A ketorolac patch composition, a ketorolac patch, and a preparation method and application thereof

Abstract

The present invention provides a ketorolac patch composition, a ketorolac patch, and a preparation method and application thereof. The ketorolac patch composition of the present invention comprises an active ingredient and a matrix material; the active ingredient comprises at least one of ketorolac, ketorolac acid salt, and ketorolac acid ester derivatives; the matrix material is a solvent-based matrix material; the solvent-based matrix material comprises at least one of acrylic acid and its derivatives, silicone and its derivatives; the ketorolac patch composition of the present invention can be used to prepare the ketorolac patch, which is a transdermal preparation, which can avoid gastrointestinal side effects, reduce bleeding risks, is easy to use, improves patient compliance, maintains local high concentrations, has strong pertinence, improves the safety of long-term use, and expands the applicable population.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular 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 strong analgesic and moderate anti-inflammatory properties. In order to improve its water solubility, it is usually prepared into tromethamine salt. Ketorolac tromethamine is converted into ketorolac in the body, which exerts analgesic and anti-inflammatory effects by inhibiting the synthesis of prostaglandins. It can be used to relieve a variety of moderate to severe acute pain and postoperative pain. Ketorolac tromethamine mainly acts on peripheral cyclooxygenase receptors, has no effect on the central nervous system, and is not addictive. Due to its strong analgesic effect and effective inhibition of various inflammations, it has received much favor and attention in recent years and has been marketed and used in nearly 20 countries.

[0003] The marketed dosage forms of ketorolac tromethamine include tablets (oral), injections, eye drops, and nasal sprays. Ketorolac tromethamine has strong gastrointestinal side effects after oral administration, which may cause bleeding and perforation; intramuscular injection of ketorolac tromethamine can effectively relieve postoperative pain, but due to the short half-life of ketorolac (4 to 6 hours), repeated injections are required, patient compliance is poor and the risk of infection is increased; nasal sprays can be used for short-term analgesia, and the effect is equivalent to intravenous injection, but the drug has a short retention time in the nasal cavity, is not fully absorbed, and requires frequent administration, which is inconvenient for patients to use.

[0004] Based on the defects of the current pharmaceutical dosage forms containing the active ingredient of ketorolac tromethamine, it is necessary to improve this. Summary of the invention

[0005] The present invention aims to solve a problem in the related art at least to a certain 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, comprising an active ingredient and a matrix material;

[0007] The active ingredient comprises at least one of ketorolac, ketorolac acid salts, and ketorolac acid 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, silicone and its derivatives.

[0010] Preferably, it also includes pharmaceutically acceptable external preparation excipients;

[0011] The auxiliary materials include at least one of a viscosity regulator, a crystallization inhibitor, a skin penetration enhancer, an antioxidant, and a preservative.

[0012] Preferably, the active ingredient comprises at least one of ketorolac and ketorolac tromethamine;

[0013] And / or, the viscosity regulator includes at least one of povidone K90, povidone K30, povidone VA64, sodium carboxymethyl cellulose, and liquid paraffin;

[0014] And / or, the crystallization inhibitor comprises at least one of butyl methacrylate-methyl methacrylate copolymer, levulinic acid, and crotamiton;

[0015] And / or, the transdermal enhancer includes at least one of lactic acid, oleic acid, propylene glycol, lauryl alcohol, oleyl alcohol, isostearyl alcohol, methyl laurate, hexyl laurate, lauric acid diethanolamide, isopropyl myristate, sorbitan laurate 20, propylene glycol, propylene glycol monolaurate, monolinoleyl glyceryl, diisopropyl adipate, triethyl citrate, propyl acetate, and L-menthol;

[0016] And / or, the antioxidant comprises at least one of butylated hydroxytoluene, ascorbic acid, tocopherol, tocopherol ester derivatives, butylated hydroxyanisole, and 2-mercaptobenzimidazole;

[0017] And / or, the preservative includes at least one of methylparaben, ethylparaben, and propylparaben;

[0018] And / or, the mass fraction of the active ingredient in the ketorolac patch composition is 1 to 15%.

[0019] Preferably, the composition comprises the following components in mass fractions: 40-85% solvent-based matrix material, 1-15% active ingredient, 0.1-15% transdermal enhancer, 0.1-15% crystallization inhibitor, 0-20% viscosity regulator, 0-5% preservative, and 0-5% antioxidant.

[0020] Preferably, the solvent-based matrix material includes at least one of an acrylate pressure-sensitive adhesive and a silicone pressure-sensitive adhesive.

[0021] Preferably, the acrylic pressure-sensitive adhesive includes at least one of DURO-TAK 87-235A acrylic pressure-sensitive adhesive, DURO-TAK 387-2054 acrylic pressure-sensitive adhesive, DURO-TAK 387-4098 acrylic pressure-sensitive adhesive, DURO-TAK 387-2510 acrylic pressure-sensitive adhesive, DURO-TAK 387-2287 acrylic pressure-sensitive adhesive, DURO-TAK 87-6908 acrylic pressure-sensitive adhesive, DURO-TAK 87-2852 acrylic pressure-sensitive adhesive, DURO-TAK 87-2074 acrylic pressure-sensitive adhesive, and DURO-TAK 87-2677 acrylic pressure-sensitive adhesive;

[0022] And / or, the organic silicone pressure-sensitive adhesive includes at least one of BIO-PSA 7-4202 organic silicone pressure-sensitive adhesive and BIO-PSA 7-4302 organic silicone pressure-sensitive adhesive.

[0023] In a second aspect, the present invention also provides a method for preparing the ketorolac patch composition, comprising the following steps:

[0024] Adding the active ingredient to the solvent and stirring, then adding a transdermal enhancer, a crystallization inhibitor, an antioxidant, a preservative and a solvent-based matrix material, continuing to stir, and drying to remove the solvent to obtain a ketorolac patch composition;

[0025] The solvent includes at least one of methanol, ethanol and ethyl acetate.

[0026] In a third aspect, the present invention further provides a ketorolac patch, comprising:

[0027] A release film, on which the ketorolac patch composition is coated;

[0028] A backing layer is adhered to the ketorolac patch composition.

[0029] In a fourth aspect, the present invention further provides a method for preparing the ketorolac patch, comprising the following steps:

[0030] Adding the active ingredient to the solvent and stirring, then adding the transdermal enhancer, the crystallization inhibitor, the antioxidant, the preservative and the solvent-based matrix material, and continuing to stir to obtain a drug solution;

[0031] applying the drug solution onto the release film, and drying to remove the solvent and form a ketorolac patch composition;

[0032] A backing layer is attached to the ketorolac patch composition.

[0033] In a fifth aspect, the present invention also provides a ketorolac patch composition or use of the ketorolac patch in preparing a drug for treating or relieving muscle tissue and joint pain caused by inflammation.

[0034] The present invention has the following beneficial effects compared with the prior art:

[0035] 1. The ketorolac patch composition of the present invention comprises an active ingredient and a matrix material; the active ingredient comprises at least one of ketorolac, ketorolac acid salts, and ketorolac acid ester derivatives; the matrix material is a solvent-based matrix material; the solvent-based matrix material comprises at least one of acrylic acid and its derivatives, silicone and its derivatives; the ketorolac patch composition of the present invention can be used to prepare a ketorolac patch, which is a transdermal preparation, can avoid gastrointestinal side effects, reduce bleeding risks, is easy to use, improves patient compliance, can significantly increase the drug concentration in subcutaneous local tissues, has significant local therapeutic effects, and has a smaller dosage than oral and injection administration; and the ketorolac patch of the present invention has a long onset time, a stable blood drug concentration, can avoid gastrointestinal adverse reactions, has strong pertinence, improves the safety of long-term use, and expands the applicable population;

[0036] 2. In the ketorolac patch of the present invention, the solvent-based matrix material includes but is not limited to at least one of an acrylate pressure-sensitive adhesive and a silicone pressure-sensitive adhesive; the acrylate pressure-sensitive adhesive includes DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, DURO-TAK387-2054 acrylate pressure-sensitive adhesive, DURO-TAK 87-235A acrylate pressure-sensitive adhesive, DURO-TAK 87-2677 acrylate pressure-sensitive adhesive, DURO-TAK 87-2074 acrylate pressure-sensitive adhesive and other carboxyl-containing acrylate pressure-sensitive adhesives; ketorolac tromethamine performs well in a pressure-sensitive adhesive system containing carboxyl groups at the terminal groups and is substantially free of crystallization;

[0037] 3. The permeability of the ketorolac patch of the present invention increases with the increase of the content of ketorolac tromethamine in the patch; the patch prepared with ketorolac has better transdermal diffusion performance than the patch prepared with ketorolac tromethamine at the same dose; as for the penetration enhancer, the penetration enhancing effect of isopropyl myristate is better than that of sorbitan laurate 20. DETAILED DESCRIPTION

[0038] The following will be combined with 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.

[0039] It should be noted that the order of description of the following embodiments is not intended to limit the preferred order of the embodiments. In addition, in the description of the present application, the term "including" means "including but not limited to". Various embodiments of the present invention may be 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 understood as a rigid limitation on the scope of the present invention; therefore, it should be considered that the range description has specifically disclosed all possible sub-ranges and single numerical values ​​within the 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., as well as single numbers within the numbered ranges, such as 1, 2, 3, 4, 5 and 6, which apply regardless of the range. In addition, whenever a numerical range is indicated in this article, it is meant to include any cited numbers (fractions or integers) within the indicated range.

[0040] The present application embodiment provides a ketorolac patch composition, including an active ingredient and a matrix material;

[0041] The active ingredient includes at least one of ketorolac, ketorolac salts, and ketorolac ester derivatives;

[0042] The matrix material is a solvent-based matrix material;

[0043] The solvent-based matrix material includes at least one of acrylic acid and its derivatives, silicone and its derivatives.

[0044] In some embodiments, it also includes pharmaceutically acceptable external preparation excipients;

[0045] The auxiliary materials include at least one of a viscosity regulator, a crystallization inhibitor, a skin penetration enhancer, an antioxidant, and a preservative.

[0046] In some embodiments, the active ingredient comprises at least one of ketorolac, ketorolac tromethamine.

[0047] In some embodiments, the viscosity regulator includes but is not limited to at least one of povidone K90, povidone K30, povidone VA64, sodium carboxymethyl cellulose, and liquid paraffin.

[0048] In some embodiments, the crystallization inhibitor includes but is not limited to at least one of butyl methacrylate-methyl methacrylate copolymer, levulinic acid, and crotamiton.

[0049] In some embodiments, the transdermal enhancer includes but is not limited to at least one of lactic acid, oleic acid, propylene glycol, lauryl alcohol, oleyl alcohol, isostearyl alcohol, methyl laurate, hexyl laurate, lauric acid diethanolamide, isopropyl myristate, sorbitan laurate 20 (i.e., Span 20), propylene glycol, propylene glycol monolaurate, monolinoleinyl glyceryl, diisopropyl adipate, triethyl citrate, propyl acetate, and L-menthol; preferably, the transdermal enhancer includes but is not limited to one or more of isopropyl myristate, sorbitan laurate 20, propylene glycol, propylene glycol monolaurate, monolinoleinyl glyceryl, diisopropyl adipate, and triethyl citrate.

[0050] In some embodiments, the antioxidant includes but is not limited to at least one of butylated hydroxytoluene, ascorbic acid, tocopherol, tocopherol ester derivatives, butylated hydroxyanisole, and 2-mercaptobenzimidazole.

[0051] In some embodiments, the preservative includes, but is not limited to, at least one of methylparaben, ethylparaben, and propylparaben.

[0052] In some embodiments, the mass fraction of the active ingredient in the ketorolac patch composition is 1 to 15%.

[0053] In some embodiments, the ketorolac patch composition comprises the following components in mass fractions: 40-85% solvent-based matrix material, 1-15% active ingredient, 0.1-15% transdermal enhancer, 0.1-15% crystallization inhibitor, 0-20% viscosity regulator, 0-5% preservative, and 0-5% antioxidant.

[0054] In some embodiments, the solvent-based matrix material includes, but is not limited to, at least one of an acrylate pressure-sensitive adhesive and a silicone pressure-sensitive adhesive.

[0055] In some embodiments, the acrylate pressure-sensitive adhesive includes but is not limited to 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-TAK387-2510 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, and DURO-TAK 87-2074 acrylate pressure-sensitive adhesive.

[0056] Preferably, the acrylate pressure-sensitive adhesive includes carboxyl-containing acrylate pressure-sensitive adhesives such as DURO-TAK 87-2852 acrylate pressure-sensitive adhesive, DURO-TAK 387-2054 acrylate pressure-sensitive adhesive, DURO-TAK 87-235A acrylate pressure-sensitive adhesive, DURO-TAK 87-2677 acrylate pressure-sensitive adhesive, and DURO-TAK 87-2074 acrylate pressure-sensitive adhesive.

[0057] Specifically, the DURO-TAK series acrylate pressure-sensitive adhesives in the above embodiments are all German Henkel DURO-TAK series acrylate pressure-sensitive adhesives.

[0058] In some embodiments, the silicone pressure-sensitive adhesive includes but is not limited to at least one of BIO-PSA 7-4202 silicone pressure-sensitive adhesive and BIO-PSA 7-4302 silicone pressure-sensitive adhesive. Both BIO-PSA 7-4202 silicone pressure-sensitive adhesive and BIO-PSA 7-4302 silicone pressure-sensitive adhesive are DuPont TM Liveo TM BIO-PSA pressure sensitive adhesive.

[0059] Based on the same inventive concept, the present invention also provides a method for preparing the ketorolac patch composition, comprising the following steps:

[0060] Adding the active ingredient to the solvent and stirring, then adding a transdermal enhancer, a crystallization inhibitor, an antioxidant, a preservative and a solvent-based matrix material, continuing to stir, and drying to remove the solvent to obtain a ketorolac patch composition;

[0061] The solvent includes at least one of methanol, ethanol and ethyl acetate.

[0062] Based on the same inventive concept, the present invention also provides a ketorolac patch, comprising:

[0063] A release film, on which the ketorolac patch composition is coated;

[0064] A backing layer is adhered to the ketorolac patch composition.

[0065] Based on the same inventive concept, the present invention also provides a method for preparing the ketorolac patch, comprising the following steps:

[0066] Adding the active ingredient to the solvent and stirring, then adding the transdermal enhancer, the crystallization inhibitor, the antioxidant, the preservative and the solvent-based matrix material, and continuing to stir to obtain a drug solution;

[0067] applying the drug solution onto the release film, and drying to remove the solvent and form a ketorolac patch composition;

[0068] A backing layer is attached to the ketorolac patch composition.

[0069] In some embodiments, the active ingredient is added to a solvent and stirred, and then a transdermal enhancer, a crystallization inhibitor, an antioxidant, a preservative and a solvent-based matrix material are added and stirred continuously to obtain a drug solution; the drug solution is in a transparent colloidal state, coated on a suitable release film, and dried at 60 to 70° C. for 15 to 25 minutes to completely evaporate the solvent (methanol, ethanol, ethyl acetate, etc.) to form a ketorolac patch composition.

[0070] In some embodiments, the release film includes a PET release film, and the backing layer includes a PET polyester cloth.

[0071] Based on the same inventive concept, the present invention also provides the above-mentioned ketorolac patch composition or the use of the above-mentioned ketorolac patch in the preparation of a drug for treating or relieving muscle tissue and joint pain caused by inflammation.

[0072] The ketorolac patch composition, ketorolac patch and preparation method thereof of the present invention are further described below with specific examples. This part further illustrates the present invention in conjunction with specific examples, but should not be construed as limiting the present invention. If not otherwise specified, the technical means adopted in the embodiments are conventional means well known to those skilled in the art. Unless otherwise specified, the reagents, methods and equipment adopted in the present invention are conventional reagents, methods and equipment in the art.

[0073] Examples 1 to 10

[0074] Examples 1 to 10 provide a ketorolac patch composition, comprising the following components by mass fraction: 97.5% solvent-based matrix material, 2.5% active ingredient;

[0075] The active ingredient is ketorolac tromethamine;

[0076] The solvent-based matrix material is an acrylic pressure-sensitive adhesive or a silicone pressure-sensitive adhesive.

[0077] This embodiment also provides a method for preparing the above-mentioned ketorolac patch composition, comprising the following steps:

[0078] Ketorolac tromethamine was dissolved in methanol, mixed with the acrylic pressure-sensitive adhesive or silicone pressure-sensitive adhesive in Examples 1 to 10 for 4 hours, and dried at 70° C. for 25 minutes to completely evaporate the solvent methanol to form a ketorolac patch composition.

[0079] This embodiment also provides a method for preparing a ketorolac patch, comprising the following steps:

[0080] Dissolve ketorolac tromethamine in methanol, and mix with the acrylate pressure-sensitive adhesive or silicone pressure-sensitive adhesive in Examples 1 to 10 for 4 hours to obtain a drug solution;

[0081] The drug solution is coated on a PET release film, and dried to remove the solvent methanol and form a ketorolac patch composition;

[0082] A backing layer (specifically PET polyester cloth) was attached to the ketorolac patch composition and cut into 10 cm×10 cm (length 10 cm, width 10 cm), with a drug content (ketorolac tromethamine) of 12.5 mg / patch, thereby obtaining a patch.

[0083] The specific active ingredients, solvent-based matrix materials and solvents in Examples 1 to 10 are shown in Table 1.

[0084] Table 1 - Specific types of active ingredients, solvent-based matrix materials and solvents in Examples 1 to 10

[0085]

[0086]

[0087] Embodiment 11

[0088] This embodiment provides a ketorolac patch composition, comprising the following components by mass fraction: 73% of DURO-TAK87-2852 acrylate pressure-sensitive adhesive, 5% of isopropyl myristate, 5% of propylene glycol, 5% of ketorolac tromethamine, 10% of levulinic acid, and 2% of povidone K90;

[0089] This embodiment also provides a method for preparing the above-mentioned ketorolac patch composition, comprising the following steps:

[0090] Ketorolac tromethamine was dissolved in methanol, and then levulinic acid, isopropyl myristate, propylene glycol, povidone K90 and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive were added in sequence and mixed for 4 hours, and dried at 70°C for 25 minutes to completely evaporate the solvent methanol to form a ketorolac patch composition.

[0091] This embodiment also provides a method for preparing a ketorolac patch, comprising the following steps:

[0092] Dissolve ketorolac tromethamine in methanol, then add levulinic acid, isopropyl myristate, propylene glycol, povidone K90 and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive in sequence and mix for 4 hours to obtain a drug solution;

[0093] The drug solution is coated on a PET release film, and dried to remove the solvent methanol and form a ketorolac patch composition;

[0094] A backing layer (specifically PET polyester cloth) was attached to the ketorolac patch composition and cut into 10 cm×10 cm (length 10 cm, width 10 cm), with a drug content (ketorolac tromethamine) of 25 mg / patch, thereby obtaining a patch.

[0095] Specifically, the raw materials and solvents used in the preparation of the ketorolac patch composition in Example 11 are shown in Table 2.

[0096] Table 2 - Mass fraction of each raw material in the ketorolac patch composition in Example 11

[0097] DURO-TAK 87-2852 Acrylic Pressure Sensitive Adhesive 73％ Isopropyl myristate 5％ Propylene glycol 5％ Ketorolac Tromethamine 5％ Levulinic acid 10％ Povidone K90 2％ Methanol (solvent) 0(remove after drying)

[0098] Example 12

[0099] This embodiment provides a ketorolac patch composition, comprising the following components by mass fraction: 70.5% of DURO-TAK87-2852 acrylate pressure-sensitive adhesive, 5% of isopropyl myristate, 5% of propylene glycol, 7.5% of ketorolac tromethamine, 10% of levulinic acid, and 2% of povidone K90;

[0100] This embodiment also provides a method for preparing the above-mentioned ketorolac patch composition, comprising the following steps:

[0101] Ketorolac tromethamine was dissolved in methanol, and then levulinic acid, isopropyl myristate, propylene glycol, povidone K90 and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive were added in sequence and mixed for 4 hours, and dried at 70°C for 25 minutes to completely evaporate the solvent methanol to form a ketorolac patch composition.

[0102] This embodiment also provides a method for preparing a ketorolac patch, comprising the following steps:

[0103] Dissolve ketorolac tromethamine in methanol, then add levulinic acid, isopropyl myristate, propylene glycol, povidone K90 and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive in sequence and mix for 4 hours to obtain a drug solution;

[0104] The drug solution is coated on a PET release film, and dried to remove the solvent methanol and form a ketorolac patch composition;

[0105] A backing layer (specifically PET polyester cloth) was attached to the ketorolac patch composition and cut into 10 cm×10 cm (length 10 cm, width 10 cm), with a drug content (ketorolac tromethamine) of 37.5 mg / patch, thereby obtaining a patch.

[0106] Specifically, the raw materials and solvents used in the preparation of the ketorolac patch composition in Example 12 are shown in Table 3.

[0107] Table 3 - Mass fraction of each raw material in the ketorolac patch composition in Example 12

[0108] DURO-TAK 87-2852 Acrylic Pressure Sensitive Adhesive 70.5％ Isopropyl myristate 5％ Propylene glycol 5％ Ketorolac Tromethamine 7.5％ Levulinic acid 10％ Povidone K90 2％ Methanol (solvent) 0(remove after drying)

[0109] Embodiment 13

[0110] This embodiment provides a ketorolac patch composition, comprising the following components by mass fraction: 68% of DURO-TAK87-2852 acrylate pressure-sensitive adhesive, 5% of isopropyl myristate, 5% of propylene glycol, 10% of ketorolac tromethamine, 10% of levulinic acid, and 2% of povidone K90;

[0111] This embodiment also provides a method for preparing the above-mentioned ketorolac patch composition, comprising the following steps:

[0112] Ketorolac tromethamine was dissolved in methanol, and then levulinic acid, isopropyl myristate, propylene glycol, povidone K90 and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive were added in sequence and mixed for 4 hours, and dried at 70°C for 25 minutes to completely evaporate the solvent methanol to form a ketorolac patch composition.

[0113] This embodiment also provides a method for preparing a ketorolac patch, comprising the following steps:

[0114] Dissolve ketorolac tromethamine in methanol, then add levulinic acid, isopropyl myristate, propylene glycol, povidone K90 and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive in sequence and mix for 4 hours to obtain a drug solution;

[0115] The drug solution is coated on a PET release film, and dried to remove the solvent methanol and form a ketorolac patch composition;

[0116] A backing layer (specifically PET polyester cloth) was attached to the ketorolac patch composition and cut into 10 cm×10 cm (length 10 cm, width 10 cm), with a drug content (ketorolac tromethamine) of 50 mg / patch, thereby obtaining a patch.

[0117] Specifically, the raw materials and solvents used in the preparation of the ketorolac patch composition in Example 13 are shown in Table 4.

[0118] Table 4 - Mass fraction of each raw material in the ketorolac patch composition in Example 13

[0119] DURO-TAK 87-2852 Acrylic Pressure Sensitive Adhesive 68％ Isopropyl myristate 5％ Propylene glycol 5％ Ketorolac Tromethamine 10％ Levulinic acid 10％ Povidone K90 2％ Methanol (solvent) 0(remove after drying)

[0120] Embodiment 14

[0121] This embodiment provides a ketorolac patch composition, comprising the following components by mass fraction: 71% of DURO-TAK87-2852 acrylate pressure-sensitive adhesive, 5% of isopropyl myristate, 5% of propylene glycol, 7% of ketorolac, 10% of levulinic acid, and 2% of povidone K90;

[0122] This embodiment also provides a method for preparing the above-mentioned ketorolac patch composition, comprising the following steps:

[0123] Ketorolac was dissolved in ethanol, and then levulinic acid, isopropyl myristate, propylene glycol, povidone K90 and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive were added in sequence and mixed for 4 hours, and dried at 70°C for 25 minutes to completely evaporate the solvent ethanol to form a ketorolac patch composition.

[0124] This embodiment also provides a method for preparing a ketorolac patch, comprising the following steps:

[0125] Dissolve ketorolac in ethanol, then add levulinic acid, isopropyl myristate, propylene glycol, povidone K90 and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive in sequence and mix for 4 hours to obtain a drug solution;

[0126] The drug solution is applied onto a PET release film, and dried to remove the solvent ethanol and form a ketorolac patch composition;

[0127] A backing layer (specifically PET polyester cloth) was attached to the ketorolac patch composition and cut into 10 cm×10 cm (length 10 cm, width 10 cm) with a drug content (ketorolac) of 35 mg / patch to obtain a patch.

[0128] Specifically, the raw materials and solvents used in the preparation of the ketorolac patch composition in Example 14 are shown in Table 5.

[0129] Table 5 - Mass fraction of each raw material in the ketorolac patch composition in Example 14

[0130] DURO-TAK 87-2852 Acrylic Pressure Sensitive Adhesive 71％ Isopropyl myristate 5％ Propylene glycol 5％ Ketorolac 7％ Levulinic acid 10％ Povidone K90 2％ Ethanol (solvent) 0(remove after drying)

[0131] Embodiment 15

[0132] This embodiment provides a ketorolac patch composition, comprising the following components by mass fraction: 71% of DURO-TAK87-2852 acrylate pressure-sensitive adhesive, 205% of sorbitan laurel, 5% of propylene glycol, 7% of ketorolac, 10% of levulinic acid, and 2% of povidone K90;

[0133] This embodiment also provides a method for preparing the above-mentioned ketorolac patch composition, comprising the following steps:

[0134] Ketorolac was dissolved in ethanol, and then levulinic acid, sorbitan laurate 20, propylene glycol, povidone K90 and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive were added in sequence and mixed for 4 hours, and dried at 70°C for 25 minutes to completely evaporate the solvent ethanol to form a ketorolac patch composition.

[0135] This embodiment also provides a method for preparing a ketorolac patch, comprising the following steps:

[0136] Dissolve ketorolac in ethanol, then add levulinic acid, sorbitan laurate 20, propylene glycol, povidone K90 and DURO-TAK 87-2852 acrylate pressure-sensitive adhesive in sequence and mix for 4 hours to obtain a drug solution;

[0137] The drug solution is applied onto a PET release film, and dried to remove the solvent ethanol and form a ketorolac patch composition;

[0138] A backing layer (specifically PET polyester cloth) was attached to the ketorolac patch composition and cut into 10 cm×10 cm (length 10 cm, width 10 cm) with a drug content (ketorolac) of 35 mg / patch to obtain a patch.

[0139] Specifically, the raw materials and solvents used in the preparation of the ketorolac patch composition in Example 15 are shown in Table 6.

[0140] Table 6 - Mass fraction of each raw material in the ketorolac patch composition in Example 15

[0141] DURO-TAK 87-2852 Acrylic Pressure Sensitive Adhesive 71％ Laurel Sorbitan 20 5％ Propylene glycol 5％ Ketorolac 7％ Levulinic acid 10％ Povidone K90 2％ Ethanol (solvent) 0(remove after drying)

[0142] Crystallization investigation

[0143] Ketorolac patches were prepared according to the methods of Examples 1 to 10, and placed at room temperature for 10 months to observe their crystallization. The results are shown in Table 7.

[0144] Table 7 - Crystallization of Ketorolac Patches Prepared in Examples 1 to 10

[0145] Example Pressure sensitive adhesive type Crystallization 1 DURO-TAK 87-235A Acrylic Pressure Sensitive Adhesive ND 2 DURO-TAK 387-2054 Acrylic Pressure Sensitive Adhesive ND 3 DURO-TAK 387-4098 Acrylic Pressure Sensitive Adhesive + 4 DURO-TAK 387-2510 Acrylic Pressure Sensitive Adhesive + 5 DURO-TAK 387-2287 acrylic pressure sensitive adhesive + 6 DURO-TAK 87-6908 acrylic pressure sensitive adhesive + 7 DURO-TAK 87-2852 Acrylic Pressure Sensitive Adhesive ND 8 DURO-TAK 87-2074 Acrylic Pressure Sensitive Adhesive ND 9 BIO-PSA 7-4202 silicone pressure sensitive adhesive + 10 BIO-PSA 7-4302 silicone pressure sensitive adhesive +

[0146] In Table 7: a + represents that the crystallization accounts for 10% of the entire patch; ND represents no crystallization.

[0147] As can be seen from Table 7, ketorolac tromethamine performs well in a pressure-sensitive adhesive system containing carboxyl groups at the terminal groups.

[0148] Transdermal diffusion experiment:

[0149] The Franz diffusion cell method was used, and the ex vivo skin of Bama miniature pigs was used as a barrier. The ketorolac patches prepared in Examples 7, 11 to 15 were punched into circular patches with a diameter of 14 mm and applied to the ex vivo skin of Bama miniature pigs. A phosphate buffer solution with a pH of 7.4 was used as the dissolution medium, and the sampling time points were set as: 1h, 2h, 4h, 8h, 12h, and 24h to collect the transdermal diffusion data of the homemade products. The results are shown in Table 8.

[0150] Table 8 - Transdermal diffusion data of ketorolac patches prepared in different embodiments

[0151]

[0152]

[0153] Analysis of the transdermal diffusion data of Example 7, Example 11, Example 12, and Example 13 shows that the permeability of the patch increases with the increase in the content of ketorolac tromethamine in the patch; analysis of the transdermal diffusion data of Example 13, Example 14, and Example 15 shows that the patch prepared with ketorolac has better transdermal diffusion performance than the patch prepared with ketorolac tromethamine at the same dose; in terms of penetration enhancers, the penetration enhancing effect of isopropyl myristate is better than that of sorbitan laurel 20.

[0154] Pharmacodynamics test

[0155] 20 rats were randomly divided into 2 groups, i.e., a control group and a treatment group, with 10 rats in each group. In the control group, the rats were treated with a blank patch (i.e., a patch without an active ingredient). In the treatment group, the rats were treated with the ketorolac patch prepared in Example 13. Specifically, the experimental process was as follows: the control group used a blank patch, the treatment group used the ketorolac patch prepared in Example 13, and the control group and the treatment group both used corresponding patches on the right hind foot of the rats. After 3 hours of administration, the rats in the control group and the treatment group were subcutaneously injected with 1% carrageenan (0.1 mL) at the right hind foot pad.

[0156] The toe volume was measured using a toe volume meter before (0 hour) and 1, 2, 3, 4 and 6 hours after the carrageenan injection.

[0157] The degree of paw swelling is calculated as follows:

[0158]

[0159] Among them, v t is the volume of the paw at each time point after carrageenan injection, and v is the volume of the paw before carrageenan injection.

[0160] The swelling results are shown in Table 9 below.

[0161] Table 9 - Swelling results of the control group and the treatment group

[0162]

[0163]

[0164] As can be seen from Table 9, the swelling degree of rats was significantly reduced when the patch of the present invention was used compared with the blank patch, indicating that the patch of the present invention has a significant effect on reducing the swelling of rat toes and exhibits a good anti-inflammatory effect.

[0165] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A ketorolac patch composition, characterized in that: The composition comprises the following components in mass fractions: 68-71% of solvent-based matrix material, 7-10% of active ingredient, 10% of transdermal enhancer, 10% of crystallization inhibitor, and 2% of viscosity regulator; The solvent-based matrix material includes an acrylate pressure-sensitive adhesive; The acrylic pressure-sensitive adhesive includes at least one of DURO-TAK 87-2852 acrylic pressure-sensitive adhesive, DURO-TAK 87-2074 acrylic pressure-sensitive adhesive, DURO-TAK 87-235A acrylic pressure-sensitive adhesive, and DURO-TAK 387-2054 acrylic pressure-sensitive adhesive; The active ingredient comprises at least one of ketorolac and ketorolac tromethamine; The viscosity regulator is povidone K90; The crystallization inhibitor is levulinic acid; The transdermal enhancer includes propylene glycol and isopropyl myristate, or the transdermal enhancer includes sorbitan laurel 20 and propylene glycol.

2. A method for preparing the ketorolac patch composition according to claim 1, characterized in that: The following steps are involved: Adding the active ingredient to the 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.

3. A ketorolac patch, characterized in that, include: A release film, on which the ketorolac patch composition according to claim 1 is coated; A backing layer is adhered to the ketorolac patch composition.

4. The method for preparing the ketorolac patch according to claim 3, wherein: The following steps are involved: Add the active ingredient to the solvent and stir, then add the transdermal enhancer, the crystallization inhibitor and the solvent-based matrix material, and continue stirring to obtain a drug solution; applying the drug solution onto the release film, and drying to remove the solvent and form a ketorolac patch composition; A backing layer is attached to the ketorolac patch composition.

5. Use of the ketorolac patch composition according to claim 1 or the ketorolac patch according to claim 4 in preparing a drug for treating or relieving muscle tissue and joint pain caused by inflammation.

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