Loratadine tablet and preparation method thereof

Abstract

The invention relates to a loratadine tablet and a preparation method thereof, and belongs to the technical field of medicine, in particular to the loratadine tablet and the preparation method thereof, the loratadine tablet takes loratadine with the particle size D90 not larger than 10 micrometers as a main component, auxiliary materials comprise a filling agent, an adhesive and a lubricating agent, the adhesive is a 10% povidone K30 aqueous solution, and the lubricating agent is an aqueous solution of magnesium stearate. The composition is prepared through a wet granulation process. The preparation method provided by the invention is simple and convenient in process steps and convenient for commercialized production, simultaneously overcomes the problem of low dissolution rate of loratadine in a weak acid solution, and can greatly improve the dissolution rate of loratadine tablets, thereby improving the in-vivo bioavailability.

Description

Technical Field

[0001] The invention mainly relates to the technical field of medicine and pharmaceuticals, and in particular to a loratadine tablet and a preparation method thereof. Background Art

[0002] Loratadine, chemically known as 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cycloheptyl[1,2-B]pyridine-11-ylidene)-1-piperidinecarboxylic acid ethyl ester. Loratadine is a highly effective and long-lasting tricyclic antihistamine (antiallergic) drug. It is used to relieve symptoms associated with allergic rhinitis, such as sneezing, runny nose, itchy nose, nasal congestion, and itchy and burning eyes. After oral administration, nasal and eye symptoms and signs are rapidly relieved. It is also suitable for relieving symptoms and signs of chronic urticaria, itchy skin diseases and other allergic skin diseases.

[0003] Loratadine is a water-insoluble substance, which is almost insoluble in water and weak acid solutions, and only soluble in strong acid solutions. The solubility of commercially available loratadine tablets is high only in stronger hydrochloric acid solutions (pH=1~2), but its solubility is low in weak acid and neutral environments. Patients with hyposecretion of gastric juice or hyposecretion of gastric juice caused by iatrogenic factors have increased intragastric pH. For example, if the patient's gastric juice is in a low-acid state, the pH in the stomach changes to 3.5-7. Once these patients take ordinary loratadine tablets, the release behavior of the preparation in the stomach may be affected by the increase in pH. Once the drug enters the intestine, the release of loratadine tablets will be lower, and its clinical effect will also be affected. At present, the existing developed loratadine tablets are mainly invented for how to improve the dissolution performance of loratadine tablets, so as to improve the bioavailability in the body. For example, the invention patent with publication number CN103230378A is "a method for preparing loratadine tablets", which adopts the method of jointly encapsulating loratadine with citric acid, so that loratadine is first encapsulated into an acid inclusion complex, and then the auxiliary materials are optimized, cross-linked polyvinylpyrrolidone is used as a disintegrant, and copolyvinylpyrrolidone is used as a binder, which can ensure that the solubility of loratadine tablets is high in weak acid environment and neutral environment, thereby improving the bioavailability in the body.

[0004] The invention patent with publication number CN107648191A is "A loratadine tablet and its preparation process". Loratadine is dissolved in anhydrous ethanol and sorbitol is dissolved in water. Under stirring conditions, the sorbitol aqueous solution is added to the loratadine ethanol solution. Since the solubility of sorbitol in cold ethanol is reduced, fine crystals will precipitate and suspend in the loratadine ethanol solution. The suspension is concentrated under reduced pressure using a rotary evaporator. As the ethanol evaporates, loratadine precipitates and is distributed on the surface of sorbitol, thereby forming tiny mixed particles of loratadine wrapped in sorbitol. Since sorbitol has good water solubility, the prepared tiny mixed particles can quickly dissolve from the inside out in water, thereby greatly improving the solubility of loratadine and significantly improving the dissolution performance of loratadine. The invention mainly utilizes the difference in solubility between sorbitol and loratadine.

[0005] The invention patent with publication number CN104523644A is "A fast-dissolving loratadine tablet and its preparation process". Loratadine and copovidone are dissolved in ethanol, and polyethylene glycol is dissolved in water. The two solutions are then mixed to obtain a drug-containing coating solution, and then a high-efficiency coating machine is used to spray the coating solution onto a blank tablet core containing a filler, a disintegrant and a lubricant. That is, the dispersion preparation method is used to improve the solubility of loratadine, thereby preparing loratadine tablets that can significantly improve solubility.

[0006] The present invention is also based on improving the solubility of loratadine, thereby inventing a new loratadine tablet and a preparation method thereof, so that the prepared loratadine tablet has high solubility, stable quality, simple process flow, and is convenient for commercial production. Summary of the invention

[0007] The present invention provides a loratadine tablet and a preparation method thereof. The loratadine tablet has a particle size D 90 The main component is loratadine no larger than 10 microns, and the auxiliary materials include fillers, adhesives and lubricants, wherein the adhesive is 10% povidone K 30 Aqueous solution, prepared by wet granulation process.

[0008] The preparation method of the present invention has simple process steps and is convenient for commercial production. At the same time, the problem of low solubility of loratadine in weakly acidic solutions is overcome. The method of the present invention can greatly improve the solubility of loratadine tablets, thereby improving the in vivo bioavailability.

[0009] The present invention provides a loratadine tablet and a preparation method thereof, and the specific preparation method steps are as follows: 1) Pretreatment of raw materials and auxiliary materials: crushing of raw materials, particle size D after crushing 90 No larger than 10 microns; starch, lactose, microcrystalline cellulose, and lubricant are sieved through a 60-mesh sieve and set aside; 2) Preparation of adhesive: Weigh the prescribed amount of povidone K 30 Add to purified water to make 10% Povidone K 30 Aqueous solution should be uniform in color, free of water precipitation, spots, and lumps, and must be sieved before use; 3) Premixing: Add the crushed API, sieved starch, lactose and microcrystalline cellulose into the wet granulator and mix evenly; 4) Wet granulation: After the raw materials and excipients are pre-mixed evenly, the binder is slowly added using a fixed funnel, and the stirring and shearing time is 180-240s. The obtained wet granules are then passed through a 30-mesh nylon sieve by a swing granulator for secondary granulation; 5) Drying and granulation: Dry at 55℃~65℃ until the moisture content of the granules is less than 3%, and granulate through a 30-mesh steel sieve; 6) Mixing: Add lubricant to the granulated particles and mix them in a two-dimensional mixer to make them uniform; 7) Tablet compression: Use a 6mm, shallow concave die to compress the tablets. The tablet weight is 100 mg and the tablet weight variation is ±5.0%. DETAILED DESCRIPTION

[0010] Unless otherwise specified, the auxiliary materials used in the following examples are all common commercially available materials, and the methods used are all conventional methods in the art.

[0011] Example 1 and Comparative Example 1: Preparation of 10 mg loratadine tablets

[0012] Example 1 Preparation process: 1) Pretreatment of raw materials and auxiliary materials: crushing of raw materials, particle size D after crushing 90 No larger than 10 microns; starch, lactose, microcrystalline cellulose, magnesium stearate are sieved through a 60-mesh sieve and set aside; 2) Preparation of adhesive: Weigh the prescribed amount of povidone K 30 Add to purified water to make 10% Povidone K 30 Aqueous solution, which is required to be uniform in color, free of water precipitation, spots, and lumps, must be sieved before use (to ensure that the binder is fully dissolved, the binder must be prepared at least 8 hours before wet granulation);

[0013] 3) Premixing: Add the crushed API, sieved starch, lactose and microcrystalline cellulose into the wet granulator and mix evenly;

[0014] 4) Wet granulation: After the raw materials and excipients are pre-mixed evenly, the binder is slowly added using a fixed funnel, and the stirring and shearing time is 180-240s. The obtained wet granules are then passed through a 30-mesh nylon sieve by a swing granulator for secondary granulation;

[0015] 5) Drying and granulation: Dry at 55℃~65℃ until the moisture content of the granules is less than 3%, and granulate through a 30-mesh steel sieve;

[0016] 6) Mixing: Add magnesium stearate to the granulated particles and mix them in a two-dimensional mixer for 5 minutes to make them uniform;

[0017] 7) Tablet compression: Use a 6mm, shallow concave die to compress the tablets. The tablet weight is 100 mg and the tablet weight variation is ±5.0%.

[0018] Comparative Example 1 Preparation process: 1) Pretreatment of auxiliary materials: starch, lactose, microcrystalline cellulose, and magnesium stearate are sieved through a 60-mesh sieve and set aside; 2) Preparation of adhesive: Weigh the prescribed amount of povidone K 30 Add to purified water to make 10% Povidone K 30 Aqueous solution, which is required to be uniform in color, free of water precipitation, spots, and lumps, must be sieved before use (to ensure that the binder is fully dissolved, the binder must be prepared at least 8 hours before wet granulation);

[0019] 3) Premixing: Add the API loratadine and the sieved starch, lactose and microcrystalline cellulose into the wet granulator and mix evenly;

[0020] 4) Wet granulation: After the raw materials and excipients are pre-mixed evenly, the binder is slowly added using a fixed funnel, and the stirring and shearing time is 180-240s. The obtained wet granules are then passed through a 30-mesh nylon sieve by a swing granulator for secondary granulation;

[0021] 5) Drying and granulation: Dry at 55℃~65℃ until the moisture content of the granules is less than 3%, and granulate through a 30-mesh steel sieve;

[0022] 6) Mixing: Add magnesium stearate to the granulated particles and mix them in a two-dimensional mixer for 5 minutes to make them uniform;

[0023] 7) Tablet compression: Use a 6mm, shallow concave die to compress the tablets. The tablet weight is 100 mg and the tablet weight variation is ±5.0%;

[0024] Example 2 and Comparative Example 2: Preparation of 10 mg loratadine tablets

[0025] Example 2 Preparation process: 1) Pretreatment of raw materials and auxiliary materials: crushing of raw materials, particle size D after crushing 90 No larger than 10 microns; starch, lactose, microcrystalline cellulose, magnesium stearate are sieved through a 60-mesh sieve and set aside; 2) Preparation of adhesive: Weigh the prescribed amount of povidone K 30 Add to purified water to make 10% Povidone K 30 Aqueous solution, which is required to be uniform in color, free of water precipitation, spots, and lumps, must be sieved before use (to ensure that the binder is fully dissolved, the binder must be prepared at least 8 hours before wet granulation); 3) Premixing: Add the crushed API, sieved starch, lactose and microcrystalline cellulose into the wet granulator and mix evenly; 4) Wet granulation: After the raw materials and excipients are pre-mixed evenly, the binder is slowly added using a fixed funnel, and the stirring and shearing time is 180-240s. The obtained wet granules are then passed through a 30-mesh nylon sieve by a swing granulator for secondary granulation; 5) Drying and granulation: Dry at 55℃~65℃ until the moisture content of the granules is less than 3%, and granulate through a 30-mesh steel sieve; 6) Mixing: Add magnesium stearate to the granulated particles and mix them in a two-dimensional mixer for 5 minutes to make them uniform; 7) Tablet compression: Use a 6mm, shallow concave die to compress the tablets. The tablet weight is 100 mg and the tablet weight variation is ±5.0%.

[0026] Comparative Example 2 Preparation Process: 1) Pretreatment of raw materials and auxiliary materials: crushing of raw materials, particle size D after crushing 90 No larger than 10 microns; starch, lactose, microcrystalline cellulose, povidone K 30 , magnesium stearate is passed through a 60-mesh sieve and set aside; 2) Preparation of wetting agent: Use appropriate amount of purified water as wetting agent; 3) Premixing: Mix the crushed API with sieved starch, lactose, microcrystalline cellulose, and povidone K. 30 Add to the wet granulator and mix evenly; 4) Wet granulation: After the raw materials and excipients are pre-mixed evenly, purified water is slowly added using a fixed funnel, and the stirring and shearing time is 180-240s. The obtained wet granules are then passed through a 30-mesh nylon sieve by a swing granulator for secondary granulation; 5) Drying and granulation: Dry at 55℃~65℃ until the moisture content of the granules is less than 3%, and granulate through a 30-mesh steel sieve; 6) Mixing: Add magnesium stearate to the granulated particles and mix them in a two-dimensional mixer for 5 minutes to make them uniform; 7) Tablet compression: Use a 6mm, shallow concave die to compress the tablets. The tablet weight is 100 mg and the tablet weight variation is ±5.0%; 8) Example 3 and Comparative Example 3: Preparation of 10 mg loratadine tablets

[0027] Example 3 Preparation process: 1) Pretreatment of raw materials and auxiliary materials: crushing of raw materials, particle size D after crushing 90 No larger than 10 microns; starch, lactose, microcrystalline cellulose, magnesium stearate are sieved through a 60-mesh sieve and set aside; 2) Preparation of adhesive: Weigh the prescribed amount of povidone K 30 Add to purified water to make 10% Povidone K 30 Aqueous solution, which is required to be uniform in color, free of water precipitation, spots, and lumps, must be sieved before use (to ensure that the binder is fully dissolved, the binder must be prepared at least 8 hours before wet granulation); 3) Premixing: Add the crushed API, sieved starch, lactose and microcrystalline cellulose into the wet granulator and mix evenly; 4) Wet granulation: After the raw materials and excipients are pre-mixed evenly, the binder is slowly added using a fixed funnel, and the stirring and shearing time is 180-240s. The obtained wet granules are then passed through a 30-mesh nylon sieve by a swing granulator for secondary granulation; 5) Drying and granulation: Dry at 55℃~65℃ until the moisture content of the granules is less than 3%, and granulate through a 30-mesh steel sieve; 6) Mixing: Add magnesium stearate to the granulated particles and mix them in a two-dimensional mixer for 5 minutes to make them uniform; 7) Tablet compression: Use a 6mm, shallow concave die to compress the tablets. The tablet weight is 100 mg and the tablet weight variation is ±5.0%.

[0028] Comparative Example 3 Preparation Process: 1) Pretreatment of raw materials and auxiliary materials: crushing of raw materials, particle size D after crushing 90 No larger than 10 microns; starch, lactose, microcrystalline cellulose, magnesium stearate are sieved through a 60-mesh sieve and set aside; 2) Preparation of adhesive: weigh the prescribed amount of povidone K 30 Add to purified water to make 5% Povidone K 30 Aqueous solution, which is required to be uniform in color, free of water precipitation, spots, and lumps, must be sieved before use (to ensure that the binder is fully dissolved, the binder must be prepared at least 8 hours before wet granulation); 3) Premixing: Add the crushed API, sieved starch, lactose and microcrystalline cellulose into the wet granulator and mix evenly; 4) Wet granulation: After the raw materials and excipients are pre-mixed evenly, the binder is slowly added using a fixed funnel, and the stirring and shearing time is 180-240s. The obtained wet granules are then passed through a 30-mesh nylon sieve by a swing granulator for secondary granulation; 5) Drying and granulation: Dry at 55℃~65℃ until the moisture content of the granules is less than 3%, and granulate through a 30-mesh steel sieve; 6) Mixing: Add magnesium stearate to the granulated particles and mix them in a two-dimensional mixer for 5 minutes to make them uniform; 7) Tablet compression: Use a 6mm, shallow concave die to compress the tablets. The tablet weight is 100 mg and the tablet weight variation is ±5.0%.

[0029] Example 4 and Comparative Example 4: Preparation of 10 mg loratadine tablets

[0030] Example 4 Preparation process: 1) Pretreatment of raw materials and auxiliary materials: crushing of raw materials, particle size D after crushing 90 No larger than 10 microns; starch, lactose, microcrystalline cellulose, sodium stearate fumarate are sieved through a 60-mesh sieve and set aside; 2) Preparation of adhesive: Weigh the prescribed amount of povidone K 30 Add to purified water to make 10% Povidone K 30 Aqueous solution, which is required to be uniform in color, free of water precipitation, spots, and lumps, must be sieved before use (to ensure that the binder is fully dissolved, the binder must be prepared at least 8 hours before wet granulation); 3) Premixing: Add the crushed API, sieved starch, lactose and microcrystalline cellulose into the wet granulator and mix evenly; 4) Wet granulation: After the raw materials and excipients are pre-mixed evenly, the binder is slowly added using a fixed funnel, and the stirring and shearing time is 180-240s. The obtained wet granules are then passed through a 30-mesh nylon sieve by a swing granulator for secondary granulation; 5) Drying and granulation: Dry at 55℃~65℃ until the moisture content of the granules is less than 3%, and granulate through a 30-mesh steel sieve; 6) Mixing: Add the granulated particles to sodium stearate fumarate and mix them in a two-dimensional mixer for 5 minutes to make them uniform; 7) Tablet compression: Use a 6mm, shallow concave die to compress the tablets. The tablet weight is 100 mg and the tablet weight variation is ±5.0%.

[0031] Comparative Example 4 Preparation Process: 1) Pretreatment of raw materials and auxiliary materials: crushing of raw materials, particle size D after crushing 90 No larger than 10 microns; starch, lactose, microcrystalline cellulose, sodium stearate fumarate are sieved through a 60-mesh sieve and set aside; 2) Preparation of adhesive: Weigh the prescribed amount of povidone K 30 Add to purified water to make 10% Povidone K 30Aqueous solution, which is required to be uniform in color, free of water precipitation, spots, and lumps, must be sieved before use (to ensure that the binder is fully dissolved, the binder must be prepared at least 8 hours before wet granulation); 3) Premixing: Add the crushed API, sieved starch, mannitol and microcrystalline cellulose into a wet granulator and mix evenly; 4) Wet granulation: After the raw materials and excipients are pre-mixed evenly, the binder is slowly added using a fixed funnel, and the stirring and shearing time is 180-240s. The obtained wet granules are then passed through a 30-mesh nylon sieve by a swing granulator for secondary granulation; 5) Drying and granulation: Dry at 55℃~65℃ until the moisture content of the granules is less than 3%, and granulate through a 30-mesh steel sieve; 6) Mixing: Add the granulated particles to sodium stearate fumarate and mix them in a two-dimensional mixer for 5 minutes to make them uniform; 7) Tablet compression: Use a 6mm, shallow concave die to compress the tablets. The tablet weight is 100 mg and the tablet weight variation is ±5.0%; 8) Table 1 Compressibility test results of loratadine tablets prepared in various examples and comparative examples

[0032] Table 2 Dissolution test results of loratadine tablets prepared in various examples and comparative examples

[0033] Table 3 Stability test results:

[0034] Experimental results and conclusions: The experimental results in Table 2 show that the dissolution of the embodiment is significantly faster than that of the comparative embodiment, which shows that the preparation method provided by the present invention can improve the particle size of the raw material by crushing the particle size of the raw material and using povidone K 30 The aqueous solution of is used as a binder, so that the dissolution of the prepared loratadine tablets is greatly improved, which solves the problem that ethanol is often used as a solvent to dissolve the raw material drug that is insoluble in water in the preparation method of the commercially available loratadine tablets, and other preparation methods are used to solve the solubility problem of the loratadine tablets. The preparation method provided by the present invention has a simple process flow, and the materials used are all commonly used auxiliary materials for preparation of preparations and ethanol is not used, which is easier for commercial production.

[0035] Since loratadine is easily hydrolyzed in alkaline solution to produce impurities, controlling the growth of impurities during the preparation process has also become a major challenge. The stability test results in Table 3 show that the loratadine tablets prepared by the present invention have good stability and controllable quality.

[0036] The present invention further illustrates, through the preparation of comparative examples, that within the required scope of the present invention, the prepared loratadine tablets have high solubility and controllable quality.

Claims

1. A loratadine tablet and a preparation method thereof, characterized in that: The loratadine tablets have a particle size D 90 The main component is loratadine no larger than 10 microns, and the auxiliary materials include fillers, adhesives and lubricants, wherein the adhesive is 10% povidone K 30 Aqueous solution, prepared by wet granulation process.

2. A loratadine tablet according to claim 1, characterized in that: The main ingredient of the loratadine raw material is crushed to a particle size of D 90 No larger than 10 microns.

3. A loratadine tablet according to claim 1, characterized in that: The usage of the adhesive is 17.0% to 20.0%.

4. The adhesive according to claims 1 and 3, characterized in that The quality requirements of the adhesive are uniform color, no water precipitation, no spots, and no lumps, and it must be sieved before use.

5. A loratadine tablet according to claim 1, characterized in that: The filler consists of starch, lactose and microcrystalline cellulose, wherein the amount of lactose is 60.0-65.0%, the amount of starch is 10.0-15.0%, and the amount of microcrystalline cellulose is 8.0-13.0%.

6. A loratadine tablet according to claim 1, characterized in that: The lubricant is composed of one or more of magnesium stearate, sodium stearate fumarate or silicon dioxide.

7. A loratadine tablet and a preparation method thereof according to claim 1, characterized in that: The preparation process is wet granulation, and the binder is 10% povidone K 30 Aqueous solution.

8. The method for preparing a loratadine tablet according to claim 7, characterized in that: The wet granulation process steps are as follows: 1) Pretreatment of raw materials and auxiliary materials: crushing of raw materials, particle size D after crushing 90 No larger than 10 microns; starch, lactose, microcrystalline cellulose, and lubricant are sieved through a 60-mesh sieve and set aside; 2) Preparation of adhesive: weigh the prescribed amount of povidone K 30 Add to purified water to make 10% Povidone K 30 Aqueous solution should be uniform in color, free of water precipitation, spots, and lumps, and must be sieved before use; 3) Premixing: Add the crushed API, sieved starch, lactose and microcrystalline cellulose into a wet granulator and mix evenly; 4) Wet granulation: After the raw materials and excipients are pre-mixed evenly, the binder is slowly added using a fixed funnel, and the mixing and shearing time is 180-240s. The obtained wet granules are then passed through a 30-mesh nylon sieve by a swing granulator for secondary granulation; 5) Drying and granulation: Dry at 55℃~65℃ until the moisture content of the granules is less than 3%, and granulate through a 30-mesh steel sieve; 6) Mixing: Add lubricant to the granulated particles and mix them in a two-dimensional mixer to make them uniform; 7) Tablet compression: Use a 6mm, shallow concave die to compress the tablets. The tablet weight is 100 mg and the tablet weight variation is ±5.0%.

Images