Analgesic cold compress patch and preparation method thereof

Abstract

The invention provides an analgesic type cold compress patch and a preparation method thereof, which are used for solving the problem of rapid and long-acting release of analgesic drugs in a macromolecular hydrogel cold compress patch and improving the analgesic effect of the cold compress patch. The invention relates to an analgesic type cold compress patch and a preparation method thereof, the cold compress patch is of an integrated structure formed by interpenetrating external reinforced gel used for reinforcing and fixing and an internal hydrogel carrier located on the inner side of the external reinforced gel, and the lower surface of the internal hydrogel carrier is provided with uniformly arranged concave holes. The concave holes are used for filling analgesic drugs, and analgesic microspheres are loaded in the inner hydrogel carrier.

Description

Technical Field

[0001] The present invention relates to the technical field of medical devices, and in particular to an analgesic cold compress patch and a preparation method thereof. Background Art

[0002] There are two main types of cold compresses at present. One is to use a refrigerant for cold compresses, such as ice crystals or ice cubes; the other is to achieve the cooling effect through the volatilization of water or cooling ingredients, which usually requires a polymer gel as a carrier. The second method is gradually gaining favor in clinical practice because it is more portable and can be better attached to the skin.

[0003] However, the cold compress with polymer hydrogel as carrier still has the problem of unsatisfactory analgesic effect. The main reason is that the analgesic drugs cannot fully penetrate into the skin. For example, the problem is mentioned in patent CN107375250A, but the patent believes that better fit with the skin is the key to better drug penetration into the skin. Therefore, the patent cross-links the oil phase and the water phase under the catalysis of a catalyst to form a three-dimensional network structure, so that the product has better viscosity and can better contact with the skin, and then achieves the analgesic effect by adding analgesic-related drugs.

[0004] On the premise of fully ensuring the contact between the cold compress and the skin, how to better release the analgesic drugs quickly and long-lastingly to the skin surface and penetrate into the skin has become a key issue that needs to be solved in the development of analgesic cold compresses. Summary of the invention

[0005] The present invention provides an analgesic cold compress patch and a preparation method thereof, which are used to solve the problem of rapid and long-lasting release of analgesic drugs in a polymer hydrogel cold compress patch and improve the analgesic effect of the cold compress patch.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions: A pain-relieving cold compress and a preparation method thereof. The cold compress is an integrated structure formed by the interpenetration of an external reinforcing gel for reinforcing fixation and an internal hydrogel carrier located inside the external reinforcing gel. The lower surface of the internal hydrogel carrier has evenly arranged concave holes, the concave holes are used to fill analgesic drugs, and the internal hydrogel carrier is loaded with analgesic microspheres.

[0007] Furthermore, the preparation method of the cold compress patch is: S1: Preparation of the pre-gel solution of the internal hydrogel carrier: mixing the hydrogel monomers polyethylene glycol diacrylate and 1-hydroxycyclohexyl phenyl ketone with deionized water to prepare a solution of 10% by mass of polyethylene glycol diacrylate and 1% by volume of 1-hydroxycyclohexyl phenyl ketone; S2: Preparation of external reinforced gel pre-gel solution: sodium hyaluronate is added into deionized water and stirred evenly to make it fully swollen; genipin is added and stirred evenly; S3: Casting to form an integrated structure, stacking two annular molds of different sizes, filling the part between the two molds with the outer ring reinforced gel pre-gel solution, and leaving the mold to stand for 2-4 hours until the outer ring hydrogel is not completely solidified; S4: At this time, slowly pour the internal hydrogel pregel solution into the inner mold, and finally remove the inner mold until the outer ring and the internal hydrogel are completely in contact. Let it stand for 12-24 hours to allow all the hydrogels to completely gel. Finally, demold and trim neatly.

[0008] According to claim 1, an analgesic cold compress patch and a preparation method thereof are characterized in that the method for preparing the concave holes is: placing a template on the lower surface of an internal hydrogel carrier, and then irradiating the template with a 65mW / cm2 UV cross-linking device, the irradiation interval is 5cm, the wavelength is 365nm, and the irradiation time is 30s; then removing the template to obtain an internal hydrogel carrier with concave holes on the surface.

[0009] Furthermore, the template is composed of a main body and a plurality of hollow cylindrical open microtubes uniformly and vertically fixed on the surface of the main body.

[0010] Furthermore, the diameter of the microstructure is 500 μm and the height is 250 μm.

[0011] Furthermore, the template preparation method is: printing the main body with PMMA, printing the microtubes upward along the surface of the main body, and after printing, filling the microtubes with GPTMS with a needle.

[0012] Furthermore, the preparation method of the analgesic microspheres is: PCEC and analgesics are dissolved in a mixed solvent, and the weight ratio of PCEC and analgesics is 3:1; a spray dryer is used to prepare microspheres, and the atomizing gas is compressed air, the pressure is controlled at 0.3-0.5MPa, the inlet temperature is 120-150℃, the outlet temperature is 70-90℃, and the flow rate is 5-10mL / min; the microspheres are dried in an environment with a vacuum degree of -0.08~-0.1MPa to remove a small amount of solvent remaining on the surface of the microspheres.

[0013] Furthermore, the mixed solvent is a solvent formed by mixing ethanol, acetone and dimethyl sulfoxide in a volume ratio of 7:2:1.

[0014] Furthermore, the method of loading analgesic microspheres into the internal hydrogel carrier includes: solution immersion or pressure perfusion.

[0015] Furthermore, the analgesic drug includes: ibuprofen or ropivacaine hydrochloride or lidocaine.

[0016] Compared with the prior art, the present invention has the following beneficial effects: The present invention solves the problem of both rapid analgesia and long-acting analgesia through the organic combination of concave holes, analgesic microspheres and internal hydrogel carriers, and has an analgesic effect, and can also reduce the burden on patients and the amount of medical expenses. The present invention adds a circle of external reinforcing gel around the internal hydrogel carrier, and the gel forms an integrated structure of an interpenetrating network through reaction, so that the cold compress has a stronger fixing effect on the skin surface, and the internal hydrogel carrier can be in closer contact with the skin, thereby bringing about a better analgesic effect; The method for preparing the concave holes used in the present invention is simple, fast and safe. The holes are removed by polymer reaction. The advantage is that the desired concave holes of expected shape and size and expected distribution can be obtained. The shell of the analgesic microspheres of the present invention is made of PCEC material, which can enhance skin permeability by hydrating with the skin and can also better penetrate into the skin due to its fat-soluble characteristics; at the same time, it is not affected by the characteristics of the drugs, and can encapsulate both water-soluble drugs and fat-soluble drugs, and can also load two types of drugs at the same time, thereby improving the application range of the microspheres. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is a schematic structural diagram of an analgesic cold compress patch according to Embodiment 2 of the present invention; Figure 2 This is a schematic diagram of the structure of a template required for preparing an analgesic cold compress patch in Example 2 of the present invention; Figure 3 This is a scanning electron microscope image of a concave hole in an analgesic cold compress patch according to Example 2 of the present invention; Figure 4 This is a scanning electron microscope image of analgesic microspheres in an analgesic cold compress patch according to Example 3 of the present invention; Figure 5 This is a graph showing the in vitro experimental results of the drug release of analgesic microspheres in an analgesic cold compress patch according to Example 3 of the present invention.

[0018] Among them, 10-external reinforced gel, 20-internal hydrogel carrier, 100-concave hole, 200-analgesic microspheres, 300-template, 310-plate, 320-microtube. DETAILED DESCRIPTION

[0019] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Example 1

[0020] In this embodiment, the analgesic cold compress is an integrated structure formed by an outer ring of viscous reinforced gel and an inner hydrogel carrier through an interpenetrating network. The outer ring of viscous reinforced gel has stronger viscosity than the inner hydrogel carrier, and can better fit on the skin.

[0021] The specific preparation method is: S1: Preparation of internal hydrogel pregel solution: mixing hydrogel monomers polyethylene glycol diacrylate and 1-hydroxycyclohexyl phenyl ketone with deionized water to prepare a solution of 10% polyethylene glycol diacrylate by mass and 1% 1-hydroxycyclohexyl phenyl ketone by volume; S2: Preparation of the pre-gel solution of the outer ring viscosity-enhanced gel: sodium hyaluronate is added to deionized water and stirred evenly to fully swell; genipin is added and stirred evenly; S3: Casting to form an integrated structure, stacking two annular molds of different sizes, filling the part between the two molds with the outer ring viscous reinforced gel pre-gel solution, and leaving the mold to stand for 2-4 hours until the outer ring hydrogel is not completely solidified; S4: At this time, slowly pour the internal hydrogel pregel solution into the inner mold, and finally remove the inner mold until the outer ring and the internal hydrogel are completely in contact. Let it stand for 12-24 hours to allow all the hydrogels to completely gel. Finally, demold and trim it neatly.

[0022] In this embodiment, the shape of the annular mold can be square or circular, and there is no limitation in this aspect. This embodiment ensures that the cold compress patch can be firmly attached to the skin surface, which is a prerequisite for the rapid and long-term release of analgesics. Example 2

[0023] Based on Example 1, this example focuses on optimizing the rapid and long-acting release indexes of the analgesic drug, with the aim of increasing the speed and duration of the drug contacting and penetrating into the skin.

[0024] like Figure 1As shown, the hydrogel carrier inside the analgesic cold compress is the area where the drug is distributed. Specifically, this part is composed of an internal hydrogel carrier 20 and an external reinforced gel 10. On the basis of Example 1, there are several recessed holes 100 on the lower surface (the side contacting the wound surface) of the internal hydrogel carrier 20, and the recessed holes 100 are used to fill the analgesic drug.

[0025] The concave hole 100 is prepared by the following method: Figure 2 The template 300 shown in FIG. 1 is placed on the lower surface of the inner hydrogel carrier 20 and then heated to 65 mW / cm 2 The template is irradiated with a UV cross-linking apparatus, with an irradiation interval of 5 cm, a wavelength of 365 nm, and an irradiation time of 30 s; then the template 300 is removed to obtain an internal hydrogel carrier 20 with concave holes 100 on the surface.

[0026] The template 300 is made of polymethyl methacrylate (PMMA) with a molecular weight of 100,000 by 3D printing, and its main body 310 is a flat plate. On one side of the flat plate 310, there are several evenly distributed microtubes 320 with hollow cylindrical openings. The diameter of the microtubes 320 is 500 μm and the height is 250 μm.

[0027] The template 300 is completed in two steps during 3D printing. First, PMMA is used to print the main body 310, and the microtubes 320 are printed upward along the surface of the main body 310. After printing, γ-glycidyloxypropyltrimethoxysilane (GPTMS) is filled into the microtubes 320 with a syringe and dried naturally for use.

[0028] Of course, in order to reduce the workload of filling, it can also be achieved by optimizing the steps of 3D printing. Using double-head printing, when printing the micro-tube 320, the inner circle is printed with PMMA material that has been pre-soaked and mixed with γ-glycidyloxypropyltrimethoxysilane (GPTMS), and a protective layer of PMMA material is printed next to the inner circle; at this time, it is only necessary to ensure that the inner diameter of the microtube 320 is 500μm.

[0029] Figure 3 The scanning electron microscope morphology image of the concave hole 100 prepared by the method of this embodiment is shown. From the result, it can be seen that the hole-forming effect is basically uniform.

[0030] The concave hole 100 of this embodiment is used to fill analgesic drugs. There are many ways to achieve drug filling, including filling and compacting powder, immersion and filling of liquid medicine, and filling and smoothing of plasters. The core is to use the concave hole 100 so that the drug contained in the concave hole 100 can directly contact the wound surface, thereby achieving a rapid analgesic effect. Moreover, the size of the concave hole 100 prepared by the microtube 320 itself is not large, so as to ensure that the dosage is within a safe range and provide safe analgesia to the wound surface. Example 3

[0031] Example 2 provides a solution for providing timely analgesia, which solves some of the problems raised by the present invention. If continuous analgesia is required, the solution needs to be further optimized, such as Figure 1 As shown, there are several analgesic microspheres 200 evenly distributed inside the internal hydrogel carrier 20, and the analgesic microspheres 200 are composed of a shell and an analgesic drug inside. The analgesic microspheres 200 are loaded into the internal hydrogel carrier 20 by soaking or pressure perfusion. Of course, the analgesic microspheres 200 can also be added when the internal hydrogel carrier 20 is prepared. This part adopts the common method in the art, so it will not be repeated.

[0032] Analgesic microspheres 200 are prepared by the following method: In this embodiment, polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL) triblock copolymer (PCEC) is used to prepare the shell, and PCEC and analgesics are dissolved in a mixed solvent; wherein the mixed solvent is ethanol, acetone and dimethyl sulfoxide mixed in a volume ratio of 7:2:1; the ratio of PCEC to analgesics is 3:1 by weight. A spray dryer is used to prepare the microspheres, wherein the atomizing gas is compressed air, the pressure is controlled at 0.3-0.5MPa, the inlet temperature is 120-150°C, the outlet temperature is 70-90°C, and the flow rate is 5-10mL / min. The microspheres obtained by spray drying are post-treated and dried in an environment with a vacuum degree of -0.08~-0.1MPa to remove a small amount of solvent remaining on the surface of the microspheres. The microspheres prepared in this embodiment have a uniform particle size between 25-45μm, and their morphology is as follows Figure 4 shown.

[0033] The shell material is amphiphilic, which can enhance skin permeability by hydrating with the skin, and can also better penetrate into the skin due to its fat-soluble characteristics; at the same time, it is not affected by the characteristics of the drug, and can encapsulate both water-soluble and fat-soluble drugs, and can also load two types of drugs at the same time, thereby increasing the scope of application of the microspheres. In this embodiment, the encapsulated analgesic drug is ibuprofen, and drugs such as ropivacaine hydrochloride and lidocaine can also be selected.

[0034] Of course, when used as a cold compress, the internal hydrogel carrier 20 should also be loaded with cooling factors such as mint, which will not be elaborated here.

[0035] In vitro sustained release test: In order to verify the sustained-release effect of analgesic microspheres, an in vitro sustained-release experiment was performed. 50 mg of ibuprofen was weighed and dissolved in 10 mL of PBS buffer solution. The samples were diluted to 5 × 10 -5 , 1×10 -5, 5×10 -4 , 1×10 -4 , 5×10 -3 , 1×10 -3 , measure the absorbance A at 265nm, draw a standard curve based on the A value, and the obtained standard curve equation is A=0.2631+42.6193C[c / (mg·mL)], R=0.87431. Weigh 50mg of analgesic microspheres into a dialysis bag, add 10mL of PBS buffer solution, put the dialysis bag into 90mL of PBS buffer solution, place it in a shaker at 37℃ and 60r / min, and take 4mL of samples at 0h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 16h, 24h, 30h, 48h, 72h, 96h, and 120h, respectively. After each sampling, add 4mL of PBS buffer solution. The samples taken out are also measured for absorbance A at 265nm, substituted into the standard curve equation, and the corresponding solubility is calculated to draw the analgesic drug release curve, as shown in Figure 5 As shown in the results, it can be seen that the analgesic drug has a release rate of about 50% within 12 hours of contact with the PBS buffer solution, which can quickly achieve the effect of supplementing the analgesic drug and is basically fully released within 120 hours, thereby achieving a long-term analgesic effect.

[0036] In summary, the present invention is a combined solution, but it is not a simple splicing. It is related to the practical problem to be solved. In the development of analgesic cold compresses, it is necessary to improve the analgesic effect. Whether it is rapid analgesia in the short term or long-term analgesia, it is very necessary for analgesic cold compresses. Rapid analgesia in the short term is the basic requirement of analgesic cold compresses, but long-term analgesia can increase the time of analgesia and avoid frequent replacement of dressings. It can not only reduce the economic pressure of patients, but also help reduce the generation of medical waste. It can achieve the dual effects of short-term and long-term analgesia, which is based on the properties of the hydrogel carrier. The hydrogel carrier itself is a porous material, which can provide space and passages for the storage and release of microspheres; secondly, the hydrogel carrier can allow the template to be inserted, thereby realizing the preparation of concave holes.

Claims

1. An analgesic cold compress patch and a preparation method thereof, characterized in that: The cold compress patch is an integrated structure formed by the interpenetration of an external reinforcing gel for reinforcing fixation and an internal hydrogel carrier located inside the external reinforcing gel. The lower surface of the internal hydrogel carrier has evenly arranged concave holes, the concave holes are used to fill analgesic drugs, and the internal hydrogel carrier is loaded with analgesic microspheres.

2. The analgesic cold compress patch and preparation method thereof according to claim 1, characterized in that: The preparation method of the cold compress patch is as follows: S1: Preparation of the pre-gel solution of the internal hydrogel carrier: mixing the hydrogel monomers polyethylene glycol diacrylate and 1-hydroxycyclohexyl phenyl ketone with deionized water to prepare a solution of 10% by mass of polyethylene glycol diacrylate and 1% by volume of 1-hydroxycyclohexyl phenyl ketone; S2: Preparation of external reinforced gel pre-gel solution: sodium hyaluronate is added into deionized water and stirred evenly to make it fully swollen; genipin is added and stirred evenly; S3: Casting to form an integrated structure, stacking two annular molds of different sizes, filling the part between the two molds with the outer ring reinforced gel pre-gel solution, and leaving the mold to stand for 2-4 hours until the outer ring hydrogel is not completely solidified; S4: At this time, slowly pour the internal hydrogel pregel solution into the inner mold, and finally remove the inner mold until the outer ring and the internal hydrogel are completely in contact. Let it stand for 12-24 hours to allow all the hydrogels to completely gel. Finally, demold and trim neatly.

3. The analgesic cold compress patch and preparation method thereof according to claim 1, characterized in that: The concave holes are prepared by placing the template on the lower surface of the internal hydrogel carrier and then 2 The template was irradiated with a UV cross-linking instrument with an irradiation interval of 5 cm, a wavelength of 365 nm, and an irradiation time of 30 s; then the template was removed to obtain an internal hydrogel carrier with concave holes on the surface.

4. The analgesic cold compress gel patch and the preparation method thereof according to claim 3, characterized in that: The template is composed of a main body and a plurality of hollow cylindrical opening microtubes evenly and vertically fixed on the surface of the main body.

5. The analgesic cold compress patch and preparation method thereof according to claim 4, characterized in that: The diameter of the microstructure is 500 μm and the height is 250 μm.

6. The analgesic cold compress patch and preparation method thereof according to claim 5, characterized in that: The template preparation method is as follows: the main body is printed with PMMA, the microtubes are printed upward along the surface of the main body, and after the printing is completed, GPTMS is filled into the microtubes with a needle.

7. The analgesic cold compress patch and the preparation method thereof according to claim 1, characterized in that: The preparation method of the analgesic microspheres is: PCEC and analgesics are dissolved in a mixed solvent, and the weight ratio of PCEC and analgesics is 3:1; a spray dryer is used to prepare microspheres, and the atomizing gas is compressed air, the pressure is controlled at 0.3-0.5MPa, the inlet temperature is 120-150℃, the outlet temperature is 70-90℃, and the flow rate is 5-10mL / min; the microspheres are dried in an environment with a vacuum degree of -0.08~-0.1MPa to remove a small amount of solvent remaining on the surface of the microspheres.

8. The analgesic cold compress patch and preparation method thereof according to claim 7, characterized in that: The mixed solvent is a solvent prepared by mixing ethanol, acetone and dimethyl sulfoxide in a volume ratio of 7:2:

1.

9. The analgesic cold compress patch and the preparation method thereof according to claim 8, characterized in that: The method of loading analgesic microspheres with the internal hydrogel carrier includes: solution immersion or pressure perfusion.

10. The analgesic cold compress patch and the preparation method thereof according to claim 1, characterized in that: The analgesic drugs include: ibuprofen or ropivacaine hydrochloride or lidocaine.

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