Doxylamine succinate pyridoxine enteric-coated tablet and preparation method thereof

Abstract

The doxylamine succinate pyridoxine enteric-coated tablet comprises a tablet core and a coating layer, the coating layer comprises a first isolation layer, an enteric-coated layer and a second isolation layer, the materials of the enteric-coated layer comprise a plasticizer, an anti-sticking agent, a defoaming agent and a flexible coating material, and the flexible coating material accounts for 24-28% of the mass of the tablet core. By adding the flexible coating material, the stability of the pharmaceutical preparation is improved, the difference between batches is reduced, the drug dissolution rate reaches 90% or above, and the pharmaceutical preparation can be quickly released.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, in particular to doxylamine succinate and pyridoxine enteric-coated tablets and a preparation method thereof. Background Art

[0002] Nausea and vomiting (NVP) in pregnancy (also known as "morning sickness") is very common. It affects 50% to 80% of pregnant women to varying degrees. Usually occurring within the first 4 to 16 weeks of pregnancy, about 20% of women will continue to experience NVP for a long period of time. Some women may suffer from NVP until the end of their pregnancy. Nausea and vomiting have serious side effects. In severe cases, NVP can cause dehydration along with related salt and vitamin imbalances, seriously affecting the health of the woman and the fetus.

[0003] Doxylamine succinate: Doxylamine succinate is an ethanolamine antihistamine used to treat insomnia and allergic symptoms. It is often used in compound prescriptions. It has obvious sedative effects and also has mild antispasmodic and local anesthetic effects.

[0004] Pyridoxine hydrochloride: also known as vitamin B6, pyridoxal and pyridoxamine, exists in the body in the form of phosphate ester. It is a water-soluble vitamin that is stable in the air and easily decomposed and sublimated by light. Vitamin B6 preparations are used clinically to improve vitamin B6 deficiency and treat nausea and vomiting during pregnancy.

[0005] The drug currently sold in Canada under the trade name Diclectin (Duchesnay Inc.) is the mainstream preparation for the treatment of NVP, including the above-mentioned active ingredients: pyridoxine hydrochloride and doxylamine succinate. The preparation also includes the following excipients: cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, magnesium trisilicate, silicon dioxide and magnesium stearate. The compound preparation of doxylamine succinate / pyridoxine hydrochloride is named "DS-P". It is mainly a tablet and an enteric-coated preparation. Its safety and effectiveness in the treatment of NVP are recognized by the medical community. The enteric coating of the enteric-coated preparation can protect the tablet core from corrosion by gastric acid, so that it can safely pass through the stomach and eventually reach the intestines, dissolve in the alkaline environment of the intestines, and safely release the active ingredients to improve the bioavailability of the drug. The currently listed "DS-P" has the defects of too long enteric coating time, large in vitro dissolution variability, poor stability and slow dissolution rate during the production process.

[0006] CN1229112C provides an aqueous enteric-coated rapid-acting preparation containing doxylamine succinate and pyridoxine hydrochloride. The dissolution rate of the method is unstable and the batch-to-batch difference is large.

[0007] CN106794148B provides a solid oral dosage form, which has a complex content composition, a complicated preparation process and high cost.

[0008] Therefore, how to reduce the intra-batch and inter-batch dissolution differences, improve stability, and increase dissolution rate have become urgent issues to be solved in the preparation of doxylamine succinate and pyridoxine enteric-coated tablets. Summary of the invention

[0009] The object of the present invention is to provide a doxylamine succinate pyridoxine enteric-coated tablet and a preparation method thereof, so that the preparation has better stability and higher solubility.

[0010] To achieve the purpose of the present invention, the technical solution is as follows:

[0011] A doxylamine succinate and pyridoxine enteric-coated tablet comprises a tablet core and a coating layer, wherein the coating layer comprises a first isolation layer, an enteric layer and a second isolation layer, wherein the materials of the first isolation layer and the second isolation layer are both selected from one or more of a gastric-soluble film coating premix, gastric-soluble HPMC, HPC, PEG or PVP; the enteric layer materials comprise a plasticizer, an anti-adhesive agent, a defoamer and a flexible coating material, wherein the flexible coating material is selected from one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, carboxymethyl ethyl cellulose, methyl methacrylate-methylacrylate copolymer, methacrylate-ethyl acrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and shellac, and the flexible coating material accounts for 24-28% of the tablet core mass.

[0012] Further, the plasticizer is selected from polyethylene glycol or triethyl citrate; the anti-adherent is selected from talc; the defoamer is selected from simethicone. The plasticizer accounts for 0.1% to 2% of the mass of the tablet core; the anti-adherent accounts for 0.1% to 5% of the mass of the tablet core; the defoamer accounts for 0.01% to 1% of the mass of the tablet core. The plasticizer accounts for 0.1% to 2% of the mass of the tablet core, preferably 0.5% to 1.5%, and more preferably 0.7% to 1%. The anti-adherent accounts for 0.1% to 5% of the mass of the tablet core, preferably 0.5% to 4%, and more preferably 1% to 3%. The defoamer accounts for 0.01% to 1% of the mass of the tablet core, preferably 0.02% to 0.5%, and more preferably 0.03% to 0.1%.

[0013] Furthermore, the first isolation layer and the second isolation layer materials together account for 0.1% to 10% of the tablet core mass, preferably 1% to 8%, and more preferably 2% to 7%. Preferably, the first isolation layer is selected from the gastric soluble film coating premix YS-1-7474-CN, and the second isolation layer is selected from the gastric soluble film coating premix YS-1-7003-CN; the first isolation layer accounts for 3 to 4.5% of the tablet core mass; the second isolation layer accounts for 1 to 2% of the tablet core mass.

[0014] Further, the flexible coating material is selected from methacrylic acid-ethyl acrylate copolymer aqueous dispersion and ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, and the mass ratio of methacrylic acid-ethyl acrylate copolymer aqueous dispersion to ethyl acrylate-methyl methacrylate copolymer aqueous dispersion is (12-2): 1. Further, the mass ratio of methacrylic acid-ethyl acrylate copolymer aqueous dispersion to ethyl acrylate-methyl methacrylate copolymer aqueous dispersion is (12-10): 1.

[0015] Further, the tablet core includes pyridoxine hydrochloride, doxylamine succinate and excipients. The excipients include cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, magnesium trisilicate, silicon dioxide and magnesium stearate. Among them, the mass proportions of doxylamine succinate, pyridoxine hydrochloride, magnesium trisilicate, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate are 6.9%, 6.9%, 18.2%, 62.1%, 2.5%, 2.8% and 0.7% respectively.

[0016] The present application also provides a method for preparing doxylamine succinate pyridoxine enteric-coated tablets, the method comprising: mixing pyridoxine hydrochloride, doxylamine succinate and an excipient and compressing them into tablets to prepare tablet cores;

[0017] The tablet core is coated, including a first isolation layer, an enteric layer and a second isolation layer, wherein the materials of the first isolation layer and the second isolation layer are selected from one or more of gastric soluble film coating premix, gastric soluble HPMC, HPC, PEG or PVP; the enteric layer material includes a plasticizer, an anti-adherent agent, a defoamer and a flexible coating material, wherein the flexible coating material is selected from one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, carboxymethyl ethyl cellulose, methyl methacrylate-methacrylate copolymer, methacrylate-ethyl acrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and shellac, and the flexible coating material accounts for 24-28% of the tablet core mass.

[0018] Preferably, the first isolation layer is prepared by preparing a gastric-soluble film coating premix with a solid content of 8%, and coating the prepared tablet core with the first isolation layer; the enteric layer is prepared by mixing the flexible coating materials, adding the slip plasticizer, anti-adhesive agent, and defoaming agent into water, stirring evenly, adding them to the flexible coating material and stirring, and coating the tablet core coated with the first isolation layer with the enteric layer; the second isolation layer is prepared by preparing a gastric-soluble film coating premix with a solid content of 10%, and coating the tablet core coated with the first isolation layer and the enteric layer.

[0019] Furthermore, the tablet core preparation includes the following steps: mixing doxylamine succinate and silicon dioxide to obtain a premix; mixing the premix with pyridoxine hydrochloride to obtain an active ingredient mixture; mixing the active ingredient mixture with microcrystalline cellulose, magnesium trisilicate, croscarmellose sodium, and magnesium stearate in sequence; and tableting.

[0020] Compared with the prior art, the present invention has the following significant advantages: the stability of the drug preparation is improved by adding a flexible coating material: during the accelerated 3-month and 6-month process, the total impurities change less and the stability is better; the batch difference is small; the dissolution RSD value is small, the dissolution difference is small, and the dissolution is relatively stable; the dissolution rate of the drug preparation is improved, the dissolution reaches more than 90% in 15 minutes, and it can be released quickly to achieve a rapid antiemetic effect. DETAILED DESCRIPTION

[0021] Embodiments of the present invention will be described in detail below.

[0022] Example 1

[0023] The preparation method of doxylamine succinate pyridoxine enteric-coated tablets comprises the following steps:

[0024] ① Tablet preparation:

[0025] The prescribed amount of doxylamine succinate and colloidal silicon dioxide were manually mixed in a PE bag for 5 minutes, added to a crushing and granulating machine, passed through a 40-mesh sieve, and collected in a PE bag. The prescribed amount of pyridoxine hydrochloride was then added to the crushing and granulating machine, passed through a 40-mesh sieve, and added to the above PE bag, and continued to be manually mixed for 5 minutes;

[0026] Grind the prescribed amount of microcrystalline cellulose through a 40-mesh sieve and divide it into two equal parts, one part is then added to the above premix containing the two active ingredients, mixed evenly, and then the other part of microcrystalline cellulose is added and mixed;

[0027] After mixing, add the prescribed amount of magnesium trisilicate and croscarmellose sodium to the hopper mixer for mixing;

[0028] After mixing, add the prescribed amount of magnesium stearate to the hopper mixer for further mixing;

[0029] Tablets were compressed to a total core weight of 145 mg.

[0030] ② Preparation of coating layer:

[0031] Preparation of the first isolation layer: prepare a gastric-soluble film coating premix (transparent) with a solid content of 8%, place it in a coating barrel, control the tablet bed temperature at 37-45°C, and coat the prepared tablet cores with the first isolation layer, controlling the coating weight gain to be 3-4% of the tablet core weight;

[0032] Preparation of enteric layer: Add the prescribed amount of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion into methacrylic acid-ethyl acrylate copolymer aqueous dispersion while stirring to obtain a polymer aqueous dispersion of the mixture.

[0033] Add talcum powder, PEG400 and simethicone to an appropriate amount of purified water, homogenize with a homogenizer at 10000rpm for 5-10min to make them evenly dispersed, add them to the polymer water dispersion of the mixture while stirring for more than 1 hour before use to obtain the enteric coating solution, place the prepared enteric solution in a coating barrel, stir, control the tablet bed temperature at 34-42℃, place the tablet core wrapped with the first isolation layer, and start coating. The coating weight gain is 8-10% of the tablet core weight;

[0034] Preparation of the second isolation layer: prepare a gastric-soluble film coating premix (white) with a solid content of 10%, place it in a coating barrel, control the tablet bed temperature at 37-45°C, place the tablet cores coated with the first isolation layer and enteric layer, and start coating. The coating weight gain is 0.8-1.4% of the tablet core weight.

[0035] The specific tablet core and each coating layer prescription are shown in Table 1:

[0036] Table 1

[0037]

[0038] Example 2

[0039] The preparation method of doxylamine succinate pyridoxine enteric-coated tablets is the same as that of Example 1, except that the formulations of the coating layers of the enteric-coated tablets are shown in Table 2:

[0040] Table 2

[0041]

[0042] Example 3

[0043] The preparation method of doxylamine succinate pyridoxine enteric-coated tablets is the same as that of Example 1, except that the formulations of the coating layers of the enteric-coated tablets are shown in Table 3.

[0044] Table 3

[0045]

[0046] Example 4

[0047] The preparation method of doxylamine succinate pyridoxine enteric-coated tablets is the same as that of Example 1, except that the formulations of the coating layers of the enteric-coated tablets are shown in Table 4.

[0048] Table 4

[0049]

[0050] Example 5

[0051] The preparation method of doxylamine succinate pyridoxine enteric-coated tablets is the same as that of Example 1, except that the formulations of the coating layers of the enteric-coated tablets are shown in Table 5.

[0052] Table 5

[0053]

[0054] Example 6

[0055] The preparation method of doxylamine succinate pyridoxine enteric-coated tablets is the same as that of Example 1, except that the formulations of the coating layers of the enteric-coated tablets are shown in Table 6.

[0056] Table 6

[0057]

[0058] Example 7

[0059] The preparation method of doxylamine succinate pyridoxine enteric-coated tablets is the same as that of Example 1, except that the formulations of the coating layers of the enteric-coated tablets are shown in Table 7.

[0060] Table 7

[0061]

[0062] Comparative Example 1

[0063] The reference preparation of doxylamine succinate and pyridoxine enteric-coated tablets, with a trade name of Diclegis and a specification of 10 mg / 10 mg, is licensed by Duchesnay USA Inc. and is a drug marketed in the United States. The preparation method thereof comprises the following steps:

[0064] ① Tablet preparation:

[0065] Doxylamine succinate and silica NF were premixed in a blender. The premix was then milled through a Quadro Co mill (model 196S) equipped with a 40 mesh screen.

[0066] Pyridoxine HCl was ground by a Quadro Co grinder (Model 196S) equipped with a 40 mesh screen and the ground pyridoxine HCl was then combined and blended with the doxylamine / silicon dioxide NF premix.

[0067] The microcrystalline cellulose was ground through a 40 mesh screen and divided into two equal portions. One portion was then added to a premix containing the two active ingredients for mixing, and then the other portion of the microcrystalline cellulose was added. After mixing, magnesium trisilicate and croscarmellose sodium were added. The newly formed mixture was stirred, magnesium stearate was added, and further mixed to complete the preparation of the core formulation, and tableted, with a total core weight of 145 mg.

[0068] ② Preparation of coating layer:

[0069] Preparation of the first isolation layer: prepare a gastric-soluble film coating premix (transparent) with a solid content of 8%, place it in a coating barrel, control the tablet bed temperature at 37-45°C, and coat the prepared tablet cores with the first isolation layer, controlling the coating weight gain to be 3-4% of the tablet core weight;

[0070] Preparation of Estacryl 30D enteric coating layer: Prepare a solution with a solid content of 30% by using the prescribed amount of Estacryl 30D enteric coating solution.

[0071] Add talcum powder, PEG400 and simethicone to appropriate amount of purified water, homogenize with a homogenizer at 10000rpm for 5-10min to make them evenly dispersed, add them to the polymer water dispersion of the mixture while stirring for more than 1 hour before use to obtain the enteric coating solution, place the prepared enteric solution in a coating barrel, stir, control the tablet bed temperature at 34-42℃, place the tablet core wrapped with the first isolation layer, and start coating. The coating weight gain is 10.5-11.5% of the tablet core weight;

[0072] Preparation of the second isolation layer: prepare a gastric-soluble film coating premix (white) with a solid content of 10%, place it in a coating barrel, control the tablet bed temperature at 37-45°C, place the tablet cores coated with the first isolation layer and enteric layer, and start coating. The coating weight gain is 0.8-1.4% of the tablet core weight.

[0073] The total weight of the obtained doxylamine succinate pyridoxine enteric-coated tablets was 167.47 mg, and the prescription was shown in Table 8.

[0074] Table 8

[0075]

[0076] Example 8

[0077] The doxylamine succinate pyridoxine enteric-coated tablets obtained in Examples 1-7 and Comparative Example 1 were subjected to impurity, acid resistance and drug dissolution tests.

[0078] Under accelerated conditions (temperature 40°C, humidity 75%), samples were taken at 0, 1 and 3 months to test the acid resistance and total impurities of the samples.

[0079] Dissolution determination method: Refer to the "General Rules of Part Four of the Chinese Pharmacopoeia 2020 Edition 0931 Method 1" and the "Technical Guidelines for Dissolution Test of Ordinary Solid Preparations" for dissolution studies, and evaluate according to the following dissolution method: paddle method (with sinker), rotation speed 100 rpm, medium temperature: 37±0.5℃, medium: pH 6.8 phosphate buffer (50pm), time 15min.

[0080] Acid resistance test method: Determine according to the dissolution and release test method (Method 2, Part 4 General Rules 0931, Chinese Pharmacopoeia 2020 Edition).

[0081] Impurity determination method: High performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512) was used for determination.

[0082] The total impurities, acid resistance, solubility and RSD values ​​of Examples 1-7 and Comparative Example 1 are shown in Table 9:

[0083] Table 9

[0084]

[0085] As can be seen from Table 9, when the ratio of methacrylic acid-ethyl acrylate copolymer water dispersion to ethyl acrylate-methyl methacrylate copolymer water dispersion is (12~2):1, the acid resistance of the preparation is good; the stability is good during the accelerated process of 1 month and 3 months; and the dissolution is relatively rapid, which can achieve the effect of rapid release, the RSD of dissolution is small, the batch difference is small, and the dissolution is relatively stable. In particular, when the ratio of methacrylic acid-ethyl acrylate copolymer water dispersion to ethyl acrylate-methyl methacrylate copolymer water dispersion is (12~10):1, the stability and solubility of the preparation are more excellent.

Claims

1. A doxylamine succinate and pyridoxine enteric-coated tablet, characterized in that: The doxylamine succinate and pyridoxine enteric-coated tablets include a tablet core and a coating layer, wherein the coating layer includes a first isolation layer, an enteric layer and a second isolation layer, wherein the materials of the first isolation layer and the second isolation layer are selected from one or more of a gastric-soluble film coating premix, gastric-soluble HPMC, HPC, PEG or PVP; the enteric layer materials include a plasticizer, an anti-adhesive agent, a defoaming agent and a flexible coating material, wherein the flexible coating material is selected from one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, carboxymethyl ethyl cellulose, methyl methacrylate-methylacrylate copolymer, methacrylate-ethyl acrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and shellac, and the flexible coating material accounts for 24-28% of the tablet core mass.

2. The doxylamine succinate and pyridoxine enteric-coated tablets according to claim 1, characterized in that: The plasticizer is selected from polyethylene glycol or triethyl citrate; the anti-adhesive agent is selected from talc; and the defoaming agent is selected from simethicone.

3. Doxylamine succinate and pyridoxine enteric-coated tablets according to claim 2, characterized in that: The plasticizer accounts for 0.1% to 2% of the tablet core mass; the anti-sticking agent accounts for 0.1% to 5% of the tablet core mass; and the defoaming agent accounts for 0.01% to 1% of the tablet core mass.

4. The doxylamine succinate and pyridoxine enteric-coated tablets according to claim 1, characterized in that: The materials of the first isolation layer and the second isolation layer together account for 0.1% to 10% of the core mass.

5. The doxylamine succinate and pyridoxine enteric-coated tablets according to claim 4, characterized in that: The first isolation layer is selected from the gastric soluble film coating premix YS-1-7474-CN, and the second isolation layer is selected from the gastric soluble film coating premix YS-1-7003-CN; the first isolation layer accounts for 3~4.5% of the tablet core mass; the second isolation layer accounts for 1~2% of the tablet core mass.

6. The doxylamine succinate and pyridoxine enteric-coated tablets according to claim 1, characterized in that: The flexible coating material is selected from methacrylic acid-ethyl acrylate copolymer aqueous dispersion and ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, and the mass ratio of methacrylic acid-ethyl acrylate copolymer aqueous dispersion and ethyl acrylate-methyl methacrylate copolymer aqueous dispersion is (12~2):

1.

7. The doxylamine succinate pyridoxine enteric-coated tablets according to claim 1, characterized in that: The mass ratio of methacrylic acid-ethyl acrylate copolymer aqueous dispersion to ethyl acrylate-methyl methacrylate copolymer aqueous dispersion is (12~10):

1.

8. The doxylamine succinate and pyridoxine enteric-coated tablets according to claim 1, characterized in that: The tablet core comprises pyridoxine hydrochloride, doxylamine succinate and excipients.

9. A method for preparing doxylamine succinate pyridoxine enteric-coated tablets, characterized in that: The pyridoxine hydrochloride, doxylamine succinate and excipients are mixed and compressed into tablets to prepare tablet cores; the tablet cores are coated, including a first isolation layer, an enteric layer and a second isolation layer, wherein the materials of the first isolation layer and the second isolation layer are selected from one or more of gastric soluble film coating premix, gastric soluble HPMC, HPC, PEG or PVP; the enteric layer materials include plasticizers, anti-adhesive agents, defoamers and flexible coating materials, wherein the flexible coating materials are selected from one or more of hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, carboxymethyl ethyl cellulose, methyl methacrylate-methacrylate copolymer, methacrylate-ethyl acrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and shellac, and the flexible coating materials account for 24-28% of the mass of the tablet core.

10. A method for preparing doxylamine succinate pyridoxine enteric-coated tablets, characterized in that: Preparation of the first isolation layer: prepare a gastric soluble film coating premix with a solid content of 8%, and coat the prepared tablet core with the first isolation layer; Preparation of enteric layer: After mixing the flexible coating materials, add the slip plasticizer, anti-adhesive agent and defoamer into water, stir evenly, add into the flexible coating materials and stir, and coat the tablet core coated with the first isolation layer with the enteric layer; Preparation of the second isolation layer: prepare a gastric-soluble film coating premix with a solid content of 10%, and coat the tablet cores that have been coated with the first isolation layer and the enteric layer.

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