Azithromycin water-free swallowing granules and preparation method thereof

Abstract

The invention provides azithromycin water-free swallowing granules and a preparation method thereof, and belongs to the field of pharmaceutical preparations. The azithromycin water-free swallowing granules are prepared by mixing medicine-containing taste-masking pellets and taste-modifying granules. The medicine-containing taste-masking pellet sequentially comprises a medicine-containing pellet core, an isolating layer and a taste-masking layer from inside to outside, and the medicine-containing pellet core is prepared through a centrifugal pelleting process. The technical problem to be solved is that the azithromycin water-free swallowing granule can realize water-free rapid swallowing, keeps good taste in the whole process, remarkably improves medication convenience and patient compliance, and is particularly suitable for children and other groups with difficulty in swallowing.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to an azithromycin anhydrous swallowing granule and a preparation method thereof. BACKGROUND

[0002] For understanding the technical content of the present application: Azithromycin belongs to semi-synthetic macrolide antibacterial drugs, which is mainly used for treating respiratory tract infections, urinary system infections, skin and soft tissue infections and other diseases in clinic. Azithromycin has the advantages of strong tissue penetration, long half-life and small toxic and side effects, and has broad market prospects.

[0003] Oral administration is the most commonly used administration method, which has the advantages of safe and convenient medication, easy to be accepted by patients and easy to be adopted, but has certain limitations: the drug absorption is slow, generally showing effect in half an hour after oral administration, and the drug is easy to be destroyed in the gastrointestinal tract, and has strong stimulation to the gastrointestinal tract, has an unpleasant odor, or the drug with poor absorption in the gastrointestinal tract cannot reach the required therapeutic concentration, which is not suitable for preparing oral preparations. The oral preparations include tablet, capsule, granule, oral solution and other dosage forms.

[0004] Azithromycin was discovered and developed by Pliva in 1980, and after Pfizer acquired the sales right, it was approved for listing in China in 1996 with the trade name of Zithromax. It is widely used in pediatric clinical application and is the first choice for treating mycoplasma pneumonia in children. The azithromycin dry suspension (Zithromax) produced by Pfizer is prepared by direct physical mixing and dispensing process. The drug in this dosage form is exposed to the outside, which inevitably comes into direct contact with the taste buds in the oral cavity when taken, and strong unpleasant taste remains in the oral cavity after taking.

[0005] At present, azithromycin preparations on the market have various dosage forms such as tablets, dispersible tablets or capsules. Among them, tablets, dispersible tablets and capsules have the risk of swallowing difficulty, suffocation and other risks for patients including children, the elderly, patients with incomplete or degenerative swallowing ability, and people with temporary or long-term swallowing difficulty caused by congenital developmental imperfection, diseases, physical damage, etc. If it is prepared into a dosage form that can be dissolved or dispersed into fine particles in water, such as effervescent tablets, granules, solutions or suspensions, although the swallowing problem can be solved, since azithromycin has a strong bitter taste and the above preparations are difficult to mask the bitter taste, the drug administration compliance of patients, especially children, cannot be improved, and water is needed when taking the medicine, which is not convenient for patients who have difficulty in getting water.

[0006] The searched relevant patent documents are as follows: The document discloses an azithromycin anhydrous swallowing taste-masking granules, which are prepared by mixing coated micro-pellets containing azithromycin and flavoring and smoothing excipients. Although the bitter taste of the drug can be masked, the in-vitro dissolution of the product is significantly slow, and after taking the medicine, the product cannot be quickly released in the gastrointestinal tract, which may not achieve good therapeutic effect.

[0007] The document discloses a preparation method of azithromycin taste-masking microspheres. The invention can obtain microspheres with smaller particle size than ordinary wet granulation or hot melt extrusion granulation by heating and melting azithromycin and excipients, then freezing and spraying, so that the microspheres have good taste-masking effect and can be better swallowed. However, the invention only reduces the particle size of the microspheres to achieve good swallowing, and the taste-masking effect is poor to some extent. Moreover, the invention does not measure the stability and solubility of the drug.

[0008] The document discloses an azithromycin taste-masking micro-particle and a preparation method thereof. The invention first prepares azithromycin drug-containing pellet cores with good flowability, good dispersibility, high roundness, and high mechanical strength by emulsification solvent evaporation method, so that they can maintain their shape during fluidized coating. The azithromycin taste-masking micro-particles obtained by further coating the azithromycin drug-containing pellet cores with a separation layer and a taste-masking layer in a fluidized bed can achieve good taste-masking effect. However, special production equipment is needed in the production process of the product, which increases the complexity of the process.

[0009] In solving the above problems or overcoming the above defects, the present invention has encountered the following difficulties and obstacles: During the preparation of azithromycin anhydrous swallowing granules, the release speed is prone to be too slow or the stability is poor, which may be related to the composition, content and proportion of the components. For example, when the proportion of silicon dioxide is higher than 80%, the friability will be too large; a higher content of microcrystalline cellulose will affect the drug release rate. For some drugs that need to take effect quickly, the slow release rate will affect the therapeutic effect, and the interaction between microcrystalline cellulose and some drugs will affect the chemical stability of the drug and reduce the drug efficacy; in addition, there is a certain interaction between microcrystalline cellulose and colloidal silicon dioxide.

[0010] Therefore, it is of great practical significance to develop an azithromycin anhydrous swallowing granule with simple preparation process, which can significantly improve the medication compliance of patients, such as children, the elderly, people with incomplete or degraded self-swallowing ability, and people with temporary or long-term swallowing difficulties caused by congenital developmental imperfection, diseases, physical damage, etc., has fast release speed, high stability and high safety effect. SUMMARY

[0011] The present application aims to provide: An azithromycin anhydrous swallowing granule and a preparation method thereof, and related technologies, to solve the technical problems or combinations of the prior art, such as poor taste masking effect, slow drug effect, poor stability, and swallowing difficulty.

[0012] Terminology: Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims belongs. Unless otherwise indicated, all patents, patent applications, publications, and data cited are hereby incorporated by reference in their entirety. If there is a plurality of definitions for a term herein, then the definitions in this section prevail.

[0013] It should be understood that the above brief summary and the following detailed description are illustrative and are not restrictive of the subject matter of the present application. In this application, the use of the singular includes the plural unless specifically stated otherwise. It should also be noted that in this application, the use of "or" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "including" as well as other forms such as "include", "includes" and "included" is not limiting.

[0014] Unless specifically defined, the use of each of the terms given herein is used according to the standard in the art. For example, the use of reagents kits can be carried out according to the manufacturer's instructions, or in accordance with well-known ways in the art or the instructions of the present application. In general, the above-mentioned techniques and methods can be carried out according to the descriptions in the multiple summary and more specific literature cited and discussed in this specification, according to the conventional methods well known in the art.

[0015] The term "optional" or "optionally" used herein means that the event or situation described subsequently can occur or can not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation.

[0016] The term "inflammation" as used herein refers to the activation of the immune response in mammals following exposure to a stimulus, such as an infection, irritant, allergen, or cell damage. Inflammation can be considered a type of innate immunity as opposed to adaptive immunity, which is a specific response to a particular pathogen. Inflammation can be considered acute or chronic, the former generally mediated by granulocytes and the latter by mononuclear cells, including monocytes and lymphocytes.

[0017] The term "treatment" as used herein generally refers to obtaining a desired pharmacological and / or physiologic effect. The effect can be prophylactic in terms of preventing or partially preventing a disease, symptom or condition, such as dermatitis, but does not necessarily have to be prophylactic. The effect can also be therapeutic in terms of partially or completely curing a disease, condition, symptom or adverse effect attributed to the disease, condition or symptom. Specifically, the term "treatment" can include any treatment of a relevant condition or disease in a subject, particularly a human, and can include any one or more of: (a) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing the symptoms or condition associated with the disease to reverse.

[0018] The term "prevention" as used herein refers to the act of administering a pharmaceutical agent as an active ingredient to a healthy individual who is not suffering from a disease or is in good health at the time of administration.

[0019] The term "sweetener" as used herein refers to a class of substances that can impart a sweet taste to food, beverage and other products, by stimulating the sweet taste receptors to produce a sweet sensation, widely used in food, medicine, daily chemical and other fields, the core function of which is to replace or partially replace sugar (such as sucrose) to provide sweetness, while adjusting the mouthfeel of the product, reducing calories or meeting the needs of specific groups of people.

[0020] The term "plasticizer" as used herein refers to a substance that can insert between polymer molecular chains, reduce intermolecular forces, and thus enhance the flexibility, plasticity and processability of the material, avoiding material embrittlement. It is commonly used in the fields of plastics (such as adding plasticizers to PVC to make it soft), coatings (to improve the ductility of the coating film), pharmaceutical films (to adjust the brittleness of the film), etc.

[0021] The term "purified water" as used herein refers to water treated by distillation, reverse osmosis, ion exchange and other deep purification processes, with very low content of impurities (such as minerals, microorganisms, organic matter). Due to its high purity, it is widely used in pharmaceuticals (as a diluent for preparations, cleaning water), food processing (high cleanliness production link), laboratory analysis and other scenarios, and needs to meet specific quality standards (such as those specified in the pharmacopoeia).

[0022] The term "mixing" as used herein refers to the process of intermingling two or more different substances (which can be solid, liquid, gas, or a combination of different states) by physical or mechanical means to form a macroscopically uniform or relatively uniform dispersion.

[0023] The term "drying" as used herein refers to the process of reducing the moisture content of a material by means of heating, ventilation, vacuum, etc. The drying method can be selected according to the characteristics of the material, such as hot air drying, freeze drying (to preserve heat-sensitive components), vacuum drying (suitable for materials susceptible to oxidation), etc. The purpose of drying is to extend the shelf life (e.g. for food) or to facilitate material solidification (e.g. for pharmaceutical molding).

[0024] The term "stirring" as used herein refers to the operation of mixing multiple substances uniformly by mechanical or manual agitation, specifically by forming a flow in a container with the aid of external force (such as rotating blades, stirring rods, air flow, etc.) to achieve uniform mixing of solids, liquids, or gases.

[0025] In a first aspect, the present application provides an azithromycin anhydrous swallow granule, which comprises a drug-containing taste-masking granule and a flavoring granule. The drug-containing taste-masking granule comprises a drug-containing pellet core, a separation layer, and a taste-masking layer from inside to outside.

[0026] As a preferred embodiment, the drug-containing pellet core is prepared by a centrifugal pelletization process.

[0027] As a preferred embodiment, the coating weight gain of the separation layer is selected from any value or range between 2-20%; Preferably, the coating weight gain of the separation layer is selected from any value or range between 2-10%; More preferably, the coating weight gain of the separation layer is selected from any value or range between 2-10%, specifically from 2%, 3%, 4%, 5%, 7%, 9%, 10%, or any range between any two of them. Further preferably, the coating weight gain of the separation layer is selected from any value or range between 2-10%, specifically from 2%, 3%, 4%, 5%, 7%, 9%, 10%, or any range between any two of them. Still further preferably, the coating weight gain of the separation layer is selected from any value or range between 2-10%, specifically from 2%, 3%, 10%, or any range between any two of them. Still further preferably, the coating weight gain of the separation layer is 3%.

[0028] As a preferred embodiment, the coating weight gain of the taste-masking layer is selected from any value or range between 1-20%; Preferably, the coating weight of the taste-masking layer is selected from any value or range between 1-10%; More preferably, the coating weight of the taste-masking layer is selected from any value or range between 1-10%, in particular from 1%, 3%, 6%, 8%, 10% or any range between any two of them. Further preferably, the coating weight of the taste-masking layer is selected from any value or range between 1-10%, in particular from 1%, 3%, 6%, 8%, 10% or any range between any two of them. Still further preferably, the coating weight of the taste-masking layer is selected from any value or range between 1-10%, in particular from 1%, 3%, 10% or any range between any two of them. Still further preferably, the coating weight of the taste-masking layer is 3%.

[0029] As a preferred embodiment, the drug-containing pellet core comprises azithromycin and excipients; The excipients are selected from one or more of fillers, pH-adjusting agents, disintegrants, binders and glidants; Preferably, the fillers are selected from one or more of lactose, starch, microcrystalline cellulose and mannitol; More preferably, the fillers are microcrystalline cellulose; Preferably, the pH-adjusting agents are selected from one or more of sodium carbonate, anhydrous trisodium phosphate, sodium hydroxide and magnesium oxide; More preferably, the pH-adjusting agents are anhydrous trisodium phosphate; Preferably, the disintegrants are selected from one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone; More preferably, the disintegrants are low-substituted hydroxypropyl cellulose; Preferably, the binders are selected from one or more of hydroxypropyl cellulose, povidone and hydroxypropyl methyl cellulose; More preferably, the binders are hydroxypropyl methyl cellulose; Preferably, the glidants are selected from one or more of colloidal silicon dioxide, talc and microfine silica gel; More preferably, the glidants are colloidal silicon dioxide.

[0030] As a preferred embodiment, the drug-containing pellet core comprises azithromycin and excipients; azithromycin 100 parts; microcrystalline cellulose 40.0-150.0 parts; anhydrous sodium phosphate tribasic 5.0-15.0 parts; low-substituted hydroxypropyl cellulose 5.0-25.0 parts; hydroxypropyl methyl cellulose 5.0-20.0 parts; and colloidal silicon dioxide 1.0-5.0 parts.

[0031] More preferably, the drug-containing pellet core consists of the following components in parts by weight: azithromycin 100 parts; microcrystalline cellulose 70.0-130.0 parts; anhydrous sodium phosphate tribasic 8.0-12.0 parts; low-substituted hydroxypropyl cellulose 8.0-15.0 parts; hydroxypropyl methyl cellulose 12.0-18.0 parts; and colloidal silicon dioxide 1.0-3.0 parts.

[0032] Preferably, the microcrystalline cellulose is selected from any value or range between 70.0-130.0 parts by weight, and in particular, from 80 parts, 84.0 parts, 85 parts, 90 parts, 95 parts, 97.5 parts, 110.0 parts, 117.5 parts, 120 parts, 125 parts, 130 parts, 133.0 parts, 135 parts, 140 parts, 145 parts, 150.0 parts, or any range between any two of these values. More preferably, the microcrystalline cellulose is selected from any value or range between 40.0-150.0 parts by weight, and in particular, from 84.0 parts, 95 parts, 97.5 parts, 110.0 parts, 117.5 parts, 120 parts, 130 parts, 133.0 parts, 140 parts, 145 parts, 150.0 parts, or any range between any two of these values. Further preferably, the microcrystalline cellulose is selected from any value or range between 40.0-150.0 parts by weight, and in particular, from 84.0 parts, 95 parts, 97.5 parts, 110.0 parts, 117.5 parts, 120 parts, 130 parts, 133.0 parts, 140 parts, 145 parts, 150.0 parts, or any range between any two of these values. Still further preferably, the microcrystalline cellulose is selected from any value or range between 40.0-150.0 parts by weight, and in particular, from 84.0 parts, 97.5 parts, 110.0 parts, 117.5 parts, 133.0 parts, 150.0 parts, or any range between any two of these values. Still further preferably, the microcrystalline cellulose is 110.0 parts by weight.

[0033] Preferably, the anhydrous trisodium phosphate is selected from any value or range between 5.0-15.0 parts by weight, specifically selected from: 5.0 parts, 6.0 parts, 7.0 parts, 8.0 parts, 9.0 parts, 10.0 parts, 11.0 parts, 12.0 parts, 13.0 parts, 14.0 parts, 15.0 parts, or a range between any two thereof; More preferably, the anhydrous trisodium phosphate is selected from any value or range between 5.0-15.0 parts by weight, specifically selected from: 5.0 parts, 8.0 parts, 9.0 parts, 10.0 parts, 11.0 parts, 15.0 parts, or a range between any two thereof; Further preferably, the anhydrous trisodium phosphate is selected from any value or range between 5.0-15.0 parts by weight, specifically selected from: 5.0 parts, 9.0 parts, 10.0 parts, 15.0 parts, or a range between any two thereof; Still further preferably, the anhydrous trisodium phosphate is selected from any value or range between 5.0-15.0 parts by weight, specifically selected from: 5.0 parts, 9.0 parts, 15.0 parts, or a range between any two thereof; Still further preferably, the anhydrous trisodium phosphate is 9.0 parts by weight.

[0034] Preferably, the low-substituted hydroxypropyl cellulose is selected from any value or range between 5.0-25.0 parts by weight, specifically selected from: 5.0 parts, 7.0 parts, 9.0 parts, 11.0 parts, 12.5 parts, 13.0 parts, 15.0 parts, 17.0 parts, 19.0 parts, 21.0 parts, 25.0 parts, or a range between any two thereof; More preferably, the low-substituted hydroxypropyl cellulose is selected from any value or range between 5.0-25.0 parts by weight, specifically selected from: 5.0 parts, 9.0 parts, 11.0 parts, 12.5 parts, 13.0 parts, 15.0 parts, 17.0 parts, 25.0 parts, or a range between any two thereof; Further preferably, the low-substituted hydroxypropyl cellulose is selected from any value or range between 5.0-25.0 parts by weight, specifically selected from: 5.0 parts, 9.0 parts, 11.0 parts, 12.5 parts, 13.0 parts, 25.0 parts, or a range between any two thereof; Still further preferably, the low-substituted hydroxypropyl cellulose is selected from any value or range between 5.0-25.0 parts by weight, specifically selected from: 5.0 parts, 8.0 parts, 9.0 parts, 10.0 parts, 11.0 parts, 15.0 parts, or a range between any two thereof; Still further preferably, the low-substituted hydroxypropyl cellulose is 12.5 parts by weight.

[0035] Preferably, the hydroxypropyl methylcellulose is selected from any value or range between 5.0-20.0 parts by weight, in particular from 5.0 parts, 7.0 parts, 9.0 parts, 11.0 parts, 13.0 parts, 15.0 parts, 17.0 parts, 19.0 parts, 20.0 parts or a range between any two of these values; More preferably, the hydroxypropyl methylcellulose is selected from any value or range between 8.0-18.0 parts by weight, in particular from 5.0 parts, 11.0 parts, 13.0 parts, 15.0 parts, 17.0 parts, 20.0 parts or a range between any two of these values; Further preferably, the hydroxypropyl methylcellulose is selected from any value or range between 5.0-20.0 parts by weight, in particular from 5.0 parts, 13.0 parts, 15.0 parts, 20.0 parts or a range between any two of these values; Still further preferably, the hydroxypropyl methylcellulose is selected from any value or range between 5.0-20.0 parts by weight, in particular from 5.0 parts, 8.0 parts, 9.0 parts, 10.0 parts, 11.0 parts, 15.0 parts or a range between any two of these values; Still further preferably, the hydroxypropyl methylcellulose is 15.0 parts by weight.

[0036] Preferably, the colloidal silicon dioxide is selected from any value or range between 1.0-5.0 parts by weight, in particular from 1.0 parts, 1.5 parts, 2.0 parts, 2.5 parts, 3.0 parts, 3.5 parts, 4.0 parts, 4.5 parts, 5.0 parts or a range between any two of these values; More preferably, the colloidal silicon dioxide is selected from any value or range between 1.0-5.0 parts by weight, in particular from 1.0 parts, 1.5 parts, 2.0 parts, 2.5 parts, 3.0 parts, 4.5 parts or 5.0 parts or a range between any two of these values; Further preferably, the colloidal silicon dioxide is selected from any value or range between 1.0-5.0 parts by weight, in particular from 1.0 parts, 2.5 parts or 5.0 parts or a range between any two of these values; Still further preferably, the colloidal silicon dioxide is 2.5 parts by weight.

[0037] As a preferred embodiment, the release layer comprises an adhesive or / and an anti-adhesive; Preferably, the adhesive is selected from one or several of hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone; More preferably, the adhesive is hydroxypropyl methylcellulose; Preferably, the anti-tacking agent is selected from one or more of talc, titanium dioxide, and magnesium stearate. More preferably, the anti-tacking agent is talc.

[0038] As a preferred embodiment, the release layer consists of, by weight parts, hydroxypropyl methylcellulose 1.0-12.5 parts and talc 1.0-12.5 parts.

[0039] Preferably, the hydroxypropyl methylcellulose is selected from any value or range between 1.0-12.5 parts by weight, specifically selected from 1.0 part, 1.5 parts, 2.0 parts, 2.5 parts, 3.0 parts, 3.7 parts, 4.0 parts, 4.5 parts, 5.0 parts, 5.5 parts, 6.0 parts, 6.5 parts, 7.0 parts, 7.5 parts, 8.0 parts, 8.5 parts, 9.0 parts, 9.5 parts, 10.0 parts, 11.0 parts, 12.0 parts, 12.5 parts, or any range between any two of these values. More preferably, the hydroxypropyl methylcellulose is selected from any value or range between 1.0-12.5 parts by weight, specifically selected from 1.0 part, 2.0 parts, 2.5 parts, 3.0 parts, 3.7 parts, 4.0 parts, 4.5 parts, 5.0 parts, 5.5 parts, 6.0 parts, 6.5 parts, 7.0 parts, 11.0 parts, 12.0 parts, 12.5 parts, or any range between any two of these values. Further preferably, the hydroxypropyl methylcellulose is selected from any value or range between 1.0-12.5 parts by weight, specifically selected from 2.5 parts, 3.7 parts, 12.5 parts, or any range between any two of these values. Still further preferably, the hydroxypropyl methylcellulose is 3.7 parts by weight.

[0040] Preferably, the talc is selected from any value or range between 1.0-12.5 parts by weight, specifically selected from 1.0 part, 2.0 parts, 2.5 parts, 3.0 parts, 3.7 parts, 4.0 parts, 4.5 parts, 5.0 parts, 5.5 parts, 6.0 parts, 6.5 parts, 7.0 parts, 7.5 parts, 8.0 parts, 8.5 parts, 9.0 parts, 9.5 parts, 10.0 parts, 10.5 parts, 11.0 parts, 12.0 parts, 12.5 parts, or any range between any two of these values. More preferably, the talc is selected from any value or range between 1.0-12.5 parts by weight, specifically selected from 1.0 part, 2.0 parts, 2.5 parts, 3.0 parts, 3.7 parts, 4.0 parts, 4.5 parts, 5.0 parts, 5.5 parts, 6.0 parts, 6.5 parts, 7.0 parts, 11.0 parts, 12.0 parts, 12.5 parts, or any range between any two of these values. Further preferably, the talc is selected from any value or range between 1.0 and 12.5 parts by weight, in particular from 2.5 parts, 3.7 parts, 12.5 parts or a range between any two of these values. Still further preferably, the talc is 3.7 parts by weight.

[0041] As a preferred embodiment, the taste masking layer comprises one or more of a plasticizer, an anti-tacking agent and an acrylic resin polymer. Preferably, the plasticizer is selected from one or more of polyethylene glycol, triethyl citrate and diethyl phthalate. Still preferably, the plasticizer is polyethylene glycol. Preferably, the anti-tacking agent is selected from one or more of talc, titanium dioxide and magnesium stearate. Still preferably, the anti-tacking agent is talc. Preferably, the acrylic resin polymer is selected from one or more of Eudragit E100, Eudragit EPO, Eudragit L30D and Eudragit L30D-55. Still preferably, the acrylic resin polymer is Eudragit E100.

[0042] Preferably, the taste masking layer consists of 0.4 to 5.0 parts by weight of polyethylene glycol, 0.4 to 5.0 parts by weight of talc and 1.8 to 20.0 parts by weight of Eudragit E100.

[0043] Preferably, the polyethylene glycol is selected from any value or range between 0.4 and 5.0 parts by weight, in particular from 0.4 parts, 0.5 parts, 1.1 parts, 1.3 parts, 2.0 parts, 2.3 parts, 2.6 parts, 3.3 parts, 3.6 parts, 4.0 parts, 4.4 parts, 5.0 parts or a range between any two of these values. Still preferably, the polyethylene glycol is selected from any value or range between 0.4 and 5.0 parts by weight, in particular from 0.4 parts, 0.5 parts, 1.1 parts, 1.3 parts, 2.0 parts, 2.3 parts, 2.6 parts, 3.3 parts, 3.6 parts, 4.0 parts, 4.4 parts, 5.0 parts or a range between any two of these values. Further preferably, the polyethylene glycol is selected from any value or range between 0.4 and 5.0 parts by weight, in particular from 0.4 parts, 0.5 parts, 1.1 parts, 1.3 parts, 3.3 parts, 3.6 parts, 4.0 parts, 4.4 parts, 5.0 parts or a range between any two of these values. Still further preferably, the polyethylene glycol is selected from any value or range between 0.4 and 5.0 parts by weight, specifically selected from 0.4 parts, 1.1 parts, 3.6 parts, or a range between any two of these. Still further preferably, the polyethylene glycol is 1.1 parts by weight.

[0044] Preferably, the talc is selected from any value or range between 0.4 and 5.0 parts by weight, specifically selected from 0.4 parts, 0.5 parts, 0.6 parts, 0.8 parts, 1.0 parts, 1.2 parts, 1.4 parts, 1.8 parts, 2.4 parts, 2.8 parts, 3.2 parts, 3.5 parts, 3.7 parts, 4.0 parts, 4.5 parts, 5.0 parts, or a range between any two of these. Still preferably, the talc is selected from any value or range between 0.4 and 5.0 parts by weight, specifically selected from 0.4 parts, 0.5 parts, 0.6 parts, 1.0 parts, 1.2 parts, 1.4 parts, 1.8 parts, 2.4 parts, 2.8 parts, 3.2 parts, 3.5 parts, 3.7 parts, 4.0 parts, or a range between any two of these. Further preferably, the talc is selected from any value or range between 0.4 and 5.0 parts by weight, specifically selected from 0.4 parts, 0.5 parts, 1.0 parts, 1.2 parts, 1.4 parts, 3.5 parts, 3.7 parts, 4.0 parts, or a range between any two of these. Still further preferably, the talc is selected from any value or range between 0.4 and 5.0 parts by weight, specifically selected from 0.4 parts, 1.2 parts, 3.7 parts, or a range between any two of these. Still further preferably, the talc is 1.2 parts by weight.

[0045] Preferably, the uterine E100 is selected from any value or range between 1.8 and 20.0 parts by weight, specifically selected from 1.8 parts, 2.0 parts, 2.3 parts, 2.5 parts, 3.0 parts, 3.5 parts, 4.0 parts, 4.5 parts, 5.0 parts, 5.5 parts, 6.0 parts, 7.0 parts, 8.0 parts, 9.0 parts, 10.0 parts, 11.0 parts, 12.0 parts, 13.0 parts, 14.0 parts, 15.0 parts, 15.5 parts, 16.0 parts, 16.5 parts, 17.0 parts, 17.5 parts, 18.0 parts, 18.3 parts, 18.7 parts, 19.0 parts, 20.0 parts, or a range between any two of these. More preferably, the Uutect E100 is selected from any value or range between 1.8 and 20.0 parts by weight, in particular from 1.8 parts, 2.0 parts, 2.5 parts, 4.5 parts, 5.0 parts, 5.5 parts, 6.0 parts, 7.0 parts, 8.0 parts, 9.0 parts, 10.0 parts, 11.0 parts, 12.0 parts, 13.0 parts, 14.0 parts, 16.0 parts, 16.5 parts, 17.0 parts, 17.5 parts, 18.0 parts, 18.3 parts, 18.7 parts or any range between any two of them. Further preferably, the Uutect E100 is selected from any value or range between 1.8 and 20.0 parts by weight, in particular from 1.8 parts, 2.0 parts, 5.0 parts, 5.5 parts, 6.0 parts, 18.0 parts, 18.3 parts, 18.7 parts or any range between any two of them. Still further preferably, the Uutect E100 is selected from any value or range between 1.8 and 20.0 parts by weight, in particular from 1.8 parts, 5.5 parts, 18.3 parts or any range between any two of them. Still further preferably, the Uutect E100 is 5.5 parts by weight.

[0046] As a preferred embodiment, the flavouring particles comprise one or more of a flavouring agent, a sweetener and a flavouring essence. Preferably, the flavouring agent is selected from one or more of sorbitol, mannitol and maltodextrin. More preferably, the flavouring agent is sorbitol. Preferably, the sweetener is selected from one or more of aspartame, sucralose and acesulfame potassium. More preferably, the sweetener is sucralose. Preferably, the flavouring essence is selected from one or more of a strawberry flavouring essence, a banana flavouring essence, a sweet orange flavouring essence and a mixed fruit flavouring essence. More preferably, the flavouring essence is a strawberry flavouring essence.

[0047] As a preferred embodiment, the flavouring particles consist of 150.0 to 400.0 parts by weight of sorbitol, 0.5 to 5.0 parts by weight of sucralose and 0.5 to 5.0 parts by weight of a strawberry flavouring essence.

[0048] Preferably, the sorbitol is selected from any value or range between 150.0 and 400.0 parts by weight, specifically selected from the group consisting of: 150.0 parts, 200.0 parts, 230.0 parts, 250.0 parts, 260.0 parts, 265.0 parts, 275.5 parts, 277.2 parts, 287.0 parts, 297.5 parts, 345.0 parts, 350.0 parts, 360.0 parts, 370.0 parts, 380.5 parts, 385 parts, 390.5 parts, 400.0 parts, or a range between any two of these values. More preferably, the sorbitol is selected from any value or range between 150.0 and 400.0 parts by weight, specifically selected from the group consisting of: 150.0 parts, 200.0 parts, 275.5 parts, 277.2 parts, 287.0 parts, 297.5 parts, 345.0 parts, 350.0 parts, 360.0 parts, 385 parts, 390.5 parts, 400.0 parts, or a range between any two of these values. Further preferably, the sorbitol is selected from any value or range between 150.0 and 400.0 parts by weight, specifically selected from the group consisting of: 150.0 parts, 275.5 parts, 277.2 parts, 287.0 parts, 297.5 parts, 345.0 parts, 350.0 parts, 400.0 parts, or a range between any two of these values. Still further preferably, the sorbitol is selected from any value or range between 150.0 and 400.0 parts by weight, specifically selected from the group consisting of: 150.0 parts, 277.2 parts, 400.0 parts, or a range between any two of these values. Still further preferably, the sorbitol is 277.2 parts by weight.

[0049] Preferably, the sucralose is selected from any value or range between 0.5 and 5.0 parts by weight, specifically selected from the group consisting of: 0.5 parts, 1.0 parts, 1.4 parts, 2.0 parts, 2.5 parts, 3.0 parts, 3.5 parts, 4.0 parts, 4.5 parts, 5.0 parts, or a range between any two of these values. More preferably, the sucralose is selected from any value or range between 0.5 and 5.0 parts by weight, specifically selected from the group consisting of: 0.5 parts, 1.0 parts, 1.4 parts, 2.0 parts, 2.5 parts, 4.5 parts, 5.0 parts, or a range between any two of these values. Further preferably, the sucralose is selected from any value or range between 0.5 and 5.0 parts by weight, specifically selected from the group consisting of: 0.5 parts, 1.0 parts, 1.4 parts, 4.5 parts, 5.0 parts, or a range between any two of these values. Further preferably, the sucralose is selected from any value or range between 0.5-5.0 parts by weight, in particular from 0.5 parts, 1.4 parts, 5.0 parts or a range between any two of them. More preferably, the sucralose is 1.4 parts by weight.

[0050] Preferably, the strawberry flavor is selected from any value or range between 0.5-5.0 parts by weight, in particular from 0.5 parts, 1.0 parts, 1.4 parts, 2.0 parts, 2.5 parts, 3.0 parts, 3.5 parts, 4.0 parts, 4.5 parts, 5.0 parts or a range between any two of them. More preferably, the strawberry flavor is selected from any value or range between 0.5-5.0 parts by weight, in particular from 0.5 parts, 1.0 parts, 1.4 parts, 2.0 parts, 2.5 parts, 4.5 parts, 5.0 parts or a range between any two of them. Further preferably, the strawberry flavor is selected from any value or range between 0.5-5.0 parts by weight, in particular from 0.5 parts, 1.0 parts, 1.4 parts, 4.5 parts, 5.0 parts or a range between any two of them. Further more preferably, the strawberry flavor is selected from any value or range between 0.5-5.0 parts by weight, in particular from 0.5 parts, 1.4 parts, 5.0 parts or a range between any two of them. More preferably, the strawberry flavor is 1.4 parts by weight.

[0051] As a preferred embodiment, the azithromycin anhydrous oral granules are composed of the following components by weight: The drug-containing pellet core: azithromycin 100 parts; microcrystalline cellulose 110.0 parts; anhydrous trisodium phosphate 9.0 parts; low-substituted hydroxypropyl cellulose 12.5 parts; hydroxypropyl methyl cellulose 15.0 parts; and colloidal silicon dioxide 2.5 parts; The isolation layer: hydroxypropyl methyl cellulose 3.7 parts and talc 3.7 parts; The taste-masking layer: polyethylene glycol 1.1 parts; talc 1.2 parts and Eudragit E100 5.5 parts; The flavored granules: sorbitol 277.2 parts; sucralose 1.4 parts and strawberry flavor 1.4 parts.

[0052] In a second aspect, the present application provides a preparation method of azithromycin anhydrous oral granules, i.e. centrifugal granulation of the drug-containing pellet core, fluidized bed coating of the isolation layer and the taste-masking layer to obtain drug-containing taste-masking granules; and mixing the obtained drug-containing taste-masking granules with the flavored granules.

[0053] Specifically comprising the following steps: (1) Preparation of drug-containing pellets: 1.1 Dissolve 1%-5% of the binder in water to obtain solution A, ready for use; 1.2 Mix aridomycin, filler, pH regulator, disintegrant, glidant and the remaining binder through a 20-mesh sieve to obtain a premix powder; 1.3 Take solution A and the premix powder to perform centrifugal granulation, dry and sieve to obtain the drug-containing pellets; (2) Preparation of isolated pellets: 2.1 Dissolve the binder in water, and after complete dissolution, add the anti-adhesion agent and disperse uniformly to obtain solution B; 2.2 Place the drug-containing pellets in a fluidized bed and use solution B to perform isolated coating in the form of bottom-spraying coating of the fluidized bed, and dry to obtain the isolated pellets; (3) Preparation of drug-containing taste-masked granules: 3.1 Dissolve the acrylic resin polymer in ethanol, and after complete dissolution, add the plasticizer and anti-adhesion agent and disperse uniformly to obtain solution C; 3.2 Place the isolated pellets in a fluidized bed and use solution C to perform taste-masking coating in the form of bottom-spraying coating of the fluidized bed, and dry to obtain the drug-containing taste-masked granules; (4) Preparation of flavored granules: Mix the flavoring agent, sweetening agent and essence to obtain the flavored granules; (5) Mix the prepared drug-containing taste-masked granules with the flavoring materials to obtain the azithromycin anhydrous swallowing granules.

[0054] As a preferred embodiment, the water in steps 1.1 and 2.1 is purified water.

[0055] As a preferred embodiment, the specific operation of step 1.2 is as follows: pass aridomycin, microcrystalline cellulose, hydroxypropyl methyl cellulose, anhydrous trisodium phosphate, colloidal silicon dioxide and low-substituted hydroxypropyl cellulose through a 20-mesh sieve, add the sieved materials into a mixing hopper, set the mixing rotation speed to 10 revolutions per minute and mix for 10 minutes to obtain the premix powder.

[0056] As a preferred embodiment, the specific operation of step 1.3 is as follows: add 1 / 3 of the premix powder into the bottom plate of the centrifugal pelletizer, add the remaining premix powder into the feeder, spray solution A and the premix powder to perform centrifugal granulation, add the prepared drug-containing pellet cores into the fluidized bed to perform drying, set the inlet air temperature to 60°C during the drying process, sieve the dried drug-containing pellet cores with a stainless steel sieve, remove the large particles at 30 mesh and remove the fine powder at 80 mesh to obtain the drug-containing pellets.

[0057] As a preferred embodiment, the material temperature of the isolating coating process in step 2.2 is 35-60℃. Preferably, the material temperature of the isolating coating process is 40-50℃.

[0058] As a preferred embodiment, the specific operation of step 2.2 is as follows: the drug-containing pellets are added to the fluidized bed, the isolating coating process is performed by using the bottom-spraying coating method of the fluidized bed, the sprayed liquid is solution B, the material temperature is controlled to be 35-60℃ during the coating process, preferably, the material temperature is controlled to be 40-50℃, and after the isolating coating is completed, the pellets are dried for 10 minutes.

[0059] As a preferred embodiment, the degree of the ethanol in step 3.1 is 95°.

[0060] As a preferred embodiment, the material temperature of the taste-masking coating process in step 3.2 is 20-40℃. Preferably, the material temperature of the taste-masking coating process is 20-30℃.

[0061] As a preferred embodiment, the specific operation of step 3.2 is as follows: the isolating pellets are added to the fluidized bed, the taste-masking coating process is performed by using the bottom-spraying coating method of the fluidized bed, the sprayed liquid is solution C, the material temperature is controlled to be 20-40℃ during the coating process, preferably, the material temperature is controlled to be 20-30℃, and after the taste-masking coating is completed, the pellets are dried for 10 minutes.

[0062] In a third aspect, the present application provides the use of the azithromycin anhydrous swallowing granules in the preparation of a medicine for preventing bacterial infection or treating mycoplasma pneumoniae pneumonia, reducing inflammation caused by bacterial infection, and improving the medication compliance of patients, including children, the elderly, patients with incomplete or degraded self-swallowing ability, and people with temporary or long-term swallowing difficulties caused by congenital developmental imperfection, diseases, physical damage, etc.

[0063] Based on further solving or simultaneously solving multiple technical problems of the technical problem of the present application, in the technical solution provided in the first aspect of the present application, the preferred scheme includes: The first preferred scheme: an azithromycin anhydrous swallowing granule adopts a specific auxiliary material type matching and ratio and a specific coating weight, which further solves the technical problem of "slow drug effect and poor safety" on the basis of solving the technical problems of "inconvenient medication, swallowing difficulty, and poor taste-masking effect".

[0064] The second priority scheme is a preparation method of azithromycin anhydrous swallowing granules, which adopts a specific preparation process of centrifugal granulation. On the basis of solving the technical problems of slow drug effect and poor safety, the technical problem of poor drug stability is further solved.

[0065] Embodiments 1-9 in the present application support the protection scope of claims 1-2 at least.

[0066] For claims 1-2: The technical feature "the drug-containing pellet core of azithromycin anhydrous swallowing granules is prepared by centrifugal pelletizing process" is summarized by the aforementioned explanation and / or the corresponding technical feature "the drug-containing pellet core of azithromycin anhydrous swallowing granules is prepared by centrifugal pelletizing process" in embodiments 1-9 through the common feature "the preparation process of the drug-containing pellet core of azithromycin anhydrous swallowing granules". Therefore, the skilled in the art can reasonably infer that the technical feature "the drug-containing pellet core of azithromycin anhydrous swallowing granules is prepared by centrifugal pelletizing process", the drug-containing pellet core of azithromycin anhydrous swallowing granules prepared by centrifugal pelletizing process, its subordinate concept and its basically equivalent technical means, and the technical means of replacing "the drug-containing pellet core of azithromycin anhydrous swallowing granules is prepared by centrifugal pelletizing process" based on the existing technical level within the conventional technical means and common knowledge, all should belong to the protection scope of claims 1-2, for example, under the condition that other technical features remain unchanged, replacing "the drug-containing pellet core of azithromycin anhydrous swallowing granules is prepared by centrifugal pelletizing process" with "the drug-containing pellet core of azithromycin anhydrous swallowing granules is prepared by centrifugal granulation process" and the like, which still belongs to the protection scope of claims 1-2 of the present application.

[0067] The technical feature "the coating weight of the composition of the azithromycin anhydrous swallowing granules and the isolation layer thereof is 2-20%" is generalized from the corresponding technical features "the coating weight of the isolation layer of the azithromycin anhydrous swallowing granules is 2%, 3%, 10%" and the like in the foregoing explanations and / or examples 1-5 by the common feature "the coating weight of the composition of the azithromycin anhydrous swallowing granules and the isolation layer thereof". Therefore, the skilled in the art can reasonably infer that the technical feature "the coating weight of the composition of the azithromycin anhydrous swallowing granules and the isolation layer thereof is 2-20%", the lower concept thereof and the basically equivalent technical means, and the technical means of replacing "the coating weight of the composition of the azithromycin anhydrous swallowing granules and the isolation layer thereof is 2-20%" within the conventional technical means and the common general knowledge based on the existing technical level shall all belong to the protection scope of claims 1-2, for example, replacing "the coating weight of the composition of the azithromycin anhydrous swallowing granules and the isolation layer thereof is 2-20%" with "the coating weight of the composition of the azithromycin anhydrous swallowing granules and the isolation layer thereof is 9%, 15%" and the like under the condition that other technical features remain unchanged, which still belongs to the protection scope of claims 1-2 of the present application.

[0068] The technical feature "the coating weight of the composition of the azithromycin anhydrous swallowing granules and the taste masking layer thereof is 1-20%" is generalized from the corresponding technical features "the coating weight of the taste masking layer of the azithromycin anhydrous swallowing granules is 1%, 3%, 10%" and the like in the foregoing explanations and / or examples 1-5 by the common feature "the coating weight of the composition of the azithromycin anhydrous swallowing granules and the taste masking layer thereof". Therefore, the skilled in the art can reasonably infer that the technical feature "the coating weight of the composition of the azithromycin anhydrous swallowing granules and the taste masking layer thereof is 1-20%", the lower concept thereof and the basically equivalent technical means, and the technical means of replacing "the coating weight of the composition of the azithromycin anhydrous swallowing granules and the taste masking layer thereof is 1-20%" within the conventional technical means and the common general knowledge based on the existing technical level shall all belong to the protection scope of claims 1-2, for example, replacing the coating weight of the composition of the azithromycin anhydrous swallowing granules and the taste masking layer thereof is 1-20% with the coating weight of the composition of the azithromycin anhydrous swallowing granules and the isolation layer thereof is 9%, 15% and the like, which still belongs to the protection scope of claims 1-2 of the present application.

[0069] The examples 1-9 in the present application support at least the protection scope of claim 12.

[0070] For the claim 12: The technical feature "azithromycin 100.0 parts, microcrystalline cellulose 40.0-150.0 parts, anhydrous sodium phosphate tribasic 5.0-15.0 parts, low-substituted hydroxypropyl cellulose 5.0-25.0 parts, hydroxypropyl methyl cellulose 5.0-20.0 parts, and colloidal silicon dioxide 1.0-5.0 parts" is generalized from the aforementioned explanations and / or the corresponding technical features "azithromycin 100.0 parts, microcrystalline cellulose 110.0 parts, anhydrous sodium phosphate tribasic 9.0 parts, low-substituted hydroxypropyl cellulose 12.5 parts, hydroxypropyl methyl cellulose 15.0 parts, and colloidal silicon dioxide 2.5 parts", "azithromycin 100.0 parts, microcrystalline cellulose 117.5 parts, anhydrous sodium phosphate tribasic 9.0 parts, low-substituted hydroxypropyl cellulose 5.0 parts, hydroxypropyl methyl cellulose 15.0 parts, and colloidal silicon dioxide 2.5 parts", "azithromycin 100.0 parts, microcrystalline cellulose 97.5 parts, anhydrous sodium phosphate tribasic 9.0 parts, low-substituted hydroxypropyl cellulose 25.0 parts, hydroxypropyl methyl cellulose 15.0 parts, and colloidal silicon dioxide 2.5 parts", "azithromycin 100 parts, microcrystalline cellulose 133.0 parts, anhydrous sodium phosphate tribasic 5.0 parts, low-substituted hydroxypropyl cellulose 5.0 parts, hydroxypropyl methyl cellulose 5.0 parts, and colloidal silicon dioxide 2.5 parts", "azithromycin 100 parts, microcrystalline cellulose 84.0 parts, anhydrous sodium phosphate tribasic 15.0 parts, low-substituted hydroxypropyl cellulose 25.0 parts, hydroxypropyl methyl cellulose 20.0 parts, and colloidal silicon dioxide 5.0 parts" in Examples 1-9 by the common feature "azithromycin anhydrous oral granules consisting of a drug-containing pellet core and the weight parts thereof".Therefore, the skilled in the art can reasonably deduce that the technical features "azithromycin 100.0 parts, microcrystalline cellulose 40.0-150.0 parts, anhydrous trisodium phosphate 5.0-15.0 parts, low-substituted hydroxypropyl cellulose 5.0-25.0 parts, hydroxypropyl methyl cellulose 5.0-20.0 parts and colloidal silicon dioxide 1.0-5.0 parts", its subordinate concept and its substantially equivalent technical means, the technical means of replacing "azithromycin 100.0 parts, microcrystalline cellulose 40.0-150.0 parts, anhydrous trisodium phosphate 5.0-15.0 parts, low-substituted hydroxypropyl cellulose 5.0-25.0 parts, hydroxypropyl methyl cellulose 5.0-20.0 parts and colloidal silicon dioxide 1.0-5.0 parts" within the conventional technical means and the common general knowledge based on the prior art level, should all belong to the protection scope of claim 12, for example, under the condition that other technical features remain unchanged, replacing azithromycin 100.0 parts, microcrystalline cellulose 40.0-150.0 parts, anhydrous trisodium phosphate 5.0-15.0 parts, low-substituted hydroxypropyl cellulose 5.0-25.0 parts, hydroxypropyl methyl cellulose 5.0-20.0 parts and colloidal silicon dioxide 1.0-5.0 parts with "azithromycin 100.0 parts, microcrystalline cellulose 45.0 parts, anhydrous trisodium phosphate 6.5 parts, low-substituted hydroxypropyl cellulose 24 parts, hydroxypropyl methyl cellulose 14 parts and colloidal silicon dioxide 4 parts", "azithromycin 100.0 parts, microcrystalline cellulose 65 parts, anhydrous trisodium phosphate 10.5 parts, low-substituted hydroxypropyl cellulose 16 parts, hydroxypropyl methyl cellulose 18 parts and colloidal silicon dioxide 4.4 parts" and the like, still belongs to the protection scope of claim 12 of the present application.

[0071] The technical features "hydroxypropyl methyl cellulose 1.0-12.5 parts and talc 1.0-12.5 parts" are generalized from the aforementioned explanations and / or the corresponding technical features "hydroxypropyl methyl cellulose 3.7 parts and talc 3.7 parts", "hydroxypropyl methyl cellulose 2.5 parts and talc 2.5 parts", "hydroxypropyl methyl cellulose 12.5 parts and talc 12.5 parts" and the like in embodiments 1-9 by the common feature "the composition of azithromycin anhydrous oral granules with a barrier layer and the parts by weight thereof". Therefore, the skilled in the art can reasonably deduce that the technical features "hydroxypropyl methyl cellulose 1.0-12.5 parts and talc 1.0-12.5 parts", its subordinate concept and its substantially equivalent technical means, the technical means of replacing "hydroxypropyl methyl cellulose 1.0-12.5 parts and talc 1.0-12.5 parts" within the conventional technical means and the common general knowledge based on the prior art level, should all belong to the protection scope of claim 12, for example, under the condition that other technical features remain unchanged, replacing hydroxypropyl methyl cellulose 1.0-12.5 parts and talc 1.0-12.5 parts with "hydroxypropyl methyl cellulose 1.0 parts and talc 1.0 parts" "hydroxypropyl methyl cellulose 9.0 parts and talc 10.0 parts" and the like, still belongs to the protection scope of claim 12 of the present application.

[0072] The technical feature "0.4-5.0 parts of polyethylene glycol; 0.4-5.0 parts of talcum powder; and 1.8-20.0 parts of Eudragit E100" is generalized from the aforementioned technical features "1.1 parts of polyethylene glycol; 1.2 parts of talcum powder; and 5.5 parts of Eudragit E100", "0.4 parts of polyethylene glycol; 0.4 parts of talcum powder; and 1.8 parts of Eudragit E100", "3.6 parts of polyethylene glycol; 3.7 parts of talcum powder; and 18.3 parts of Eudragit E100", etc. in the embodiments 1-9 by the common feature "composition of the taste-masking layer of the azithromycin anhydrous swallowing granules and the parts by weight thereof". Therefore, according to the reasonable presumption of the person skilled in the art, the technical feature "0.4-5.0 parts of polyethylene glycol; 0.4-5.0 parts of talcum powder; and 1.8-20.0 parts of Eudragit E100", the lower concept thereof, and the technical means substantially equivalent thereto, and the technical means of "0.4-5.0 parts of polyethylene glycol; 0.4-5.0 parts of talcum powder; and 1.8-20.0 parts of Eudragit E100" that can be replaced based on the prior art level within the conventional technical means and common general knowledge, should all belong to the protection scope of claim 12, for example, under the condition that other technical features remain unchanged, replacing "0.4-5.0 parts of polyethylene glycol; 0.4-5.0 parts of talcum powder; and 1.8-20.0 parts of Eudragit E100" with "3.5 parts of polyethylene glycol; 4.5 parts of talcum powder; and 16.5 parts of Eudragit E100", "4.0 parts of polyethylene glycol; 4.0 parts of talcum powder; and 19 parts of Eudragit E100", "4.5 parts of polyethylene glycol; 4.5 parts of talcum powder; and 20 parts of Eudragit E100", etc., still belongs to the protection scope of claim 12 of the present application.

[0073] The beneficial effects of the present application are: Compared with the prior art, the present application has the following beneficial effects: (1) The azithromycin anhydrous swallowing granules provided by the present application are prepared by the centrifugal pelletization process to prepare a drug-containing pellet core, and are coated with a specific isolation layer and a taste-masking layer in sequence, and the taste of the sample is adjusted and matched by a flavoring granule composition, thereby realizing the technical feature of anhydrous swallowing and improving the medication compliance of patients, especially children.

[0074] (2) The azithromycin anhydrous swallowing granules provided by the present application have a fast release speed and high stability, which ensures the fastest and safest exertion of the azithromycin efficacy. The present application fills the domestic blank, provides a better formulation selection for the takers, increases the range of applicable population, changes the traditional dosage form, and makes the carrying and taking of the patients more convenient.

[0075] In addition, based on the case of the present application: 1. Based on the comparison of Examples 1-9 and Comparative Example 1, the present application solves the release rate and safety problems of azithromycin anhydrous swallowing granules by selecting specific auxiliary material types, combinations and ratios, and specific coating weight combinations from a wide range of different types of pharmaceutical excipients and their components disclosed in the prior art, achieving unexpected technical effects.

[0076] 2. Based on the comparison of Examples 1-9 and Comparative Example 2, the present application uses technical means such as centrifugal pelletization process, specific auxiliary material types, combinations and ratios, and specific coating weight combinations to achieve the technical characteristics of anhydrous swallowing, which can significantly improve the medication compliance of patients, including children, the elderly, patients with incomplete or degenerative swallowing ability, and people with temporary or long-term swallowing difficulties due to congenital developmental imperfections, diseases, physical damage, etc. BRIEF DESCRIPTION OF DRAWINGS

[0077] Figure 1 Dissolution curve of azithromycin anhydrous swallowing granules prepared in Examples 1-9 and the control preparation (Zithromax).

[0078] Figure 2 Dissolution curve of azithromycin anhydrous swallowing granules prepared in Examples 1, Comparative Examples 1-2 and the control preparation (Zithromax). DETAILED DESCRIPTION

[0079] The following non-limiting examples can provide a more comprehensive understanding of the present application to those of ordinary skill in the art, but in no way limit the present application. The following content is only an exemplary description of the scope of the present application, and those skilled in the art can make various changes and modifications to the present application based on the disclosed content, which should also be within the scope of the present application.

[0080] The present application will be further described in the following specific examples. The various instruments, devices, equipment, reagents, products, etc. used in the examples of the present application are obtained through conventional commercial channels unless otherwise specified.

[0081] In order to better understand and illustrate the present application, the following exemplary description is given for the azithromycin anhydrous swallowing granules provided by the present application, but it should not be understood as limiting the content of the invention.

[0082] The purchase manufacturers and models of the raw materials used in the following examples are shown in Table 1 below.

[0083] Table 1

[0084] Examples 1-5: Azithromycin anhydrous swallowing granules and methods for preparing the same The prescription is shown in Table 2: Table 2 Prescription of azithromycin anhydrous oral granules

[0085] Preparation method: The drug-containing pellet cores are prepared by centrifugal granulation, the isolation layer and the taste-masking layer are prepared by fluidized bed coating, and finally the obtained taste-masking granules are mixed with the flavoring materials. The specific steps include the following: (1) Preparation of drug-containing pellets: 1.1 Dissolve 5% hydroxypropyl methylcellulose E5 in purified water. After the hydroxypropyl methylcellulose E5 is completely dissolved, a solution A is obtained for standby use; 1.2 Screen azithromycin, microcrystalline cellulose, anhydrous trisodium phosphate, colloidal silicon dioxide, low-substituted hydroxypropyl cellulose, and the remaining hydroxypropyl methylcellulose E5 through a 20-mesh sieve. The sieved materials are added to a mixing hopper, and the mixing speed is set to 10 revolutions per minute for 10 minutes; 1.3 Add about 1 / 3 of the premixed powder to the bottom plate of the centrifugal pelletizer, and add the remaining about 2 / 3 of the premixed powder to the feeder. Start spraying solution A and scattering powder, and perform centrifugal pelletization. During the centrifugal granulation process, the prepared drug-containing pellet cores are added to the fluidized bed for drying. The inlet air temperature is set to 60°C during the drying process. The dried drug-containing pellet cores are sieved with a stainless steel sieve. The large particles are removed through a 30-mesh sieve, and the fine powder is removed through an 80-mesh sieve.

[0086] (2) Preparation of isolation pellets: 2.1 Dissolve hydroxypropyl methylcellulose E5 in purified water. After the hydroxypropyl methylcellulose E5 is completely dissolved, add talc, an anti-adhesion agent, under stirring to disperse evenly, and a solution B is obtained.

[0087] 2.2 Add the drug-containing pellets to the fluidized bed. Perform the isolation coating process by bottom spraying of the solution B. The material temperature is controlled at 45±5°C during the coating process. After the isolation coating is completed, continue to dry the pellets for not less than 10 minutes.

[0088] (3) Preparation of drug-containing taste-masking granules: 3.1 Dissolve Eudragit E100 in 95% ethanol. After the Eudragit E100 is completely dissolved, add polyethylene glycol and talc under stirring to disperse evenly, and a solution C is obtained.

[0089] 3.2 Add the isolation pellets to the fluidized bed. Perform the taste-masking coating process by bottom spraying of the solution C. The material temperature is controlled at 25±5°C during the coating process. After the taste-masking coating is completed, continue to dry the pellets for not less than 10 minutes.

[0090] (4) Preparation of flavoring granules: Mixing the flavoring agent, sweetening agent and essence, the flavored granules are obtained. (5) Mixing the prepared drug-containing taste-masked granules with the flavored granules, the azithromycin anhydrous swallowing granules are obtained.

[0091] Example 6-7: Azithromycin anhydrous swallowing granules and a preparation method thereof The prescription is shown in Table 3: Table 3 Prescription of azithromycin anhydrous swallowing granules

[0092] The preparation method is the same as that of Example 1.

[0093] Example 8-9: Azithromycin anhydrous swallowing granules and a preparation method thereof The prescription is shown in Table 4: Table 4 Prescription of azithromycin anhydrous swallowing granules

[0094] The preparation method is the same as that of Examples 1-3.

[0095] Comparative Example 1 The prescription and the preparation method are different from those of Example 1: The prescription is shown in Table 5: Table 5 Prescription of azithromycin anhydrous swallowing granules

[0096] (1) Preparation of drug-containing pellet cores: 1.1 Dissolve hydroxypropyl methyl cellulose E5 and low-substituted hydroxypropyl cellulose in purified water, and after complete dissolution, add azithromycin under stirring to uniformly disperse the azithromycin.

[0097] 2.2 Add sucrose pellet cores to the fluidized bed, and perform the medicine feeding process of the suspension in the form of bottom-spraying coating. The material temperature is controlled at 35-60°C during the medicine feeding process, and after the medicine feeding process, the pellets are continuously dried for not less than 10 minutes.

[0098] The other steps are the same as those of Example 1.

[0099] Comparative Example 2 The preparation method is different from that of Example 1: (1) Preparation of drug-containing pellet cores: 1.2 Add azithromycin, microcrystalline cellulose, hydroxypropyl methyl cellulose, anhydrous trisodium phosphate, colloidal silicon dioxide and low-substituted hydroxypropyl cellulose to the wet granulator, start the wet granulation, and add hydroxypropyl methyl cellulose E5 adhesive solution during the granulation process to obtain wet soft material; 1.3 The wet soft material is added to the extruder and extruded with a screen size of 0.8 mm. The extruded strip material is added to a roller compactor and set to a rotation speed of 1200 rpm for 30 s to obtain wet granules; 1.4 The prepared wet granules are added to a fluidized bed for drying. The inlet air temperature is set to 60°C during the drying process. The dried pellet cores are sieved with a stainless steel screen. The large particles are removed at 20 mesh and the fine powder is removed at 80 mesh.

[0100] The prescription and other steps are the same as in Example 1.

[0101] Effect Example 1: Preparation effect evaluation: dissolution, taste, and waterless swallowing effect 1. Experimental method 1.1 Dissolution: determined according to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part Four General Rules 0931 Second Method). 900 ml of pH 6.0 phosphate buffer is used as the dissolution medium, the rotation speed is 50 revolutions per minute, and the operation is carried out according to the law. Sample at 5, 10, 15, 20, and 30 minutes. Take the dissolution liquid, filter, and take the filtrate as the test solution. Take the azithromycin control substance, accurately weigh, dissolve and quantitatively dilute to prepare a solution containing about 0.1 mg of azithromycin per 1 ml, as the control solution. High performance liquid chromatography is used for dissolution determination, and the specific results are shown in Table 6 and Figure 1 .

[0102] Dissolution in artificial saliva: determined according to the dissolution and release determination method (Chinese Pharmacopoeia, 2020 Edition Part Four General Rules, 0931, Second Method). Artificial saliva (containing enzymes), that is, take calcium chloride 0.795 g, sodium dihydrogen phosphate dihydrate 0.78 g, sodium sulfide dihydrate 5 mg, potassium chloride 0.4 g, urea 1 g, sodium chloride 0.4 g, alpha-amylase 1 g, dissolve and dilute with water to 1000 ml, adjust the pH value to 6.8 with sodium hydroxide test solution (during the pH adjustment process, a small amount of precipitate will be produced in the solution), 500 ml as the dissolution medium, the rotation speed is 50 revolutions per minute, and the operation is carried out according to the law. Sample at 1 minute. Take the dissolution liquid, filter, and take the filtrate as the test solution. Take the amoxia and clenbuterol hydrochloride control substance, accurately weigh, dissolve and quantitatively dilute to prepare a solution containing about 7.5 μg of amoxia hydrochloride and 0.1 μg of clenbuterol hydrochloride per 1 ml, as the control solution. High performance liquid chromatography is used for dissolution determination, and the specific results are shown in Table 7.

[0103] 1.2 Waterless swallowing effect: 20 healthy volunteers are selected to test the waterless swallowing effect of the drug.

[0104] 2. Experimental results 2.1 Dissolution test results are as follows: From the data in Table 6, it can be seen that the azithromycin anhydrous swallow granules prepared in Examples 1-9 have a cumulative dissolution of more than 95% in pH 6.0 phosphate buffer medium within 15 minutes, meeting the requirements for rapid drug release, and also meeting the effect of rapid drug release in the stomach, achieving rapid onset of action. Comparative Example 2 uses an extrusion-spheronization process, which shows a slow dissolution rate.

[0105] From the data in Table 7, it can be seen that the azithromycin anhydrous swallow granules prepared in Examples 1-9 have a dissolution of less than 5% in artificial saliva medium within 1 minute, while the control preparation (Zithromax) has a dissolution of more than 10% in artificial saliva medium within 1 minute; Comparative Example 1 uses a fluidized bed process and changes the drug formulation, resulting in a dissolution of slightly more than 1 minute in artificial saliva medium.

[0106] By comparing Examples 1-9 with Comparative Example 1, it can be seen that changing the composition of the drug-containing pellet core components slows down the dissolution rate in pH 6.0 phosphate buffer medium. It is speculated that the reason is that microcrystalline cellulose and colloidal silicon dioxide have a synergistic effect within a certain proportion range, which can enhance the flowability and accelerate the disintegration.

[0107] By comparing Examples 1-9 with Comparative Example 2, it can be seen that the product prepared by the centrifugal pelletization process has a significantly faster dissolution than the product prepared by the extrusion-spheronization process.

[0108] Table 6 pH 6.0 phosphate buffer dissolution curve experimental results

[0109] Table 7 Artificial saliva medium dissolution test results

[0110] 2.2 Anhydrous swallowing effect results are as follows: Twenty healthy volunteers were found to test the drugs prepared in Examples 1-9, and it was found that the drugs prepared in Examples 1-9 had no bitter taste or odor in the oral cavity within 30 minutes, and after taking the drugs, the volunteers all felt a cool and light sensation in the oral cavity, indicating that the drugs achieved the effect of masking the bad taste. After taking the control preparation (Zithromax), there was a significant bitter taste left in the oral cavity.

[0111] After the drug preparation products prepared in Examples 1-9 were administered orally to 20 volunteers, they were all successfully swallowed within 1 minute in the anhydrous swallowing state, indicating that the drugs met the quality requirements in terms of taste masking and swallowing effect after contacting with saliva.

[0112] Example 2 Preparation Effect Evaluation: Stability 1. Experimental method Experimental material: The azithromycin anhydrous swallowing granules prepared in Examples 1-3 were taken for stability test.

[0113] Experimental condition: Temperature: 50℃±2℃, humidity: 75%RH±5%RH, the observation time was 4 weeks, and the samples were taken at 0 day, 2 weeks and 4 weeks for stability observation, and the results are shown in Table 8.

[0114] 2. Experimental results According to the stability test results in Table 8 below, compared with Comparative Examples 1-2 and the control preparation, the aspirin anhydrous swallowing granules prepared in Examples 1-9 have good stability, and the total impurities are not more than 0.9 under the condition of 50℃±2℃ / 75%RH±5%RH for 4 weeks, so that the children can take it more safely.

[0115] Table 8 Stability results

[0116] According to the above test results, only the specific combination and ratio of the auxiliary materials and the specific centrifugal pill-making process are used, the technical characteristics of anhydrous swallowing are realized, the patient compliance of patients, including children, the elderly, patients with incomplete or degenerative self-swallowing ability, and people with temporary or long-term swallowing difficulties caused by congenital developmental imperfection, disease, physical damage, etc. can be significantly improved, and the release speed is fast and the stability is high, which ensures the fastest and safest play of azithromycin efficacy.

[0117] Finally, it should be noted that the above content is only used to illustrate the technical solutions of the present application, and is not a limitation on the protection scope of the present application. Simple modifications or equivalent replacements of the technical solutions of the present application made by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.

Claims

1. Anhydrous azithromycin swallowable granules, characterized in that, The azithromycin anhydrous oral granules comprise drug-containing taste-masking granules and flavoring granules, wherein the drug-containing taste-masking granules comprise, from inside to outside, a drug-containing core, a separation layer and a taste-masking layer. The drug-containing core is prepared by centrifugal pelletization process. The separation layer has a coating weight gain of 2-20%, and the taste-masking layer has a coating weight gain of 1-20%.

2. The azithromycin anhydrous swallowable granules according to claim 1, characterized in that, The separation layer has a coating weight gain of 2-10%, and the taste-masking layer has a coating weight gain of 1-10%.

3. The azithromycin anhydrous swallow granules according to claim 1, characterized in that, The drug-containing core comprises azithromycin and excipients, wherein the excipients are selected from one or more of fillers, pH regulators, disintegrants, binders and glidants. The fillers are selected from one or more of lactose, starch, microcrystalline cellulose and mannitol. The pH regulators are selected from one or more of sodium carbonate, anhydrous trisodium phosphate, sodium hydroxide and magnesium oxide. The disintegrants are selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked povidone. The binders are selected from one or more of hydroxypropyl cellulose, povidone and hypromellose. The glidants are selected from one or more of colloidal silicon dioxide, talc and micro-powder silica gel.

4. The azithromycin anhydrous oral granules according to claim 3, wherein the fillers are microcrystalline cellulose; the pH regulators are anhydrous trisodium phosphate; the disintegrants are low-substituted hydroxypropyl cellulose; the binders are hypromellose; and the glidants are colloidal silicon dioxide. The drug-containing core comprises azithromycin, microcrystalline cellulose, anhydrous trisodium phosphate, low-substituted hydroxypropyl cellulose, hypromellose and colloidal silicon dioxide. The separation layer comprises binders or / and anti-adherents. The binders are selected from one or more of hypromellose, hydroxypropyl cellulose and povidone. The anti-adherents are selected from one or more of talc, titanium dioxide and magnesium stearate. The binders are hypromellose, and the anti-adherents are talc.

5. The azithromycin anhydrous swallow granules according to claim 4, characterized in that, The separation layer comprises hypromellose and talc.

6. The azithromycin anhydrous swallow granules according to claim 1, wherein The taste-masking layer comprises one or more of plasticizers, anti-adherents and acrylic resin polymers. The plasticizers are selected from one or more of polyethylene glycol, triethyl citrate and diethyl phthalate. The anti-adherents are selected from one or more of talc, titanium dioxide and magnesium stearate.

7. The azithromycin anhydrous swallow granules according to claim 6, characterized in that, The acrylic resin polymers are selected from one or more of Eudragit E100, Eudragit EPO, Eudragit L30D and Eudragit L30D-55.

8. The azithromycin anhydrous swallow granules according to claim 7, characterized in that, The plasticizers are polyethylene glycol, the anti-adherents are talc, and the acrylic resin polymers are Eudragit E100.

9. The azithromycin anhydrous swallow granules according to claim 1, characterized in that, The taste-masking layer comprises polyethylene glycol, talc and Eudragit E100. In terms of weight fractions: The drug-containing core comprises the following components: azithromycin 100.0 parts, microcrystalline cellulose 40.0-150.0 parts, anhydrous trisodium phosphate 5.0-15.0 parts, low-substituted hydroxypropyl cellulose 5.0-25.0 parts, hypromellose 5.0-20.0 parts and colloidal silicon dioxide 1.0-5.0 parts; 10. The azithromycin anhydrous swallow granules according to claim 9, characterized in that, ​ 11. The azithromycin anhydrous swallow granules according to claim 10, characterized in that, ​ 12. The azithromycin anhydrous swallowable granules according to claim 5, 8 or 11, characterized in that, ​ ​ ​ The isolation layer is composed of the following components: Hydroxypropyl methyl cellulose 1.0-12.5 parts and talc 1.0-12.5 parts; The taste-masking layer is composed of the following components: Polyethylene glycol 0.4-5.0 parts; talc 0.4-5.0 parts and Eudragit E100 1.8-20.0 parts.

13. The azithromycin anhydrous swallow granules according to claim 12, characterized in that, By weight fraction: The drug-containing pellet core is composed of the following components: Azithromycin 100.0 parts; microcrystalline cellulose 110.0 parts; anhydrous trisodium phosphate 9.0 parts; low-substituted hydroxypropyl cellulose 12.5 parts; hydroxypropyl methyl cellulose 15.0 parts and colloidal silicon dioxide 2.5 parts; The isolation layer is composed of the following components: Hydroxypropyl methyl cellulose 3.7 parts and talc 3.7 parts; The taste-masking layer is composed of the following components: Polyethylene glycol 1.1 parts; talc 1.2 parts and Eudragit E100 5.5 parts.

14. The azithromycin anhydrous swallow granules according to claim 1, wherein The taste-correcting granules include one or several of the following: flavoring agent, sweetening agent and essence; The flavoring agent is selected from one or several of the following: sorbitol, mannitol and maltodextrin; The sweetening agent is selected from one or more of the following: aspartame, sucralose and acesulfame potassium; The essence is selected from one or several of the following: strawberry essence, banana essence, sweet orange essence and mixed fruit essence.

15. The azithromycin anhydrous swallow granules according to claim 14, characterized in that, The taste-correcting granules are composed of sorbitol, sucralose and strawberry essence; by weight fraction: sorbitol 150.0-400.0 parts; sucralose 0.5-5.0 parts and strawberry essence 0.5-5.0 parts.

16. The azithromycin anhydrous swallow granules according to claim 15, characterized in that, By weight fraction: sorbitol 277.2 parts, sucralose 1.4 parts and strawberry essence 1.4 parts.

17. A process for the preparation of azithromycin anhydrous swallowable granules according to any one of claims 1 to 16, characterized in that, The preparation method is as follows: The drug-containing pellet core is centrifugally granulated, the isolation layer and the taste-masking layer are coated in a fluidized bed to obtain drug-containing taste-masking granules; the obtained drug-containing taste-masking granules are mixed with the taste-correcting granules to obtain the azithromycin anhydrous swallowing granules.

18. The method of claim 17, wherein, The following steps are included: (1) Preparation of drug-containing pellets: 1.1 Dissolve 1%-5% of the binder in water to obtain solution A for standby; 1.2 Mix azithromycin, filler, pH regulator, disintegrant, glidant and the remaining binder through a 20-mesh sieve to obtain a premix powder; 1.3 Centrifugally granulate solution A and the premix powder, dry and sieve to obtain the drug-containing pellets; (2) Preparation of isolation pellets: 2.1 Dissolve the binder in water, and after complete dissolution, add the anti-adhesion agent and disperse uniformly to obtain solution B; 2.2 Place the drug-containing pellets in a fluidized bed, and use solution B to perform isolation coating in the form of bottom-spraying coating in the fluidized bed, and dry to obtain the isolation pellets; (3) Preparation of drug-containing taste-masking granules: 3.1 Dissolve the acrylic resin polymer in ethanol, and after complete dissolution, add the plasticizer and anti-adhesion agent and disperse uniformly to obtain solution C; 3.2 Place the isolation pellets in a fluidized bed, and use solution C to perform taste-masking coating in the form of bottom-spraying coating in the fluidized bed, and dry to obtain the drug-containing taste-masking granules; (4) Preparation of taste-correcting granules: Mix the flavoring agent, sweetening agent and essence to obtain the taste-correcting granules; (5) Mix the prepared drug-containing taste-masking granules with the taste-correcting material to obtain the azithromycin anhydrous swallowing granules.

19. The method of claim 18, wherein, The dried inlet air temperature described in Step 1.3 is 60°C; the material temperature of the isolating coating process described in Step 2.2 is 35°C-60°C; the material temperature of the taste masking coating process described in Step 3.2 is 20°C-40°C.

20. Use of azithromycin anhydrous swallow granules as claimed in any one of claims 1-16 in the preparation of a medicament for preventing bacterial infection or treating mycoplasma pneumoniae pneumonia.

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