Clarithromycin orally disintegrating tablet and preparation method thereof

Abstract

According to the clarithromycin orally disintegrating tablet and the preparation method thereof, a complex two-step granulation process is simplified, and a one-step granulation method is adopted, so that the production efficiency is improved, and the production cost is reduced. Secondly, aiming at the problem of obvious bitter taste of clarithromycin, the taste problem is fundamentally solved through enteric coating treatment and addition of a taste modifying and masking agent, and the medication compliance of a patient is obviously improved. The orally disintegrating tablet can be quickly disintegrated in the oral cavity, can also be taken after being dispersed by adding water, has the advantages of tablets and oral solutions, is particularly suitable for children, old people and other patients with dysphagia or poor medication compliance, and is more convenient to carry and store compared with the oral solutions.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, in particular to a clarithromycin orally disintegrating tablet and a preparation method thereof. Background Art

[0002] Clarithromycin is a derivative of erythromycin, which was developed by Taisho Pharmaceutical Co., Ltd. of Japan in the early 1990s and registered under the trade name Clarith. Subsequently, Taisho transferred its technology to Abbott Laboratories of the United States. It was launched in Ireland and Italy in 1990, approved by the FDA in October 1991, and launched in Hong Kong, China under the name Klacid in 1993. Currently, it has been launched in more than 50 countries and regions around the world, and the market consumption has increased steadily, playing an important role in clinical practice. Currently, the dosage forms of clarithromycin include tablets, granules, dispersible tablets, sustained-release tablets, injections, and dry suspensions.

[0003] Clarithromycin is a 14-membered ring macrolide antibiotic that inhibits protein synthesis by blocking the binding of the 50S subunit of nuclear proteins, thereby exerting antibacterial effects. This drug has inhibitory effects on Gram-positive bacteria such as Staphylococcus aureus, Streptococcus, and Streptococcus pneumoniae, and also has inhibitory effects on some Gram-negative bacteria such as Haemophilus influenzae, Bordetella pertussis, Neisseria gonorrhoeae, Legionella pneumophila, and some anaerobic bacteria such as Bacteroides fragilis, Streptococcus constellatus, and Propionibacterium acnes. In addition, it also has an inhibitory effect on mycoplasma. The characteristic of this drug is that its in vitro antibacterial activity is similar to that of erythromycin, but its in vivo antibacterial activity against some bacteria such as Staphylococcus aureus, Streptococcus, and Haemophilus influenzae is stronger than that of erythromycin.

[0004] Clarithromycin has a very obvious bitter taste, and it is difficult for patients to swallow the products prepared by ordinary preparation technologies, which directly affects the medication compliance of patients. In addition, clarithromycin is unstable in acid and is extremely easy to degrade. Therefore, the bioavailability of ordinary gastric-soluble preparations is relatively low. The clarithromycin enteric-coated dry suspension developed by Abbott Laboratories has better solved the problems of poor taste and acid instability of clarithromycin, but the preparation process is complex, the production cost is relatively high, and it needs to be diluted with water to form a suspension before taking. The storage time limit of the prepared suspension is only 14 days, which is not conducive to patients to carry and take. Summary of the Invention

[0005] In order to overcome the above-mentioned disadvantages of the prior art, the purpose of the present invention is to provide a clarithromycin orally disintegrating tablet and a preparation method thereof.

[0006] The technical solution adopted by the present invention to solve its technical problems is as follows: A clarithromycin orally disintegrating tablet, comprising the following materials in parts by mass: 125 parts of clarithromycin, 50-75 parts of carbomer, 5.6-14 parts of povidone, 70-140 parts of enteric coating material, 3-14 parts of plasticizer, 120-200 parts of filler, 20-60 parts of disintegrant, 2-6 parts of sweetener, 1-3 parts of essence, and 1-3 parts of lubricant.

[0007] The present invention also includes a preparation method of a clarithromycin orally disintegrating tablet, which is characterized by comprising the following steps:

[0008] (1) Prepare clarithromycin granules;

[0009] (2) Coat the clarithromycin granules with enteric coating;

[0010] (3) Add excipients to the clarithromycin enteric granules and press into orally disintegrating tablets.

[0011] As a further improvement of the present invention: The preparation of the clarithromycin granules in step (1) includes the following preparation steps:

[0012] 1) Weigh clarithromycin and carbomer, add them to a wet granulator, start stirring at 2-5 rpm, and mix for 5-20 min;

[0013] 2) Dissolve povidone in purified water to prepare a solution with a concentration of 2-5%, add it to the wet granulator for granulation; the addition amount of the binder solution is 1.2-1.8 times the powder amount, set the stirring at 2-5 rpm, the shearing at 20-40 rpm, granulate for 30-60 min, and discharge the material;

[0014] 3) After granulation, place the material in an oven for drying, the drying temperature is 60±5°C, and dry until the loss on drying ≤ 5.0%;

[0015] 4) After drying, screen the material through a 40-mesh sieve and collect the granules between 40-80 meshes.

[0016] As a further improvement of the present invention: The coating of the clarithromycin granules with enteric coating in step (2) includes the following preparation steps:

[0017] ① Prepare a coating solution with a solid content of 8-12% from the enteric coating material and plasticizer; the total amount of the coating solution is prepared according to a coating weight gain of 40-70%;

[0018] ② Add the clarithromycin granules to a fluidized bed, set the inlet air temperature at 50-70°C, the inlet air speed at 30-40 m 3 / h, and preheat the material temperature to 35-45°C;

[0019] ③ Set the inlet air temperature at 50-70°C, the inlet air speed at 30-40 m3 at a spraying rate of 10 - 20 g / min and an atomizing pressure of 1000 - 3000 mBar for coating; during the coating process, the material temperature is controlled within the range of 30 - 45°C, and the loss on drying is not more than 5.0%;

[0020] ④ After the spraying of the liquid is completed, set the inlet air temperature at 50 - 70°C and the inlet air speed at 30 - 40 m 3 / h, and continue drying for 5 - 20 min until the loss on drying is not more than 5.0%;

[0021] ⑤ Collect the coated granules passing through a 30 - mesh sieve.

[0022] As a further improvement of the present invention: in the step ①, the coating solvent includes but is not limited to ethanol, isopropanol, acetone and their mixtures, preferably ethanol, and 5 - 20% of water is added.

[0023] As a further improvement of the present invention: in the step (3), adding excipients to the clarithromycin enteric - coated granules and pressing them into orally disintegrating tablets includes the following preparation steps:

[0024] ㈠ Calculate the addition amount of clarithromycin granules according to the content of the coated granules, and add excipients such as fillers, disintegrants, binders, flavoring agents, sweeteners, lubricants, etc.;

[0025] ㈡ Mix the enteric - coated granules containing clarithromycin and the added excipients evenly;

[0026] ㈢ Adjust the tablet weight as needed, select appropriate punches and dies, and press tablets of different specifications; during the tableting process, detect the friability and disintegration time limit, which meet the requirements of the pharmacopoeia.

[0027] As a further improvement of the present invention: in the step ㈠, the added filler includes but is not limited to microcrystalline cellulose, lactose, starch, dextrin, preferably microcrystalline cellulose.

[0028] As a further improvement of the present invention: in the step ㈠, the disintegrant includes but is not limited to sodium carboxymethylcellulose, low - substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, preferably sodium carboxymethylcellulose.

[0029] As a further improvement of the present invention: in the step ㈠, the binder includes but is not limited to povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, preferably povidone.

[0030] As a further improvement of the present invention: in the step ㈠, the lubricant includes but is not limited to magnesium stearate, colloidal silicon dioxide, sodium stearyl fumarate, preferably magnesium stearate.

[0031] Compared with the prior art, the beneficial effects of the present invention are:

[0032] 1) The original granulation method of clarithromycin involves two-step granulation, two drying processes, and two pulverization steps, which is a rather cumbersome process with low production efficiency and high costs. This study simplifies the granulation process of the original preparation. By adopting the one-step granulation method, smooth coating can be achieved, greatly improving production efficiency and reducing production costs.

[0033] 2) The bitterness of clarithromycin is very prominent. With conventional taste masking methods, such as adding flavoring and taste masking agents, it is very difficult to solve the problem of its unpalatable taste. Currently, relevant clarithromycin dispersible tablets have not been taste masked, and good taste is a very important quality attribute for dispersible tablets, which can greatly improve the medication compliance of patients. In this application, the granules containing clarithromycin are coated with enteric coating, fundamentally solving the problem of the poor taste of clarithromycin, and adding flavoring and taste masking agents to further optimize the taste of this product, greatly improving the medication compliance of patients.

[0034] 3) The dosage form developed in this study is an orally disintegrating tablet, which can rapidly disintegrate in the mouth or can be taken after being dispersed in water. It combines the advantages of tablets and oral solutions, and is particularly suitable for patients with swallowing difficulties, such as children and the elderly, or those with poor medication compliance. Compared with oral solutions, it is also convenient for carrying and storage. Detailed implementation manners

[0035] The principles and features of the present invention are described below in conjunction with specific embodiments. The examples given are only for explaining the present invention and are not intended to limit the scope of the present invention.

[0036] It should be understood that the terms used in the present invention are only for describing particular embodiments and are not intended to limit the present invention. Additionally, for the numerical ranges in the present invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each intermediate value within any stated value or stated range, as well as each smaller range between any other stated value or intermediate value within the stated range, is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded from the range.

[0037] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. Although the present invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein can also be used in the implementation or testing of the present invention. Reagents not specifically described in detail in this application are all conventional reagents and can be obtained commercially; methods not specifically described in detail are all conventional experimental methods and can be learned from the prior art.

[0038] According to the original patent WO9716174A1, the granulation method of clarithromycin adopts a process of two-step granulation, two drying steps, and two pulverization steps. Although this process is effective, due to the numerous steps and cumbersome process, it leads to low production efficiency and high costs. For large-scale production, especially in terms of cost control, this process is undoubtedly a restrictive factor. Therefore, the production cost and production efficiency of clarithromycin preparations still need to be optimized. Currently, relevant domestic patents for clarithromycin dispersible tablets (such as CN104337778A, CN104586791A, CN104784129A, CN104784132A, CN106265552A, CN108853039A, CN114948887A) generally do not involve taste masking treatment, which has an important impact on the quality of the dispersible tablet dosage form. Since clarithromycin itself has a relatively significant bitter taste, as a dosage form that is convenient to take, if effective taste masking treatment is not carried out, it will directly affect the patient's medication compliance. For oral dosage forms such as dispersible tablets, good taste can greatly improve the patient's compliance, thus ensuring the therapeutic effect.

[0039] Although there have been some advancements in the development of clarithromycin preparations in the existing technology, there is still significant room for improvement in solving the taste problem, increasing production efficiency, and reducing costs. In particular, the application of taste masking technology can effectively improve the patient acceptance of dispersible tablets. At the same time, improving the granulation method, simplifying the production process, and reducing costs are also key directions in the future research and development of clarithromycin preparations.

[0040] The present invention will be further described in conjunction with the embodiments:

[0041] Embodiment:

[0042] Step 1, prepare clarithromycin granules:

[0043] 1) Prescription

[0044]

[0045] 2) Preparation process

[0046] ① Mixing

[0047] Weigh the prescribed amount of clarithromycin and carbomer, add them to a wet granulator, start stirring at 2 - 5 rpm, and mix for 5 - 20 minutes;

[0048] ② Granulation

[0049] Dissolve the prescribed amount of povidone in purified water to prepare a solution with a concentration of 2-5%, and add it to a wet granulator for granulation. The addition amount of the binder solution is 1.2-1.8 times the powder amount. Set the stirring speed at 2-5 rpm, the shearing speed at 20-40 rpm, granulate for 30-60 minutes, and discharge the material.

[0050] ③ Drying

[0051] After granulation, place the material in an oven for drying at a drying temperature of 60±5°C until the loss on drying is ≤5.0%.

[0052] ④ Screening

[0053] After drying, screen the material through a 40-mesh sieve and collect the granules between 40 and 80 meshes.

[0054] Step 2: Coating clarithromycin granules with enteric coating

[0055] 1) Coating prescription

[0056]

[0057] 2) Preparation process

[0058] ① Prepare the coating solution

[0059] Refer to the prescription dosage, prepare a coating solution with a solid content of 8-12% by mixing hydroxypropyl methylcellulose phthalate and castor oil, and the solvent is 80% ethanol; the total amount of the coating solution is prepared according to a coating weight gain of 40-70% for the granules.

[0060] ② Preheat

[0061] Add clarithromycin granules to the fluidized bed, set the inlet air temperature at 50-70°C, the inlet air speed at 30-40 m3 / h, and preheat the material temperature to 35-45°C.

[0062] ③ Coating

[0063] Set the inlet air temperature at 50-70°C, the inlet air speed at 30-40 m3 / h, the spraying speed at 10-20 g / min, and the atomization pressure at 1000-3000 mBar for coating. During the coating process, control the material temperature within the range of 30-45°C, and the loss on drying is not more than 5.0%.

[0064] ④ Drying

[0065] After spraying, set the inlet air temperature at 50-70°C, the inlet air speed at 30-40 m3 / h, and continue drying for 5-20 minutes until the loss on drying is not more than 5.0%.

[0066] ⑤ Collect the coated granules below 30 meshes.

[0067] Step 3: Add excipients to clarithromycin enteric-coated granules and press them into orally disintegrating tablets

[0068] 1) Prescription

[0069] Name of raw and auxiliary materials Dosage (parts) Function Clarithromycin 125 Active ingredient Microcrystalline cellulose 120-200 Filler Sodium carboxymethyl cellulose 20-60 Disintegrant Polyvinylpyrrolidone 15-30 Binder Aspartame 2-6 Sweetener Flavor 1-3 Flavoring agent Magnesium stearate 1-3 Lubricant

[0070] Calculate the addition amount of clarithromycin granules according to the content of coated granules, and add excipients such as microcrystalline cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, aspartame, essence, magnesium stearate, etc.

[0071] 2) Tabletting

[0072] ① Mixing

[0073] Fully mix the enteric-coated granules containing clarithromycin and the added excipients evenly;

[0074] ② Tabletting

[0075] Adjust the tablet weight as needed, select appropriate punches and dies, and press tablets of different specifications (such as: 30mg, 60mg, 120mg, etc.); During the tabletting process, detect the friability and disintegration time limit, which meet the requirements of the pharmacopoeia.

[0076] Detect the clarithromycin orally disintegrating tablets prepared by the above preparation steps, and evaluate whether this study achieves the expected effect by detecting the following items;

[0077] 1) Free clarithromycin content in the drug-containing granules before coating

[0078] The lower the free clarithromycin content in the clarithromycin granules before coating, the more fully clarithromycin is complexed with carbomer. Compared with the reference preparation, this study simplifies the granulation process, but the free clarithromycin content in the granules before coating is still low. It shows that the process of this study can replace the process of the reference preparation.

[0079]

[0080] 2) Taste

[0081] The samples prepared in this study have a good taste and no bitterness, solving the problem of poor taste of existing dispersible tablets.

[0082] 3) Disintegration time limit

[0083] Detect the disintegration time limit with reference to the pharmacopoeia standard, which meets the pharmacopoeia standard.

[0084] 4) Acid resistance qualified

[0085] Clarithromycin is unstable in an acidic environment and prone to degradation. Passing the acid resistance test indicates that the process of this study can achieve the insolubility of clarithromycin in acid, thus achieving enteric-coated effect, effectively solving the stability problem of the drug in the gastric acid environment, greatly improving the bioavailability, and providing a more reliable efficacy guarantee for the oral preparation of clarithromycin. Meanwhile, in the non-enteric-coated medium, the dissolution amount of clarithromycin is low, further indicating that there is no taste problem for the sample of this study as an orally disintegrating tablet.

[0086]

[0087] The property of the sample of this invention being insoluble in gastric acid provides it with an enteric-coated effect. This means that the drug can pass through the stomach relatively intact and be released in the intestine, ensuring that it exerts the best efficacy in the absorption area. This optimization effectively avoids the destruction of the drug by gastric acid, improves the bioavailability of the drug, and greatly enhances the absorption efficiency of clarithromycin in the body.

[0088] The dissolution amount of clarithromycin in the non-enteric-coated medium is low, which further indicates that clarithromycin will not be rapidly released during oral disintegration of this preparation, thus avoiding the common bitter taste problem in traditional preparations. In this way, the taste of clarithromycin is significantly improved, enabling this preparation to significantly improve the medication compliance of patients when used as an orally disintegrating tablet.

[0089] In summary, after reading the documents of this invention, various other corresponding transformation schemes made by those of ordinary skill in the art without creative mental labor according to the technical solutions and technical concepts of this invention all fall within the scope protected by this invention.

Claims

1. A clarithromycin orally disintegrating tablet, characterized in that: The invention comprises the following materials in parts by weight: 125 parts of clarithromycin, 50-75 parts of carbomer, 5.6-14 parts of povidone, 70-140 parts of enteric coating material, 3-14 parts of plasticizer, 120-200 parts of filler, 20-60 parts of disintegrant, 15-30 parts of binder, 2-6 parts of sweetener, 1-3 parts of flavor and 1-3 parts of lubricant.

2. A method for preparing a clarithromycin orally disintegrating tablet, characterized in that: The following steps are involved: (1) preparing clarithromycin granules; (2) clarithromycin granules with enteric coating; (3) Adding excipients to the clarithromycin enteric-coated granules to form orally disintegrating tablets.

3. The method for preparing a clarithromycin orally disintegrating tablet according to claim 2, characterized in that: The step (1) of preparing clarithromycin granules comprises the following preparation steps: 1) Weigh clarithromycin and carbomer, add into a wet granulator, start stirring at 2-5 rpm, and mix for 5-20 minutes; 2) dissolving povidone in purified water to prepare a solution with a concentration of 2-5%, adding the solution to a wet granulator for granulation; the amount of the binder solution added is 1.2-1.8 times the amount of the powder, setting the stirring speed to 2-5 rpm, the shear speed to 20-40 rpm, granulating for 30-60 minutes, and discharging; 3) After granulation, the material is placed in an oven for drying at a temperature of 60±5°C until the loss on drying is ≤5.0%; 4) After drying, the material is sieved through a 40-mesh screen and particles between 40 and 80 mesh are collected.

4. The method for preparing a clarithromycin orally disintegrating tablet according to claim 2, characterized in that: The step (2) of enteric coating clarithromycin granules comprises the following preparation steps: ① Prepare a coating solution with a solid content of 8 to 12% by using the enteric coating material and the plasticizer; the total amount of the coating solution is prepared so that the coating weight gain is 40 to 70%; ② Add clarithromycin granules to the fluidized bed, set the air inlet temperature to 50-70°C and the air inlet speed to 30-40m / s. 3 / h, the material temperature is preheated to 35-45℃; ③Set the air inlet temperature to 50-70℃ and the air inlet speed to 30-40m 3 / h, spraying speed 10-20g / min, atomization pressure 1000-3000mBar, coating; during the coating process, the material temperature is controlled within the range of 30-45℃, and the drying loss is not greater than 5.0%; ④After spraying, set the air inlet temperature to 50-70℃ and the air inlet speed to 30-40m 3 / h, continue drying for 5-20min until the loss on drying is no more than 5.0%; ⑤ Collect coated particles below 30 mesh.

5. The method for preparing a clarithromycin orally disintegrating tablet according to claim 4, characterized in that: The coating solvent in step ① is ethanol or isopropanol or acetone or a mixture thereof.

6. The method for preparing a clarithromycin orally disintegrating tablet according to claim 2, characterized in that: The step (3) of adding excipients to the clarithromycin enteric-coated granules to compress the orally disintegrating tablets comprises the following preparation steps: (i) Calculate the amount of clarithromycin granules added based on the content of the coated granules, and add fillers, disintegrants, binders, flavoring agents, sweeteners, and lubricant excipients; (ii) Fully mix the enteric-coated granules containing clarithromycin and the added excipients; ㈢Adjust tablet weight as needed, select appropriate punches and dies, and compress tablets of different specifications; test friability and disintegration time during tableting to ensure compliance with pharmacopoeia requirements.

7. The method for preparing a clarithromycin orally disintegrating tablet according to claim 6, characterized in that: The external filler in step (i) comprises microcrystalline cellulose or lactose or starch or dextrin.

8. The method for preparing a clarithromycin orally disintegrating tablet according to claim 6, characterized in that: In the step (i), the disintegrant comprises sodium carboxymethylcellulose or low-substituted hydroxypropyl cellulose or cross-linked polyvinylpyrrolidone or sodium carboxymethyl starch.

9. The method for preparing a clarithromycin orally disintegrating tablet according to claim 6, characterized in that: In the step (i), the binder comprises povidone or hydroxypropyl cellulose or hydroxypropyl methylcellulose.

10. The method for preparing a clarithromycin orally disintegrating tablet according to claim 6, characterized in that: In the step (i), the lubricant comprises magnesium stearate or colloidal silicon dioxide or sodium stearyl fumarate.

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