Gel patch and its preparation method

Abstract

This invention discloses a gel patch and its preparation method. By weight percentage, the gel patch is prepared from raw materials comprising the following components: 0.05%-5% active ingredient, 2%-50% propylene glycol, 0.2%-2% pH adjuster, 0.5%-5% first thickener, 0.01%-5% crosslinking regulator, 10%-40% glycerin, 3%-10% matrix material, 0.5%-6% second thickener, 0.2%-4% filler, 0.01%-1.0% crosslinking agent, and water to 100%; the active ingredient is pramipexole and / or pramipexole hydrochloride. This gel patch exhibits good sustained-release transdermal absorption, maintaining a stable and effective blood drug concentration for a relatively long period after epidermal administration, and has a high cumulative permeability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and in particular relates to a pramipexole / prampexole hydrochloride gel patch and its preparation method. Background Technology

[0002] Parkinson's disease (PD), also known as paralysis agitans, is a common neurodegenerative disease in middle-aged and elderly people. The primary lesions occur in the substantia nigra and striatum. Tremor, rigidity, and bradykinesia are the main clinical features of this disease. Parkinson's disease is the fourth most common neurodegenerative disease among the elderly. Current treatment primarily involves medications such as dopamine receptor agonists, including pramipexole, levodopa, rotivatin, and ropinirole.

[0003] Dopamine receptor agonists are currently the first-line treatment recommended by domestic and international guidelines for the treatment of Parkinson's disease (PD). Pramipexole, in particular, has been extensively supported by clinical evidence for its efficacy in improving motor symptoms, PD depression, and preventing motor complications. It has been highly recommended by the European Federation of Neurological Societies (EFNS) and the Movement Disorders Society (MDS).

[0004] Pramipexole has the chemical name (6S)-6-N-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine, with the molecular formula C10H17N3S and a relative molecular mass of 211.33. Its chemical structure is shown below:

[0005]

[0006] Pramipexole is currently mainly available in oral formulations, such as immediate-release and extended-release tablets. The Chinese Guidelines for the Treatment of Parkinson's Disease (4th Edition) recommend a starting dose of 0.375 mg / day for pramipexole. -1 The effective dose is 1.50–2.25 mg / day. -1 The maximum dose should not exceed 4.5 mg / day. -1 This translates to a starting dose of 0.267 mg / day for pramipexole. -1 The effective dose is 1.07–1.60 mg / day. -1 The maximum dose should not exceed 3.2 mg / day. -1 However, due to the short half-life of pramipexole and the fact that PD patients need to take the medication for a long time or even for life, as well as the accompanying symptoms such as tremor, muscle rigidity, and bradykinesia, oral administration brings serious inconvenience to PD patients and their caregivers. Summary of the Invention

[0007] Based on this, the present invention provides a gel patch with pramipexole or pramipexole hydrochloride as the main drug and a specific amount of propylene glycol as a penetration enhancer. The gel patch has a good sustained-release transdermal absorption effect, and can maintain a stable and effective blood drug concentration for a long time when administered through the epidermis, and has a high cumulative permeability.

[0008] Specifically, the present invention includes the technical solutions described above.

[0009] A gel patch, by weight percentage, wherein the gel patch is prepared from raw materials comprising the following components:

[0010]

[0011] The active ingredient is pramipexole and / or pramipexole hydrochloride.

[0012] In some embodiments, the gel patch is prepared from raw materials comprising the following components:

[0013]

[0014]

[0015] In some embodiments, the gel patch is prepared from raw materials comprising the following components:

[0016]

[0017] In some embodiments, the propylene glycol is 8% to 22% by weight.

[0018] In some of these embodiments, the active ingredient is pramipexole, and the propylene glycol is present in a weight percentage of 8% to 12%.

[0019] In some of these embodiments, the active ingredient is pramipexole, and the propylene glycol is present in a weight percentage of 9% to 11%.

[0020] In some of these embodiments, the active ingredient is pramipexole, and the propylene glycol is 10% by weight.

[0021] In some embodiments, the active ingredient is pramipexole hydrochloride, and the propylene glycol is present in a weight percentage of 15% to 22%.

[0022] In some embodiments, the active ingredient is pramipexole hydrochloride, and the propylene glycol is present in a weight percentage of 18% to 22%.

[0023] In some embodiments, the active ingredient is pramipexole hydrochloride, and the propylene glycol is present in a weight percentage of 19% to 21%.

[0024] In some embodiments, the active ingredient is pramipexole hydrochloride, and the propylene glycol is 20% by weight.

[0025] In some embodiments, the pH adjuster is L-tartaric acid.

[0026] In some embodiments, the first tackifier and the second tackifier are each independently selected from at least one of sodium carboxymethyl cellulose, gum arabic, polyvinyl alcohol, povidone K90 and gelatin.

[0027] In some embodiments, the first thickener is gelatin; the second thickener is sodium carboxymethyl cellulose.

[0028] In some embodiments, the crosslinking regulator is disodium edetate.

[0029] In some embodiments, the skeleton material is partially neutralized sodium polyacrylate NP-700.

[0030] In some embodiments, the filler is selected from at least one of kaolin, titanium dioxide, micronized silica gel, and talc.

[0031] In some embodiments, the crosslinking agent is aluminum hydroxyl and / or aluminum hydroxide.

[0032] The present invention also provides a method for preparing the above-mentioned gel patch, including the following technical solution.

[0033] A method for preparing the above-mentioned gel patch includes the following steps:

[0034] (1) Preparation of raw material solution: Add the propylene glycol to an appropriate amount of water, then add the active ingredient, stir and mix to obtain raw material solution;

[0035] (2) Preparation of the first tackifier solution: The crosslinking regulator, pH regulator and the first tackifier are added to the remaining water in sequence and stirred and mixed at a certain temperature to obtain the first tackifier solution;

[0036] (3) Preparation of glycerol suspension: The skeleton material, the second thickener, the filler and the crosslinking agent are added to glycerol in sequence and stirred to obtain glycerol suspension;

[0037] (4) The raw material solution and the first thickener solution are stirred and mixed to obtain a mixed matrix;

[0038] (5) Add the glycerol suspension to the mixed matrix and stir to obtain a gel paste;

[0039] (6) The gel paste is applied in a coating machine to obtain the gel plaster.

[0040] In some embodiments, the mixing time in step (1) is 40 min to 60 min.

[0041] In some embodiments, the stirring and mixing time in step (2) is 40 min to 90 min, and the temperature is 45°C to 55°C.

[0042] In some embodiments, the mixing time in step (3) is 40 min to 90 min.

[0043] In some embodiments, the stirring and mixing time in step (4) is 3 min to 8 min, and the frequency is 10 Hz to 20 Hz.

[0044] In some embodiments, the stirring and mixing time in step (5) is 10 min to 20 min, and the frequency is 10 Hz to 20 Hz.

[0045] The gel patch of the present invention has the following beneficial effects:

[0046] This invention uses a specific amount of propylene glycol as a penetration enhancer, combined with pH adjuster, crosslinking adjuster, crosslinking agent, matrix material, thickener, filler and other raw materials, to prepare pramipexole or its hydrochloride into a gel patch. The gel patch has a good sustained-release transdermal absorption effect, and can maintain a stable and effective blood drug concentration for a long time when administered through the epidermis, and has a high cumulative permeability.

[0047] The gel patch of this invention has advantages such as convenient administration, high safety, few side effects, and improved patient compliance in PD patients. Compared with traditional transdermal patches, it has a longer transdermal duration of action, better skin permeability, higher transdermal absorption rate, higher drug loading capacity, and less irritation, which is conducive to the more stable and better efficacy of pramipexole or its hydrochloride. Detailed Implementation

[0048] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments are merely illustrative of the present invention and should not be construed as limiting the invention.

[0049] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0050] The terms "comprising" and "having," and any variations thereof, are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product, or device that includes a series of steps is not limited to the steps or modules listed, but may optionally include steps not listed, or may optionally include other steps inherent to such process, method, product, or device.

[0051] In this invention, "multiple" refers to two or more. "And / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A alone, A and B simultaneously, or B alone. The character " / " generally indicates that the preceding and following related objects have an "or" relationship.

[0052] The following are specific examples.

[0053] Preparation of Pramipexole Gel Patch (Examples 1-8)

[0054] Table 1. Formulation composition of the pramipexole gel patches in Examples 1-8 (by weight percentage)

[0055]

[0056] The preparation method includes the following steps:

[0057] 1) Solution preparation

[0058] Active pharmaceutical ingredient solution: Add the prescribed amount of propylene glycol to 30% of the prescribed amount of water, then add pramipexole, mix and stir for 45 minutes, and set aside.

[0059] Gelatin solution: Add the prescribed amounts of disodium edetate, L-tartaric acid, and gelatin to 70% of the prescribed amount of water in sequence, heat to 50°C while stirring, and then stir at a constant temperature for 60 minutes.

[0060] Glycerin suspension: Add the prescribed amount of sodium polyacrylate NP-700, sodium carboxymethyl cellulose, titanium dioxide, kaolin, and aluminum hydroxyl to glycerin in sequence, and mix and stir at 500 rpm ± 50 rpm for 60 min, then set aside.

[0061] 2) Ointment preparation process

[0062] Preparation Step 1: First, place the raw material solution and gelatin solution in a mixer and mix (15 Hz, 5 min); to obtain Mixed Matrix I.

[0063] Step 2: Add the glycerol suspension to the mixed matrix I in Step 1 and stir to mix (15 Hz, 15 min) to obtain a gel paste.

[0064] 3) Coating

[0065] The gel paste is applied in a coating machine, with each paste weighing 10g and cut to a size of 14cm*10cm.

[0066] Examples 9-16: Preparation of Pramipexole Hydrochloride Gel Patch

[0067] Table 2. Formulation composition (by weight percentage) of the pramipexole hydrochloride gel patches in Examples 9-16.

[0068]

[0069]

[0070] The preparation method includes the following steps:

[0071] 1) Solution preparation

[0072] Active pharmaceutical ingredient solution: Add the prescribed amount of propylene glycol to 30% of the prescribed amount of water, then add pramipexole hydrochloride, mix and stir for 45 minutes, and set aside.

[0073] Gelatin solution: Add the prescribed amounts of disodium edetate, L-tartaric acid, and gelatin to 70% of the prescribed amount of water in sequence, heat to 50°C while stirring, and then stir at a constant temperature for 60 minutes.

[0074] Glycerin suspension: Add the prescribed amount of sodium polyacrylate NP-700, sodium carboxymethyl cellulose, titanium dioxide, kaolin, and aluminum hydroxyl to glycerin in sequence, and mix and stir at 500 rpm ± 50 rpm for 60 min, then set aside.

[0075] 2) Ointment preparation process

[0076] Preparation Step 1: First, place the raw material solution and gelatin solution in a mixer and mix (15 Hz, 5 min); to obtain Mixed Matrix I.

[0077] Step 2: Add the glycerol suspension to the mixed matrix I in Step 1 and stir to mix (15 Hz, 15 min) to obtain a gel paste.

[0078] 3) Coating

[0079] The gel paste was applied using a coating machine, with each patch weighing 10g and cut to a size of 14cm x 10cm. Preparation of Comparative Examples 1-5: Pramipexole Gel Patches

[0080] Table 3 shows the formulation composition (by weight percentage) of the pramipexole gel patches used in Comparative Examples 1-5.

[0081]

[0082] Comparative Examples 1-3 replaced the propylene glycol in Example 6 with N-methylpyrrolidone, crombutin, and menthol, respectively, while the other raw materials were the same as in Example 6. Correspondingly, the only difference in their preparation methods was that the propylene glycol in the solution preparation step was replaced with N-methylpyrrolidone, crombutin, or menthol, while the other preparation steps were the same as in Example 6.

[0083] Comparative Example 4, without the addition of propylene glycol, was prepared as follows:

[0084] 1) Solution preparation

[0085] Active pharmaceutical ingredient solution: Add the prescribed amount of pramipexole to 30% of the prescribed amount of water, mix and stir for 45 minutes, and set aside.

[0086] Gelatin solution: Add the prescribed amounts of disodium edetate, L-tartaric acid, and gelatin to 70% of the prescribed amount of water in sequence, heat to 50°C while stirring, and then stir at a constant temperature for 60 minutes.

[0087] Glycerin suspension: Add the prescribed amount of sodium polyacrylate NP-700, sodium carboxymethyl cellulose, titanium dioxide, kaolin, and aluminum hydroxyl to glycerin in sequence, and mix and stir at 500 rpm ± 50 rpm for 60 min, then set aside.

[0088] 2) The ointment preparation process and 3) the coating steps are the same as in the example.

[0089] Comparative Example 5, without the addition of water, was prepared as follows:

[0090] 1) Solution preparation

[0091] Active pharmaceutical ingredient solution: Add the prescribed amount of pramipexole to 20% of the prescribed amount of propylene glycol, mix and stir for 45 minutes, and set aside.

[0092] Gelatin suspension: Add the prescribed amounts of disodium edetate, L-tartaric acid, and gelatin sequentially to 80% of the prescribed amount of propylene glycol. Heat to 50°C while stirring, then maintain the temperature and stir for 60 minutes. The gelatin will not completely dissolve, and large gelatin particles will remain.

[0093] Glycerin suspension: Add the prescribed amount of sodium polyacrylate NP-700, sodium carboxymethyl cellulose, titanium dioxide, kaolin, and aluminum hydroxyl to glycerin in sequence, and mix and stir at 500 rpm ± 50 rpm for 60 min, then set aside.

[0094] 2) The ointment preparation process and 3) the coating steps are the same as in the example. After coating, the surface of the ointment is rough, and a dense gel skeleton cannot be formed, resulting in poor formability.

[0095] Example 17 In vitro transdermal experiments of pramipexole gel patch and pramipexole hydrochloride gel patch.

[0096] The modified Franz diffusion cell method (diffusion cell volume 9 ml, effective diffusion area 1.776) was used to conduct in vitro transdermal tests on the pramipexole / praprazole hydrochloride gel patch prepared in the examples, using isolated pig skin as a barrier. Three parallel tests were performed.

[0097] Measurement method:

[0098] Sample preparation: Take one patch of this product, lay it flat on a plastic mat, place the mat on a die-cutting machine, and use a special mold to cut a 14mm diameter circular slice from the center of the patch as a transdermal sample.

[0099] The conditions for in vitro transdermal experiments are as follows:

[0100] Sample: Pramipexole / Pramipexole Hydrochloride Gel Patch

[0101] Medium: pH 7.4 phosphate buffer

[0102] Temperature: 32℃

[0103] Sampling mode: Full exhaust and full complement

[0104] Media volume: 9ml

[0105] Sample volume: 4ml

[0106] Skin: Miniature pig skin (back)

[0107] Sampling time: 6h, 12h, 24h.

[0108] The chromatographic conditions were as follows: column: C18 column; injection volume: 10 μL; flow rate: 1.5 ml / min; wavelength: 262 nm; column temperature: 40 ℃; time: 20 min.

[0109] Test method:

[0110] After the diffusion cell is installed, add an appropriate amount of medium, approximately 2 / 3 of the diffusion cell volume. Set the rotation speed and temperature, and once the temperature stabilizes, take one sample, remove the plastic cover, and place the sample in the center of a 25mm diameter pigskin. Lay the pigskin flat on the diffusion cell, aligning it with the center. Place the sealing gasket and jacket, and tighten the screws to secure the diffusion cell, pigskin, sealing gasket, and jacket. Alternately release the test and reference formulations. Add excess receiving medium to fill the diffusion cell, ensuring complete contact between the pigskin and the receiving medium surface (no air bubbles). The medium should completely fill the diffusion cell; any excess release medium should be discharged through the drain pipe. At the start of the experiment, take samples for testing at 6h, 12h, and 24h.

[0111] The experimental results are shown in Tables 4-1 to 4-5.

[0112] Table 4-1: Cumulative permeability of pramipexole gel patches with different drug loadings (n=3)

[0113]

[0114] As shown in Table 4-1, the cumulative permeability of 12 mg / patch pramipexole gel patch over 24 hours was 3.58 ± 0.9%, 16 mg / patch was 5.81 ± 1.1%, 32 mg / patch was 6.63 ± 1.5%, and 64 mg / patch was 10.17 ± 2.1%. The data in Table 4-1 indicate that as the drug loading of the pramipexole gel patch increases, the cumulative permeability also increases accordingly.

[0115] Table 4-2: Cumulative permeability of pramipexole gel patches with different propylene glycol dosages (n=3)

[0116]

[0117] Table 4-2 shows that the cumulative permeation rate of pramipexole gel patch (64 mg / patch) containing 5% propylene glycol was 1.56 ± 0.6% after 24 hours; the cumulative permeation rate of pramipexole gel patch (64 mg / patch) containing 10% propylene glycol was 13.34 ± 2.1% after 24 hours; the cumulative permeation rate of pramipexole gel patch (64 mg / patch) containing 20% ​​propylene glycol was 2.78 ± 0.9% after 24 hours; and the cumulative permeation rate of pramipexole gel patch (64 mg / patch) containing 40% propylene glycol was 2.39 ± 1.2% after 24 hours. The pramipexole gel patch (64 mg / patch) without propylene glycol showed almost no permeation through the skin after 24 hours. When only propylene glycol is added without water, the gel patch has poor formability, making it impossible to prepare a fully formed gel patch formulation, and its transdermal permeation rate is very low. The above data shows that the pramipexole gel patch containing 10% propylene glycol has the highest cumulative transdermal penetration rate over 24 hours.

[0118] Table 4-3: Cumulative permeation rate of pramipexole gel patches with different penetration enhancers (n=3)

[0119]

[0120] As shown in Table 4-3, the cumulative permeation rate of pramipexole gel patch (64mg / patch) containing 10% propylene glycol in 24 hours is 13.34±2.1%. When propylene glycol is replaced with other penetration enhancers or when propylene glycol is not present, the cumulative permeation rate of pramipexole gel patch (64mg / patch) in 24 hours is very low, and it hardly permeates the skin.

[0121] Table 4-4: Cumulative permeability of pramipexole hydrochloride gel patches with different drug loadings (n=3)

[0122]

[0123] Table 4-4 shows that the cumulative permeation rate of 45 mg / patch pramipexole hydrochloride gel patch over 24 hours was 1.38 ± 0.6%, 90 mg / patch was 1.59 ± 0.9%, 180 mg / patch was 1.81 ± 0.8%, and 360 mg / patch was 2.88 ± 1.0%. The data indicate that compared to pramipexole gel patch, the transdermal effect of pramipexole hydrochloride gel patch is significantly worse, requiring a higher drug loading to achieve a certain therapeutic effect.

[0124] Table 4-5: Cumulative permeability of pramipexole hydrochloride gel patches with different propylene glycol dosages (n=3)

[0125]

[0126] Table 4-5 shows that the cumulative permeability of pramipexole hydrochloride gel patch (45 mg / patch) without propylene glycol was 0.15 ± 0.1% over 24 hours; the cumulative permeability of pramipexole hydrochloride gel patch (45 mg / patch) containing 10% propylene glycol was 1.23 ± 0.5% over 24 hours; the cumulative permeability of pramipexole hydrochloride gel patch (45 mg / patch) containing 20% ​​propylene glycol was 1.95 ± 0.9% over 24 hours; and the cumulative permeability of pramipexole hydrochloride gel patch (45 mg / patch) containing 40% propylene glycol was 0.39 ± 0.2% over 24 hours. The data indicate that the pramipexole hydrochloride gel patch containing 20% ​​propylene glycol had the highest cumulative permeability over 24 hours.

[0127] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0128] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A gel patch, characterized in that, The gel patch, by weight percentage, is prepared from the following raw materials: ； The active ingredient is pramipexole; The first tackifier and the second tackifier are each independently selected from at least one of sodium carboxymethyl cellulose, gum arabic, polyvinyl alcohol, povidone K90 and gelatin; The crosslinking regulator is disodium edetate; The skeleton material is partially neutralized sodium polyacrylate NP-700; The crosslinking agent is aluminum hydroxyl and / or aluminum hydroxide.

2. The gel patch according to claim 1, characterized in that, The gel patch is prepared from the following raw materials: 。 3. The gel patch according to claim 1 or 2, characterized in that, The propylene glycol has a weight percentage of 8% to 22%.

4. The gel patch according to claim 3, characterized in that, The propylene glycol has a weight percentage of 8% to 12%.

5. The gel patch according to claim 4, characterized in that, The propylene glycol has a weight percentage of 9% to 11%.

6. A gel patch, characterized in that, The gel patch, by weight percentage, is prepared from the following raw materials: ； The active ingredient is pramipexole hydrochloride; The first tackifier and the second tackifier are each independently selected from at least one of sodium carboxymethyl cellulose, gum arabic, polyvinyl alcohol, povidone K90 and gelatin; The crosslinking regulator is disodium edetate; The skeleton material is partially neutralized sodium polyacrylate NP-700; The crosslinking agent is aluminum hydroxyl and / or aluminum hydroxide.

7. The gel patch according to claim 6, characterized in that, The gel patch is prepared from the following raw materials: 。 8. The gel patch according to claim 6 or 7, characterized in that, The propylene glycol has a weight percentage of 15% to 22%.

9. The gel patch according to claim 8, characterized in that, The weight percentage of propylene glycol is 19% to 21%.

10. The gel patch according to any one of claims 1-2 and 6-7, characterized in that, The pH adjuster is L-tartaric acid; and / or, The filler is selected from at least one of kaolin, titanium dioxide, micronized silica gel and talc.

11. A method for preparing the gel patch according to any one of claims 1-10, characterized in that, Includes the following steps: (1) Preparation of raw material solution: Add the propylene glycol to an appropriate amount of water, then add the active ingredient, stir and mix to obtain raw material solution; (2) Preparation of the first tackifier solution: The crosslinking regulator, pH regulator and the first tackifier are added to the remaining water in sequence and stirred and mixed at a certain temperature to obtain the first tackifier solution; (3) Preparation of glycerol suspension: The skeleton material, the second thickener, the filler and the crosslinking agent are added to glycerol in sequence and stirred to obtain glycerol suspension; (4) The raw material solution and the first thickener solution are stirred and mixed to obtain a mixed matrix; (5) Add the glycerol suspension to the mixed matrix and stir to obtain a gel paste; (6) The gel paste is applied in a coating machine to obtain the gel plaster.

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