Microneedle patch with imrecoxib included by modified cyclodextrin as well as preparation method and application of microneedle patch

Abstract

The invention discloses a microneedle patch with imrecoxib included by modified cyclodextrin as well as a preparation method and application of the microneedle patch, and relates to the technical field of biological medicines. The invention relates to a microneedle patch with imrecoxib included by modified cyclodextrin. The medicament of the microneedle patch is prepared from imrecoxib, crotamiton, carborane-beta-cyclodextrin and water. The carborane-beta-cyclodextrin clathrates imrecoxib and prepares the microneedle patch, so that the water solubility and transdermal efficiency of the fat-soluble drug imrecoxib can be remarkably improved, the first-pass effect and gastrointestinal reaction of oral administration can be avoided, and an efficient and safe local treatment scheme is provided for diseases such as knee osteoarthritis.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, in particular to a modified cyclodextrin-encapsulated micro-needle patch of etoricoxib and a preparation method and application thereof. BACKGROUND

[0002] Knee osteoarthritis is a common degenerative joint disease, the pathological process of which involves chronic damage to bone tissue, synovial membrane, joint capsule and surrounding soft tissue, usually leading to joint function limitation and seriously affecting the quality of life of patients. As a selective cyclooxygenase-2 inhibitor, etoricoxib has shown significant efficacy in the treatment of orthopedics, especially knee osteoarthritis, and can effectively relieve symptoms such as joint pain, stiffness and dysfunction.

[0003] However, the inventors believe that the oral administration of etoricoxib has some inherent defects: after the drug is absorbed in the gastrointestinal tract, it needs to undergo first-pass metabolism in the liver, resulting in a decrease in bioavailability; in addition, long-term oral administration of the drug can cause systemic toxic side effects, and some patients may experience adverse reactions in the gastrointestinal tract.

[0004] Therefore, the inventors propose that if etoricoxib is prepared into a form of external patch for administration, the liver first-pass effect can be avoided, the burden on the gastrointestinal tract can be avoided, and the local drug effect can be sustained and the use can be convenient, which becomes an ideal administration form of etoricoxib.

[0005] However, since etoricoxib is a fat-soluble drug, the skin itself has a strong barrier function, especially the stratum corneum has poor permeability to fat-soluble substances, which makes it difficult to prepare etoricoxib into an external patch. How to solve the above technical problems is a technical problem that needs to be solved in the field at present.

[0006] The information disclosed in this BACKGROUND section is only intended to increase an understanding of the general context of the application and is not to be taken in any way as an acknowledgment or any form of suggestion that this information forms prior art widely known as of the priority date of the application. SUMMARY

[0007] In view of the above technical problems, the present application provides a modified cyclodextrin-encapsulated micro-needle patch of etoricoxib and a preparation method and application thereof to solve the problems in the above background.

[0008] The present application provides the following technical solutions: a modified cyclodextrin-encapsulated micro-needle patch of etoricoxib, the pharmaceutical composition of the micro-needle patch comprising: etoricoxib, cromolyn, carborane-β-cyclodextrin and water.

[0009] Preferably, the medicine composition of the microneedle patch comprises, in parts by mass, 1 part of irinotecan, 5 parts of crotamiton, 5 parts of carborane-β-cyclodextrin, and 89 parts of water.

[0010] A preparation method of the modified cyclodextrin inclusion irinotecan microneedle patch described above, comprising the following steps:

[0011] S31: hydrophobic modification of the arachnoid carborane to β-cyclodextrin to obtain a carborane-β-cyclodextrin solution;

[0012] S32: dissolving irinotecan in crotamiton to obtain an irinotecan solution;

[0013] S33: adding the irinotecan solution to the carborane-β-cyclodextrin solution to obtain an inclusion complex solution by high-pressure homogenization;

[0014] S34: adding the inclusion complex solution to a microneedle mold to prepare a soluble microneedle patch. The material of the microneedle mold is polydimethylsiloxane.

[0015] Preferably, the preparation method of carborane-β-cyclodextrin in step S31 specifically comprises:

[0016] S41: deprotonation of arachnoid carborane with a strong base to generate a carbon anion intermediate of arachnoid carborane;

[0017] S42: reacting the carbon anion intermediate of arachnoid carborane with CO2 to generate arachnoid carborane carboxylic acid;

[0018] S43: activation of the carboxyl group in arachnoid carborane carboxylic acid to generate a reactive intermediate;

[0019] S44: reaction of the reactive intermediate with β-cyclodextrin to obtain a carborane-β-cyclodextrin solution.

[0020] Preferably, the reactive intermediate in step S43 comprises acyl chloride or NHS ester.

[0021] Preferably, in step S33, the high-pressure homogenization conditions include a homogenization pressure of 30 MPa, a homogenization frequency of 5 times, a homogenization time of 10 min each time, and a homogenization temperature of 25°C.

[0022] Preferably, the step of adding the inclusion complex solution to the microneedle mold to prepare a soluble microneedle patch specifically comprises:

[0023] S71: taking 200 μL of the inclusion complex solution and adding it to the microneedle mold, centrifuging at 4500 r / min for 15 min to inject the inclusion complex solution into the needle tip cavities of the microneedle mold, and scraping off the inclusion complex solution outside the needle tip cavities;

[0024] S72: 200 μL of the inclusion complex solution was taken and added to the microneedle mold as a backing layer solution, and centrifuged at 4500 r / min for 5 min to prepare the backing layer of the microneedle;

[0025] S73: The microneedle mold loaded with the inclusion complex solution was placed in a 25℃ oven and dried for 12 h, and the microneedle patch was demolded.

[0026] Preferably, the microneedle mold comprises a plurality of microneedle cavities; the microneedle cavities are conical; the top of the microneedle cavity is provided with a cubic cavity in communication with the microneedle cavity; the cubic cavity is used as a backing layer for preparing the microneedle.

[0027] The application provides a modified cyclodextrin-encapsulated arixiibum microneedle patch for use in the treatment of knee osteoarthritis.

[0028] Preferably, the microneedle patch is used to be attached to the outside of the knee joint of a patient with knee osteoarthritis, and the microneedles on the microneedle patch dissolve and release the internal medicament after piercing the skin of the patient.

[0029] The modified cyclodextrin-encapsulated arixiibum microneedle patch provided by the application has the following beneficial effects:

[0030] 1. The arixiibum is encapsulated by modified cyclodextrin to prepare a soluble microneedle patch, the microneedle can pierce the stratum corneum of the skin to form a drug delivery channel, and the modified cyclodextrin can improve the water solubility of the drug, so that the inclusion complex dissolves quickly after the needle tip pierces the skin, realizes efficient transdermal release of the drug, and breaks through the limitation of the traditional transdermal barrier.

[0031] 2. After the arixiibum is encapsulated by the modified cyclodextrin, a soluble microneedle patch is prepared, and the microneedle and the backing layer are both the inclusion complex, a large amount of drug is encapsulated in the needle tip of the microneedle, and the drug is stored in the backing layer of the microneedle as a reservoir, so that the drug loading capacity is further increased.

[0032] 3. The high-pressure homogenization process (30 MPa, 5 times x 10 min, 25℃) disperses the inclusion complex of the modified cyclodextrin and the arixiibum into uniform nanoparticles with a size of 100-500 nm through high-frequency mechanical shearing and cavitation effect, which can significantly improve the encapsulation efficiency.

[0033] 4. After the arixiibum is dissolved by using chremophor as a solvent, the modified β-cyclodextrin is combined, and the introduction of the spider web type carborane increases the hydrophobic cavity volume of the β-cyclodextrin, thereby improving the drug loading efficiency and solving the problem of low drug loading capacity of the microneedle.

[0034] 5. The preparation method of the modified cyclodextrin improves the water solubility, prolongs the circulation time or stability of the drug by connecting the spider web type carborane to the β-cyclodextrin to form a derivative.

[0035] 6. Arachno-carborane with the structure of open pentagonal bipyramidal cage, more easily chemically modified due to the absence of two vertices, to achieve the purpose of combining with cyclodextrin. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1 Process flow chart for preparing microneedle patch by two-step centrifugation method in the present application;

[0037] Figure 2 Puncture experiment result graph of the microneedle patch in the present application; wherein, Figure 2 A is the puncture experiment result graph; Figure 2 B is a local enlarged view of rat skin;

[0038] Figure 3 Puncture experiment result graph of ordinary microneedle patch;

[0039] Figure 4 Dissolution change graph of the microneedle patch in the present application over time;

[0040] Figure 5 Dissolution change graph of ordinary microneedle patch over time. DETAILED DESCRIPTION

[0041] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0042] In view of the problems mentioned in the above background art, the embodiments of the present application provide a modified cyclodextrin-encapsulated arixicab tag microneedle patch and a preparation method and application of the microneedle patch to solve the above technical problems, and the specific implementation technical solutions are as follows:

[0043] The materials, reagents, etc. used in the following embodiments can be obtained from commercial channels unless otherwise specified.

[0044] Example 1: β-cyclodextrin modification method

[0045] (1) Lithiation: The C-H bond of arachno-C2B7H 13 ) can be deprotonated by a strong base (such as n-BuLi) to generate a carbanion intermediate arachno-C2B7H 12 Li, which then reacts with an electrophilic reagent, reaction conditions: low temperature (-78℃), THF solvent, inert atmosphere (N2 / Ar).

[0046] (2) Carboxylation: The carbanion intermediate arachno-C2B7H12 Li with CO2 to form carboxylic acid arachno-C2B7H 12 COOH; work-up: quench with dilute acid (e.g. HCl) to give the carboxylic acid derivative.

[0047] (3) Activation of the carboxyl group: activation of the carboxyl group of arachno-C2B7H 12 COOH to form a reactive intermediate (e.g. an acid chloride or NHS ester): SOCl2or (COCl)2, DMF catalysis arachno-C2B7H 12 COOH to form arachno-C2B7H 12 COCl; conditions: room temperature, inert atmosphere, solvent (e.g. anhydrous THF or DCM).

[0048] (4) Reaction with the hydroxyl groups of β-cyclodextrin (β-CD): the primary hydroxyl groups (C6-OH) of β-CD are more nucleophilic and preferentially participate in the reaction; arachno-C2B7H 12 COCl + HO-β-CD to form arachno-C2B7H 12 COO-β-CD; conditions: anhydrous solvent (DCM or DMF), 0°C to room temperature, reaction time 12-24 hours.

[0049] Example 2: Preparation of the microneedle patch of the present application

[0050] (1) The pharmaceutical composition of the microneedle patch of the present application, in parts by mass, is shown in Table 1.

[0051] Table 1

[0052] Name Amount Aprepitant 1 part Cromolyn 5 parts Carborane-β-cyclodextrin 5 parts Water 89 parts Total weight 100 parts

[0053] (2) Preparation of the carborane-β-cyclodextrin inclusion complex solution:

[0054] Step 1: Prepare a saturated aqueous solution of carborane-β-cyclodextrin at 50°C; the preparation scheme is shown in the β-cyclodextrin modification method in Example 1;

[0055] Step 2: Dissolve eribulin in crotamiton to obtain an eribulin solution, and slowly add the eribulin solution to the carborane-β-cyclodextrin aqueous solution obtained in Step 1;

[0056] Step 3: High-pressure homogenization under the conditions of a homogenization pressure of 30 MPa, 5 times of homogenization, 10 min each time, and a temperature of 25°C to obtain the inclusion complex;

[0057] (3) Preparation of the microneedle patch:

[0058] The microneedle patch microneedle mold size is: 10x10 array, single needle is conical, height 800 μm, bottom diameter 320 μm. The preparation method of the microneedle patch is as shown in Figure 1 The preparation method of the microneedle patch is as shown in

[0059] First, about 200 μL of the inclusion compound is taken out with a pipette gun into the microneedle mold, and centrifuged at 4500 r / min for 15 min, so that the solution is injected into the needle tip cavity of the mold, and the excess solution at the edge is scraped off;

[0060] Second, about 200 μL of the inclusion compound is taken out as a backing layer solution, and centrifuged at 4500 r / min for 5 min to prepare a microneedle backing layer. After the two-step centrifugation is completed, the microneedle mold is taken out, dried in a 25°C oven for 12 h, and then demolded to obtain the microneedle patch.

[0061] Example 3: Preparation of ordinary microneedle patch, used as a comparative example

[0062] (1) The pharmaceutical composition of the ordinary microneedle patch, by mass fraction, is shown in Table 2;

[0063] Table 2

[0064]

[0065]

[0066] (2) Preparation of β-cyclodextrin inclusion compound solution

[0067] Erixiyibu is dissolved in crotamiton to obtain an Erixiyibu solution, and the Erixiyibu solution is slowly added to the β-cyclodextrin aqueous solution; homogenization is performed to obtain a microneedle material.

[0068] (3) Preparation of ordinary microneedle patch:

[0069] The microneedle mold size of the ordinary microneedle patch is: 10x10 array, single needle is conical, height 800 μm, bottom diameter 320 μm. The preparation method of the ordinary microneedle patch is as shown in Figure 1 The preparation method of the microneedle patch is as shown in

[0070] First, about 200 μL of the inclusion compound is taken out with a pipette gun into the microneedle mold, and centrifuged at 4500 r / min for 15 min, so that the solution is injected into the needle tip cavity of the mold, and the excess solution at the edge is scraped off;

[0071] Second, about 200 μL of the inclusion compound is taken out as a backing layer solution, and centrifuged at 4500 r / min for 5 min to prepare a microneedle backing layer. After the two-step centrifugation is completed, the microneedle mold is taken out, dried in a 25°C oven for 12 h, and then demolded to obtain the microneedle patch.

[0072] Example 4: Test results of drug distribution and drug loading efficiency of the microneedle patch of the present invention and ordinary microneedle patches

[0073] Six microneedle patches and six ordinary microneedle patches from the same batch were scraped, and the needle body and backing were fully dissolved in 6 ml of mobile phase. After ultrasonic extraction for 10 min, the drug content was determined by HPLC after filtration.

[0074] The test results are shown in Table 3. The drug loading of each of the prepared etoricoxib soluble microneedles is 495.97 μg.

[0075] The microneedle patch of this invention has a higher drug loading capacity than ordinary microneedle patches, and its overall drug loading effect is also better than that of ordinary microneedle patches.

[0076] Table 3

[0077] Group Needle drug loading μg Backer drug loading μg Actual drug loading μg Theoretical drug loading μg Drug loading efficiency % The microneedle patch of the present application 456.85 39.12 495.97 500 99.19 Common microneedle patch 409.88 45.04 454.92 500 90.98

[0078] Example 5: Puncture Performance Evaluation

[0079] The solvent water in the microneedle patch of this invention and ordinary microneedle patches was replaced with a 0.4% trypan blue aqueous solution. Then, the trypan blue-containing microneedles were placed on excised rat skin, and a force of approximately 40 N was applied vertically for 2 minutes before removal. The appearance of stained pores on the skin surface was observed to determine whether the microneedles could penetrate the rat skin.

[0080] like Figure 2 As shown, the microneedles of the microneedle patch of the present invention form clear blue dot-like holes on the skin of rats, indicating that the prepared microneedles have good puncture ability; Figure 3 As shown, ordinary microneedles only leave a few scattered blue dot-like pores on the rat's skin; [the rest of the text appears to be incomplete and requires further context.] Figure 2 and Figure 3 The comparison shows that the microneedle patch prepared in Example 2 has better puncture ability than the ordinary microneedle patch prepared in Example 3.

[0081] Example 6: Solubility Test

[0082] Based on the puncture experiment results, the dissolution performance of the microneedles was further investigated. The dissolution performance of microneedles is an important indicator affecting their efficacy; good dissolution performance facilitates the dissolution of the microneedle within the body, thereby releasing the drug to achieve a therapeutic effect.

[0083] Healthy SD rats were selected as experimental subjects, and their abdominal hair was removed before the experiment. After anesthetizing the rats, the microneedles of the microneedle patch of this invention were applied to the abdominal skin of the live rats with a certain force. After a certain time (0.5-20 min), the microneedles were removed, and the remaining length of the microneedles was observed and analyzed using an optical microscope.

[0084] likeFigure 4 As shown, the microneedles of the microneedle patch of the present application gradually dissolve after piercing the rat skin, about 50% of the needle body has been dissolved at 4 min, and almost all of the needle body has been dissolved at 20 min. It can be seen that the microneedle tip of the microneedle patch of the present application has good dissolving ability, and can dissolve rapidly after piercing the skin to release the drug.

[0085] Figure 5 As shown, the dissolving performance of the common microneedles prepared in Example 3 is significantly poorer than that of the microneedle patch prepared in Example 2, specifically, the dissolving rate is slow, the uniformity is poor, and the residual amount is high.

[0086] From the above, it can be seen that the microneedle patch prepared in Example 2 has better piercing ability than the common microneedle patch prepared in Example 3. Figure 4 Figure 5 From the above, it can be seen that the microneedle patch prepared in Example 2 has better piercing ability than the common microneedle patch prepared in Example 3.

[0087] In summary, the present application successfully solves the transdermal delivery problem of the fat-soluble drug eribulin through the synergy of carborane-modified cyclodextrin and microneedle technology, and is significantly better than the common microneedle patch in terms of drug loading capacity, piercing ability and dissolving performance.

[0088] The above is only a preferred embodiment of the present application, and is not used to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. within the spirit and principle of the present application shall be included in the protection scope of the present application.​

Claims

1. A microneedle patch containing modified cyclodextrin and atorcobacterium, characterized in that, The microneedle patch consists of: etoricoxib, clomiphene, carborane-β-cyclodextrin, and water.

2. The microneedle patch with modified cyclodextrin encapsulated in etoricoxib according to claim 1, characterized in that, The microneedle patch consists of the following components by weight: 1 part of etoricoxib, 5 parts of clomiphene, 5 parts of carborane-β-cyclodextrin, and 89 parts of water.

3. A method for preparing a microneedle patch containing modified cyclodextrin and atorvaxib as described in claim 1, characterized in that, Includes the following steps: S31: The spider web-like carborane is attached to β-cyclodextrin for hydrophobic modification to obtain a carborane-β-cyclodextrin solution; S32: Dissolve etoricoxib in clomiphene to obtain etoricoxib solution; S33: Add the etoricoxib solution to the carborane-β-cyclodextrin solution and homogenize under high pressure to obtain the inclusion complex solution; S34: Add the inclusion complex solution into the microneedle mold to prepare a soluble microneedle patch.

4. The method for preparing the microneedle patch with modified cyclodextrin encapsulated in etoricoxib according to claim 3, characterized in that, The preparation method of carborane-β-cyclodextrin in step S31 specifically includes: S41: Deprotonation of cobweb carborane with a strong base to generate a carbanion intermediate of cobweb carborane; S42: React the carbanion intermediate of the cobweb carborane with CO2 to generate cobweb carborane carboxylic acid; S43: Activates the carboxyl group in the cobweb-like carborane carboxylic acid to generate an active intermediate; S44: The reactive intermediate reacts with β-cyclodextrin to give a carborane-β-cyclodextrin solution.

5. The method for preparing the microneedle patch with modified cyclodextrin encapsulated in etoricoxib according to claim 4, characterized in that, The reactive intermediate in step S43 includes acyl chlorides or NHS esters.

6. The method for preparing the microneedle patch with modified cyclodextrin encapsulated in etoricoxib according to claim 3, characterized in that, In step S33, the conditions for high-pressure homogenization include: homogenization pressure of 30 MPa, homogenization times of 5, time of 10 min per time, and homogenization temperature of 25 °C.

7. The method for preparing the microneedle patch with modified cyclodextrin encapsulated in etoricoxib according to claim 3, characterized in that, In step S34, the step of adding the inclusion complex solution into the microneedle mold to prepare a soluble microneedle patch specifically includes: S71: Add 200 μL of inclusion complex solution to the microneedle mold, centrifuge at 4500 r / min for 15 min to inject the inclusion complex solution into the needle tip cavity of the microneedle mold, and scrape off the inclusion complex solution outside the needle tip cavity; S72: Take 200 μL of inclusion complex solution and add it to the microneedle mold as a backing solution. Centrifuge at 4500 r / min for 5 min to prepare the backing layer of the microneedles. S73: Place the microneedle mold loaded with the inclusion complex solution in an oven at 25 ℃ and dry for 12 h. Demold to obtain the microneedle patch.

8. The method for preparing the microneedle patch with modified cyclodextrin encapsulated in etoricoxib according to claim 7, characterized in that, The microneedle mold includes several microneedle cavities; the microneedle cavities are conical; a cubic cavity communicating with the microneedle cavity is provided at the top of the microneedle cavity; the cubic cavity is used as a backing layer for preparing microneedles.

9. The application of a microneedle patch containing modified cyclodextrin and atorcob as described in claim 1 in the treatment of knee osteoarthritis.

10. The application of the modified cyclodextrin-encapsulated arbutin microneedle patch according to claim 9 in the treatment of knee osteoarthritis, characterized in that, Microneedle patches are applied to the outside of the knee joint of patients with knee osteoarthritis. The microneedles on the patch pierce the patient's skin, dissolve, and release the medication inside.

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