Transdermal delivery system with good stability and preparation method and use thereof

Abstract

The application discloses a transdermal drug delivery system with good stability, which comprises a backing layer, a drug-containing matrix layer and a release layer; wherein the drug-containing matrix layer comprises an active ingredient, a pressure-sensitive adhesive, a polymer compound and an antioxidant, and the active ingredient is ambroxol or a pharmaceutically acceptable salt thereof. The transdermal system containing ambroxol provided by the application fills the technical blank of ambroxol preparations in the field of patches, and helps to further promote the application of ambroxol drugs.

Description

Technical Field

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

[0002] Ambroxol is a commonly used expectorant in clinical practice. It has the characteristics of good efficacy, high safety, few adverse reactions, stable quality, reasonable price and convenient use. It is now a national essential drug and can meet the basic and necessary clinical needs.

[0003] Currently, ambroxol preparations available in China mainly include oral solutions, tablets, capsules, sustained-release capsules, inhalation solutions, injection solutions, and lyophilized powder for injection.

[0004] Transdermal drug delivery is a superior route of administration compared to oral administration. It maintains a constant drug concentration in the bloodstream by continuously delivering the drug throughout the body. Transdermal delivery reduces fluctuations in blood drug concentration between peaks and troughs and avoids the first-pass effect. Furthermore, because it avoids direct contact between the drug and excipients and the gastrointestinal system, it significantly reduces or eliminates side effects commonly associated with oral administration, such as nausea and vomiting. Another advantage of transdermal delivery is that it is unaffected by food intake. Administration can be easily discontinued by removing the transdermal patch from the skin if necessary. Moreover, transdermal patches improve patient compliance by reducing the frequency of administration, which is particularly important for pediatric patients.

[0005] Currently, there is limited research on transdermal drug delivery formulations of ambroxol. 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. Research on this formulation revealed poor transdermal permeability, hindering its efficacy. Further research on transdermal ambroxol drug delivery formulations has revealed a tendency for crystallization and the growth of related substances. Quality control is required for raw materials, processes, and degradation-related substances in the formulation. Therefore, impurities in ambroxol raw materials and formulations require close monitoring. In recent years, drug safety has become an increasingly important focus for society and a primary basis for clinical drug selection. The impurity status of drugs is the most direct indicator for evaluating drug safety.

[0006] In summary, given the limited research on transdermal formulations of ambroxol, it is essential to develop a transdermal drug delivery formulation with superior overall performance. Summary of the Invention

[0007] One of the objectives 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 good transdermal absorption and adhesion, can achieve bioequivalence with oral formulations, and its stability is further improved.

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

[0009] Another object of the present invention is to provide the use of a transdermal drug delivery system of a matrix type containing ambroxol or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment or prevention of respiratory diseases.

[0010] In a first aspect, the present invention provides a transdermal drug delivery system, which adopts the following technical solution:

[0011] A stable transdermal drug delivery system, comprising:

[0012] 1) Backing layer;

[0013] 2) A drug-containing matrix layer comprising an active ingredient, pressure-sensitive adhesive, polymer, and antioxidant dispersed amorphously in the matrix layer; wherein the active ingredient is ambroxol or a pharmaceutically acceptable salt thereof; and comprising the following components relative to the total weight of the drug-containing matrix layer:

[0014]

[0015] And 3) Peeling layer.

[0016] The components of the drug-containing matrix layer of the transdermal drug delivery system of the present invention exhibit superior transdermal efficacy, stability, and adhesion properties in the aforementioned weight proportions.

[0017] In a further embodiment, the antioxidant includes one or more of tocopherol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite, and propyl gallate.

[0018] In a further embodiment, the amount of the antioxidant is 0.01 to 5% relative to the total weight of the drug-containing matrix layer; preferably 0.05 to 2%.

[0019] In this invention, the use of tocopherol or propyl gallate as antioxidants, or the use of antioxidants containing tocopherol and propyl gallate, yields the best effect in reducing the growth of related substances in the ambroxol transdermal absorption system.

[0020] In a further embodiment, the pressure-sensitive adhesive is selected from one or more of silicone pressure-sensitive adhesives and styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesives.

[0021] In a further embodiment, the pressure-sensitive adhesive is an organosilicon pressure-sensitive adhesive, which is formed by the condensation reaction of polydimethylsiloxane (PDMS) and MQ resin with silanol groups.

[0022] 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).

[0023] In a further embodiment, the silicone pressure-sensitive adhesive is Liveo. TM BIO-PSA type silicone pressure-sensitive adhesive. Further preferably, 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.

[0024] In a further embodiment, the amount of pressure-sensitive adhesive used is 55-93.9% relative to the total weight of the drug-containing matrix layer.

[0025] In this invention, the pressure-sensitive adhesive is an organosilicon pressure-sensitive adhesive, which has high compatibility with the active ingredient of ambroxol. It can not only ensure the transdermal permeability of the active ingredient, but also promote the release of the active ingredient.

[0026] In a further embodiment, the polymer compound is selected from one or more of the following:

[0027] 1) Polyvinylpyrrolidone or copolymers containing polyvinylpyrrolidone, preferably polyvinylpyrrolidone K12, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90 or copolyvinylpyrrolidone VA64;

[0028] 2) Resins, preferably hydrogenated rosin resin or aminoalkyl methacrylate copolymer E100;

[0029] 3) Cellulose, preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose and ethyl cellulose.

[0030] In a further embodiment, the polymer is polyvinylpyrrolidone, and the molecular weight of polyvinylpyrrolidone is 2,000 to 1,500,000.

[0031] In a further embodiment, the amount of the polymer compound is 3-30% relative to the total weight of the drug-containing matrix layer; preferably 3-20%.

[0032] In this invention, polyvinyl ketone or hydrogenated rosin resin is used as a polymer compound, which has better compatibility with pressure-sensitive adhesive and active ingredients. While inhibiting the active ingredient ambroxol and its salt crystallization, it does not significantly affect its transdermal permeability, thereby ensuring the bioavailability of the drug. Moreover, the addition of polymer compounds can further improve the adhesion performance of the drug composition.

[0033] In a further embodiment, the backing layer comprises one or more composite films of a light-shielding coating or an aluminized layer; the backing layer material is preferably one or more of polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, and ethylene-vinyl acetate copolymer; preferably, the backing layer is selected from one or more of coated PE / AL / PET, coated PE / PET, and PE / AL / PET.

[0034] In a further embodiment, the ambroxol transdermal absorption composition is packaged in a container, the air in the container being replaced by an inert gas selected from at least one of nitrogen, argon, and helium. Preferably, the inert gas is nitrogen.

[0035] The present invention further fills the packaging container with an inert gas, which can essentially remove oxygen from the packaging container, thereby further reducing the oxidative degradation of ambroxol, reducing the growth of related substances, and improving the stability of the transdermal absorption composition.

[0036] 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 .

[0037] In a further embodiment, the transdermal drug delivery system delivers about 10 mg to about 100 mg of the active ingredient daily to the subject's circulatory system, preferably about 10 mg to about 50 mg of the active ingredient.

[0038] Secondly, the present invention provides a method for preparing a transdermal drug delivery system, comprising the following steps:

[0039] S1: Mix ambroxol or its pharmaceutically acceptable salt, polymer, antioxidant, and solvent until homogeneous to obtain solution 1;

[0040] S2: Add solution 1 from step S1 to the pressure-sensitive adhesive and mix well to obtain a mixture;

[0041] 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 ambroxol transdermal patch.

[0042] In a further embodiment, the method for preparing the transdermal drug delivery system further includes step S4: adding the ambroxol transdermal patch from step S3 into a packaging container, filling it with inert gas, and sealing it.

[0043] In a further embodiment, in step S1, the solvent is a pyrrolidone, alcohol, polyol, ether, amine, or amide; preferably one or more of anhydrous ethanol, N,N-dimethylacetamide, diethylene glycol monoethyl ether, and N-methylpyrrolidone.

[0044] Thirdly, the present invention provides the use of the transdermal drug delivery system of therapeutically effective amount in the preparation of a medicament for treating respiratory diseases.

[0045] In a further implementation, the respiratory diseases mentioned include, but are not limited to, acute and chronic bronchitis, bronchial asthma, bronchiectasis, emphysema, pulmonary 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.

[0046] In a further embodiment, the transdermal drug delivery system is administered once every 12 hours and 24 hours.

[0047] In a further embodiment, the transdermal drug delivery system delivers about 10 mg to about 100 mg of ambroxol or a pharmaceutically acceptable salt thereof to the circulatory system of the subject daily, preferably about 10 mg to about 50 mg of ambroxol or a pharmaceutically acceptable salt thereof to the circulatory system of the subject daily.

[0048] Surprisingly, the transdermal drug delivery system of the present invention can deliver ambroxol or a pharmaceutically acceptable salt thereof at a high skin flux for about 12 hours, 24 hours or longer.

[0049] In addition, the transdermal drug delivery system of the present invention has durable and good skin adhesion properties during continuous delivery of ambroxol or a pharmaceutically acceptable salt thereof.

[0050] Furthermore, the transdermal drug delivery system of the present invention does not cause skin irritation or sensitization during continuous delivery of ambroxol or a pharmaceutically acceptable salt thereof.

[0051] Surprisingly, by optimizing the type and dosage of antioxidants, this invention achieves high compatibility with the active ingredient (ambroxol or its pharmaceutically acceptable salt). The resulting transdermal drug delivery system not only ensures the transdermal permeability of the active ingredient and promotes its release, but also exhibits excellent adhesion, achieving bioequivalence to oral formulations. Furthermore, it addresses the issue of elevated levels of related substances during storage, further enhancing the product's stability.

[0052] The beneficial effects of this invention are:

[0053] (1) The transdermal drug delivery system containing ambroxol and its pharmaceutically acceptable salts 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.

[0054] (2) The transdermal drug delivery system of the present invention can not only ensure the transdermal permeability of active ingredients and promote the release of active ingredients, but also has good adhesion and can achieve bioequivalence with oral preparations. It can also solve the problem of the rise of related substances in the product during storage, thereby further improving its stability. Attached Figure Description

[0055] Figure 1 A schematic diagram of the three-layer matrix type transdermal drug delivery system described in this invention is shown. Detailed Implementation

[0056] definition

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] As used herein, the term "drug-containing matrix layer" includes ambroxol and its pharmaceutically acceptable salts, pressure-sensitive adhesives, polymers, antioxidants, and optionally penetration enhancers and any other additives.

[0063] 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, anti-skin irritants, cohesion promoters, plasticizers, thickeners, etc.

[0064] 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.

[0065] The structural formula of ambroxol in this invention is shown below.

[0066]

[0067] The "organosilicon pressure-sensitive adhesive" described in this invention is a compound with a silicone backbone.

[0068] As an organosilicon pressure-sensitive adhesive, for example, polydimethylsiloxane (PDMS) and MQ resin can be produced by silanol condensation reaction.

[0069] 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.

[0070] 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).

[0071] As an organosilicon pressure-sensitive adhesive, Liveo can be cited as an example. TM The 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.

[0072] 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 7-4201 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.

[0073] The average molecular weight of polyvinylpyrrolidone K12 is 2000-3000; the average molecular weight of polyvinylpyrrolidone K30 is 28000-340000; and the average molecular weight of polyvinylpyrrolidone K90 is 1000000-1500000.

[0074] In this invention, "optional" indicates that an additive may or may not be added. For example, "optional" with "penetration enhancer" indicates that a penetration enhancer may or may not be added.

[0075] In this invention, impurities A to E are impurities AE in EP.

[0076] As a styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive, it includes styrene-isoprene-styrene block copolymer (SIS), tackifier and softener, wherein the tackifier includes, but is not limited to, polyisobutylene, polybutene, petroleum resin, hydrogenated rosin glycerol ester, rosin resin, alicyclic saturated or hydrocarbon resin; the softener includes, but is not limited to, liquid paraffin, olive oil, peanut oil or polyethylene glycol.

[0077] As a styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive, relative to the total weight of the styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive, the content of styrene-isoprene-styrene block copolymer (SIS) is 10-60%, preferably 15-40%, the content of tackifier is 5-50%, preferably 10-40%, and the content of softener is 15-60%, preferably 20-50%.

[0078] 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 styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive, the styrene-isoprene-styrene block copolymer (SIS) content is 35%, the hydrogenated rosin glycerol ester content is 30%, and the liquid paraffin content is 35%.

[0079] The detection method involved in this invention is as follows:

[0080] 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. Each group of samples was tested in triplicate.

[0081] Crystallization detection: visual inspection.

[0082] Adhesion performance test:

[0083] 1) Adhesion: The adhesion was determined according to the third method in the General Chapter 0952 of the Chinese Pharmacopoeia.

[0084] 2) Adhesion: The adhesion was determined according to the second method in the General Chapter 0952 of the Chinese Pharmacopoeia.

[0085] Related substances were determined by high performance liquid chromatography (Chinese Pharmacopoeia, Part IV, General Chapter 0512).

[0086] Test solution: Take 3 tablets of this product, peel off the protective layer, immediately place the backing layer in a stoppered conical flask, accurately add 45 ml of extraction solvent [isopropanol-methyl tert-butyl ether (4:1)], seal, sonicate in a cold water bath for 20 minutes, then accurately add 45 ml of 0.01 mol / L diammonium hydrogen phosphate solution (adjust the pH to 7.0 with phosphorus) to prepare a solution containing approximately 1 mg of ambroxol per ml, shake well, centrifuge at 4000 rpm for 10 minutes, and take the supernatant.

[0087] Diluent: 0.01 mol / L diammonium hydrogen phosphate solution (pH 7.0) - Extractant [isopropanol-methyl tert-butyl ether (4:1)] (1:1)

[0088] Control solution: Accurately measure an appropriate amount of the test sample, dilute it with diluent to prepare a solution containing approximately 10 μg of ambroxol per 1 ml, and shake well.

[0089] System suitability solution: Weigh appropriate amounts of ambroxol, impurity A, impurity B, impurity D, and impurity E, dissolve and dilute them with acetonitrile to prepare a stock solution containing approximately 0.2 mg of ambroxol hydrochloride, impurity A, impurity D, and impurity E, and approximately 0.3 mg of impurity B per ml. Take an appropriate amount of impurity C, dissolve and dilute it with isopropanol to prepare a stock solution containing approximately 0.2 mg of impurity C per ml. Measure 1 ml of each of the above stock solutions, place them in a 100 ml volumetric flask, dilute to the mark with the mobile phase, and shake well.

[0090] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Agilent Eclispe XDB-C). 18 (250mm × 4.6mm, 5μm or equivalent column): 0.01mol / L diammonium hydrogen phosphate solution (pH 7.0) as mobile phase A, acetonitrile as mobile phase B, gradient elution; flow rate 1.0ml / min; detection wavelength 248nm; column temperature 30℃; injection volume 20μl; gradient table as follows:

[0091] Table 1 Gradient Table

[0092] Time (min) Mobile phase A% Mobile phase B% 0 60 40 15 60 40 25 55 45 35 45 55 70 45 55 75 60 40 80 60 40

[0093] System suitability requirements: In the system suitability solution chromatogram, impurities A, B, ambroxol, D, C, and E should elute in sequence, and the resolution between each impurity peak should meet the requirements.

[0094] Assay: Accurately measure the system suitability solution, sensitivity solution, reference solution and test solution, and inject them into the liquid chromatograph separately, and record the chromatograms.

[0095] Examples 1-7

[0096] Examples 1-7 and Comparative Example 1 are shown in Table 2.

[0097] Table 2 Components and weight percentages of Examples 1-7 and Comparative Example 1

[0098]

[0099] The specific preparation method is as follows:

[0100] S1: Add ambroxol to N,N-dimethylacetamide solvent and stir to dissolve to obtain solution 1; add polyvinylpyrrolidone K30 and antioxidant to anhydrous ethanol and stir to dissolve to obtain solution 2.

[0101] 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.

[0102] 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.

[0103] The in vitro transdermal, crystallization, adhesion and stability of the ambroxol transdermal patches in Examples 1-7 and Comparative Example 1 were tested, and the results are shown in Tables 3-6.

[0104] Table 3. Cumulative in vitro permeation of Examples 1-7 and Comparative Example 1

[0105]

[0106] Table 4. Crystallization observation of Examples 1-7 and Comparative Example 1

[0107]

[0108]

[0109] Table 5. Adhesion test results of Examples 1-7 and Comparative Example 1

[0110] Examples and Comparative Examples Adhesion force (N) Holding power (min) Example 1 13.8 45 Example 2 14.2 40 Example 3 13.5 43 Example 4 15.1 38 Example 5 15.0 40 Example 6 15.5 44 Example 7 15.7 43 Comparative Example 1 14.8 42

[0111] Table 6. Stability tests of Examples 1-7 and Comparative Example 1

[0112]

[0113]

[0114] The results in Tables 3-6 show that the cumulative transmittance per unit area over 24 hours for Examples 1-7 is 170.4 ug / cm². 2-191.5ug / cm 2 Within the range, the transdermal effect is good; and no crystallization occurred after 12 months of stability testing at 30°C; the adhesion performance is also good; the increase of related substances in Examples 1-7 at a high temperature of 60°C is significantly less than that in Comparative Example 1, indicating that the addition of antioxidants has a significant improving effect on the growth of related substances during the stability process.

[0115] Examples 8-12

[0116] See Table 7 for examples 8-12.

[0117] Table 7 Components and weight percentages of Examples 8-12

[0118]

[0119] The specific preparation method is as follows:

[0120] S1: Add ambroxol to diethylene glycol monoethyl ether solvent and stir to dissolve to obtain solution 1; add the polymer compound (polyvinylpyrrolidone, hydrogenated rosin glycerol ester or aminoalkyl methacrylate copolymer E100) and antioxidant to anhydrous ethanol and stir to dissolve to obtain solution 2.

[0121] 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.

[0122] 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.

[0123] The stability of the ambroxol transdermal patches in Examples 8-12 was tested, and the results are shown in Table 8.

[0124] Table 8 Stability tests of Examples 8-12

[0125]

[0126] As shown in Table 8, different polymer compounds were added in Examples 8-12, and the increase in the related substances did not change significantly under the high temperature of 60°C, indicating that different polymer compounds had no difference in their effect on the growth of related substances.

[0127] Examples 13-15

[0128] See Table 9 for examples 13-15.

[0129] Table 9. Components and weight percentages of Examples 13-15

[0130]

[0131]

[0132] Note: The composition of the styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive in Example 15 is: 35% styrene-isoprene-styrene block copolymer (SIS), 30% hydrogenated rosin glycerol ester, and 35% liquid paraffin.

[0133] The specific preparation method is as follows:

[0134] S1: Add ambroxol to N,N-dimethylacetamide solvent and stir to dissolve to obtain solution 1; add polyvinylpyrrolidone K30 and antioxidant to anhydrous ethanol and stir to dissolve to obtain solution 2.

[0135] S2: Mix solution 1 and solution 2 evenly, add them to the pressure-sensitive adhesive, stir evenly, and degas to obtain the adhesive mixture.

[0136] 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.

[0137] The adhesion, stability, crystallization, and related substances of the ambroxol transdermal patches in Examples 13-15 were tested, and the results are shown in Tables 10-12.

[0138] Table 10. Investigation of crystallization in Examples 13-15

[0139]

[0140] Table 11: Adhesion force test results for Examples 13-15

[0141] Example Adhesion force (N) Holding power (min) Example 13 13.5 36 Example 14 14.3 37 Example 15 15.2 40

[0142] Table 12 Stability tests of Examples 13-15

[0143]

[0144]

[0145] As shown in Tables 10-12, the transdermal drug delivery system of the present invention is applicable to different pressure-sensitive adhesive systems. Whether it is an organosilicon pressure-sensitive adhesive system or a styrene-isoprene-styrene block copolymer (SIS) hot melt pressure-sensitive adhesive system, the adhesion performance of the transdermal drug delivery system is relatively good, the growth trend of related substances is basically consistent, and it is basically controllable.

[0146] Examples 16-20

[0147] The formulations of Examples 16-20 and the comparative examples are shown in Table 13.

[0148] Table 13 Components and weight percentages of Examples 16-20 and Comparative Example 1

[0149]

[0150] The preparation method is the same as in Example 9.

[0151] The in vitro transdermal, crystallization, adhesion and stability of the ambroxol transdermal patches in Examples 16-20 and Comparative Example 1 were tested, and the results are shown in Tables 14-16.

[0152] Table 14. Cumulative in vitro permeation of Examples 16-20 and Comparative Example 1

[0153]

[0154] Table 15 shows the crystallization conditions of Examples 16-20 and Comparative Example 1.

[0155]

[0156]

[0157] Table 16 Stability tests of Examples 16-20 and Comparative Example 1

[0158]

[0159]

[0160] As shown in Tables 13-16, compared with Comparative Example 1 without antioxidants, the increase in related substances in the ambroxol transdermal patches prepared with antioxidants in Examples 16-20 was significantly slower than that in Comparative Example 1 during the stability study.

[0161] Example 21

[0162] Investigating the effect of nitrogen-filled packaging on stability

[0163] The ambroxol transdermal patches prepared in Examples 6, 9, 13, 17, and Comparative Example 1 were placed in packaging bags and nitrogen-filled, and were then designated as Examples 6', 9', 13', 17', and Comparative Example 1'. The formulation and process of Comparative Example 2 were the same as those in Example 17, except that the ambroxol transdermal patch prepared in Comparative Example 2 was not nitrogen-filled. The antioxidant properties of Examples 6', 9', 13', 17', Comparative Example 1', and Comparative Example 2 were tested, and the results are shown in Table 17.

[0164] Table 17 Stability tests of Examples 6', 9', 13', 17', Comparative Example 1', and Comparative Example 2

[0165]

[0166]

[0167] The results in Table 17 show that, compared with the ambroxol transdermal patch with antioxidants but not nitrogen-filled packaging in Comparative Example 1', the ambroxol transdermal patch without antioxidants in nitrogen-filled packaging exhibited a greater increase in related substances during the stability study period. Examples 6', 9', 13', and 17', the ambroxol transdermal patches with antioxidants and nitrogen-filled packaging, compared with Comparative Example 1' (without antioxidants and nitrogen-filled packaging) and Comparative Example 2 (with antioxidants and not nitrogen-filled packaging), reduced the oxidative degradation of ambroxol, further slowed the growth of related substances, and improved the stability of the transdermal absorption composition.

Claims

1. A stable transdermal drug delivery system, comprising: 1) Backing layer; 2) A drug-containing matrix layer comprising an active ingredient, pressure-sensitive adhesive, polymer compound, and antioxidant dispersed in the matrix layer in an amorphous state; wherein the active ingredient is ambroxol or a pharmaceutically acceptable salt thereof; The total weight relative to the drug-containing matrix layer includes the following components:

2. The transdermal drug delivery system according to claim 1, characterized in that, The antioxidants include one or more of tocopherol, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite, and propyl gallate.

3. The transdermal drug delivery system according to claim 1, characterized in that, The amount of antioxidant used is 0.05-2% relative to the total weight of the drug-containing matrix layer.

4. The transdermal drug delivery system according to any one of claims 1 to 3, characterized in that, The pressure-sensitive adhesive is selected from silicone pressure-sensitive adhesives and / or styrene-isoprene-styrene block copolymer hot melt pressure-sensitive adhesives.

5. The transdermal drug delivery system according to claim 4, characterized in that, The silicone pressure-sensitive adhesive is formed by the condensation reaction of polydimethylsiloxane (PDMS) and MQ resin via silanol groups; preferably, the weight ratio of PDMS to MQ resin in the silicone pressure-sensitive adhesive is approximately 35:65 (w / w) to 45:55 (w / w); further preferably, Liveo... TM BIO-PSA type silicone pressure-sensitive adhesive.

6. The transdermal drug delivery system according to any one of claims 1 to 5, characterized in that, The polymer compound is selected from one or more of the following: 1) Polyvinylpyrrolidone or copolymers containing polyvinylpyrrolidone, preferably polyvinylpyrrolidone K12, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90 or copolyvinylpyrrolidone VA64; 2) Resins, preferably hydrogenated rosin resin or aminoalkyl methacrylate copolymer E100; 3) Cellulose, preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose and ethyl cellulose.

7. The transdermal drug delivery system according to claim 6, characterized in that, The polymer is polyvinylpyrrolidone, with a molecular weight of 2,000 to 1,500,000.

8. The transdermal drug delivery system according to any one of claims 1-7, wherein the backing layer comprises one or more composite films of a light-shielding coating or an aluminized layer; the backing layer material is preferably one or more selected from polyurethane, polyester, polyvinyl acetate, polyvinylidene chloride, polyethylene, and ethylene-vinyl acetate copolymer; preferably, the backing layer is selected from one or more of coated PE / AL / PET, coated PE / PET, and PE / AL / PET.

9. The transdermal drug delivery system according to any one of claims 1 to 8, 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.

10. A method for preparing a transdermal drug delivery system according to any one of claims 1-9, comprising the following steps: S1: Mix ambroxol or its pharmaceutically acceptable salt, polymer, antioxidant, and solvent until homogeneous to obtain solution 1; S2: Add solution 1 from step S1 to the pressure-sensitive adhesive and mix well 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 ambroxol transdermal patch.

11. The preparation method according to claim 10, characterized in that, In step S1, the solvent is a pyrrolidone, alcohol, polyol, ether, amine, or amide; preferably one or more of anhydrous ethanol, N,N-dimethylacetamide, diethylene glycol monoethyl ether, and N-methylpyrrolidone.

12. Use of a transdermal drug delivery system according to any one of claims 1-11 in the preparation of a medicament for treating respiratory diseases.

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