Loratadine tablet and preparation process thereof

Abstract

The invention provides a loratadine tablet and a preparation process thereof. The preparation method specifically comprises the following steps: adding loratadine, lactose anhydrous and a first batch of corn starch into a wet granulator, and uniformly stirring to obtain a wet mixture; adding purified water at a certain temperature into the second batch of corn starch, uniformly stirring to form a dispersion liquid, mixing the dispersion liquid with the boiled purified water, and uniformly stirring to obtain corn starch slurry; taking the prepared corn starch slurry as an adhesive, adding the adhesive into a wet granulator, and stirring and granulating; granulating the granulated granules by using a first screen, and drying by using a fluidized bed; granulating the dried granules again by using a second screen, uniformly mixing the granules with the disintegrating agent, uniformly mixing the granules with the lubricant, and tabletting to obtain the tablet. By adopting the method provided by the invention to prepare the loratadine tablet, the problems of poor stability and high related substance content of the loratadine tablet are solved. The whole production process method is simple, efficient, low in required energy consumption, easy to operate and especially suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a loratadine tablet. The present invention also provides a preparation process of loratadine tablets suitable for industrial production. Background Art

[0002] Loratadine (English: Loratadine), with Chinese and English trade names such as Claritin, Hismanal, Clarityn, and Lomidine, is a second-generation antihistamine drug commonly used to treat allergic symptoms. Compared with the first-generation antihistamine drugs, one of its major characteristics is the absence of obvious drowsiness effect.

[0003] Loratadine tablets are solid preparations containing loratadine as the active ingredient, and are used for the symptomatic treatment of various allergies. It relieves the symptoms caused by allergic rhinitis, such as sneezing, runny nose, nasal itching, nasal congestion, as well as eye itching and burning sensation in the eyes. It is used for the symptomatic treatment of chronic urticaria, pruritic skin diseases, and other allergic skin diseases. Other allergic symptoms can also be used as prescribed by a doctor.

[0004] At present, a variety of preparation methods of loratadine tablets have been disclosed or patented, for example: CN202310690086.4 discloses a process flow for preparing loratadine tablets by spray granulation, drying, and tabletting. CN201710891739.X discloses a method for preparing loratadine tablets by a quasi-wet granulation method, which does not require granulation and sizing steps, simplifies the process flow, and reduces costs. CN201710402283.6 discloses a method for solving the problem of low solubility and slow dissolution rate of loratadine tablets in acidic medium by dissolving loratadine and then granulating. Although the above-mentioned preparation methods of loratadine tablets have been disclosed or patented, these methods still have some deficiencies. For example, dissolving loratadine and then granulating may lead to crystal form transformation. And the excessive use of excipients may cause allergic reactions of patients to the excipients in the tablets.

[0005] Therefore, how to develop a new preparation method of loratadine tablets to improve the quality and production efficiency of loratadine tablets is an urgent problem to be solved by those skilled in the art. Summary of the Invention

[0006] The object of the present invention is to provide a preparation method of loratadine tablets. This method has a simple process, low energy consumption, and is particularly suitable for large-scale industrial production. The loratadine tablets prepared by the scheme of the present invention can show a high dissolution rate under different conditions, and the product has excellent quality, good stability, very small differences among batches, and low related substances.

[0007] To achieve the above object, the present invention provides a preparation method of loratadine tablets, comprising the following steps:

[0008] Add loratadine, anhydrous lactose and the first batch of corn starch into a wet granulator, stir evenly to obtain a wet mixture;

[0009] Add purified water at a certain temperature to the second batch of corn starch, stir evenly to form a dispersion, and then mix the dispersion with boiling purified water, stir evenly to obtain a corn starch paste;

[0010] Use the prepared corn starch paste as a binder, add it to the wet granulator, and stir to granulate;

[0011] After sizing the granulated particles with a first sieve, dry them in a fluidized bed;

[0012] After sizing the dried particles with a second sieve again, first mix them evenly with a disintegrant, and then mix them evenly with a lubricant, and press tablets to obtain the product.

[0013] In a preferred embodiment, the particle size D of the loratadine 90 <10 μm; the particle size of the anhydrous lactose is 200 mesh; the drying loss of the first batch of corn starch and / or the second batch of corn starch is less than 7.0%. Among them, there is no distinction in the order of the process steps for the first batch of corn starch and the second batch of corn starch, only as a difference in the addition amount of corn starch in different steps.

[0014] In the present invention, by controlling the particle size of loratadine, the dissolution efficiency of loratadine tablets can be effectively controlled; the purpose of selecting 200-mesh anhydrous lactose is to increase the particle fluidity, thereby improving the mixing quality and further improving the dissolution efficiency of loratadine tablets. By controlling the drying loss of corn starch, the influence of the drying loss on the feeding content can be effectively avoided. If ordinary lactose is selected or the lactose mesh number is not controlled, it is easy to cause unqualified premix mixing uniformity, and if the drying loss of corn starch is not controlled, it is easy to cause a high content of loratadine tablets, resulting in unqualified drugs.

[0015] In a preferred embodiment, in the step of preparing the wet mixture, the mass ratio of the loratadine, anhydrous lactose and the first batch of corn starch is 10:(70 - 75):(10 - 15).

[0016] In a preferred embodiment, in the step of preparing the wet mixture, the stirring conditions include: mixing rotation speed 90 - 120 rpm, cutter rotation speed 250 - 350 rpm, and mixing time 10 - 20 min.

[0017] In a preferred embodiment, in the step of preparing the corn starch slurry, the mass ratio of the second batch of corn starch, purified water at a certain temperature, and boiling purified water is 1:(0.5 - 1.5):(8 - 12). Preferably, the certain temperature is 40 - 50°C.

[0018] The purpose of using corn starch as a binder in the present invention is as follows: First, corn starch is a natural substance with high safety, suitable for sensitive populations and long-term medication. Moreover, corn starch can be used directly, with a simple process and easy production control. Further, the corn starch used in the present invention can not only be used as a binder but also has a certain disintegrating effect, which can accelerate disintegration while ensuring the tablet hardness. Furthermore, the present invention adopts the wet granulation process, and corn starch is not sensitive to humidity and has good stability. Finally, the inventors of this case found through a large number of experiments that using corn starch can form a smooth tablet appearance and has good long-term stability.

[0019] In the prior art, polyvinylpyrrolidone K30 is usually used as a binder. It belongs to synthetic polymer materials, and some patients may be sensitive to synthetic substances. Moreover, K30 usually needs to be dissolved into a solution before use, with a complex process and strict control of solvent residues required. On the other hand, K30 has strong binding force but poor disintegrating property, which will affect the drug release rate. Finally, K30 is sensitive to humidity and easy to absorb moisture. Using the process of this case will affect the storage and stability of the tablets, resulting in sticky tablet surfaces or failure in high-humidity environments.

[0020] In summary, using corn starch as a binder in the present invention can not only reduce costs but also improve the disintegrating property, stability, and production process of the tablets, especially suitable for oral preparations such as loratadine tablets that require rapid disintegration.

[0021] In a preferred embodiment, in the step of stirring and granulating, the mass ratio of the wet mixture and the corn starch slurry is 10:(1 - 3).

[0022] In a preferred embodiment, in the step of stirring and granulating, the granulation conditions include: the stirring paddle speed is 100 - 150 rpm, the cutter speed is 1000 - 2000 rpm, and the granulation time is 10 - 30 min.

[0023] In a preferred embodiment, the aperture of the first sieve is 10 mm, and the aperture of the second sieve is 1.0 - 1.2 mm. In the present invention, by controlling the aperture of the first sieve at 10 mm, the drying efficiency of the wet granules is improved. By controlling the aperture of the second sieve at 1.0 - 1.2 mm, the product particle size distribution is controlled, and thus the product dissolution quality is controlled.

[0024] In a preferred embodiment, the fluidized bed drying conditions include: inlet air temperature of 80 - 90 °C, inlet air humidity of 5 - 8 g / kg, fluidization air volume of 800 - 1200 m 3 / h. When the temperature of the material to be dried reaches 40 - 42 °C, the weight loss of the dried particles is required to be less than 3%.

[0025] In a preferred embodiment, the mass ratio of the particles after re-granulation, disintegrant and lubricant is 50:(1.5 - 3):(0.1 - 0.5).

[0026] In a preferred embodiment, the disintegrant includes at least one of microcrystalline cellulose, sodium carboxymethyl starch, microcrystalline cellulose or corn starch.

[0027] In a preferred embodiment, the conditions for mixing with the disintegrant include: mixing rotation speed of 5 - 20 rpm and mixing time of 10 - 30 min.

[0028] In a preferred embodiment, the lubricant includes at least one of sodium lauryl sulfate, magnesium stearate or polyethylene glycol.

[0029] In a preferred embodiment, the conditions for mixing with the lubricant include: mixing rotation speed of 5 - 20 rpm and mixing time of 2 - 4 min.

[0030] In a preferred embodiment, the tableting conditions include: average hardness of 2 - 6 kg, weight difference of ±5%; friability should not be greater than 0.8%.

[0031] Another object of the present invention is to provide a loratadine tablet prepared by the method described in any one of the above.

[0032] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0033] In the solution of the present invention, loratadine, anhydrous lactose and corn starch are wet granulated, then dried and re-granulated using a fluidized bed. After the second mixing with the disintegrant, the third mixing with the lubricant is carried out, and a loratadine tablet is obtained after tableting. By using the method provided by the present invention to prepare loratadine tablets, the problems of poor stability and high related substances of loratadine tablets are solved. Moreover, the overall production process method is simple, efficient, with low energy consumption required, easy to operate, and especially suitable for large-scale industrial production. Specific Embodiments

[0034] In order to enable those skilled in the art to better understand the present invention, the present invention will be further described in detail below in conjunction with specific embodiments. However, it should be understood that the protection scope of the present invention is not limited by the specific embodiments.

[0035] The technical solution of the present application will be described in detail below through specific embodiments:

[0036] Unless otherwise specified, the technical means used in the present invention are conventional means well-known to those skilled in the art. All kinds of raw materials, reagents, instruments and equipment used in the present invention can be obtained through market purchase or can be prepared by existing methods. The reagents used in the present invention are all analytical pure unless otherwise specified.

[0037] Example 1: Preparation of loratadine tablets (specification 10mg, hardness 2.0 - 3.5kg)

[0038] 6.01 kg of loratadine, 43 kg of anhydrous lactose, and 8 kg of corn starch were successively added to a high-efficiency wet granulator, and the stirring speed was set at 90 rpm, the cutting speed was set at 300 rpm, and the mixture was stirred for 15 min.

[0039] 1 kg of corn starch for paste was poured into a beaker, and an equal amount of purified water (40°C - 50°C) was added, and it was stirred to disperse evenly to form a dispersion for standby; 10 kg of purified water (boiling water) was poured into a stirring bucket, stirring was started, and then the above-mentioned starch dispersion was slowly poured in, the lid was closed, and it was stirred for 5 min to prepare a starch paste, and the prepared starch paste was added to the wet granulator.

[0040] The time for adding the paste was controlled at 5 min. After adding the paste, the stirring paddle speed was set at 110 r / min, the cutter speed was set at 1100 r / min, and the machine was stopped after 10 min, the lid was opened, and the inner wall was cleaned. At 20 min, the machine was stopped, and the wet material was taken out. A 10 mm square hole sieve was installed and the fluidized bed was set with an inlet air temperature of 80°C, an inlet air humidity of 5 g / kg - 8.0 g / kg, and a fluidization air volume of 800 m 3 / h - 1200 m 3 / h. When the material temperature reached 40°C - 42°C, the drying loss of the granules (rapid moisture analyzer, 80°C, 10 min) was required to be less than or equal to 3%; if the result > 3%, continue drying until it meets the requirements.

[0041] Dry screening was carried out using a 1.0 mm round hole V-shaped sieve. The granulated particles were added to the hopper of the mixer, 2.52 kg of corn starch was added, and the mixing speed was set at 10 rpm for mixing, and the mixing time was 20 min. After mixing, 0.30 kg of magnesium stearate was added for final mixing, the mixing speed was set at 10 rpm, and the final mixing time was 3 min. Using a 7.6 mm * 5 mm punch, the average hardness was 2.0 - 3.5 kg, and the weight difference was ±5%; the friability should not be greater than 0.8%.

[0042] Example 2: Preparation of loratadine tablets (specification 10mg, hardness 3.5 - 6.0kg)

[0043] Add 6.01 kg of loratadine, 43 kg of anhydrous lactose, and 8 kg of corn starch into a high-efficiency wet granulator in sequence, set the stirring speed at 90 rpm and the cutting speed at 300 rpm, and mix for 15 minutes.

[0044] Pour 1 kg of corn starch for paste into a beaker, add a single volume of purified water (40°C - 50°C), stir to disperse it evenly to form a dispersion for standby; pour 10 kg of purified water (boiling water) into a stirring bucket, start stirring, then slowly pour the above starch dispersion into it, close the lid, and stir for 5 minutes to prepare the starch paste, and add the prepared starch paste into the wet granulator.

[0045] Control the slurry addition time at 5 minutes. After adding the slurry, set the stirring paddle speed at 110 r / min and the cutter speed at 1100 r / min, stop the machine at 10 minutes, open the lid, and clean the inner wall. At 20 minutes, stop the machine and take out the wet material. Install a 10 mm square hole sieve mesh and set the inlet air temperature of the fluidized bed at 80°C, the inlet air humidity at 5 g / kg - 8.0 g / kg, and the fluidization air volume at 800 m 3 / h - 1200 m 3 / h. When the material temperature reaches 40°C - 42°C, the drying loss of the granules (using a rapid moisture analyzer at 80°C for 10 minutes) should be less than or equal to 3%; if the result > 3%, continue drying until it meets the requirements.

[0046] Use a 1.0 mm round hole V-shaped sieve mesh for dry granulation. Add the granulated particles into the hopper of the mixer, add 2.52 kg of corn starch, set the mixing rotation speed at 10 rpm for mixing, and the mixing time at 20 minutes. After mixing, add 0.30 kg of magnesium stearate for final mixing, set the mixing rotation speed at 10 rpm, and the final mixing time at 3 minutes. Use a punch of 7.6 mm * 5 mm, with an average hardness of 3.5 - 6.0 kg and a weight difference of ±5%; the friability should not be greater than 0.8%.

[0047] Example 3: Preparation of loratadine tablets (specification 10 mg, hardness 3 - 5 kg)

[0048] Add 6.01 kg of loratadine, 43 kg of anhydrous lactose, and 8 kg of corn starch into a high-efficiency wet granulator in sequence, set the stirring speed at 90 rpm and the cutting speed at 300 rpm, and mix for 15 minutes.

[0049] Pour 1.1 kg of corn starch for paste into a beaker, add a single volume of purified water (40°C - 50°C), stir to disperse it evenly to form a dispersion for standby; pour 9.8 kg of purified water (boiling water) into a stirring bucket, start stirring, then slowly pour the above starch dispersion into it, close the lid, and stir for 5 minutes to prepare the starch paste, and add the prepared starch paste into the wet granulator.

[0050] Control the slurry addition time to 5 min. After adding the slurry, set the stirring paddle speed to 110 r / min and the cutter speed to 1100 r / min. Stop the machine after 10 min, open the lid, and clean the inner wall. Stop the machine at 20 min and take out the wet material. Install a 10 mm square hole sieve mesh and set the inlet air temperature of the fluidized bed to 80 °C, the inlet air humidity to 5 g / kg - 8.0 g / kg, and the fluidization air volume to 800 m 3 / h - 1200 m 3 / h. When the material temperature reaches 40 °C - 42 °C, the drying loss of the granules (using a rapid moisture analyzer at 80 °C for 10 min) should be less than or equal to 3%; if the result > 3%, continue drying until the requirement is met.

[0051] Use a 1.0 mm round hole V-shaped sieve mesh for dry granulation. Add the granulated particles to the hopper of the mixer, add 2.52 kg of corn starch, and set the mixing speed to 10 rpm for mixing. The mixing time is 20 min. After mixing, add 0.30 kg of magnesium stearate for final mixing. Set the mixing speed to 10 rpm and the final mixing time to 3 min. Use a 7.6 mm * 5 mm punch, with an average hardness of 3.5 - 6.0 kg and a weight difference of ±5%; the friability should not be greater than 0.8%.

[0052] Comparative Example 1: Prepare loratadine tablets (specification 10 mg, hardness 2.0 - 3.5 kg)

[0053] Add 6.01 kg of loratadine, 43 kg of anhydrous lactose, and 8 kg of corn starch to a high-efficiency wet granulation mixer in sequence. Set the stirring speed to 90 rpm and the cutting speed to 300 rpm, and mix for 15 min.

[0054] Pour 1 kg of polyvinylpyrrolidone K30 into a beaker, add a single volume of purified water (40 °C - 50 °C), stir to disperse it evenly to form a dispersion, and set aside; pour 10 kg of purified water (boiling water) into the stirring bucket, start stirring, then slowly pour the above dispersion into it, close the lid, and stir for 5 min to prepare the binder. Add the prepared binder to the wet granulation machine.

[0055] Control the slurry addition time to 5 min. After adding the slurry, set the stirring paddle speed to 110 r / min and the cutter speed to 1100 r / min. Stop the machine after 10 min, open the lid, and clean the inner wall. Stop the machine at 20 min and take out the wet material. Install a 10 mm square hole sieve mesh and set the inlet air temperature of the fluidized bed to 80 °C, the inlet air humidity to 5 g / kg - 8.0 g / kg, and the fluidization air volume to 800 m 3 / h - 1200 m 3 / h. When the material temperature reaches 40°C - 42°C, the loss on drying of the granules (using a rapid moisture analyzer at 80°C for 10 minutes) should be less than or equal to 3%; if the result > 3%, continue drying until the requirement is met.

[0056] Use a 1.0 mm round hole V-shaped sieve for dry granulation. Add the granulated particles to the hopper of the mixer, add 2.52 kg of corn starch, set the mixing speed at 10 rpm for mixing, and the mixing time is 20 minutes. After mixing, add 0.30 kg of magnesium stearate for final mixing, set the mixing speed at 10 rpm, and the final mixing time is 3 minutes. Use a 7.6 mm * 5 mm punch, with an average hardness of 2.0 - 3.5 kg and a weight difference of ±5%; the friability should not be greater than 0.8%.

[0057] Application Example 1

[0058] Perform in vitro dissolution tests on the loratadine tablets prepared in Examples 1 - 3 and Comparative Example 1 of the present invention. The test process and test results are as follows:

[0059] (I) Test process:

[0060] 1. Medium: PH1.2: Take 7 ml of hydrochloric acid and 2 g of sodium chloride, dissolve in water and dilute to 1000 ml, shake well, and degas to obtain. PH4.5: Weigh about 6.81 g of potassium dihydrogen phosphate, dissolve in degassed water and dilute to 1000 ml to obtain. PH6.8: Take 1.7 g of potassium dihydrogen phosphate and 4.5 g of disodium hydrogen phosphate dodecahydrate, dissolve in water and dilute to 1000 ml to obtain. Water: Water.

[0061] 2. Dissolution conditions: Medium volume: 900 ml; rotation speed: 50 rpm; paddle method.

[0062] (II) Test results:

[0063] 1. Dissolution results at PH1.2 are shown in Table 1

[0064] Table 1: Dissolution results at PH1.2

[0065]

[0066] 2. Dissolution results at PH4.5 are shown in Table 2

[0067] Table 2: Dissolution results at PH4.5

[0068]

[0069] 3. Dissolution results at PH6.8 are shown in Table 3

[0070] Table 3: Dissolution results at PH6.8

[0071]

[0072]

[0073] 4. Dissolution results in water are shown in Table 4

[0074] Table 4: Dissolution results in water

[0075]

[0076] (III) Results and Discussion

[0077] As can be seen from Tables 1 - 4, the loratadine tablets prepared in Examples 1 - 3 showed high dissolution rates under different conditions (pH 1.2, pH 4.5, pH 6.8, and water), with excellent product quality and reliable stability, and very little difference between batches. Thus, it can be seen that the loratadine tablets with different particle hardness and different binder ratios prepared by the method of the present invention all have excellent drug dissolution performance.

[0078] In Comparative Example 1, povidone K30 was used as the binder. Although it has strong binding force, its disintegration property is poor. Especially in the acidic pH of human gastric acid, the dissolution rate of the loratadine tablets prepared in Comparative Example 1 is significantly lower than that of the loratadine tablets prepared in the examples of the present invention.

[0079] Application Example 2

[0080] For the loratadine tablets prepared in Examples 1 - 3 of the present invention, related substance tests, product properties, and particle size analysis were carried out. The test methods and test results are as follows:

[0081] (I) Test method:

[0082] The execution standard for related substance analysis and detection is: the related substance detection method for loratadine tablets in the 2020 Edition of the Chinese Pharmacopoeia.

[0083] (II) Test results:

[0084] 1. The analysis results of related substances in the loratadine tablets are shown in Table 5:

[0085] Table 5: Analysis results of related substances

[0086] Project Example 1 Example 2 Example 3 Single impurity 0.2％ ≤0.1％ 0.01％ Total impurity 0.6％ ≤0.5％ 0.05％

[0087] 2. The analysis results of product properties and particle mesh of the loratadine tablets are shown in Table 6:

[0088] Table 6: Analysis results of product properties and particle mesh

[0089]

[0090]

[0091] As can be seen from Table 5-6, the content of related substances in the loratadine tablets prepared in Examples 1-3 is extremely low, fully demonstrating the fineness and stability of the process. Moreover, the results of the particle mesh analysis of the obtained products are uniform, the particle size distribution is accurate, and the product quality can fully meet the requirements for high-quality drugs.

[0092] The foregoing description of specific exemplary embodiments of the invention has been presented for purposes of illustration and example. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that, according to the above teaching, many changes and variations are possible. The purpose of selecting and describing the exemplary embodiments is to explain the specific principles of the invention and its practical application, so that those skilled in the art can implement and utilize the various different exemplary embodiments of the invention, as well as various different selections and changes. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A method for preparing loratadine tablets, characterized in that: The following steps are involved: Add loratadine, anhydrous lactose and the first batch of corn starch into a wet granulator and stir evenly to obtain a wet mixture; Adding purified water at a certain temperature to the second batch of corn starch, stirring evenly to form a dispersion, then mixing the dispersion with boiling purified water, stirring evenly to obtain a corn starch slurry; The prepared corn starch slurry is used as a binder, added into a wet granulator, and stirred for granulation; The granulated particles are sized using a first screen and then dried using a fluidized bed; The dried granules are re-sized using a second sieve, first mixed evenly with a disintegrant, then mixed evenly with a lubricant, and compressed into tablets.

2. The method for preparing loratadine tablets according to claim 1, wherein The particle size D of loratadine 90 <10 μm; the anhydrous lactose particle size is 200 mesh; the drying loss of the first batch of corn starch and / or the second batch of corn starch is less than 7.0%.

3. The method for preparing loratadine tablets according to claim 1, wherein In the step of preparing the wet mix, the mass ratio of the loratadine, anhydrous lactose and the first batch of corn starch is 10:(70-75):(10-15).

4. The method for preparing loratadine tablets according to claim 1, wherein In the step of preparing corn starch slurry, the mass ratio of the second batch of corn starch, the purified water at a certain temperature and the boiling purified water is 1:(0.5-1.5):(8-12); the certain temperature is 40-50°C.

5. The method for preparing loratadine tablets according to claim 1, characterized in that: In the stirring granulation step, the mass ratio of the wet mixture to the corn starch slurry is 10:(1-3).

6. The method for preparing loratadine tablets according to claim 1, characterized in that: The aperture of the first sieve is 10 mm, and the aperture of the second sieve is 1.0-1.2 mm.

7. The method for preparing loratadine tablets according to claim 1, characterized in that: The fluidized bed drying conditions include: inlet air temperature 80-90°C, inlet air humidity 5-8g / kg, fluidizing air volume 800-1200m 3 / h, when the material temperature reaches 40-42℃, the particle drying loss is required to be below 3%.

8. The method for preparing loratadine tablets according to claim 1, characterized in that: The mass ratio of the re-granulated particles, disintegrant and lubricant is 50:(1.5-3):(0.1-0.5).

9. The method for preparing loratadine tablets according to claim 8, characterized in that: The disintegrant comprises at least one of microcrystalline cellulose, sodium carboxymethyl starch, microcrystalline cellulose or corn starch; and the lubricant comprises at least one of sodium lauryl sulfate, magnesium stearate or polyethylene glycol.

10. Loratadine tablets prepared by the method according to any one of claims 1 to 9.

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