Cleaning method of patch equipment

Abstract

The invention discloses a cleaning method of patch equipment in the technical field of transdermal patches, and aims to solve the problem that the patch equipment is difficult to clean in the prior art. The method comprises the following steps: tearing off colloid adhered to the surface of patch equipment; cleaning the patch device with a sodium bicarbonate solution; cleaning the patch device with purified water; cleaning patch equipment by using a high-concentration ethanol solution; the oil-soluble patch cleaning agent is suitable for cleaning oil-soluble patch equipment, and can achieve the effect of preventing chemical residues of the equipment from influencing the quality of the patch.

Description

Technical Field

[0001] This invention relates to the field of transdermal patch technology, and more particularly to a cleaning method for patch devices, applicable to the cleaning of oil-soluble patch devices. Background Technology

[0002] Patches generally consist of a matrix, a backing layer, and an anti-stick protective layer. The matrix of oil-soluble patches contains a variety of high molecular polymers, such as acrylic polymers, silicone polymers, natural rubber, polybutene, and styrene-isoprene-styrene block copolymers (SIS), styrene-butadiene-styrene block copolymers (SBS), polyisobutylene, and other high molecular substances. The colloids prepared using this type of matrix in the production process have high viscosity, and it is difficult to find a solvent that can completely dissolve the colloid directly. The equipment for producing patches is difficult to clean, and cross-contamination can easily occur between production batches. Summary of the Invention

[0003] The purpose of this invention is to provide a cleaning method for patch preparation equipment, so as to achieve cleaning of the preparation equipment and avoid cross-contamination between production batches.

[0004] To achieve the above objectives, the present invention is implemented using the following technical solution:

[0005] This invention provides a cleaning method for a patch device, comprising the following steps:

[0006] Peel off the adhesive residue adhering to the surface of the patch application device;

[0007] Clean the patch device with sodium bicarbonate solution;

[0008] Use water-based cleansing patch equipment;

[0009] Clean the patch application equipment using a high-concentration ethanol solution.

[0010] In the above technical solution, sodium bicarbonate solution and high-concentration ethanol are used as cleaning agents, which clean the equipment surface relatively smoothly. At the same time, sodium bicarbonate is also a water-soluble substance, which is easy to remove and leaves no residue. It can dissolve the colloid without leaving any residue, thus achieving the cleaning of the patching equipment and avoiding cross-contamination between production batches.

[0011] Optionally, the patch is an oil-soluble patch, and the compounds contained in the oil-soluble patch include nonsteroidal anti-inflammatory analgesics, such as aspirin, loxoprofen, indomethacin, ketoprofen, meloxicam, celecoxib, etoricoxib, piroxicam, meloxicam, sulindac, flurbiprofen, diclofenac, and ibuprofen, as well as one or more combinations of pharmaceutically acceptable salts of the above compounds.

[0012] Furthermore, the removal of the adhesive adhering to the surface of the patch device includes tearing by hand or by using a cleaning spatula.

[0013] In the above technical solutions, the cleaning shovel is faster for cleaning large equipment, and tearing it by hand is less likely to scratch the equipment.

[0014] Furthermore, the cleaning is performed using a mercerized towel or a polyester fiber cloth.

[0015] In the above technical solutions, mercerized towels or polyester fiber cloths can absorb cleaning agents well, and the soft material will not leave scratches that are difficult to clean on the surface of the equipment. Using mercerized towels or polyester fiber cloths to apply external force after the cleaning agent has dissolved can achieve a more thorough cleaning.

[0016] Furthermore, in the process of using sodium bicarbonate solution to clean the patch equipment, the ratio of sodium bicarbonate solution usage to equipment area is 0.02 kg / 100 cm². 2 .

[0017] In the above technical solutions, using too little sodium bicarbonate solution makes cleaning difficult, while using too much solution can easily result in sodium bicarbonate residue.

[0018] Furthermore, the sodium bicarbonate solution has a volume fraction of 5%.

[0019] The sodium bicarbonate solution within the volume fraction range of the above technical solution can effectively clean the colloidal residue on the equipment surface without producing sodium bicarbonate residue, which would affect the subsequent production of the patch.

[0020] Furthermore, the device using purified water to clean the patch is cleaned at least three times.

[0021] In the above technical solution, cleaning more than 3 times can better remove the residue of sodium bicarbonate solution.

[0022] Furthermore, cleaning methods include one or a combination of wiping and rinsing.

[0023] In the above technical solutions, wiping is convenient for small equipment and saves cleaning time, while rinsing is suitable for large equipment and is easy and simple to operate.

[0024] Furthermore, in the device for cleaning the patch using a high-concentration ethanol solution, the ratio of the high-concentration ethanol solution usage to the device area is 0.03 kg / 100 cm². 2

[0025] In the above technical solutions, the ratio is less than 0.03 kg / 100 cm 2 It can leave chemical residues that are difficult to clean.

[0026] Furthermore, the volume fraction of the high-concentration ethanol solution is 80% to 95%.

[0027] In the above technical solutions, if the volume fraction of the ethanol solution is too small, it is difficult to dissolve chemical residues and clean them thoroughly.

[0028] Furthermore, after cleaning the patch device with a high-concentration ethanol solution, there are no visible residues on the device surface.

[0029] In the above technical solutions, the absence of visible residue on the equipment surface is a simple indicator for evaluation. Equipment that achieves this level of cleanliness will generally meet the standards for chemical residue during testing.

[0030] Compared with the prior art, the beneficial effects achieved by the present invention are as follows:

[0031] Using sodium bicarbonate solution and high-concentration ethanol as cleaning agents, the equipment surface is cleaned relatively smoothly. Sodium bicarbonate is also a water-soluble substance, which is easy to remove and leaves little residue. It can dissolve the colloid without leaving any residue, thus achieving the cleaning of the patch equipment, avoiding cross-contamination between production batches, and solving the quality problems caused by the difficulty in cleaning the production equipment. Attached Figure Description

[0032] To more clearly illustrate the technical solutions in the embodiments of this disclosure or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this disclosure. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0033] Figure 1 This is a chromatogram of the reference solution 1 of the detection example 1 of the cleaning method for the flurbiprofen patch device provided by the present invention;

[0034] Figure 2 This is a chromatogram of the reference solution 2 of the detection example 1 of the cleaning method for the flurbiprofen patch device provided by the present invention;

[0035] Figure 3 This is the chromatogram of sample 250801-H01 from Example 1 of the detection method for the cleaning method of the flurbiprofen patch device provided by the present invention.

[0036] Figure 4 This is the chromatogram of sample 250801-H02 from Example 1 of the detection method for the cleaning method of the flurbiprofen patch device provided by the present invention.

[0037] Figure 5 This is the chromatogram of sample 250801-H03 from test example 1 of the cleaning method for the flurbiprofen patch device provided by the present invention.

[0038] Figure 6 This is the chromatogram of sample 250801-H04 from Example 1 of the detection method for the cleaning method of the flurbiprofen patch device provided by the present invention. Detailed Implementation

[0039] The above content is further illustrated below with specific embodiments, but it should not be construed as limiting the scope of the invention to the following embodiments. All technologies implemented based on the above content of this invention fall within the scope of this invention.

[0040] It should be understood that all experimental procedures not detailed in the experiment are routine experimental procedures well known to those skilled in the art.

[0041] Example 1

[0042] This embodiment uses flurbiprofen patches as an example to provide the equipment and cleaning supplies needed for cleaning flurbiprofen patches, including the following:

[0043] 1. Preparation of a simulation device for producing flurbiprofen patches, comprising the following steps:

[0044] Five kg each of the colloidal matrix prepared using 2% flurbiprofen, 30% SIS, 10% polyisobutylene, 18% terpene resin and 40% liquid paraffin were added to three 20L stainless steel drums. The colloidal matrix was melted by heating to 150°C and stirred to ensure that the colloidal matrix fully contacts the inner wall of the stainless steel drum. The resulting stainless steel drum with the colloidal matrix adhering to the inner wall was used as a simulation device for the production of flurbiprofen patches.

[0045] 2. Prepare a silk towel as a cleaning tool.

[0046] 3. Prepare liquid paraffin, purified water, 95% ethanol, 5% sodium bicarbonate solution, and 2% sodium hydroxide solution as cleaning agents.

[0047] Example 2

[0048] This embodiment provides a cleaning method for flurbiprofen patches, including the following steps:

[0049] First, use your hands to peel off the main part of the adhesive adhering to the inner wall of the stainless steel bucket. Then, use a silk towel soaked in 0.5 kg of 5% sodium bicarbonate solution to wipe away the remaining adhesive on the inner wall. Next, wipe it three times with 5.0 kg of purified water to remove the remaining sodium bicarbonate solution. Finally, use a silk towel soaked in 0.8 kg of 95% ethanol to wipe away the remaining adhesive on the inner wall until there is no visible adhesive left.

[0050] In some other embodiments, the cleaning method may be replaced by rinsing instead of wiping.

[0051] Comparative Example 1

[0052] This comparative example provides a cleaning method for flurbiprofen patches, including the following steps:

[0053] First, use your hands to peel off the main part of the adhesive adhering to the inner wall of the stainless steel bucket. Then, use a silk towel dipped in 0.2 kg of liquid paraffin to wipe away the remaining adhesive on the inner wall until there is no visible adhesive left. Finally, use a silk towel dipped in 5.0 kg of purified water to wipe the surface three times.

[0054] Comparative Example 2

[0055] This comparative example provides a cleaning method for flurbiprofen patches, including the following steps:

[0056] First, use your hands to peel off the main part of the adhesive adhering to the inner wall of the stainless steel bucket. Then, use a silk towel soaked in 0.8 kg of 95% ethanol to wipe away the remaining adhesive on the inner wall until no visible adhesive remains.

[0057] Comparative Example 3

[0058] This comparative example provides a cleaning method for flurbiprofen patches, including the following steps:

[0059] First, use your hands to peel off the main part of the adhesive adhering to the inner wall of the stainless steel bucket. Then, use a silk towel soaked in 0.5 kg of 2% sodium hydroxide solution to wipe away the remaining adhesive on the inner wall. Next, wipe it three times with 5.0 kg of purified water to remove the remaining sodium hydroxide solution. Finally, use 0.8 kg of 95% ethanol to wipe away the remaining adhesive on the inner wall until there is no visible adhesive left.

[0060] Detection Example 1

[0061] This test example provides a method for detecting chemical residues after cleaning using the cleaning methods of Examples 2 and Comparative Examples 1-3, including the following:

[0062] 1. Chemical residue sampling

[0063] (1) Preparation of materials and equipment: dust-free cotton swabs, 50ml of 75% ethanol (including bottle / test tube), stoppered test tubes or sampling bottles;

[0064] (2) Sampling method: The sampling personnel soaked the cotton swab in 75% ethanol. After the cotton swab was saturated, it was pressed against the mouth of the test tube to squeeze out the excess solvent. Holding the cotton swab, within a 5cm×5cm sampling area on the inner wall, the head of the cotton swab was pressed against the sampling surface and slightly bent (to generate a certain friction force between the cotton swab and the equipment). The sampling surface was wiped steadily and slowly, moving from one side to the other while moving forward. The surface of the stainless steel bucket within the pre-marked area was wiped evenly with force, and the wiping process should cover the entire surface. The cotton swab was flipped over so that the other side was also wiped, but perpendicular to the direction of the previous wiping. The wiped cotton swab was cut off and placed into a marked stoppered test tube, sealed, and the tube was sealed to avoid external contamination. The sampling batch numbers of Example 2 and Comparative Examples 1-3 are shown in Table 1.

[0065] 2. Chemical residue detection

[0066] (1) The experimental materials are shown in Table 1.

[0067] Table 1: Testing instruments, reagents and samples.

[0068]

[0069] (2) Chromatographic conditions

[0070] Chromatographic column: Agilent Eclipse XDB-C18 (4.6×250mm, 5μm), QCLC250402; mobile phase: mobile phase A: water-glacial acetic acid (60:5, v:v), mobile phase B: acetonitrile; flow rate: 1.0 ml / min; column temperature: 35℃; injection volume: 10 μl; wavelength: 245 nm; gradient elution program is shown in Table 2.

[0071] Table 2: Gradient elution procedure for detecting chemical residues.

[0072]

[0073] (3) Preparation of reagents and samples

[0074] Mobile phase A: Measure 1800 ml of purified water and 150 ml of glacial acetic acid, place them in a beaker, mix well, and sonicate to obtain mobile phase A.

[0075] Diluent: Ethyl acetate-methanol (60:40, v:v): Measure 600 ml of ethyl acetate and 400 ml of methanol and mix well.

[0076] Blank solution: Measure 1 ml of diluent, place it in a 10 ml volumetric flask, dilute to the mark with methanol, and shake well.

[0077] Reference solution: Accurately weigh approximately 20 mg of flurbiprofen reference standard and transfer it entirely to a 50 ml volumetric flask. Dilute to the mark with ethyl acetate:methanol = 30:20 to prepare the flurbiprofen reference stock solution. Accurately measure 1 ml of the reference stock solution and transfer it to a 10 ml volumetric flask. Dilute to the mark with methanol and mix well (containing approximately 0.04 mg / ml of flurbiprofen). Prepare two parallel solutions.

[0078] 250801-H01 solution: Take 250801-H01 (a wiping swab placed in a clean centrifuge tube), accurately measure 10 ml of methanol to immerse it, stopper and seal, sonicate for 10 min, filter with a syringe filter, and collect the filtrate.

[0079] 250801-H02 solution: Take 250801-H02 (a wiping swab placed in a clean centrifuge tube), accurately measure 10 ml of methanol to immerse it, stopper and seal, sonicate for 10 min, filter with a syringe filter, and collect the filtrate.

[0080] 250801-H03 solution: Take 250801-H03 (placed in a clean centrifuge tube with a wiping swab), accurately measure 10 ml of methanol to immerse it, stopper and seal, sonicate for 10 min, filter with a syringe filter, and collect the filtrate.

[0081] 250801-H04 solution: Take 250801-H04 (placed in a clean centrifuge tube with a wiping swab), accurately measure 10 ml of methanol to immerse it, stopper and seal, sonicate for 10 min, filter with a syringe filter, and collect the filtrate.

[0082] (3) HPLC analysis

[0083] Accurately measure 20 μl of each of the above solutions and inject them into the high-performance liquid chromatograph, and record the chromatograms.

[0084] Calculate the residual amount of flurbiprofen in the test sample using the following formula:

[0085] R = (M 对照 ×1000×P 对照 ×A 供试品 ×V 供试品 ) / (V 对照 ×A 对均 ×S 擦 ×L);

[0086] In the formula, R: flurbiprofen residue, μg / cm³ 2 ;

[0087] M 对照 The sample weight of flurbiprofen corresponding to reference solution 1, in mg;

[0088] P 对照Flurbiprofen reference standard content, %

[0089] A 供试品 : The peak area of ​​flurbiprofen in the chromatogram of the test solution;

[0090] V 供试品 The dilution factor of the test solution;

[0091] V 对照 The dilution factor of the reference solution;

[0092] A 对均 The average peak area of ​​the six flurbiprofen injections in the chromatogram of reference solution 1;

[0093] S 擦 Wiping area, cm 2 ;

[0094] L: Wipe recovery rate (minimum average recovery rate).

[0095] Acceptable standards for chemical residues: Flurbiprofen residue ≤ 9.91 μg / cm³ 2 .

[0096] 3. Results of chemical residue detection

[0097] The chemical residue detection results after cleaning the flurbiprofen patch (250801) simulation equipment using the cleaning methods of Examples 2 and Comparative Examples 1-3 are shown in Table 3. The chromatograms of the reference solution and samples 250801-H01~250801-H04 are shown in Table 3. Figures 1-6 As shown, 250801-H03 is the sample from Example 2, 250801-H01 is the sample from Comparative Example 1, 250801-H02 is the sample from Comparative Example 2, and 250801-H04 is the sample from Comparative Example 3. The calculation process is illustrated using 250801-H04 as an example:

[0098] Residual amount (μg / cm) 2 = (20.24 × 1000 × 99.9% × 32.53 × 10) / (500 × 1760.29 × 25);

[0099] Table 3: Detection results of chemical residues.

[0100]

[0101] A flurbiprofen patch simulation device was prepared by directly contacting the colloid of the patch with a stainless steel surface. Four cleaning methods, as described in Example 2 and Comparative Examples 1-3, were used for cleaning. After cleaning, samples were taken from the surface of the simulation device using a wiping method, and analyzed according to the validated cleaning residue analysis method, HPLC. The results showed that only Comparative Example 3, using a 2% sodium hydroxide solution for cleaning, detected residues. The other three methods did not detect any residues.

[0102] The following analysis examines the drawbacks of the three cleaning methods that yielded no detected residue: Comparative Example 1, using liquid paraffin as a cleaning agent, while yielding no detected residue, still carries the risk of residual liquid paraffin on the equipment surface due to its insolubility, which cannot be completely removed with purified water. Comparative Example 2, using only 95% ethanol as a cleaning agent, also yielded no detected residue, but the equipment surface remained uncleaned, with oily substances remaining. In contrast, Example 2, using a 5% sodium bicarbonate solution and 95% ethanol as cleaning agents, resulted in a smoother equipment surface. Furthermore, sodium bicarbonate is water-soluble, making it easy to remove and less likely to leave residue.

[0103] Therefore, the cleaning method of Example 2 was used for the flurbiprofen patch production equipment: First, manually peel off the adhesive adhering to the surface of the equipment until there are no large pieces of adhesive. Then, use a silk towel dipped in 5% sodium bicarbonate solution to wipe the remaining adhesive on the inner wall. Next, wipe it three times with purified water to remove the remaining sodium bicarbonate solution. Finally, use a silk towel dipped in 95% ethanol to wipe the remaining inner wall until there is no visible adhesive.

[0104] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for cleaning a patch application device, characterized in that, Includes the following steps: Peel off the adhesive residue adhering to the surface of the patch application device; Clean the patch device with sodium bicarbonate solution; Use purified water to clean the patch device; Clean the patch application equipment using a high-concentration ethanol solution.

2. The cleaning method for the patch device according to claim 1, characterized in that, The removal of the adhesive adhering to the surface of the patch device includes tearing by hand or using a cleaning spatula.

3. The cleaning method for the patch device according to claim 1, characterized in that, The cleaning is performed using a mercerized towel or polyester fiber cloth.

4. The cleaning method for the patch device according to claim 1, characterized in that, The ratio of sodium bicarbonate solution usage to the area of ​​the cleaning patch device is 0.02 kg / 100 cm². 2 .

5. The cleaning method for the patch device according to claim 4, characterized in that, The sodium bicarbonate solution has a volume fraction of 5%.

6. The cleaning method for the patch device according to claim 1, characterized in that, The device uses purified water to clean the patches, and cleans them more than 3 times.

7. The cleaning method for the patch device according to claim 1, characterized in that, Cleaning methods include wiping and rinsing, or a combination thereof.

8. The cleaning method for the patch device according to claim 1, characterized in that, The ratio of high-concentration ethanol solution usage to the area of ​​the cleaning patch device is 0.03 kg / 100 cm². 2 .

9. The cleaning method for the patch device according to claim 8, characterized in that, The volume fraction of the high-concentration ethanol solution is 80%~95%.

10. The cleaning method for the patch device according to claim 1, characterized in that, The device is cleaned with a high-concentration ethanol solution until no visible residue remains on the surface.

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