Microcapsule self-suspending theophylline sustained-release granules and preparation method thereof

Abstract

A microcapsule-type self-suspending theophylline sustained-release granule and a preparation method thereof belong to the field of pharmaceutical preparations. The sustained-release granule comprises a capsule core, a drug-carrying layer, a sustained-release layer and a suspension layer, and is prepared by a fluidized bed air suspension microencapsulation process. The present invention also discloses a preparation method of the microcapsule-type theophylline sustained-release granule, comprising: (1) mixing theophylline with an auxiliary material to form a suspension-type layering liquid, spraying and layering the suspension onto the capsule core to prepare drug-carrying granules; (2) mixing a sustained-release capsule material with other auxiliary materials to obtain a capsule material suspension, spraying and layering the suspension onto drug-carrying granules to prepare sustained-release granules; (3) mixing a polymer material with other auxiliary materials in water, and layering the mixture onto the surface of the sustained-release granules in the form of an air-suspended coating to form a microcapsule-type self-suspending theophylline sustained-release granule. Compared with the original preparation, the present invention adopts a one-step layering and coating method, has a simple preparation process, and has a particle size suitable for patients with difficulty swallowing.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to microcapsule-type self-suspended theophylline sustained-release particles and a preparation method thereof. Background Art

[0002] Asthma is the most common chronic respiratory disease in the world and a public health issue that medical professionals around the world focus on. The main symptoms are paroxysmal wheezing, chest tightness, and shortness of breath. Bronchial asthma is a chronic inflammatory disease of the airways caused by multiple cells such as eosinophils, T lymphocytes, and airway epithelial cells and their cell components.

[0003] The chemical name of theophylline is 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (hereinafter referred to as theophylline), and its molecular formula is C7H8N4O2. Its relative molecular mass is 180g / mol. Its main pharmacological effects are phosphodiesterase (PDE) inhibitor, adenosine receptor antagonist, inhibition of inflammatory factors such as prostaglandins, etc., and direct action on bronchial smooth muscle to gradually relax it, thereby achieving the purpose of dilating the bronchi and treating asthma.

[0004] However, theophylline has large individual differences after administration, short half-life, unstable blood drug concentration after administration, and narrow therapeutic window of theophylline itself. Therefore, the development of theophylline sustained-release preparations has received extensive attention.

[0005] Patent application CN111202716A discloses a method for preparing a theophylline sustained-release tablet. Theophylline is mixed with a skeleton material by hot melt extrusion technology to prepare granules, and then the granules are mixed with a lubricant, a filler, and a disintegrant and pressed into tablets. However, the patent uses tablets as the final administration form, which is obviously intended for normal adults and is not suitable for children and the elderly with dysphagia, frequent and severe asthma.

[0006] Patent application CN108478535A discloses a theophylline sustained-release dry suspension. Taking into account the patient's medication experience, the theophylline and excipients are mixed in a trough mixer by centrifugal granulation, and then dried and granulated to prepare the theophylline sustained-release dry suspension. However, due to the centrifugal granulation process, the sustained-release particles are too large, and the final granulation is a 20-mesh sieve, which does not really improve the patient's medication experience; and because the particles obtained by centrifugal granulation are relatively loose, more than 60% are released in 1 hour during the release process, and no more release is made subsequently, which cannot achieve the expected effect for theophylline that needs sustained release.

[0007] Therefore, there is an urgent need to develop a theophylline sustained-release preparation with simpler production process, easier operation, lower cost, environmental friendliness, suitability for industrial production, and suitable for special medication populations. Summary of the invention

[0008] In view of the shortcomings of the prior art, the present invention provides a novel microcapsule-type self-suspending theophylline sustained-release granules and a preparation method thereof. The microcapsule-type self-suspending theophylline sustained-release granules are characterized in that the microcapsule-type self-suspending theophylline sustained-release granules adopt membrane-controlled insoluble sustained-release materials, and the preparation using the microcapsule-type self-suspending theophylline sustained-release granules has stable drug release. At the same time, the preparation process of the microcapsule-type self-suspending theophylline sustained-release granules is simple, has high reproducibility, and is suitable for industrial production.

[0009] The purpose of the present invention is to provide a novel microcapsule-type self-suspending theophylline sustained-release granule to solve the problems that ordinary sustained-release tablets and sustained-release granules are not suitable for special drug-administered populations and have poor safety.

[0010] A microcapsule-type self-suspending theophylline sustained-release granule is a granule prepared by sequentially fluidizing a core material to coat a drug-carrying layer, a sustained-release layer, and a suspension layer. The drug-carrying layer is prepared from a layered suspension, the sustained-release layer is prepared from a sustained-release capsule material suspension, and the suspension layer is prepared from a polymer suspension, wherein theophylline is mainly enriched in the drug-carrying layer.

[0011] The weight proportion of each layer of the microcapsule type self-suspending theophylline sustained-release granules is as follows: the suspension layer accounts for 1-10% of the microcapsule type self-suspending theophylline sustained-release granules, the sustained-release layer accounts for 30%-50% of the microcapsule type self-suspending theophylline sustained-release granules, the drug-carrying layer accounts for 5%-30% of the microcapsule type self-suspending theophylline sustained-release granules, and the capsule core material accounts for 1-10% of the microcapsule type self-suspending theophylline sustained-release granules, which is 100% in total. Theophylline is in the drug-carrying layer.

[0012] The capsule core material is selected from sucrose, microcrystalline cellulose 301, microcrystalline cellulose 302, CP102, TP102 and TP203.

[0013] The theophylline content of the microcapsule self-suspending particles is 1%-30% of the prescribed amount.

[0014] The layered suspension comprises 1-50 parts of theophylline, 1-20 parts of a binder, 1-5 parts of an anti-adhesive agent, 0.1-0.5 parts of a charge stabilizer, and 50-500 parts of water by weight.

[0015] Wherein, the adhesive is one or more of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, and cross-linked polyvinylpyrrolidone; the anti-adhesive agent is one or more of talc, magnesium stearate, and micro-powder silica gel; and the charge stabilizer is sodium dodecyl sulfate.

[0016] The adhesive is a pharmaceutical excipient that uses its own viscosity to give appropriate viscosity to materials without viscosity or insufficient viscosity.

[0017] The anti-adhesive agent is a pharmaceutical excipient that reduces the self-adhesiveness of the rubber or adhesive, reduces surface adhesion, and has the effect of producing a slightly rough surface.

[0018] The sustained-release capsule material comprises 1-20 parts of sustained-release material, 1-5 parts of pore-forming agent, 1-10 parts of anti-adhesive agent and 50-100 parts of water in parts by weight.

[0019] Wherein, the sustained-release material is one or more of ethyl cellulose, methacrylic acid copolymer, and hydroxypropyl cellulose phthalate; and the pore-forming agent is one or more of polyethylene glycol, hydroxypropyl cellulose, and povidone.

[0020] The sustained-release material is a pharmaceutical excipient that delays and controls the release of drugs, reduces the number of dosing times, or improves patients' compliance with medication or therapeutic effects.

[0021] The pore-forming agent is a pharmaceutical excipient that increases the pore structure of the preparation and accelerates the release rate of the preparation.

[0022] The polymer suspension comprises 0.4-5 parts of polymer material, 1-5 parts of sunscreen, 1-10 parts of flavoring agent and 100-1000 parts of water by weight, and may further contain anti-adhesive agent, colorant and aromatic agent.

[0023] Wherein, the polymer material is one or more of xanthan gum, gum arabic and sodium alginate; and the sunscreen is titanium dioxide.

[0024] like Figure 2 As shown, the particle size of the microcapsule-type self-suspending theophylline sustained-release granules of the present invention is 1 μm-1000 μm.

[0025] The method for preparing the microcapsule-type self-suspending theophylline sustained-release granules of the present invention comprises the following steps:

[0026] (1) Preparation of layered suspension:

[0027] The binder is added into water and heated to dissolve, theophylline and other excipients are added into the binder solution, and after being evenly dispersed, the mixture is transferred into a basket grinder to micronize the drug to obtain a layered suspension;

[0028] Alternatively, theophylline is crushed mechanically or by air flow, and the crushed drug and other excipients are added to the binder solution, and after being evenly dispersed, a layered suspension is obtained;

[0029] (2) Preparation of theophylline drug-loaded particles:

[0030] The capsule core material is loaded into the fluidized bed for fluidization, and the layered suspension is sprayed onto the surface of the capsule core material and dried; the parameters in the fluidized bed fluidization chamber are set as follows: air inlet volume 900-1100rpm, atomization pressure 0.1-0.15mpa, and material temperature 38-43°C;

[0031] (3) Preparation of theophylline sustained-release granules:

[0032] The sustained-release material is mixed with other excipients to prepare a sustained-release capsule material solution, which is sprayed onto the surface of theophylline-loaded particles and dried; the parameters in the fluidized bed fluidization chamber are set as follows: air inlet volume 1100-1500rpm, atomization pressure 0.1-0.14mpa, material temperature 40-45°C;

[0033] (4) Preparation of suspended particles:

[0034] The polymer material is mixed with other auxiliary materials to prepare a polymer suspension, which is sprayed onto the surface of theophylline sustained-release particles and dried; the parameters in the fluidized bed fluidization chamber are set as follows: air inlet volume 1100-1500rpm, atomization pressure 0.1-0.14mpa, and material temperature 40-45°C.

[0035] The three kinds of particles are fluidized coated, dried and taken out, and then sieved. The theophylline drug-loaded particles are sieved through a 100-120 mesh sieve; the microcapsule type theophylline sustained-release particles are sieved through a 80-100 mesh sieve; the microcapsule type self-suspended theophylline sustained-release particles are sieved through a 70-80 mesh sieve.

[0036] Beneficial effects of the present invention:

[0037] Theophylline sustained-release tablets, capsules, and dry suspensions currently on the market in China have the disadvantages of average sustained-release effect, difficulty in taking, and high technical barriers. In clinical practice, they have the disadvantages of large differences in human bodies, low therapeutic index, large toxic side effects, and difficulty in mastering dosage and usage, which have led to many drug safety accidents. In recent years, the proportion of children suffering from asthma has increased year by year, and the call for improving theophylline preparations into preparations with uniform release and high safety has become increasingly strong.

[0038] The invention relies on water dispersion membrane control technology, and has good drug sustained release effect. It adopts the administration form of multi-unit self-suspended microcapsule particles, which is not easy to cause sudden release and has high safety. Theophylline sustained-release microparticles with stable quality and industrialization are obtained by wet grinding combined with fluidized bed liquid phase layering and microencapsulation technology, which are suitable for children's medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 The dissolution curves in water of the microcapsule-type self-suspending theophylline sustained-release granules prepared in Examples 3-5 and the theophylline sustained-release granules marketed in Japan (reference preparation) are compared.

[0040] Figure 2 Laser scattering particle size analyzer is used to detect the particle size and distribution of microcapsule self-suspended theophylline sustained-release particles.

[0041] Figure 3 Scanning electron micrographs of theophylline sustained-release granules; a) uncoated granules, b) coated granules, c) surface of coated granules. DETAILED DESCRIPTION

[0042] The technical solution of the present invention is further described below through specific embodiments.

[0043] Example 1

[0044] The invention discloses a theophylline drug-loaded particle, comprising a capsule core material and a drug-loaded layer prepared by a layered suspension, wherein the capsule core material is microcrystalline cellulose CP102, in the preparation process of the drug-loaded layer, ultrafine talcum powder is selected as an anti-adhesive agent, and hydroxypropyl methylcellulose is selected as an adhesive, and theophylline is mainly enriched in the drug-loaded layer.

[0045] The prescription of theophylline drug-loaded granules in this embodiment is shown in Table 1;

[0046] Table 1 Prescription of Example 1 Theophylline Drug-Carrying Granules

[0047] Raw materials name model Content g Experimental dosage g Technical drug Theophylline / 40 40 Core material Microcrystalline Cellulose CP102 100 100 Anti-sticking agent Ultrafine talcum powder / 4 4 Adhesive Hydroxypropyl methylcellulose E5 6 6 Charge Stabilizer Sodium Lauryl Sulfate / 0.2 0.2 Solvents water / 200 200

[0048] The method for preparing theophylline drug-loaded particles described in this embodiment comprises the following steps:

[0049] 1. Preparation of layered suspension:

[0050] Heat the prescribed amount of water to 80°C, weigh the prescribed amount of hydroxypropyl methylcellulose and add it to the heated water, stirring until it is completely dissolved, cool to room temperature, and set aside;

[0051] Add the prescribed amount of theophylline, ultrafine talc and sodium lauryl sulfate to the hydroxypropyl methylcellulose aqueous solution which has been cooled to room temperature, and mix for 10 minutes to obtain a coarse layered suspension;

[0052] The coarse layered suspension was transferred to a basket mill, the grinding was started, the grinding frequency was adjusted to 40 Hz, and the grinding was continued for 2 h to obtain theophylline layered suspension.

[0053] 2. Preparation of theophylline drug-loaded particles:

[0054] Add the prescribed amount of microcrystalline cellulose into the fluidizing chamber of the fluidized bed, adjust the air intake to 900-1100rpm, the atomization pressure to 0.1-0.15mpa, and the material temperature to 38-43°C, then turn on the fan, and when the material temperature reaches 40°C, start spraying until the coating weight gain reaches more than 30% to end the coating, continue drying, and pass the dried particles through a 100-120 mesh sieve to obtain theophylline drug-loaded particles, which are stored for later use. Coating weight gain mass fraction (%) = (mass of solids in the sprayed coating liquid / mass of the plain pills) × 100%.

[0055] Example 2

[0056] A microcapsule type theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer and a sustained-release layer, wherein theophylline is mainly enriched in the drug-carrying layer, and the drug-carrying granules are wrapped with an ethyl cellulose aqueous dispersion through a fluidized bed air suspension method to obtain the microcapsule type theophylline sustained-release granule.

[0057] The prescription of the microencapsulated theophylline sustained-release granules of this embodiment is shown in Table 2.

[0058] Table 2 Example 2 Microencapsulated theophylline sustained-release granules prescription

[0059]

[0060] The preparation method of the microcapsule theophylline sustained-release granules of this embodiment comprises the following steps:

[0061] 1. Preparation of sustained-release capsule suspension:

[0062] Add the prescribed amount of water to the prescribed amount of ethylcellulose aqueous dispersion, mix well, add other excipients, continue stirring until uniform, prepare a sustained-release capsule material solution, and spray it onto the surface of theophylline drug-loaded particles;

[0063] 2. Preparation of microcapsule theophylline sustained-release granules:

[0064] The theophylline drug-loaded particles are added into the fluidizing chamber of the fluidized bed, and the fan, atomization pressure and material temperature are adjusted (air intake volume 1100-1500 rpm, atomization pressure 0.1-0.14 MPa, material temperature 40-45° C.), and the fan is turned on. When the material temperature reaches 38° C., the spraying is turned on until the weight gain reaches more than 70% to complete the coating, and the drying is continued. The dried particles are passed through an 80-100 mesh sieve to obtain theophylline sustained-release particles, which are stored for later use.

[0065] Example 3

[0066] A microcapsule type self-suspending theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer, a sustained-release layer and a suspension layer, wherein theophylline is mainly enriched in the drug-carrying layer; the sustained-release granules are wrapped with a polymer material through a fluidized bed air suspension method to obtain the microcapsule type self-suspending theophylline sustained-release granule.

[0067] The prescription of the microcapsule self-suspending theophylline sustained-release granules of this embodiment is shown in Table 3.

[0068] Table 3 Prescription of Microcapsule Self-Suspending Theophylline Sustained Release Granules of Example 3

[0069]

[0070]

[0071] The preparation method of the microcapsule self-suspending theophylline sustained-release granules of this embodiment comprises the following steps:

[0072] 1. Preparation of polymer suspension:

[0073] Heat the prescribed amount of water to 80°C, weigh the prescribed amount of xanthan gum and other excipients and add them to the heated water, stirring until all dissolved;

[0074] 2. Preparation of microcapsule self-suspending theophylline sustained-release granules:

[0075] Spray it onto the surface of theophylline sustained-release particles in the prescribed amount, add it into the fluidizing chamber of the fluidized bed, adjust the fan, atomization pressure, and material temperature (air intake volume 1100-1500rpm, atomization pressure 0.1-0.14mpa, material temperature 40-45°C), turn on the fan, and when the material temperature reaches 40°C, start spraying until the weight gain reaches more than 10% to end the coating, continue drying, pass the dried particles through an 80-mesh sieve to obtain self-suspended theophylline sustained-release particles, and store them for later use.

[0076] Example 4

[0077] A microcapsule type self-suspending theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer, a sustained-release layer and a suspension layer, wherein theophylline is mainly enriched in the drug-carrying layer; a suspension of a drug and an adhesive is used to wrap the sustained-release granule through a fluidized bed air suspension method to obtain the microcapsule type self-suspending theophylline sustained-release granule.

[0078] The prescription of the microcapsule self-suspending theophylline sustained-release granules of this embodiment is shown in Table 4-6.

[0079] Table 4 Prescription of Example 4 Theophylline Drug-Carrying Granules

[0080] Raw materials name model Content g Experimental dosage g Technical drug Theophylline / 40 40 Core material Microcrystalline Cellulose CP102 100 100 Anti-sticking agent Ultrafine talcum powder / 4 4 Adhesive Hydroxypropyl methylcellulose E5 6 6 Charge Stabilizer Sodium Lauryl Sulfate / 0.2 0.2 Solvents water / 200 200

[0081] Table 5 Prescription of Example 4 Microencapsulated Theophylline Sustained Release Granules

[0082]

[0083]

[0084] Table 6 Prescription of Example 4 Microcapsule Self-Suspending Theophylline Sustained Release Granules

[0085] Raw materials name model Content g Experimental dosage g Input materials Theophylline sustained-release granules / 20.00 20.00 Polymer Materials Xanthan gum / 0.400 0.400 Sunscreen Titanium Dioxide / 1.00 1.00 Flavoring agents Sucralose / 0.500 0.500 Solvents water / 100 100

[0086] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 2, the amount of ethyl cellulose aqueous dispersion added as the sustained-release material of the sustained-release layer is reduced by 30g, so the weight gain will be reduced, the sustained-release effect will be different, and the release of the sustained-release particles will be accelerated.

[0087] Example 5

[0088] A microcapsule type self-suspending theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer, a sustained-release layer and a suspension layer, wherein theophylline is mainly enriched in the drug-carrying layer; the sustained-release granules are coated with a suspension of a drug and an adhesive through a fluidized bed air suspension method to obtain the microcapsule type self-suspending theophylline sustained-release granules.

[0089] The prescription of the microcapsule self-suspending theophylline sustained-release granules of this embodiment is shown in Tables 7-9.

[0090] Table 7 Prescription of Example 5 Theophylline Drug-Loaded Granules

[0091] Raw materials name model Content g Experimental dosage g Technical drug Theophylline / 40 40 Core material Microcrystalline Cellulose CP102 100 100 Anti-sticking agent Ultrafine talcum powder / 4 4 Adhesive Hydroxypropyl methylcellulose E5 6 6 Charge Stabilizer Sodium Lauryl Sulfate / 0.2 0.2 Solvents water / 200 200

[0092] Table 8 Prescription of Example 5 Microencapsulated Theophylline Sustained Release Granules

[0093]

[0094] Table 9 Prescription of Example 5 Microcapsule Self-Suspending Theophylline Sustained Release Granules

[0095] Raw materials name model Content g Experimental dosage g Input materials Theophylline sustained-release granules / 20.00 20.00 Polymer Materials Xanthan gum / 0.400 0.400 Sunscreen Titanium Dioxide / 1.00 1.00 Flavoring agents Sucralose / 0.500 0.500 Solvents water / 100 100

[0096] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 2, the amount of pore-forming agent added to the sustained-release layer is increased by 10 g. The pore-forming agent has the effect of accelerating drug release, so increasing the amount of pore-forming agent added can improve the release of the prepared sustained-release particles.

[0097] Example 6

[0098] A microcapsule type self-suspending theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer, a sustained-release layer and a suspension layer, wherein theophylline is mainly enriched in the drug-carrying layer; a suspension of a drug and an adhesive is used to wrap the sustained-release granule through a fluidized bed air suspension method to obtain the microcapsule type self-suspending theophylline sustained-release granule.

[0099] The prescription of the microcapsule self-suspending theophylline sustained-release granules of this embodiment is shown in Tables 10-12.

[0100] Table 10 Prescription of Example 6 Theophylline Drug-Loaded Granules

[0101] Raw materials name model Content g Experimental dosage g Technical drug Theophylline / 40 40 Core material Microcrystalline Cellulose CP102 100 100 Anti-sticking agent Ultrafine talcum powder / 4 4 Adhesive Sodium Carboxymethyl Cellulose / 6 6 Charge Stabilizer Sodium Lauryl Sulfate / 0.2 0.2 Solvents water / 200 200

[0102] Table 11 Prescription of Example 6 Microencapsulated Theophylline Sustained Release Granules

[0103]

[0104] Table 12 Prescription of Example 6 Microcapsule Self-Suspending Theophylline Sustained Release Granules

[0105] Raw materials name model Content g Experimental dosage g Input materials Theophylline sustained-release granules / 20.00 20.00 Polymer Materials Xanthan gum / 0.400 0.400 Sunscreen Titanium Dioxide / 1.00 1.00 Flavoring agents Sucralose / 0.500 0.500 Solvents water / 100 100

[0106] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 1, the drug-carrying layer binder is changed from the original hydroxypropyl methylcellulose to sodium carboxymethyl cellulose. Although both have the function of binders, due to certain differences in properties, they will have different effects on the dissolution results of the prepared preparations. The specific effects are recorded in Example 16.

[0107] Example 7

[0108] A microcapsule type self-suspending theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer, a sustained-release layer and a suspension layer, wherein theophylline is mainly enriched in the drug-carrying layer; a suspension of a drug and an adhesive is used to wrap the sustained-release granule through a fluidized bed air suspension method to obtain the microcapsule type self-suspending theophylline sustained-release granule.

[0109] The prescription of the microcapsule self-suspending theophylline sustained-release granules of this embodiment is shown in Tables 13-15.

[0110] Table 13 Prescription of Example 7 Theophylline Drug-Loaded Granules

[0111] Raw materials name model Content g Experimental dosage g Technical drug Theophylline / 40 40 Core material Microcrystalline Cellulose CP102 100 100 Anti-sticking agent Ultrafine talcum powder / 4 4 Adhesive Polyvinylpyrrolidone / 6 6 Charge Stabilizer Sodium Lauryl Sulfate / 0.2 0.2 Solvents water / 200 200

[0112] Table 14 Prescription of Example 7 Microencapsulated Theophylline Sustained Release Granules

[0113]

[0114] Table 15 Prescription of Example 7 Microcapsule Self-Suspending Theophylline Sustained Release Granules

[0115]

[0116]

[0117] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 1, the drug-carrying layer binder is changed from the original hydroxypropyl methylcellulose to polyvinyl pyrrolidone. Although both have the function of binders, due to certain differences in properties, they will have different effects on the dissolution results of the prepared preparations. The specific effects are recorded in Example 16.

[0118] Example 8

[0119] A microcapsule type self-suspending theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer, a sustained-release layer and a suspension layer, wherein theophylline is mainly enriched in the drug-carrying layer; a suspension of a drug and an adhesive is used to wrap the sustained-release granule through a fluidized bed air suspension method to obtain the microcapsule type self-suspending theophylline sustained-release granule.

[0120] The prescription of the microcapsule self-suspending theophylline sustained-release granules of this embodiment is shown in Tables 16-18.

[0121] Table 16 Prescription of Example 8 Theophylline Drug-Loaded Granules

[0122] Raw materials name model Content g Experimental dosage g Technical drug Theophylline / 40 40 Core material Microcrystalline Cellulose CP102 100 100 Anti-sticking agent Ultrafine talcum powder / 4 4 Adhesive Crospovidone / 6 6 Charge Stabilizer Sodium Lauryl Sulfate / 0.2 0.2 Solvents water / 200 200

[0123] Table 17 Prescription of Example 8 Microencapsulated Theophylline Sustained Release Granules

[0124]

[0125] Table 18 Prescription of Example 8 Microcapsule Self-Suspending Theophylline Sustained Release Granules

[0126]

[0127]

[0128] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 1, the drug-carrying layer binder is changed from the original hydroxypropyl methylcellulose to cross-linked polyvinylpyrrolidone. Although both have the function of binders, due to certain differences in properties, they will have different effects on the dissolution results of the prepared preparations. The specific effects are recorded in Example 16.

[0129] Example 9

[0130] A microcapsule type self-suspending theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer, a sustained-release layer and a suspension layer, wherein theophylline is mainly enriched in the drug-carrying layer; a suspension of a drug and an adhesive is used to wrap the sustained-release granule through a fluidized bed air suspension method to obtain the microcapsule type self-suspending theophylline sustained-release granule.

[0131] The prescription of the microcapsule self-suspending theophylline sustained-release granules of this embodiment is shown in Tables 19-21.

[0132] Table 19 Prescription of Example 9 Theophylline Drug-Loaded Granules

[0133] Raw materials name model Content g Experimental dosage g Technical drug Theophylline / 40 40 Core material Microcrystalline Cellulose CP102 100 100 Anti-sticking agent Micro powder silica gel / 4 4 Adhesive Hydroxypropyl methylcellulose / 6 6 Charge Stabilizer Sodium Lauryl Sulfate / 0.2 0.2 Solvents water / 200 200

[0134] Table 20 Prescription of Example 9 Microencapsulated Theophylline Sustained Release Granules

[0135]

[0136] Table 21 Prescription of Example 9 Microcapsule Self-Suspending Theophylline Sustained Release Granules

[0137]

[0138]

[0139] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Examples 1 and 2, the types of anti-adhesive agents in the drug-loading layer and the sustained-release layer are changed, and micro-powdered silica gel replaces talcum powder. The effects and functions are similar, but due to the differences in properties, different effects will be produced on the dissolution results of the prepared preparations. The specific effects are recorded in Example 16.

[0140] Example 10

[0141] A microcapsule type self-suspending theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer, a sustained-release layer and a suspension layer, wherein theophylline is mainly enriched in the drug-carrying layer; a suspension of a drug and an adhesive is used to wrap the sustained-release granule through a fluidized bed air suspension method to obtain the microcapsule type self-suspending theophylline sustained-release granule.

[0142] The prescription of the microcapsule self-suspending theophylline sustained-release granules of this embodiment is shown in Tables 22-24.

[0143] Table 22 Prescription of Example 10 Theophylline Drug-Loaded Granules

[0144] Raw materials name model Content g Experimental dosage g Technical drug Theophylline / 40 40 Core material Microcrystalline Cellulose CP102 100 100 Anti-sticking agent Magnesium Stearate / 4 4 Adhesive Hydroxypropyl methylcellulose / 6 6 Charge Stabilizer Sodium Lauryl Sulfate / 0.2 0.2 Solvents water / 200 200

[0145] Table 23 Prescription of Example 10 Microencapsulated Theophylline Sustained Release Granules

[0146]

[0147] Table 24 Prescription of Example 10 Microcapsule Self-Suspending Theophylline Sustained Release Granules

[0148]

[0149]

[0150] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Examples 1 and 2, the types of anti-adhesive agents in the drug-carrying layer and the sustained-release layer are changed, and magnesium stearate replaces talc. The effects and functions are similar, but due to the differences in properties, different effects will be produced on the dissolution results of the prepared preparations. The specific effects are recorded in Example 16.

[0151] Embodiment 11

[0152] A microcapsule type self-suspending theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer, a sustained-release layer and a suspension layer, wherein theophylline is mainly enriched in the drug-carrying layer; a suspension of a drug and an adhesive is used to wrap the sustained-release granule through a fluidized bed air suspension method to obtain the microcapsule type self-suspending theophylline sustained-release granule.

[0153] The prescription of the microcapsule self-suspending theophylline sustained-release granules of this embodiment is shown in Tables 25-27.

[0154] Table 25 Prescription of Example 11 Theophylline Drug-Loaded Granules

[0155] Raw materials name model Content g Experimental dosage g Technical drug Theophylline / 40 40 Core material Microcrystalline Cellulose CP102 100 100 Anti-sticking agent Ultrafine talcum powder / 4 4 Adhesive Hydroxypropyl methylcellulose / 6 6 Charge Stabilizer Sodium Lauryl Sulfate / 0.2 0.2 Solvents water / 200 200

[0156] Table 26 Prescription of Example 11 Microencapsulated Theophylline Sustained Release Granules

[0157]

[0158] Table 27 Prescription of Example 11 Microcapsule Self-Suspending Theophylline Sustained Release Granules

[0159]

[0160]

[0161] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 2, the type of sustained-release material in the sustained-release layer is changed, and methyl methacrylate copolymer replaces ethyl cellulose gum. The effect and function are the same, but because of the different properties, it will affect the dissolution result of the prepared preparation. The specific effects are recorded in Example 16.

[0162] Example 12

[0163] A microcapsule type self-suspending theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer, a sustained-release layer and a suspension layer, wherein theophylline is mainly enriched in the drug-carrying layer; a suspension of a drug and an adhesive is used to wrap the sustained-release granule through a fluidized bed air suspension method to obtain the microcapsule type self-suspending theophylline sustained-release granule.

[0164] The prescription of the microcapsule self-suspending theophylline sustained-release granules of this embodiment is shown in Tables 28-30.

[0165] Table 28 Prescription of Example 12 Theophylline Drug-Loaded Granules

[0166] Raw materials name model Content g Experimental dosage g Technical drug Theophylline / 40 40 Core material Microcrystalline Cellulose CP102 100 100 Anti-sticking agent Ultrafine talcum powder / 4 4 Adhesive Hydroxypropyl methylcellulose / 6 6 Charge Stabilizer Sodium Lauryl Sulfate / 0.2 0.2 Solvents water / 200 200

[0167] Table 29 Prescription of Example 12 Microencapsulated Theophylline Sustained Release Granules

[0168]

[0169] Table 30 Prescription of Example 12 Microcapsule Self-Suspending Theophylline Sustained Release Granules

[0170] Raw materials name model Content g Experimental dosage g Input materials Theophylline sustained-release granules / 20.00 20.00 Polymer Materials Xanthan gum / 0.400 0.400 Sunscreen Titanium Dioxide / 1.00 1.00 Flavoring agents Sucralose / 0.500 0.500 Solvents water / 100 100

[0171] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 2, the type of sustained-release layer pore-forming agent is changed, and polyethylene glycol replaces low-cross-linked hydroxypropyl cellulose. Their effects and functions are the same, but because of their different properties, they will affect the dissolution results of the prepared preparations. The specific effects are recorded in Example 16.

[0172] Embodiment 13

[0173] A microcapsule type self-suspending theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer, a sustained-release layer and a suspension layer, wherein theophylline is mainly enriched in the drug-carrying layer; a suspension of a drug and an adhesive is used to wrap the sustained-release granule through a fluidized bed air suspension method to obtain the microcapsule type self-suspending theophylline sustained-release granule.

[0174] The prescription of the microcapsule self-suspending theophylline sustained-release granules of this embodiment is shown in Tables 31-33.

[0175] Table 31 Prescription of Example 13 Theophylline Drug-Loaded Granules

[0176] Raw materials name model Content g Experimental dosage g Technical drug Theophylline / 40 40 Core material Microcrystalline Cellulose CP102 100 100 Anti-sticking agent Ultrafine talcum powder / 4 4 Adhesive Hydroxypropyl methylcellulose / 6 6 Charge Stabilizer Sodium Lauryl Sulfate / 0.2 0.2 Solvents water / 200 200

[0177] Table 32 Prescription of Example 13 Microcapsule Theophylline Sustained Release Granules

[0178]

[0179] Table 33 Prescription of Example 13 Microcapsule Self-Suspending Theophylline Sustained Release Granules

[0180] Raw materials name model Content g Experimental dosage g Input materials Theophylline sustained-release granules / 20.00 20.00 Polymer Materials Xanthan gum / 0.400 0.400 Sunscreen Titanium Dioxide / 1.00 1.00 Flavoring agents Sucralose / 0.500 0.500 Solvents water / 100 100

[0181] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 2, the type of sustained-release layer pore-forming agent is changed, and polyvidone replaces low-cross-linked hydroxypropyl cellulose. Their effects and functions are the same, but because of their different properties, they will affect the dissolution results of the prepared preparations. The specific effects are recorded in Example 16.

[0182] Embodiment 14

[0183] A microcapsule type self-suspending theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer, a sustained-release layer and a suspension layer, wherein theophylline is mainly enriched in the drug-carrying layer; a suspension of a drug and an adhesive is used to wrap the sustained-release granule through a fluidized bed air suspension method to obtain the microcapsule type self-suspending theophylline sustained-release granule.

[0184] The prescription of the microcapsule self-suspending theophylline sustained-release granules of this embodiment is shown in Tables 34-36.

[0185] Table 34 Prescription of Example 14 Theophylline Drug-Loaded Granules

[0186] Raw materials name model Content g Experimental dosage g Technical drug Theophylline / 40 40 Core material Microcrystalline Cellulose CP102 100 100 Anti-sticking agent Ultrafine talcum powder / 4 4 Adhesive Hydroxypropyl methylcellulose / 6 6 Charge Stabilizer Sodium Lauryl Sulfate / 0.2 0.2 Solvents water / 200 200

[0187] Table 35 Prescription of Example 14 Microencapsulated Theophylline Sustained Release Granules

[0188]

[0189] Table 36 Prescription of Example 14 Microcapsule Self-Suspending Theophylline Sustained Release Granules

[0190] Raw materials name model Content g Experimental dosage g Input materials Theophylline sustained-release granules / 20.00 20.00 Polymer Materials Gum Arabic / 0.400 0.400 Sunscreen Titanium Dioxide / 1.00 1.00 Flavoring agents Sucralose / 0.500 0.500 Solvents water / 100 100

[0191] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 3, the type of polymer material of the suspension layer is changed, and gum arabic replaces xanthan gum. Their effects and functions are the same, but because of their different properties, they will affect the dissolution results of the prepared preparation, as can be seen in Example 16.

[0192] Embodiment 15

[0193] A microcapsule type self-suspending theophylline sustained-release granule comprises a capsule core material, a drug-carrying layer, a sustained-release layer and a suspension layer, wherein theophylline is mainly enriched in the drug-carrying layer; a suspension of a drug and an adhesive is used to wrap the sustained-release granule through a fluidized bed air suspension method to obtain the microcapsule type self-suspending theophylline sustained-release granule.

[0194] The prescription of the microcapsule self-suspending theophylline sustained-release granules of this embodiment is shown in Tables 37-39.

[0195] Table 37 Prescription of Example 15 Theophylline Drug-Loaded Granules

[0196] Raw materials name model Content g Experimental dosage g Technical drug Theophylline / 40 40 Core material Microcrystalline Cellulose CP102 100 100 Anti-sticking agent Ultrafine talcum powder / 4 4 Adhesive Hydroxypropyl methylcellulose / 6 6 Charge Stabilizer Sodium Lauryl Sulfate / 0.2 0.2 Solvents water / 200 200

[0197] Table 38 Prescription of Example 15 Microencapsulated Theophylline Sustained Release Granules

[0198]

[0199] Table 39 Prescription of Example 15 Microcapsule Self-Suspending Theophylline Sustained Release Granules

[0200] Raw materials name model Content g Experimental dosage g Input materials Theophylline sustained-release granules / 20.00 20.00 Polymer Materials Sodium alginate / 0.400 0.400 Sunscreen Titanium Dioxide / 1.00 1.00 Flavoring agents Sucralose / 0.500 0.500 Solvents water / 100 100

[0201] Preparation process and method: Same as Examples 1-3, the main difference is that compared with Example 3, the type of polymer material of the suspension layer is changed, and sodium alginate replaces xanthan gum. Their effects and functions are the same, but because of their different properties, they will affect the dissolution results of the prepared preparation, as can be seen in Example 16.

[0202] Example 16

[0203] The dissolution curves of the microcapsule self-suspending theophylline sustained-release granules prepared in Example 3-5 and the theophylline sustained-release granules marketed in Japan (reference preparation) in water are compared as follows: Figure 1 As shown in the figure, it can be seen that the in vitro release of the microcapsule self-suspending theophylline sustained-release granules prepared by the present invention is consistent with the Japanese marketed product. The scanning electron micrograph of theophylline sustained-release granules is shown in Figure 3In addition, by adjusting the formulation of the coating solution, the dissolution results were different, which confirmed the effect of various excipients. For example, if more pore-forming agent is added, the release will be faster.

[0204] Determination of in vitro cumulative release of the microcapsule self-suspending theophylline sustained-release granules prepared in Example 3-15 and theophylline sustained-release granules marketed in Japan (reference preparation):

[0205] The determination method is as follows: Take the microcapsule self-suspending theophylline sustained-release granules prepared in Example 3-15, and follow the dissolution determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931, Dissolution and Release Determination Method, Method 2), 900 mL of water is used as the dissolution medium, the rotation speed is 50 revolutions per minute, and the operation is carried out according to the law. After 0.5, 1, 2, 4, 6, 8, 12, and 24 hours, 6 mL of the solution is taken respectively, passed through a 0.45 μm filter membrane, and the absorbance is measured.

[0206] The f2 similarity factor method was used for comparison.

[0207] The release results are shown in Table 40.

[0208] Table 40 Release results

[0209]

[0210]

[0211] The results showed that the in vitro release similarity f2 of the microcapsule self-suspending theophylline sustained-release granules prepared in Example 3 and the reference preparation was greater than 50, and the similarity was good.

[0212] In summary, the present invention uses ethyl cellulose aqueous dispersion as the membrane control material to prepare self-suspended microcapsule sustained-release particles by drug micronization and microencapsulation. Since the drug is administered in the form of a multi-unit preparation, the crushing of a single particle will not have a significant impact on the whole, and the particle size is smaller than an 80-mesh sieve, which is suitable for patients who are inconvenient to take orally; the production process of the present invention is simple, and a safe and environmentally friendly ethyl cellulose aqueous dispersion is used for coating, while also reducing its toxic side effects; the present invention can be slowly released in vitro, which helps to stabilize the blood drug concentration in vivo.

[0213] The preferred embodiments and principles of the present invention are described in detail above. For those skilled in the art, according to the ideas provided by the present invention, there may be changes in the specific implementation methods, and these changes should also be regarded as the protection scope of the present invention.

Claims

1. A microcapsule-type self-suspending theophylline sustained-release granule, characterized in that: The microcapsule type self-suspending theophylline sustained-release granules are granules prepared by sequentially fluidizing the core material to coat a drug-carrying layer, a sustained-release layer and a suspended layer; theophylline is enriched in the drug-carrying layer, the drug-carrying layer is prepared from a layered suspension, the sustained-release layer is prepared from a sustained-release capsule material suspension, the suspended layer is prepared from a polymer suspension, and the sustained-release granules are wrapped with a polymer material by a fluidized bed air suspension method to prepare the microcapsule type self-suspending theophylline sustained-release granules; the particle size of the microcapsule type self-suspending theophylline sustained-release granules is less than 80 meshes overall; The layered suspension comprises 40 parts of theophylline, 6 parts of a binder, 4 parts of an anti-adherent, 0.2 parts of a charge stabilizer, and 200 parts of water by weight; The sustained-release capsule suspension comprises 70 parts of sustained-release material, 5 parts of pore-forming agent, 8 parts of anti-adhesive agent and 50 parts of water in parts by weight; The polymer suspension comprises 0.4 parts of polymer material, 1 part of sunscreen, 0.5 parts of flavoring agent and 100 parts of water by weight; The capsule core material is microcrystalline cellulose CP102; The anti-sticking agent is talcum powder; The charge stabilizer is sodium dodecyl sulfate; The binder is hydroxypropyl methylcellulose; The sustained-release material is an aqueous dispersion of ethylcellulose; The pore-forming agent is hydroxypropyl cellulose; The polymer material is xanthan gum; The sunscreen is titanium dioxide; The flavoring agent is sucralose; The preparation method of the microcapsule type self-suspending theophylline sustained-release granules comprises the following steps: (1) Preparation of layered suspension: Add the binder to water in proportion, heat and dissolve, add theophylline and other excipients to the binder solution in proportion, disperse evenly, transfer to a grinder, micronize the drug, and obtain a layered suspension; Alternatively, theophylline is crushed, and the crushed drug and other excipients are added to the binder solution in proportion, and after being evenly dispersed, a layered suspension is obtained; (2) Preparation of theophylline drug-loaded particles: 100 portions of capsule core material were loaded into the fluidized bed for fluidization, and the layered suspension was sprayed onto the surface of the capsule core material until the coating weight gain reached more than 30%, and then the coating was finished and dried; the parameters in the fluidized bed fluidization chamber were set as follows: air inlet volume 900-1100rpm, atomization pressure 0.1-0.15mpa, and material temperature 38-43°C; (3) Preparation of theophylline sustained-release granules: The sustained-release material is mixed with other excipients to prepare a sustained-release capsule material solution, which is sprayed onto the surface of theophylline-loaded particles until the weight gain reaches more than 70%, and the coating is completed and dried; the parameters in the fluidized bed fluidization chamber are set as follows: air inlet volume 1100-1500rpm, atomization pressure 0.1-0.14mpa, and material temperature 40-45℃; (4) Preparation of microcapsule self-suspending theophylline sustained-release granules: The polymer material is mixed with other auxiliary materials to prepare a polymer suspension, which is sprayed onto the surface of theophylline sustained-release particles until the weight gain reaches more than 10%, and the coating is completed and dried; the parameters in the fluidized bed fluidization chamber are set as follows: air inlet volume 1100-1500rpm, atomization pressure 0.1-0.14mpa, material temperature 40-45℃; The theophylline drug-loaded granules, theophylline sustained-release granules, and microcapsule-type self-suspended theophylline sustained-release granules are fluidized-coated, dried, and then sieved. The theophylline drug-loaded granules are sieved through a 100-120 mesh sieve; the theophylline sustained-release granules are sieved through an 80-100 mesh sieve; and the microcapsule-type self-suspended theophylline sustained-release granules are sieved through an 80 mesh sieve.

2. The microcapsule-type self-suspending theophylline sustained-release granules according to claim 1, characterized in that: The theophylline content of the microcapsule self-suspending theophylline sustained-release granules is 1%-30% of the prescribed amount.

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