Ketorolac patch composition, ketorolac patch as well as preparation method and application of ketorolac patch

Abstract

The invention provides a ketorolac patch composition, a ketorolac patch as well as a preparation method and application of the ketorolac patch. The ketorolac patch composition comprises an active component, a matrix material and a transdermal enhancer, the transdermal enhancer comprises at least two of lactic acid, oleic acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, malic acid, isopropyl myristate, propylene glycol monolaurate, glyceryl monolinoleate, glyceryl triacetate, diisopropyl adipate, triethyl citrate, polyglycerol oleate and sorbitan oleate (Span 80); preferably, the transdermal enhancer is prepared from at least two of isopropyl myristate, triethyl citrate, polyglycerol oleate, glyceryl triacetate, oleic acid, sorbitan oleate (Span 80), lactic acid and citric acid; the transdermal enhancer provided by the invention comprises the compounding of at least two of the substances, so that the transdermal diffusion performance of the ketorolac patch composition can be greatly improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a ketorolac patch composition, a ketorolac patch, and a preparation method and application thereof. Background Art

[0002] Ketorolac is a non-steroidal active ingredient with potent analgesic and moderate anti-inflammatory effects. To improve its water solubility, it is usually prepared into tromethamine salt. Ketorolac tromethamine is converted into ketorolac in vivo and exerts analgesic and anti-inflammatory effects by inhibiting the synthesis of prostaglandins. It can be used to relieve various moderate to severe acute pains and postoperative pains. Ketorolac tromethamine mainly acts on the peripheral cyclooxygenase receptor, has no effect on the central nervous system, and does not cause addiction. Due to its strong analgesic effect and effective inhibition of various inflammations, it has been favored and concerned in recent years and has been marketed and used in nearly 20 countries.

[0003] Currently, the prior art has disclosed a ketorolac patch composition, which includes an active ingredient, a matrix material, excipients, etc. The active ingredient includes ketorolac, ketorolac salts, ketorolac esters, etc. The matrix material is a solvent-based matrix material, and the excipients include a viscosity regulator, a crystallization inhibitor, a transdermal enhancer, etc. However, the transdermal diffusion performance of this ketorolac patch composition is poor.

[0004] Based on the defects of the current ketorolac patch composition, it is necessary to improve it. Summary of the Invention

[0005] The present invention aims to solve at least one problem in the related art to some extent, and provides a ketorolac patch composition, a ketorolac patch, and a preparation method and application thereof.

[0006] In a first aspect, the present invention provides a ketorolac patch composition, which includes an active ingredient, a matrix material, and a transdermal enhancer;

[0007] The active ingredient includes at least one of ketorolac, ketorolac tromethamine, other ketorolac salts, and ketorolac ester derivatives;

[0008] The matrix material is a solvent-based matrix material;

[0009] The solvent-based matrix material includes at least one of acrylic acid and its derivatives;

[0010] The transdermal enhancer includes at least two of lactic acid, oleic acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, malic acid, isopropyl myristate, propylene glycol monolaurate, glycerol monooleate, triacetin, diisopropyl adipate, triethyl citrate, polyglycerol oleate, and sorbitan oleate.

[0011] Preferably, the transdermal penetration enhancer comprises at least two of isopropyl myristate, glyceryl triacetate, and polyglyceryl oleate.

[0012] Preferably, it further comprises pharmaceutically acceptable excipients for topical preparations;

[0013] The excipients include crystal inhibitors;

[0014] The crystal inhibitor comprises at least one of butyl methacrylate-methyl methacrylate copolymer, levulinic acid, benzoic acid and its salts, and salicylic acid and its salts.

[0015] Preferably, it comprises the following components in mass fractions: 30-85% of a solvent-based matrix material, 5-20% of an active ingredient, 1-15% of a transdermal penetration enhancer, and 1-15% of a crystal inhibitor.

[0016] In a second aspect, the present invention also provides a method for preparing the ketorolac patch composition as described above, comprising the following steps:

[0017] Adding the active ingredient to a solvent and stirring, then adding the transdermal penetration enhancer, the crystal inhibitor, and the solvent-based matrix material, and continuing to stir, and drying to remove the solvent to obtain the ketorolac patch composition;

[0018] The solvent comprises at least one of methanol, ethanol, and ethyl acetate.

[0019] In a third aspect, the present invention also provides a ketorolac patch, comprising:

[0020] A release film, on which the ketorolac patch composition as described above is coated;

[0021] A backing layer, which is adhered to the ketorolac patch composition.

[0022] In a fourth aspect, the present invention also provides a method for preparing the ketorolac patch as described above, comprising the following steps:

[0023] Adding the active ingredient to a solvent and stirring, then adding the transdermal penetration enhancer, the crystal inhibitor, and the solvent-based matrix material, and continuing to stir to obtain a drug solution;

[0024] Coating the drug solution on the release film, and drying to remove the solvent and form the ketorolac patch composition;

[0025] Adhering the backing layer to the ketorolac patch composition.

[0026] In a fifth aspect, the present invention also provides an application of the ketorolac patch composition as described above or the ketorolac patch in the preparation of a drug for treating or alleviating moderate to severe pain, and the pain includes pain caused by cancer, postoperative pain, and other chronic pain.

[0027] The present invention has the following beneficial effects compared with the prior art:

[0028] 1. The ketorolac patch composition of the present invention comprises an active ingredient, a matrix material, and a transdermal enhancer. The transdermal enhancer includes at least two of lactic acid, oleic acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, malic acid, isopropyl myristate, propylene glycol monolaurate, glyceryl monooleate, glyceryl triacetate, diisopropyl adipate, triethyl citrate, polyglyceryl oleate, sorbitan oleate (Span 80); preferably, the transdermal enhancer includes at least two of isopropyl myristate, triethyl citrate, polyglyceryl oleate, glyceryl triacetate, oleic acid, sorbitan oleate (Span 80), lactic acid, and citric acid. The combination of at least two of the above substances as the transdermal enhancer of the present invention can greatly improve the transdermal diffusion performance of the ketorolac patch composition.

[0029] 2. For the ketorolac patch of the present invention, the transdermal enhancer preferably includes at least two of isopropyl myristate, glyceryl triacetate, and polyglyceryl oleate. The introduction of polyglyceryl oleate, isopropyl myristate, and glyceryl triacetate, due to the competitive binding of polyglyceryl oleate, isopropyl myristate, glyceryl triacetate and the drug to the matrix material, and the interaction between levulinic acid and polyglyceryl oleate, isopropyl myristate, glyceryl triacetate and the skin, makes the drug more likely to penetrate through the skin barrier and enter the blood circulation, thereby improving the transdermal diffusion performance of the ketorolac patch composition.

[0030] 3. The ketorolac patch composition or the ketorolac patch of the present invention can be used to treat or relieve moderate to severe pain, including pain caused by cancer, postoperative pain, and other chronic pain.

[0031] 4. The effective action duration of the ketorolac patch of the present invention is 24 - 168 h / patch. Detailed implementation manners

[0032] Next, in combination with the implementation manners of the present invention, the technical solutions in the implementation manners of the present invention will be clearly and completely described. Obviously, the described implementation manners are only a part of the implementation manners of the present invention, rather than all the implementation manners. Based on the implementation manners in the present invention, all other implementation manners obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0033] It should be noted that the description order of the following embodiments does not limit the preferred order of the embodiments. Additionally, in the description of this application, the term "comprising" means "including but not limited to". The various embodiments of the present invention may exist in the form of a range; it should be understood that the description in the form of a range is only for convenience and brevity and should not be construed as a rigid limitation on the scope of the present invention; therefore, it should be considered that the described range description has specifically disclosed all possible sub-ranges and individual values within that range. For example, it should be considered that the range description from 1 to 6 has specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and individual numbers within the range, such as 1, 2, 3, 4, 5, and 6, which applies regardless of the range. Additionally, whenever a numerical range is indicated herein, it means including any cited number (fraction or integer) within the indicated range.

[0034] An embodiment of the present application provides a ketorolac patch composition, comprising an active ingredient, a matrix material, and a transdermal enhancer;

[0035] The active ingredient includes at least one of ketorolac, tromethamine ketorolac, other ketorolac salts, and ketorolac ester derivatives;

[0036] The matrix material is a solvent-based matrix material;

[0037] The solvent-based matrix material includes at least one of acrylic acid and its derivatives;

[0038] The transdermal enhancer includes at least two of lactic acid, oleic acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, malic acid, isopropyl myristate, propylene glycol monolaurate, glyceryl monooleate, triacetin, diisopropyl adipate, triethyl citrate, polyglyceryl oleate, and sorbitan oleate.

[0039] The ketorolac patch composition of the present invention comprises an active ingredient, a matrix material, and a transdermal enhancer. The transdermal enhancer includes at least two of lactic acid, oleic acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, malic acid, isopropyl myristate, propylene glycol monolaurate, glyceryl monooleate, triacetin, diisopropyl adipate, triethyl citrate, polyglyceryl oleate, and sorbitan oleate (span-80); preferably, the transdermal enhancer includes at least two of isopropyl myristate, triethyl citrate, polyglyceryl oleate, triacetin, oleic acid, sorbitan oleate (span-80), lactic acid, and citric acid; the transdermal enhancer of the present invention includes the compounding of at least two of the above substances, which can greatly improve the transdermal diffusion performance of the ketorolac patch composition.

[0040] In some embodiments, the active ingredient includes at least one of ketorolac and tromethamine ketorolac.

[0041] In some embodiments, the transdermal penetration enhancer comprises at least two of isopropyl myristate, glyceryl triacetate, and polyglyceryl oleate.

[0042] In some embodiments, it further comprises pharmaceutically acceptable excipients for topical preparations;

[0043] The excipients include crystallization inhibitors;

[0044] The crystallization inhibitors include at least one of butyl methacrylate-methyl methacrylate copolymer, levulinic acid, benzoic acid and its salts, and salicylic acid and its salts.

[0045] In some embodiments, the ketorolac patch composition comprises the following components in mass fractions: 30-85% of a solvent-based matrix material, 5-20% of an active ingredient, 1-15% of a transdermal penetration enhancer, and 1-15% of a crystallization inhibitor.

[0046] In some embodiments, the transdermal penetration enhancer comprises a mixture of isopropyl myristate and glyceryl triacetate, wherein the mass ratio of isopropyl myristate to glyceryl triacetate is (1-2):(1-2).

[0047] In some embodiments, the transdermal penetration enhancer comprises a mixture of glyceryl triacetate and polyglyceryl oleate, wherein the mass ratio of glyceryl triacetate to polyglyceryl oleate is (1-2):(1-2).

[0048] In some embodiments, the transdermal penetration enhancer comprises a mixture of isopropyl myristate and polyglyceryl oleate, wherein the mass ratio of isopropyl myristate to polyglyceryl oleate is (1-2):(1-2).

[0049] In some embodiments, the crystallization inhibitor is preferably levulinic acid, and levulinic acid also serves as a co-solvent, greatly increasing the solubility of the drug (i.e., the active ingredient, such as ketorolac, tromethamine ketorolac, etc.), and avoiding the precipitation of the drug during the storage of the patch; the transdermal penetration enhancer preferably comprises at least two of isopropyl myristate (chemical formula C 17 H 34 O2), glyceryl triacetate (chemical formula C9H 14 O6), and polyglyceryl oleate. The introduction of polyglyceryl oleate, isopropyl myristate, and glyceryl triacetate, due to the competitive binding of polyglyceryl oleate, isopropyl myristate, glyceryl triacetate and the drug to the matrix material, and the interaction between levulinic acid and polyglyceryl oleate, isopropyl myristate, glyceryl triacetate and the skin, makes the drug more likely to penetrate through the skin barrier into the blood circulation, thereby improving the transdermal diffusion performance of the ketorolac patch composition.

[0050] In some embodiments, the polyglyceryl oleate is specifically polyglyceryl fatty acid ester, with the model number PLUROL OLEIQUE, produced by Gattefosse, a French company.

[0051] In some embodiments, the solvent-based matrix material includes acrylate pressure-sensitive adhesive;

[0052] The acrylate pressure-sensitive adhesive includes at least one of DURO-TAK 87-235A acrylate pressure-sensitive adhesive, DURO-TAK 387-2054 acrylate pressure-sensitive adhesive, DURO-TAK 387-4098 acrylate pressure-sensitive adhesive, DURO-TAK 387-2510 acrylate pressure-sensitive adhesive, DURO-TAK 387-2287 acrylate pressure-sensitive adhesive, DURO-TAK 87-6908 acrylate pressure-sensitive adhesive, DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, DURO-TAK 87-2074 acrylate pressure-sensitive adhesive, and DURO-TAK 87-2677 acrylate pressure-sensitive adhesive.

[0053] Specifically, the DURO-TAK series acrylate pressure-sensitive adhesives in the above embodiments are all DURO-TAK series acrylate pressure-sensitive adhesives of Henkel Germany.

[0054] In some embodiments, the ketorolac patch composition includes the following components in mass fractions: 55-85% of the solvent-based matrix material, 5-20% of the active ingredient, 5-10% of the transdermal enhancer, and 5-15% of the crystallization inhibitor.

[0055] Based on the same inventive concept, the present invention provides a preparation method of the above-mentioned ketorolac patch composition, including the following steps:

[0056] Add the active ingredient to the solvent and stir, then add the transdermal enhancer, crystallization inhibitor, and solvent-based matrix material, continue to stir, and dry to remove the solvent to obtain the ketorolac patch composition;

[0057] The solvent includes at least one of methanol, ethanol, and ethyl acetate.

[0058] Based on the same inventive concept, the present invention further provides a ketorolac patch, including:

[0059] A release film, on which the above-mentioned ketorolac patch composition is coated;

[0060] A backing layer, which is adhered to the ketorolac patch composition.

[0061] Based on the same inventive concept, the present invention further provides a preparation method of the above-mentioned ketorolac patch, including the following steps:

[0062] The active ingredient is added to the solvent and stirred, and then a transdermal penetration enhancer, a crystallization inhibitor, and a solvent-based matrix material are added, and stirring is continued to obtain a drug solution;

[0063] The drug solution is coated on a release film and dried to remove the solvent and form a ketorolac patch composition;

[0064] A backing layer is laminated on the ketorolac patch composition.

[0065] In some embodiments, the active ingredient is added to the solvent and stirred, and then a transdermal penetration enhancer, a crystallization inhibitor, and a solvent-based matrix material are added, and stirring is continued to obtain a drug solution; the drug solution is in a transparent colloidal state, coated on a suitable release film, and dried at 60-70 °C for 15-25 min to completely volatilize the solvent (such as methanol, ethanol, ethyl acetate, etc.) to form a ketorolac patch composition.

[0066] In some embodiments, the release film includes a PET release film, etc., and the backing layer includes a PET polyester cloth.

[0067] Based on the same inventive concept, the present invention also provides an application of the above-mentioned ketorolac patch composition or the above-mentioned ketorolac patch in the preparation of a drug for treating or alleviating moderate to severe pain, and the pain includes pain caused by cancer, postoperative pain, and other chronic pain.

[0068] The following further illustrates the ketorolac patch composition, the ketorolac patch and its preparation method of the present invention with specific examples. This part further illustrates the content of the present invention in combination with specific examples, but should not be construed as a limitation to the present invention. Unless otherwise specified, the technical means adopted in the examples are conventional means well known to those skilled in the art. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0069] In the following examples, polyglyceryl oleate is specifically polyglyceryl fatty acid ester, model PLUROL OLEIQUE, produced by Gattefosse, France.

[0070] Example 1

[0071] This example provides a ketorolac patch composition, including the following components in mass fraction: 85% of a solvent-based matrix material, 5% of an active ingredient, 5% of a transdermal penetration enhancer, and 5% of a crystallization inhibitor;

[0072] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0073] The active ingredient is ketorolac tromethamine;

[0074] The transdermal penetration enhancer is isopropyl myristate;

[0075] The crystallization inhibitor is levulinic acid;

[0076] The preparation method of the above-mentioned ketorolac patch composition comprises the following steps:

[0077] Dissolve ketorolac tromethamine in methanol, and then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol, thereby forming the ketorolac patch composition.

[0078] This example also provides a preparation method of a ketorolac patch, comprising the following steps:

[0079] Dissolve ketorolac tromethamine in methanol, and then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0080] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a ketorolac patch composition;

[0081] Attach a backing layer (specifically, a PET polyester cloth) to the ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), and the drug content (ketorolac tromethamine) is 30 mg / patch, thereby obtaining the patch.

[0082] The mass fractions of the raw materials in the specific Example 1 are shown in Table 1.

[0083] Table 1 - Mass fractions of the raw materials in Example 1

[0084] Raw materials in Example 1 Mass fraction DURO-TAK87-2852 acrylate pressure-sensitive adhesive 85％ Isopropyl myristate 5％ Ketorolac tromethamine 5％ Levulinic acid 5％ Methanol (solvent) 0 (removed after drying)

[0085] Example 2

[0086] This example provides a ketorolac patch composition, comprising the following components in mass fractions: 85% of a solvent-based matrix material, 5% of an active ingredient, 5% of a transdermal penetration enhancer, and 5% of a crystallization inhibitor;

[0087] The solvent-based matrix material is DURO-TAK 87-235A acrylate pressure-sensitive adhesive;

[0088] The active ingredient is ketorolac tromethamine;

[0089] The transdermal penetration enhancer is isopropyl myristate;

[0090] The crystallization inhibitor is levulinic acid;

[0091] The preparation method of the above-mentioned ketorolac patch composition comprises the following steps:

[0092] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-235A acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol, thereby forming the ketorolac patch composition.

[0093] This example also provides a preparation method of a ketorolac patch, comprising the following steps:

[0094] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-235A acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0095] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form the ketorolac patch composition;

[0096] Bond a backing layer (specifically a PET polyester cloth) onto the ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), with a drug content (tromethamine ketorolac) of 30 mg / patch, thereby obtaining the patch.

[0097] The mass fractions of the raw materials in specific Example 2 are shown in Table 2.

[0098] Table 2 - Mass fractions of the raw materials in Example 2

[0099]

[0100]

[0101] Example 3

[0102] This example provides a ketorolac patch composition, comprising the following components by mass fraction: 85% of a solvent-based matrix material, 5% of an active ingredient, 5% of a transdermal penetration enhancer, and 5% of a crystallization inhibitor;

[0103] The solvent-based matrix material is DURO-TAK 387-2054 acrylate pressure-sensitive adhesive;

[0104] The active ingredient is tromethamine ketorolac;

[0105] The transdermal penetration enhancer is isopropyl myristate;

[0106] The crystallization inhibitor is levulinic acid;

[0107] The preparation method of the above-mentioned ketorolac patch composition comprises the following steps:

[0108] Dissolve tromethamine ketorolac in methanol, and then successively add levulinic acid, isopropyl myristate, and DURO-TAK 387-2054 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a tromethamine ketorolac patch composition.

[0109] This example also provides a method for preparing a tromethamine ketorolac patch, which includes the following steps:

[0110] Dissolve tromethamine ketorolac in methanol, and then successively add levulinic acid, isopropyl myristate, and DURO-TAK 387-2054 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0111] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0112] Bond a backing layer (specifically, a PET polyester cloth) to the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length is 10 cm, width is 10 cm), and the drug content (tromethamine ketorolac) is 30 mg / patch, thereby obtaining the patch.

[0113] The mass fractions of the raw materials in specific Example 3 are shown in Table 3.

[0114] Table 3 - Mass fractions of the raw materials in Example 3

[0115] Raw materials in Example 3 Mass fraction DURO-TAK387-2054 acrylate pressure-sensitive adhesive 85％ Isopropyl myristate 5％ Ketorolac tromethamine 5％ Levulinic acid 5％ Methanol (solvent) 0 (removed after drying)

[0116] Example 4

[0117] This example provides a tromethamine ketorolac patch composition, which includes the following components by mass fraction: 85% of a solvent-based matrix material, 5% of an active ingredient, 5% of a transdermal penetration enhancer, and 5% of a crystallization inhibitor;

[0118] The solvent-based matrix material is DURO-TAK 87-2074 acrylate pressure-sensitive adhesive;

[0119] The active ingredient is tromethamine ketorolac;

[0120] The transdermal penetration enhancer is isopropyl myristate;

[0121] The crystallization inhibitor is levulinic acid;

[0122] The method for preparing the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0123] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-2074 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a tromethamine ketorolac patch composition.

[0124] This example also provides a preparation method of a tromethamine ketorolac patch, including the following steps:

[0125] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-2074 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0126] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0127] Bond a backing layer (specifically PET polyester cloth) on the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length is 10 cm, width is 10 cm), and the drug content (tromethamine ketorolac) is 30 mg / patch to obtain the patch.

[0128] The mass fractions of the raw materials in specific Example 4 are shown in Table 4.

[0129] Table 4 - Mass fractions of the raw materials in Example 4

[0130] Raw materials in Example 4 Mass fraction DURO-TAK87-2074 acrylate pressure-sensitive adhesive 85％ Isopropyl myristate 5％ Ketorolac tromethamine 5％ Levulinic acid 5％ Methanol (solvent) 0 (removed after drying)

[0131] Example 5

[0132] This example provides a tromethamine ketorolac patch composition, including the following components in mass fractions: 75% of a solvent-based matrix material, 10% of an active ingredient, 5% of a transdermal enhancer, and 10% of a crystallization inhibitor;

[0133] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0134] The active ingredient is tromethamine ketorolac;

[0135] The transdermal enhancer is isopropyl myristate;

[0136] The crystallization inhibitor is levulinic acid;

[0137] The preparation method of the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0138] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a tromethamine ketorolac patch composition.

[0139] This example also provides a preparation method of a tromethamine ketorolac patch, including the following steps:

[0140] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0141] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0142] Bond a backing layer (specifically PET polyester cloth) on the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length is 10 cm, width is 10 cm), and the drug content (tromethamine ketorolac) is 60 mg / patch, thus obtaining the patch.

[0143] The mass fractions of each raw material in specific Example 5 are shown in Table 5.

[0144] Table 5 - Mass fractions of each raw material in Example 5

[0145] Raw materials in Example 5 Mass fraction DURO-TAK87-2852 acrylate pressure-sensitive adhesive 75％ Isopropyl myristate 5％ Ketorolac tromethamine 10％ Levulinic acid 10％ Methanol (solvent) 0 (removed after drying)

[0146] Example 6

[0147] This example provides a tromethamine ketorolac patch composition, including the following components by mass fraction: 75% of a solvent-based matrix material, 10% of an active ingredient, 5% of a transdermal penetration enhancer, and 10% of a crystallization inhibitor;

[0148] The solvent-based matrix material is DURO-TAK 87-235A acrylate pressure-sensitive adhesive;

[0149] The active ingredient is tromethamine ketorolac;

[0150] The transdermal penetration enhancer is isopropyl myristate;

[0151] The crystallization inhibitor is levulinic acid;

[0152] The preparation method of the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0153] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-235A acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol, thereby forming a tromethamine ketorolac patch composition.

[0154] This example also provides a preparation method of a tromethamine ketorolac patch, including the following steps:

[0155] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-235A acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0156] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0157] Bond a backing layer (specifically PET polyester cloth) on the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length is 10 cm, width is 10 cm), and the drug content (tromethamine ketorolac) is 60 mg / patch, thereby obtaining the patch.

[0158] The mass fractions of the raw materials in the specific Example 6 are shown in Table 6.

[0159] Table 6 - Mass fractions of the raw materials in Example 6

[0160]

[0161]

[0162] Example 7

[0163] This example provides a tromethamine ketorolac patch composition, including the following components in mass fractions: 75% of a solvent-based matrix material, 10% of an active ingredient, 5% of a transdermal penetration enhancer, and 10% of a crystallization inhibitor;

[0164] The solvent-based matrix material is DURO-TAK 387-2054 acrylate pressure-sensitive adhesive;

[0165] The active ingredient is tromethamine ketorolac;

[0166] The transdermal penetration enhancer is isopropyl myristate;

[0167] The crystallization inhibitor is levulinic acid;

[0168] The preparation method of the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0169] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 387-2054 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a tromethamine ketorolac patch composition.

[0170] This example also provides a method for preparing a tromethamine ketorolac patch, including the following steps:

[0171] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 387-2054 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0172] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0173] Bond a backing layer (specifically, a PET polyester cloth) on the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length is 10 cm, width is 10 cm), and the drug content (tromethamine ketorolac) is 60 mg / patch, thereby obtaining the patch.

[0174] Specifically, the mass fractions of the raw materials in Example 7 are shown in Table 7.

[0175] Table 7 - Mass fractions of the raw materials in Example 7

[0176] Raw materials in Example 7 Mass fraction DURO-TAK387-2054 acrylate pressure-sensitive adhesive 75％ Isopropyl myristate 5％ Ketorolac tromethamine 10％ Levulinic acid 10％ Methanol (solvent) 0 (removed after drying)

[0177] Example 8

[0178] This example provides a tromethamine ketorolac patch composition, including the following components in mass fractions: 75% of a solvent-based matrix material, 10% of an active ingredient, 5% of a transdermal penetration enhancer, and 10% of a crystallization inhibitor;

[0179] The solvent-based matrix material is DURO-TAK 87-2074 acrylate pressure-sensitive adhesive;

[0180] The active ingredient is tromethamine ketorolac;

[0181] The transdermal penetration enhancer is isopropyl myristate;

[0182] The crystallization inhibitor is levulinic acid;

[0183] The preparation method of the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0184] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-2074 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol, forming a tromethamine ketorolac patch composition.

[0185] This example also provides a preparation method of a tromethamine ketorolac patch, including the following steps:

[0186] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-2074 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0187] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0188] Bond a backing layer (specifically PET polyester cloth) on the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length is 10 cm, width is 10 cm), and the drug content (tromethamine ketorolac) is 60 mg / patch, thereby obtaining the patch.

[0189] The mass fractions of each raw material in specific Example 8 are shown in Table 8.

[0190] Table 8 - Mass fractions of each raw material in Example 8

[0191] Raw materials in Example 8 Mass fraction DURO-TAK87-2074 acrylate pressure-sensitive adhesive 75％ Isopropyl myristate 5％ Ketorolac tromethamine 10％ Levulinic acid 10％ Methanol (solvent) 0 (removed after drying)

[0192] Example 9

[0193] This example provides a tromethamine ketorolac patch composition, including the following components by mass fraction: 73% of a solvent-based matrix material, 7% of an active ingredient, 5% of a transdermal enhancer, and 15% of a crystallization inhibitor;

[0194] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0195] The active ingredient is ketorolac;

[0196] The transdermal enhancer is isopropyl myristate;

[0197] The crystallization inhibitor is levulinic acid;

[0198] The preparation method of the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0199] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a tromethamine ketorolac patch composition.

[0200] This example also provides a preparation method for a tromethamine ketorolac patch, which includes the following steps:

[0201] Dissolve ketorolac in methanol, then successively add levulinic acid, isopropyl myristate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0202] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0203] Bond a backing layer (specifically, a PET polyester cloth) to the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), with a drug content (tromethamine ketorolac) of 42 mg / patch, thereby obtaining the patch.

[0204] The mass fractions of the raw materials in specific Example 9 are shown in Table 9.

[0205] Table 9 - Mass fractions of the raw materials in Example 9

[0206] Raw materials in Example 9 Mass fraction DURO-TAK87-2852 acrylate pressure-sensitive adhesive 73％ Isopropyl myristate 5％ Ketorolac 7％ Levulinic acid 15％ Methanol (solvent) 0 (removed after drying)

[0207] Example 10

[0208] This example provides a tromethamine ketorolac patch composition, which includes the following components by mass fraction: 70% of a solvent-based matrix material, 10% of an active ingredient, 10% of a transdermal enhancer, and 10% of a crystallization inhibitor;

[0209] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0210] The active ingredient is tromethamine ketorolac;

[0211] The transdermal enhancer is isopropyl myristate;

[0212] The crystallization inhibitor is levulinic acid;

[0213] The preparation method for the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0214] Dissolve tromethamine ketorolac in methanol, and then sequentially add levulinic acid, isopropyl myristate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a tromethamine ketorolac patch composition.

[0215] This example also provides a method for preparing a tromethamine ketorolac patch, which includes the following steps:

[0216] Dissolve tromethamine ketorolac in methanol, and then sequentially add levulinic acid, isopropyl myristate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0217] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0218] Bond a backing layer (specifically, a PET polyester cloth) to the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), and the drug content (tromethamine ketorolac) is 60 mg / patch, thereby obtaining the patch.

[0219] The mass fractions of the raw materials in specific Example 10 are shown in Table 10.

[0220] Table 10 - Mass fractions of the raw materials in Example 10

[0221] Raw materials in Example 10 Mass fraction DURO-TAK87-2852 acrylate pressure-sensitive adhesive 70％ Isopropyl myristate 10％ Ketorolac tromethamine 10％ Levulinic acid 10％ Methanol (solvent) 0 (removed after drying)

[0222] Example 11

[0223] This example provides a tromethamine ketorolac patch composition, which includes the following components in mass fractions: 70% of a solvent-based matrix material, 10% of an active ingredient, 10% of a transdermal penetration enhancer, and 10% of a crystallization inhibitor;

[0224] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0225] The active ingredient is tromethamine ketorolac;

[0226] The transdermal penetration enhancer is polyglyceryl oleate;

[0227] The crystallization inhibitor is levulinic acid;

[0228] The method for preparing the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0229] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, polyglyceryl oleate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a tromethamine ketorolac patch composition.

[0230] This example also provides a preparation method of a tromethamine ketorolac patch, including the following steps:

[0231] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, polyglyceryl oleate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0232] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0233] Bond a backing layer (specifically a PET polyester cloth) to the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), and the drug content (tromethamine ketorolac) is 60 mg / patch to obtain the patch.

[0234] The mass fractions of the raw materials in specific Example 11 are shown in Table 11.

[0235] Table 11 - Mass fractions of raw materials in Example 11

[0236] Raw materials in Example 11 Mass fraction DURO-TAK87-2852 acrylate pressure-sensitive adhesive 70％ Polyglycerol oleate 10％ Ketorolac tromethamine 10％ Levulinic acid 10％ Methanol (solvent) 0 (removed after drying)

[0237] Example 12

[0238] This example provides a tromethamine ketorolac patch composition, including the following components by mass fraction: 70% of a solvent-based matrix material, 10% of an active ingredient, 10% of a transdermal penetration enhancer, and 10% of a crystallization inhibitor;

[0239] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0240] The active ingredient is tromethamine ketorolac;

[0241] The transdermal penetration enhancer is oleic acid;

[0242] The crystallization inhibitor is levulinic acid;

[0243] The preparation method of the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0244] Dissolve tromethamine ketorolac in methanol, then sequentially add levulinic acid, oleic acid, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol, forming a tromethamine ketorolac patch composition.

[0245] This example also provides a method for preparing a tromethamine ketorolac patch, including the following steps:

[0246] Dissolve tromethamine ketorolac in methanol, then sequentially add levulinic acid, oleic acid, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0247] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0248] Bond a backing layer (specifically PET polyester cloth) on the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), with a drug content (tromethamine ketorolac) of 60 mg / patch, thereby obtaining the patch.

[0249] The mass fractions of the raw materials in specific Example 12 are shown in Table 12.

[0250] Table 12 - Mass fractions of the raw materials in Example 12

[0251] Raw materials in Example 12 Mass fraction DURO-TAK87-2852 acrylate pressure-sensitive adhesive 70％ Oleic acid 10％ Ketorolac tromethamine 10％ Levulinic acid 10％ Methanol (solvent) 0 (removed after drying)

[0252] Example 13

[0253] This example provides a tromethamine ketorolac patch composition, including the following components by mass fraction: 70% of a solvent-based matrix material, 10% of an active ingredient, 10% of a transdermal penetration enhancer, and 10% of a crystallization inhibitor;

[0254] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0255] The active ingredient is tromethamine ketorolac;

[0256] The transdermal penetration enhancer is sorbitan oleate (Span 80);

[0257] The crystallization inhibitor is levulinic acid;

[0258] The preparation method of the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0259] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, sorbitan oleate (Span 80), and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol, forming a tromethamine ketorolac patch composition.

[0260] This example also provides a preparation method of a tromethamine ketorolac patch, including the following steps:

[0261] Dissolve tromethamine ketorolac in methanol, then successively add levulinic acid, sorbitan oleate (Span 80), and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0262] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0263] Bond a backing layer (specifically a PET polyester cloth) on the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), and the drug content (tromethamine ketorolac) is 60 mg / patch, thus obtaining the patch.

[0264] The mass fractions of the raw materials in specific Example 13 are shown in Table 13.

[0265] Table 13 - Mass fractions of the raw materials in Example 13

[0266] Raw materials in Example 13 Mass fraction DURO-TAK87-2852 acrylate pressure-sensitive adhesive 70％ Sorbitan oleate (Span 80) 10％ Ketorolac tromethamine 10％ Levulinic acid 10％ Methanol (solvent) 0 (removed after drying)

[0267] Example 14

[0268] This example provides a tromethamine ketorolac patch composition, including the following components by mass fraction: 70% of a solvent-based matrix material, 10% of an active ingredient, 10% of a transdermal penetration enhancer, and 10% of a crystallization inhibitor;

[0269] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0270] The active ingredient is tromethamine ketorolac;

[0271] The transdermal penetration enhancer is triethyl citrate;

[0272] The crystallization inhibitor is levulinic acid;

[0273] The preparation method of the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0274] Dissolve tromethamine ketorolac in methanol, and then successively add levulinic acid, triethyl citrate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a tromethamine ketorolac patch composition.

[0275] This example also provides a preparation method of a tromethamine ketorolac patch, including the following steps:

[0276] Dissolve tromethamine ketorolac in methanol, and then successively add levulinic acid, triethyl citrate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0277] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0278] Bond a backing layer (specifically a PET polyester cloth) on the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), and the drug content (tromethamine ketorolac) is 60 mg / patch to obtain the patch.

[0279] The mass fractions of the raw materials in specific Example 14 are shown in Table 14.

[0280] Table 14 - Mass fractions of the raw materials in Example 14

[0281] Raw materials in Example 14 Mass fraction DURO-TAK87-2852 acrylate pressure-sensitive adhesive 70％ Triethyl citrate 10％ Ketorolac tromethamine 10％ Levulinic acid 10％ Methanol (solvent) 0 (removed after drying)

[0282] Example 15

[0283] This example provides a tromethamine ketorolac patch composition, including the following components in mass fractions: 70% of a solvent-based matrix material, 10% of an active ingredient, 10% of a transdermal penetration enhancer, and 10% of a crystallization inhibitor;

[0284] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0285] The active ingredient is tromethamine ketorolac;

[0286] The transdermal penetration enhancer is glyceryl triacetate;

[0287] The crystallization inhibitor is levulinic acid;

[0288] The preparation method of the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0289] Dissolve tromethamine ketorolac in methanol, then sequentially add levulinic acid, glyceryl triacetate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a tromethamine ketorolac patch composition.

[0290] This example also provides a method for preparing a tromethamine ketorolac patch, including the following steps:

[0291] Dissolve tromethamine ketorolac in methanol, then sequentially add levulinic acid, glyceryl triacetate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0292] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0293] Bond a backing layer (specifically, a PET polyester cloth) on the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (10 cm in length and 10 cm in width), with a drug content (tromethamine ketorolac) of 60 mg / patch, thereby obtaining the patch.

[0294] The mass fractions of the raw materials in specific Example 15 are shown in Table 15.

[0295] Table 15 - Mass fractions of the raw materials in Example 15

[0296]

[0297]

[0298] Example 16

[0299] This example provides a tromethamine ketorolac patch composition, including the following components in mass fractions: 70% of a solvent-based matrix material, 10% of an active ingredient, 10% of a transdermal penetration enhancer, and 10% of a crystallization inhibitor;

[0300] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0301] The active ingredient is tromethamine ketorolac;

[0302] The transdermal penetration enhancer is diethylene glycol monoethyl ether;

[0303] The crystallization inhibitor is levulinic acid;

[0304] The method for preparing the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0305] Dissolve tromethamine ketorolac in methanol, and then successively add levulinic acid, diethylene glycol monoethyl ether, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a tromethamine ketorolac patch composition.

[0306] This example also provides a preparation method of a tromethamine ketorolac patch, including the following steps:

[0307] Dissolve tromethamine ketorolac in methanol, and then successively add levulinic acid, diethylene glycol monoethyl ether and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0308] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0309] Bond a backing layer (specifically PET polyester cloth) on the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length is 10 cm, width is 10 cm), and the drug content (tromethamine ketorolac) is 60 mg / patch, thus obtaining the patch.

[0310] The mass fractions of the raw materials in specific Example 16 are shown in Table 16.

[0311] Table 16 - Mass fractions of the raw materials in Example 16

[0312] Raw materials in Example 16 Mass fraction DURO-TAK87-2852 acrylate pressure-sensitive adhesive 70％ Diethylene glycol monoethyl ether 10％ Ketorolac tromethamine 10％ Levulinic acid 10％ Methanol (solvent) 0 (removed after drying)

[0313] Example 17

[0314] This example provides a tromethamine ketorolac patch composition, including the following components in mass fractions: 70% of a solvent-based matrix material, 10% of an active ingredient, 10% of a transdermal enhancer, and 10% of a crystallization inhibitor;

[0315] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0316] The active ingredient is tromethamine ketorolac;

[0317] The transdermal enhancer includes isopropyl myristate and glyceryl triacetate; the mass ratio of isopropyl myristate to glyceryl triacetate is 1:1, that is, the mass fraction of isopropyl myristate in the tromethamine ketorolac patch composition is 5%, and the mass fraction of glyceryl triacetate is 5%;

[0318] The crystallization inhibitor is levulinic acid;

[0319] The preparation method of the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0320] Dissolve tromethamine ketorolac in methanol, and then sequentially add levulinic acid, isopropyl myristate, glyceryl triacetate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a tromethamine ketorolac patch composition.

[0321] This example also provides a preparation method of a tromethamine ketorolac patch, which includes the following steps:

[0322] Dissolve tromethamine ketorolac in methanol, and then sequentially add levulinic acid, isopropyl myristate, glyceryl triacetate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0323] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0324] Bond a backing layer (specifically a PET polyester cloth) on the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), and the drug content (tromethamine ketorolac) is 60 mg / patch to obtain the patch.

[0325] The mass fractions of the raw materials in the specific Example 17 are shown in Table 17.

[0326] Table 17 - Mass fractions of raw materials in Example 17

[0327] Raw materials in Example 17 Mass fraction DURO-TAK87-2852 acrylate pressure-sensitive adhesive 70％ Isopropyl myristate 5％ Glycerol triacetate 5％ Ketorolac tromethamine 10％ Levulinic acid 10％ Methanol (solvent) 0 (removed after drying)

[0328] Example 18

[0329] This example provides a tromethamine ketorolac patch composition, which includes the following components in mass fractions: 70% of a solvent-based matrix material, 10% of an active ingredient, 10% of a transdermal penetration enhancer, and 10% of a crystallization inhibitor;

[0330] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0331] The active ingredient is tromethamine ketorolac;

[0332] The transdermal penetration enhancer includes polyglyceryl oleate and glyceryl triacetate; the mass ratio of polyglyceryl oleate to glyceryl triacetate is 1:1, that is, the mass fraction of polyglyceryl oleate in the tromethamine ketorolac patch composition is 5%, and the mass fraction of glyceryl triacetate is 5%;

[0333] The crystallization inhibitor is levulinic acid;

[0334] The preparation method of the above-mentioned tromethamine ketorolac patch composition includes the following steps:

[0335] Dissolve tromethamine ketorolac in methanol, and then successively add levulinic acid, polyglyceryl oleate, glyceryl triacetate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a tromethamine ketorolac patch composition.

[0336] This example also provides a method for preparing a tromethamine ketorolac patch, which includes the following steps:

[0337] Dissolve tromethamine ketorolac in methanol, and then successively add levulinic acid, polyglyceryl oleate, glyceryl triacetate, and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0338] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a tromethamine ketorolac patch composition;

[0339] Bond a backing layer (specifically a PET polyester cloth) to the tromethamine ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), and the drug content (tromethamine ketorolac) is 60 mg / patch, thereby obtaining the patch.

[0340] The mass fractions of the raw materials in specific Example 18 are shown in Table 18.

[0341] Table 18 - Mass fractions of the raw materials in Example 18

[0342] Raw materials in Example 18 Mass fraction DURO-TAK87-2852 acrylate pressure-sensitive adhesive 70％ Polyglycerol oleate 5％ Glycerol triacetate 5％ Ketorolac tromethamine 10％ Levulinic acid 10％ Methanol (solvent) 0 (removed after drying)

[0343] Example 19

[0344] This example provides a tromethamine ketorolac patch composition, which includes the following components in mass fractions: 70% of a solvent-based matrix material, 10% of an active ingredient, 10% of a transdermal penetration enhancer, and 10% of a crystallization inhibitor;

[0345] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0346] The active ingredient is tromethamine ketorolac;

[0347] The transdermal penetration enhancer includes isopropyl myristate and polyglyceryl oleate, and the mass ratio of isopropyl myristate to polyglyceryl oleate is 1:1, that is, the mass fraction of isopropyl myristate in the tromethamine ketorolac patch composition is 5%, and the mass fraction of polyglyceryl oleate is 5%;

[0348] The crystallization inhibitor is levulinic acid;

[0349] The preparation method of the above-mentioned ketorolac patch composition comprises the following steps:

[0350] Dissolve tromethamine ketorolac in methanol, and then successively add levulinic acid, isopropyl myristate, polyglyceryl oleate and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol, thereby forming the ketorolac patch composition.

[0351] This example also provides a preparation method of a ketorolac patch, which comprises the following steps:

[0352] Dissolve tromethamine ketorolac in methanol, and then successively add levulinic acid, isopropyl myristate, polyglyceryl oleate and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0353] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form the ketorolac patch composition;

[0354] Bond a backing layer (specifically PET polyester cloth) on the ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), and the drug content (tromethamine ketorolac) is 120 mg / patch, thereby obtaining the patch.

[0355] The mass fractions of the raw materials in the specific Example 19 are shown in Table 19.

[0356] Table 19 - Mass fractions of the raw materials in Example 19

[0357] Raw materials in Example 19 Mass fraction DURO-TAK 87-2852 Acrylate Pressure Sensitive Adhesive 70％ Isopropyl Myristate 5％ Polyglycerol Oleate 5％ Ketorolac Tromethamine 10％ Levulinic Acid 10％ Methanol (solvent) 0 (removed after drying)

[0358] Example 20

[0359] This example provides a ketorolac patch composition, which comprises the following components in mass fractions: 60% of a solvent-based matrix material, 15% of an active ingredient, 10% of a transdermal penetration enhancer, and 15% of a crystallization inhibitor;

[0360] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0361] The active ingredient is tromethamine ketorolac;

[0362] The transdermal penetration enhancer includes isopropyl myristate and glyceryl triacetate, and the mass ratio of isopropyl myristate to glyceryl triacetate is 1:1, that is, the mass fraction of isopropyl myristate in the ketorolac patch composition is 5%

[0363] and the mass fraction of glyceryl triacetate is 5%;

[0364] The crystallization inhibitor is levulinic acid;

[0365] The preparation method of the above-mentioned ketorolac patch composition comprises the following steps:

[0366] Dissolve ketorolac tromethamine in methanol, and then successively add levulinic acid, isopropyl myristate, triacetin and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a ketorolac patch composition.

[0367] This example also provides a preparation method of a ketorolac patch, comprising the following steps:

[0368] Dissolve ketorolac tromethamine in methanol, and then successively add levulinic acid, isopropyl myristate, triacetin and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0369] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a ketorolac patch composition;

[0370] Attach a backing layer (specifically a PET polyester cloth) to the ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), and the drug content (ketorolac tromethamine) is 90 mg / patch, thus obtaining the patch.

[0371] The mass fractions of the raw materials in the specific Example 20 are shown in Table 20.

[0372] Table 20 - Mass fractions of the raw materials in Example 20

[0373]

[0374]

[0375] Example 21

[0376] This example provides a ketorolac patch composition, comprising the following components in mass fractions: 60% of a solvent-based matrix material, 15% of an active ingredient, 10% of a transdermal penetration enhancer, and 15% of a crystallization inhibitor;

[0377] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0378] The active ingredient is ketorolac tromethamine;

[0379] The transdermal penetration enhancer includes polyglyceryl oleate and glyceryl triacetate, and the mass ratio of polyglyceryl oleate to glyceryl triacetate is 1:1, that is, the mass fraction of polyglyceryl oleate in the ketorolac patch composition is 5%, and the mass fraction of glyceryl triacetate is 5%;

[0380] The crystallization inhibitor is levulinic acid;

[0381] The preparation method of the above-mentioned ketorolac patch composition includes the following steps:

[0382] Dissolve ketorolac tromethamine in methanol, and then successively add levulinic acid, polyglyceryl oleic acid, glyceryl triacetate and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form a ketorolac patch composition.

[0383] This example also provides a preparation method of a ketorolac patch, including the following steps:

[0384] Dissolve ketorolac tromethamine in methanol, and then successively add levulinic acid, polyglyceryl oleic acid, glyceryl triacetate and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0385] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a ketorolac patch composition;

[0386] Bond a backing layer (specifically, PET polyester cloth) to the ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), and the drug content (ketorolac tromethamine) is 90 mg / patch, thus obtaining the patch.

[0387] The mass fractions of the raw materials in the specific Example 21 are shown in Table 21.

[0388] Table 21 - Mass fractions of the raw materials in Example 21

[0389] Raw materials in Example 21 Mass fraction DURO-TAK 87-2852 Acrylate Pressure Sensitive Adhesive 60％ Polyglycerol Oleate 5％ Glycerol Triacetate 5％ Ketorolac Tromethamine 15％ Levulinic Acid 15％ Methanol (solvent) 0 (removed after drying)

[0390] Example 22

[0391] This example provides a ketorolac patch composition, including the following components in mass fractions: 60% of a solvent-based matrix material, 15% of an active ingredient, 10% of a transdermal penetration enhancer, and 15% of a crystallization inhibitor;

[0392] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0393] The active ingredient is ketorolac tromethamine;

[0394] The transdermal enhancer includes polyglyceryl oleate and isopropyl myristate, and the mass ratio of polyglyceryl oleate to isopropyl myristate is 1:1, that is, the mass fraction of polyglyceryl oleate in the ketorolac patch composition is 5%, and the mass fraction of isopropyl myristate is 5%;

[0395] The crystallization inhibitor is levulinic acid;

[0396] The preparation method of the above-mentioned ketorolac patch composition includes the following steps:

[0397] Dissolve ketorolac tromethamine in methanol, and then sequentially add levulinic acid, polyglyceryl oleate, isopropyl myristate and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form the ketorolac patch composition.

[0398] This example also provides a preparation method of a ketorolac patch, including the following steps:

[0399] Dissolve ketorolac tromethamine in methanol, and then sequentially add levulinic acid, polyglyceryl oleate, isopropyl myristate and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0400] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a ketorolac patch composition;

[0401] Attach a backing layer (specifically PET polyester cloth) to the ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), and the drug content (ketorolac tromethamine) is 90 mg / patch, thus obtaining the patch.

[0402] The mass fractions of the raw materials in the specific Example 22 are shown in Table 22.

[0403] Table 22 - Mass fractions of the raw materials in Example 22

[0404] Raw materials in Example 22 Mass fraction DURO-TAK 87-2852 Acrylate Pressure Sensitive Adhesive 60％ Polyglycerol Oleate 5％ Isopropyl Myristate 5％ Ketorolac Tromethamine 15％ Levulinic Acid 15％ Methanol (solvent) 0 (removed after drying)

[0405] Example 23

[0406] This example provides a ketorolac patch composition, including the following components in mass fractions: 55% of a solvent-based matrix material, 20% of an active ingredient, 10% of a transdermal enhancer, and 15% of a crystallization inhibitor;

[0407] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0408] The active ingredient is ketorolac tromethamine;

[0409] The transdermal enhancer includes isopropyl myristate and glyceryl triacetate, and the mass ratio of isopropyl myristate to glyceryl triacetate is 1:1, that is, the mass fraction of isopropyl myristate in the ketorolac patch composition is 5%, and the mass fraction of glyceryl triacetate is 5%;

[0410] The crystallization inhibitor is levulinic acid;

[0411] The preparation method of the above-mentioned ketorolac patch composition includes the following steps:

[0412] Dissolve ketorolac tromethamine in methanol, and then sequentially add levulinic acid, isopropyl myristate, glyceryl triacetate and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form the ketorolac patch composition.

[0413] This example also provides a preparation method of a ketorolac patch, including the following steps:

[0414] Dissolve ketorolac tromethamine in methanol, and then sequentially add levulinic acid, isopropyl myristate, glyceryl triacetate and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0415] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a ketorolac patch composition;

[0416] Bond a backing layer (specifically PET polyester cloth) on the ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), and the drug content (ketorolac tromethamine) is 120 mg / patch, thereby obtaining the patch.

[0417] The mass fractions of the raw materials in the specific Example 23 are shown in Table 23.

[0418] Table 23 - Mass fractions of raw materials in Example 23

[0419] Raw materials in Example 23 Mass fraction DURO-TAK 87-2852 Acrylate Pressure Sensitive Adhesive 55％ Glycerol Triacetate 5％ Isopropyl Myristate 5％ Ketorolac Tromethamine 20％ Levulinic Acid 15％ Methanol (solvent) 0 (removed after drying)

[0420] Example 24

[0421] This example provides a ketorolac patch composition, including the following components in mass fractions: 55% of a solvent-based matrix material, 20% of an active ingredient, 10% of a transdermal enhancer, and 15% of a crystallization inhibitor;

[0422] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0423] The active ingredient is tromethamine ketorolac;

[0424] The transdermal penetration enhancer includes polyglyceryl oleate and glyceryl triacetate, and the mass ratio of polyglyceryl oleate to glyceryl triacetate is 1:1, that is, the mass fraction of polyglyceryl oleate in the ketorolac patch composition is 5%, and the mass fraction of glyceryl triacetate is 5%;

[0425] The crystal growth inhibitor is levulinic acid;

[0426] The preparation method of the above-mentioned ketorolac patch composition includes the following steps:

[0427] Dissolve tromethamine ketorolac in methanol, and then sequentially add levulinic acid, polyglyceryl oleate, glyceryl triacetate and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form the ketorolac patch composition.

[0428] This example also provides a preparation method of a ketorolac patch, including the following steps:

[0429] Dissolve tromethamine ketorolac in methanol, and then sequentially add levulinic acid, polyglyceryl oleate, glyceryl triacetate and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0430] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a ketorolac patch composition;

[0431] Bond a backing layer (specifically PET polyester cloth) on the ketorolac patch composition, cut it into 10 cm × 10 cm (length 10 cm, width 10 cm), and the drug content (tromethamine ketorolac) is 120 mg / patch, thus obtaining the patch.

[0432] The mass fractions of the raw materials in the specific Example 24 are shown in Table 24.

[0433] Table 24 - Mass fractions of raw materials in Example 24

[0434] Raw materials in Example 24 Mass fraction DURO-TAK 87-2852 Acrylate Pressure Sensitive Adhesive 55％ Glycerol Triacetate 5％ Polyglycerol Oleate 5％ Ketorolac Tromethamine 20％ Levulinic Acid 15％ Methanol (solvent) 0 (removed after drying)

[0435] Example 25

[0436] This example provides a ketorolac patch composition, including the following components in mass fractions: 55% of a solvent-based matrix material, 20% of an active ingredient, 10% of a transdermal penetration enhancer, and 15% of a crystal growth inhibitor;

[0437] The solvent-based matrix material is DURO-TAK 87-2852 acrylate pressure-sensitive adhesive;

[0438] The active ingredient is tromethamine ketorolac;

[0439] The transdermal penetration enhancer includes polyglyceryl oleate and isopropyl myristate, and the mass ratio of polyglyceryl oleate to isopropyl myristate is 1:1, that is, the mass fraction of polyglyceryl oleate in the ketorolac patch composition is 5% and the mass fraction of isopropyl myristate is 5%;

[0440] The crystallization inhibitor is levulinic acid;

[0441] The preparation method of the above-mentioned ketorolac patch composition includes the following steps:

[0442] Dissolve tromethamine ketorolac in methanol, and then sequentially add levulinic acid, polyglyceryl oleate, isopropyl myristate and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h, and dry at 70 °C for 25 min to completely volatilize the solvent methanol to form the ketorolac patch composition.

[0443] This embodiment also provides a preparation method of a ketorolac patch, including the following steps:

[0444] Dissolve tromethamine ketorolac in methanol, and then sequentially add levulinic acid, polyglyceryl oleate, isopropyl myristate and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, stir and mix for 4 h to obtain a drug solution;

[0445] Coat the drug solution on a PET release film, and dry at 70 °C for 25 min to remove the solvent methanol and form a ketorolac patch composition;

[0446] Bond a backing layer (specifically PET polyester cloth) on the ketorolac patch composition, cut it into 10 cm × 10 cm (length is 10 cm, width is 10 cm), and the drug content (tromethamine ketorolac) is 120 mg / patch, thereby obtaining the patch.

[0447] The mass fractions of the raw materials in the specific Example 24 are shown in Table 24.

[0448] Table 24 - Mass fractions of the raw materials in Example 24

[0449] Raw materials in Example 24 Mass fraction DURO-TAK 87-2852 Acrylate Pressure Sensitive Adhesive 55％ Isopropyl Myristate 5％ Polyglycerol Oleate 5％ Ketorolac Tromethamine 20％ Levulinic Acid 15％ Methanol (solvent) 0 (removed after drying)

[0450] Performance test

[0451] 1. Transdermal diffusion experiment:

[0452] Using the Franz diffusion cell method, with the ex vivo skin of Bama mini-pigs as the barrier, the ketorolac patches prepared in Examples 1, 5, 9 to 12, and 15 were punched into circular patches with a diameter of 14 mm and applied to the ex vivo skin of Bama mini-pigs. Using a phosphate buffer solution with pH 7.4 as the dissolution medium, and setting the sampling time points as: 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h, the transdermal diffusion data of the patches were collected. Table 25 below shows the in vitro transdermal test data at 72 h.

[0453] Table 25 - Transdermal Diffusion Data of Ketorolac Patches Prepared in Different Examples

[0454]

[0455] It can be seen from Table 25 that by analyzing the transdermal diffusion data of Example 1 and Example 5, it can be known that the patch permeation rate increases with the increase in the content of tromethamine ketorolac in the patch; by analyzing the transdermal diffusion data of Example 9 and Example 10, it can be known that for the patches prepared with ketorolac as the feedstock, compared with the patches prepared with tromethamine ketorolac as the feedstock at the same dose, the latter shows better transdermal diffusion performance in 3 days; by analyzing the transdermal diffusion data of Example 10, Example 11, Example 12, and Example 15, it can be known that in terms of penetration enhancers, isopropyl myristate, glyceryl triacetate, and polyglyceryl oleate have obvious penetration-enhancing effects on the ketorolac patch.

[0456] According to the same method above, the ketorolac patches prepared in Examples 10, 11, 15, 17 to 20, and 23 were punched into circular patches with a diameter of 14 mm and applied to the ex vivo skin of Bama mini-pigs. Using a phosphate buffer solution with pH 7.4 as the dissolution medium, and setting the sampling time points as: 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, the transdermal diffusion data of the patches were collected. Table 26 below shows the in vitro transdermal test data at 72 h and 168 h.

[0457] Table 26 - Transdermal Diffusion Data of Ketorolac Patches Prepared in Different Examples

[0458]

[0459]

[0460] As can be seen from Table 26, the transdermal diffusion data of Example 17, Example 20, and Example 23 further verified that the transdermal permeability of the patch increased with the increase in the content of tromethamine ketorolac in the patch; by analyzing Examples 10-11, 15, and Examples 17-19, it was found that the combination of penetration enhancers with different penetration enhancement mechanisms had a better penetration enhancement effect. Specifically, in Example 10, the penetration enhancer was isopropyl myristate with a mass fraction of 10%, and the corresponding patch had a permeability of 48.92% at 72 h; in Example 11, the penetration enhancer was polyglyceryl oleate with a mass fraction of 10%, and the corresponding patch had a permeability of 46.83% at 72 h; in Example 15, the penetration enhancer was glyceryl triacetate with a mass fraction of 10%, and the corresponding patch had a permeability of 47.13% at 72 h; in Example 17, the penetration enhancer included 5% isopropyl myristate and 5% glyceryl triacetate, and the corresponding patch had a permeability of 51.85% at 72 h; in Example 18, the penetration enhancer included 5% polyglyceryl oleate and 5% glyceryl triacetate, and the corresponding patch had a permeability of 51.29% at 72 h; in Example 19, the penetration enhancer included 5% isopropyl myristate and 5% polyglyceryl oleate, and the corresponding patch had a permeability of 50.74% at 72 h; by comparing Examples 10-11, 15 with Examples 17-19, it can be seen that the combination of any two of isopropyl myristate, glyceryl triacetate, and polyglyceryl oleate had a better penetration enhancement effect and better transdermal diffusion performance than a single penetration enhancer.

[0461] 2. Pharmacodynamic animal experiment:

[0462] Select healthy adult Sprague-Dawley rats, weighing 200-250 g, with an equal number of males and females. They were randomly divided into 4 groups (normal control group, model control group, positive control group, and patch administration group), with 10 rats in each group. Except for the normal control group, the other 3 groups of rats were anesthetized by intraperitoneal injection of sodium pentobarbital, and 10 μL of rat breast cancer Walker-256 cell suspension was slowly injected into the bone marrow cavity of the proximal right tibia for modeling. 7 days after cell inoculation, the patch administration group was given the ketorolac patch of Example 17, and the patch administration group 2 was given the ketorolac patch of Example 23, with 1 patch changed daily; the positive control group was intraperitoneally injected with morphine once a day, and the normal control group and the model control group were intraperitoneally injected with an equal amount of normal saline once a day. Continuous administration was carried out for 14 days. Thermal hyperalgesia tests were performed every day. Using a hot plate instrument, the temperature was set at 52 °C, the rats were placed on the hot plate, and the latency from placement to foot licking and foot lifting (thermal withdrawal latency, TWL) was recorded. The interval between each test was 10 minutes, and the average value was taken after repeating 3 times. The results are shown in Table 27 below.

[0463] Table 27 - Latency of foot licking and foot lifting in different groups

[0464] Group TWL (s) before modeling TWL (s) 7 days after modeling TWL (s) 14 days after drug administration Normal control group 12.5±1.5 12.3±1.4 12.6±1.3 Model control group 12.7±1.3 7.2±0.7 7.0±0.8 Positive control group 12.4±1.6 7.0±0.6 11.5±1.2 Patch drug administration group 1 12.5±1.5 7.1±0.5 9.9±1.3 Patch drug administration group 2 12.6±1.4 7.1±0.8 10.8±1.0

[0465] As can be seen from Table 27, there were no significant differences in the baseline TWL among the groups before modeling, indicating that the grouping was balanced. Seven days after modeling, the TWL of the model control group shortened, indicating that the bone cancer pain model successfully induced pain hypersensitivity. Fourteen days after drug administration, the TWL of the positive control group increased significantly, confirming the effectiveness of morphine; there was a certain improvement in the patch group, initially indicating that ketorolac patch has a certain therapeutic effect on cancer pain.

[0466] 3. Pharmacodynamic animal experiment:

[0467] Healthy adult Sprague-Dawley rats weighing 200 - 250 g, with an equal number of males and females, were randomly divided into 4 groups (normal control group, model control group, positive control group, and patch administration group), with 10 rats in each group. Except for the normal control group, the remaining 3 groups of rats were anesthetized by intraperitoneal injection of sodium pentobarbital, and 10 μL of rat breast cancer Walker-256 cell suspension was slowly injected into the bone marrow cavity of the proximal right tibia for modeling. Seven days after cell inoculation, the patch administration group 1 was given the ketorolac patch of Example 17, and the patch administration group 2 was given the ketorolac patch of Example 23, and 1 patch was changed every 7 days; the positive control group was intraperitoneally injected with morphine once a day, and the normal control group and the model control group were intraperitoneally injected with an equal amount of normal saline once a day. Drug administration continued for 14 days. Thermal hyperalgesia tests were performed every day. Using a hot plate instrument, the temperature was set at 52°C, the rats were placed on the hot plate, and the latency from placement to the appearance of foot licking and foot lifting (thermal withdrawal latency, TWL) was recorded. The interval between each test was 10 minutes, and the average value was taken after repeating 3 times. The results are shown in Table 28 below.

[0468] Table 28 - Latency of foot licking and foot lifting in different groups

[0469] Group TWL (s) before modeling TWL (s) 7 days after modeling TWL (s) 14 days after drug administration Normal control group 12.3±1.4 12.1±1.5 12.5±1.6 Model control group 12.4±1.3 7.1±0.8 7.0±0.8 Positive control group 12.4±1.4 7.1±0.6 11.3±1.3 Patch drug administration group 1 12.3±1.6 7.1±0.7 9.6±1.6 Patch drug administration group 2 12.4±1.6 7.0±0.8 10.1±1.2

[0470] As can be seen from Table 28, there were no significant differences in the baseline TWL among the groups before modeling, indicating that the grouping was balanced. Seven days after modeling, the TWL of the model control group shortened, indicating that the bone cancer pain model successfully induced pain hypersensitivity. Fourteen days after drug administration, the TWL of the positive control group increased significantly, confirming the effectiveness of morphine; there was a certain improvement in the patch group, initially indicating that ketorolac patch has a certain therapeutic effect on cancer pain.

[0471] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A ketorolac patch composition, characterized in that, It includes an active ingredient, a matrix material, and a transdermal enhancer; The active ingredient includes at least one of ketorolac, tromethamine ketorolac, other ketorolac salts, and ketorolac ester derivatives; The matrix material is a solvent-based matrix material; The solvent-based matrix material includes at least one of acrylic acid and its derivatives; The transdermal enhancer includes at least two of lactic acid, oleic acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, malic acid, isopropyl myristate, propylene glycol monolaurate, glyceryl monooleate, glyceryl triacetate, diisopropyl adipate, triethyl citrate, polyglyceryl oleate, and sorbitan oleate.

2. The ketorolac patch composition according to claim 1, wherein, The transdermal enhancer includes at least two of isopropyl myristate, glyceryl triacetate, and polyglyceryl oleate.

3. The ketorolac patch composition according to claim 1, wherein It also includes pharmaceutically acceptable excipients for topical preparations; The excipients include a crystallization inhibitor; The crystallization inhibitor includes at least one of butyl methacrylate-methyl methacrylate copolymer, levulinic acid, benzoic acid and its salts, and salicylic acid and its salts.

4. The ketorolac patch composition according to claim 3, characterized in that, It includes components with the following mass fractions: 30 - 85% of the solvent-based matrix material, 5 - 20% of the active ingredient, 1 - 15% of the transdermal enhancer, and 1 - 15% of the crystallization inhibitor.

5. The ketorolac patch composition according to claim 4, characterized in that, The transdermal enhancer includes a mixture of isopropyl myristate and glyceryl triacetate, wherein the mass ratio of isopropyl myristate to glyceryl triacetate is (1 - 2):(1 - 2); Or, the transdermal enhancer includes a mixture of glyceryl triacetate and polyglyceryl oleate, wherein the mass ratio of glyceryl triacetate to polyglyceryl oleate is (1 - 2):(1 - 2); Or, the transdermal enhancer includes a mixture of isopropyl myristate and polyglyceryl oleate, wherein the mass ratio of isopropyl myristate to polyglyceryl oleate is (1 - 2):(1 - 2).

6. The ketorolac patch composition according to claim 1, wherein The solvent-based matrix material includes an acrylate pressure-sensitive adhesive; The acrylate pressure-sensitive adhesive includes at least one of DURO-TAK 87-235A acrylate pressure-sensitive adhesive, DURO-TAK 387-2054 acrylate pressure-sensitive adhesive, DURO-TAK 387-4098 acrylate pressure-sensitive adhesive, DURO-TAK 387-2510 acrylate pressure-sensitive adhesive, DURO-TAK 387-2287 acrylate pressure-sensitive adhesive, DURO-TAK 87-6908 acrylate pressure-sensitive adhesive, DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, DURO-TAK 87-2074 acrylate pressure-sensitive adhesive, and DURO-TAK 87-2677 acrylate pressure-sensitive adhesive.

7. A method for preparing the ketorolac patch composition according to any one of claims 1 to 6, characterized in that, It includes the following steps: Adding the active ingredient to a solvent and stirring, then adding the transdermal enhancer, the crystallization inhibitor, and the solvent-based matrix material, continuing to stir, and drying to remove the solvent to obtain a ketorolac patch composition; The solvent includes at least one of methanol, ethanol, and ethyl acetate.

8. A ketorolac patch, characterized in that, It includes: A release liner, on which the ketorolac patch composition according to any one of claims 1 - 6 is coated; A backing layer, which is adhered to the ketorolac patch composition.

9. The preparation method of the ketorolac patch according to claim 8, characterized in that, It includes the following steps: The active ingredient is added to a solvent and stirred, and then a transdermal penetration enhancer, a crystallization inhibitor and a solvent-based matrix material are added, and stirring is continued to obtain a drug solution; The drug solution is coated on a release film and dried to remove the solvent and form a ketorolac patch composition; A backing layer is laminated on the ketorolac patch composition.

10. Use of a ketorolac patch composition according to any one of claims 1 to 6 or the ketorolac patch according to claim 8 in the preparation of a drug for treating or alleviating moderate to severe pain, said pain including pain caused by cancer, postoperative pain and other chronic pain.

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