Medicine convenient for patients to take

Abstract

The invention provides a medicine convenient for patients to take, which is prepared by processing an effective dose of propranolol or physiologically acceptable salts thereof and pharmaceutically acceptable pharmaceutic adjuvants through a proper process. The propranolol injection is characterized by comprising one or more of propranolol or physiologically acceptable salt thereof, a filler or diluent, an adhesive and a lubricant. The propranolol tablet disclosed by the invention has the characteristics of convenience in administration, stable curative effect, reduced adverse reaction, improvement of patient compliance and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of oral solid preparations, and particularly to a drug that is convenient for patients to take. Technical Background

[0002] Infantile hemangioma (IH) is one of the most common benign tumors in infants and young children globally, with an incidence rate of about 4%-5% in newborns and showing an increasing trend year by year. The disease is more common in females, with a male-to-female ratio of 1:3 to 1:5, and about 60% occurs in the head and neck. Hemangioma is a benign vascular tumor characterized by endothelial cell proliferation, generally occurring within one week to one month after the baby is born. The early manifestation is a small red spot, which then rapidly enlarges and undergoes rapid proliferation at 1 month and 4-5 months of age in the child. Although some hemangiomas can regress spontaneously, local erythema, pigment changes, capillary dilation, atrophic scars, and fibroadipose tissue neoplasms often remain after regression, posing a risk of affecting the child's appearance or even disfiguring, bringing obvious psychosocial harm to children in the growth and development stage and their parents. Approximately 10% of severe hemangiomas can cause serious functional impairments. When IH occurs in a large area or in special anatomical locations (eyes, respiratory tract), it may cause local compressive obstruction, thereby possibly leading to organ dysfunction (such as amblyopia or even blindness, respiratory obstruction or even failure), and seriously threatening the life of the child when severe.

[0003] The drug of the present invention is a drug that is convenient for patients to take, and its active ingredient is propranolol, with the English name Propranolol, the chemical name being 1-isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride, and its molecular formula being C 16 H 21 NO2·HCl, with a molecular weight of 295.81, and the chemical structural formula being:

[0004]

[0005] Propranolol hydrochloride tablets (プロプラノロール塩酸塩 / Propranolol hydrochloride) is a β-blocker developed by ICI (now AstraZeneca) in the UK for the treatment of hypertension, angina pectoris, arrhythmia, etc. Propranolol hydrochloride tablets were initially approved in the UK in 1965 and subsequently marketed. In August 1966, Propranolol hydrochloride tablets of AstraZeneca were first marketed in Japan, with a specification of 10 mg and the trade name In November 1967, the FDA first approved Propranolol tablets of WYETH PHARMS INC for marketing in the US, with marketed specifications of 10 mg, 20 mg, and 40 mg and the trade name

[0006] In 2008, Leaute-Labreze C, a doctor at Bordeaux Children's Hospital in France, first reported in The New England Journal of Medicine that propranolol can be used to treat IH (infantile hemangioma)! This is one of the most significant discoveries in the history of hemangioma treatment!

[0007] Propranolol is used to treat IH, with significant efficacy and no obvious complications - this is another new clinical application discovery of propranolol, a classic compound! This discovery also obtained the patent for the new indication of propranolol for the treatment of infantile hemangioma. In April 2014, the US FDA accelerated the approval of Hemangeol (propranolol hydrochloride oral solution) from Pierre Fabre, France, as an orphan drug, which was the world's first drug for the treatment of infantile hemangioma. Since then, Hemangeol has quickly become the first-line treatment drug for infantile hemangioma and has been included in the treatment guidelines and expert consensus of infantile hemangioma in various countries.

[0008] The following problems exist when using propranolol hydrochloride oral solution:

[0009] (1) For non-medical personnel, using a syringe to extract a solution with an accuracy of 0.1 ml, it is uncertain whether the volume of liquid extracted can meet the treatment needs.

[0010] (2) The drug is administered by placing the oral administration syringe on the inside of the child's cheek and then slowly pushing the propranolol hydrochloride oral solution into the child's mouth. This method requires controlling the administration speed, which is not conducive to parents administering the drug. If parents use too much force, it will cause the child to choke and cough, and in severe cases it may be life-threatening.

[0011] (3) As the child grows, there is uncertainty as to whether the syringe outlet can be accurately placed close to the inside of the cheek. If the syringe outlet is not placed close to the inside of the cheek, the child may choke and cough, which may be life-threatening in severe cases.

[0012] (4) When the infant is young, the dosage is small. When a 5 ml syringe is used for administration, there will be residual solution on the tube wall and the syringe cone, and the therapeutic dose may not be reached.

[0013] It can be seen that the existing propranolol hydrochloride oral solution is not suitable for children, patients with dysphagia, etc.

[0014] Traditional solid dosage forms such as tablets and capsules are considered inappropriate due to swallowing difficulties in children. Therefore, drugs acceptable to pediatric patients are usually formulated as suspensions, oral granules, oral solutions, and more recently, microtablets. To date, the most commonly prescribed formulations for pediatric patients are liquid formulations because of the ease of administration. Liquids are the most commonly used pediatric formulations; however, they have many disadvantages such as chemical, physical, and microbiological instability, palatability of solutions, accuracy of dosage, lack of controlled release, and increased toxicological risks. There are also limitations on the use of excipients, preservatives, and solvents in pediatric formulations.

[0015] In a recent study, it was reported that microtablets were superior to syrups in the administration of drugs to children and could be a flexible delivery vehicle for single-unit or multi-unit complexes. Therefore, microtablets offer a very promising option in liquid formulations for administration to children of different age groups.

[0016] "Microtablets" generally refer to miniature tablets with a standard tablet diameter between 1 and 3 (mm). Microtablets combine the advantages of solid and liquid formulations because they allow for precise and individual dosing based on age, weight, body surface area, dosage adjustments, and therapeutic needs. They can improve patient compliance because they are easy to swallow or mix with food. In addition to the advantages of drug delivery, microtablets have many other advantages, such as customized delivery methods based on release rate and mechanism to target release to different parts of the gastrointestinal tract.

[0017] Microtablet production and quality control have higher requirements than ordinary tablets. In particular, the content uniformity of small-sized microtablets is a technical problem. The use of the above-mentioned preparation process will make it difficult to control the content uniformity of microtablets and easily produce products with unqualified content uniformity.

[0018] Therefore, providing a propranolol microtablet with stable product quality, reliable efficacy, qualified content uniformity, reasonable dissolution and simple preparation process to meet the medication needs of children, patients with dysphagia, etc. has significant economic and social benefits. Summary of the invention

[0019] The present invention discloses a medicine which is convenient for patients to take; the medicine is prepared from an effective dose of propranolol or a physiologically acceptable salt thereof and a pharmaceutically acceptable pharmaceutical excipient by a suitable preparation method, and is characterized in that the medicine is composed of one or more of propranolol or a physiologically acceptable salt thereof, a filler or a diluent, a binder and a lubricant.

[0020] The drug of the present invention is characterized in that: its main drug is propranolol or a physiologically acceptable salt thereof, and the physiologically acceptable salt of propranolol is preferably propranolol hydrochloride.

[0021] The effective dosage of the drug of the present invention, calculated as propranolol, is 0.5 mg to 5 mg, preferably 1 mg.

[0022] The medicine of the present invention is characterized in that:

[0023] The filler or diluent can be selected from one or more of microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl acetate phthalate, polyethylene glycol, sodium alginate, chitosan, sucrose, lactose, starch, dextrin, powdered sugar, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, and titanium dioxide, preferably microcrystalline cellulose, mannitol, and lactose.

[0024] The binder can be selected from one or more of water, ethanol, anhydrous ethanol, methanol, starch slurry, povidone, copovidone, cross-linked polyvinyl pyrrolidone, hydroxypropyl cellulose, microcrystalline cellulose, gelatin, ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and / or other celluloses, preferably water, povidone, gelatin.

[0025] The lubricant can be selected from one or more of magnesium stearate, stearic acid, micro-powder silica gel, talc, hydrogenated vegetable oil, polyethylene glycols, colloidal silicon dioxide, silicon dioxide, sodium stearyl fumarate, and magnesium sulfate, preferably magnesium stearate and stearic acid.

[0026] The medicine of the present invention is characterized in that, calculated by weight percentage, it consists of:

[0027]

[0028] The method for preparing the medicine of the present invention comprises the following steps:

[0029] (1) An effective dose of propranolol or a physiologically acceptable salt thereof and a filler are ground for later use; a lubricant is passed through an 80-mesh sieve;

[0030] (2) Preparation of adhesive: Weigh an appropriate amount of adhesive, add it into a container containing purified water, soak it for 15 minutes, heat and stir until it is completely dissolved, and the concentration of the adhesive is 10% by mass, and set aside;

[0031] (3) The above effective dose of propranolol or its physiologically acceptable salt and filler are mixed evenly and added into a fluidized bed with a fluidizing air volume of 120 m 3 / h, control the inlet air temperature to 55℃ to form a fluidized state; spray granulation: spray the binder solution into the fluidized bed through a nozzle, the spray speed is 15mL / min, and the spray pressure is 2.0bar; the binder contacts the fluidized powder to form wet granules; after the binder is sprayed, dry and granulate to obtain granules; sieve the dried granules to obtain granules of the desired particle size, and the bulk density of the granules is between 0.3-0.4g / cm 3 The characteristics of the invention are narrow particle size distribution and high sphericity, which can improve the filling uniformity during tableting, reduce the tablet weight difference, and help improve the tablet disintegration rate and drug dissolution performance;

[0032] (4) mixing the granules obtained in step (3) with a lubricant for 3 to 10 minutes;

[0033] (5) Tableting: control the tablet hardness to 2-7 kg and the mold filling diameter to 1.5 mm-3 mm.

[0034] The drug preparation method of the present invention is characterized in that the propranolol hydrochloride microtablet has a tablet weight of 13.2 mg and a microtablet diameter of 2 mm.

[0035] In the above scheme, the preparation method of the preferred embodiment comprises the following steps:

[0036] 1. Grind propranolol hydrochloride and mannitol with a grinder equipped with a 0.8 mm sieve plate for later use. Pass stearic acid and magnesium stearate through an 80-mesh sieve.

[0037] 2. Preparation of adhesive: Add purified water and adhesive into a stainless steel barrel in sequence, and heat in a large stainless steel barrel hot water bath until the gelatin is completely dissolved before use to prepare an adhesive solution, which should be kept warm for later use.

[0038] 3. Mix propranolol hydrochloride and mannitol evenly and add them into the fluidized bed; adjust the inlet air temperature to 55°C, the outlet air temperature to 40°C, and the fluidizing air volume to 120m 3 / h, wind pressure 1.5kPa, to form a fluidized state; spray granulation: the binder solution is sprayed into the fluidized bed through a nozzle, the spray rate is 15mL / min, and the spray pressure is 2.0bar; the binder contacts the fluidized powder to form wet granules; after the binder is sprayed, it is dried (the moisture content of the granules is ≤2%), and granules are obtained; the dried granules are sieved to obtain granules of the desired particle size.

[0039] 4. Place the granulated dry granules and lubricant in a mixer and mix for 5 minutes.

[0040] 5. Use Φ2.0mm shallow concave round punch to press the tablets and control the tablet hardness to 2-5kg.

[0041] The present invention discloses for the first time a method for preparing micro-tablets, which avoids the inaccuracy of weight and content of propranolol hydrochloride tablets after dosing, the problems of dosing stability and microbial contamination of propranolol hydrochloride tablets, and the occupational exposure risk of pharmacists in drug dosing.

[0042] The micro-tablet of the present invention obtained by adopting the above technical solution can ideally produce the purpose and technical effect to be achieved by the present invention. Specifically, the drug of the present invention which is convenient for patients to take can produce:

[0043] (1) The preparation method has strong applicability, stable process and strong quality reproducibility;

[0044] (2) Propranolol hydrochloride microtablets are only half the size of a rice grain, making them more convenient for infants and young children to take.

[0045] Compared with the prior art, the present invention has the following beneficial effects:

[0046] 1. The present invention optimizes the granulation process to prepare propranolol hydrochloride microtablets with good content uniformity and stability, good medication compliance, suitable for children and patients with dysphagia, and suitable for commercial production, and can continuously and effectively produce this product.

[0047] 2. The present invention makes the active ingredient of propranolol hydrochloride microtablets have a dissolution behavior that is not inferior to that of the control drug through the selection of fillers, especially the dissolution is fast and complete in the medium where the active ingredient is poorly soluble.

[0048] 3. The propranolol hydrochloride microtablets of the present invention are multi-unit preparations, which have the advantages of both ordinary tablets and micropills, have precise dosage, are easy to swallow, can improve patient compliance, and are particularly suitable for the elderly and children. Compared with micropills, microtablets have higher product quality and economic benefits.

[0049] 4. The propranolol hydrochloride microtablets of the present invention have a small diameter, a smooth surface, a small volume, and are convenient to transport, carry, and store.

[0050] 5. The propranolol hydrochloride microtablets of the present invention are not inferior to the original propranolol hydrochloride tablets in terms of quality and efficacy.

[0051] 6. The fluidized bed process used in the present invention can obtain particles with narrow particle size distribution and high sphericity, which can improve the filling uniformity during tableting and reduce the tablet weight difference. The particles have a high porosity, which is conducive to improving the tablet disintegration rate and drug dissolution performance.

[0052] It should be noted that, in order to enable persons skilled in the art to more clearly understand the content and technical connotation of the present invention, the inventors of the present invention provide the following explanations of the professional terms, symbols, reagents, consumables and instruments involved:

[0053] “Day 0”: refers to the time when sample preparation is completed;

[0054] “Long-term conditions”: refers to a temperature of 30°C ± 2°C and a relative humidity of 65% ± 5%;

[0055] “Accelerated conditions”: refers to a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%; DETAILED DESCRIPTION

[0056] The present invention is described below through specific implementation schemes. Unless otherwise specified, the technical means used in the present invention are methods known to those skilled in the art. In addition, the implementation scheme should be understood as illustrative rather than limiting the scope of the present invention, and the essence and scope of the present invention are only limited by the claims. For those skilled in the art, various changes or modifications to the material components and dosages in these implementation schemes, without departing from the essence and scope of the present invention, also fall within the scope of protection of the present invention. The raw materials and reagents used in the present invention are all commercially available. In order to facilitate the understanding of the present invention by those skilled in the art to which the present invention belongs, the present invention provides the following specific implementation scheme to further illustrate the drug and its preparation method that are convenient for patients to take: Example 1

[0057] Name of raw materials Dosage per tablet (mg) scope Propranolol hydrochloride (measured as propranolol) 1.14 (based on propranolol 1mg) 9.7％ Mannitol 10.26 87.7％ gelatin 0.185 1.6％ Stearic acid 0.057 0.5％ Magnesium Stearate 0.057 0.5％ water 1.665

[0058] Preparation method:

[0059] 1. Grind propranolol hydrochloride and mannitol with a grinder equipped with a 0.8 mm sieve plate for later use. Pass stearic acid and magnesium stearate through an 80-mesh sieve.

[0060] 2. Adhesive preparation: Weigh an appropriate amount of gelatin, add it into a container containing purified water, soak it for 15 minutes, heat and stir until it is completely dissolved, and the concentration of the adhesive is 10% by mass. Set aside;

[0061] 3. Mix propranolol hydrochloride and mannitol evenly and add them into the fluidized bed with a fluidizing air volume of 120m 3 / h, control the inlet air temperature to 55°C, the outlet air temperature to 40°C, and the wind pressure to 1.5 kPa to form a fluidized state; spray granulation: spray the binder solution into the fluidized bed through a nozzle, the spray rate is 15 mL / min, and the spray pressure is 2.0 bar; the binder contacts the fluidized powder to form wet granules; after the binder is sprayed, it is dried (the moisture content of the granules is ≤2%), and granules are obtained; the dried granules are sieved to obtain granules of a desired particle size.

[0062] 4. Place the whole dry granules, stearic acid and magnesium stearate in a mixer and mix for 5 minutes.

[0063] 5. Use Φ2.0mm shallow concave round punch to press the tablets and control the tablet hardness to 2-5kg.

[0064] Example 2

[0065] Name of raw materials Dosage per tablet (mg) scope Propranolol hydrochloride (measured as propranolol) 2.28 (2 mg as propranolol) 12.8％ Microcrystalline Cellulose 101 14 78.7％ Povidone 1 5.6％ Magnesium Stearate 0.5 2.8％ water 9.0

[0066] Preparation method:

[0067] 1. Grind propranolol hydrochloride and microcrystalline cellulose 101 with a grinder equipped with a 0.8 mm sieve plate for later use, and pass magnesium stearate through an 80-mesh sieve.

[0068] 2. Weigh an appropriate amount of povidone, add it into a container containing purified water, soak it for 15 minutes, heat and stir until it is completely dissolved, and prepare a povidone solution (concentration of 10% by mass) for later use;

[0069] 3. Mix propranolol hydrochloride and microcrystalline cellulose 101 evenly and add them into the fluidized bed with a fluidizing air volume of 150m 3 / h, control the inlet air temperature to 55°C, the outlet air temperature to 40°C / h, and the wind pressure to 2.0 kPa to form a fluidized state; spray granulation: spray the binder solution into the fluidized bed through a nozzle, the spray rate is 20 mL / min, and the spray pressure is 2.0 bar; the binder contacts the fluidized powder to form wet granules; after the binder is sprayed, it is dried (the moisture content of the granules is ≤2%), and granules are obtained; the dried granules are sieved to obtain granules of a desired particle size.

[0070] 4. Place the whole dry granules and magnesium stearate in a mixer and mix for 6 minutes.

[0071] 5. Use Φ2.5mm shallow concave round punch to press the tablets and control the tablet hardness to 4-7kg.

[0072] Example 3

[0073] Name of raw materials Dosage per tablet (mg) scope Propranolol hydrochloride (measured as propranolol) 3.42 (3 mg as propranolol) 17.08％ lactose 15 74.93％ Povidone 1 5.00％ Magnesium Stearate 0.6 17.08％ water 7.5

[0074] Preparation method:

[0075] 1. Grind propranolol hydrochloride and lactose with a grinder equipped with a 0.8 mm sieve plate for later use, and pass magnesium stearate through an 80-mesh sieve.

[0076] 2. Preparation of adhesive: Add purified water and povidone into a stainless steel barrel in sequence, and heat it in a large stainless steel barrel in a hot water bath until the povidone is completely dissolved before use to prepare a povidone solution, which should be kept warm for later use.

[0077] 3. Add propranolol hydrochloride and lactose to the wet granulator and mix them evenly; add the prepared binder solution to the wet granulator for wet granulation: set the stirring speed to 120.0 r / min, set the granulating knife speed to 1500.0 r / min, and the wet mixing time to 180 s; dry the wet granules in a boiling bed or a fluidized bed, control the inlet air temperature and the material temperature, and stop drying and granulate when the granule moisture standard is <1.50%.

[0078] 4. Place the whole dry granules and magnesium stearate in a mixer and mix for 5 minutes.

[0079] 5. Use Φ3.0mm shallow concave round punch to press the tablets and control the tablet hardness to 2-7kg.

[0080] Comparative Example:

[0081] Name of raw materials Dosage per tablet (mg) scope Propranolol hydrochloride (measured as propranolol) 1.14 (based on propranolol 1mg) 9.7％ Mannitol 10.26 87.7％ gelatin 0.185 1.6％ Stearic acid 0.057 0.5％ Magnesium Stearate 0.057 0.5％ water 1.665

[0082] Preparation method:

[0083] 1. Grind propranolol hydrochloride and mannitol with a grinder equipped with a 0.8 mm sieve plate for later use. Pass stearic acid and magnesium stearate through an 80-mesh sieve.

[0084] 2. Adhesive preparation: Weigh an appropriate amount of gelatin, add it into a container containing purified water, soak it for 15 minutes, heat and stir until it is completely dissolved, and the concentration of the adhesive is 10% by mass. Set aside;

[0085] 3. Add propranolol hydrochloride and mannitol into a wet granulator and mix them evenly; add the prepared binder solution into the wet granulator for wet granulation: set the stirring speed to 120.0 r / min, set the granulating knife speed to 1500.0 r / min, and the wet mixing time to 180 s; dry the wet granules in a fluidized bed or fluidized bed, control the inlet air temperature and material temperature, and stop drying and granulate when the granule moisture standard is <1.50%.

[0086] 4. Place the whole dry granules, stearic acid and magnesium stearate in a mixer and mix for 5 minutes.

[0087] 5. Use Φ2.0mm shallow concave round punch to press the tablets and control the tablet hardness to 2-5kg.

[0088] Test Example 1

[0089] Content uniformity check:

[0090] According to the content uniformity inspection method under the relevant items in the current "Chinese Pharmacopoeia", the content uniformity of Examples 1 to 3 was inspected, and the results are as follows:

[0091]

[0092]

[0093] The content uniformity under the relevant items in the current "Chinese Pharmacopoeia" stipulates that A+2.2S≤15.0; the content uniformity A+2.2S of the samples in Examples 1 to 3 is less than 15.0, which has excellent content uniformity.

[0094] Test Example 2

[0095] Dissolution test:

[0096] According to the dissolution test method under the relevant items in the current "Chinese Pharmacopoeia", the test was carried out and the results are as follows:

[0097] Serial number Comparative Example Example 1 Example 2 Example 3 1 85％ 95％ 89％ 95％ 2 86％ 96％ 88％ 94％ 3 87％ 97％ 91％ 97％ 4 85％ 95％ 85％ 94％ 5 80％ 98％ 86％ 96％ 6 82％ 99％ 89％ 97％

[0098] According to the dissolution regulations under the relevant items in the current "Chinese Pharmacopoeia", the dissolution rate of the sample in Example 3 of the present invention after 15 minutes is higher than 90%, which has an excellent dissolution effect.

[0099] Test Example 2

[0100] Bulk density check:

[0101]

[0102] Test Example 3

[0103] Related material inspection:

[0104] Examples 1 to 3 were packaged as sold commercially, placed under long-term conditions and accelerated conditions, respectively, and taken out after 6 months to detect related substances; according to the related substance inspection method under the relevant items in the current "Chinese Pharmacopoeia", the results are as follows:

[0105] Example 1 Sample accelerated test results

[0106]

[0107] Example 2 Sample accelerated test results

[0108]

[0109] Example 3 Sample accelerated test results

[0110]

[0111] Example 1 Long-term test results of samples

[0112]

[0113] Example 2 Long-term test results of samples

[0114]

[0115] Example 3 Long-term test results of samples

[0116]

[0117] The results of the related substance inspection show that the content of the maximum single impurity and total impurities in the related substances of the samples of Examples 1 to 3 increased slightly after 6 months under long-term conditions and accelerated conditions, indicating that the preparation method in this patent can obtain samples with good related substance levels and high stability.

[0118] Test Example 4

[0119] Content uniformity

[0120] According to the requirements of the Pharmacopoeia, the content uniformity test results of Examples 1-3 were tested by double testing, and the data are as follows:

[0121]

[0122] It can be seen from the test results that the content difference of micro-tablets of different specifications prepared with different excipients is very small. The content of the present invention can meet the medication needs of children and patients with dysphagia.

[0123] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A drug convenient for patients to take; it is prepared by an effective dose of propranolol or a physiologically acceptable salt thereof and a pharmaceutically acceptable pharmaceutical excipient by a suitable preparation method, characterized in that The invention is composed of one or more of propranolol or a physiologically acceptable salt thereof, a filler or a diluent, a binder and a lubricant.

2. The drug according to claim 1, characterized in that: The main drug is propranolol or a physiologically acceptable salt thereof, and the physiologically acceptable salt of propranolol is preferably the hydrochloride of propranolol.

3. The drug according to claims 1-2, calculated as propranolol, has an effective dose of 0.5 mg to 5 mg, preferably 1 mg.

4. The drug according to any one of claims 1 to 3, characterized in that: The filler or diluent can be selected from one or more of microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl acetate phthalate, polyethylene glycol, sodium alginate, chitosan, sucrose, lactose, starch, dextrin, powdered sugar, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, and titanium dioxide, preferably microcrystalline cellulose, mannitol, and lactose. The binder can be selected from one or more of water, ethanol, anhydrous ethanol, methanol, starch slurry, povidone, copovidone, cross-linked polyvinyl pyrrolidone, hydroxypropyl cellulose, microcrystalline cellulose, gelatin, ethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and / or other celluloses, preferably water, povidone, gelatin. The lubricant can be selected from one or more of magnesium stearate, stearic acid, micro-powder silica gel, talc, hydrogenated vegetable oil, polyethylene glycols, colloidal silicon dioxide, silicon dioxide, sodium stearyl fumarate, and magnesium sulfate, preferably magnesium stearate and stearic acid.

5. The drug according to claim 1, characterized in that Calculated by weight percentage, its composition is:

6. A method for preparing the drug according to any one of claims 1 to 5, comprising the following steps: (1) An effective dose of propranolol or a physiologically acceptable salt thereof and a filler are ground for later use; a lubricant is passed through an 80-mesh sieve; (2) Preparation of adhesive: Weigh an appropriate amount of adhesive, add it into a container containing purified water, soak it for 15 minutes, heat and stir until it is completely dissolved, and the concentration of the adhesive is 10% by mass, and set aside; (3) The above effective dose of propranolol or its physiologically acceptable salt and filler are mixed evenly and added into a fluidized bed with a fluidizing air volume of 120 m 3 / h, control the inlet air temperature to 55℃ to form a fluidized state; spray granulation: spray the binder solution into the fluidized bed through a nozzle, the spray speed is 15mL / min, and the spray pressure is 2.0bar; the binder contacts the fluidized powder to form wet granules; after the binder is sprayed, dry and granulate to obtain granules; sieve the dried granules to obtain granules of the desired particle size, and the bulk density of the granules is between 0.3-0.4g / cm 3 between, characterized by The medium particles have a narrow particle size distribution and high sphericity, which improves the filling uniformity during tableting, reduces the tablet weight difference, and is beneficial to improving the tablet disintegration rate and drug dissolution performance; (4) mixing the granules obtained in step (3) with a lubricant for 3 to 10 minutes; (5) Tableting: control the tablet hardness to 2-7 kg and the mold filling diameter to 1.5 mm-3 mm.

7. The method for preparing a drug according to claim 6, characterized in that The tablet weight of propranolol hydrochloride microtablets is 13.2 mg and the diameter of the microtablets is 2 mm.

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