Hydrobromic acid lappaconitine transdermal patch and preparation method thereof

Abstract

The application belongs to the technical field of transdermal patches, and particularly relates to a transdermal patch of hydrobromic acid high lappaconitine and a preparation method thereof. The transdermal patch of hydrobromic acid high lappaconitine comprises, from top to bottom, a film backing layer, a drug layer and a controlled-release film layer; the drug layer comprises hydrobromic acid high lappaconitine microcrystals and a gel body; the particle size of the hydrobromic acid high lappaconitine microcrystals is 0.5-1 microns; and the gel body comprises a gel base, a penetration enhancer, a preservative, a pH regulator and water. The transdermal patch of hydrobromic acid high lappaconitine can facilitate constant-speed and stable release of hydrobromic acid high lappaconitine.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of transdermal patches, and particularly relates to a hydrobromic acid high-vomiting peptide transdermal patch and a preparation method thereof. BACKGROUND

[0002] Hydrobromic acid high-vomiting peptide is a non-narcotic analgesic. Since it has analgesic effect comparable to morphine or dolantin, and has advantages such as no dependence, it is widely used in the treatment of severe pain after surgery. Since the therapeutic index of hydrobromic acid high-vomiting peptide is small, the preparation of a transdermal patch can effectively avoid the liver first-pass effect under oral administration, avoid damage to the gastrointestinal tract, and reduce drug toxicity. There is sufficient evidence that high-vomiting peptide can achieve effective blood drug concentration in the body after percutaneous absorption, thereby playing a role in analgesia. Due to the water-insoluble nature of hydrobromic acid high-vomiting peptide and its short elimination half-life in the body, it is difficult for a transdermal patch product to have both improved percutaneous absorption and controlled stable and constant release. Although the existing high-vomiting peptide transdermal patch product can achieve good percutaneous absorption and maintain drug release for 72 hours, the drug release rate is not constant, and the drug release rate is fast at first and then slow, which easily leads to an unstable blood drug concentration in the body, with a high drug concentration in the early stage and a low drug concentration in the later stage, thereby affecting the analgesic maintenance effect during the drug release process. SUMMARY

[0003] In order to overcome the defects of the prior art, the technical problem to be solved by the present application is to provide a hydrobromic acid high-vomiting peptide transdermal patch capable of stable drug release.

[0004] In order to solve the above technical problems, the technical scheme adopted by the present application is as follows: a hydrobromic acid high-vomiting peptide transdermal patch, comprising a film backing layer, a drug layer and a controlled release film layer arranged in sequence from top to bottom;

[0005] The drug layer comprises hydrobromic acid high-vomiting peptide microcrystals and a gel body.

[0006] The particle size of the hydrobromic acid high-vomiting peptide microcrystals is 0.5-1 μm.

[0007] The gel body comprises a gel matrix, a penetration enhancer, a preservative, a pH adjuster and water.

[0008] Further provided is a preparation method of the hydrobromic acid high-vomiting peptide transdermal patch, comprising the following steps:

[0009] S1, preparing hydrobromic acid high-vomiting peptide microcrystals;

[0010] S2, after the gel matrix is fully swollen in water, the penetration enhancer and the preservative are added and stirred, and the pH adjuster is continuously added dropwise to neutral during stirring to obtain a gel body;

[0011] S3, the hydrogen bromide lappaconitine microcrystal is suspended in the gel body to obtain a liquid medicine;

[0012] S4, the liquid medicine is cast on a film backing layer to form a medicine layer;

[0013] S5, a controlled-release film layer is compounded on the surface of the medicine layer to obtain a hydrogen bromide lappaconitine transdermal patch.

[0014] The particle size of the hydrogen bromide lappaconitine microcrystal is 0.5-1 μm.

[0015] The hydrogen bromide lappaconitine is prepared into crystalline particles with a particle size of 0.5-1 μm, the surface area of the hydrogen bromide lappaconitine in contact with the skin surface is increased, and the transdermal absorption of the hydrogen bromide lappaconitine is facilitated. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 The figure shows a structure diagram of an SPG external pressure module in the specific embodiment of the application.

[0017] Figure 2 The figure shows a penetration amount broken line graph of each example and the comparative example within 72 hours in the detection example of the application.

[0018] Label explanation: 1, outer tube; 2, inner tube. DETAILED DESCRIPTION

[0019] To describe the technical content, the purposes and effects of the application in detail, the following embodiments are described.

[0020] The hydrogen bromide lappaconitine transdermal patch comprises a film backing layer, a medicine layer and a controlled-release film layer arranged from top to bottom; the medicine layer comprises hydrogen bromide lappaconitine microcrystals and a gel body; the particle size of the hydrogen bromide lappaconitine microcrystals is 0.5-1 μm; and the gel body comprises a gel base, a penetration enhancer, a preservative, a pH regulator and water.

[0021] The hydrogen bromide lappaconitine microcrystal is mixed with a gel to prepare the drug layer, and the drug layer is coated on a thin film backing layer and compounded with a controlled release film layer to obtain the hydrogen bromide lappaconitine transdermal patch. The hydrogen bromide lappaconitine microcrystal wrapped by the gel can be effectively absorbed transdermally under the action of the penetration enhancer. The controlled release film can slow down the drug release to some extent and prolong the release duration of the drug, but its drug release control effect is limited. The hydrogen bromide lappaconitine is made into microcrystal to further delay the transdermal absorption process, so that the absorption of the drug and the blood drug concentration are more stable and persistent. Of course, adhesion is necessary for the normal use of the transdermal patch, so it should be understood that the hydrogen bromide lappaconitine transdermal patch described herein has an adhesive layer formed by an adhesive layer formed by a pressure-sensitive adhesive, and a release film attached to the surface of the adhesive layer. The adhesive layer can be coated by any commercially available medical pressure-sensitive adhesive. For example, the adhesive layer is formed by hot melting coating of silicone pressure-sensitive adhesive (BIO-PSA7-4302). In order to avoid the influence of the adhesive layer on the transdermal permeability of hydrogen bromide lappaconitine, in one embodiment, the adhesive layer is formed around the controlled release film layer, that is, in this embodiment, the controlled release film layer directly contacts the skin of the patient. The formation method of the adhesive layer in this embodiment is a conventional technology, which is not described herein. It should be noted that in the following examples, the adhesive layer is prepared by the above-mentioned adhesive layer preparation method and the above-mentioned adhesive layer structure.

[0022] The penetration enhancer can be a conventional penetration enhancer for hydrogen bromide lappaconitine transdermal patch, such as azone.

[0023] The controlled release film layer is a polymer film, such as ethylene-vinyl acetate copolymer (EVA), polyvinyl chloride (PVC), etc.

[0024] The backing layer and the release layer are both conventional materials, such as non-woven fabric, release paper, etc.

[0025] The mass ratio of the hydrogen bromide lappaconitine microcrystal to the gel is 3.0-5.0:100, preferably 3.2:100.

[0026] In one embodiment, the hydrogen bromide lappaconitine microcrystal is prepared as follows:

[0027] S1, preparing a hydrogen bromide lappaconitine methanol solution as a dispersed phase;

[0028] S2, preparing a protective agent aqueous solution as a continuous phase;

[0029] S3, pressing the dispersed phase into the outside of the SPG tube, so that the hydrogen bromide lappaconitine microcrystal is precipitated in the inner wall of the SPG tube and the continuous phase, and the hydrogen bromide lappaconitine microcrystal is collected after vacuum filtration.

[0030] The average pore size of the SPG tube is 0.9-1.0 μm, preferably 0.9 μm; the dispersed phase is pressed into the outside of the SPG tube at a pressure of 0.98 MPa, and the flow rate of the continuous phase is 0.8-1.2 mL / s, preferably 1.0 mL / h. In this embodiment, the average pore size of the SPG tube, the pressure of the dispersed phase, and the flow rate of the continuous phase are adjusted to control the particle size of the lappaconitine hydrobromide microcrystals.

[0031] It should be noted that in this text, the SPG membrane is complexly formed into a tube. In one embodiment, lappaconitine hydrobromide microcrystals are prepared using an SPG external pressure module (SPG External Pressure Module, purchased from SPG Technology Co., Ltd) or a self-made platform similar in structure to the SPG external pressure module. The structure of the SPG external pressure module is shown in Figure 1 The structure of the SPG external pressure module is shown in FIG. 1, which includes an outer tube 1 and an inner tube 2. The inner tube 2 is an SPG tube, and the continuous phase flows in the inner tube 2. The dispersed phase is pressed into the inner tube 2 from the space between the outer tube 1 and the inner tube 2.

[0032] Preferably, the volume ratio of the dispersed phase to the continuous phase is 1:10.

[0033] In one embodiment, the gel matrix is selected from one of carbomer, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and carboxyethyl cellulose.

[0034] In one embodiment, the preservative is at least one of nipagin esters, such as sodium methylparaben, methylparaben, ethylparaben, propylparaben, and the like. Preferably, it is a combination of methylparaben and ethylparaben at a mass ratio of 1:1. More preferably, the amount of methylparaben and ethylparaben added is 0.1-0.2 wt%.

[0035] In one embodiment, the pH regulator includes, but is not limited to, citric acid and the like.

[0036] In one alternative embodiment, the lappaconitine hydrobromide microcrystals are prepared by the following method:

[0037] The hydrogen bromide lappaconitine 3.2 g is dissolved in methanol 96 ml to obtain a solution as the dispersed phase; the protective agent is dissolved in water, and is fully swollen at room temperature, and is mixed uniformly under constant stirring to obtain a continuous phase; the flow rate of the circulating pump is adjusted to realize the stable circulation of the continuous phase at a flow rate of 0.8-1.2 mL / s, and the dispersed phase is pressurized into the outside of the SPG tube at a pressure of 0.98 MPa, the dispersed phase liquid penetrating through the pores of the SPG membrane with an average pore size of 0.9-1.0 μm in the membrane tube, due to the difference in solubility of the hydrogen bromide lappaconitine in the dispersed phase and the continuous phase, the hydrogen bromide lappaconitine microcrystals are continuously precipitated in the continuous phase and on the inner wall of the SPG tube, and due to the small flow rate of the continuous phase, the hydrogen bromide lappaconitine microcrystals are allowed to grow in the continuous phase or on the inner wall of the SPG tube to form the desired size. Finally, the hydrogen bromide lappaconitine microcrystals are fully mixed in the continuous phase to form a suspension, and the suspension is collected and vacuum filtered through a 0.22 μm filter membrane, and the continuous phase and the substances dissolved in the continuous phase are removed to obtain the hydrogen bromide lappaconitine microcrystals.

[0038] The protective agent includes a steric protective agent and a charge protective agent, the steric protective agent is selected from poloxamer 407 and poloxamer 188, and the charge protective agent is selected from sodium docusate (DOSS) or sodium dodecyl sulfate (SDS). Preferably, the mass ratio of the hydrogen bromide lappaconitine to the steric protective agent is 1:5, and the mass ratio of the hydrogen bromide lappaconitine to the charge protective agent is 1:2.

[0039] The stirring speed is 1000-1300 rpm, and preferably 1200 rpm.

[0040] In the preparation method, the 0.22 μm filter membrane separates the hydrogen bromide lappaconitine microcrystals from the solution containing methanol and the protective agent.

[0041] Preferably, the gel body is prepared from the following raw materials:

[0042] The gel matrix is 1.0-3.0 wt%, the penetration enhancer is 4.0-6.0 wt%, the preservative is 0.2-0.4 wt%, the pH regulator is 1.5-2.0 wt%, and the balance is water.

[0043] The preparation method of the hydrogen bromide lappaconitine transdermal patch includes the following steps:

[0044] S1, preparing hydrogen bromide lappaconitine microcrystals;

[0045] S2, after the gel matrix is fully swollen in water, the penetration enhancer and the preservative are added, and the pH regulator is continuously added to neutralization under stirring to obtain a gel body;

[0046] S3, the hydrogen bromide lappaconitine microcrystals are suspended in the gel body to obtain a liquid medicine;

[0047] S4, casting the drug liquid on the film backing layer to form a drug layer;

[0048] S5, compounding a controlled release film layer on the surface of the drug layer, compounding an adhesive layer around the controlled release film layer, and compounding a release film on the surface of the adhesive layer and the surface of the controlled release film layer to obtain the transdermal patch of hydrobromic acid lappaconitine.

[0049] Specifically, the preparation method comprises the following steps:

[0050] S1, dissolving hydrobromic acid lappaconitine in methanol to obtain a solution as a dispersed phase; dissolving a proper amount of a protective agent in water, fully swelling it at room temperature, and continuously stirring to mix it, as a continuous phase; adjusting the flow of a circulating pump to realize the stable circulation of the continuous phase at a flow rate of 0.8-1.2 mL / s, press the dispersed phase into the outside of an SPG tube at a pressure of 0.98 MPa, and penetrate through the fine pores of an SPG membrane with an average pore size of 0.9-1.0 μm. Collecting the hydrobromic acid lappaconitine microcrystal suspension, vacuum filtering the suspension through a 0.22 μm filter membrane, removing the continuous phase and the substances dissolved in the continuous phase, to obtain the hydrobromic acid lappaconitine microcrystal;

[0051] S2, fully swelling the gel matrix in water, adding azone and a preservative, and stirring, continuously adding a pH regulator to neutralize during stirring, to obtain a gel body;

[0052] S3, mixing the hydrobromic acid lappaconitine microcrystal into the gel body to obtain a microcrystal suspension drug liquid;

[0053] S4, casting the microcrystal suspension drug liquid on a film backing layer to form a drug layer on the film backing layer, compounding a controlled release film layer on the surface of the drug layer, and obtaining the transdermal patch of hydrobromic acid lappaconitine.

[0054] The hydrobromic acid lappaconitine microcrystal is a crystalline particle with a particle size of 0.5-1 μm uniformly dispersed in the gel matrix.

[0055] Example 1

[0056] The preparation method of the transdermal patch of hydrobromic acid lappaconitine comprises the following steps:

[0057] S1, preparation of hydrobromic acid lappaconitine microcrystal

[0058] S11, dissolving 3.2 g of hydrobromic acid lappaconitine in 96 mL of methanol as a dispersed phase;

[0059] S12, dissolving 16 g of poloxamer 407 and 6.4 g of DOSS in 960 mL of water, placing it at room temperature for 4 h to fully swell, and continuously stirring at 1200 rpm to mix it, as a continuous phase;

[0060] S13, adjust the circulating pump flow to achieve continuous phase with 1 mL / s flow rate stable circulation, the dispersed phase is pressed into the outside of the SPG tube (0.9 μm average pore size, Φ10 mm, purchased from SPG Technology Co., Ltd) under the pressure of 0.98 MPa. Collecting the suspension of lappaconitine hydrobromide microcrystal, the suspension is filtered through a 0.22 μm filter under vacuum, and the continuous phase and the substances dissolved in the continuous phase are removed, thereby obtaining lappaconitine hydrobromide microcrystal, which is ready for use;

[0061] S2, preparation of blank gel body

[0062] 1 g of carbomer 940 is fully swollen with 84.8 mL of water, 4 g of azone, 0.1 g of methyl nipagin, and 0.1 g of ethyl nipagin are dissolved in the gel matrix, and citric acid is added to adjust the pH to 7.0, thereby obtaining a blank gel body;

[0063] S3, mixing lappaconitine hydrobromide microcrystal and blank gel body in a mass ratio of 3.2:100, thereby obtaining a drug solution;

[0064] S4, casting the drug solution on the backing layer of the film, and compounding EVA (3M Co Tran TM 9728) on the surface of the drug solution, thereby obtaining a lappaconitine hydrobromide patch, wherein the thickness of the drug layer is 0.5 mm.

[0065] Example 2

[0066] The preparation method of the lappaconitine hydrobromide transdermal patch comprises the following steps:

[0067] S1, preparation of lappaconitine hydrobromide microcrystal

[0068] S11, dissolving 3.2 g of lappaconitine hydrobromide in 96 mL of methanol as a dispersed phase;

[0069] S12, dissolving 16 g of poloxamer 188 and 6.4 g of SDS in 960 mL of water, and placing it at room temperature for 4 h to allow it to swell, and continuously stirring it at 1200 rpm to mix it evenly, as a continuous phase;

[0070] S13, adjusting the circulating pump flow to achieve continuous phase with 1 mL / s flow rate stable circulation, the dispersed phase is pressed into the outside of the SPG tube (same as example 1) under the pressure of 0.98 MPa. Collecting the suspension of lappaconitine hydrobromide microcrystal, the suspension is filtered through a 0.22 μm filter under vacuum, and the continuous phase and the substances dissolved in the continuous phase are removed, thereby obtaining lappaconitine hydrobromide microcrystal, which is ready for use;

[0071] S2, preparation of blank gel body

[0072] 3g Carbomer 940 was swelled with 75.6 mL water, 6g azone, 0.2g methylparaben, 0.2g ethylparaben were dissolved in the gel base, and citric acid was added to adjust the pH to 7.0 to obtain a blank gel body;

[0073] S3, the microcrystalline of hydrobromic acid lappaconitine and the blank gel body were mixed in a mass ratio of 3.2:100 to obtain a drug solution;

[0074] S4, the drug solution was cast on the film backing layer, and EVA (3M CoTran TM 9728) was compounded on the surface of the drug solution to obtain a hydrobromic acid lappaconitine patch, wherein the thickness of the drug layer was 0.5 mm.

[0075] Comparative Example 1

[0076] The preparation method of the hydrobromic acid lappaconitine transdermal patch was different from that of Example 1 in that the hydrobromic acid lappaconitine was completely dissolved in the gel body and did not form microcrystals.

[0077] The preparation method of the hydrobromic acid lappaconitine transdermal patch comprises the following steps:

[0078] S1, preparation of a hydrobromic acid lappaconitine solution

[0079] 3.2g of hydrobromic acid lappaconitine was dissolved in 300 mL of ethanol, and after ultrasonic dissolution, a hydrobromic acid lappaconitine solution was obtained for standby use;

[0080] S2, preparation of a blank gel body

[0081] 1g Carbomer 940 was swelled with 84.8 mL water, 4g azone, 0.1g methylparaben, 0.1g ethylparaben were dissolved in the gel base, and citric acid was added to adjust the pH to 7.0 to obtain a blank gel body;

[0082] S3, the hydrobromic acid lappaconitine solution and the blank gel body were mixed in a mass ratio of 3.2:100 to obtain a drug solution;

[0083] S4, the drug solution was cast on the film backing layer, and EVA (3M CoTran TM 9728) was compounded on the surface of the drug solution to obtain a hydrobromic acid lappaconitine patch, wherein the thickness of the drug layer was 0.5 mm.

[0084] Test Example

[0085] Franz diffusion cells were used, and mouse isolated skin (2cm 2The transdermal patch was attached to the junction of the supply and receiving pools, with the stratum corneum facing the supply pool. 30% ethanol was used as the receiving solution, and the patch was equilibrated for 30 minutes before testing. The temperature was set at 32±0.5℃, and the constant stirring speed was set at 200 rpm. The hydrobromic acid-rich aconitine transdermal patches prepared in Examples 1 and 2 and Comparative Example 1 were pre-attached to mouse ex vivo skin (before the mouse ex vivo skin was attached to the aforementioned junction). Samples were taken at 4h, 8h, 16h, 24h, 32h, 40h, 48h, 56h, 64h, and 72h for HPLC analysis, and an equal amount of blank receiving solution was added. The cumulative permeation was calculated using the following formula, and the results are shown in Table 1. Figure 2 As shown.

[0086]

[0087] Among them, Q n This represents the cumulative permeation amount over the nth time.

[0088] C n The concentration of hydrobromic acid guanosine in the receiving solution during the nth sampling;

[0089] C i The concentration of hydrobromic acid guanylic acid in the receiving solution during the i-th sampling;

[0090] V is the total volume of the receiving liquid;

[0091] V i Let be the volume of the i-th sample.

[0092] A represents the effective diffusion area (based on the total area of ​​mouse skin ex vivo).

[0093] Table 1

[0094]

[0095] from Figure 2 As shown in Table 1, the cumulative transdermal penetration of Comparative Example 1 within 24 hours was significantly higher than that of Examples 1 and 2, especially between 8 and 16 hours. The cumulative transdermal penetration of the drug in the 24-hour test was 449.0 μg / cm³. 2 Subsequently, drug release gradually slowed down, and after 32 hours, the release level was 40–60 μg / cm³. 2 The drug release was maintained between 4 and 72 hours. In the example group, the drug release was maintained at 70–90 μg / cm³ from 4 to 72 hours. 2 The drug release was stable throughout. This indicates that the hydrobromic acid aconitine microcrystals in the gel of this technical solution are more conducive to the constant-rate release of hydrobromic acid aconitine, thus resulting in a better and more consistent analgesic effect.

[0096] In summary, the present application coats the microcrystals of hydrobromic acid high lappaconitine in the gel body, so that a certain amount of microcrystals in the gel body always contact the skin, and the drug release and absorption speed is kept relatively stable. Thus, the problem of the drug release being fast at first and then slow, and the transdermal absorption speed being unstable, caused by the full dissolution of hydrobromic acid high lappaconitine in the gel body and the continuous full contact with the skin, is overcome.

[0097] The above description is only an embodiment of the present application, and does not limit the patent scope of the present application. Any equivalent transformation or direct or indirect application in the related technical field based on the content of the present application is also included in the patent protection scope of the present application.

Claims

1. A transdermal patch of hydrobromic acid homoharringtonine, characterized in that, The drug layer comprises hydrogen bromide high lappaconitine microcrystal and gel body. The drug layer comprises hydrogen bromide high lappaconitine microcrystal and gel body. The particle size of the hydrogen bromide high lappaconitine microcrystal is 0.5-1 μm. The hydrogen bromide high lappaconitine microcrystal is prepared by the following method: S1, preparing a hydrogen bromide high lappaconitine methanol solution as a dispersed phase; S2, preparing a protective agent aqueous solution as a continuous phase; the protective agent aqueous solution comprises a protective agent and water, the protective agent comprises a steric protective agent and a charge protective agent, the steric protective agent is poloxamer 407 or poloxamer 188, and the charge protective agent is sodium docusate or sodium dodecyl sulfate; S3, continuously circulating the continuous phase in the SPG tube at a flow rate of 0.8-1.2 mL / s, and pressurizing the dispersed phase outside the SPG tube to make the hydrogen bromide high lappaconitine microcrystal precipitate on the inner wall of the SPG tube and in the continuous phase, collecting the hydrogen bromide high lappaconitine microcrystal, and then vacuum filtering to obtain the hydrogen bromide high lappaconitine microcrystal; The gel body comprises a gel matrix, a penetration enhancer, a preservative, a pH regulator, and water. The controlled release film layer is ethylene-vinyl acetate copolymer or polyvinyl chloride. The mass ratio of the hydrogen bromide high lappaconitine microcrystal to the gel body is 3.0-5.0:

100.

2. The hydrobromic acid high-aconitine transdermal patch according to claim 1, characterized in that, The average pore size of the SPG tube is 0.9-1.0 μm.

3. The hydrobromic acid high-coixanol transdermal patch according to claim 1, characterized in that, The dispersed phase is pressurized to the outside of the SPG tube at a pressure of 0.98 MPa.

4. The hydrobromic acid high-coixanol transdermal patch according to claim 1, characterized in that, The volume ratio of the dispersed phase to the continuous phase is 1:

10.

5. The hydrobromic acid high-aconitine transdermal patch according to claim 1, characterized in that, The gel matrix is selected from one of carbomer, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and carboxyethyl cellulose.

6. The method for preparing the transdermal patch of hypaconitine hydrobromide according to claim 1, wherein the step of dissolving the hypaconitine hydrobromide in the solvent is performed at a temperature of 20-30°C. The method comprises the following steps: S1, preparing hydrogen bromide high lappaconitine microcrystal; S2, fully swelling the gel matrix in water, adding a penetration enhancer and a preservative, and stirring, and continuously adding a pH regulator to neutralize while stirring to obtain a gel body; S3, suspending the hydrogen bromide high lappaconitine microcrystal in the gel body to obtain a drug solution; S4, casting the drug solution on a film backing layer to form a drug layer; S5, compounding a controlled release film layer on the surface of the drug layer to obtain a hydrogen bromide high lappaconitine transdermal patch.

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