Hyaluronic acid composition for ultrasonic introduction and capable of generating bubbles in situ and patch of hyaluronic acid composition

Abstract

The invention belongs to the technical field of medicines, provides an in-situ bubble generation hyaluronic acid composition for ultrasonic introduction and a patch thereof, and relates to the hyaluronic acid composition, a method for preparing and introducing the patch from the composition and an ultrasonic introduction method. The hyaluronic acid composition comprises the following raw materials: hyaluronic acid, a foaming agent and a penetration enhancer, the preparation method of the lead-in patch comprises the steps of mixing the components and applying. The ultrasonic leading-in method comprises the steps of setting ultrasonic leading-in instrument parameters and leading-in time, and carrying out specific ultrasonic leading-in operation. According to the ultrasonic introduction mode, bubbles are generated in situ, the efficiency is higher than that of pure ultrasonic introduction, and the concentration of hyaluronic acid in the articular cavity can be rapidly increased. Compared with hyaluronic acid injection administration, the administration technology is noninvasive, painless, good in clinical compliance, simple and convenient to operate and low in cost; compared with oral administration of hyaluronic acid, the composition has the advantages of good directionality, accurate and controllable action range and small gastrointestinal irritation.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to a hyaluronic acid composition for ultrasonic introduction capable of in-situ generating bubbles and a patch thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Ultrasound introduction is a common non-invasive drug delivery method. The basic principle is to vibrate molecules and cells through the pressure and shear force generated by ultrasound, thereby reducing the barrier effect of the skin's stratum corneum and improving the permeability of the skin on the one hand, and promoting blood flow and capillary dilation on the other hand, promoting the diffusion of drug molecules, and ultimately improving the transdermal absorption efficiency of drugs. In addition, the cavitation effect is also an important principle of ultrasound introduction - during the propagation of ultrasound, due to changes in sound pressure and sound intensity, bubbles (or cavities) are generated in the liquid. These bubbles (or cavities) are constantly formed, grown and collapsed in the sound field, generating shock waves and vortices, which cause local high temperature and high pressure, thereby promoting drug introduction.

[0004] Traditional subcutaneous introduction of hyaluronic acid (such as in the medical beauty industry) is mostly based on mechanical effects, thermal effects, simple diffusion, etc., but hyaluronic acid is a macromolecular substance and is more difficult to penetrate than existing ultrasound-introduced drugs (such as hormones, non-steroidal anti-inflammatory drugs, local anesthetics, Chinese medicine preparations, etc.). More importantly, ultrasound introduction into the joint cavity is fundamentally different from introduction into the subcutaneous cavity - the target location is deeper and the introduction barrier is higher. Therefore, the introduction effect based solely on mechanical effects, thermal effects, simple diffusion, etc. still needs to be improved.

[0005] Patent CN109893612A reports a gel preparation for ultrasonic introduction to treat gouty arthritis, but it is not a transdermal patch, and the active ingredient of the gel is a Chinese medicine component, not hyaluronic acid; Patent CN116898750A reports a slightly painful Thermage treatment, which uses ultrasonic introduction of hyaluronic acid, but is not joint-related. Patent CN114728085A reports that the cavitation effect promotes drug introduction, but the bubbles used in this patent are micro / nano bubbles, and the drug-loading method is that the drug is first coupled with the components in the micro / nano bubbles using ester bonds, and then mixed with other components to form drug-loaded micro / nano bubbles and introduce them using ultrasound. In summary, there is no report on hyaluronic acid compositions and patches for ultrasonic introduction that generate bubbles in situ. Summary of the invention

[0006] In view of the above problems, the present invention uses the cavitation effect of in-situ generated bubbles (i.e., the hyaluronic acid and the foaming agent are mixed on the skin surface) to improve the efficiency of ultrasonic introduction of hyaluronic acid into the joint cavity, so as to achieve a higher introduction efficiency than that without bubbles ( Figure 1 The method avoids the wound and pain caused by joint injection of hyaluronic acid, as well as the low bioavailability and gastrointestinal irritation of oral hyaluronic acid. The present invention includes the steps of selecting an ultra-low molecular weight hyaluronic acid composition, preparing an ultrasonic introduction patch from the composition, and ultrasonic introduction.

[0007] The present invention is mainly based on the cavitation effect produced by "in situ generation" of bubbles - the mixing of hyaluronic acid and a foaming agent to produce bubbles. Compared with the method widely used in existing clinical ultrasound detection, in which microbubbles (or nanobubbles) are mixed (or coupled) with hyaluronic acid and then directly applied to the joints and then introduced using ultrasound, the method of "in situ generation" of bubbles of the present invention has lower production costs. Compared with using a component that decomposes itself to produce bubbles as a foaming agent, the method of "in situ generation" of bubbles of the present invention not only has a higher introduction efficiency, but also avoids the problem of skin irritation caused by the decomposition products of the foaming agent and the heat absorption and release effects during decomposition.

[0008] In order to achieve the above-mentioned purpose, the present invention adopts the following technical scheme: In the first aspect of the present invention, a hyaluronic acid composition for ultrasonic introduction with in-situ bubble generation is provided, which is composed of the following raw materials in mass percentage: 1.0-5.0% of hyaluronic acid and its derivatives with a molecular weight ≤6000D, 0.01-0.2% of a foaming agent, 0.1-0.2% of a penetration enhancer, and the rest is a solvent.

[0009] In order to neutralize hyaluronic acid with the foaming agent and generate CO2 in situ, thereby effectively enhancing the permeability of the skin, on the one hand, the carboxyl group of D-glucuronic acid in the hyaluronic acid and its derivatives must be in a protonated state, rather than a deprotonated state to form a hyaluronate (e.g., sodium hyaluronate) with a cation; on the other hand, the molecular weight of the hyaluronic acid needs to be controlled, and therefore, the molecular weight of the hyaluronic acid in the present invention is ≤6000D.

[0010] In some embodiments, the foaming agent is selected from at least one of carbonates and their hydrates, bicarbonates and their hydrates, magnesium, aluminum, calcium, iron, nickel, zinc, strontium, tin, and barium.

[0011] In some embodiments, the carbonate is selected from at least one of sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, zinc carbonate, and ferrous carbonate;

[0012] In some embodiments, the bicarbonate is selected from at least one of sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate.

[0013] In some embodiments, the penetration enhancer is selected from at least one of ethanol, propylene glycol, glycerol, dimethyl sulfoxide, azone, borneol, camphor, menthol, limonene, lauric acid, oleic acid, linoleic acid, and lauryl alcohol.

[0014] In some embodiments, the solvent is water or an aqueous solution with a water content of ≥50%.

[0015] Preferably, the hyaluronic acid is ultra-low molecular weight hyaluronic acid (molecular weight ≤ 3000D).

[0016] Preferably, the foaming agent is sodium bicarbonate.

[0017] Preferably, the penetration enhancer is glycerol.

[0018] Preferably, the patch carrier is a non-woven fabric.

[0019] Preferably, the mass percentages of the components are: 1.0% ultra-low molecular weight hyaluronic acid, 0.1% sodium bicarbonate, 0.2% glycerol, and the rest is water.

[0020] Preferably, the mass percentages of the components are: 3.0% ultra-low molecular weight hyaluronic acid, 0.2% sodium carbonate, 0.1% borneol, and the rest is water.

[0021] Preferably, the mass percentages of the components are: 2.0% ultra-low molecular weight hyaluronic acid, 0.05% magnesium chips, 0.1% glycerol, and the rest is water.

[0022] The second aspect of the present invention provides a method for preparing a hyaluronic acid composition for ultrasonic introduction with in-situ bubble generation, comprising:

[0023] Dissolve hyaluronic acid, foaming agent and penetration enhancer in solvents respectively to obtain corresponding solutions.

[0024] The hyaluronic acid and penetration enhancer solutions are first added dropwise to the patch carrier, and then the foaming agent solution is added dropwise to the patch carrier before ultrasonic introduction.

[0025] The present invention has been found that the order of mixing hyaluronic acid, foaming agent and penetration enhancer has a greater impact on the introduction effect. If hyaluronic acid and foaming agent are mixed first, at this time, bubbles are immediately generated, the bubbles loaded on the patch carrier are reduced, and the introduction effect is not good. Therefore, the present invention first adds hyaluronic acid and penetration enhancer dropwise to the patch carrier in sequence, and then adds the foaming agent solution dropwise to the patch carrier before ultrasonic introduction, effectively improving the bubble loading and obtaining a better introduction effect.

[0026] The third aspect of the present invention provides an ultrasound introduction patch, comprising:

[0027] Patch carrier;

[0028] The patch carrier is loaded with the above-mentioned hyaluronic acid composition.

[0029] In some embodiments, the patch carrier is selected from at least one of non-woven fabrics, cotton fabrics, silk, and paper.

[0030] The fourth aspect of the present invention provides the use of the above-mentioned hyaluronic acid composition and / or the above-mentioned ultrasound introduction patch in the preparation of ultrasound introduction drugs or medical dressings for joint cavity.

[0031] The ultrasound introduction method of the ultrasound introduction patch comprises the following steps:

[0032] Step 1: Setting of ultrasonic introduction instrument parameters: According to individual differences, appropriate ultrasonic introduction parameters can be selected, and programmed introduction plans can be customized for different situations through programming.

[0033] Step 2: Place the ultrasound introduction device probe on the patch carrier, and use ultrasound to introduce it into the joint cavity for 5 to 30 minutes, once a day, 1 patch at a time, and keep the patch for 0.5 to 3 hours. A course of treatment is 5 to 10 days.

[0034] Step 3: Skin examination: When applying the introduction patch, during the introduction process, and after the first introduction, check whether there are adverse reactions and irritation reactions to the skin at the patch site, as well as the subject's feelings about the ultrasonic introduction process. Based on this, adjust the composition of the hyaluronic acid composition, application time, introduction time, etc. to minimize skin irritation and achieve the best introduction effect.

[0035] Preferably, the operating frequency of the ultrasonic introduction instrument is 10-100kHz, 1-10MHz, the duty cycle is 10-50%, and the power is 0.1-2W / cm 2 .

[0036] Beneficial effects of the present invention

[0037] (1) The hyaluronic acid contained in the ultrasonic introduction patch of the present invention has the functions of inhibiting inflammation, promoting cartilage regeneration, retaining water and locking water. Through ultrasonic introduction, hyaluronic acid can be introduced into the joint cavity efficiently, non-invasively and painlessly. During the drug permeation process, the stratum corneum on the surface of the skin hinders the transdermal process of hyaluronic acid, but under the action of ultrasound, the bubbles on the surface of the skin - hyaluronic acid and the CO2 generated in situ by the neutralization of the foaming agent - cavitation can enhance the permeability of the skin and promote the transdermal absorption of hyaluronic acid. In addition, the non-irritating penetration enhancer changes the arrangement structure of the stratum corneum by interacting with the stratum corneum lipids, thereby further improving the ultrasonic introduction efficiency of hyaluronic acid, thereby quickly reaching the therapeutic concentration.

[0038] (2) The preparation method of the present invention is simple, practical and easy to promote. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention, and the exemplary embodiments of the present invention and their description are used to explain the present invention and do not constitute improper limitations on the present invention.

[0040] Figure 1 Schematic diagram of the in situ foamed hyaluronic acid combination facilitating ultrasound introduction into the joint cavity.

[0041] Figure 2 This is a live picture of ultrasonic introduction of hyaluronic acid (labeled with rhodamine) into the joint cavity of Bama pigs.

[0042] Figure 3 Comparison of in-situ bubble generation before and after mixing hyaluronic acid and foaming agent (A: before mixing, B: after mixing).

[0043] Figure 4 Comparison of the effects of hyaluronic acid introduction in three groups: pure hyaluronic acid (A), hyaluronic acid introduced with ultrasound (B), and hyaluronic acid added with foaming agent followed by ultrasound (C) (the upper part is the field of view under light microscope, the lower part is the field of view under fluorescence microscope).

[0044] Figure 5 1(A) and 2(B) are graphs comparing the concentrations of hyaluronic acid in the joint cavity of each treatment group. DETAILED DESCRIPTION

[0045] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0046] The present invention will be further described in detail below in conjunction with specific embodiments. It should be noted that the specific embodiments are intended to explain the present invention rather than to limit it.

[0047] Example 1

[0048] (1) A method for ultrasonically introducing hyaluronic acid into a joint cavity with in situ bubble generation, comprising a hyaluronic acid composition, a method for preparing an ultrasonic introduction patch from the composition, and a method for ultrasonic introduction of the patch. The hyaluronic acid composition comprises hyaluronic acid, a foaming agent, and a penetration enhancer. The hyaluronic acid is an ultra-low molecular weight hyaluronic acid (molecular weight ≤ 3000D), the foaming agent is sodium bicarbonate, the penetration enhancer is glycerol, and the patch carrier is a non-woven fabric. The mass percentage of each component is: 1.0% ultra-low molecular weight hyaluronic acid, 0.1% sodium bicarbonate, 0.2% glycerol, and the rest is water.

[0049] (2) The experimental animals were Bama miniature pigs (3 weeks old), and the introduction site was the limb joints. The surface hair was thoroughly removed before introduction. Figure 2 ). In order to more conveniently measure the concentration of hyaluronic acid introduced into the joint cavity, 10 mg of rhodamine isothiocyanate B (RITC, CAS: 36877-69-7) was mixed with 500 mg of ultra-low molecular weight hyaluronic acid at room temperature in advance to obtain rhodamine B-labeled hyaluronic acid, which was used as the introduced hyaluronic acid. After the introduction is completed, the introduction patch is peeled off and the unintroduced liquid is wiped off with sterile gauze (to prevent the hyaluronic acid remaining on the skin surface from continuing to penetrate, thereby causing errors). After cleaning and disinfecting the skin on the joint surface, local anesthetic is injected, and 100 μL of joint cavity fluid is extracted with a puncture needle and stored in a refrigerator (-20°C).

[0050] (3) To evaluate whether the present invention improves the efficiency of hyaluronic acid introduction, 20 μL of joint cavity fluid was taken and diluted with 2 mL of deionized water, and the absorbance of rhodamine B (A 554 ), combined with the standard curve (Rhodamine B concentration is the same as A 554 ) Calculate the concentration of hyaluronic acid introduced into the joint cavity fluid and compare it with the control group to determine whether there is a statistically significant difference.

[0051] (4) A method for preparing a drug delivery patch, comprising the following steps:

[0052] Step 1: Place the patch carrier on the knee joint and soak it with an appropriate amount of water (about 1 mL) to make it completely close to the skin.

[0053] Step 2: Dissolve rhodamine B-labeled hyaluronic acid (0.1 g) in 4 mL of water, dissolve sodium bicarbonate (0.01 g) in 4 mL of water, and mix glycerol (20 μL) with 1 mL of water.

[0054] Step 3: Add hyaluronic acid, penetration enhancer and foaming agent to the patch carrier in sequence.

[0055] In order to prove the bubble-generating effect of the foaming agent, hyaluronic acid and sodium bicarbonate were mixed on the skin surface, and bubbles were immediately generated visible to the naked eye ( Figure 3 A and B. Bubbles are more common in Figure 3 (in the white circle in B).

[0056] (5) The ultrasound introduction method of the patch comprises the following steps:

[0057] Step 1: Setting of ultrasonic induction instrument parameters: operating frequency is 1 MHz, duty cycle is 50%, power is 1.0 W / cm 2 .

[0058] Step 2: Place the ultrasound introduction device probe on the patch carrier and ensure coupling. Use ultrasound to introduce the joint for 5 minutes, 3 times a day, 1 patch at a time, and keep the patch on for 0.5 hours. 5 days is a course of treatment.

[0059] Step 3: Skin examination: When applying the ultrasonic introduction patch, during the introduction process, and after the first introduction, check whether the patch site has any adverse reactions and irritation to the skin. Adjust the ingredients of the hyaluronic acid composition, application time, introduction time, etc. accordingly to minimize skin irritation and achieve the best introduction effect.

[0060] The tissue sections of the skin after introduction are shown in Figure 4 .Compare Figure 4 It can be seen from the fluorescence intensity (i.e., derived from rhodamine B coupled to hyaluronic acid) that the ultrasound introduction group has a higher fluorescence intensity than the simple application group, that is, the hyaluronic acid transdermal efficiency is improved. In addition, the method of the present invention, i.e., based on the cavitation effect of bubbles generated by hyaluronic acid and a foaming agent, has a higher fluorescence intensity than the ordinary ultrasound introduction group, and the highest hyaluronic acid transdermal efficiency is obtained, and there is no skin damage after the ultrasound introduction.

[0061] The results of the determination of hyaluronic acid concentration in the joint cavity are shown in Figure 5 Middle A. Figure 5 As can be seen from A, ultrasonic introduction of hyaluronic acid can significantly increase the concentration of hyaluronic acid in the joint cavity compared with simple application of hyaluronic acid (p<0.01). The method involved in the present invention, i.e., the cavitation effect caused by bubbles generated by hyaluronic acid and a foaming agent, can significantly increase the concentration of hyaluronic acid in the joint cavity compared with the ordinary ultrasonic introduction group (p<0.05).

[0062] Example 2

[0063] (1) The method for ultrasonically introducing hyaluronic acid into the joint cavity with in situ generation of bubbles, except for the hyaluronic acid composition, other components (patch carrier, etc.) and operations (preparation of fluorescent labeled hyaluronic acid, extraction of joint fluid, etc.) are the same as those in Example 1. The hyaluronic acid composition includes hyaluronic acid, a foaming agent, and a penetration enhancer. The hyaluronic acid is an ultra-low molecular weight hyaluronic acid (molecular weight ≤ 3000D), the foaming agent is nano magnesium powder, and the penetration enhancer is glycerol. The mass percentage of each component is: ultra-low molecular weight hyaluronic acid 2.0%, nano magnesium powder 0.01%, glycerol 0.2%, and the rest is water.

[0064] (2) A method for preparing an ultrasound-introducing patch comprises the following steps:

[0065] Step 1: Place the patch carrier on the joint and soak it with an appropriate amount of water (about 1 mL) to make it completely adhere to the skin.

[0066] Step 2: Dissolve rhodamine B-labeled hyaluronic acid (0.2 g) in 5 mL of water and mix glycerol (20 μL) with 4 mL of water.

[0067] Step 3: Add hyaluronic acid and penetration enhancer to the patch carrier in sequence, and then add the foaming agent (1 mg nano magnesium powder) evenly and slowly in batches to the patch carrier.

[0068] (3) The ultrasound introduction method of the drug delivery patch comprises the following steps:

[0069] Step 1: Setting of ultrasonic induction instrument parameters: operating frequency is 1 MHz, duty cycle is 50%, power is 1.0 W / cm 2 .

[0070] Step 2: Place the ultrasound introduction device probe on the patch carrier and ensure coupling. Use ultrasound to introduce the joint for 5 minutes, 3 times a day, 1 patch at a time, and keep the patch on for 0.5 hours. A course of treatment is 7 days.

[0071] Step 3: Skin examination: When applying the ultrasonic introduction patch, during the introduction process, and after the first introduction, check whether the patch site has any adverse reactions and irritation to the skin. Adjust the ingredients of the hyaluronic acid composition, application time, introduction time, etc. accordingly to minimize skin irritation and achieve the best introduction effect.

[0072] The results of the determination of hyaluronic acid concentration in the joint cavity are shown in Figure 5 Middle B. Figure 5 As can be seen from Figure B, ultrasonic introduction of hyaluronic acid can significantly increase the concentration of hyaluronic acid in the joint cavity compared with simple application of hyaluronic acid (p<0.01). The method of the present invention, i.e., the cavitation effect caused by bubbles generated by hyaluronic acid and a foaming agent, can significantly increase the concentration of hyaluronic acid in the joint cavity compared with the ordinary ultrasonic introduction group (p<0.05).

[0073] It can be seen that the foaming agents (i.e., nano magnesium powder and sodium bicarbonate) used in Example 1 and Example 2 can both neutralize hyaluronic acid to form foams, and then enhance the effect of ultrasonic introduction by generating bubbles in situ. Based on the above results, the method of the present invention has the characteristics of being non-invasive and painless, rapid onset, simple operation, low cost, good joint orientation, and low gastrointestinal irritation, and is suitable for non-invasive joint administration of hyaluronic acid and even other macromolecular drugs.

[0074] Comparative Example 1

[0075] The difference from Example 1 is that a salt (ammonium bicarbonate) that can self-decompose and produce bubbles is used instead of sodium bicarbonate as the foaming agent. Using the same operating steps, the final concentration of hyaluronic acid in the joint cavity was measured to be 0.021±0.003 mg mL -1 .

[0076] It can be seen that although the concentration of Comparative Example 1 is higher than that of the untreated group and the group with simple dripping of hyaluronic acid, there is no statistical difference. The main reason for this phenomenon is that the rate of ammonium bicarbonate self-decomposition to generate bubbles is significantly slower than that of Examples 1 and 2, so the in-situ generation of bubbles is weak. In addition, the ammonia odor of ammonium bicarbonate itself and the ammonia produced after decomposition have a strong irritating odor, which is not suitable for being added to the hyaluronic acid patch as a foaming agent.

[0077] Comparative Example 2

[0078] The difference from Example 1 is that the molecular weight of hyaluronic acid is 6000-10000D. The concentration of hyaluronic acid is 0.015±0.003mg mL -1 .

[0079] It can be seen that there is no statistical difference in the concentration of Comparative Example 2 compared with the untreated group and the group with simple addition of hyaluronic acid. The main reason for this phenomenon is that the low molecular weight hyaluronic acid used in Examples 1 and 2 has a better transdermal rate than the high molecular weight hyaluronic acid in Comparative Example 2.

[0080] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A hyaluronic acid composition for ultrasonic introduction with in-situ bubble generation, characterized in that: The invention is composed of the following raw materials in percentage by mass: 1.0-5.0% of hyaluronic acid and its derivatives with a molecular weight of ≤6000D, 0.01-0.2% of a foaming agent, 0.1-0.2% of a penetration enhancer, and the rest being a solvent.

2. The hyaluronic acid composition for ultrasonic introduction with in-situ bubble generation according to claim 1, characterized in that: The foaming agent is selected from carbonates and their hydrates, bicarbonates and their hydrates, magnesium, aluminum, calcium, iron, nickel, zinc, strontium, tin, barium, salts that can self-decompose to produce bubbles, materials that can break to produce bubbles, and at least one of the derivatives and derived materials of the above materials.

3. The hyaluronic acid composition for ultrasonic introduction with in-situ bubble generation according to claim 2, characterized in that: The carbonate is selected from at least one of sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, zinc carbonate and ferrous carbonate.

4. The hyaluronic acid composition for ultrasonic introduction with in-situ bubble generation according to claim 2, characterized in that: The bicarbonate is selected from at least one of sodium bicarbonate, potassium bicarbonate and cesium bicarbonate.

5. The hyaluronic acid composition for ultrasonic introduction with in-situ bubble generation according to claim 2, characterized in that: The molecular weight of the hyaluronic acid is ≤3000D.

6. The hyaluronic acid composition for ultrasonic introduction with in-situ bubble generation according to claim 1, characterized in that: The penetration enhancer is selected from at least one of ethanol, propylene glycol, glycerol, dimethyl sulfoxide, azone, borneol, camphor, menthol, limonene, lauric acid, oleic acid, linoleic acid, and lauryl alcohol.

7. The hyaluronic acid composition for ultrasonic introduction with in-situ bubble generation according to claim 1, characterized in that: The solvent is water or an aqueous solution with a water content of ≥50%.

8. A method for preparing a hyaluronic acid composition for ultrasonic introduction with in-situ bubble generation, characterized in that: include: Dissolving hyaluronic acid, a foaming agent, and a penetration enhancer in a solvent respectively to obtain corresponding solutions; The hyaluronic acid and penetration enhancer solutions are first added dropwise to the patch carrier, and then the foaming agent solution is added dropwise to the patch carrier before ultrasonic introduction.

9. An ultrasound introduction patch, characterized in that: include: Patch carrier; The patch carrier is loaded with the hyaluronic acid composition according to any one of claims 1 to 7.

10. Use of the hyaluronic acid composition according to any one of claims 1 to 7 and / or the ultrasound introduction patch according to claim 9 in the preparation of ultrasound introduction drugs or medical dressings for joint cavity.

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