CN111228227A

CN111228227A - Salbutamol sulfate oral disintegrating tablet and preparation method thereof

Info

Publication number: CN111228227A
Application number: CN202010152865.5A
Authority: CN
Inventors: 陈用芳; 杨绪凤; 胡延贵; 吴奇财
Original assignee: Chongqing Conquer Pharmaceutical Co Ltd
Current assignee: Chongqing Conquer Pharmaceutical Co Ltd
Priority date: 2020-03-06
Filing date: 2020-03-06
Publication date: 2020-06-05

Abstract

The invention provides a salbutamol sulfate orally disintegrating tablet and a preparation method thereof, wherein the tablet comprises the following steps: weighing raw materials of salbutamol sulfate and auxiliary materials, sieving, pre-mixing the raw materials and the auxiliary materials, and tabletting, wherein the tabletting adopts a powder direct compression process. The invention has the following advantages: the direct pressing process has the advantages of less working procedures, simple equipment and easy commercial production; the fluidity and compressibility of the granules are greatly improved after the particle size of the auxiliary materials is controlled; the impurity level after the improved process is lower than that of the original product; the safety of the patient is improved, and potential safety hazards are avoided.

Description

Salbutamol sulfate oral disintegrating tablet and preparation method thereof

Technical Field

The invention relates to the technical field of biological pharmacy, in particular to a salbutamol sulfate tablet and a preparation method thereof.

Background

Salbutamol sulfate, the Chinese alias, sulindac sulfate; the little turpentine sulfate; 1- (4-hydroxy-3-hydroxymethylphenyl) -2- (tert-butylamino) ethanoldi-c; salbutamol sulphate of formula

The bronchial asthma is a common disease and frequently encountered disease, the worldwide statistics of the morbidity of the bronchial asthma is greatly different and is between 0.7 and 9.9 percent, along with the wide development of industrialization, the bronchial asthma gradually becomes a main disease of most industrialized countries, the morbidity and the mortality of the bronchial asthma are continuously increased in nearly 20 years, the number of patients with global bronchial asthma is over 3, the mortality of the patients with the global bronchial asthma exceeds 30/10 ten thousands, the respiratory system (lung cancer) is the first to live in the world, the morbidity and the mortality of the respiratory system diseases are high in China, the respiratory system (lung cancer) is the first to live in the city, the environmental pollution and other factors, the respiratory system diseases are the first to live in the world, the respiratory system diseases (lung cancer) is the first to live in the world, the respiratory system diseases) is the chronic obstructive pulmonary disease, the lung cancer is the first to live in the world, the lung cancer is the chronic obstructive pulmonary disease, the lung cancer is the chronic obstructive pulmonary disease, the chronic pulmonary asthma, the lung cancer is the chronic obstructive pulmonary asthma, the chronic pulmonary asthma of the chronic pulmonary disease of people who live in the old people who live in the world, the chronic pulmonary asthma of the old people who live in the countryside, the chronic pulmonary asthma of the old people, the chronic pulmonary asthma of the chronic pulmonary diseases of the old people.

In recent years, various pharmaceutical imitation enterprises enter the field of salbutamol sulfate production. In the prior art, salbutamol sulfate orally disintegrating tablets, ambroxol salbutamol orally disintegrating tablets, compound tranilast orally disintegrating tablets, levosalbutamol hydrochloride sustained-release orally disintegrating tablets and levosalbutamol and ambroxol compound compositions already appear in the market. At present, salbutamol sulphate drugs are on the market, usually in the form of an aerosol. The orally disintegrating tablet has the advantages of accurate dosage, convenient carrying and the like, and is particularly not limited to be used in special places. For example, the orally disintegrating tablet has no use limitation when passing aircraft safety inspection, so the preparation has certain market advantage.

The orally disintegrating tablet is a tablet which can be quickly disintegrated or dissolved in the oral cavity without water, is convenient to take, has quick response, high bioavailability and good mouthfeel, is a quick-release dosage form which is developed quickly at present due to no irritation to oral mucosa, particularly does not need water (the saliva can be disintegrated or dissolved) when the orally disintegrating tablet is taken, provides convenience for the old, children, patients with dysphagia and people who cannot take water conveniently, and is an ideal administration dosage form. The existing pharmacopoeia has the following technical requirements for orally disintegrating tablets: 1. the buccal tablet has no gravel feeling in the oral cavity, good taste, easy swallowing and no stimulation to the mucous membrane of the oral cavity; 2. the disintegration time is short (within 1 minute); 3. other tablet requirements.

Generally, the hardness of orally disintegrating tablets is in direct proportion to the disintegration time, and when the hardness is small, the disintegration time is short, and when the hardness is large, the disintegration time is long. In the market segment, the chinese patent application with patent publication No. CN106913551A in the prior art adopts a wet granulation process to solve the flowability and compressibility of granules, and salbutamol sulfate is added externally to avoid the degradation of raw materials during drying to some extent. However, the excipients may also degrade during the drying process, resulting in increased impurities in the final formulation, thereby affecting the safety of the drug. Meanwhile, the method has the advantages of more working procedures, long time consumption and higher impurity level.

The conventional wet granulation process for the tablet technology is relatively complex, and has the main defects of more process steps, in order to obtain uniform, stable and beautiful tablets, the flowability of active ingredient and auxiliary material (main filling agent) powder is firstly improved, the powder is required to be prepared into granules for improving the flowability, a wet adhesive (usually aqueous solution) is required to be added for preparing the granules into a soft material, and the wet granules are required to be dried and dehumidified for tabletting into dry granules. This presents stability concerns for moisture and heat sensitive drugs. In addition, the investment of equipment, manpower, space and energy is increased. More importantly, every time a process link is added, corresponding complex and complicated process verification and parameter control are required, so that the product cost is increased, and the quality assurance of the product is reduced.

The orally disintegrating tablet in the field of salbutamol sulfate still needs continuous technical improvement. The technical scheme that the disintegrant is uniformly dispersed in the tablet by using a process technology, the uniformity of the disintegration time limit of a product is improved, and the difference between tablets is small is still a hot spot direction for technical improvement in the field.

Disclosure of Invention

In order to further solve the problem that the impurity content and other indexes in the preparation process of the orally disintegrating tablet are mutually coordinated, the inventor of the application conducts technical research and creatively discovers that the direct compression process in the preparation process of the salbutamol sulfate orally disintegrating tablet can avoid the degradation of auxiliary materials in the wet granulation drying process, and simultaneously controls the particle size of direct compression mannitol and microcrystalline cellulose to ensure the fluidity and compressibility of the total mixed particles. Based on the creative discovery, the invention provides a preparation method of salbutamol sulfate orally disintegrating tablets, which can reduce the content of impurities and simultaneously does not influence other quality indexes, and the salbutamol sulfate orally disintegrating tablets prepared by the preparation method.

The technical scheme for realizing the purpose of the invention is as follows:

in a first aspect, the invention provides a preparation method of salbutamol sulfate orally disintegrating tablets, which comprises the following steps: weighing raw materials of salbutamol sulfate and auxiliary materials, sieving, pre-mixing the raw materials and the auxiliary materials, and tabletting, wherein the tabletting adopts a powder direct compression process.

The direct powder compression method refers to a method of directly compressing a mixture of a drug and an auxiliary material without a granulation process. The direct powder compression method avoids the granulation process, has the outstanding advantages of simple operation, short production period, low production cost, strong technological adaptability, time and energy conservation, simple and convenient process, less working procedures, suitability for the medicines with unstable damp and heat and the like, and is considered to be the most popularized preparation process of the tablet at present.

The physicochemical properties of most medicines can not meet the requirement of direct powder compression, so that a novel auxiliary material with excellent performance is required to be selected to improve the fluidity and compressibility of the medicines, and the invention realizes direct compression by selecting and improving the auxiliary material and the like.

Preferably, the hardness is controlled to be 1 to 5kgf when the tablet is compressed by the direct compression process.

In any of the above schemes, preferably, the hardness is controlled to be 1-3kgf, the friability is less than or equal to 1%, the disintegration time is less than or equal to 1 minute, and the weight difference is controlled to be +/-5% during tabletting by the direct compression process.

In any of the above embodiments, it is preferable that the hardness is controlled to 1.5 to 2.5kgf when the tablet is compressed by the direct compression method.

In any of the above embodiments, it is preferable that the hardness is controlled to 1.5kgf when the tablet is compressed by the direct compression method.

In any of the above embodiments, it is preferable that the controlled hardness is 2kgf when the tablet is compressed by the direct compression method.

In any of the above embodiments, it is preferable that the controlled hardness is 2.5kgf when the tablet is compressed by the direct compression method.

In any of the above embodiments, it is preferable that the controlled hardness is 3kgf when the tablet is compressed by the direct compression method.

In any of the above embodiments, the friability is preferably less than or equal to 0.8%.

In any of the above embodiments, the friability is preferably 0.8%.

In any of the above embodiments, the friability is preferably 0.5%.

In any of the above embodiments, the disintegration time is preferably 50 seconds.

In any of the above embodiments, the disintegration time is preferably 40 seconds.

In any of the above embodiments, the disintegration time is preferably 30 seconds.

In any of the above schemes, preferably, the raw and auxiliary materials are premixed and mixed in a three-dimensional mixer. Mixing with KCSH-10 type three-dimensional mixer at main shaft speed of 5-15rpm for 30-60 min.

In any of the above schemes, preferably, the auxiliary material comprises one or more of a filler, a binder, a disintegrant and a lubricant.

In any of the above schemes, preferably, the weight percentages of the components are as follows: 0.5-5% of salbutamol sulfate, 2-4% of lubricant, 70-90% of filler and 7-20% of disintegrating agent.

In any of the above schemes, preferably, the weight percentages of the components are as follows: 0.5 percent of salbutamol sulfate, 2.5 percent of lubricant, 90 percent of filler and 7 percent of disintegrant.

In any of the above schemes, preferably, the weight percentages of the components are as follows: 2% of salbutamol sulfate, 3% of lubricant, 75% of filler and 20% of disintegrant.

In any of the above schemes, preferably, the weight percentages of the components are as follows: 5% of salbutamol sulfate, 4% of lubricant, 80% of filler and 11% of disintegrant. Also here, a list of point values is given in support of the scope of protection of the claims.

In any of the above schemes, preferably, the filler is selected from one or more of sorbitol, mannitol, corn starch, anhydrous lactose, dextrin, lactose, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, sewage calcium hydrogen phosphate, and pregelatinized starch.

In any of the above schemes, preferably, the filler is one or more of sorbitol, mannitol, corn starch and anhydrous lactose.

In any of the above schemes, preferably, the lubricant is selected from one or more of magnesium stearate, aerosil, sodium stearyl fumarate, zinc stearate, calcium stearate, silicon dioxide, talc powder and hard paraffin.

In any of the above schemes, preferably, the lubricant is one or more of magnesium stearate, aerosil and sodium stearyl fumarate.

In any of the above schemes, preferably, the filler is mannitol and microcrystalline cellulose, the disintegrant is crospovidone and low-substituted hydroxypropylcellulose, and the lubricant is silicon dioxide and magnesium stearate.

In any of the above schemes, preferably, the components are as follows by weight percent: 0.5-5% of salbutamol sulfate, 10-65% of mannitol, 10-65% of microcrystalline cellulose, 2-10% of low-substituted hydroxypropyl cellulose, 5-20% of crospovidone, 0.5-2% of silicon dioxide and 0.5-2% of magnesium stearate.

In any of the above embodiments, the mannitol preferably has an average particle size of 100 to 200 μm.

In any of the above embodiments, the mannitol preferably has an average particle size of 120 to 180 μm.

In any of the above embodiments, the mannitol preferably has an average particle size of 130 to 150 μm.

In any of the above embodiments, the microcrystalline cellulose preferably has an average particle size of 70 to 200 μm.

In any of the above embodiments, the microcrystalline cellulose preferably has an average particle size of 100 to 180 μm.

In any of the above embodiments, the microcrystalline cellulose preferably has an average particle size of 120 to 160 μm.

In a second aspect, the invention also provides the salbutamol sulfate orally disintegrating tablet prepared by the preparation method of the first aspect.

Preferably, the adjuvants include a filler, a binder, a disintegrant, and a lubricant.

In any of the above schemes, preferably, the weight percentages of the components are as follows: 5% of salbutamol sulfate, 4% of lubricant, 80% of filler and 11% of disintegrant. Also here is an enumeration of point values in support of the claims. In any of the above schemes, preferably, the filler is mannitol and microcrystalline cellulose, the disintegrant is crospovidone and low-substituted hydroxypropylcellulose, and the lubricant is silicon dioxide and magnesium stearate.

In any of the above schemes, the preferable content is as follows: 0.5-5% of salbutamol sulfate, 0.5-5% of silicon dioxide, 10-65% of mannitol, 10-65% of microcrystalline cellulose, 2-10% of low-substituted hydroxypropyl cellulose, 5-20% of crospovidone and 0.5-2% of magnesium stearate.

In any of the above schemes, preferably, the components are, by weight, 1% of salbutamol sulfate, 50% of direct compression mannitol, 35% of microcrystalline cellulose, 4% of low-substituted hydroxypropylcellulose, 8% of crospovidone, 1% of magnesium stearate, and 1% of silicon dioxide.

In any of the above schemes, preferably, the components are, by weight, 3% of salbutamol sulfate, 50% of direct compression mannitol, 30% of microcrystalline cellulose, 1% of low-substituted hydroxypropylcellulose, 12% of crospovidone, 2% of magnesium stearate and 2% of silicon dioxide.

In any of the above embodiments, the mannitol preferably has an average particle size of 100 to 200 μm, and the microcrystalline cellulose preferably has an average particle size of 70 to 200 μm.

In any of the above embodiments, the mannitol preferably has an average particle size of 100 μm.

In any of the above embodiments, preferably, the mannitol has an average particle size of 120 μm.

In any of the above embodiments, preferably, the mannitol has an average particle size of 150 μm.

In any of the above embodiments, the mannitol preferably has an average particle size of 200 μm.

In any of the above embodiments, the microcrystalline cellulose preferably has an average particle size of 80 μm.

In any of the above embodiments, the microcrystalline cellulose preferably has an average particle size of 100 μm.

In any of the above embodiments, the microcrystalline cellulose preferably has an average particle size of 150 μm.

In any of the above embodiments, the microcrystalline cellulose preferably has an average particle size of 200 μm.

Advantageous effects

The preparation method of the salbutamol sulfate orally disintegrating tablet based on the direct compression process has the following advantages:

1. the direct pressing process has the advantages of less working procedures, simple equipment and easy commercial production;

2. the fluidity and compressibility of the granules are greatly improved after the particle size of the auxiliary materials is controlled;

3. the impurity level after the improved process is lower than that of the original product;

4. the safety of the patient is improved, and potential safety hazards are avoided.

The advantages of the direct powder compression method adopted by the invention are as follows;

(1) improving the disintegration property of the tablet

Disintegration of tablets is primarily dependent on the disintegrant in the tablet to facilitate tablet disintegration by capillary or swelling action. When the powder direct compression method is adopted to prepare the tablet, the disintegrant does not reduce the disintegration performance due to the contact with water in the early stage, thereby ensuring good disintegration property.

(2) Improving the dissolution performance of the insoluble drug tablet

Since the drug with low solubility is greatly influenced by its specific surface area and the surface properties of the finished drug product. By adopting a direct powder tabletting process and selecting an auxiliary material (such as lactose) with good hydrophilicity as a filler, the medicament and the lactose powder are uniformly dispersed in water on the premise of ensuring the rapid disintegration of the tablet, and then the lactose is dissolved and forms hydrogen bonds on the surface of the medicament by virtue of Van der Waals force and water, so that the hydrophobicity of the medicament is reduced, and the dissolution rate of the medicament is improved.

(3) Solves the difficult problem of developing the damp-heat unstable medicinal preparation

The medicine with unstable chemical properties is easy to hydrolyze in the wet granulation process or damaged by heating in the drying process, the preparation process by adopting the powder direct compression method does not need granulation and drying, and the medicine is not influenced by the heat of humidity, so that the stability of the medicine is better protected.

(4) Energy saving, consumption reduction and economic benefit improvement

The direct powder tabletting process not only reduces the equipment and operation cost, saves time and energy, but also reduces the use of workshop space.

(5) And the vertical compression process can better control the impurity level and improve the safety of patients.

Wherein the hardness is controlled to be 1 to 5kgf, preferably 1 to 3kgf, during tabletting.

The particle size of the auxiliary material can affect the compressibility and flowability of the tablet. If the particle size is too small when tabletting is performed, the tablets are likely to be rejected.

Although the direct powder tabletting method is good, the method cannot be handled by every enterprise, the maximum resistance comes from the technology itself, and the method mainly comprises the powder control (such as compressibility, fluidity, dilution potential, content uniformity, lubrication sensitivity and the like), the production efficiency (such as tabletting speed), the production line utilization rate and the like of raw and auxiliary materials. Therefore, the mastering of the direct pressing process and the formation of the technical scheme agglomerate the creative labor of the inventor.

The direct powder compression method requires that all excipients must have good flowability, excellent compressibility, good lubricity and large drug holding capacity, and usually a single excipient is difficult to satisfy the requirements at the same time. Applying powder engineering to physically modify or pre-mix the original auxiliary materials is often a necessary step.

In addition, when the particle size, the crystal form and the like of the medicine are not suitable for direct powder compression, the characteristics of the particle size, the form and the like of the medicine can be changed by a proper technical means, such as crushing, recrystallization, spray drying, freeze drying and the like, so that better fluidity and compressibility can be obtained, and therefore, the auxiliary materials with proper particle size can meet the requirements of a direct compression process.

Detailed Description

In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way. All features of each aspect of the invention apply to all other aspects, mutatis mutandis. The practice of the invention is not limited to the following examples, and any modification or variation of the invention may be made without departing from the scope of the invention; and the methods in the following examples are conventional in the art unless otherwise specified.

Example 1:

the salbutamol sulfate orally disintegrating tablet comprises the following components in percentage by weight: 1% of salbutamol sulfate, 50% of direct-compression mannitol, 35% of microcrystalline cellulose, 4% of low-substituted hydroxypropyl cellulose, 8% of crospovidone, 1% of magnesium stearate and 1% of silicon dioxide.

The mannitol under direct pressure is Pearlitol 200SD (average particle size 180 μm) produced by Rogat, and the microcrystalline cellulose is PH112(70-100 μm) of Shandong chat West.

The preparation method of the salbutamol sulfate orally disintegrating tablet comprises the following steps:

uniformly mixing salbutamol sulfate, direct-compression mannitol, microcrystalline cellulose, magnesium stearate, silicon dioxide, crospovidone and low-substituted hydroxypropyl cellulose in a three-dimensional mixer according to the proportion; tabletting with DP30A single punch tablet machine, wherein the hardness is controlled at 1-3kgf, the friability is less than or equal to 1%, the disintegration time is less than or equal to 1 min, and the weight difference is controlled at + -5%.

1000 tablets are prepared by the formula. The hardness of the tablet is 1.5-3.0kgf measured by a hardness tester, the friability is less than 1%, the disintegration time is 30-37 seconds, the weight difference is-1.8% -2.1%, and the total impurities are as follows: 0.60 percent and better mouthfeel.

Example 2:

the salbutamol sulfate orally disintegrating tablet comprises the following components in percentage by weight: 1% of salbutamol sulfate, 50% of mannitol, 35% of microcrystalline cellulose, 4% of low-substituted hydroxypropyl cellulose, 8% of crospovidone, 1% of magnesium stearate and 1% of silicon dioxide.

Mannitol is common mannitol (75-90 μm) produced by Guangxi Nanning, and microcrystalline cellulose is ZW-301 (average particle size 65 μm) produced by Huzhou.

uniformly mixing salbutamol sulfate, common mannitol, microcrystalline cellulose, magnesium stearate, silicon dioxide, crospovidone and low-substituted hydroxypropyl cellulose in a three-dimensional mixer according to the proportion; and (6) tabletting.

1000 tablets are prepared by the formula. The hardness of the tablet is measured to be 0.5-1.7kgf, the compressibility during tabletting is poor, the actual hardness is lower, the friability is more than 1%, the disintegration time is 24-30 seconds, the weight difference is-2.2% -2.3%, and the total impurities are as follows: 0.69 percent and better mouthfeel.

Example 3:

an orally disintegrating tablet of salbutamol sulfate, similar to example 1, except that the particle size of the filler is larger, wherein the components are as follows by weight percent: 1% of salbutamol sulfate, 50% of mannitol, 35% of microcrystalline cellulose, 4% of low-substituted hydroxypropyl cellulose, 8% of crospovidone, 1% of magnesium stearate and 1% of silicon dioxide.

In this example, the mannitol was Pearlitol 300DC (particle size 200- & lt 500 & gtμ m) produced by Rogat, and microcrystalline cellulose (average particle size 250 μm).

uniformly mixing salbutamol sulfate, direct-compression mannitol, microcrystalline cellulose, magnesium stearate, silicon dioxide, crospovidone and low-substituted hydroxypropyl cellulose in a three-dimensional mixer according to the proportion; the DP30A single punch tablet machine is used for tabletting, the hardness is controlled to be 1-3kgf when tabletting, the disintegration time is less than or equal to 1 percent and less than or equal to 1 minute when the friability is less than or equal to 1 percent, and the weight difference is controlled to be +/-5 percent. 1000 tablets are prepared by the formula. The hardness of the tablet is 1.5-3.0kgf measured by a hardness tester, the friability is less than 1%, the disintegration time is 33-38 seconds, the weight difference is-4.5% -4.3%, and the total impurities are as follows: 0.70%, has a sandy sense.

Example 4:

an orally disintegrating tablet of salbutamol sulfate, similar to example 1, except that mannitol is replaced by pregelatinized starch, wherein the components are calculated by weight percent: 1% of salbutamol sulfate, 50% of pregelatinized starch, 35% of microcrystalline cellulose, 4% of low-substituted hydroxypropyl cellulose, 8% of crospovidone, 1% of magnesium stearate and 1% of silicon dioxide.

In this embodiment, the pregelatinized starch is starch 1500 (particle size 50-150 μm) from Carlekang Shanghai, and the microcrystalline cellulose is PH112(70-100 μm) from Shandong chat West.

uniformly mixing salbutamol sulfate, pregelatinized starch, microcrystalline cellulose, magnesium stearate, silicon dioxide, crospovidone and low-substituted hydroxypropyl cellulose in a three-dimensional mixer according to the proportion; the DP30A single punch tablet machine is used for tabletting, the hardness is controlled to be 1-3kgf when tabletting is carried out, the friability is less than or equal to 1 percent, the disintegration time is less than or equal to 1 minute, and the weight difference is controlled to be +/-5 percent.

1000 tablets are prepared by the formula. The hardness of the tablet is 1.5-3.0kgf measured by a hardness tester, the friability is less than 1%, the disintegration time is 45-51 seconds, the weight difference is-2.5% -3.3%, and the total impurities are as follows: 0.80%, has sandy sense.

Example 5: wet granulation Process control

The salbutamol sulfate orally disintegrating tablet comprises the following components in percentage by weight: salbutamol sulfate 1%, mannitol 50%, microcrystalline cellulose 35%, low-substituted hydroxypropyl cellulose 4%, crospovidone 8%, magnesium stearate 1%, silicon dioxide 1%, and water in appropriate amount (added to the mixture to be kneaded into a mass, and then dispersed when touching).

In this example, the mannitol under direct pressure was Pearlitol 200SD (average particle size 180 μm) produced by Rogat, and the microcrystalline cellulose was PH112(70-100 μm) of Shandong chat West.

1. firstly, screening treatment is carried out: the salbutamol sulfate and the silicon dioxide are mixed according to the proportion, crushed, sieved by a 120-mesh sieve and weighed for standby.

2. Adding the direct-compression mannitol, the microcrystalline cellulose, 50% of the low-substituted hydroxypropyl cellulose and 50% of the crospovidone into a high-efficiency wet granulator according to the proportion, mixing for 20 minutes, adding a proper amount of purified water into the wet granulator within 1-3 minutes under a stirring state to prepare a soft material, and sieving the soft material with a 30-mesh sieve to prepare wet granules. Drying at 80-90 deg.C to obtain dry granules, weighing,

3. adding magnesium stearate, the rest amount of low-substituted hydroxypropyl cellulose and crospovidone, and the sieved mixture of salbutamol sulfate and silicon dioxide, mixing uniformly, and tabletting.

1000 tablets are prepared by the formula, and the hardness of the tablets is 1.5-3.0kgf, the friability is less than 1%, the disintegration time is 25-47 seconds, the weight difference is-3.1% -2.9%, and the total impurities are: 1.15 percent and better taste.

Example 6: wet granulation Process control

An orally disintegrating tablet of salbutamol sulfate, similar to example 3, except that the components are as follows by weight percentage: salbutamol sulfate 1%, mannitol 50%, microcrystalline cellulose 35%, low-substituted hydroxypropyl cellulose 4%, crospovidone 8%, magnesium stearate 1%, silicon dioxide 1%, and water in appropriate amount (added to the soft material to be kneaded into a mass, and then the mass is dispersed when the mass is touched).

In this example, mannitol was plain mannitol (75-90 μm) produced by Guangxi Nanning, and microcrystalline cellulose was ZW-301 (average particle size 65 μm) produced by Huzhou.

2. Adding mannitol, microcrystalline cellulose, 50% of low-substituted hydroxypropyl cellulose and 50% of crospovidone into a high-efficiency wet granulator according to the proportion, mixing for 20 minutes, adding a proper amount of purified water into the wet granulator within 1-3 minutes under a stirring state to prepare a soft material, and sieving the soft material with a 30-mesh sieve to prepare wet granules. Drying at 80-90 deg.c to obtain dry granule, and weighing.

1000 tablets are prepared by the formula, and the hardness of the tablets is 1.5-3.0kgf, the friability is less than 1%, the disintegration time is 29-50 seconds, the weight difference is-2.8% -3.4%, and the total impurities are: 1.22 percent and better mouthfeel.

Example 7 comparison of the products obtained in examples 1 to 6

Table 1 comparison of data obtained from samples prepared in each example

As can be seen from table 1, the total impurities can be significantly reduced after the direct pressure process is used in examples 1 and 4. However, the filler is required to have a particle size, and the hardness is low (the friability is not satisfactory) and the weight variation is increased easily in tableting. The invention unexpectedly discovers that the total impurity content is reduced, and simultaneously maintains the particle size parameters of the filler with qualified hardness and friability, and obtains the preparation method of the salbutamol sulfate orally disintegrating tablet based on the direct compression process.

Claims

1. A preparation method of salbutamol sulfate orally disintegrating tablets comprises the following steps: weighing salbutamol sulfate and auxiliary materials, sieving, pre-mixing the raw materials and the auxiliary materials, and tabletting by adopting a powder direct compression process.

2. The process for preparing an orally disintegrating tablet of salbutamol sulfate according to claim 1, wherein the hardness is controlled to 1-5kgf, the friability is less than or equal to 1%, the disintegration time is less than or equal to 1 minute, and the weight difference is controlled to ± 5% during tabletting by the direct compression technique.

3. The method for preparing the salbutamol sulfate orally disintegrating tablet as claimed in claim 1, wherein the pre-mixing of the raw materials and the auxiliary materials is to mix the sieved raw material salbutamol sulfate and the sieved auxiliary materials uniformly in a three-dimensional mixer.

4. The process for preparing salbutamol sulfate orally disintegrating tablets as claimed in claim 3, wherein the auxiliary materials comprise one or more of a filler, a binder, a disintegrant and a lubricant.

5. The preparation method of the salbutamol sulfate orally disintegrating tablet according to claim 4, which is characterized in that the weight percentages of the components are as follows: 0.5-5% of salbutamol sulfate, 2-4% of lubricant, 70-90% of filler and 7-20% of disintegrating agent.

6. The process for preparing an orally disintegrating tablet of salbutamol sulfate as claimed in claim 5, wherein the filler is one or more selected from sorbitol, mannitol, corn starch, anhydrous lactose, dextrin, lactose, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, and pregelatinized starch.

7. The process for preparing an orally disintegrating tablet of salbutamol sulfate according to claim 5, wherein the filler comprises mannitol and microcrystalline cellulose, the disintegrant is crospovidone and low substituted hydroxypropylcellulose, and the lubricant is silicon dioxide and magnesium stearate.

8. The preparation method of the salbutamol sulfate orally disintegrating tablet according to claim 7, which is characterized in that the weight percentages of the components are as follows: 0.5-5% of salbutamol sulfate, 10-65% of mannitol, 10-65% of microcrystalline cellulose, 2-10% of low-substituted hydroxypropyl cellulose, 5-20% of crospovidone, 0.5-2% of silicon dioxide and 0.5-2% of magnesium stearate.

9. The process for preparing an orally disintegrating tablet of salbutamol sulfate according to claim 8, wherein the mannitol has an average particle size of 100 to 200 μm, and the microcrystalline cellulose has an average particle size of 70 to 200 μm.

10. An orally disintegrating tablet of salbutamol sulfate, which is obtained by the preparation method of any one of claims 1 to 9.