A kind of temperature control antipyretic patch and preparation method thereof

Abstract

The present invention discloses a temperature-controlled antipyretic patch and a preparation method thereof, and relates to the field of medical technology. It includes the following components: component A and component B; the weight ratio of component A to component B is 1-10:1; component A is measured by weight: 50-110 parts of silicone gel, 0-1.5 parts of inhibitor, 10-20 parts of filler, 20-30 parts of phase-change polymer material inclusion compound containing antipyretic analgesic, and 0-1.5 parts of transdermal agent; component B is measured by weight: 0-60 parts of silicone gel, 5-10 parts of catalyst, 20-25 parts of filler, and 0-10 parts of thermal conductive material. The silicone gel developed by the present invention can be cured at room temperature, meeting the process requirements for constructing an intelligent temperature-controlled drug release system. The phase-change polymer material inclusion compound containing antipyretic analgesic is prevented from melting in a heated preparation environment, affecting the inclusion compound structure and drug release rate.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a temperature-controlled antipyretic patch and a preparation method thereof. Background Art

[0002] Oral antipyretic and analgesic drugs cannot be completely absorbed by the gastrointestinal tract, and some of them are lost through the first-pass effect of the liver after absorption, and only 50% to 80% may enter the blood in the end; at the same time, they have side effects on the gastrointestinal tract. Using thermosensitive phase change materials as drug carriers and utilizing the structural characteristics of polymer materials, antipyretic and analgesic drugs are mixed with thermosensitive materials and hidden in the structure of polymer materials to form inclusion compounds and used in transdermal patches. Transdermal absorption allows antipyretic and analgesic drugs to achieve intelligent temperature-controlled drug release, with stable efficacy and no gastrointestinal side effects. Therefore, the research and development of thermosensitive smart drugs has great potential.

[0003] Silicone gel is a high-end medical adhesive, a type of viscous polymer, which has been used in the pharmaceutical industry since 1950. It not only has good adhesion, moisture resistance and biocompatibility, but also has physical and chemical compatibility with drugs, and can be used with drugs without affecting its adhesive properties. The network structure of silicone gel produces a large free space, which makes it have high moisture permeability and oxygen permeability, which can reduce the closure of the skin. It also has good drug permeability and is mainly used in the adhesive layer to closely combine the skin with the drug delivery system.

[0004] However, the prior art generally uses heating and curing process conditions, and the temperature-controlled inclusion complex formed by the thermosensitive phase change material and the drug will melt after heating, destroying the structure of the inclusion complex itself and affecting the drug release efficiency.

[0005] Therefore, providing a temperature-controlled antipyretic patch prepared under room temperature conditions is an urgent problem to be solved by those skilled in the art. Summary of the invention

[0006] In view of this, the present invention provides a temperature-controlled antipyretic patch and a preparation method thereof.

[0007] In order to achieve the above object, the present invention adopts the following technical solution:

[0008] A temperature-controlled antipyretic patch comprising the following components:

[0009] Component A, component B;

[0010] The weight ratio of component A to component B is 1-10:1;

[0011] The component A is calculated by weight: 50-110 parts of silicone gel, 0-1.5 parts of inhibitor, 10-20 parts of filler, 20-30 parts of phase change polymer material inclusion compound containing antipyretic and analgesic, and 0-1.5 parts of transdermal agent;

[0012] The B component is calculated by weight: 0-60 parts of silicone gel, 5-10 parts of catalyst, 20-25 parts of filler, and 0-10 parts of thermal conductive material.

[0013] Further, the silicone gel of component A is any one of the following combinations, and the weight ratio of the combination is:

[0014] Vinyl silicone oil;

[0015] Vinyl silicone oil: hydrogen silicone oil = 50-100: 1-10;

[0016] Vinyl silicone oil: hydroxy silicone oil: hydrogen silicone oil = 50-100: 10-30: 1-10;

[0017] Hydroxy silicone oil: alkoxy silicone oil: silane coupling agent and its oligomer: hydrogen-containing silicone oil = 9-110: 1-10: 0.1-10;

[0018] The silane coupling agent and its oligomers are at least two of functional group-containing silanes with general formulas of (C2H5O)3Si-RX, (C2H5O)2Si(CH3)-RX, (C2H5O)3SiY and (C2H5O)2Si(CH3)Y, and oligomers of the homopolymer or copolymer structure of the functional group silanes; R is an alkylene group, including -CH2-, -CH2-CH2-CH2-, and a phenylene group; X is a functional group, including a dimethylamino group, a diethylamino group, a methacryloxy group, and a urea group; and Y includes a vinyl group, a phenyl group, a chloromethyl group, and a dichloromethyl group.

[0019] Furthermore, in parts by weight, the silicone gel of component B is at least one of vinyl silicone oil and hydroxy silicone oil.

[0020] Furthermore, the vinyl silicone oil is any one of the following:

[0021] ViSiMe2O-(SiMe2O)n-SiMe2Vi;

[0022] Vi-SiMe2O-(SiMe2O)n-(SiMeViO)m-SiMe2Vi;

[0023] Vi-SiMe2O-(SiMe2O)n-(SiMeViO)m-(SiMePhO)p-SiMe2Vi;

[0024] HOSiMe2O-(SiMe2O)n-SiMe2OH;

[0025] HOSiMe2O-(SiMe2O)n-(SiMeViO)m-SiMe2OH;

[0026] HO-SiMe2O-(SiMe2O)n-(SiMeViO)m-(SiMePhO)p-SiMe2OH;

[0027] Me3SiO-(SiMe2O)n-SiMe3;

[0028] Me3SiO-(SiMe2O)n-(SiMeViO)m-SiMe3;

[0029] Me3SiO-(SiMe2O)n-(SiMePhO)m-SiMe3;

[0030] Me3SiO-(SiMe2O)n-(SiMeViO)m-(SiMePhO)m-SiMe3;

[0031] The Vi- is vinyl, the Me- is methyl, and the Ph- is phenyl.

[0032] Further, the hydrogen-containing silicone oil is any one of the following:

[0033] Me3SiO-(SiHMeO)n-SiMe3;

[0034] Me3SiO-(SiHMeO)n-(SiMeViO)q-SiMe3;

[0035] HMe2SiO-(SiMe2O)n-SiMe2H;

[0036] HMe2SiO-(SiMe2O)n-(SiMeViO)q-SiMe2H;

[0037] Me3SiO-(SiMe2O)n-(SiHMeO)m-SiMe3;

[0038] Me3SiO-(SiMe2O)n-(SiHMeO)m-(SiMeViO)q-SiMe3;

[0039] HMe2SiO-(SiMe2O)n-(SiHMeO)m-SiMe2H;

[0040] HMe2SiO-(SiMe2O)n-(SiHMeO)m-(SiMeViO)q-SiMe2H;

[0041] Me3SiO-(SiMe2O)n-(SiHMeO)m-(SiMePhO)p-SiMe3;

[0042] Me3SiO-(SiMe2O)n-(SiHMeO)m-(SiMePhO)p-(SiMeViO)q-SiMe3;

[0043] HMe2SiO-(SiMe2O)n-(SiHMeO)m-(SiMePhO)p-SiMe2H;

[0044] HMe2SiO-(SiMe2O)n-(SiHMeO)m-(SiMePhO)p-(SiMeViO)q-SiMe2H;

[0045] The Me- is a methyl group, and the Ph- is a phenyl group.

[0046] Furthermore, the A component inhibitor is any one of caryophyllene, myrcene, limonene, 9-decene alcohol, linalool, acetylene cyclohexanol, 3.7.11-trimethyldodecene-3-ol, nerolidol, and tetramethyltetravinylcyclotetrasiloxane; the A component filler is at least one of MQ methyl resin, MQ vinyl resin, methyl resin, white carbon black, and nano-calcium carbonate; and the transdermal agent is at least one of menthol, eucalyptus oil, and lauryl azone.

[0047] Furthermore, the phase change polymer material inclusion compound containing antipyretic and analgesic drugs in component A comprises the following components:

[0048] Composite temperature-sensitive phase change materials, active drug molecules, packaging materials;

[0049] The drug release temperature of the phase-change polymer material inclusion compound containing the antipyretic and analgesic drug is 38.4±0.4°C.

[0050] Furthermore, the B component catalyst is at least one of chloroplatinic acid-tetramethyl-tetravinylcyclotetrasiloxane and chloroplatinic acid-isopropanol complex; the B component filler is at least one of MQ methyl resin, MQ vinyl resin, methyl resin, vinyl resin, white carbon black, and nano-calcium carbonate; and the B component thermal conductive material is graphene.

[0051] A method for preparing a temperature-controlled antipyretic patch comprises the following steps:

[0052] The component A and the component B are mixed in a weight ratio of 1-10:1, and the mixture is quickly stirred and mixed within 5 minutes at 26° C., applied to the backing material, vulcanized for 5-10 minutes, and cut according to specifications to obtain a temperature-controlled antipyretic patch.

[0053] It can be seen from the above technical solution that, compared with the prior art, the beneficial effects of the present invention are:

[0054] The present invention uses an adhesive (preferably silicone gel) as a carrier, and an antipyretic analgesic with a combination of a thermosensitive phase change material and a polymer compound as a fever-reducing component. With the assistance of a thermal conductive material and a transdermal absorption promoter, the antipyretic analgesic realizes intelligent temperature-controlled drug release through transdermal absorption; the excellent properties of silicone gel materials are used to construct an intelligent temperature-controlled system for transdermal drug delivery. The inclusion compound in the core drug-carrying part of the system can automatically sense changes in human body temperature, and when the temperature perception is accurate to 38.0-38.8°C, the system responds to phase changes, and at the same time, the drug is delivered through this phase change process to promote transdermal absorption of antipyretic analgesics, thereby exerting the drug effect; after the antipyretic analgesics take effect, the body temperature returns to normal, and the system stops releasing the drug, achieving the effect of intelligent temperature-controlled drug release. The present invention can not only realize the body's own immune response when the fever is low, but also automatically administer the drug in a timely manner without human intervention when the fever is high, and has no gastrointestinal side effects, which brings great convenience to patients. This invention is a precise temperature control for antipyretic analgesics, and shows great potential in intelligent drug delivery.

[0055] The temperature-controlled inclusion compound formed by the thermosensitive phase change material and the drug cannot be cured by heating. The silicone gel developed by the present invention can be cured at room temperature, meeting the process requirements for building an intelligent temperature-controlled drug release system. It can prevent the phase change polymer material inclusion compound containing antipyretic analgesic drugs from melting in the heating preparation environment, which will affect the inclusion compound structure and drug release rate.

[0056] Silicone gel is a polysiloxane compound, a cutting-edge high-end new material for medical pressure-sensitive adhesives. It can be used as a substrate for artificial skin, has good biocompatibility, is non-toxic, non-irritating, and non-sensitizing to the skin; has certain sweat resistance, temperature resistance, good adhesion, certain air permeability, can be repeatedly pasted, has low peel force and drug permeability, etc., and will be widely used in transdermal drug delivery preparations. More importantly, the material has the property of achieving cross-linking at room temperature and will not destroy the inclusion system formed by the temperature-sensitive material.

[0057] Adding graphene to silicone gel can give full play to its thermal conductivity in the intelligent temperature-controlled drug release system, allowing the temperature to be quickly transferred in the adhesive layer, ensuring that the temperature-controlled inclusion complex responds to phase changes in a timely manner. The drug release rate is increased after adding graphene. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0059] Figure 1The attached figure shows the cumulative dissolution rate of ibuprofen in the temperature-controlled antipyretic patch.

[0060] Figure 2 The attached figure shows the changes in body temperature of mice in each group after administration. DETAILED DESCRIPTION

[0061] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. 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.

[0062] Example 1

[0063] Raw materials in parts by weight:

[0064] Component A: 50 parts of vinyl silicone oil, 1.0 part of hydrogenated silicone oil, 0.5 parts of inhibitor caryophyllene, 10 parts of filler MQ methyl resin, 20 parts of phase change polymer material inclusion complex containing antipyretic and analgesic (phase change material: eicosane, heneicosane, antipyretic and analgesic: ibuprofen, inclusion material: β-cyclodextrin. The weight ratio of phase change material to ibuprofen is 10:1; the volume ratio of ibuprofen-phase change material mixture solution to saturated aqueous solution of β-cyclodextrin is 1:20).

[0065] Component B: 50 parts of vinyl silicone oil, 10 parts of catalyst chloroplatinic acid-tetramethyl-tetravinylcyclotetrasiloxane, and 25 parts of filler MQ vinyl resin.

[0066] Components A and B are mixed in a ratio of 1:1, stirred and applied to the backing material, vulcanized at room temperature (26°C) for 10 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 1.

[0067] Example 2

[0068] Raw materials in parts by weight:

[0069] Component A: 60 parts of vinyl silicone oil, 2.0 parts of hydrogen silicone oil, 1.0 parts of inhibitor myrcene, 10 parts of filler MQ methyl resin, 25 parts of phase change polymer material inclusion compound containing antipyretic analgesic (phase change material: eicosane, heneicosane, antipyretic analgesic: aspirin, inclusion material: β-cyclodextrin).

[0070] Component B: 60 parts of vinyl silicone oil, 12 parts of catalyst chloroplatinic acid-divinyltetramethyldisiloxane, 5 parts of filler methyl resin, 10 parts of vinyl resin, 10 parts of white carbon black, 2 parts of graphene

[0071] Components A and B are mixed in a ratio of 1:1, stirred, and applied to the backing material, vulcanized at room temperature (26°C) for 6 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 2.

[0072] Example 3

[0073] Raw materials in parts by weight:

[0074] Component A: 80 parts of vinyl silicone oil, 3.0 parts of hydrogen silicone oil, 1.5 parts of inhibitor limonene, 10 parts of filler methyl resin, 30 parts of phase change polymer material inclusion compound containing antipyretic analgesic (phase change material: eicosane, heneicosane, docosane, antipyretic analgesic: aspirin, inclusion material: β-cyclodextrin), 1 part of transdermal agent menthol;

[0075] Component B: 50 parts of vinyl silicone oil, 10 parts of catalyst chloroplatinic acid-divinyltetramethyldisiloxane, 3 parts of filler MQ methyl resin, 15 parts of MQ vinyl resin, and 5 parts of nano calcium carbonate.

[0076] Components A and B are mixed in a ratio of 1:1, stirred and applied to the backing material, vulcanized at room temperature (26°C) for 10 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 3.

[0077] Example 4

[0078] Raw materials in parts by weight:

[0079] Component A: 50 parts of vinyl silicone oil, 10 parts of hydroxy silicone oil, 1.0 parts of hydrogen-containing silicone oil, 0.5 parts of inhibitor 9-decene alcohol, 10 parts of filler MQ vinyl resin, 20 parts of phase change polymer material inclusion compound containing antipyretic and analgesic drugs (phase change materials: eicosane, heneicosane, docosane, antipyretic and analgesic drug: ibuprofen, inclusion material: β-cyclodextrin).

[0080] Component B: 50 parts of vinyl silicone oil, 10 parts of catalyst chloroplatinic acid-divinyltetramethyldisiloxane, 10 parts of filler MQ methyl resin, 10 parts of MQ vinyl resin, and 2 parts of graphene.

[0081] Components A and B are mixed in a ratio of 1:1, stirred and applied to the backing material, vulcanized at room temperature (26°C) for 10 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 4.

[0082] Example 5

[0083] Raw materials in parts by weight:

[0084] Component A: 50 parts of vinyl silicone oil, 10 parts of hydroxy silicone oil, 1.0 parts of hydrogen-containing silicone oil, 0.5 parts of inhibitor linalool, 6 parts of filler MQ vinyl resin, 4 parts of white carbon black, 20 parts of phase change polymer inclusion compound containing antipyretic and analgesic (phase change material: eicosane, heneicosane, tetradecanol, antipyretic and analgesic: ibuprofen, inclusion material: β-cyclodextrin), 0.5 parts of transdermal agent, eucalyptus oil, and 0.5 parts of laurocapram.

[0085] Component B: 50 parts of vinyl silicone oil, 10 parts of catalyst chloroplatinic acid-divinyltetramethyldisiloxane, 5 parts of filler MQ methyl resin, 15 parts of MQ vinyl resin, and 2 parts of ethene.

[0086] Components A and B are mixed in a ratio of 1:1, stirred and applied to the backing material, vulcanized at room temperature (26°C) for 10 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 5.

[0087] Example 6

[0088] Raw materials in parts by weight:

[0089] Component A: 50 parts of vinyl silicone oil, 10 parts of hydroxy silicone oil, 1.0 parts of hydrogen-containing silicone oil, 0.5 parts of inhibitor acetylene cyclohexanol, 10 parts of filler MQ methyl resin, 20 parts of phase change polymer inclusion complex containing antipyretic and analgesic drugs (phase change materials: eicosane, docosane, tetradecanol, antipyretic and analgesic drug: ibuprofen, inclusion material: glucosyl-β-cyclodextrin).

[0090] Component B: 50 parts of vinyl silicone oil, 10 parts of chloroplatinic acid-divinyltetramethyldisiloxane catalyst, 5 parts of MQ methyl resin filler, 10 parts of MQ vinyl resin, 5 parts of white carbon black, 5 parts of nano calcium carbonate, and 5 parts of charcoal.

[0091] Components A and B are mixed in a ratio of 1:1, stirred and applied to the backing material, vulcanized at room temperature (26°C) for 10 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 6.

[0092] Example 7

[0093] Raw materials in parts by weight:

[0094] Component A: 90 parts of hydroxy silicone oil, 10 parts of alkoxy silicone oil, 5 parts of silane coupling agent and its oligomer, 0.4 parts of hydrogen silicone oil, 15 parts of filler MQ methyl resin, 5 parts of white carbon black, 30 parts of phase change polymer inclusion compound containing antipyretic and analgesic (phase change material: eicosane, docosane, tetradecanol, antipyretic and analgesic: aspirin, inclusion material: β-cyclodextrin), transdermal agent mixture 0.5 parts of menthol, 0.5 parts of eucalyptus oil and 0.5 parts of laurocapram.

[0095] Component B: 10 parts of catalyst chloroplatinic acid-isopropanol complex, 5 parts of filler MQ methyl resin, 15 parts of MQ vinyl resin, and 6 parts of graphene.

[0096] Components A and B are mixed in a ratio of 10:1, stirred and applied to the backing material, vulcanized at room temperature (26°C) for 6 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 7.

[0097] Example 8

[0098] Raw materials in parts by weight:

[0099] Component A: 60 parts of hydroxy silicone oil, 10 parts of alkoxy silicone oil, 3 parts of silane coupling agent and its oligomer, 0.4 parts of hydrogen silicone oil, 18 parts of filler MQ methyl resin, 25 parts of phase change polymer inclusion compound containing antipyretic and analgesic (phase change material: eicosane, docosane, heneicosane, antipyretic and analgesic: indomethacin, inclusion material: β-cyclodextrin), and 1 part of transdermal agent laurocapram.

[0100] Component B: 10 parts of catalyst chloroplatinic acid-tetramethyl-tetravinylcyclotetrasiloxane, 5 parts of filler MQ methyl resin, and 15 parts of MQ vinyl resin.

[0101] Components A and B are mixed in a ratio of 10:1, stirred and applied to the backing material, vulcanized at room temperature (26°C) for 6 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 8.

[0102] Example 9

[0103] Raw materials in parts by weight:

[0104] Component A: 50 parts of hydroxy silicone oil, 5 parts of alkoxy silicone oil, 1 part of silane coupling agent and its oligomer, 0.3 parts of hydrogen-containing silicone oil, 15 parts of filler MQ methyl resin, 2 parts of white carbon black, 3 parts of nano calcium carbonate, 20 parts of phase change polymer inclusion compound containing antipyretic and analgesic (phase change material: eicosane, docosane, tetradecanol, antipyretic and analgesic: paracetamol, inclusion material: hydroxypropyl-β-cyclodextrin), and 1 part of transdermal eucalyptus oil.

[0105] Component B: 10 parts of catalyst chloroplatinic acid-tetramethyl-tetravinylcyclotetrasiloxane and 20 parts of filler nano calcium carbonate.

[0106] Mix components A and B in a ratio of 10:1, stir and apply to the backing material, vulcanize at room temperature (26°C) for 6 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 9.

[0107] Example 10

[0108] Raw materials in parts by weight:

[0109] Component A: 50 parts of hydroxy silicone oil, 5 parts of alkoxy silicone oil, 1 part of silane coupling agent and its oligomer, 0.3 parts of hydrogen silicone oil, 20 parts of fillers methyl resin, nano calcium carbonate and white carbon black, 20 parts of phase change polymer inclusion compound containing antipyretic and analgesic (phase change material: eicosane, heneicosane, antipyretic and analgesic: indomethacin, inclusion material: β-cyclodextrin), 0.5 parts of transdermal menthol and 0.5 parts of laurocapram.

[0110] Component B: 10 parts of catalyst chloroplatinic acid-tetramethyl-tetravinylcyclotetrasiloxane, 2 parts of filler MQ methyl resin, 18 parts of MQ vinyl resin, 8 parts of graphene

[0111] Components A and B are mixed in a ratio of 10:1, stirred and applied to the backing material, vulcanized at room temperature (26°C) for 5 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 10.

[0112] Example 11

[0113] The following raw materials by weight:

[0114] Component A: 80 parts of hydroxy silicone oil, 10 parts of alkoxy silicone oil, 1 part of silane coupling agent and its oligomers, 0.3 parts of hydrogen-containing silicone oil, 10 parts of filler methyl resin, 3 parts of vinyl resin, 7 parts of white carbon black, 30 parts of phase change polymer inclusion complex containing antipyretic and analgesic drugs (phase change materials: eicosane, heneicosane, mixed fatty acid glyceride type 36, antipyretic and analgesic drug: indomethacin, inclusion material: 2,6-diethyl-β-cyclodextrin).

[0115] Component B: 10 parts of catalyst chloroplatinic acid-tetramethyl-tetravinylcyclotetrasiloxane, 6 parts of filler MQ methyl resin, 10 parts of MQ vinyl resin, 4 parts of nano calcium carbonate, 10 parts of graphene

[0116] Mix components A and B in a ratio of 10:1, stir and apply to the backing material, vulcanize at room temperature (26°C) for 5 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 11.

[0117] Example 12

[0118] Raw materials in parts by weight:

[0119] Component A: 50 parts of vinyl silicone oil, 10 parts of hydroxy silicone oil, 1.0 part of hydrogen-containing silicone oil, 1.5 parts of inhibitor 3.7.11-trimethyldodecene-3-ol, 5 parts of filler MQ methyl resin, 5 parts of MQ vinyl resin, 30 parts of phase change polymer material inclusion complex containing antipyretic and analgesic drugs (phase change materials: eicosane, heneicosane, mixed fatty acid glyceride type 38, antipyretic and analgesic drug: indomethacin, inclusion material: β-cyclodextrin).

[0120] Component B: 40 parts of vinyl silicone oil, 10 parts of hydroxy silicone oil, 10 parts of catalyst chloroplatinic acid-tetramethyl-tetravinylcyclotetrasiloxane, 15 parts of filler MQ methyl resin, 5 parts of MQ vinyl resin, and 2 parts of graphene.

[0121] Mix components A and B in a ratio of 1:1, stir and apply to the backing material, vulcanize at room temperature (26°C) for 10 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 12.

[0122] Embodiment 13

[0123] Raw materials in parts by weight:

[0124] Component A: 50 parts of vinyl silicone oil, 10 parts of hydroxy silicone oil, 1.0 part of hydrogenated silicone oil, 0.5 parts of inhibitor nerolidol, 15 parts of filler MQ methyl resin, 5 parts of MQ vinyl resin, 25 parts of phase change polymer inclusion complex containing antipyretic and analgesic (phase change material: eicosane, docosane, mixed fatty acid glyceride type 36, antipyretic and analgesic: ibuprofen, inclusion material: β-cyclodextrin), and 1 part of transdermal agent menthol.

[0125] Component B: 50 parts of vinyl silicone oil, 10 parts of chloroplatinic acid-isopropanol complex as catalyst, 5 parts of MQ methyl resin as filler, 10 parts of MQ vinyl resin, 5 parts of nano calcium carbonate, and 4 parts of charcoal.

[0126] Mix components A and B in a ratio of 1:1, stir and apply to the backing material, vulcanize at room temperature (26°C) for 10 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 13.

[0127] Embodiment 14

[0128] Raw materials in parts by weight:

[0129] Component A: 30 parts of vinyl silicone oil, 20 parts of hydroxy silicone oil, 3.0 parts of hydrogen-containing silicone oil, 1.5 parts of inhibitor tetramethyltetravinylcyclotetrasiloxane, 10 parts of filler MQ methyl resin, 5 parts of MQ vinyl resin, 5 parts of nano calcium carbonate, 20 parts of phase change polymer inclusion complex containing antipyretic and analgesic drugs (phase change materials: eicosane, heneicosane, mixed fatty acid glyceride type 36, antipyretic and analgesic drug: aspirin, inclusion materials: amylose and modified chitosan).

[0130] Component B: 40 parts of vinyl silicone oil, 10 parts of catalyst chloroplatinic acid-isopropanol complex, 15 parts of filling MQ methyl resin, 3 parts of MQ vinyl resin, 2 parts of nano calcium carbonate, and 6 parts of hectorite.

[0131] Mix components A and B in a ratio of 1:1, stir and apply to the backing material, vulcanize at room temperature (26°C) for 10 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 14.

[0132] Embodiment 15

[0133] Raw materials in parts by weight:

[0134] Component A: 50 parts of vinyl silicone oil, 1.0 part of hydrogenated silicone oil, 0.5 parts of inhibitor caryophyllene, MQ methyl resin, 10 parts of MQ vinyl resin, 20 parts of phase change polymer material inclusion complex containing antipyretic and analgesic (phase change material: eicosane, heneicosane, antipyretic and analgesic: ibuprofen, inclusion material: β-cyclodextrin. The weight ratio of phase change material to ibuprofen is 5:1; the volume ratio of ibuprofen-phase change material mixture solution to saturated aqueous solution of β-cyclodextrin is 1:20).

[0135] Component B: 50 parts of vinyl silicone oil, 10 parts of catalyst, 25 parts of filler MQ methyl resin and MQ vinyl resin.

[0136] Mix components A and B in a ratio of 1:1, stir and apply them on the backing material, vulcanize at room temperature (26°C) for 10 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 15.

[0137] Example 16

[0138] Raw materials in parts by weight:

[0139] Component A: 50 parts of vinyl silicone oil, 1.0 part of hydrogenated silicone oil, 0.5 parts of inhibitor caryophyllene, MQ methyl resin, 10 parts of MQ vinyl resin, 20 parts of phase change polymer material inclusion complex containing antipyretic and analgesic (phase change material: eicosane, heneicosane, antipyretic and analgesic: ibuprofen, inclusion material: β-cyclodextrin. The weight ratio of phase change material to ibuprofen is 18.75:1; the volume ratio of ibuprofen-phase change material mixture solution to saturated aqueous solution of β-cyclodextrin is 1:20).

[0140] Component B: 50 parts of vinyl silicone oil, 10 parts of catalyst, 25 parts of filler MQ methyl resin and MQ vinyl resin.

[0141] Mix components A and B in a ratio of 1:1, stir and apply to the backing material, vulcanize at room temperature (26°C) for 10 minutes, and cut according to specifications to obtain the temperature control patch disclosed in Example 16.

[0142] Comparative Example 1

[0143] Raw materials in parts by weight:

[0144] 80 parts of terminal vinyl ether silicone oil, 1 part of cationic photoinitiator, 30 parts of phase change polymer inclusion compound containing antipyretic and analgesic drug and skin penetration promoter (phase change material: eicosane, heneicosane, mixed fatty acid glyceride type 38, antipyretic and analgesic drug: aspirin, inclusion material: β-cyclodextrin), and 10 parts of graphene.

[0145] The above materials are mixed and stirred and applied on the backing material, and then vulcanized under ultraviolet light for 5 minutes at room temperature to obtain a temperature control patch, which is cut according to the required specifications. Comparative Example 1 discloses a temperature control patch.

[0146] Comparative Example 2

[0147] Raw materials in parts by weight:

[0148] Component A: 80 parts of vinyl-terminated silicone oil, 1 part of hydrogen-containing silicone oil, 10 parts of filler MQ methyl resin, 5 parts of MQ vinyl resin, 5 parts of white carbon black, 1 part of citronellol, 25 parts of phase-change polymer inclusion complex containing antipyretic and analgesic drug penetration promoter (phase-change material: eicosane, mixed fatty acid glyceride type 36, antipyretic and analgesic: ibuprofen, inclusion material: β-cyclodextrin).

[0149] Component B: 15 parts of catalyst chloroplatinic acid-isopropanol complex, 20 parts of fillers MQ methyl resin, MQ vinyl resin and nano calcium carbonate, 10 parts of graphene

[0150] Mix components A and B in a ratio of 10:1, stir and apply them on the backing material, and vulcanize them under ultraviolet light at room temperature for 5 minutes to obtain a temperature control patch, which can be cut according to the required specifications. Comparative Example 2 discloses a temperature control patch.

[0151] Comparative Example 3

[0152] Raw materials in parts by weight:

[0153] Component A: 80 parts of vinyl-terminated silicone oil, 1 part of hydrogen-containing silicone oil, 0.8 parts of linalool, 10 parts of filler MQ methyl resin, 2 parts of MQ vinyl resin, 3 parts of white carbon black, 30 parts of phase-change polymer inclusion compound containing antipyretic and analgesic drug and skin penetration promoter (phase-change material: eicosane, mixed fatty acid glyceride type 38, antipyretic and analgesic drug: ibuprofen, inclusion material: β-cyclodextrin).

[0154] Component B: 10 parts of catalyst chloroplatinic acid-isopropanol complex, 3 parts of filler MQ methyl resin, 10 parts of MQ vinyl resin, 7 parts of white carbon black, 10 parts of graphene

[0155] Mix components A and B in a ratio of 10:1, stir and apply them on the backing material, and vulcanize them under ultraviolet light at room temperature for 5 minutes to obtain a temperature control patch, which can be cut according to the required specifications. Comparative Example 3 discloses a temperature control patch.

[0156] Comparative Example 4

[0157] Raw materials in parts by weight:

[0158] Component A: 80 parts of vinyl-terminated silicone oil, 1 part of hydrogen-containing silicone oil, 1 part of citronellol, 10 parts of filler MQ methyl resin, 5 parts of MQ vinyl resin, 3 parts of nano calcium carbonate, 25 parts of phase change polymer inclusion compound containing antipyretic and analgesic drug and skin penetration promoter (phase change material: heneicosane, docosane, antipyretic and analgesic: ibuprofen, inclusion material: β-cyclodextrin).

[0159] Component B: 10 parts of catalyst chloroplatinic acid-tetramethyl-tetravinylcyclotetrasiloxane, 20 parts of filler MQ vinyl resin, 10 parts of graphene

[0160] Mix components A and B in a ratio of 10:1, stir and apply them on the backing material, and irradiate and vulcanize them under ultraviolet light at room temperature for 5 minutes to obtain a temperature control patch, which can be cut according to the required specifications. Comparative Example 4 discloses a temperature control patch.

[0161] Table 1 Drug release temperature of phase-change polymer inclusion complex containing antipyretic and analgesic drugs and skin permeation promoter

[0162] Example Phase change materials Melting temperature(℃) 1 Eicosane, Heneicosane 38.0 2 Eicosane, Heneicosane 38.0 3 Eicosane, Heneicosane, Docosane 38.0 4 Eicosane, Heneicosane, Docosane 38.0 5 Eicosane, Heneicosane, Tetradecanol 38.1 6 Eicosane, docosane, tetradecanol 38.3 7 Eicosane, docosane, tetradecanol 38.3 8 Eicosane, Heneicosane, Docosane 38.0 9 Eicosane, docosane, tetradecanol 38.3 10 Eicosane, Heneicosane 38.0 11 Eicosane, Heneicosane, Mixed Fatty Acid Glycerides Type 36 38.4 12 Eicosane, Heneicosane, Mixed Fatty Acid Glycerides Type 38 38.3 13 Eicosane, docosane, mixed fatty acid glyceride type 36 38.3 14 Eicosane, Heneicosane, Mixed Fatty Acid Glycerides Type 36 38.2 15 Eicosane, Heneicosane 38.0 16 Eicosane, Heneicosane 38.0 Comparative Example 1 Eicosane, Heneicosane, Mixed Fatty Acid Glycerides Type 38 38.4 Comparative Example 2 Eicosane, mixed fatty acid glyceride type 36 38.2 Comparative Example 3 Eicosane, mixed fatty acid glyceride type 38 38.0 Comparative Example 4 Heneicosane, docosane 38.1

[0163] Transdermal test

[0164] (1) Preparation of ex vivo rat skin

[0165] Rats were killed by cervical dislocation, and the abdominal hair was removed with an electric shaver until the epidermis was smooth. The epidermis was cut off, and two filter papers of equal size were placed at the bottom of the culture dish. 20 ml of 0.1% trypsin solution (dissolved in 0.5% sodium bicarbonate solution) was prepared and the filter papers were soaked with the epidermis facing up and spread flat. The dish was placed in a 37°C water bath and enzymatically hydrolyzed for 3 hours to remove fat and connective tissue.

[0166] (2) In vitro transdermal test

[0167] The Franz diffusion cell was filled with water and preheated to 38 ° C. The embodiment 1 intelligent temperature control antipyretic patch implementation 1 (containing 7.5 mg of ibuprofen) was attached to the surface of the mouse skin, sandwiched between the supply chamber and the receiving chamber, and the clamp was adjusted to clamp it to prevent leakage. A small rotor was placed in the receiving chamber, and 5 ml of normal saline was placed in the receiving chamber as the receiving solution; the speed was adjusted to 200 r / min, and the timing was started after 15 minutes of equilibrium. Samples were taken at fixed intervals, 5 ml each time, and the same volume of blank receiving solution was added to the receiving chamber. The sampling time points were 5 min, 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, and 8 h.

[0168] The sample was centrifuged at 10000 r / min for 10 min, and the supernatant was injected, and the sample concentration was determined by HPLC.

[0169] Chromatographic conditions:

[0170] Agilent C18 UPLC Proshell column (4.6×50 mm, 2.7 μm); flow rate: 0.8 mL / min; injection volume: 10 μL; detection wavelength: 220 nm; column temperature: 40° C. Mobile phase: potassium dihydrogen phosphate (88 mmol / L, pH 2.5): acetonitrile = 50:50 (V / V).

[0171] (3) Experimental results

[0172] The cumulative dissolution rate of ibuprofen in the temperature-controlled antipyretic patch is shown in Figure 1 .

[0173] The experimental results show that the cumulative dissolution rate of ibuprofen from the intelligent temperature-controlled antipyretic patch is 95.2% in 8 hours, and the transdermal effect is good.

[0174] Antipyretic effect

[0175] (1) Experimental methods

[0176] Male rats were adaptively raised at 23°C for 3 days. On the 4th and 5th days, the rectal temperature was measured once in the morning and evening every day. Animals whose body temperature fluctuation did not exceed 38°C and whose body temperature fluctuation did not exceed 1°C between two times were selected for the experiment.

[0177] The experimental mice were shaved with a shaver one day before and then depilated with a razor. The depilatory area was 3cm x 4cm. A layer of grease was applied to the depilatory area after depilation. The rats with normal skin condition and no redness and swelling in the experimental area were randomly divided into 6 groups, 10 in each group, AF group, and the animals were fasted overnight and had free access to water. Group A was the blank group, subcutaneously injected with normal saline, the injection volume was 10ml / kg; Group B was the control group, and Group CF was the experimental group, all of which were subcutaneously injected with 2,4-dinitrophenol, the injection volume was 15mg / kg. The body temperature was measured 30 minutes after the subcutaneous injection, and the animals with a body temperature of more than 38℃ in Group BF were selected for the experiment.

[0178] The body temperature of the experimental group rats was measured twice before administration, and the average value was taken as the initial temperature. The prepared patch was applied to the exposed skin on the back of the fever rats at the predetermined administration time point, wherein the A and B groups were applied with blank patches, the C group was applied with a patch loaded with 15 mg of ibuprofen (Example 15), the D group was applied with a patch loaded with 7.5 mg of ibuprofen (Example 1), the E group was applied with a patch loaded with 4 mg of ibuprofen (Example 16), and the F group was given a 37.5 mg / kg (in terms of ibuprofen) oral administration of Merlin suspension. The rectal temperature of the rats was measured at 30, 60, 90, 120, 150, and 180 min after administration, and the average body temperature change curve of the rats was drawn.

[0179] (2) Experimental results

[0180] Table 2 Changes in body temperature of mice in each group after administration

[0181]

[0182] Results Figure 2 The experimental results show that the intelligent temperature-controlled antipyretic patch disclosed in the present invention has a significant inhibitory effect on the fever of rats caused by 2,4-dinitrophenol. The antipyretic effect of the high-dose group is stronger than that of 37.5 mg / kg of ibuprofen, and the effect is long-lasting.

[0183] Ibuprofen blood concentration measurement

[0184] (1) Plasma sample collection

[0185] At 30, 60, 90, 120, 150, and 180 minutes after administration of 2,4-dinitrophenol-induced fever model rats, about 0.3 mL of blood was collected from the retinal venous plexus using a capillary tube and placed in a pre-heparinized 1.5 mL conical bottom centrifuge tube. The tube was centrifuged at 4000 rpm for 10 minutes, and the upper plasma was transferred to a non-heparinized centrifuge tube and stored in a -4°C refrigerator for later use.

[0186] (2) Processing of plasma samples

[0187] Accurately pipette 190 μl of plasma sample into a centrifuge tube, add 10 μl of internal standard solution and 600 μl of methanol solution, vortex mix for 3 min, centrifuge at 12000 r / min for 5 min, and take 10 μl of supernatant for injection testing.

[0188] (3) Determination of Ibuprofen Blood Concentration

[0189] ①Chromatographic conditions

[0190] Agilent C18 UPLC Proshell column (4.6×50 mm, 2.7 μm); flow rate: 0.8 mL / min; injection volume: 10 μL; detection wavelength: 220 nm; column temperature: 40° C. Mobile phase: potassium dihydrogen phosphate (88 mmol / L, pH 2.5): acetonitrile = 50:50 (V / V).

[0191] Table 3 Changes in blood concentration of ibuprofen in each group of mice after administration

[0192]

[0193] The experimental results show that after administration, the ibuprofen in each group of mice reached the maximum blood concentration within 1 hour, the drug took effect quickly, and the ibuprofen in the smart temperature-controlled cooling patch could be released accurately, which had a cooling effect.

[0194] The drug application speed with and without the addition of thermal conductive material in the embodiment was measured. The results showed that the modified graphene does have good biocompatibility. The addition of graphene to silicone gel can give full play to its thermal conductivity in the intelligent temperature-controlled drug release system, so that the temperature can be quickly transferred in the adhesive layer, ensuring that the temperature-controlled inclusion compound responds to phase changes in time. The drug release speed increased by 20% after the addition of graphene.

[0195] Comparative Examples 1-4 are transdermal patches made of photosensitive materials, which can only be cured under ultraviolet light conditions compared to Examples 1-16 of the present invention, and the photosensitive materials have certain toxicity. The present invention can be cured by stirring at room temperature and has no phototoxicity.

[0196] The above description of the disclosed embodiments enables one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A temperature-controlled antipyretic patch, characterized in that: Includes the following components: Component A, component B; The weight ratio of component A to component B is 1-10:1; The component A is calculated by weight: 50-110 parts of silicone gel, 0-1.5 parts of inhibitor, 10-20 parts of filler, 20-30 parts of phase change polymer material inclusion compound containing antipyretic and analgesic, and 0-1.5 parts of transdermal agent; The B component is calculated by weight: 0-60 parts of silicone gel, 5-10 parts of catalyst, 20-25 parts of filler and 0-10 parts of thermal conductive material; The silicone gel of component A is any one of the following combinations, and the weight ratio of the combination is: Vinyl silicone oil: hydrogen silicone oil = 50-100: 1-10; Vinyl silicone oil: hydroxy silicone oil: hydrogen silicone oil = 50-100: 10-30: 1-10; The silicone gel of component B is at least one of vinyl silicone oil and hydroxy silicone oil; The A component inhibitor is any one of caryophyllene, myrcene, limonene, 9-decene alcohol, linalool, ethynyl cyclohexanol, 3,7,11-trimethyldodecene-3-ol, nerolidol, and tetramethyltetravinylcyclotetrasiloxane; the A component filler is at least one of MQ vinyl resin, methyl resin, white carbon black, and nano-calcium carbonate; the transdermal agent is at least one of menthol, eucalyptus oil, and laurocapron; The phase-change polymer material inclusion compound containing antipyretic and analgesic drugs in component A comprises the following components: Composite thermosensitive phase change materials, active drug molecules and encapsulation materials; The composite temperature-sensitive phase change material is any one of the following combinations: Eicosane, heneicosane, docosane; Eicosane, heneicosane, tetradecanol; Eicosane, heneicosane, mixed fatty acid glyceride type 36; Eicosane, heneicosane, mixed fatty acid glycerides type 38; Eicosane, mixed fatty acid glyceride type 36; Eicosane, mixed fatty acid glyceride type 38; Heneicosane, docosane; The packaging material is any of the following: β-cyclodextrin; glucosyl-β-cyclodextrin; hydroxypropyl-β-cyclodextrin; 2,6-diethyl-β-cyclodextrin; The drug release temperature of the phase change polymer material inclusion compound containing the antipyretic and analgesic drug is 38.4±0.4°C; The B component catalyst is at least one of chloroplatinic acid-tetramethyl-tetravinylcyclotetrasiloxane and chloroplatinic acid-isopropanol complex; the B component filler is at least one of methyl resin, vinyl resin, white carbon black and nano calcium carbonate; the B component thermal conductive material is graphene.

2. A method for preparing the temperature-controlled antipyretic patch according to claim 1, characterized in that: The following steps are involved: The component A and the component B are mixed in a weight ratio of 1-10:1, and the mixture is quickly stirred and mixed within 5 minutes at 26° C., applied to the backing material, vulcanized for 5-10 minutes, and cut according to specifications to obtain a temperature-controlled antipyretic patch.

Images