effective amount of urate oxidase, the stability of the pharmaceutical composition in the microneedles and during storage of the microneedles can be assessed.
The test result shows that: the effective amount of urate oxidase in the freshly prepared polymer microneedle patch is more than 95 percent; the effective amount of the urate oxidase in the polymer microneedle patch after being placed at 4 ℃ for 10 days is still more than 85%; while the effective amount of urate oxidase in the negative control test polymer microneedle patch is only about 2%. Therefore, the polymer microneedle patch of the embodiment can be stored at 4 ℃, so that the stability of the medicine in the polymer microneedle patch can be better guaranteed.
This example also tested urate oxidase after the prepared polymer microneedle patch was left at room temperature (about 25 ℃) for 20 hours, 96 hours, and 5 days, respectively. The test method is that the microneedles of the polymer microneedle patch are inserted and soaked in a PBS solution (containing 20% methanol by volume) with a pH of 7.4 concentration of 20mM for 2 hours to sufficiently dissolve the drug to be released in the PBS solution, and then the urate oxidase is analyzed using an HPLC system. Wherein, the HPLC system is the same as the '2. encapsulation rate detection'.
The results are shown in fig. 5 to 7, where fig. 5 shows the results of measurement after leaving at room temperature for 20 hours, fig. 6 shows the results of measurement after leaving at room temperature for 96 hours, and fig. 7 shows the results of measurement after leaving at room temperature for 5 days. The results show that urate oxidase can be detected after being placed at room temperature for 5 days, which indicates that the polymer microneedle of the present example has good stability and can be placed at room temperature for a long time.
4. Polymer microneedle in vitro transdermal drug delivery experiment
In order to evaluate the time-dependent intradermal release rate of the microneedle urate oxidase, the sample was spiked with urate oxidase microneedles labeled with Cy3, and then the transfer efficiency and the drug release kinetics curve of the Cy 3-labeled urate oxidase were determined by measuring the fluorescence change of Cy3 in the pigskin sample at different time intervals.
Dividing the polymer microneedle patch prepared in the embodiment into 9 groups, and sequentially and respectively staying for 10s, 30s, lmin, 2min, 5min, l0min, 15min, 20min and 25min after each group is pricked into the pigskin; the polymer microneedle patch was then pulled out. And observing the appearance of the tip end of the micro needle of the pulled polymer micro needle patch and the entering and distribution conditions of the drugs in the pig skin by using a microscope, and detecting the content of the drugs in the micro needle patch before and after treatment by using a spectral fluorescence instrument.
Partial statistical results are shown in fig. 8, as the retention time increases, the microneedle patch absorbs tissue water in the pigskin and slowly dissolves to release tip drugs, and the fluorescence of the tip end of the microneedle slowly weakens; accordingly, the fluorescence intensity of the pig intradermal drug is gradually increased. In this example, about 50% of the urate oxidase embedded in the microneedle tip was released into the skin within 5 minutes, the peak release was between 10 and 20 minutes, and about 75% of the urate oxidase was released into the skin microenvironment.
Nanoparticle urate oxidase microneedle in vitro release experiment:
in order to further test the in vitro release characteristics of the nano-material coated uricase composition particles, polymeric microneedles of polylactic-co-glycolic acid (PLGA) coated pharmaceutical composition and polymeric microneedles of sodium carboxymethylcellulose (SCMC) coated pharmaceutical composition were prepared and tested. The preparation method of the sodium carboxymethylcellulose-coated composition refers to the existing conventional sodium carboxymethylcellulose microspheres.
In this example, microneedles of the polymer microneedle patch were inserted and immersed in 60 μ M uric acid solution preheated at 37 ℃ for 30min, and timing was started, and absorbance readings were taken at intervals of time from the uric acid solution, and changes in absorbance at 293nm were measured. The measured amount of uricase was then divided by the total amount of uricase loaded in the microneedles to calculate the cumulative uricase release rate.
The results are shown in fig. 9 and 10, where fig. 9 is a graph of the statistical results of the polymer microneedles in which the PLGA encapsulated pharmaceutical composition, and fig. 10 is a graph of the statistical results of the polymer microneedles in which the SCMC encapsulated pharmaceutical composition. The experimental results show that rapid dissolution of poly (lactic-co-glycolic acid) uricase particles in PBS, complete release of uricase in the sample within 30 minutes, as shown in figure 9, is consistent with our histological observations. On the other hand, uricase in SCMC microneedles showed biphasic release profiles, as shown in fig. 10, with approximately 60% and 80% of uricase released at 1 hour and 24 hours, respectively, and another 10% released slowly over the course of 7 days of the experiment.
5. Distribution test of drug released by polymer microneedle after skin penetration
Two groups of rats of 3 rats each under the same conditions were used in this example to perform a molecular distribution test after skin permeation of the drug released from the microneedle patch. Specifically, microneedle patches loaded with urate oxidase are applied to back skins of two groups of rats respectively, the microneedle patches are pulled out after 10 minutes, and the skins near penetrating positions of the two groups are dissected and prepared for imaging after 2 hours and 6 hours of treatment respectively; the frozen sections were imaged by confocal microscopy (EVOS M7000) to determine the distribution of released urate oxidase.
The results show that after 2 hours of treatment, there is a deposition of fluorescent molecules in the dermis at a depth of about 100 μm; after 6 hours of treatment, continued diffusion of the fluorescent molecules was observed in a larger area within the dermis layer near the needle puncture site. It can be seen that the microneedle patch of this example can stably carry a drug and deliver drug molecules into the skin.
6. Polymeric microneedle skin irritation test
In this example, the prepared microneedle patch was applied to the same position of the back skin of the rat once a day for 3 consecutive days in such a manner that the microneedle patch was attached for 10 minutes and then pulled out. The safety of the polymer microneedle patch of this example was evaluated by observing whether there was visible skin irritation on the skin treated with the microneedle patch.
The results showed that no visible irritation was observed on the skin treated with the polymer microneedle patch of this example, compared to the skin without any treatment. Dissecting the skin around the microneedle puncture site, performing histological examination, observing whether skin inflammatory cell infiltration exists, and using untreated skin as a control group; the results show that no significant infiltration of skin inflammatory cells was observed on skin repeatedly inserted with microneedle patches compared to untreated skin. The above test results show that the polymer microneedle patch of this example does not induce a significant inflammatory reaction in the skin, and is highly safe.
7. Uricase activity assay in polymeric microneedles
In this example, an equivalent amount of the pharmaceutical composition without nanomaterial encapsulation was used to prepare a polymer microneedle patch for testing the activity of urate oxidase in the polymer microneedle patch. The preparation of the polymer microneedle is the same as that of the polymer microneedle preparation 1.
Uric acid oxidase catalyzes uric acid degradation, uric acid has a characteristic absorption peak at 293nm, and the product after uric acid degradation has no absorption peak at the wavelength, so the amount of uric acid degraded by uric acid oxidase can be determined according to the decrease of the light absorption value at 293nm, then the uric acid concentration is calculated by using the molar extinction coefficient of uric acid, and the activity of uric acid oxidase can be calculated according to the change of the uric acid concentration.
Before testing, the UV spectrophotometer was adjusted to 293nm, preheated for 30min, and zeroed using boric acid-sodium borate buffer as a blank.
In this example, microneedles of the prepared polymer microneedle patch were inserted and immersed in 60 μ M uric acid solution preheated at 37 ℃ for 30min, timing was started, the absorbance reading of the uric acid solution was measured every 1min, and the change in absorbance at 293nm within 5min was measured.
Meanwhile, the example adopts the pig urate oxidase as a positive control, 3mL of the pig urate oxidase with the concentration of lmg/mL is added into 60 mu M uric acid solution preheated at 37 ℃ for 30min, timing is started, the uric acid solution is taken every 1min to measure the light absorption value reading, and the change condition of the light absorption at 293nm within 5min is measured.
In the example, PBS buffer solution is used as a negative control, 3mL of PBS buffer solution is added into 60 mu M uric acid solution preheated at 37 ℃ for 30min, timing is started, the uric acid solution is taken every 1min to measure the light absorption value reading, and the change of light absorption at 293nm within 5min is measured.
The amount of enzyme converting 1. mu. mol uric acid per minute to allantoin at 37 ℃ and pH8.5 was defined as one International Unit (IU). Uricase activity was calculated according to the following formula.
U＝(A0-A)÷5×Vt×df÷(11.254×Ve)
In the above formula: u is uricase activity unit; a0 is OD at the beginning of the reaction293Light absorption value, A is OD after 5min of reaction293The light absorption value of (a); vt is the total volume (mL) of the reaction solution; df is the dilution factor; 11.254 is micromolar extinction coefficient of uric acid at wavelength of 293 nm; ve is the volume of enzyme solution (mL).
The calculation results are shown in table 1.
TABLE 1 uricase Activity test results
| Detecting an object | Specific enzyme Activity (IU/mg) |
| Positive control | 4.53 |
| Polymeric microneedles | 6.37 |
| |
0 |
The results in table 1 show that the polymer microneedles of this example contain urate oxidase having catalytic activity, and the activity is significantly higher than that of the positive control. It can be understood that if the pharmaceutical composition coated by the nano material is adopted, the prepared polymer microneedle also has high-activity urate oxidase and a slow-release effect, and can better aim at the pathological parts deposited with urate crystals, such as gout joints and the like, so that the crystal dissolving effect and the drug utilization rate are improved.
8. Test for in-vitro degradation of high-concentration uric acid by urate oxidase in polymer microneedle
Uric acid oxidase catalyzes uric acid degradation, uric acid has a characteristic absorption peak at 293nm, and a product after uric acid degradation has no absorption peak at the wavelength, so the amount of uric acid degraded by the uric acid oxidase in the microneedle can be determined according to the decrease of the light absorption value at 293 nm. The example adopts uric acid with the concentration of 540 mu mol/L to simulate the in vitro dissolution curve of high-concentration uric acid crystals; pig urate oxidase 20mg was used as a positive control, and PBS buffer was used as a negative control.
Specifically, the present example tests the residual uric acid amounts of the microneedle patch, the positive control, and the negative control after high-concentration uric acid action for 0.5h, 1.0h, 2.0h, 4h, 8h, 12h, 24h, 48h, 72h, 96h, and 120h, respectively. The mode of the microneedle patch acting on high-concentration uric acid is that the microneedle of the microneedle patch is soaked in high-concentration uric acid, and the specific reference is '7. uricoxidase activity test in polymer microneedle'; the pig urate oxidase and PBS buffer solution are directly added into high-concentration uric acid.
The test results are shown in fig. 11, in which the abscissa of fig. 11 is the action time and the ordinate is the ratio of residual uric acid/uric acid in the original high-concentration uric acid solution. The results in fig. 11 show that the polymer microneedles of this example contain catalytically active uricase, and although the rate of uric acid degradation by the microneedle patch of this example is slightly slower than that of the positive control, the same uric acid-lowering effect can be achieved by both the microneedle patch and the positive control, pig uricase, after 12 hours of action.
It can be understood that the microneedle patch of the present application has a slow release effect, and thus, the degradation speed of uric acid is slightly slower than that of the positive control pig uricase directly added to high-concentration uric acid; however, the final uric acid lowering effect was consistent, with no significant difference, consistent with expectations.
9. Polymer microneedle chamber thermal stability testing
In this example, the uricase activity of freshly prepared polymer microneedles was tested, and then the uricase activity of the polymer microneedles after being left at 30 ℃ for 5 days was tested, and the enzyme activity retention rate was calculated. Meanwhile, biochemical reagent grade pig urate oxidase is used as a positive control, the activity of the pig urate oxidase lmg/mL is tested, the activity of the urate oxidase is obtained after the pig urate oxidase is placed at 30 ℃ for 5 days, and the enzyme activity retention rate is calculated. The test results are shown in table 2.
Among them, the enzyme activity test was the same as "uricase activity test in polymer microneedles" and the enzyme activity retention rate ═ 100% (enzyme activity measured after leaving at 30 ℃ for 5 days/enzyme activity before leaving).
TABLE 2 test results of room temperature thermal stability
| Urate oxidase product | Specific activity retention rate of enzyme |
| Positive control | 73％ |
| Polymeric microneedles | 88％ |
The results in table 2 show that the polymer microneedles of this example have better thermal stability.
The foregoing is a detailed description of the present application in connection with specific embodiments thereof, and implementations of the present application are not to be considered limited to those descriptions. It will be apparent to those skilled in the art from this disclosure that many more simple derivations or substitutions can be made without departing from the basic inventive concepts herein.
Claims (10)
1. A polymer microneedle for rapidly dissolving tophus, characterized in that: the needle tip of the polymer microneedle is embedded with a medicinal composition for reducing uric acid, which is wrapped by a nano material;
the pharmaceutical composition contains 0.005-0.05 weight parts of urate oxidase, 0.05-0.15 weight parts of sodium carbonate, 0.05-0.30 weight parts of sodium bicarbonate, 0.15-0.5 weight parts of magnesium chloride, and vitamin B6 accounting for 1-2% of the urate oxidase.
2. A polymeric microneedle according to claim 1, characterized in that: the medicine composition also contains trace elements, wherein the trace elements are at least one of organic germanium, manganese, copper, selenium, zinc and potassium elements.
3. A polymeric microneedle according to claim 2, characterized in that: the dosage of each element in the trace elements is 0.1-0.5% of the weight of the urate oxidase.
4. A polymeric microneedle according to claim 1, characterized in that: the nano material is polylactic acid-glycolic acid copolymer.
5. A polymeric microneedle according to any one of claims 1 to 4, characterized in that: the polymeric microneedles are prepared from sodium carboxymethylcellulose.
6. Use of the polymer microneedle according to any one of claims 1 to 5 for the preparation of a medicament for treating borderline hyperuricemia, or gouty arthritis.
7. A method of manufacturing polymeric microneedles in any one of claims 1-5, wherein: comprises the following steps of (a) carrying out,
preparing a pharmaceutical composition, which comprises mixing urate oxidase and phosphoric acid buffer pair according to a ratio, adding polylactic acid-glycolic acid copolymer solution, dispersing uniformly, and preparing first nanoparticles by a spray dryer; mixing sodium carbonate, sodium bicarbonate, magnesium chloride, vitamin B6 and trace elements, adding polylactic acid-glycolic acid copolymer solution, dispersing uniformly, and preparing into second nanoparticles by a spray dryer; uniformly mixing the first nanoparticles and the second nanoparticles in proportion to obtain a pharmaceutical composition;
a step of coating the pharmaceutical composition, which comprises dissolving the polylactic acid-glycolic acid copolymer in an organic solvent to prepare a coating material solution; uniformly dispersing the prepared nanoparticles of the pharmaceutical composition into the prepared wrapping material solution, and adding a vitamin E polyethylene glycol succinate solution to form nanoparticles, so as to obtain the pharmaceutical composition wrapped by the nanoparticles;
preparing polymer microneedles, namely adding the pharmaceutical composition wrapped by the nanomaterials into a sodium carboxymethylcellulose solution according to the dosage of each polymer microneedle to prepare a mixed solution, pouring the mixed solution into a microneedle patch mould, and then carrying out centrifugal treatment in a centrifugal machine to ensure that the mixed solution enters a pinhole cavity of the microneedle patch mould and most of the pharmaceutical composition wrapped by the nanomaterials is deposited at a needle point; and then curing, forming and demolding to obtain the polymer microneedle.
8. The method of claim 7, wherein: in the step of coating the pharmaceutical composition, the organic solvent is ethyl acetate.
9. The method of claim 7, wherein: in the step of coating the pharmaceutical composition, the nanoparticles are prepared at a temperature of about 0 ℃ and about 3 ℃.
10. The production method according to any one of claims 7 to 9, characterized in that: in the preparation of the polymer microneedle, the centrifugal treatment condition is 5000-6000rpm for 3-6 min.
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