A high permeability transdermal delivery system and its preparation method and use

Abstract

The application discloses a high-transmittance transdermal drug delivery system and a preparation method and application thereof. The transdermal drug delivery system comprises a backing layer, a drug-containing matrix layer and a release layer; wherein the drug-containing matrix layer comprises an active ingredient, pressure-sensitive adhesive and a high-molecular compound. The active ingredient (ambroxol or a pharmaceutically acceptable salt thereof) has high compatibility with the pressure-sensitive adhesive, which can not only improve the transmittance of the active ingredient, but also promote the release of the active ingredient. The high-molecular compound is further added in the application, which can ensure the transmittance of the active ingredient, prevent the active ingredient from crystallizing and further improve the stability and bioavailability of the active ingredient. Moreover, the high-molecular compound can further improve the adhesion of the product.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a transdermal drug delivery system with high permeability, its preparation method, and its uses. Background Technology

[0002] Transdermal drug delivery is a novel route of administration that allows drugs to be absorbed through the skin into the bloodstream, achieving effective blood drug concentrations for disease treatment or prevention. Generally, compared to oral administration, transdermal delivery offers the advantage of maintaining a more continuous blood drug concentration and avoiding the first-pass effect of the liver. Furthermore, transdermal absorption is unaffected by food intake. Based on these characteristics, transdermal drug delivery has become the third major drug delivery system after oral and injectable administration.

[0003] Transdermal drug delivery systems require sufficient drug to penetrate the skin to exert their activity. Therefore, the permeability of the drug itself must be considered when developing transdermal drug delivery systems, or the addition of penetration enhancers to promote drug penetration. However, the effects of additives can vary significantly depending on the type of drug, making the development of transdermal drug delivery systems extremely challenging.

[0004] Ambroxol is currently the most commonly used expectorant. Domestically available ambroxol formulations mainly include oral solutions, tablets, capsules, inhalers, injections, and lyophilized powder for injection. Oral administration can be accompanied by gastrointestinal adverse reactions such as nausea, vomiting, and indigestion. Injection offers rapid onset of action but is inconvenient for clinical use and causes some discomfort to patients. Lung administration can bypass the first-pass effect of the liver, increasing bioavailability; however, due to the complex anatomy of the respiratory system, inhaled administration involves a complex combination of drug and device administration, and also carries risks of high drug exposure and prolonged drug retention, as well as poor patient compliance. Given the shortcomings of these various dosage forms, developing a new dosage form is essential.

[0005] Patent CN1950076A discloses a pharmaceutical composition of ambroxol and its pharmacologically acceptable salts that can be directly applied to the skin and / or mucous membranes. Examples 5 and 6 disclose a mucosal adhesive ointment formulation, but the patent does not disclose its specific effects. Through research on its formulation, it was found that its transdermal penetration rate is poor and it is difficult to exert its efficacy.

[0006] In conclusion, given the current lack of transdermal formulations of ambroxol and its salts, it is essential to develop a transdermal formulation of ambroxol with good transdermal efficacy. Summary of the Invention

[0007] The purpose of this invention is to provide a transdermal drug delivery system in which the active ingredient is ambroxol or a pharmaceutically acceptable salt thereof; this transdermal drug delivery system has the advantage of good transdermal permeability and can achieve bioequivalence with oral formulations, thereby improving drug compliance.

[0008] One object of the present invention is to provide a matrix-type transdermal drug delivery system that can continuously deliver ambroxol or a pharmaceutically acceptable salt thereof at a therapeutically effective blood concentration over an extended period of time.

[0009] In a first aspect, the present invention provides a transdermal drug delivery system with high permeability, comprising:

[0010] 1) Backing layer;

[0011] 2) A drug-containing matrix layer comprising an active ingredient, a pressure-sensitive adhesive, and a polymeric compound dispersed in the matrix layer in an amorphous state, wherein the active ingredient is ambroxol or a pharmaceutically acceptable salt thereof;

[0012] And 3) Peeling layer.

[0013] In a further embodiment, the amount of the active ingredient is 3-15% relative to the total weight of the drug-containing matrix layer.

[0014] This invention employs a pressure-sensitive adhesive as the drug-carrying matrix. The pressure-sensitive adhesive is selected from one or more combinations of silicone pressure-sensitive adhesives and styrene-isoprene-styrene block copolymer (SIS) hot-melt pressure-sensitive adhesives. Silicone pressure-sensitive adhesives or styrene-isoprene-styrene block copolymer (SIS) hot-melt pressure-sensitive adhesives have high compatibility with the active ingredient ambroxol, ensuring not only the transdermal permeability of the active ingredient but also promoting its release.

[0015] In a further embodiment, the pressure-sensitive adhesive is a mixture containing silicone pressure-sensitive adhesive and styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive.

[0016] In a further embodiment, the amount of pressure-sensitive adhesive is 55-94% relative to the total weight of the drug-containing matrix layer; preferably 70-85%.

[0017] In a further embodiment, the silicone pressure-sensitive adhesive is formed by the condensation reaction of polydimethylsiloxane (PDMS) and MQ resin with silanol groups; preferably, the weight ratio of polymer to resin in the silicone pressure-sensitive adhesive is about 35:65 (w / w) to 45:55 (w / w); more preferably, Liveo... TM BIO-PSA type silicone pressure-sensitive adhesive.

[0018] In a further embodiment, the pressure-sensitive adhesive is selected from silicone pressure-sensitive adhesives, which are formed by the condensation reaction of polydimethylsiloxane (PDMS) and MQ resin with silanol groups.

[0019] In a further embodiment, the weight ratio of polydimethylsiloxane (PDMS) to MQ resin in the silicone pressure-sensitive adhesive is approximately 35:65 (w / w) to 45:55 (w / w).

[0020] In a further embodiment, the silicone pressure-sensitive adhesive is Liveo. TM BIO-PSA type silicone pressure-sensitive adhesive.

[0021] In a further implementation, the Liveo TM BIO-PSA type silicone pressure-sensitive adhesives are one or more of the following models: 7-4302, 7-4301, 7-4101, 7-4102, 7-4201, 7-4202, 7-4401, 7-4402, 7-4501, 7-4502, 7-4601, and 7-4602.

[0022] In this invention, a polymer compound is added to the transdermal drug delivery system. This compound has better compatibility with the pressure-sensitive adhesive and the active ingredient, allowing the active ingredient to be uniformly dispersed in the pressure-sensitive adhesive matrix. This prevents the active ingredient from crystallizing while essentially not affecting its transdermal permeability, thereby ensuring the bioavailability of the drug formulation. Furthermore, the addition of the polymer compound can further synergistically improve the adhesion performance of the transdermal drug delivery system.

[0023] In a further embodiment, the polymer compound is selected from one or more of the following:

[0024] 1) Resins, preferably hydrogenated rosin resin or aminoalkyl methacrylate copolymer E100;

[0025] 2) Polyvinylpyrrolidone or copolymers containing polyvinylpyrrolidone;

[0026] 3) Cellulose, preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose and ethyl cellulose.

[0027] In a further embodiment, the polymer compound is preferably polyvinylpyrrolidone, and the molecular weight of polyvinylpyrrolidone is 2,000 to 1,500,000.

[0028] In a further embodiment, the amount of the polymer compound is 3 to 30% relative to the total weight of the drug-containing matrix layer.

[0029] In a further embodiment, the present invention provides a transdermal drug delivery system containing ambroxol or a pharmaceutically acceptable salt thereof, comprising the following components relative to the total weight of the drug-containing matrix layer:

[0030] 1) Active ingredient 3-15%;

[0031] 2) Pressure-sensitive adhesive 55-94%;

[0032] 3) Polymer compounds 3-30%.

[0033] In a further embodiment, the transdermal drug delivery system comprises the following components relative to the total weight of the drug-containing matrix layer:

[0034] 1) Active ingredient 3-15%;

[0035] 2) Pressure-sensitive adhesive 55-94%;

[0036] 3) 3-30% polymeric compounds;

[0037] The pressure-sensitive adhesive is selected from one or more combinations of silicone pressure-sensitive adhesive and styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive.

[0038] In a further embodiment, when the pressure-sensitive adhesive is a styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive, it includes styrene-isoprene-styrene block copolymer (SIS), tackifiers, and softeners, wherein the tackifiers include, but are not limited to, polybutene, polyisobutene, petroleum resin, hydrogenated rosin glycerol ester, rosin resin, alicyclic saturated or hydrocarbon resins; and the softeners include, but are not limited to, liquid paraffin, olive oil, peanut oil, or polyethylene glycol.

[0039] In a further embodiment, when the pressure-sensitive adhesive is a styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive, the content of the styrene-isoprene-styrene block copolymer (SIS) is 10-60%, preferably 15-40%, relative to the total weight of the SIS hot melt pressure-sensitive adhesive; the content of the tackifier is 5-50%, preferably 10-40%; and the content of the softener is 15-60%, preferably 20-50%.

[0040] As a styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive, for example, the following can be listed: relative to the total weight of the SIS hot melt pressure-sensitive adhesive, wherein styrene-isoprene-styrene block copolymer (SIS) 35%, hydrogenated rosin glycerol ester 30%, and liquid paraffin 35%.

[0041] In a further embodiment, the transdermal drug delivery system is packaged in a packaging container, the air in which is replaced by an inert gas, preferably nitrogen.

[0042] In a further embodiment, the transdermal drug delivery system has a drug-containing matrix layer coating weight of 30.0 g / m³. 2 Up to 150.0 g / m 2 50.0g / m 2 Up to 100.0g / m 2 .

[0043] In a further embodiment, the active ingredient is delivered daily in doses of about 10 mg to about 100 mg to the circulatory system of the subject, preferably about 10 mg to about 50 mg to the circulatory system of the subject.

[0044] In another aspect, a method for preparing the transdermal drug delivery system described above is provided, comprising:

[0045] S1: Stir and dissolve the active ingredient and solvent evenly to obtain an API solution; stir the polymer compound and solvent evenly to obtain a polymer compound solution, combine the solutions, and stir evenly.

[0046] S2: Add the mixed solution from step S1 to the pressure-sensitive adhesive and mix thoroughly to obtain a mixture;

[0047] S3: Coat the mixture obtained in step S2 onto the release film, dry it, and then press the backing layer; after pressing the backing film, cut it into the set shape and size to obtain the final product.

[0048] In a further embodiment, in step S1, the solvent is a pyrrolidone, alcohol, polyol, ether, amine, or amide; preferably one or more of ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, and diethylene glycol monoethyl ether.

[0049] In another aspect, the use of the transdermal drug delivery system in the preparation of a medicament for treating respiratory diseases is provided in a therapeutically effective amount.

[0050] In a further implementation, the respiratory diseases include acute and chronic bronchitis, bronchial asthma, bronchiectasis, emphysema, tuberculosis, pneumoconiosis, postoperative difficulty in expectoration, intraoperative pulmonary complications, pulmonary fibrosis caused by chemotherapy or radiotherapy for lung tumors, silicosis, and lung damage caused by other etiologies.

[0051] In a further embodiment, the ambroxol or its pharmaceutically acceptable salt transdermal delivery system is administered once every 12 hours and 24 hours.

[0052] In a further embodiment, the transdermal drug delivery system delivers 10 mg to about 100 mg of the active ingredient to the subject's circulatory system daily, preferably about 10 mg to about 50 mg of the active ingredient to the subject's circulatory system.

[0053] The beneficial effects of this invention are:

[0054] 1) The active pharmaceutical ingredient (ambroxol or its pharmaceutically acceptable salt) of the present invention has high compatibility with pressure-sensitive adhesive, which can not only improve the permeability of the active ingredient, but also promote the release of the active ingredient.

[0055] 2) The present invention incorporates a polymer compound, which, while ensuring the permeability of the active ingredient, prevents the active ingredient from crystallizing, thereby further improving the stability and bioavailability of the active ingredient; moreover, the addition of the polymer compound in the present invention can further enhance the adhesion performance of the product.

[0056] 3) The transdermal drug delivery system containing ambroxol provided in this invention fills the current technological gap in the field of ambroxol preparations in the patch field, and helps to further promote the application of ambroxol drugs.

[0057] 4) A comparison of pharmacokinetic parameters between the transdermal drug delivery system of ambroxol or its pharmaceutically acceptable salts and the corresponding oral solution in this invention demonstrates that the transdermal patch has a higher systemic exposure than the oral solution, indicating that preparing ambroxol into a transdermal drug delivery formulation can replace traditional oral and injectable formulations. Therefore, developing ambroxol into a transdermal patch will solve problems such as the first-pass effect and gastrointestinal inactivation that may occur with oral administration, the peak-and-trough phenomenon in blood drug concentration caused by injection, the high toxicity and side effects, the inconvenience of pulmonary administration, poor patient compliance, and potential stimulation of the cough reflex. Furthermore, the patch formulation allows for continuous control of the administration rate and flexible dosing (which can be interrupted at any time), making it particularly suitable for infants, the elderly, and patients who have difficulty taking oral medications. Therefore, the development of transdermal patches of ambroxol or its pharmaceutically acceptable salts in this invention has significant clinical value and broad application prospects. Attached Figure Description

[0058] Figure 1 A schematic diagram of the three-layer matrix type transdermal drug delivery system described in this invention is shown.

[0059] Figure 2 The skin flux measurement curves of the transdermal drug delivery systems described in Examples 1-8 are shown.

[0060] Figure 3 The skin flux measurement curves of the transdermal drug delivery systems described in Examples 9-13 and Comparative Example 1 are shown.

[0061] Figure 4The skin flux measurement curves of the transdermal drug delivery systems described in Examples 14-16 are shown. Detailed Implementation

[0062] definition

[0063] As used herein, the term “pharmaceutically acceptable salt” means that salts are suitable for exposure to subjects (e.g., human subjects) without excessive toxicity, irritation, allergic reactions, etc., within the bounds of reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0064] The "pharmaceutically acceptable salts" described in this invention include inorganic acid addition salts and organic acid addition salts, which can be prepared in situ during the final separation and purification of the compound, or prepared by reacting a purified compound (e.g., ambroxol and its pharmaceutically acceptable salts) in free base form with a suitable organic or inorganic acid and then separating the resulting salt. Examples of inorganic acid addition salts include, but are not limited to, sulfates, hydrochlorides, nitrates, hydrobromides, phosphates, etc. Examples of organic acid addition salts include saturated or unsaturated C1 to C2 salts. 30 Fatty acid salts, including but not limited to monocarboxylic acid salts or dicarboxylic acid salts. Non-limiting examples include formates, acetates, acrylates, maleates, tartrates, citrates, and combinations thereof.

[0065] As used herein, the term “therapeutic effective amount” means an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents a particular disease, condition or disorder, (ii) reduces, improves or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein.

[0066] As used herein, the term “about” refers to plus or minus 10% of the indicated number. For example, “about 10%” could mean a range of 9% to 11%, and “about 1” could mean 0.9 to 1.1.

[0067] As used herein, the term “treatment” refers to a clinical intervention that attempts to alter the natural course of the disease in the individual being treated, and may be for prevention or in the course of clinicopathology. The desired effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the disease state, and mitigating or improving prognosis.

[0068] As used herein, the term "drug-containing matrix layer" includes ambroxol and its pharmaceutically acceptable salts, pressure-sensitive adhesives, and polymers.

[0069] In addition, the drug-containing matrix layer may also contain one or more other pharmaceutically acceptable additives. Non-limiting examples of additives include penetration enhancers, antioxidants, fillers, anti-skin irritants, cohesion promoters, plasticizers, thickeners, etc.

[0070] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are one module embodiment of the present invention, not all embodiments. Elements and features described in one embodiment of the present invention can be combined with elements and features shown in one or more other embodiments. It should be noted that, for clarity, representations and descriptions of components and processes unrelated to the present invention and known to those skilled in the art are omitted in the description. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0071] The structural formula of ambroxol in this invention is shown below.

[0072]

[0073] The "organosilicon pressure-sensitive adhesive" described in this invention is a compound with a siloxane backbone.

[0074] As an organosilicon pressure-sensitive adhesive, for example, polydimethylsiloxane (PDMS) and MQ resin can be produced by silanol condensation reaction.

[0075] As an organosilicon pressure-sensitive adhesive, Liveo can be cited as an example. TM BIO-PSA type silicone pressure-sensitive adhesive, with one or more of the following models: 7-4302, 7-4301, 7-4101, 7-4102, 7-4201, 7-4202, 7-4401, 7-4402, 7-4501, 7-4502, 7-4601, and 7-4602.

[0076] As an example of an organosilicone pressure-sensitive adhesive, the weight ratio of polydimethylsiloxane (PDMS) to MQ resin in such an adhesive is approximately 35:65 (w / w) to 45:55 (w / w).

[0077] As an organosilicon pressure-sensitive adhesive, Liveo can be cited as an example. TMThe weight ratio of polymer to resin in BIO-PSA type silicone pressure-sensitive adhesives includes, but is not limited to, BIO-PSA 7-4301, BIO-PSA 7-4302, BIO-PSA 7-4601, or BIO-PSA 7-4602, for example, a PDMS polymer:MQ resin (w / w) ratio of 45:55; PDMS polymer:MQ resin (w / w) ratio of 40:60, for example, BIO-PSA 7-4201, BIO-PSA 7-4202, BIO-PSA 7-4501, or BIO-PSA 7-4502; and PDMS polymer:MQ resin (w / w) ratio of 35:65, for example, BIO-PSA 7-4101, BIO-PSA 7-4102, BIO-PSA 7-4401, or BIO-PSA 7-4402.

[0078] The organosilicon pressure-sensitive adhesive (Liveo) described in this invention TM BIO-PSA is typically a wet adhesive with a certain siloxane solid content (e.g., BIO-PSA 7-4301 has a solid content of 72%). Therefore, the weight of the silicone pressure-sensitive adhesive matrix is ​​calculated based on its solid content. (Silicone pressure-sensitive adhesive Liveo) TM BIO-PSA was purchased from DuPont in the United States.

[0079] In this invention, the pressure-sensitive adhesive is selected from one or more combinations of organosilicon pressure-sensitive adhesives and styrene-isoprene-styrene block copolymer hot melt pressure-sensitive adhesives.

[0080] As a styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive, the styrene-isoprene-styrene (SIS) content is 10-60%, preferably 15-40%, relative to the total weight of the SIS hot melt pressure-sensitive adhesive; the tackifier content is 5-50%, preferably 10-40%; and the softener content is 15-60%, preferably 20-50%.

[0081] As a styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive, for example, it can be listed that, relative to the total weight of the SIS hot melt pressure-sensitive adhesive, styrene-isoprene-styrene block copolymer (SIS) 35%, hydrogenated rosin glycerol ester 30%, and liquid paraffin 35%.

[0082] The ambroxol hydrochloride oral solution used in the pharmacokinetic experiments of this invention was manufactured by Delpharm Reims.

[0083] The organosilicon pressure-sensitive adhesive (Liveo) used in this invention TMBIO-PSA is typically a wet adhesive with a certain solid content of siloxane (e.g., BIO-PSA 7-4301 has a solid content of 72%). Therefore, the weight of the silicone pressure-sensitive adhesive matrix is ​​calculated based on the weight of its solid content.

[0084] The detection method involved in this invention is as follows:

[0085] In vitro transdermal assay: The 24-hour in vitro transdermal diffusion assay was performed using a fully automated transdermal diffusion system on the skin of healthy miniature pigs. The receiving solution was PBS solution with a pH of 7.4. The temperature was set at 32±0.1℃, and the rotation speed was 600 rpm. Samples were taken at 6, 12, and 24 hours. Each sample group was replicated in six parts.

[0086] Crystallization detection: visual inspection.

[0087] Adhesion performance test:

[0088] 1) Adhesion: The adhesion was determined using the third method in the General Chapter 0952 of the Chinese Pharmacopoeia.

[0089] 2) Adhesion: The adhesion was determined using the second method in the General Chapter 0952 of the Chinese Pharmacopoeia.

[0090] Pharmacokinetic Study: Twelve rabbits, weighing 1.5–1.7 kg (half male and half female), were divided into two groups. The transdermal administration group received 30 mg / rabbit of transdermal patch once daily, while the gavage administration group received 4.5 mg / rabbit of ambroxol hydrochloride oral solution. The transdermal administration group received 30 mg / pattern of ambroxol transdermal patch once daily. Rabbits with intact dorsal skin were selected for the experiment. Before administration, the treatment area (back) was shaved and cleaned, with the shaved area not less than the treatment area. During administration, the test drug was applied to the treatment area (back), ensuring full contact between the drug and the administration site, and secured with breathable medical adhesive tape. The drug was removed 24 hours after administration. Administration was performed three times daily via gavage. Blood collection time points for the percutaneous drug administration group were set as follows: 0h before administration, 4h, 8h, 12h, 16h, 20h, 24h, 28h, 32h, 36h, 48h, and 72h after administration. Blood collection time points for the gavage drug administration group were set as follows: 0h before administration, 0.25h, 0.5h, 1h, 4h, 8h (before the second administration), 8.5h, 9.5h, 12h, 16h (before the third administration), 16.5h, 17.5h, 24h, 48h, and 72h after administration. Approximately 0.5mL of blood was collected from the middle auricular artery, centrifuged at 2480g for 5min at 4℃ to separate plasma, and plasma drug concentration was determined by LC-MS / MS. Concentration values ​​below the analyte quantitation limit (BQL) were considered zero before reaching the peak Cmax and below the BQL after reaching the peak. Phoenixwinnonlin 8.0 software was used to calculate pharmacokinetic parameters.

[0091] Examples 1-8

[0092] As shown in Table 1 of Examples 1-8,

[0093] Table 1. Components and weight percentages of Examples 1-8

[0094]

[0095]

[0096] Note: In Examples 7 and 8, the styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive, relative to the total weight of the SIS hot melt pressure-sensitive adhesive, contains 35% styrene-isoprene-styrene block copolymer (SIS), 30% hydrogenated rosin glycerol ester, and 35% liquid paraffin.

[0097] The specific preparation method is as follows:

[0098] S1: Stir and dissolve the active ingredient and solvent evenly to obtain an API solution; stir polyvinylpyrrolidone and solvent evenly to obtain a polyvinylpyrrolidone solution, combine the solutions, and stir evenly.

[0099] S2: Add the mixed solution from step S1 to the pressure-sensitive adhesive, stir evenly, and degas to obtain the adhesive mixture.

[0100] S3: Apply the adhesive mixture from step S2 onto the release film, dry it at 40℃-80℃ for more than 10 minutes, and then cover it with a backing film; after the film is covered, cut it into a certain shape and size to obtain the ambroxol transdermal patch.

[0101] The in vitro transdermal and crystallization properties of the ambroxol transdermal patches prepared in Examples 1-8 were tested, and the results are shown in Tables 2-3 and 3. Figure 2 .

[0102] Table 2. Cumulative transmittance per unit area for Examples 1-8

[0103]

[0104] Table 3. Investigation of crystallization in Examples 1-8

[0105]

[0106] Based on the test data in this embodiment, the ambroxol patches prepared using pressure-sensitive adhesives in Examples 1-8 all exhibit good permeability and can effectively promote the in vitro permeation of the active ingredient. In particular, among Examples 1-4, the ambroxol patches using silicone pressure-sensitive adhesives models 7-4201, 7-4202, 7-4301, and 7-4302 showed the best in vitro permeation.

[0107] Examples 9-13

[0108] Prescriptions 9-13 in this embodiment and Comparative Example 1 are shown in Table 4.

[0109] Table 4. Components and weight percentages of Examples 9-13 and Comparative Example 1

[0110]

[0111] The specific preparation method is as follows:

[0112] S1: Stir and dissolve the active ingredients and solvent evenly to obtain solution 1; add the polymer compounds (polyvinylpyrrolidone, hydroxypropyl cellulose, hydrogenated rosin glycerol ester, aminoalkyl methacrylate copolymer E100 and copolyvinylpyrrolidone) to the solvent, stir and dissolve to obtain solution 2.

[0113] S2: Mix solution 1 and solution 2 evenly, add them to the silicone pressure-sensitive adhesive, stir evenly, degas, and the adhesive mixture is obtained.

[0114] S3: Apply the adhesive mixture from step S2 onto the release film, dry it at 40℃-80℃ for more than 10 minutes, and then cover it with a backing film; after the film is covered, cut it into a certain shape and size to obtain the ambroxol transdermal patch.

[0115] The in vitro transdermal, crystallization, and adhesion properties of the ambroxol transdermal patches prepared in Examples 9-13 and Comparative Example 1 were tested, and the results are shown in Tables 5-7. Figure 3 .

[0116] Table 5. Cumulative transmittance per unit area for Examples 9-13 and Comparative Example 1.

[0117]

[0118] Table 6 shows the crystallization conditions of Examples 9-13 and Comparative Example 1.

[0119]

[0120] Table 7 examines the adhesion test results of Examples 9-13 and Comparative Example 1.

[0121] Example Adhesion force (N) Holding power (min) Example 9 13.9 30 Example 10 15.2 33 Example 11 15.5 35 Example 12 14.8 31 Example 13 15.0 32 Comparative Example 1 10.2 23

[0122] Based on the test data in this embodiment, Comparative Example 1, without the addition of a polymer compound, exhibited crystallization after being placed at 30°C for one month. This crystallization affects the stability of the patch. In Examples 9-13, the addition of a polymer compound did not result in crystallization, indicating better stability. The adhesiveness of Comparative Example 1, without the addition of a polymer compound, was also lower than that of Examples 9-13, suggesting that the addition of a polymer compound can further improve the adhesive performance of the ambroxol patch without affecting its penetration performance.

[0123] Examples 14-16

[0124] See Table 8 for examples 14-16.

[0125] Table 8. Components and weight percentages of Examples 14-16

[0126]

[0127] The preparation method is the same as in Example 12.

[0128] The in vitro transdermal, crystallization, and adhesion properties of the ambroxol transdermal patches prepared in Examples 14-16 were tested, and the results are shown in Tables 9-11 and 16. Figure 4 .

[0129] Table 9. Cumulative transmittance per unit area for Examples 14-16

[0130]

[0131] Table 10. Crystallization observation of Examples 14-16

[0132]

[0133] Table 11: Adhesion test results of Examples 14-16

[0134] Example Adhesion force (N) Holding power (min) Example 14 10.7 26 Example 15 15.2 36 Example 16 18.5 41

[0135] Based on the test data in this embodiment, when the API content is between 3.0% and 15%, the polymer compounds all have a good effect on inhibiting crystal formation and have no significant impact on the permeability. In summary, the ambroxol patches prepared in Examples 14 to 16 all have good comprehensive performance.

[0136] Example 17

[0137] The patch prepared in Example 15 was subjected to pharmacokinetic experiments with ambroxol hydrochloride oral solution, and the results are shown in Table 12:

[0138] Table 12 Pharmacokinetic Experiment Data Results

[0139]

[0140] In female experimental rabbits, after transdermal administration of 30 mg / rabbit of ambroxol transdermal patch and oral gavage administration of 4.5 mg / rabbit of ambroxol hydrochloride oral solution, compared with the gavage group, the transdermal group had a faster time to peak concentration, a shorter mean residence time (MRTt), and a much higher in vivo exposure than the gavage group, with an exposure ratio of 1.0:0.05.

[0141] In male experimental rabbits, after transdermal administration of 30 mg / rabbit of ambroxol transdermal patch and oral gavage administration of 4.5 mg / rabbit of ambroxol hydrochloride oral solution, compared with the gavage group, the transdermal group had a faster time to peak concentration, a similar half-life (t1 / 2), a shorter mean residence time (MRTt), and a much higher in vivo exposure than the gavage group, with an exposure ratio of 1.0:0.02.

[0142] In summary, under the conditions of this experiment, after rabbits were administered 30 mg / rabbit of ambroxol transdermal patch via dermal administration and 4.5 mg / rabbit of ambroxol hydrochloride oral solution via oral gavage, the in vivo exposure in the transdermal administration group was much higher than that in the gavage administration group.

Claims

1. A transdermal drug delivery system with high permeability, comprising: 1) Backing layer; 2) A drug-containing matrix layer comprising an active ingredient, a pressure-sensitive adhesive, and a polymeric compound dispersed in the matrix layer in an amorphous state, wherein the active ingredient is ambroxol or a pharmaceutically acceptable salt thereof; And 3) Peeling layer.

2. The transdermal drug delivery system according to claim 1, characterized in that, The pressure-sensitive adhesive is selected from one or more combinations of silicone pressure-sensitive adhesives and styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesives.

3. The transdermal drug delivery system according to claim 2, characterized in that, The silicone pressure-sensitive adhesive is formed by the condensation reaction of polydimethylsiloxane (PDMS) and MQ resin with silanol groups; preferably, the weight ratio of polymer to MQ resin in the silicone pressure-sensitive adhesive is about 35:65 (w / w) to 45:55 (w / w); more preferably, Liveo... TM BIO-PSA type silicone pressure-sensitive adhesive.

4. The transdermal drug delivery system according to claim 1, characterized in that, The polymer compound is selected from one or more of the following: 1) Resins, preferably hydrogenated rosin resin or aminoalkyl methacrylate copolymer E100; 2) Polyvinylpyrrolidone or copolymers containing polyvinylpyrrolidone; 3) Cellulose, preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose and ethyl cellulose.

5. The transdermal drug delivery system according to any one of claims 1 to 4, characterized in that, The total weight relative to the drug-containing matrix layer includes the following components: 1) Active ingredient 3-15%; 2) Pressure-sensitive adhesive 55-94%; 3) Polymer compounds 3-30%.

6. The transdermal drug delivery system according to any one of claims 1 to 5, characterized in that, The transdermal drug delivery system is packaged in a packaging container, and the air in the packaging container is replaced by an inert gas, preferably nitrogen.

7. The transdermal drug delivery system according to any one of claims 1 to 6, wherein the coating weight of the drug-containing matrix layer is 30.0 g / m². 2 Up to 150.0 g / m 2 50.0g / m 2 Up to 100.0g / m 2 .

8. The transdermal drug delivery system according to any one of claims 1 to 7, wherein the active ingredient delivers about 10 mg to about 100 mg of the active ingredient to the circulatory system of the subject daily, preferably about 10 mg to about 50 mg of the active ingredient to the circulatory system of the subject.

9. A method for preparing a transdermal drug delivery system according to any one of claims 1 to 8, comprising: S1: Stir and dissolve the active ingredient and solvent evenly to obtain an API solution; stir the polymer compound and solvent evenly to obtain a polymer compound solution, combine the solutions, and stir evenly. S2: Add the mixed solution from step S1 to the pressure-sensitive adhesive and mix thoroughly to obtain a mixture; S3: Coat the mixture obtained in step S2 onto the release film, dry it, and then press the backing layer; after pressing the backing film, cut it into the set shape and size to obtain the final product.

10. The method for preparing the transdermal drug delivery system according to claim 9, characterized in that, In step S1, the solvent is a pyrrolidone, alcohol, polyol, ether, amine, or amide; preferably one or more of ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, and diethylene glycol monoethyl ether.

11. Use of a therapeutically effective amount of the transdermal drug delivery system according to any one of claims 1 to 10 in the preparation of a medicament for treating respiratory diseases.

12. The use as claimed in claim 11, wherein the respiratory diseases include acute and chronic bronchitis, bronchial asthma, bronchiectasis, emphysema, tuberculosis, pneumoconiosis, postoperative dysphagia, intraoperative pulmonary complications, pulmonary fibrosis caused by chemotherapy or radiotherapy for lung tumors, silicosis, and lung damage caused by other etiologies.

13. The use according to claim 11 or 12, wherein the transdermal drug delivery system delivers 10 mg to about 100 mg of the active ingredient to the circulatory system of the subject daily, preferably about 10 mg to about 50 mg of the active ingredient to the circulatory system of the subject.

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