Pantoprazole Sodium Sublingual Tablet Pharmaceutical Composition and Its Preparation Method

Abstract

The present invention relates to pantoprazole sodium preparations, and relates to a sublingual tablet containing pantoprazole sodium, at least one diluent, at least two flavoring agents, at least one taste masking agent, at least one binder, at least one disintegrant, at least one lubricant, and at least two buffer salts. The preparation contains 20 mg of pantoprazole sodium; the sublingual tablet of pantoprazole sodium in a specific ratio has a quality that meets the requirements of sublingual tablets and has a relatively fast disintegration and dissolution rate. Other advantages of the pharmaceutical preparation of the present invention are simple preparation process, stable product quality, rapid dissolution of the drug, and fast onset of action. The present invention also relates to a preparation method of the pantoprazole sodium sublingual tablet. The sample prepared by this method complies with the relevant regulations of sublingual tablets.

Description

Technical Field

[0001] The present invention relates to pantoprazole sodium sublingual tablets, and more particularly to a sublingual tablet containing pantoprazole sodium. Background Art

[0002] Gastroesophageal reflux disease is an uncomfortable symptom or complication caused by the reflux of gastric contents and is a common digestive disease. Although this disease does not endanger life, it has a great impact on the health and quality of life of patients. Currently, the most commonly used drugs for treating this disease are proton pump inhibitors, which relieve acid by inhibiting the secretion of acid by gastric parietal cells. Commonly used are a series of enteric-coated tablets and capsules such as omeprazole enteric-coated capsules, rabeprazole sodium enteric-coated tablets, lansoprazole enteric-coated tablets, and pantoprazole sodium enteric-coated tablets.

[0003] The above-mentioned pantoprazole drugs are designed as enteric-coated tablets or enteric-coated capsules, mainly limited by the instability of the pantoprazole raw material in an acidic medium, which is prone to degradation and thus loses its efficacy. Therefore, it is necessary to coat the tablet or capsule content with an enteric material. Taking pantoprazole sodium enteric-coated tablets as an example, the preparation process is to first prepare the active substance tablets. Since there are many components in the enteric material and its compatibility with the raw material drug is not good, a separating layer is usually designed between the core carrier tablet and the enteric layer to ensure the stability of the drug. Therefore, the preparation process of pantoprazole sodium enteric-coated tablets is relatively complex.

[0004] Considering the complexity of the preparation process of pantoprazole enteric-coated capsules and tablets, the present invention aims to prepare pantoprazole sodium as a sublingual tablet to simplify the preparation process and avoid the first-pass effect in the gastrointestinal tract and the degradation of the drug in an acidic environment. After taking the pantoprazole sodium sublingual tablet, it quickly disintegrates and dissolves in the oral cavity, is absorbed by the rich blood vessels under the tongue, and enters the systemic circulation, thereby playing a role more quickly and quickly relieving the pain of patients.

[0005] The pantoprazole sodium raw material drug is unstable under acidic, oxidative, light, and heating conditions. Due to the nature of the raw material drug, during the preparation process or the stability period of the pantoprazole sodium sublingual tablet, the phenomenon that the related substances exceed the limit occurs. Based on the medicinal mechanism and the onset effect of the sublingual tablet, the hardness of the sublingual tablet must be able to meet both the friability requirements and the disintegration time limit as short as possible.

[0006] Through experimental research, the present invention has invented a pantoprazole sodium sublingual tablet and its preparation process. This sublingual tablet has a relatively fast dissolution in an artificial saliva medium, the preparation process is simple, the product stability is good, and it meets the quality requirements of sublingual tablets. Summary of the Invention

[0007] The object of the present invention is to provide a sublingual tablet containing pantoprazole sodium raw material drug. This preparation contains pantoprazole sodium, at least one diluent, at least two flavoring agents, at least one taste masking agent, at least one binder, at least one disintegrant, at least one lubricant, and at least two buffer salts. In addition, the present invention also includes a preparation method of the sublingual tablet.

[0008] The pharmaceutical preparation involved in the present invention is a pharmaceutical preparation for sublingual administration. Specifically, it is a sublingual tablet containing pantoprazole.

[0009] The pantoprazole sodium sublingual tablet involved in the present invention contains at least one diluent. This diluent is selected from mannitol, sorbitol, microcrystalline cellulose, and lactose. Mannitol is particularly preferred in the present invention. The preparation contains 15 - 25 parts of mannitol.

[0010] The pantoprazole sodium sublingual tablet involved in the present invention contains at least two flavoring agents. These flavoring agents are selected from sucrose, sodium saccharin, tartaric acid, aspartame, sucrose, and citric acid. Sucrose and sodium saccharin are particularly preferred in the present invention. The preparation contains 1 - 3 parts of sucrose and 1 - 3 parts of sodium saccharin.

[0011] The pantoprazole sodium sublingual tablet involved in the present invention contains at least one taste masking agent. This taste masking agent is selected from cherry essence, apple essence, orange essence, lemon essence, and strawberry essence. The pharmaceutical preparation contains 2 - 4 parts of orange essence.

[0012] The pantoprazole sodium sublingual tablet involved in the present invention contains at least one binder. This binder is selected from povidone, hypromellose, and hydroxypropyl cellulose. Povidone is particularly preferred in the present invention. The preparation contains 2 - 5 parts of povidone.

[0013] The pantoprazole sodium sublingual tablet involved in the present invention contains at least one disintegrant. This disintegrant is selected from crospovidone, sodium carboxymethyl starch, and cross - linked sodium carboxymethyl cellulose. Crospovidone is particularly preferred in the present invention. The preparation contains 2 - 6 parts of crospovidone.

[0014] The pantoprazole sodium sublingual tablet involved in the present invention contains at least one lubricant. This lubricant is selected from sodium stearyl fumarate, talc, and magnesium stearate. 2 - 4 parts of sodium stearyl fumarate are particularly preferred in the present invention.

[0015] The pantoprazole sodium sublingual tablet involved in the present invention contains at least two pH regulators. These pH regulators are selected from sodium bicarbonate, sodium carbonate, sodium hydroxide, and sodium hydrogen phosphate. 23 parts of sodium bicarbonate and 17 parts of sodium carbonate are particularly preferred in this product.

[0016] In particular, the pharmaceutical preparation of the present invention can be advantageously prepared by the following method, which is characterized in that the mixed powder of pantoprazole sodium and a preferred pH regulator is mixed, and then combined with a diluent, a flavoring agent, a binder, a disintegrant, and a taste masking agent. Finally, the above-mentioned mixed granules are uniformly mixed with at least one portion of a lubricant and tableted.

[0017] To improve the stability of the pantoprazole sodium sublingual tablet, sodium bicarbonate and sodium carbonate buffer salts are added to the formulation, and the two buffer salts are 23 parts and 17 parts by weight in the sublingual tablet, respectively. During the preparation process, the active pharmaceutical ingredient and sodium bicarbonate and sodium carbonate are first mixed to ensure that the pantoprazole sodium active pharmaceutical ingredient is in an alkaline environment during both the process preparation and the tablet storage processes, thereby enabling the product to have good stability.

[0018] Based on the medicinal mechanism of the sublingual tablet, a shorter disintegration time limit of the tablet is required. 2 - 6 parts of the disintegrant crospovidone are added to this product, which can ensure that the tablet disintegrates within a shorter time.

[0019] For the pantoprazole sodium sublingual tablet, due to the nature of the active pharmaceutical ingredient, to avoid stability problems, sodium bicarbonate and sodium carbonate buffer salts are added, and flavoring agents such as essence, sucrose, and sodium saccharin are added to improve the compliance of patients, thereby increasing the difficulty of tablet forming. To improve the compressibility of the tablet, 2 - 5 parts of the binder povidone are added to the pantoprazole sodium sublingual tablet, thereby enhancing the binding force between the excipients and improving the compressibility of the material.

[0020] The present invention has studied the proportions of different disintegrants, the proportions of different binder dosages, the hardness range of the tablet, and the mixing method. The active pharmaceutical ingredient and the buffer salts are mixed to ensure that the active pharmaceutical ingredient is in an alkaline microenvironment, guaranteeing the stability of the product. The prepared pantoprazole sodium sublingual tablet meets the quality and stability requirements.

[0021] Beneficial effects

[0022] The pantoprazole sodium sublingual tablet described in the present invention has the following advantages:

[0023] Proton pump inhibitors are unstable in acidic media. To reach the site of action, they are generally prepared as enteric-coated preparations to ensure that the drug can exert its efficacy. During the preparation process, to ensure the stability of the preparation, the preparation process is usually relatively complex, with at least two layers of coating, namely the isolation layer and the enteric layer.

[0024] The pantoprazole sodium sublingual tablet prepared by the present invention rapidly disintegrates and dissolves in the oral cavity and is absorbed through the sublingual blood vessels, avoiding contact of the drug with gastric acid. Different from the administration method of the enteric-coated preparation, the preparation process can choose the relatively simple direct powder compression process and has good stability.

[0025] The pantoprazole sodium sublingual tablets prepared by the present invention have determined the optimal prescription combination of pantoprazole sodium sublingual tablets through screening the dosage of the excipient binder povidone, the dosage of the disintegrant crospovidone, and investigating different hardnesses.

[0026] In addition, the inventor has conducted stability tests on the pantoprazole sublingual tablets of the present invention. The results show that there are no changes in the related substances and content of the pantoprazole sodium sublingual tablet composition of the present invention, and the stability is good. Description of the Drawings

[0027] Figure 1 Comparison Chart of Dissolution Curves of Pantoprazole Sodium in Examples Detailed Description of the Invention

[0028] The present invention is elaborated in detail through the following preparation examples and comparative examples, and the said examples should not be considered restrictive.

[0029] Example 1: Preparation Example

[0030] (1) Formulation of pantoprazole sodium sublingual tablets, see Table 1.

[0031] Table 1 Formulation of Pantoprazole Sodium Sublingual Tablets

[0032]

[0033] (2) Preparation process:

[0034] a. Mechanically crush sodium bicarbonate and sodium carbonate, and pass through a 40-mesh sieve. Sodium stearyl fumarate passes through a 60-mesh sieve, and the remaining excipients pass through a 40-mesh sieve. Sodium stearyl fumarate passes through a 60-mesh sieve.

[0035] b. Weigh the prescribed amounts of the active ingredient, sodium bicarbonate, and sodium carbonate and mix them.

[0036] c. Add the prescribed amounts of mannitol, sucrose, sodium saccharin, orange essence, povidone, and crospovidone to the mixed powder in step b and mix.

[0037] d. Finally, add sodium stearyl fumarate to the mixed powder in step c for final mixing. Press the above total mixed powder using a 6-mm round punch, control the theoretical tablet weight to be 100 mg, and the hardness to be 3 - 5 kg.

[0038] Example 2: Preparation Example

[0039] (1) Formulation of pantoprazole sodium sublingual tablets, see Table 2.

[0040] Table 2 Formulation of Pantoprazole Sodium Sublingual Tablets

[0041]

[0042]

[0043] (2) Preparation process

[0044] a. Mechanically crush sodium bicarbonate and sodium carbonate, and pass through a 40-mesh sieve. Sodium stearyl fumarate passes through a 60-mesh sieve, and the remaining excipients pass through a 40-mesh sieve. Sodium stearyl fumarate passes through a 60-mesh sieve.

[0045] b. Weigh the prescribed amounts of the active pharmaceutical ingredient, sodium bicarbonate, and sodium carbonate and mix them.

[0046] c. Add the prescribed amounts of mannitol, sucrose, sodium saccharin, orange essence, hypromellose, and crospovidone to the mixed powder in step b and mix.

[0047] d. Finally, add sodium stearyl fumarate to the mixed powder in step c for final mixing. Press the total mixed powder using a 6-mm round punch, control the theoretical tablet weight to be 100 mg, and the hardness to be 3 - 5 kg.

[0048] Example 3: Preparation example

[0049] (1) Sublingual tablet formula of pantoprazole sodium, see Table 3.

[0050] Table 3 Sublingual tablet formula of pantoprazole sodium

[0051]

[0052] (2) Preparation process

[0053] a. Mechanically crush sodium bicarbonate and sodium carbonate, and pass through a 40-mesh sieve. Sodium stearyl fumarate passes through a 60-mesh sieve, and the remaining excipients pass through a 40-mesh sieve. Sodium stearyl fumarate passes through a 60-mesh sieve.

[0054] b. Weigh the prescribed amounts of the active pharmaceutical ingredient, sodium bicarbonate, and sodium carbonate and mix them.

[0055] c. Add the prescribed amounts of mannitol, sucrose, sodium saccharin, orange essence, povidone, and crospovidone to the mixed powder in step b and mix.

[0056] d. Finally, add sodium stearyl fumarate to the mixed powder in step c for final mixing. Press the total mixed powder using a 6-mm round punch, control the theoretical tablet weight to be 100 mg, and the hardness to be 3 - 5 kg.

[0057] Example 4: Comparative example

[0058] Example 4a

[0059] (1) Sublingual tablet formula of pantoprazole sodium, see Table 4.

[0060] Table 4 Sublingual tablet formula of pantoprazole sodium

[0061]

[0062] (2) Preparation process

[0063] a. Mechanically crush sodium bicarbonate and sodium carbonate, and sieve through a 40-mesh sieve. Sieve sodium stearyl fumarate through a 60-mesh sieve, and sieve the remaining excipients through a 40-mesh sieve. Sieve sodium stearyl fumarate through a 60-mesh sieve.

[0064] b. Weigh the prescribed amounts of the active pharmaceutical ingredient, sodium bicarbonate, and sodium carbonate and mix them.

[0065] c. Add the prescribed amounts of mannitol, sucrose, sodium saccharin, orange essence, and povidone to the mixed powder in step b and mix.

[0066] d. Finally, add sodium stearyl fumarate to the mixed powder in step c for final mixing. Use a 6-mm round punch to compress the above total mixed powder, control the theoretical tablet weight to be 100 mg, and the hardness to be 3 - 5 kg.

[0067] Note: There is no disintegrant in this formulation.

[0068] Example 4b

[0069] (1) Pantoprazole sodium sublingual tablet formula, see Table 5.

[0070] Table 5 Pantoprazole sodium sublingual tablet formula

[0071]

[0072]

[0073] (2) Preparation process

[0074] a. Mechanically crush sodium bicarbonate and sodium carbonate, and sieve through a 40-mesh sieve. Sieve sodium stearyl fumarate through a 60-mesh sieve, and sieve the remaining excipients through a 40-mesh sieve. Sieve sodium stearyl fumarate through a 60-mesh sieve.

[0075] b. Weigh the prescribed amounts of the active pharmaceutical ingredient, sodium bicarbonate, and sodium carbonate and mix them.

[0076] c. Add the prescribed amounts of mannitol, sucrose, sodium saccharin, orange essence, povidone, and crosslinked povidone to the mixed powder in step b and mix.

[0077] d. Finally, add sodium stearyl fumarate to the mixed powder in step c for final mixing. Use a 6-mm round punch to compress the above total mixed powder, control the theoretical tablet weight to be 100 mg, and the hardness to be 3 - 5 kg.

[0078] Note: The dosage of the disintegrant in this formulation is 1.0 mg.

[0079] Example 4c

[0080] (1) Pantoprazole Sodium Sublingual Tablet Formula, see Table 6.

[0081] Table 6 Pantoprazole Sodium Sublingual Tablet Formula

[0082]

[0083] (2) Preparation Process

[0084] a. Mechanically crush sodium bicarbonate and sodium carbonate, and pass through a 40-mesh sieve. Sodium stearyl fumarate passes through a 60-mesh sieve, and the remaining excipients pass through a 40-mesh sieve. Sodium stearyl fumarate passes through a 60-mesh sieve.

[0085] b. Weigh the prescribed amounts of the active ingredient, sodium bicarbonate, and sodium carbonate and mix them.

[0086] c. Add the prescribed amounts of mannitol, sucrose, sodium saccharin, orange essence, and crospovidone to the mixed powder in step b and mix.

[0087] d. Finally, add sodium stearyl fumarate to the mixed powder in step c for final mixing. Press the above total mixed powder using a 6-mm round punch, control the theoretical tablet weight to be 100 mg, and the hardness to be 3 - 5 kg.

[0088] Note: There is no binder in this formulation.

[0089] Example 4d

[0090] (1) Pantoprazole Sodium Sublingual Tablet Formula, see Table 7.

[0091] Table 7 Pantoprazole Sodium Sublingual Tablet Formula

[0092]

[0093] (2) Preparation Process

[0094] a. Mechanically crush sodium bicarbonate and sodium carbonate, and pass through a 40-mesh sieve. Sodium stearyl fumarate passes through a 60-mesh sieve, and the remaining excipients pass through a 40-mesh sieve. Sodium stearyl fumarate passes through a 60-mesh sieve.

[0095] b. Weigh the prescribed amounts of the active ingredient, sodium bicarbonate, and sodium carbonate and mix them.

[0096] c. Add the prescribed amounts of mannitol, sucrose, sodium saccharin, orange essence, and crospovidone to the mixed powder in step b and mix.

[0097] d. Finally, add sodium stearyl fumarate to the mixed powder in step c for final mixing. Press the above total mixed powder using a 6-mm round punch, control the theoretical tablet weight to be 100 mg, and the hardness to be 3 - 5 kg.

[0098] Note: In this ratio, the adhesive is 1.0 mg.

[0099] Example 4e

[0100] Example 4e has the same prescription composition and preparation process as Example 1.

[0101] a. Mechanically crush sodium bicarbonate and sodium carbonate, and pass through a 40-mesh sieve. Sodium stearyl fumarate passes through a 60-mesh sieve, and the remaining excipients pass through a 40-mesh sieve. Sodium stearyl fumarate passes through a 60-mesh sieve.

[0102] b. Weigh the prescribed amounts of the active pharmaceutical ingredient, sodium bicarbonate, and sodium carbonate and mix them.

[0103] c. Add the prescribed amounts of mannitol, sucrose, saccharin sodium, orange essence, polyvinylpyrrolidone, and cross-linked polyvinylpyrrolidone to the mixed powder in step b and mix.

[0104] d. Finally, add sodium stearyl fumarate to the mixed powder in step c for final mixing. Press the total mixed powder using a 6-mm round punch, control the theoretical tablet weight to be 100 mg, and the hardness to be 1.5 - 2.5 kg.

[0105] In this example, the hardness of the tablets is 1.5 - 2.5 kg.

[0106] Test the samples obtained from the above examples.

[0107] (1) Hardness investigation

[0108] For the tablets prepared in Examples 1 - 2 of the present invention, test the hardness of the tablets.

[0109] (2) Disintegration time limit investigation

[0110] Determination method: Refer to the disintegration time limit inspection method in General Principles 0921 of the Fourth Part of the Chinese Pharmacopoeia (2020 Edition). Take 6 tablets of the test sample, place them in the glass tubes of the hanging basket in the disintegration tester respectively, start the disintegration tester, and record the time when the tablets are completely disintegrated.

[0111] (3) Friability investigation

[0112] Determination method: Refer to the tablet friability inspection method in General Principles 0923 of the Fourth Part of the Chinese Pharmacopoeia (2020 Edition). Weigh 6.5 g of the tablets, blow off the powder falling off the tablets with a hair dryer, weigh accurately, place the tablets in the tablet friability tester, rotate 100 times, take them out, remove the powder by sieving, and weigh accurately.

[0113] (4) Dissolution curve investigation

[0114] Assay: Take this product and, according to the dissolution and release determination method (Method 3 in Appendix 0931, Volume IV, Chinese Pharmacopoeia 2020 Edition), use 50 mL of artificial saliva with pH 6.2 as the dissolution medium, rotate at a speed of 100 rpm, operate according to the law, take a 5 mL sample every 1 minute, and detect the content by liquid phase.

[0115] Table 8 Detection Results

[0116]

[0117] Table 9 Dissolution Curve of Pantoprazole Sodium Sublingual Tablets in Artificial Saliva with pH 6.2

[0118]

[0119]

[0120] Table 10 Self - designed Quality Standard of Pantoprazole Sodium Sublingual Tablets

[0121]

[0122] In the examples, the dosage of povidone and the dosage of cross - linked povidone were investigated, and the tablet hardness was also investigated. According to the self - designed standard of pantoprazole sodium sublingual tablets, as shown in Table 10, the pantoprazole sodium sublingual tablets prepared in Example 1 meet the standard.

[0123] The present invention has been described by way of examples. It should be understood that the examples are only for illustrating the present invention. Without departing from the scope of protection of the present invention, those skilled in the art can design alternative and improved schemes according to the present invention, which should be considered to be within the scope of protection of the present invention.

[0124] (5) Stability Study of Example 1

[0125] This example provides the stability study test and its results of the pantoprazole sodium composition of Example 1.

[0126] Accelerated Test:

[0127] Referring to the "Technical Guidelines for the Stability Study of Chemical Drugs (Active Pharmaceutical Ingredients and Preparations)", take the pantoprazole sodium tablets prepared in Example 1, place them under the conditions of 40°C ± 2°C / RH 75% ± 5% for 6 months for accelerated test investigation. Sampling is carried out at the end of the 1st month, 2nd month, 3rd month, and 6th month respectively, and the appearance, moisture, content, related substances, and dissolution are detected respectively. Compared with the 0 - month results, the results are shown in Table 11.

[0128] Table 11 Stability Data of Pantoprazole Sodium Sublingual Tablets

[0129]

[0130]

Claims

1. Pantoprazole Sodium Sublingual Tablets, characterized in that, The unit dose contains the following substances in parts by weight: 20 parts of pantoprazole sodium, 15 - 25 parts of mannitol, 1 - 3 parts of sucrose, 1 - 3 parts of sodium saccharin, 2 - 4 parts of orange essence, 2 - 5 parts of polyvinylpyrrolidone, 2 - 6 parts of cross-linked polyvinylpyrrolidone, 2 - 4 parts of sodium stearyl fumarate, 23 parts of sodium bicarbonate, 17 parts of sodium carbonate.

2. The pantoprazole sodium sublingual tablet according to claim 1, characterized in that, The hardness of the sublingual tablet of pantoprazole sodium is 3 - 5 kg.

3. The preparation method of pantoprazole sodium sublingual tablets according to claim 1 or 2, characterized in that, It is achieved according to the following steps: (1) Sodium bicarbonate and sodium carbonate are mechanically pulverized and passed through a 40 - mesh sieve, sodium stearyl fumarate is passed through a 60 - mesh sieve, and the remaining excipients are passed through a 40 - mesh sieve, and sodium stearyl fumarate is passed through a 60 - mesh sieve; (2) The prescription amount of the active ingredient and the pulverized sodium bicarbonate and sodium carbonate are preliminarily mixed; (3) In the mixed powder in (2) above, the prescription amounts of mannitol, sucrose, sodium saccharin, orange essence, polyvinylpyrrolidone, and cross-linked polyvinylpyrrolidone are added for mixing; (4) In the mixed powder in (3) above, sodium stearyl fumarate is finally added for final mixing; (5) The total mixed powder above is tabletted using a 6 - mm round punch.

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