Clarithromycin sustained-release micro-tablet and preparation method thereof

Abstract

The invention relates to a clarithromycin sustained-release micro-tablet and a preparation method thereof. The clarithromycin sustained-release micro-tablet is composed of a tablet core and a modification layer, the mass ratio of the tablet core to the modification layer is (125-135): (15-20), and the tablet core is prepared from the following raw materials in parts by mass: 50-75 parts of clarithromycin, 30-50 parts of polyvinylpyrrolidone K30, 5-15 parts of an anionic surfactant, 0.1-10 parts of a filling agent, 0.5-2 parts of a lubricating agent and 0.5-2 parts of a flow aid; the modification layer is prepared from the following raw materials in parts by mass: 5-15 parts of a coating material, 0.1-1 part of a flavoring agent and 2-10 parts of an anti-sticking agent. The invention also provides a preparation method of the clarithromycin sustained-release micro-tablet. According to the clarithromycin sustained-release micro-tablet and the preparation method thereof, the polyvinylpyrrolidone K30 which is a non-sustained-release framework material is excessively used when the clarithromycin sustained-release micro-tablet is prepared for the first time, and meanwhile, the anionic surfactant is added, so that the clarithromycin sustained-release micro-tablet can uniformly release the effective component clarithromycin within 24 hours, and the sustained-release time of the clarithromycin sustained-release micro-tablet is effectively prolonged.

Description

Technical Field

[0001] The invention relates to a clarithromycin sustained-release microtablet and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Clarithromycin is a macrolide antibiotic that can bind to the 50S subunit of bacterial ribosomes, thereby inhibiting bacterial protein synthesis. It has a good antibacterial effect on a variety of aerobic / anaerobic Gram-positive or Gram-negative bacteria. It is mainly used to treat upper and lower respiratory tract infections, skin and soft tissue infections, chlamydia infections and Helicobacter pylori infections caused by various bacteria. The chance of adverse reactions when taking clarithromycin is very low, so it is currently the first choice for treating respiratory infections in children.

[0003] Currently, the commercially available dosage forms of clarithromycin include tablets, capsules, granules, dry suspensions and dispersible tablets. However, due to the strong bitter taste of clarithromycin, it is difficult to mask its bitterness by simply adding sweeteners and other flavoring agents to make granules and dry suspensions. Although ordinary coated tablets and capsules can effectively prevent the bitterness from being released into the mouth, due to their large size and specifications, they have poor compliance for children and patients with dysphagia, and the dosage cannot be adjusted flexibly and accurately.

[0004] As a microtablet with a diameter of only 1 to 3 mm, the microtablet is very small in size, making it easy to swallow, accurate in dosage, and flexible in adjustment. It is very suitable for children and patients with dysphagia. However, the extremely small size means that at the same dose, the microtablet has a huge specific surface area compared to ordinary tablets. The contact area with the dissolution medium in the in vitro dissolution experiment and the contact area with the digestive fluid in the body after the patient takes it are significantly larger than those of ordinary tablets. If the sustained-release method commonly used in ordinary tablets is followed, such as adding a commonly used skeleton sustained-release material to the tablet core or coating the surface of the tablet core with a layer of sustained-release coating, it is difficult to achieve the ideal sustained-release effect.

[0005] Polyvinyl pyrrolidone (PVP) is a non-ionic polymer compound, which is divided into four grades according to its average molecular weight. It is usually expressed as K value. Different K values ​​represent the corresponding average molecular weight range of PVP. Commonly used ones are K12, K17, K25, K30 and K90. Among them, low molecular weight PVP is often used as a binder for oral solid preparations (such as K30, etc.), and high molecular weight K90 can be used as a sustained-release material for hydrophilic gel-type sustained-release tablets, but low molecular weight PVP does not have a sustained-release effect.

[0006] The original formulation of current clarithromycin sustained-release tablets is mainly prepared with hydroxypropyl methylcellulose as a sustained-release skeleton material, and its length, width and height are 19*10*7 (mm), which is an oval tablet. The clarithromycin sustained-release tablet disclosed in Chinese patent document CN101002790A also uses hydroxypropyl methylcellulose as a skeleton sustained-release material, and releases drugs in the form of a hydrophilic gel skeleton. Hydrophilic gel skeleton tablets are commonly used in drug sustained-release forms, which can achieve relatively stable drug release, but they often require a large amount to form a gel layer with drug release holes, which limits its drug loading. And the gel material used to prepare the gel skeleton tablet is a hydrophilic macromolecular substance, when used for micro-tablet preparation, the micro-tablet causes its hydrophilic gel layer to be very thin due to its small volume, and the specific surface area is larger than that of ordinary tablets, and when it is in an aqueous medium for a long time, the gel structure is easily destroyed and loses the ability to release drugs.

[0007] Therefore, providing a sustained-release mechanism suitable for clarithromycin microtablets can effectively improve the problem of rapid drug dissolution and release caused by the small size and huge specific surface area of ​​the microtablets, which is of great significance for achieving a longer-term sustained-release effect of clarithromycin microtablets and the development of other sustained-release microtablets. Summary of the invention

[0008] In view of the shortcomings of the prior art, the present invention provides a clarithromycin sustained-release microtablet and a preparation method thereof. The sustained-release microtablet has a diameter of less than 3 mm, is conducive to dosage adjustment, and is more convenient for children and elderly patients with dysphagia to take, can overcome the shortcomings of the prior art, and enables the clarithromycin microtablet to continuously release the drug slowly within 24 hours.

[0009] The technical solution of the present invention is as follows:

[0010] A clarithromycin sustained-release microtablet, comprising a tablet core and a modified layer, wherein the mass ratio of the tablet core to the modified layer is (125-135): (15-20);

[0011] The tablet core is composed of the following raw materials in parts by weight: 50-75 parts of clarithromycin, 30-50 parts of polyvinyl pyrrolidone K30, 5-15 parts of anionic surfactant, 0.1-10 parts of filler, 0.5-2 parts of lubricant, and 0.5-2 parts of glidant;

[0012] The modification layer is composed of the following raw materials in parts by weight: 5 to 15 parts of coating material, 0.1 to 1 part of flavoring agent, and 2 to 10 parts of anti-sticking agent.

[0013] Preferably, the clarithromycin sustained-release microtablets are composed of a core tablet and a modified layer, and the mass ratio of the core tablet to the modified layer is (129.5-134.1): (18-19.2);

[0014] The tablet core is composed of the following raw materials in parts by weight: clarithromycin 70-75 parts, polyvinyl pyrrolidone K30 35-45 parts, anionic surfactant 8-12 parts, filler 5-8 parts, lubricant 1.5-1.7 parts, glidant 0.6-0.8 parts;

[0015] The modification layer is composed of the following raw materials in parts by weight: 10 to 12 parts of coating material, 0.2 to 0.8 parts of flavoring agent, and 5 to 8 parts of anti-sticking agent.

[0016] Preferably according to the present invention, the anionic surfactant is dioctyl sodium sulfosuccinate or sodium cholate.

[0017] Further preferably, the anionic surfactant is sodium cholate.

[0018] Preferably according to the present invention, the filler is a mixture of one or more of lactose, microcrystalline cellulose or starch.

[0019] Preferably according to the present invention, the lubricant is a mixture of one or more of magnesium stearate, talc, calcium stearate, zinc stearate or glyceryl behenate.

[0020] Preferably according to the present invention, the glidant is colloidal silicon dioxide.

[0021] Preferably according to the present invention, the coating material is a mixture of one or more of Eudragit E 100, Eudragit E PO, Eudragit L 30D-55, Eudragit RL 30D, ethyl cellulose or Opadry film coating premix.

[0022] Preferably according to the present invention, the flavoring agent is a mixture of one or more of sucrose, aspartame, sucralose, stevioside, saccharin sodium, glucose, fructose, apple flavor, orange flavor, tangerine flavor, lemon flavor, vanilla flavor, and strawberry flavor.

[0023] Preferably according to the present invention, the anti-sticking agent is a mixture of one or more of talc, titanium dioxide, magnesium stearate, calcium stearate and zinc stearate.

[0024] The preparation method of the above-mentioned clarithromycin sustained-release microtablets comprises the following steps:

[0025] (1) adding polyvinyl pyrrolidone K30 and anionic surfactant to 60-100 parts of purified water according to the ratio, and ultrasonically mixing at 80-90° C. and 45-55 kHz for 10-15 minutes to obtain a sustained-release material mixed solution;

[0026] (2) stirring and mixing clarithromycin and a filler according to a ratio, and then spraying the mixed solution of the sustained-release material obtained in step (1) to granulate, and after drying, obtain clarithromycin tablet core particles;

[0027] (3) After the clarithromycin tablet core particles obtained in step (2) are passed through a 24-mesh sieve, a lubricant and a glidant are added according to a ratio, the mixture is mixed evenly, and the mixture is tableted to obtain a clarithromycin tablet core;

[0028] (4) adding the coating material, flavoring agent and anti-sticking agent to 40-45 parts of purified water according to the proportion, mixing evenly, to obtain a finishing layer coating solution;

[0029] (5) The clarithromycin tablet core is coated with the modifying layer coating solution, and after packaging, clarithromycin sustained-release microtablets are obtained.

[0030] According to a preferred embodiment of the present invention, in step (2), the clarithromycin tablet core particles are prepared in a fluidized bed granulator, the liquid supply speed of the atomized spray is 20 to 30 rpm, and the air volume is 20 to 40 m 3 / h, the inlet air temperature is 55-65℃, and the atomization pressure is 2-4bar.

[0031] Preferably, in step (3), the tabletting is performed by using a punch having a diameter of 1 to 3 mm to tablet the clarithromycin tablet core particles; the hardness of the obtained clarithromycin tablet core is 10 to 15N.

[0032] Preferably, in step (5), the coating is performed by placing the clarithromycin tablet core in a coating machine, setting the liquid supply speed to 5-10 rpm, the atomization pressure to 1-2 bar, the coating pan speed to 15-30 rpm, the exhaust temperature to 30-40°C, and spraying the clarithromycin tablet core with a modified layer coating liquid.

[0033] The technical features of the present invention are as follows:

[0034] The inventor of the present application initially prepared the original formulation of clarithromycin sustained-release tablets by adding a single or multiple sustained-release skeleton materials to the tablet core according to the prior art. When conducting sustained-release research on the original formulation of clarithromycin sustained-release tablets, it was found that the slow release of clarithromycin could be achieved in the first few hours due to the presence of the sustained-release skeleton. However, since the microtablets have a large specific surface area compared to ordinary tablets, after long-term contact with the medium, the sustained-release skeleton structure of the microtablets is eroded and destroyed by the medium. Due to the disappearance of the sustained-release skeleton, the drug can no longer be slowly released but is quickly released into the medium. For a period of time thereafter, the microtablets no longer have a sustained-release effect.

[0035] In view of the limitations of the prior art, the inventors of the present application have conducted a large amount of basic research, adjusted the prescription process based on the prior art, and unexpectedly found that after ultrasonically mixing polyvinyl pyrrolidone K30 (PVP K30) and anionic surfactants in a specific ratio at 80-90°C and 45-55kHz, a sustained-release material different from conventional sustained-release matrix tablets can be obtained. The clarithromycin sustained-release microtablets prepared using the sustained-release material can uniformly release the active ingredient clarithromycin within 24 hours, effectively prolonging the sustained-release time of the clarithromycin sustained-release microtablets, and achieving the best effect under the combination of sodium cholate and PVP K30.

[0036] The specific sustained release mechanism is inferred as follows: PVP K30 is a high molecular polymer, which is usually neutral or slightly positively charged in solution, while the anionic surfactant (sodium cholate) is negatively charged. Under ultrasound and heating conditions, molecular motion intensifies, which promotes the dissociation of charges. Due to the attraction of positive and negative charges, the molecules generate electrostatic interactions and bind to each other in the solution. After binding, since PVP K30 contains hydrophobic groups, the hydrophobic chains of the anionic surfactant (sodium cholate) are also hydrophobic. In the medium, these hydrophobic groups will produce hydrophobic interactions to further form micelle structures. The formation of micelles provides a channel for the release of drugs, allowing clarithromycin to be released outward through these slow channels. Unlike the hydrophilic gel skeleton, the micelle structure is not easily destroyed by the aqueous medium due to the presence of hydrophobic groups. At the same time, the amide bonds in PVP K30 and the hydroxyl and carboxyl groups in the anionic surfactant molecules can form hydrogen bonds. The hydrogen bond interaction can enhance the binding force between PVP K30 and the anionic surfactant (sodium cholate), further improving the stability of the system. The presence of hydrophobic groups and hydrogen bonds together give the sustained-release structure better stability and durability, ensuring that the drug can maintain its structural integrity for a longer period of time in the aqueous environment of the dissolution medium or digestive fluid, thereby continuously and slowly releasing the drug.

[0037] Beneficial effects:

[0038] 1. The present invention uses polyvinyl pyrrolidone K30 (PVP K30), which is a non-sustained-release skeleton material, in excessive amounts for the first time when preparing clarithromycin sustained-release microtablets, and adds anionic surfactants at the same time. The PVP K30 and the anionic surfactants are combined with each other through the attraction of positive and negative charges, and hydrophobic interactions are generated between the hydrophobic groups of the two in the medium to further form a micellar structure. The formation of micelles provides a channel for the release of the drug, allowing clarithromycin to be released outward through these slow channels. Different from the hydrophilic gel skeleton, the micellar structure is not easily destroyed by the aqueous medium due to the presence of hydrophobic groups. At the same time, the amide bonds in PVP K30 and the hydroxyl and carboxyl groups in the anionic surfactant molecules can form hydrogen bonds, and the hydrogen bond interaction can enhance the binding force between PVP K30 and the anionic surfactant, further improving the stability of the system, so that the clarithromycin sustained-release microtablets can evenly release the active ingredient clarithromycin in 24 hours, effectively prolonging the sustained-release time of the clarithromycin sustained-release microtablets.

[0039] 2. The present invention provides a new clarithromycin sustained-release microtablet, which is small in size and easy for children and patients with dysphagia to take. At the same time, the modified layer can effectively mask the bitter taste of clarithromycin. The clarithromycin sustained-release microtablet provided by the present invention has better stability and durability than the clarithromycin sustained-release preparation with a hydrophilic gel skeleton, can stably exist in the dissolution medium for 24 hours, and continuously and slowly release the drug. The release curve shows that the cumulative drug release in 24 hours is 80-100%, which meets the release requirements of clarithromycin sustained-release tablets in the United States Pharmacopoeia.

[0040] 3. The present invention also provides a new method for preparing clarithromycin sustained-release microtablets, which has few steps, is simple to operate, and is suitable for industrial production. It also provides a new type of microtablet preparation reference for the preparation of other sustained-release drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 The release results of clarithromycin sustained-release microtablets prepared in Examples 1-2 and Comparative Examples 1-4 are shown. DETAILED DESCRIPTION

[0042] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0043] The raw materials used in the examples are all conventional raw materials, and the equipment used are all conventional equipment, which can be purchased commercially.

[0044] Example 1

[0045] A clarithromycin sustained-release microtablet, comprising a core tablet and a modified layer, wherein the mass ratio of the core tablet to the modified layer is 134.5:18;

[0046] The tablet core is composed of the following raw materials in parts by mass: clarithromycin 75.0 g, PVP K30 40.0 g, sodium cholate 10.0 g, lactose 7.0 g, talc 1.7 g, colloidal silicon dioxide 0.8 g;

[0047] The finishing layer is composed of the following raw materials in parts by mass: 10.3 g of Opadry film coating premix, 0.1 g of orange flavor, 0.5 g of stevioside, and 7.1 g of magnesium stearate.

[0048] The preparation method of the above-mentioned clarithromycin sustained-release microtablets comprises the following steps:

[0049] (1) PVP K30 and sodium cholate were added to 80 g of purified water according to the ratio, and ultrasonically mixed at 80° C. and 50 kHz for 15 minutes to obtain a mixed solution of sustained-release materials;

[0050] (2) according to the ratio, clarithromycin and lactose are stirred and mixed uniformly in a fluidized bed granulator, and then atomized and sprayed into the mixed solution of sustained-release materials obtained in step (1) for granulation, and dried until the moisture content is less than 3%, thereby obtaining clarithromycin tablet core particles;

[0051] The liquid supply speed of the atomizing spray is 15 rpm and the air volume is 30 m 3 / h, the inlet air temperature is 60℃, and the atomization pressure is 3bar;

[0052] (3) After the clarithromycin tablet core particles obtained in step (2) are passed through a 24-mesh sieve, talcum powder and colloidal silicon dioxide are added according to a ratio, mixed evenly, and the clarithromycin tablet core particles are tableted using a punch with a diameter of 2 mm to obtain clarithromycin tablet core particles with a hardness of 10 to 15 N;

[0053] (4) Add Opadry film coating premix, orange flavor, stevioside and magnesium stearate to 42 g of purified water according to the proportions and mix well to obtain a finishing layer coating solution;

[0054] (5) Place the clarithromycin tablet cores in a coating machine, set the liquid supply speed to 10 rpm, the atomization pressure to 1.5 bar, the coating pan speed to 20 rpm, and the exhaust temperature to 35° C. Spray the clarithromycin tablet cores with the modified layer coating liquid for coating, and put them into capsules or pharmaceutical composite bags to obtain 20,000 clarithromycin sustained-release microtablets.

[0055] Example 2

[0056] A clarithromycin sustained-release microtablet, comprising a core tablet and a modified layer, wherein the mass ratio of the core tablet to the modified layer is 134.1:19.2;

[0057] The tablet core is composed of the following raw materials in parts by mass: clarithromycin 75.0 g, PVP K30 40.0 g, dioctyl sodium sulfosuccinate 10.0 g, lactose 7.0 g, talc 1.5 g, colloidal silicon dioxide 0.6 g;

[0058] The finishing layer is composed of the following raw materials in parts by mass: 11.5 g of Opadry film coating premix, 0.1 g of orange flavor, 0.5 g of stevioside, and 7.1 g of magnesium stearate.

[0059] The preparation method of the above-mentioned clarithromycin sustained-release microtablets comprises the following steps:

[0060] (1) PVP K30 and sodium dioctyl sulfosuccinate were added to 80 g of purified water according to the ratio, and ultrasonically mixed at 90° C. and 50 kHz for 10 minutes to obtain a mixed solution of sustained-release material;

[0061] (2) according to the ratio, clarithromycin and lactose are stirred and mixed uniformly in a fluidized bed granulator, and then atomized and sprayed into the mixed solution of sustained-release materials obtained in step (1) for granulation, and dried until the moisture content is less than 3%, thereby obtaining clarithromycin tablet core particles;

[0062] The liquid supply speed of the atomizing spray is 15 rpm and the air volume is 30 m 3 / h, the inlet air temperature is 60℃, and the atomization pressure is 3bar;

[0063] (3) After the clarithromycin tablet core particles obtained in step (2) are passed through a 24-mesh sieve, talcum powder and colloidal silicon dioxide are added according to a ratio, mixed evenly, and the clarithromycin tablet core particles are tableted using a punch with a diameter of 2 mm to obtain clarithromycin tablet core particles with a hardness of 10 to 15 N;

[0064] (4) Add Opadry film coating premix, orange flavor, stevioside and magnesium stearate to 42 g of purified water according to the proportions and mix well to obtain a finishing layer coating solution;

[0065] (5) Place the clarithromycin tablet cores in a coating machine, set the liquid supply speed to 10 rpm, the atomization pressure to 1.5 bar, the coating pan speed to 20 rpm, and the exhaust temperature to 35° C. Spray the clarithromycin tablet cores with the modified layer coating liquid for coating, and put them into capsules or pharmaceutical composite bags to obtain 20,000 clarithromycin sustained-release microtablets.

[0066] Example 3

[0067] A clarithromycin sustained-release microtablet, comprising a core tablet and a modified layer, wherein the mass ratio of the core tablet to the modified layer is 129.5:18;

[0068] The tablet core is composed of the following raw materials in parts by mass: clarithromycin 70.0 g, PVP K30 40.0 g, sodium cholate 10.0 g, lactose 7.0 g, talc 1.7 g, colloidal silicon dioxide 0.8 g;

[0069] The finishing layer is composed of the following raw materials in parts by mass: 10.3 g of Opadry film coating premix, 0.1 g of orange flavor, 0.5 g of stevioside, and 7.1 g of magnesium stearate.

[0070] The preparation method of the above clarithromycin sustained-release microtablets is as described in Example 1.

[0071] Comparative Example 1

[0072] A clarithromycin sustained-release microtablet, the specific ingredients and preparation method are as described in Example 1, except that in step (1) of the preparation method, heating and ultrasonic mixing are not performed. Specifically, PVP K30 and sodium cholate are added to 80g of purified water according to the ratio, and the mixture is stirred and mixed at 30°C for 15 minutes to obtain a sustained-release material mixed solution.

[0073] Comparative Example 2

[0074] A clarithromycin sustained-release microtablet, comprising a core tablet and a modified layer, wherein the mass ratio of the core tablet to the modified layer is 147.5:18;

[0075] The tablet core is composed of the following raw materials in parts by mass: clarithromycin 75.0 g, PVP K30 3.0 g, hypromellose K100M 60.0 g, lactose 7.0 g, talc 1.7 g, colloidal silicon dioxide 0.8 g;

[0076] The finishing layer is composed of the following raw materials in parts by mass: 10.3 g of Opadry film coating premix, 0.1 g of orange flavor, 0.5 g of stevioside, and 7.1 g of magnesium stearate.

[0077] Compared with Example 1, in this comparative example, the sustained-release material hydroxypropyl methylcellulose K100M is used to replace the anionic surfactant sodium cholate, and the amount of PVP K30 is reduced.

[0078] The specific preparation method is the same as that of Example 1, except that the amount of purified water used in step (1) is 6 g.

[0079] Comparative Example 3

[0080] A clarithromycin sustained-release microtablet, comprising a core tablet and a modified layer, wherein the mass ratio of the core tablet to the modified layer is 134.5:18;

[0081] The tablet core is composed of the following raw materials in parts by mass: clarithromycin 75.0 g, PVP K30 40.0 g, lactose 17.0 g, talc 1.7 g, colloidal silicon dioxide 0.8 g;

[0082] The finishing layer is composed of the following raw materials in parts by mass: 10.3 g of Opadry film coating premix, 0.1 g of orange flavor, 0.5 g of stevioside, and 7.1 g of magnesium stearate.

[0083] Compared with Example 1, the anionic surfactant sodium cholate was not added in this comparative example, and the specific preparation method was the same as that of Example 1.

[0084] Comparative Example 4

[0085] A clarithromycin sustained-release microtablet, comprising a core tablet and a modified layer, wherein the mass ratio of the core tablet to the modified layer is 134.5:18;

[0086] The core tablet is composed of the following raw materials in parts by mass: clarithromycin 75.0 g, sodium cholate 10.0 g, lactose 47.0 g, talc 1.7 g, colloidal silicon dioxide 0.8 g;

[0087] The finishing layer is composed of the following raw materials in parts by mass: 10.3 g of Opadry film coating premix, 0.1 g of orange flavor, 0.5 g of stevioside, and 7.1 g of magnesium stearate.

[0088] Compared with Example 1, PVP K30 was not added in this comparative example, and the specific preparation method was the same as that of Example 1.

[0089] Experimental example

[0090] The release of clarithromycin sustained-release microtablets prepared in Examples 1 to 2 and Comparative Examples 1 to 4 was determined according to the second method of the dissolution and release determination method of the "General Rules of Part IV of the Chinese Pharmacopoeia 2020 Edition 0931". The specific method is as follows:

[0091] 900 ml of pH 6.8 phosphate buffer containing 0.5% sodium dodecyl sulfate was used as the dissolution medium. The paddle method test was performed at a temperature of 37 ± 0.5 °C and a rotation speed of 50 rpm. The operation was carried out in accordance with the law. Samples were taken at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h to determine the concentration of clarithromycin. The release curve was drawn with time as the horizontal axis and the cumulative release as the vertical axis. The results are shown in Figure 2. Figure 1 And as shown in Table 1.

[0092] Table 1

[0093]

[0094] Depend on Figure 1As shown in Table 1, in Comparative Example 1, polyvinyl pyrrolidone K30 (PVP K30) and anionic surfactant sodium cholate were not subjected to heating and ultrasonic treatment, and in Comparative Example 2, anionic surfactant sodium cholate was not added and the amount of PVP K30 was insufficient. Therefore, PVP K30 and sodium cholate in Comparative Examples 1-2 did not form a sustained-release micelle structure, and the cumulative release of clarithromycin sustained-release microtablets in Comparative Examples 1-2 was significantly higher than the cumulative release of clarithromycin sustained-release microtablets in Examples 1-2 of the present invention at 0.5h. Although Comparative Example 3 used an excessive amount of PVP K30, anionic surfactant sodium cholate was not added, and a sustained-release micelle structure was not formed. The cumulative release within 0.5-1h was still similar to that of Example 2, slightly greater than that of Example 1, but the cumulative release at 2h was significantly higher than that of Examples 1-2. Comparative Example 4 did not add PVP K30, and the cumulative release reached 48.25% at 0.5h, which was much higher than that of Examples 1-2.

[0095] In summary, the present invention is the first to use excessive amounts of non-sustained-release skeleton materials polyvinyl pyrrolidone K30 (PVP K30) and anionic surfactants when preparing clarithromycin sustained-release microtablets. The PVP K30 and anionic surfactants are combined with each other through the attraction of positive and negative charges. Hydrophobic interactions will occur between the hydrophobic groups of the two in the medium to further form a micellar structure. The formation of micelles provides a channel for the release of the drug, allowing clarithromycin to be released outward through these slow channels. Different from the hydrophilic gel skeleton, the micellar structure is not easily destroyed by the aqueous medium due to the presence of hydrophobic groups. At the same time, the amide bonds in PVP K30 and the hydroxyl and carboxyl groups in the anionic surfactant molecules can form hydrogen bonds. The hydrogen bond interaction can enhance the binding force between PVP K30 and the anionic surfactant, further improving the stability of the system, so that the clarithromycin sustained-release microtablets can evenly release the active ingredient clarithromycin in 24 hours, effectively prolonging the sustained-release time of the clarithromycin sustained-release microtablets.

Claims

1. A clarithromycin sustained-release microtablet, characterized in that: It consists of a core and a modified layer, wherein the mass ratio of the core to the modified layer is (125-135): (15-20); The tablet core is composed of the following raw materials in parts by weight: 50-75 parts of clarithromycin, 30-50 parts of polyvinylpyrrolidone K30, 5-15 parts of anionic surfactant, 0.1-10 parts of filler, 0.5-2 parts of lubricant, and 0.5-2 parts of glidant; The modification layer is composed of the following raw materials in parts by weight: 5 to 15 parts of coating material, 0.1 to 1 part of flavoring agent, and 2 to 10 parts of anti-sticking agent.

2. The clarithromycin sustained-release microtablet according to claim 1, characterized in that: The clarithromycin sustained-release microtablet is composed of a tablet core and a modified layer, and the mass ratio of the tablet core to the modified layer is (129.5-134.1): (18-19.2); The core tablet is composed of the following raw materials in parts by weight: 70-75 parts of clarithromycin, 35-45 parts of polyvinylpyrrolidone K30, 8-12 parts of anionic surfactant, 5-8 parts of filler, 1.5-1.7 parts of lubricant, and 0.6-0.8 parts of glidant; The modification layer is composed of the following raw materials in parts by weight: 10 to 12 parts of coating material, 0.2 to 0.8 parts of flavoring agent, and 5 to 8 parts of anti-sticking agent.

3. The clarithromycin sustained-release microtablet according to claim 1, characterized in that: The anionic surfactant is dioctyl sodium sulfosuccinate or sodium cholate; Further preferably, the anionic surfactant is sodium cholate.

4. The clarithromycin sustained-release microtablet according to claim 1, characterized in that: The filler is a mixture of one or more of lactose, microcrystalline cellulose or starch; the lubricant is a mixture of one or more of magnesium stearate, talc, calcium stearate, zinc stearate or glyceryl behenate.

5. The clarithromycin sustained-release microtablet according to claim 1, characterized in that: The glidant is colloidal silicon dioxide; the coating material is a mixture of one or more of Eudragit E 100, Eudragit E PO, Eudragit L 30D-55, Eudragit RL 30D, ethyl cellulose or Opadry film coating premix.

6. The clarithromycin sustained-release microtablet according to claim 1, characterized in that: The flavoring agent is a mixture of one or more of sucrose, aspartame, sucralose, stevioside, saccharin sodium, glucose, fructose, apple flavor, orange flavor, tangerine flavor, lemon flavor, vanilla flavor, and strawberry flavor; The anti-sticking agent is a mixture of one or more of talc, titanium dioxide, magnesium stearate, calcium stearate and zinc stearate.

7. The method for preparing the clarithromycin sustained-release microtablets according to claim 1, characterized in that: The steps include: (1) adding polyvinyl pyrrolidone K30 and anionic surfactant to 60-100 parts of purified water according to the ratio, and ultrasonically mixing at 80-90° C. and 45-55 kHz for 10-15 minutes to obtain a sustained-release material mixed solution; (2) stirring and mixing clarithromycin and a filler according to a ratio, and then spraying the mixed solution of the sustained-release material obtained in step (1) to granulate, and after drying, obtain clarithromycin tablet core particles; (3) After the clarithromycin tablet core particles obtained in step (2) are passed through a 24-mesh sieve, a lubricant and a glidant are added according to a ratio, the mixture is mixed evenly, and the mixture is tableted to obtain a clarithromycin tablet core; (4) adding the coating material, flavoring agent and anti-sticking agent to 40-45 parts of purified water according to the proportion, mixing evenly, to obtain a finishing layer coating solution; (5) The clarithromycin tablet core is coated with the modifying layer coating solution, and after packaging, clarithromycin sustained-release microtablets are obtained.

8. The preparation method according to claim 7, characterized in that: In step (2), the clarithromycin tablet core particles are prepared in a fluidized bed granulator, the liquid supply speed of the atomized spray is 20 to 30 rpm, and the air volume is 20 to 40 m 3 / h, the inlet air temperature is 55-65℃, and the atomization pressure is 2-4bar.

9. The preparation method according to claim 7, characterized in that: In step (3), the tableting is performed by using a punch with a diameter of 1 to 3 mm to tablet the clarithromycin tablet core particles; the hardness of the obtained clarithromycin tablet core is 10 to 15N.

10. The preparation method according to claim 7, characterized in that: In step (5), the coating is performed by placing the clarithromycin tablet core in a coating machine, setting the liquid supply speed to 5-10 rpm, the atomization pressure to 1-2 bar, the coating pan speed to 15-30 rpm, the exhaust temperature to 30-40° C., and spraying the modified layer coating liquid for the clarithromycin tablet core.

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