MULTI-LAYER TRANSDERMAL DRUG DELIVERY SYSTEM CONTAINING IBUPROFEN OR STRUCTURAL ANALOGUE THEREOF

Abstract

A multi-layer transdermal drug delivery system containing ibuprofen or a structural analogue thereof, comprising a transdermal patch containing ibuprofen or a structural analogue thereof and a second combined layer. The transdermal patch comprises a polymer matrix layer, the polymer matrix layer comprising an active ingredient, a compound containing at least one amino group, and a pressure-sensitive adhesive. All or some of active ingredient-amino compound salts or all or some of free active ingredients formed in the polymer matrix layer are kept in a uniform dissolution state in the polymer matrix, and can be stably stored before use, without recrystalization. The transdermal drug delivery system can continuously and controllably deliver a therapeutically effective amount of ibuprofen or a structural analogue thereof for 12 to 24 hours in the absence of a transdermal enhancer, has excellent wearing ability, and avoids a cold flow phenomenon.

Claims

1. A transdermal patch containing ibuprofen or a structural analogue thereof, wherein the transdermal patch comprises a polymer matrix layer comprising an active ingredient, a compound containing at least one amino group, and a pressure-sensitive adhesive; the active ingredient is ibuprofen or a structural analogue thereof; and the ibuprofen structural analogue is one or more selected from naproxen, fenoprofen, ketoprofen, flurbiprofen, and loxoprofen.

2. The transdermal patch according to claim 1, wherein the compound containing at least one amino group is a fatty amine, preferably one or more selected from the following compounds: ethanolamine, diethanolamine, triethanolamine, diethylamine, triethylamine, propane diamine, N-ethylmorpholine, N-ethylpiperidine, N-ethylpiperazine, N-hydroxyethylpiperidine, N-hydroxyethylpyrrole, dimethylpropanediamine, tetramethylpropanediamine, N-dodecylpyrrole, trihexylamine, N-dodecyl homopiperidine, pyridin-2-yl-methanol, ethylenediamine, tetramethyl ethylenediamine, spermidine, spermine, cyclen, 3-(piperazin-1-yl)propan-1,2-diol, N-hydroxyethylpiperazine, N-methylmorpholine, triethylenediamine, tris(2-aminoethyl)amine, 2-piperazinone, 3-aminopiperidine, 1,3-cyclohexanedimethylamine, propylene glycol bis(3-aminopropyl) ether, ethylene glycol bis(3-aminoethyl) ether.

3. The transdermal patch according to claim 1, wherein in the polymer matrix layer, all or part of the active ingredients form a salt with the compound containing at least one amino group; preferably, the melting point of the formed active ingredient-amino compound salt is lower than the melting point of ibuprofen or the structural analogue thereof.

4. The transdermal patch according to claim 1, wherein the polymer matrix layer contains a filler, and the filler is any one or more selected from talc, bentonite, kaolin, colloidal silicon dioxide and montmorillonite; preferably, the average particle size of the filler ranges from 300 mesh to 5,000 mesh, including 500 mesh to 3,000 mesh; preferably, the surface area of the filler ranges from 1.5 m.sup.2/g to 15 m.sup.2/g, including 3 m.sup.2/g to 10 m.sup.2/g, and 4 m.sup.2/g to 7 m.sup.2/g.

5. The transdermal patch according to claim 1, wherein the polymer matrix layer does not contain a transdermal enhancer.

6. The transdermal patch according to claim 1, wherein a molar ratio of the active ingredient in the polymer matrix layer to the amino group in the compound containing at least one amino group is 12:1 to 1:1, including 10:1 to 1.5:1, such as10:1,9:1,8:1,7:1,6:1,5:1,4:1,3:1,2:1or1.5:1;and/or, a content by weight of the compound containing at least one amino group in the polymer matrix layer is 1% to 15%, including 2% to 12%, such as 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11% or 12%; and/or, a content by weight of the active ingredient in the polymer matrix layer is 15% to 45%, including 20% to 40%, such as 20% to 35%, and a further preferred range is 25% to 35%, such as 25%, 30%, or 35%; and/or, a content by weight of the acrylic pressure-sensitive adhesive in the polymer matrix layer is 40% to 80%, preferably 45% to 75%, such as 45% to 70%, including 45%, 50%, 55%, 60%, 65% or 70%.

7. The transdermal patch according to claim 1, wherein the patch further comprises a backing layer and a protective layer; and the polymer matrix layer is located between the backing layer and the protective layer.

8. A multi-layer transdermal drug delivery system containing ibuprofen or a structural analogue thereof, wherein the multi-layer transdermal drug delivery system comprises the transdermal patch according to claim 1, and further comprises a second combined layer; the second combined layer comprises a backing layer, a protective layer, and a polymer matrix layer located between the backing layer and the protective layer; and the polymer matrix layer comprises a pressure-sensitive adhesive.

9. The multi-layer transdermal drug delivery system according to claim 8, wherein the polymer matrix layer of the second combined layer further comprises a pharmaceutically acceptable auxiliary material, and/or further comprises ibuprofen or a structural analogue thereof; preferably, a content by weight of ibuprofen or the structural analogue thereof in the polymer matrix layer of the second combined layer is <15%, for example, <10%, <8%, or <5%; preferably, the ibuprofen structural analogue is one or more selected from naproxen, fenoprofen, ketoprofen, flurbiprofen, and loxoprofen.

10. The multi-layer transdermal drug delivery system according to claim 8, wherein a peripheral width of the second combined layer is slightly wider than the peripheral width of the transdermal patch, more preferably 0.5 cm to 1.0 cm wider than the peripheral width of the transdermal patch.

11. The transdermal patch according to claim 2, wherein in the polymer matrix layer, all or part of the active ingredients form a salt with the compound containing at least one amino group; preferably, the melting point of the formed active ingredient-amino compound salt is lower than the melting point of ibuprofen or the structural analogue thereof.

12. The transdermal patch according to claim 2, wherein the polymer matrix layer contains a filler, and the filler is any one or more selected from talc, bentonite, kaolin, colloidal silicon dioxide and montmorillonite; preferably, the average particle size of the filler ranges from 300 mesh to 5,000 mesh, including 500 mesh to 3,000 mesh; preferably, the surface area of the filler ranges from 1.5 m.sup.2/g to 15 m.sup.2/g, including 3 m.sup.2/g to 10 m.sup.2/g, and 4 m.sup.2/g to 7 m.sup.2/g.

13. The transdermal patch according to claim 3, wherein the polymer matrix layer contains a filler, and the filler is any one or more selected from talc, bentonite, kaolin, colloidal silicon dioxide and montmorillonite; preferably, the average particle size of the filler ranges from 300 mesh to 5,000 mesh, including 500 mesh to 3,000 mesh; preferably, the surface area of the filler ranges from 1.5 m.sup.2/g to 15 m.sup.2/g, including 3 m.sup.2/g to 10 m.sup.2/g, and 4 m.sup.2/g to 7 m.sup.2/g.

14. The transdermal patch according to claim 2, wherein the polymer matrix layer does not contain a transdermal enhancer.

15. The transdermal patch according to claim 3, wherein the polymer matrix layer does not contain a transdermal enhancer.

16. The transdermal patch according to claim 4, wherein the polymer matrix layer does not contain a transdermal enhancer.

17. The transdermal patch according to claim 2, wherein a molar ratio of the active ingredient in the polymer matrix layer to the amino group in the compound containing at least one amino group is 12:1 to 1:1, including 10:1 to 1.5:1, such as 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1.5:1; and/or, a content by weight of the compound containing at least one amino group in the polymer matrix layer is 1% to 15%, including 2% to 12%, such as 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11% or 12%; and/or, a content by weight of the active ingredient in the polymer matrix layer is 15% to 45%, including 20% to 40%, such as 20% to 35%, and a further preferred range is 25% to 35%, such as 25%, 30%, or 35%; and/or, a content by weight of the acrylic pressure-sensitive adhesive in the polymer matrix layer is 40% to 80%, preferably 45% to 75%, such as 45% to 70%, including 45%, 50%, 55%, 60%, 65% or 70%.

18. The transdermal patch according to claim 3, wherein a molar ratio of the active ingredient in the polymer matrix layer to the amino group in the compound containing at least one amino group is 12:1 to 1:1, including 10:1 to 1.5:1, such as 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1.5:1; and/or, a content by weight of the compound containing at least one amino group in the polymer matrix layer is 1% to 15%, including 2% to 12%, such as 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11% or 12%; and/or, a content by weight of the active ingredient in the polymer matrix layer is 15% to 45%, including 20% to 40%, such as 20% to 35%, and a further preferred range is 25% to 35%, such as 25%, 30%, or 35%; and/or, a content by weight of the acrylic pressure-sensitive adhesive in the polymer matrix layer is 40% to 80%, preferably 45% to 75%, such as 45% to 70%, including 45%, 50%, 55%, 60%, 65% or 70%.

19. The transdermal patch according to claim 2, wherein the patch further comprises a backing layer and a protective layer; and the polymer matrix layer is located between the backing layer and the protective layer.

20. The multi-layer transdermal drug delivery system according to claim 9, wherein a peripheral width of the second combined layer is slightly wider than the peripheral width of the transdermal patch, more preferably 0.5 cm to 1.0 cm wider than the peripheral width of the transdermal patch.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0100] FIG. 1 shows the results of the stability experiment of Experimental Example 1;

[0101] FIG. 2 shows the results of the in vitro release experiment of Experimental Example 2;

[0102] FIG. 3 shows the results of the in vitro transdermal experiment of Experimental Example 3;

[0103] FIG. 4 shows the results of the human blood drug concentration experiment of Experimental Example 4;

[0104] FIG. 5 shows the results of fever inducing-fever reducing experiment in rats of Experimental Example 5;

[0105] FIG. 6 shows the schematic diagram of the structure of the transdermal patch containing ibuprofen (FIG. 6A) and the schematic diagram of the structure of the second combined layer (FIG. 6B) of the present invention.

SPECIFIC MODES FOR CARRYING OUT THE EMBODIMENTS

[0106] The following Examples are intended to illustrate the present invention, but are not intended to limit the scope of the present invention. If the specific technology or conditions are not indicated in the Examples, it shall be carried out according to the technology or conditions described in the literature in the art or according to the product specification. If the manufacturer is not indicated, the reagents or instruments used are conventional products that can be purchased through regular channels.

[0107] In the following examples, Dow Corning® 7-6102 is a composite of acrylic pressure-sensitive adhesive and polysilicone pressure-sensitive adhesive. Duro-tack-4098 is a pressure-sensitive adhesive of a copolymer of acrylic acid and vinyl acetate, containing no functional groups and no crosslinking agents. Duro-tack-2074 is an acrylic pressure-sensitive adhesive containing carboxyl and hydroxyl functional groups and a crosslinking agent. Duro-tack-6908 is a polyisobutylene pressure-sensitive adhesive containing no functional groups and no crosslinking agents. Bio-PSA-7-4302 is a polysilicone pressure-sensitive adhesive. Tert-butyl-4-hydroxyanisole (BHA) is an antioxidant.

EXAMPLE 1

[0108] An ibuprofen-containing transdermal patch comprises a polymer matrix layer. The polymer matrix layer comprises an active ingredient ibuprofen, a compound containing at least one amino group, and a pressure-sensitive adhesive. In the polymer matrix layer, all or part of ibuprofen forms a salt with the compound containing at least one amino group, and all or part of ibuprofen-amino compound salt and all or part of free ibuprofen formed are kept uniformly dissolved in the polymer matrix, and can be stored stably without recrystallization before use.

[0109] Further, the transdermal patch of the present Example further comprises a backing layer and a protective layer. The polymer matrix layer was located between the backing layer and the protective layer.

[0110] In the present Example, in the polymer matrix layer, the content by weight of ibuprofen was 35%, the content by weight of the pressure-sensitive adhesive was 54% (wherein the content by weight of Duro-tack-4098 was 50%, and the content by weight of Bio-PSA-7-4302 was 4%), and the content by weight of the compound containing one amino group (specifically Am 25) was 5%. In addition, the polymer matrix layer can also contain pharmaceutically acceptable auxiliary materials (such as talc, colloidal Si02, montmorillonite, and vitamin E).

[0111] The present Example also provides a preparation method of the transdermal patch, comprising: firstly, a calculated amount of a polymer pressure-sensitive adhesive was weighed, and added to an appropriate amount of ethyl acetate, and then an amino compound was added, and further auxiliary materials (if exist) such as an antioxidant (for example, vitamin E) were added while keeping stirring. The stirring time was determined by whether the mixture was uniform, generally about 15 to 30 minutes. After stirring to be completely dissolved, the active ingredient ibuprofen was added in batches. After gradually dissolving under stirring, the next batch of ibuprofen was added until all of the active ingredient ibuprofen was added and dissolved. Finally, a solid filler was added and stirred to be completely and uniformly dispersed. The prepared polymer matrix was coated on a release film, with a coating thickness determined according to the needs of the final clinical use. The coated polymer matrix was dried in an oven with exhaust function at 35° C. to 50° C. for 5 to 15 minutes to remove the organic solvent. The dried product is then combined with a suitable backing film. Finally, cutting was performed to obtain suitable specifications according to the needs of use, and the final product was packaged.

[0112] The formulations of the polymer matrix layer of a typical transdermal patch containing ibuprofen (Examples 1-10) were shown in Table 1 (for the preparation method, refer to Example 1).

TABLE-US-00002 TABLE 1 (Table 1 shows the percentage by weight.) Dow Duro-tack- Corning ®7- Bio-PSA- Colloidal Montmoril- Vitamin Example Ibuprofen 4098 6102 7-4302 Am_9 Am_13 Am_25 Talc SiO.sub.2 lonite E 1 35 50 4 5 5 1 2 20 71 5 2 1 1 3 25 69 3 2 1 4 30 63 3 3 1 5 35 54 5 5 1 6 40 45 7 7 1 7 30 60 5 4 1 8 30 60 5 4 1 9 30 57 4 5 3 1 10 35 58 2 4 1 Comparative 20 78 1 1 Example 1

Comparative Example 1

A transdermal patch containing ibuprofen, the formulation of the polymer matrix layer thereof was shown in Table 1, and for the preparation method, refer to Example 1.

EXAMPLES 11-21

[0113] The formulations of the polymer matrix layer of the transdermal patch of ibuprofen containing different types of transdermal enhancers (i.e., Examples 11-21) and the change in the penetration efficiency were shown in Table 2 (for the preparation method, refer to Example 1).

TABLE-US-00003 TABLE 2 (Table 2 shows the percentage by weight.) Diethylene glycol Duro-tack- Vitamin Silicone oil Propylene monoethyl Isopropyl Example Ibuprofen 2074 Am_10 Talc E Q7-9120 glycol ether oleate 11 35 53 5 5 1 1 12 35 53 5 5 1 1 13 35 53 5 5 1 1 14 35 53 5 5 1 1 15 35 53 5 5 1 16 35 53 5 5 1 17 35 53 5 5 1 18 35 53 5 5 1 19 35 53 5 5 1 20 35 53 5 5 1 21 35 53 5 5 1 Change in Oleic Azo methyl penetration Example Menthol Azone acid Tween-80 Urea pyrrolidone Squalane efficiency 11 C 12 B 13 B 14 A 15 1 B 16 1 B 17 1 B 18 1 C 19 1 C 20 1 C 21 1 A A = almost no change in penetration; b = slight decrease in penetration; C = significant decrease in penetration

[0114] It can be seen from the results in Table 2 that the addition of different types of transdermal enhancers basically does not improve the penetration efficiency, but hinders the penetration rate in most cases. Therefore, the present invention does not need to add any transdermal enhancer.

EXAMPLE 22

[0115] A multi-layer transdermal drug delivery system containing ibuprofen comprises a transdermal patch containing ibuprofen (referred to as a first combined layer for short) and a second combined layer. The second combined layer comprises a backing layer, a protective layer, and a polymer matrix layer located between the backing layer and the protective layer. The transdermal patch containing ibuprofen (i.e., the first combined layer) can be optionally selected from the transdermal patch containing ibuprofen in Examples 1-21.

[0116] The polymer matrix layer of the second combined layer comprises a pressure-sensitive adhesive and a pharmaceutically acceptable auxiliary material, and may also comprise active ingredients such as ibuprofen. When the polymer matrix layer of the second combined layer contains ibuprofen, the content by weight of ibuprofen is ≤15%, for example, ≤10%, ≤8%, or ≤5%.

[0117] The second combined layer can be prepared by referring to the preparation method of the transdermal patch containing ibuprofen in Example 1.

[0118] The formulations of the polymer matrix layer of a typical second combined layer (i.e., Examples 22-26) were shown in Table 3.

TABLE-US-00004 TABLE 3 (Table 3 shows the percentage by weight.) Duro-tack- Duro-tack- Duro-tack- Bio-PSA Example Ibuprofen 2074 4098 6908 7-4302 BHA 22 5 94 1 23 1 98 1 24 2 97 1 25 0 100 26 1 49 49 1

EXAMPLE 27

[0119] A schematic diagram of the structure of the transdermal patch containing ibuprofen in Example 1 is shown in FIG. 6A. A schematic diagram of the structure of the second combined layer in Example 22 is shown in FIG. 6B. The two constitute a multi-layer transdermal drug delivery system 10 containing ibuprofen.

[0120] The transdermal patch 100 containing ibuprofen and the second combined layer 200 are separate before use, and each comprises a backing layer, a protective layer, and a polymer matrix layer located between the backing layer and the protective layer.

[0121] For the transdermal patch 100 containing ibuprofen, the inner side 150 of the backing layer 110 is directly attached to one side of the polymer matrix layer 120, and the other side 140 of the backing layer 110 is exposed to the environment to protect the polymer matrix layer 120. The inner side 160 of the protective layer 130 is attached to the other side of the polymer matrix layer 120, and the polymer matrix layer 120 is located between the protective layer 130 and the backing layer 110 before use.

[0122] For the second combined layer 200, the inner side 250 of the backing layer 210 is directly attached to one side of the polymer matrix layer 220, and the other side 240 of the backing layer 210 is exposed to the environment to protect the polymer matrix layer 220. The inner side 260 of the protective layer 230 is attached to the other side of the polymer matrix layer 220, and the polymer matrix layer 220 is located between the protective layer 210 and the backing layer 230 before use.

[0123] When using, the protective layer 130 in the transdermal patch 100 containing ibuprofen is first removed, and the transdermal patch 100 is applied to the patient's skin. Then the protective layer 230 of the second combined layer 200 is removed, and the second combined layer 200 is completely covered on the first combined layer 100, so that the first combined layer 100 is completely covered by the second combined layer 200. The second combined layer is 0.5 to 1.0 cm wider than the periphery of the transdermal patch containing ibuprofen.

Experimental Example 1

Stability Experiment

[0124] The patches of Comparative Example 1 and Example 1 were stored under the same storage conditions (30±2° C., 60%±10% RH), and observed regularly by an electron microscope. The observation results were shown in FIG. 1.

[0125] The results of continuous observation showed that in the absence of amino compounds, the active ingredient was precipitated from the polymer matrix in the first week, and obvious crystals could be observed. In Example 1, there was no change during the twelve-month observation period, ibuprofen was uniformly dispersed in the adhesive matrix, no crystals were found under different magnifications of an optical microscope, and no crystallization phenomenon was observed, indicating that the patch had good stability.

Experimental Example 2

In Vitro Release Experiment

[0126] In vitro release is a basic performance index of the patch, which reflects the interaction between the active ingredient and other components in the polymer matrix. The overall properties of the polymer matrix, the interactions between ibuprofen and the polymer and other components, such as hydrogen bonds, ion pairs, and van der Waals forces, lead to different flow behaviors of ibuprofen in the polymer matrix. In vitro release is the basis of transdermal absorption, and only suitable release capacity can meet the specific requirements of transdermal absorption.

[0127] A release test (Chinese Pharmacopoeia, 2015 edition, Volume IV, general principle 0931, Fourth method-paddle over disk) was used to operate with PBS as a dissolution medium, at a temperature of 32° C. and 50 revolutions/min, and a sample of 10 ml was taken at 0.3 h, 0.5 h, 0.7 h, 1.0 h, 1.5 h, 2.0 h, 3.0 h, 6.0 h, 9.0 h, 12.0 h, 18.0 h and 24.0 h, respectively, and filtered. In addition, an appropriate amount of ibuprofen reference substance was accurately weighed and dissolved with the dissolution medium, to prepare a solution of appropriate concentration as a reference solution.

[0128] With octadecyl silane bonded silica gel as a filler, a methanol-phosphate aqueous solution (40 mmol/L potassium dihydrogen phosphate aqueous solution, phosphoric acid was used to adjust pH to 2.50) (77:23) as a mobile phase, a detection wavelength of 225 nm, a column temperature of 50° C., and the number of theoretical plates not less than 2,000 calculated by ibuprofen, determination was performed according to HPLC method (Chinese Pharmacopoeia, 2015 edition, Volume IV, general principle 0512).

[0129] The results were shown in FIG. 2. The results show that Examples 1, 2, 4, and 5 all have relatively fast release behavior, and the release is basically complete in the first 2 hours. The release behavior fully meets the requirements of transdermal absorption and will not hinder the overall transdermal absorption behavior.

Experimental Example 3

In Vitro Transdermal Experiment

[0130] The in vitro transdermal experiment was measured by a Franz vertical diffusion cell. The cuticle of the skin of the healthy adult pig ear was obtained according to the standard heat separation method. The receiving solution was a PBS solution with a pH of 7.4, the receiving cell had a volume of 7 mL, the temperature was set at 32±0.1° C., and the stirring speed was 300 revolutions/minute. Samples were taken at 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h and 24 h, respectively, each sample was of a volume of 3 mL, and then an isothermal blank receiving solution was added. Each group of samples were subjected to parallel experiment for 6 times, and meanwhile, a placebo parallel experiment was used as a control. The cumulative penetration amount at each time point was calculated based on the results.

[0131] The results were shown in FIG. 3. The results show that within the 24-hour experimental range, the patch of the present invention can regulate the release rate and the total release amount, so as to deliver an amount of ibuprofen with therapeutic effect according to the need of use.

Experimental Example 4

Human Blood Drug Concentration Experiment in Healthy Volunteers

[0132] Twelve healthy adult males, aged 24.6±2.5 (22 to 30) years old, and weighing 61.2±2.8 (58 to 65) kg were selected. The subjects had no history of drug allergy and had not used any drugs in the past two weeks. During the experiment, other drugs were forbidden, and the diet was uniform during the test period. Fenbid® was selected as the control drug (400 mg/ibuprofen sustained-release capsule, batch number: 17090198), and the subject took one capsule orally. The transdermal patches of Examples 3 and 6 were selected, and applied to the lower part of the abdomen of each subject. The 12 subjects were randomly divided into three groups, with 4 people in each group. Fenbid® was taken orally in the first group, the transdermal patch of Example 3 was applied in the second group, and the transdermal patch of Example 6 was applied in the third group.

[0133] Blood sampling method: blood was taken from upper limb vein at 0 h, 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 6 h, 9 h, and 12 h, respectively, with a blood volume of 5 mL each time.

[0134] Detection method: HPLC method; chromatographic conditions:

[0135] Chromatographic column: C18; 150*4.6 mm; 5μm; mobile phase: 5.4 g/L potassium dihydrogen phosphate aqueous solution (pH=2.50, adjusted by phosphoric acid): methanol=30:70; column temperature: 50° C.; flow rate: 1.0 mL/min; detection wavelength: 225 nm; injection volume: 20 μl; elution mode: equal concentration elution; and injection mode: automatic injection.

[0136] Sample processing method: protein precipitation method (0.2 ml of serum was added to 0.2 ml of acetonitrile, vortexing was performed to mix evenly, centrifugation was performed at 10,000 r/min for 15 min, and the supernatant was taken).

[0137] The specific results were shown in FIG. 4. The results show that compared with Fenbid® sustained-release capsules, the patch of the present invention can continuously increase the blood drug concentration within 8 hours, and then the blood drug concentration will steadily decrease in the following 4 hours, achieving a stable clinical effect for 12 hours. Meanwhile, the blood drug concentration can continue to increase within 15 hours, and then decrease steadily in the following 8 hours, achieving a stable clinical effect for 24 hours. Therefore, the patch of the present invention can deliver a therapeutically effective dose of ibuprofen within 12 to 24 hours according to the requirements of the therapeutic effect.

Experimental Example 5

Fever Inducing-Fever Reducing Experiment in Rats

[0138] Animals: Wistar rats, males, weighing 300 g±20 g, were divided into 5 groups (four rats in each group). One group was subjected to the application of the patch of Example 1, three groups were used to receive different doses of Merlin™ (5 mg, 10 mg and 20 mg, respectively) by gavage, and one group was used as a blank control after fever inducing.

[0139] Fever inducing method: subcutaneous injection of dry yeast solution at the back of the neck (4 ml of 30% dry yeast solution per 300 g was injected).

[0140] Temperature measurement method: 3 cm depth of the anus, electronic thermometer, the average value of two parallel measurements was taken (the deviation of the two measurement results was no more than ±0.1° C.).

[0141] Shaving method: After anesthesia, most of the hair was removed with an electric shaver, and then the rats was evenly applied with a depilatory cream, and rinsed with water after 3 minutes.

[0142] Mode of administration:

[0143] In the patch group, the patch of Example 1 was applied to the abdomen of the rat and fixed with gauze.

TABLE-US-00005 Information about Example 1 Patch area 15 cm.sup.2 Active ingredient content % 35 Drug loading mg/cm.sup.2 2.6

[0144] In the oral group, each group of animals were given 5 mg, 10 mg, and 20 mg of Merlin™ (Johnson & Johnson, concentration of 20 mg/ml; production batch number: 171101428) by gavage.

[0145] The specific results were shown in FIG. 5. The results show that, compared with the relatively short antipyretic effect of oral Merlin™, the patch of the present invention has a stable antipyretic effect for a long time, and the antipyretic effect is stable with a long duration.

Experimental Example 6

Application Experiment

[0146] Healthy adult subjects were selected, the application site was on the inner side of the upper arm, and the residues on skin and cold flow phenomenon were investigated.

[0147] The experimental grouping was as follows:

[0148] 1) The transdermal patches containing ibuprofen of Examples 2, 4, and 6 were used separately. Method was as follows: firstly, the protective layer was removed, and then the patch was applied to the inner side of the volunteer's upper arm.

[0149] 2) The second combined layer (the matrix formulation was the same as that of Example 22) was used separately. Method was as follows: firstly, the protective layer was removed, and then the second combined layer was applied to the inner side of the volunteer's upper arm.

[0150] 3) A multi-layer transdermal drug delivery system containing ibuprofen was used: the transdermal patches containing ibuprofen of Examples 2, 4, and 6 were respectively used as the first combined layer, in combination with the second combined layer (the matrix formulation was the same as that of Example 22). Combination use method was as follows: the protective layer of the second combined layer was removed, the second combined layer was applied to the backing layer of the transdermal patches of Examples 2, 4, and 6 as the first combined layers, respectively, and then the protective layer of the transdermal patch was removed to apply the transdermal patch to the inner side of the upper arm.

[0151] In the above groups, the patches were removed at 4 h, 8 h, 12 h and 24 h, respectively, and the residual and the degree of cold flow at the application site were observed. The observation results were shown in Table 4.

TABLE-US-00006 TABLE 4 Application time: Application time: Application time: Application time: 4 h 8 h 12 h 24 h Cold Cold Cold Cold Application Residual flow Residual flow Residual flow Residual flow Example site degree degree degree degree degree degree degree degree 2 Inner side of C C C B C B C B upper arm 4 Inner side of C C C B C A C A upper arm 6 Inner side of C B B B B A B A upper arm 22 Inner side of C C C C C C C C upper arm Combination Inner side of C C C C C C C C 2 + 22 upper arm Combination Inner side of C C C C C C C C 4 + 22 upper arm Combination Inner side of C C C C C C C B 6 + 22 upper arm A = obvious; B = slight; C = none

[0152] From the observation results, it can be seen that the patch of the present invention basically has no residues. In the absence of the second combined layer, an obvious cold flow phenomenon was observed, as shown in Example 4 and Example 6, but in the case of using the combination, the cold flow phenomenon was eliminated.

[0153] The above relevant experiments were carried out using ibuprofen as the active ingredient. Due to the similar structures, properties and functions, a person skilled in the art can foresee the structural analogues of ibuprofen: naproxen, fenoprofen, ketoprofen, flurbiprofen, and loxoprofen, can also achieve basically the same functions and achieve basically the same technical correlations. Due to space limitations, the relevant experiments could not be listed.

[0154] Although the present invention has been described in detail above with general descriptions and specific embodiments, some modifications or improvements can be made on the basis of the present invention, which is obvious to a person skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention belong to the scope of the present invention.

INDUSTRIAL APPLICABILITY

[0155] The present invention provides a multi-layer transdermal drug delivery system containing ibuprofen or a structural analogue thereof. The multi-layer transdermal drug delivery system comprises a transdermal patch containing ibuprofen or a structural analogue thereof and a second combined layer. The transdermal patch comprises a polymer matrix layer comprising an active ingredient, a compound containing at least one amino group, and a pressure-sensitive adhesive. All or part of the active ingredient-amino compound salts and all or part of free active ingredient formed in the polymer matrix layer are kept in a uniform dissolution state in the polymer matrix, and can be stably stored before use, without recrystallization. The present invention also provides the preparation method and the use method of the transdermal drug delivery system. The transdermal drug delivery system of the present invention can continuously and controllably deliver a therapeutically effective dose of ibuprofen or its structural analogue in the range of 12 to 24 hours without a transdermal enhancer. The transdermal drug delivery system of the present invention has excellent wearability, avoids a cold flow phenomenon, and has good economic value and application prospects.