A folic acid composition, a folic acid patch and a preparation method thereof

Abstract

The application discloses a folic acid composition, a folic acid patch and a preparation method thereof. The folic acid composition comprises folic acid, pressure-sensitive adhesive, a fatty compound and an alcohol compound; the fatty compound comprises a fatty acid and / or a fatty acid ester. The folic acid patch comprising the folic acid composition improves the bioavailability of folic acid, reduces the administration frequency, avoids the liver first-pass effect, has good folic acid penetration stability, and the folic acid content in the folic acid patch is basically unchanged after long-time placement.

Description

Technical Field

[0001] This invention relates to a folic acid composition, folic acid patches, and a method for preparing the same. Background Technology

[0002] Folic acid is a B vitamin that plays a vital role in human metabolism and influences neural tube development. Because the human body lacks the mechanism to synthesize folic acid, it must be obtained from external sources through nutritional supplementation. Since food contains relatively little folic acid, medication has become an important way for the body to obtain it. Studies have shown that folic acid supplementation during early pregnancy effectively prevents neural tube defects in newborns, and consistent folic acid intake throughout pregnancy has beneficial effects on the growth and development of both the mother and fetus.

[0003] After oral administration, folic acid is absorbed in the upper jejunum and must pass through the portal vein to reach the liver for further systemic circulation. This process results in partial metabolism of the drug in the liver. When large doses are required clinically, a significant amount of folic acid enters the circulatory system and is excreted through the kidneys. This increases the burden on the kidneys, potentially leading to kidney damage, and also reduces the absorption of the active ingredient, thus lowering the therapeutic effect. Clinically, increasing folic acid intake is generally desired, but the clinical efficacy is not ideal.

[0004] A domestically published patent (patent number: 97106707.4) mentions a folic acid supplement marketed under the name "Sili'an". Sili'an effectively prevents neural tube defects, but its active ingredient is released slowly, preventing pregnant women from quickly absorbing and replenishing the vitamin. Commonly available folic acid preparations are oral tablets, with relatively limited dosage forms, available in 0.4mg and 5mg strengths. It is generally recommended that pregnant women take 0.4–0.8mg of folic acid tablets daily. If there is a history of neural tube defects or other abnormalities, it is recommended to take 4mg daily. Taking a fixed daily dose of folic acid carries the risk of missed doses, potentially affecting the health of both the mother and fetus. The time to peak folic acid levels in the body after oral administration is short, ranging from 5 to 20 minutes, with a Cmax as short as 1 hour. After folic acid is broken down in the body, its plasma half-life is approximately 40 minutes, necessitating daily supplementation for pregnant women. Long-term adherence to medication requires high medication compliance from pregnant women. Frequent administration can also place a greater physiological burden on pregnant women experiencing nausea and vomiting, further reducing their compliance. Therefore, the market lacks a folic acid preparation that can reduce the frequency of folic acid administration, provide long-acting controlled release, improve folic acid bioavailability, be convenient to administer, and enhance medication compliance in pregnant women. Summary of the Invention

[0005] To address the problems of high frequency of oral folic acid administration, low bioavailability, and the first-pass effect in the liver in existing technologies, this invention proposes a folic acid composition, a folic acid patch, and a method for preparing the same. The folic acid patch containing this folic acid composition improves the bioavailability of folic acid, reduces the frequency of administration, avoids the first-pass effect in the liver, has good folic acid osmotic stability, and the folic acid content in the folic acid patch remains essentially unchanged after prolonged storage.

[0006] The present invention mainly adopts the following technical solutions to solve the above-mentioned technical problems:

[0007] The present invention provides a folic acid composition comprising folic acid, pressure-sensitive adhesive, fatty acid compound, and alcohol compound; wherein the fatty acid compound comprises fatty acid and / or fatty acid ester.

[0008] In this invention, the folic acid, the fatty compound, and the alcohol compound are preferably dispersed in the pressure-sensitive adhesive in the folic acid composition.

[0009] In this invention, the folic acid can be conventional folic acid in the art, with the molecular formula C0. 19 H 19 N7O6.

[0010] In this invention, the pressure-sensitive adhesive is a commonly used pressure-sensitive adhesive in the field of medicated patches, generally a polyacrylate pressure-sensitive adhesive.

[0011] In this invention, the weight ratio of folic acid to pressure-sensitive adhesive is preferably 1:(35-70), more preferably 1:(50-70), for example 1:35 or 1:70.

[0012] In this invention, the number of carbon atoms in the aliphatic compound is preferably 7 to 21, for example, 17.

[0013] In this invention, the fatty acid can be understood in the conventional sense in the art, and is generally represented by the chemical formula R-COOH. R is preferably a C15-C20 substituted or unsubstituted alkyl group, or a C15-C20 substituted or unsubstituted alkenyl group, for example, an unsubstituted C17 alkenyl group with 1 to 3 alkenyl groups.

[0014] Preferably, R is a straight-chain alkyl or a straight-chain alkenyl.

[0015] The fatty acid is preferably oleic acid.

[0016] In this invention, the fatty acid ester can be understood in the conventional sense in the art, and is generally represented by the chemical formula R1-COO-R2. R1 and R2 refer to substituted or unsubstituted alkyl groups of C2 to C20, or substituted or unsubstituted alkenyl groups of C2 to C20, such as substituted or unsubstituted alkyl or alkenyl groups of C2, C3, C13 or C17.

[0017] The total number of carbon atoms in R1 and R2 is 6 to 19.

[0018] The fatty acid ester is preferably one or more of isopropyl myristate, isopropyl butyrate, and ethyl oleate, for example, isopropyl myristate.

[0019] In this invention, the alcohol compounds can be understood in the conventional sense in the art, generally represented by R-(OH). n The chemical formula is represented in which n is preferably 2 to 3 and R refers to a C2 to C10 substituted or unsubstituted alkyl group, for example, a C3, C4, C5 or C6 substituted or unsubstituted alkyl group.

[0020] The alcohols preferably include one or more of ethanol, propylene glycol, isopropanol and 1,2-butanediol, for example, propylene glycol.

[0021] In this invention, the weight ratio of the folic acid to the total weight of the fatty compound and the alcohol compound is preferably 1:(3-20), more preferably 1:(4-10), for example 1:9.

[0022] In this invention, the weight ratio of the aliphatic compound to the alcohol compound is preferably 1:(1-20), more preferably 1:(1-10), for example 1:8.

[0023] In this invention, the folic acid content is preferably 0.5-20% w / w, more preferably 1-10% w / w, for example about 1.25% w / w, 2.56% w / w, 2.41% w / w, 1.1% w / w or 1.15% w / w, where the content refers to the weight ratio of folic acid in the folic acid composition.

[0024] In this invention, the folic acid composition preferably consists of the folic acid, the pressure-sensitive adhesive, the fatty compound, and the alcohol compound.

[0025] In a preferred embodiment of the present invention, the folic acid composition comprises folic acid, polyacrylate pressure-sensitive adhesive, isopropyl butyrate, and ethanol, wherein the weight ratio of folic acid to polyacrylate pressure-sensitive adhesive is 1:70, the weight ratio of folic acid to the total weight of isopropyl butyrate and ethanol is 1:9, and the weight ratio of isopropyl butyrate and ethanol is 1:8.

[0026] In a preferred embodiment of the present invention, the folic acid composition comprises folic acid, polyacrylate pressure-sensitive adhesive, isopropyl myristate, and propylene glycol, wherein the weight ratio of folic acid to polyacrylate pressure-sensitive adhesive is 1:70, the weight ratio of folic acid to the total weight of isopropyl myristate and propylene glycol is 1:9, and the weight ratio of isopropyl myristate to propylene glycol is 1:8.

[0027] In a preferred embodiment of the present invention, the folic acid composition comprises folic acid, polyacrylate pressure-sensitive adhesive, oleic acid and isopropanol, wherein the weight ratio of folic acid to polyacrylate pressure-sensitive adhesive is 1:70, the weight ratio of folic acid to the total weight of oleic acid and isopropanol is 1:9, and the weight ratio of oleic acid to isopropanol is 1:8.

[0028] In a preferred embodiment of the present invention, the folic acid composition comprises folic acid, polyacrylate pressure-sensitive adhesive, ethyl oleate, and 1,2-butanediol, wherein the weight ratio of folic acid to polyacrylate pressure-sensitive adhesive is 1:70, the weight ratio of folic acid to the total weight of ethyl oleate and 1,2-butanediol is 1:9, and the weight ratio of ethyl oleate to 1,2-butanediol is 1:8.

[0029] In a preferred embodiment of the present invention, the folic acid composition comprises folic acid, polyacrylate pressure-sensitive adhesive, isopropyl myristate, and propylene glycol, wherein the weight ratio of folic acid to polyacrylate pressure-sensitive adhesive is 1:70, the weight ratio of folic acid to the total weight of isopropyl myristate and propylene glycol is 1:3, and the weight ratio of isopropyl myristate to propylene glycol is 1:5.

[0030] In a preferred embodiment of the present invention, the folic acid composition comprises folic acid, polyacrylate pressure-sensitive adhesive, isopropyl myristate, and propylene glycol, wherein the weight ratio of folic acid to polyacrylate pressure-sensitive adhesive is 1:35, the weight ratio of folic acid to the total weight of isopropyl myristate and propylene glycol is 1:5.5, and the weight ratio of isopropyl myristate to propylene glycol is 1:10.

[0031] In a preferred embodiment of the present invention, the folic acid composition comprises folic acid, polyacrylate pressure-sensitive adhesive, isopropyl butyrate, and propylene glycol, wherein the weight ratio of folic acid to polyacrylate pressure-sensitive adhesive is 1:70, the weight ratio of folic acid to the total weight of isopropyl butyrate and propylene glycol is 1:9, and the weight ratio of isopropyl butyrate to propylene glycol is 1:8.

[0032] In a preferred embodiment of the present invention, the folic acid composition comprises folic acid, polyacrylate pressure-sensitive adhesive, ethyl oleate and propylene glycol, wherein the weight ratio of folic acid to polyacrylate pressure-sensitive adhesive is 1:70, the weight ratio of folic acid to the total weight of "ethyl oleate and propylene glycol" is 1:9, and the weight ratio of ethyl oleate to propylene glycol is 1:8.

[0033] In a preferred embodiment of the present invention, the folic acid composition comprises folic acid, polyacrylate pressure-sensitive adhesive, isopropyl myristate, and propylene glycol, wherein the weight ratio of folic acid to polyacrylate pressure-sensitive adhesive is 1:70, the weight ratio of folic acid to the total weight of isopropyl myristate and propylene glycol is 1:20, and the weight ratio of isopropyl myristate to propylene glycol is 1:19.

[0034] In a preferred embodiment of the present invention, the folic acid composition comprises folic acid, polyacrylate pressure-sensitive adhesive, isopropyl myristate, and propylene glycol, wherein the weight ratio of folic acid to polyacrylate pressure-sensitive adhesive is 1:70, the weight ratio of folic acid to the total weight of isopropyl myristate and propylene glycol is 1:16, and the weight ratio of isopropyl myristate to propylene glycol is 1:15.

[0035] In this invention, the preparation method of the folic acid composition preferably includes the following steps: mixing a dispersion containing the folic acid, the fatty compound and the alcohol compound with a solution of the pressure-sensitive adhesive, allowing it to stand to obtain a raw material composition of the folic acid composition, and then drying the raw material composition of the folic acid composition.

[0036] In this invention, the dispersant in the dispersion can be water.

[0037] Preferably, the weight percentage of water to the weight percentage of the raw material composition is 20% to 40%, for example, about 21.98%, 25%, 36.14%, or 38.46%.

[0038] In this invention, the solvent in the solution of the pressure-sensitive adhesive can be conventional in the art, preferably including one or more of ethyl acetate, heptane, hexane, methanol, ethanol and isopropanol.

[0039] In this invention, the pressure-sensitive adhesive accounts for 20-50% of the total weight of the pressure-sensitive adhesive solution.

[0040] In this invention, the mixing method can be conventional in the art, such as magnetic stirring.

[0041] In this invention, the settling time can be conventional in the art, sufficient to allow the air bubbles in the mixture obtained after mixing to completely disappear.

[0042] In this invention, the drying time can be conventional in the art, sufficient to evaporate the solvent.

[0043] The present invention also provides a folic acid patch comprising the above-mentioned folic acid composition and a protective film; wherein the folic acid composition is disposed on one side of the protective film.

[0044] As those skilled in the art will know in this invention, the folic acid composition is disposed in a layered structure on one side of the protective film.

[0045] In this invention, the protective film may be one or a mixture of polyethylene terephthalate film, polyethylene film and polypropylene film, preferably polyethylene terephthalate film.

[0046] In this invention, the surface of the protective film preferably contains fluorine and / or silicon.

[0047] In this invention, the surface of the protective film is preferably subjected to plasma treatment, fluorine coating treatment, or silicon coating treatment.

[0048] In this invention, those skilled in the art will know from the folic acid patch that the folic acid patch generally also includes a backing film. The backing film can be understood in the conventional sense, and generally the folic acid composition is disposed between the protective film and the backing film.

[0049] In this invention, the backing film may be one or more of polyethylene terephthalate, polypropylene, polyethylene, ethylene-vinyl acetate copolymer, and polyurethane.

[0050] In this invention, the backing film is preferably one or more composite films.

[0051] In this invention, the thicknesses of the folic acid composition, the protective film, and the backing film can be conventional in the art.

[0052] In this invention, the area of ​​the folic acid patch is preferably 5-100 cm². 2 More preferably 20-80cm 2 For example, 50cm 2 The area referred to is the area covered by the folic acid composition on each folic acid patch.

[0053] In this invention, the folic acid content per unit area of ​​the folic acid patch is 20-25 mg / cm². 2 .

[0054] The present invention also provides a method for preparing the folic acid patch, comprising the following steps: coating the raw material composition of the folic acid composition onto one side of the protective film, and then drying it.

[0055] The fatty compound is preferably as described above.

[0056] Preferably, the alcohol compounds are as described above.

[0057] In this invention, the protective film is preferably as described above.

[0058] In this invention, the drying temperature can be 40-50°C.

[0059] In this invention, the drying time can be 10 to 30 minutes.

[0060] In the preparation method of the folic acid patch of the present invention, after drying, a backing film is preferably attached to the upper surface of the folic acid composition.

[0061] The backing film is preferably as described above.

[0062] The present invention also provides a folic acid patch obtained by the above preparation method.

[0063] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0064] The reagents and raw materials used in this invention are all commercially available.

[0065] The positive and progressive effects of this invention are as follows:

[0066] This invention prepares folic acid in the form of a patch, using fatty compounds and alcohol compounds as a composite penetrant, and combining them with a certain weight ratio of folic acid to the composite penetrant to prepare a novel folic acid formulation.

[0067] Compared with currently available oral folic acid preparations, this product avoids the first-pass effect of the liver that may occur with oral administration, improves the bioavailability and therapeutic effect of the product, and does not produce the fluctuations in blood drug concentration caused by oral administration. The oral folic acid preparations are taken once a day, while the product of this invention prolongs the duration of drug action, reduces the frequency of administration, and enhances patient medication compliance.

[0068] The folic acid patch prepared by this invention has a high average transdermal penetration rate, and the folic acid release rate does not change over time, allowing for continuous and stable release. Furthermore, the folic acid content remains essentially unchanged after prolonged storage, demonstrating good stability of the folic acid patch. Attached Figure Description

[0069] Figure 1 The cumulative transdermal drug release-time curves for Examples 1-10 and Comparative Examples 1-4 are shown. Detailed Implementation

[0070] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0071] The reagents used in this invention are as follows:

[0072]

[0073]

[0074] The polyacrylate pressure-sensitive adhesive is polymerized from alkyl acrylate and acrylic acid; the protective film is made of a fluoropolymer anti-stick coating on one side, and the polymer is polyethylene terephthalate; the backing film is made of polyethylene.

[0075] Example 1

[0076] Take 1g of folic acid, 1g of isopropyl butyrate, and 8g of ethanol, mix them, and add them to 20ml of water to disperse thoroughly. Dissolve the polyacrylate pressure-sensitive adhesive in ethyl acetate to form a polyacrylate pressure-sensitive adhesive solution, with the polyacrylate pressure-sensitive adhesive accounting for 25% of the weight of the polyacrylate pressure-sensitive adhesive solution. Pour the above aqueous dispersion into 70g of the polyacrylate pressure-sensitive adhesive solution, stir for 20min at room temperature, sonicate for 30min, and let stand until the bubbles completely disappear to obtain a mixture. Coat the mixture evenly on a protective film, place it at 25℃ for 1h, then transfer it to an oven at 40℃ to dry for 30min, and then attach a backing film to obtain a drug content of 20mg / cm². 2 The folic acid patch has an area of ​​50cm². 2 .

[0077] The raw and auxiliary materials used in Example 1 are as follows:

[0078] raw materials Dosage folic acid 1g Polyacrylate pressure-sensitive adhesive 70g Isopropyl butyrate 1g ethanol 8g water 20ml total 100g

[0079] Example 2

[0080] Based on Example 1, isopropyl butyrate was replaced with isopropyl myristate, and ethanol was replaced with propylene glycol. All other aspects remained the same as in Example 1, resulting in a drug content of 20 mg / cm². 2 The folic acid patch has an area of ​​50cm². 2 .

[0081] The raw and auxiliary materials used in Example 2 are as follows:

[0082] raw materials Dosage folic acid 1g Polyacrylate pressure-sensitive adhesive 70g Isopropyl myristate 1g Propylene glycol 8g water 20ml total 100g

[0083] Example 3

[0084] Based on Example 1, isopropyl butyrate was replaced with oleic acid, and ethanol was replaced with isopropanol. All other aspects remained the same as in Example 1, resulting in a drug content of 20 mg / cm². 2 The folic acid patch has an area of ​​50cm². 2 .

[0085] The raw and auxiliary materials used in Example 3 are as follows:

[0086] raw materials Dosage folic acid 1g Polyacrylate pressure-sensitive adhesive 70g Oleic acid 1g Isopropanol 8g water 20ml total 100g

[0087] Example 4

[0088] Based on Example 1, isopropyl butyrate was replaced with ethyl oleate, and ethanol was replaced with 1,2-butanediol. All other aspects remained the same as in Example 1, resulting in a drug content of 20 mg / cm². 2 The folic acid patch has an area of ​​50cm². 2 .

[0089] The raw and auxiliary materials used in Example 4 are as follows:

[0090]

[0091]

[0092] Example 5

[0093] In this example, 2g of folic acid, 5g of propylene glycol, and 30ml of water were added, totaling 108g. All other components were the same as in Example 2, resulting in a drug content of 25mg / cm². 2 The folic acid patch has an area of ​​80cm². 2 .

[0094] The raw and auxiliary materials used in Example 5 are as follows:

[0095] raw materials Dosage folic acid 2g Polyacrylate pressure-sensitive adhesive 70g Isopropyl myristate 1g Propylene glycol 5g water 30ml total 108g

[0096] Example 6

[0097] In this example, 2g of folic acid, 10g of propylene glycol, and 30ml of water were added, totaling 113g. All other parameters were the same as in Example 2, resulting in a drug content of 25mg / cm². 2 The folic acid patch has an area of ​​80cm². 2 .

[0098] The raw and auxiliary materials used in Example 6 are as follows:

[0099] raw materials Dosage folic acid 2g Polyacrylate pressure-sensitive adhesive 70g Isopropyl myristate 1g Propylene glycol 10g water 30ml total 113g

[0100] Example 7

[0101] Based on Example 2, isopropyl myristate was replaced with isopropyl butyrate, while everything else remained the same as in Example 2, resulting in a drug content of 20 mg / cm². 2 The folic acid patch has an area of ​​50cm². 2 .

[0102] The raw and auxiliary materials used in Example 7 are as follows:

[0103]

[0104]

[0105] Example 8

[0106] Based on Example 2, isopropyl myristate was replaced with ethyl oleate, while everything else remained the same as in Example 2, resulting in a drug content of 20 mg / cm². 2 The folic acid patch has an area of ​​50cm². 2 .

[0107] The raw and auxiliary materials used in Example 8 are as follows:

[0108] raw materials Dosage folic acid 1g Polyacrylate pressure-sensitive adhesive 70g Ethyl oleate 1g Propylene glycol 8g water 20ml total 100g

[0109] Example 9

[0110] Based on Example 2, the amount of propylene glycol was replaced with 19g, while everything else remained the same as in Example 2, resulting in a drug content of 20mg / cm². 2 The folic acid patch has an area of ​​50cm². 2 .

[0111] The raw and auxiliary materials used in Example 9 are as follows:

[0112] raw materials Dosage folic acid 1g Polyacrylate pressure-sensitive adhesive 70g Isopropyl myristate 1g Propylene glycol 19g water 20ml total 111g

[0113] Example 10

[0114] Based on Example 2, the amount of propylene glycol was replaced with 15g, while everything else remained the same as in Example 2, resulting in a drug content of 20mg / cm². 2 The folic acid patch has an area of ​​50cm². 2 .

[0115] The raw and auxiliary materials used in Example 10 are as follows:

[0116] raw materials Dosage folic acid 1g Polyacrylate pressure-sensitive adhesive 70g Isopropyl myristate 1g Propylene glycol 15g water 20ml total 107g

[0117] Comparative Example 1

[0118] Based on Example 1, isopropyl butyrate was replaced with isopropyl myristate. 9g of isopropyl myristate was used, and ethanol was not added. All other steps remained the same as in Example 1, resulting in a drug content of 20mg / cm². 2 The folic acid patch has an area of ​​50cm². 2 .

[0119] The raw and auxiliary materials used in Comparative Example 1 are as follows:

[0120] raw materials Dosage folic acid 1g Polyacrylate pressure-sensitive adhesive 70g Isopropyl myristate 9g water 20ml total 100g

[0121] Comparative Example 2

[0122] Based on Example 1, 9g of isopropyl butyrate was used without adding ethanol, and all other steps were the same as in Example 1, resulting in a drug content of 20mg / cm². 2 The folic acid patch has an area of ​​50cm². 2 .

[0123] The raw and auxiliary materials used in Comparative Example 2 are as follows:

[0124] raw materials Dosage folic acid 1g Polyacrylate pressure-sensitive adhesive 70g Isopropyl butyrate 9g water 20ml total 100g

[0125] Comparative Example 3

[0126] Based on Example 1, 9g of ethanol was used, but isopropyl butyrate was not added; all other steps remained the same as in Example 1, resulting in a drug content of 20mg / cm². 2 The folic acid patch has an area of ​​50cm². 2 .

[0127] The raw and auxiliary materials used in Comparative Example 3 are as follows:

[0128] raw materials Dosage folic acid 1g Polyacrylate pressure-sensitive adhesive 70g ethanol 9g water 20ml total 100g

[0129] Comparative Example 4

[0130] Based on Example 1, but without isopropyl butyrate, and with ethanol replaced by propylene glycol (9g of propylene glycol), all other steps remained the same as in Example 1, resulting in a drug content of 20mg / cm². 2 The folic acid patch has an area of ​​50cm². 2 .

[0131] The raw and auxiliary materials used in Comparative Example 4 are as follows:

[0132] raw materials Dosage folic acid 1g Polyacrylate pressure-sensitive adhesive 70g Propylene glycol 9g water 20ml total 100g

[0133] Example 1

[0134] 1. In vitro transdermal permeation rate measurement:

[0135] The prepared folic acid patches were applied to the stratum corneum of nude mouse skin, sandwiched between the receiving and sample cells of a Franz vertical diffusion cell, with the dermis of the skin facing the receiving cell. The temperature was maintained at 37°C, and the receiving medium was physiological saline. Sodium penicillin was added to the medium to prevent skin necrosis. Samples were taken at 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours, and the sample concentration was determined using ultraviolet spectroscopy. A cumulative transdermal drug release-time curve was plotted, as shown below. Figure 1The type of drug release curve from each experimental group sample was determined based on the cumulative transdermal release-time linear regression equation over 12-72 hours. At the same time, the average transdermal penetration rate of each experimental group sample over 72 hours was calculated, as shown in Table 1.

[0136] Table 1. Average transdermal penetration rate of folic acid patches in Examples 1-10 and Comparative Examples 1-4 over 72 hours.

[0137]

[0138] Note: Zero-order release refers to the release rate of the active pharmaceutical ingredient not changing over time, that is, the release rate of the active pharmaceutical ingredient remains constant throughout the release cycle.

[0139] 2. Stability test:

[0140] Samples prepared in Examples 1-8 were sealed and stored at 25°C. Samples were taken at 0, 3, 6, 12 and 18 months respectively, and the folic acid content in each sample was determined by high performance liquid chromatography. The results are shown in Table 2.

[0141] Table 2 Stability test results

[0142]

[0143]

[0144] For patients, if the average transdermal penetration rate of folic acid patches is too low, the expected therapeutic effect will not be achieved, or there may be no therapeutic effect at all. The average transdermal penetration rate of the folic acid patches in Examples 1-10 of this invention is not less than 3.64 μg*cm. -2 *h -1 The maximum concentration can reach 5.75 μg*cm. -2 *h -1 This invention can meet the daily folic acid requirements of patients and achieve excellent therapeutic effects. In this invention, the weight ratio of folic acid and the composite permeabilizer formed by the "fatty compound and the alcohol compound" is 1:(3-20). Compared with existing technologies, this invention achieves a higher average transdermal penetration rate and better therapeutic effects while using less folic acid.

[0145] As shown in Table 1, the average transdermal penetration rate of Examples 1-10 was higher than that of Comparative Examples 1-4. This indicates that when only fatty compounds (Comparative Examples 1 and 2) or alcohol compounds (Comparative Examples 3 and 4) were used as permeabilizers, the average transdermal penetration rate of the samples was lower than that of Examples 1-10 when both fatty compounds and alcohol compounds were used as a combined permeabilizer, making it difficult to effectively promote the transdermal absorption of folic acid. Furthermore, compared to the single permeabilizers in the comparative examples, the combined permeabilizers of the present invention can achieve zero-order release, resulting in a sustained and stable therapeutic effect. As shown in Table 2, the folic acid degradation rate of Examples 1-10 and Comparative Examples 1-4 of the present invention was slow, with a maximum change in folic acid content of no more than 0.8% after 18 months of storage. In contrast, the two commercially available products showed changes in folic acid content of 1.54% and 1.52% respectively after 18 months of storage, indicating that the folic acid patches prepared using the method of the present invention have better stability compared to currently available commercial products.

[0146] According to the results of Examples 2, 5, 6, 9, and 10 in Table 1, the weight ratios of folic acid to the weights of the fatty compounds and alcohols in the five examples were 1:9, 1:3, 1:5.5, 1:20, and 1:16, respectively, with corresponding average transdermal penetration rates of 5.57, 4.68, 5.12, 3.64, and 4.93 μg*cm. -2 *h -1 The results above show that the dosage of the compound permeabilizer is not positively correlated with the average transdermal penetration rate of the folic acid patch. When the weight ratio of folic acid to the compound permeabilizer increases from 1:3 to 1:9, the average transdermal penetration rate increases. However, when the ratio is further increased to 1:20, the average transdermal penetration rate decreases to 3.64 μg*cm. -2 *h -1 As shown in Table 2, the changes in folic acid levels after 18 months of storage for the products of Examples 2, 5, 6, 9, and 10 were 0.49%, 0.66%, 0.58%, 0.73%, and 0.53%, respectively, indicating that the product of Example 2 had better stability. In the five examples of this invention, the optimal weight ratio of folic acid to the composite permeabilizer was 1:9, and the maximum average transdermal penetration rate was 5.57 μg*cm. -2 *h -1 It has the best stability.

[0147] Based on the results of Examples 2, 7, and 8 in Table 1, under the same conditions, the fatty compounds used in the three examples were isopropyl myristate, isopropyl butyrate, and ethyl oleate, respectively. The folic acid patches prepared using these three fatty compounds all achieved zero-order release, which is beneficial for stabilizing the therapeutic effect. However, the use of isopropyl butyrate and ethyl oleate was not conducive to improving the average transdermal penetration rate. Compared with Example 2, which used isopropyl myristate, the average transdermal penetration rate of Examples 7 and 8 decreased from 5.57 μg*cm. -2 *h -1 The concentrations decreased to 4.85 μg*cm. -2 *h -1 and 4.75μg*cm -2 *h -1 As shown in Table 2, the use of isopropyl butyrate and ethyl oleate is also detrimental to the stability of folic acid patches.

Claims

1. A folate composition, characterized in that, The folate composition comprises folate, polyacrylate pressure-sensitive adhesive, isopropyl myristate, and propylene glycol, wherein the weight ratio of folate to polyacrylate pressure-sensitive adhesive is 1:70, the weight ratio of folate to the total weight of "isopropyl myristate and propylene glycol" is 1:9, and the weight ratio of isopropyl myristate to propylene glycol is 1:

8. Alternatively, the folate composition comprises folate, polyacrylate pressure-sensitive adhesive, isopropyl myristate, and propylene glycol, wherein the weight ratio of folate to polyacrylate pressure-sensitive adhesive is 1:35, the weight ratio of folate to the total weight of "isopropyl myristate and propylene glycol" is 1:5.5, and the weight ratio of isopropyl myristate to propylene glycol is 1:

10.

2. The folate composition of claim 1, wherein, The preparation method of the folate composition comprises the following steps: mixing a dispersion liquid containing the folate, the isopropyl myristate, and the propylene glycol with a solution of the polyacrylate pressure-sensitive adhesive, and then standing to obtain a raw material composition of the folate composition, and drying the raw material composition of the folate composition.

3. The folate composition of claim 2, wherein, The solvent in the solution of the polyacrylate pressure-sensitive adhesive comprises one or more of ethyl acetate, heptane, hexane, methanol, ethanol, and isopropyl alcohol. And / or, the dispersant in the dispersion liquid is water. And / or, the polyacrylate pressure-sensitive adhesive accounts for 20% to 50% of the total weight of the solution of the polyacrylate pressure-sensitive adhesive.

4. The folate composition of claim 3, wherein, The weight percentage of the water to the raw material composition is 20% to 40%.

5. The folic acid composition according to claim 4, characterized in that, The weight percentage of the water to the raw material composition is 21.98%, 25%, 36.14%, or 38.46%.

6. A folic acid patch, characterized by It comprises the folate composition according to any one of claims 1 to 5 and a protective film; the folate composition is arranged on one side of the protective film.

7. The folic acid patch of claim 6, wherein The protective film is one or more of polyethylene terephthalate film, polyethylene film, and polypropylene film. And / or, the surface of the protective film contains fluorine and / or silicon. And / or, the surface of the protective film is subjected to plasma treatment, fluorine coating treatment, or silicon coating treatment. and / or, the area of the folic acid patch is 5-100 cm 2 ; the area refers to the area covered by the folic acid composition on each of the folic acid patches; And / or, the content of folic acid per unit area of the folic acid patch is 20-25 mg / cm 2 .

8. The folic acid patch of claim 7, wherein the folic acid is present in an amount of about 0.5 mg. The protective film is polyethylene terephthalate film.

9. The folic acid patch of claim 7, wherein the folic acid is present in an amount of about 0.5 mg. The folate patch has an area of 20-80 cm 2 .

10. The folic acid patch of claim 9, wherein the folic acid is present in an amount of about 0.5 mg. The area of the folic acid patch is 50 cm 2 .

11. A method of preparing a folic acid patch according to any one of claims 6 to 10, characterized by, It comprises the following steps: The raw material composition of the folate composition is coated on one side of the protective film, and then dried.

12. The method for preparing folic acid patches as described in claim 11, characterized in that, The drying temperature is 40 to 50°C. And / or, the drying time is 10 to 30 min. And / or, a backing film is attached to the upper surface of the folate composition after drying.

13. A folic acid patch, characterized in that, It is prepared by the preparation method according to claim 11 or 12.

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