CN118178331A

CN118178331A - Compound omeprazole dry suspension and preparation method thereof

Info

Publication number: CN118178331A
Application number: CN202410299549.9A
Authority: CN
Inventors: 靳淑萍; 吴黄焱; 许慧敏; 郑永刚
Original assignee: Beijing Haitai Tianzheng Pharmaceutical Technology Co ltd
Current assignee: Beijing Haitai Tianzheng Pharmaceutical Technology Co ltd
Priority date: 2024-03-15
Filing date: 2024-03-15
Publication date: 2024-06-14

Abstract

The invention discloses a compound omeprazole dry suspension and a preparation method thereof. The compound omeprazole dry suspension is prepared from raw materials containing active ingredients, a diluent, a stabilizer and auxiliary materials, wherein the active ingredients comprise omeprazole and sodium bicarbonate, and the stabilizer comprises a swelling adhesive and a pH regulator. According to the invention, the omeprazole and the stabilizing agent are mixed and then coated on the outer surface of the diluting agent to form the dry particles with loose porous structures on the surface, so that the problem of adsorption of raw materials is effectively solved, the problem of poor content uniformity caused by overlarge ratio difference of raw materials and auxiliary materials is avoided, and meanwhile, the stability of a product is ensured. In addition, the invention can be rapidly dispersed into uniform and stable suspension by using a small amount of water.

Description

Compound omeprazole dry suspension and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and in particular relates to a compound omeprazole dry suspension and a preparation method thereof.

Background

Digestive system diseases are a frequently occurring disease which is common in people's daily lives. With the change of life style, the proportion of modern people suffering from various digestive system diseases is continuously rising. A significant proportion of these are caused by excessive gastric acid secretion, or by particular sensitivity to gastric acid, and these digestive disorders are collectively referred to as acid-related disorders, such as gastric ulcers, duodenal ulcers, gastroesophageal reflux disease, dyspepsia, and the like. Proton Pump Inhibitors (PPIs) are listed in the multinational guidelines as the first treatment regimen for treating acid related diseases.

In order to avoid the decomposition and damage of gastric juice, the existing proton pump inhibitors are mostly oral enteric preparations, and enteric coatings are required to be coated during production, and the design has several defects: (1) Special coating equipment is needed in the production process, the process requirement is high, and the production cost is increased; (2) most enteric coated formulations are moisture sensitive; (3) The drug onset is slowed down and the peak time is delayed due to release in intestinal fluids.

Chinese patent application CNl02641286A discloses a compound omeprazole dry suspension and a preparation method thereof. The preparation method of the invention mainly controls the particle size of the omeprazole within a certain range, so that the preparation can be rapidly dissolved and absorbed in vivo. However, the problems of raw material medicine adsorption, powder flowability and mixing uniformity in the production process of the product are not studied.

Chinese patent application CN106798750A discloses a preparation method of compound omeprazole dry suspension. The preparation method comprises a wet granulation process, a drying process, a total mixing process and a dose dividing process, and finally the produced compound omeprazole dry suspension reduces the defective rate and improves the product quality and the curative effect. However, the above-mentioned processes are relatively complex and the production period is long.

Chinese patent application CN111388425A discloses a compound omeprazole dry suspension and a preparation method thereof. The invention has complex formula, in particular bamboo leaf polysaccharide and pachyman which are used as synergistic stabilizer do not belong to pharmaceutical auxiliary materials, and the preparation method has complex process flow, long production period and increased production cost.

Chinese patent application CN115487151A discloses a compound omeprazole dry suspension and a preparation method thereof, and the particle size and the proportion of auxiliary materials are controlled, so that the adsorption effect of raw materials is reduced, and the fluidity and the content uniformity of products are improved. However, the particle size control of the auxiliary materials in the invention generally involves the treatment of the auxiliary materials, and the material loss and waste are necessarily generated in the treatment process, so that the production cost is increased. The preparation process is a simple mixing process, and the components have the risk of layering segregation due to the difference in granularity and density, and particularly the layering segregation is more easy to occur under the condition of vibration or in the transferring process. In addition, the particle size D90 of the omeprazole bulk drug is controlled to be less than or equal to 10 mu m, and the risk of adsorption is still high due to the small particle size.

Therefore, there is still a need for a compound omeprazole dry suspension with excellent stability that can solve the adsorption problem of the raw materials and can be rapidly dispersed.

Disclosure of Invention

In order to solve the problem of adsorption of the raw materials in the prior art, the invention provides the compound omeprazole dry suspension and the preparation method thereof, which can effectively improve adsorption of the raw materials and improve dosage accuracy and safety. Meanwhile, the dry suspension prepared by the invention can be rapidly dispersed to form uniform suspension when in use, and is more convenient when in use. Specifically, the present invention includes the following.

According to a first aspect of the invention, a compound omeprazole dry suspension is provided, which is prepared from raw materials containing an active ingredient, a diluent, a stabilizer and auxiliary materials, wherein the active ingredient comprises omeprazole and sodium bicarbonate, the stabilizer comprises a swelling adhesive and a pH regulator, and the omeprazole and the stabilizer are coated on the outer surface of the diluent after being mixed so as to form dry particles with loose porous structures on the surfaces.

In certain embodiments, the compound omeprazole dry suspension according to the present invention, wherein the pH adjuster comprises at least one of disodium hydrogen phosphate, sodium bicarbonate, sodium acetate, sodium citrate, sodium tartrate and sodium glycinate; the swellable binder comprises carboxymethyl cellulose or a salt thereof, preferably carboxymethyl cellulose, sodium carboxymethyl cellulose and/or calcium carboxymethyl cellulose, having a viscosity number of 10-200 cP; the auxiliary materials comprise suspending agents, sweetening agents and flavoring agents.

In certain embodiments, the compound omeprazole dry suspension according to the present invention, wherein the compound omeprazole dry suspension comprises 20-40 parts by weight of the active ingredient, 50-75 parts by weight of a diluent, 0.05-0.5 parts by weight of a stabilizer, 0.1-1 parts by weight of a suspending agent, 0.1-1 parts by weight of a sweetener and 0.1-1 parts by weight of a flavoring agent.

In certain embodiments, the compound omeprazole dry suspension according to the invention, wherein the weight ratio of the binder to the pH adjustor is (1-5): 1.

In certain embodiments, the compound omeprazole dry suspension according to the invention, wherein the weight ratio of the omeprazole to the sodium bicarbonate is 1 (20-100).

In certain embodiments, the compound omeprazole dry suspension according to the present invention, wherein the diluent comprises at least one of sucrose, xylitol, lactose, glucose, fructose, maltose, mannitol, sorbitol, microcrystalline cellulose, starch, dextrin, calcium phosphate and calcium sulfate.

In a second aspect of the present invention, there is provided a method for preparing a compound omeprazole dry suspension, comprising the steps of:

(1) Providing a drug-containing suspension comprising omeprazole, a swellable binder and a pH-adjusting agent in an amount sufficient to stabilize the pH of the drug-containing suspension at 8.4-9.6;

(2) Spraying the drug-containing suspension onto the surface of a diluent through fluidized bed granulation at 35-45 ℃, continuing to dry after the drug-containing suspension is sprayed, and controlling the water content of the particles to be below 1.0%, thereby obtaining dry particles;

(3) Mixing the dry particles with sodium bicarbonate and adjuvants to obtain total mixture, and packaging.

In certain embodiments, the method for preparing the compound omeprazole dry suspension according to the present invention, wherein the pH adjuster comprises at least one of disodium hydrogen phosphate, sodium bicarbonate, sodium acetate, sodium citrate, sodium tartrate and sodium glycinate.

In certain embodiments, the method for preparing the compound omeprazole dry suspension according to the invention, wherein the swelling adhesive comprises carboxymethyl cellulose or a salt thereof, preferably carboxymethyl cellulose, sodium carboxymethyl cellulose and/or calcium carboxymethyl cellulose with a viscosity value of 10-200 cP.

In certain embodiments, the method for preparing the compound omeprazole dry suspension comprises the steps of suspending agents, sweeteners and flavoring agents.

In certain embodiments, the preparation method of the compound omeprazole dry suspension according to the invention, wherein the diluent comprises at least one of sucrose, xylitol, lactose, glucose, fructose, maltose, mannitol, sorbitol, microcrystalline cellulose, starch, dextrin, calcium phosphate and calcium sulfate.

In certain embodiments, the preparation method of the compound omeprazole dry suspension, according to the invention, wherein the preparation of the drug-containing suspension comprises the following steps: adding the pH regulator into water, stirring until the pH regulator is dissolved, continuously adding the swelling adhesive under stirring, stirring until the pH regulator is dissolved, adding the omeprazole, stirring and dispersing uniformly to obtain the drug-containing suspension.

In certain embodiments, the method for preparing a compound omeprazole dry suspension according to the present invention, wherein the fluid bed granulation comprises: the diluent is put into a fluidized bed, the air inlet temperature is set at 60-80 ℃, the air quantity is adjusted to enable the materials to be in a fluidized state, after the materials are preheated, the materials are sprayed into the medicine-containing suspension, the temperature of the materials is kept at 35-45 ℃ in the granulating process, the materials continue to be dried after the medicine-containing suspension is sprayed, the moisture of the particles is controlled to be less than 1.0%, and the obtained particles are sieved to obtain dry particles.

In certain embodiments, the method for preparing the compound omeprazole dry suspension according to the invention, wherein the suspending agent comprises xanthan gum and the sweetener comprises sucralose.

In certain embodiments, the method for preparing the compound omeprazole dry suspension according to the invention, wherein the packaging comprises packaging the total mixture with a pharmaceutical composite film and/or a bag.

According to the invention, the omeprazole is dispersed in the adhesive solution, and is subjected to top-spraying granulation by the fluidized bed, and the omeprazole bulk drug in a suspension state and the crushed diluent form uniform particles, so that the problem of adsorption of the bulk drug is effectively solved, and meanwhile, the problem of poor content uniformity caused by overlarge ratio difference of raw materials and auxiliary materials is avoided. Meanwhile, the pH value of the drug-containing suspension is regulated to be in the range of 8.4-9.6, so that the stability of the omeprazole is ensured while the omeprazole is uniformly dispersed. In addition, the fine particles prepared by the invention are spherical, the surface is loose and porous, and the fine particles can be rapidly dispersed by a small amount of water to form uniform and stable suspension. The compound omeprazole dry suspension is particularly suitable for patients with difficulty in taking common oral preparations such as tablets and capsules.

Detailed Description

Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in the present invention, it is understood that the upper and lower limits of the ranges and each intermediate value therebetween are specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.

Compound omeprazole dry suspension

In one aspect of the invention, a compound omeprazole dry suspension is provided, which is prepared from raw materials containing an active ingredient, a diluent, a stabilizer and auxiliary materials, wherein the active ingredient comprises omeprazole and sodium bicarbonate, the stabilizer comprises a swelling adhesive and a pH regulator, and the omeprazole and the stabilizer are coated on the outer surface of the diluent after being mixed so as to form dry particles with loose porous structures on the surface. The microstructure of the particles may be determined based on known techniques such as scanning electron microscopy, transmission electron microscopy, nitrogen adsorption-desorption isotherm analysis, and the like.

The dry suspension disclosed by the invention is prepared by mixing the omeprazole active ingredient and other raw materials into particles, so that the bioavailability of the omeprazole is improved, the storage life is prolonged, the concentration can be flexibly adjusted according to the needs, and the dry suspension can be dispersed into uniform and stable suspension by adding a small amount of water or other suitable dispersing media before use.

In the present invention, the swellable binder includes carboxymethyl cellulose or a salt thereof, preferably carboxymethyl cellulose, sodium carboxymethyl cellulose, and/or calcium carboxymethyl cellulose. Most preferably, the carboxymethyl cellulose is sodium carboxymethyl cellulose.

In the present invention, carboxymethyl cellulose or a salt thereof has a suitable Degree of Substitution (DS). The degree of substitution represents the average number of hydroxyl groups substituted per anhydroglucose unit. For example, in carboxymethyl cellulose or a salt thereof, each anhydroglucose unit contains 3 hydroxyl groups so as to have a maximum theoretical DS value of 3.0. In particular embodiments, the carboxymethyl cellulose or salt thereof of the present invention has a DS value of 0.50 to 0.80, e.g., 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80.

In the present invention, carboxymethyl cellulose or a salt thereof has a certain viscosity when measured in a 2% aqueous solution at 25 ℃ (rotational viscometer measurement). In a preferred embodiment, the carboxymethyl cellulose or salt thereof of the present invention is a carboxymethyl cellulose or salt thereof having a low viscosity. The term "low viscosity" refers to viscosity values in the range of 10-200cP, preferably 10-150cP, still preferably 10-120cP, more preferably 10-100cP, e.g. 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 cP.

In the present invention, carboxymethyl cellulose is available from commercial products such as sodium carboxymethyl cellulose 7LF type having a DS of 0.7 (Nanj, inc., viscosity number 34-63cP,2% aqueous solution). When the sodium carboxymethyl cellulose with the above model is used as the swelling adhesive, the compound omeprazole dry suspension with excellent performance can be prepared by the method.

In the present invention, the pH adjustor includes at least one of disodium hydrogen phosphate, sodium bicarbonate, sodium acetate, sodium citrate, sodium tartrate, and sodium glycinate. In a preferred embodiment, the pH adjuster is disodium hydrogen phosphate. Disodium hydrogen phosphate (anhydrous or hydrate) can keep the drug-containing suspension stable at 8.4-9.6 before fluidized bed granulation, and the compound omeprazole dry suspension with excellent performance can be prepared by the synergistic swelling adhesive under the pH value.

In the present invention, the diluent is not particularly limited, and examples thereof include, but are not limited to, at least one of sucrose, xylitol, lactose, glucose, fructose, maltose, mannitol, sorbitol, microcrystalline cellulose, starch, dextrin, calcium phosphate, and calcium sulfate. In a preferred embodiment, the diluent comprises sucrose and/or xylitol.

The auxiliary materials added in the invention are not particularly limited, and in the invention, the auxiliary materials comprise suspending agents, sweeteners and flavoring agents. Examples of suspending agents include, but are not limited to, xanthan gum, sodium alginate, potassium alginate, ammonium alginate, carrageenan, guar gum, pectin, sesbania gum, fenugreek seed gum, papaya seed gum, psyllium seed gum, sargassum seed gum, acacia gum, gum ghatti, dextran, welan gum, soluble starch, pregelatinized starch, carboxymethyl starch, and the like.

In the present invention, one non-limiting example of the flavoring agent is essence, and examples of the essence include, but are not limited to, juicy peach essence, strawberry essence, peppermint essence, durian essence, banana essence, lemon essence, orange essence, pineapple essence, apple essence, cantaloupe essence, hawthorn essence, fig essence, waxberry essence, raw pear essence, cherry essence, grape essence, litchi essence, mulberry essence, green plum essence, coconut essence, watermelon essence, melon essence, apricot essence, blueberry essence, green-extracted essence, blackcurrant essence, and the like.

In the present invention, the sweetener is not particularly limited, and examples thereof include, but are not limited to, sucralose, allose, deoxyribose, erythrulose, galactose, gulose, idose, lyxose, mannose, ribose, tagatose, talose, xylose, erythrose, fucoidase, gentiobiose, isomaltulose, melibiose, lactulose, altrose, laminabiose, arabinose, leuconostoc disaccharide, fucose, rhamnose, sorbose, maltulose, mannobiose, mannose, melezitose, melibiose, melezitose, aspergillus niger, raffinose, rutinose, sophorose, xylulose, threose, trehalose, trehalulose, melezitose, melibiose, sucrose, fructose, glucose-fructose syrup, high fructose corn syrup, invert sugar, psicose, arabitol, erythritol, glycerol, hydrogenated starch hydrolysates, isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol, and the like.

In a preferred embodiment, the compound omeprazole dry suspension comprises or consists of the following components: 20 to 40 parts by weight, preferably 22 to 38 parts by weight, still preferably 24 to 36 parts by weight, further preferably 26 to 34 parts by weight, for example 26, 27, 28, 29, 30, 31, 32, 33, 34 parts by weight of the active ingredient; 50 to 75 parts by weight, preferably 52 to 73 parts by weight, still preferably 54 to 71 parts by weight, further preferably 56 to 68 parts by weight, for example 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 parts by weight of a diluent; 0.05 to 0.5 part by weight, preferably 0.06 to 0.4 part by weight, still preferably 0.07 to 0.3 part by weight, further preferably 0.08 to 0.2 part by weight, for example 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2 part by weight of a stabilizer; 0.1 to 1 part by weight, preferably 0.2 to 0.9 part by weight, still preferably 0.3 to 0.8 part by weight, further preferably 0.3 to 0.7 part by weight, for example 0.3, 0.4, 0.5, 0.6, 0.7 part by weight of suspending agent; 0.1 to 1 part by weight of sweetener, preferably 0.2 to 0.9 part by weight, still preferably 0.3 to 0.8 part by weight, still preferably 0.4 to 0.7 part by weight, for example 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7 part by weight of sweetener and 0.1 to 2 parts by weight, preferably 0.2 to 1.8 part by weight, still preferably 0.3 to 1.6 part by weight, still preferably 0.4 to 1.4 part by weight, for example 0.4, 0.6, 0.8, 1.0, 1.2, 1.4 part by weight of taste modifier.

In the present invention, the weight ratio of the binder to the pH adjuster is (1-5): 1, preferably (1-4.5): 1, still preferably (1-4): 1, further preferably (1-3.5): 1, more preferably (1-3): 1, more preferably (1-2.5): 1, more preferably (1-2): 1, for example, 1:1, 1.2:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1.

In the present invention, the weight ratio of omeprazole to sodium bicarbonate is1 (20-100), preferably 1 (30-95), still preferably 1 (40-90), more preferably 1 (50-85), such as 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:76, 1:77, 1:78, 1:79, 1:80, 1:81, 1:82, 1:83, 1:84, 1:85.

In the formulation of the present invention, the swelling binder sodium carboxymethylcellulose and the pH adjuster have a synergistic effect. If only sodium carboxymethyl cellulose as a swelling adhesive is used and a pH regulator is not used, the obtained compound omeprazole dry suspension is obviously increased in maximum known and unknown degradation impurities and total impurities, and the stability of a sample is obviously reduced. If a swellable binder is not used and only anhydrous disodium hydrogen phosphate is used, the dispersibility of the obtained compound omeprazole dry suspension is affected.

Preparation method

In one aspect of the invention, a method for preparing a compound omeprazole dry suspension is provided, which comprises the steps (1) - (3). Step (1) is a step of providing a drug-containing suspension, wherein the drug-containing suspension comprises omeprazole, a swelling binder and a pH adjustor in an amount sufficient to stabilize the pH of the drug-containing suspension at a pH of 8.4-9.6, preferably at a pH of 8.5-9.5, such as 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5. In the step (2), spraying the drug-containing suspension onto the surface of a diluent through fluidized bed granulation at the temperature of 35-45 ℃, continuing to dry after the drug-containing suspension is sprayed, and controlling the water content of the particles to be less than 1.0%, thereby obtaining dry particles. In the step (3), the dry particles, sodium bicarbonate and auxiliary materials are mixed to obtain a total mixed material, and the total mixed material is packaged to obtain the finished product.

In a preferred embodiment, the production method of the present invention comprises the following steps (1) to (5).

Step (1) in the preparation method of the invention is a pretreatment step. The diluent, preferably sucrose and xylitol, are separately crushed and then passed through a 40-80 mesh screen, preferably a 45-75 mesh screen, still preferably a 50-70 mesh screen, more preferably a 55-65 mesh screen, such as a 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 mesh screen.

The step (2) in the preparation method of the invention is a step of preparing a drug-containing suspension. Adding a pH regulator, preferably anhydrous disodium hydrogen phosphate, into purified water, and stirring until the pH regulator and the anhydrous disodium hydrogen phosphate are dissolved; adding the swelling adhesive, preferably sodium carboxymethylcellulose, especially sodium carboxymethylcellulose 7LF, under stirring, and stirring until dissolved; and adding omeprazole, stirring and dispersing uniformly to obtain a drug-containing suspension. Optionally, anhydrous disodium hydrogen phosphate is added into purified water and stirred until dissolved; then adding omeprazole, stirring and dispersing uniformly; continuously adding sodium carboxymethylcellulose under stirring, and stirring until dissolving to obtain the drug-containing suspension. Alternatively, anhydrous disodium hydrogen phosphate and omeprazole are simultaneously dispersed into pure water for dissolution; adding sodium carboxymethylcellulose under stirring, and stirring to dissolve to obtain medicinal suspension. The invention discovers that the mode of dissolving anhydrous disodium hydrogen phosphate and then dissolving sodium carboxymethyl cellulose is more favorable for stabilizing the omeprazole small molecules by sodium carboxymethyl cellulose, and probably because the sodium carboxymethyl cellulose molecules are easier to form a stable alkaline environment inside after wrapping the omeprazole after dissolving the pH regulator. If sodium carboxymethyl cellulose is dissolved first, small molecules serving as a pH regulator are not easy to freely move inside and outside a cluster formed by sodium carboxymethyl cellulose, so that the alkaline environment in the cluster is influenced, and the stability of omeprazole is further influenced.

Step (3) in the preparation method of the invention is a fluidized bed granulation step. The pulverized diluent is fed into a fluidized bed, the inlet air temperature is set to 40-80 ℃, preferably 45-80 ℃, still preferably 50-80 ℃, more preferably 55-80 ℃, more preferably 60-80 ℃, such as 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80 ℃, the air quantity is adjusted to ensure that the materials are in a good fluidization state, the material temperature is preheated to 40-50 ℃, preferably 41-49 ℃, still preferably 42-48 ℃, such as 42, 43, 44, 45, 46, 47, 48 ℃, the drug-containing suspension is sprayed, the granulating process keeps the material temperature at 30-50 ℃, preferably 31-49 ℃, still preferably 32-48 ℃, more preferably 33-47 ℃, more preferably 34-46 ℃, more preferably 35-45 ℃, such as 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 ℃, and the drying is continued after the drug-containing suspension is sprayed, the particle moisture is controlled to be less than or equal to 1.0%, preferably less than 0.5%, still preferably less than or equal to 0.05%, more preferably less than or equal to 0.01%, and even no moisture is contained. The dried granules are sieved through a shaking or rotary shaking sieve of 30-50 mesh, preferably 31-49 mesh, still preferably 32-48 mesh, more preferably 33-47 mesh, more preferably 34-46 mesh, more preferably 35-45 mesh, for example 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 mesh.

Step (4) in the preparation method of the invention is a total mixing step. The sieved granules, flavoring agent (preferably essence), suspending agent (preferably xanthan gum), sweetener (preferably sucralose), sodium bicarbonate are added into a hopper mixer or a three-dimensional mixer in sequence, and mixed for 10-50 minutes, preferably 12-48 minutes, further preferably 14-46 minutes, more preferably 16-44 minutes, more preferably 18-42 minutes, more preferably 20-40 minutes, for example 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40 minutes, to obtain the total mixed material.

Step (5) in the preparation method of the invention is a packaging step. Packaging the total mixed materials by using packaging materials. Packaging includes packaging the total mix with a pharmaceutical composite film and/or bag. Among them, materials of the medicinal composite film and/or bag are not particularly limited, and examples thereof include, but are not limited to, paper, aluminum, polyethylene, polyvinyl chloride, polypropylene, polyester, and the like.

In the preparation of the drug-containing suspension, the order of adding the raw materials is not particularly limited, and in order to obtain a compound omeprazole dry suspension with excellent performance, particularly stability, a pH regulator is preferably added into water and stirred until the mixture is dissolved, a swelling adhesive is continuously added under stirring, the mixture is stirred until the mixture is dissolved, and then omeprazole is added and uniformly stirred and dispersed to prevent the degradation of the omeprazole, so that the drug-containing suspension is obtained.

Example 1

This example shows a method for preparing a compound omeprazole dry suspension.

1. Prescription composition

The prescription composition of this example is shown in Table 1.

Table 1 prescription composition in example 1

Prescription composition	Mg/bag	Percent (mass ratio)
			Omeprazole	20	0.34
Sodium bicarbonate	1680	28.97
			Carboxymethylcellulose sodium 7LF	6	0.10
Anhydrous disodium hydrogen phosphate	4	0.07
			Sucrose	2050	35.34
Xylitol	1950	33.62
			Sucralose	40	0.69
Xanthan gum	20	0.34
			Honey peach powder essence	30	0.52
Totals to	5800	100.00
			Purified water	400	/

Wherein the purified water is used as a solvent for preparing the drug-containing suspension, and is removed during the process.

2. Preparation method

(1) Pretreatment: respectively crushing sucrose and xylitol, and sieving with a 60-mesh sieve;

(2) Preparing a drug-containing suspension: adding anhydrous disodium hydrogen phosphate into purified water, and stirring until the anhydrous disodium hydrogen phosphate is dissolved; continuously adding sodium carboxymethylcellulose under stirring, and stirring until the sodium carboxymethylcellulose is dissolved; and adding omeprazole and stirring to uniformly disperse to obtain a free-flowing drug-containing suspension, wherein the pH value of the drug-containing suspension is measured to be 8.52. Wherein stirring is maintained during the granulating process;

(3) Granulating by a fluidized bed: adding crushed sucrose and xylitol into a fluidized bed, setting air inlet temperature at 60-80deg.C, regulating air volume to make the material in good fluidization state, preheating to 45 deg.C, spraying into the suspension containing medicine, granulating to maintain 35-45 deg.C, continuing drying after spraying, and controlling granule water content to be less than or equal to 1.0%. Sieving the dried granules with a 40-mesh sieve through an oscillating sieve or a rotary vibrating sieve;

(4) Total mixing: sequentially adding the sieved particles, essence, xanthan gum, sucralose and sodium bicarbonate into a hopper mixer, and mixing for 30 minutes to obtain a total mixed material;

(5) And (3) packaging: the total mixture is packed with paper/aluminum/polyethylene medicinal composite film/bag.

Example 2

This example shows a method for preparing a compound omeprazole dry suspension.

1. Prescription composition

The prescription composition of this example is shown in Table 2.

Table 2 prescription composition in example 2

Prescription composition	Mg/bag	Percent (mass ratio)
			Omeprazole	20	0.34
Sodium bicarbonate	1680	28.97
			Carboxymethylcellulose sodium 7LF	6	0.10
Anhydrous disodium hydrogen phosphate	8	0.14
			Sucrose	2046	35.28
Xylitol	1950	33.62
			Sucralose	40	0.69
Xanthan gum	20	0.34
			Honey peach powder essence	30	0.52
Totals to	5800	100.00
			Purified water	400	/

2. Preparation method

The procedure of example 1 was followed except that the pH of the drug-containing suspension was 9.47 as measured in the "procedure of preparing a drug-containing suspension" (2).

Example 3

This example shows a method for preparing a compound omeprazole dry suspension.

1. Prescription composition

The prescription composition in this example is shown in Table 3.

Table 3 prescription composition in example 3

2. Preparation method

The procedure of example 1 is followed except that the pH of the drug-containing suspension is 9.08 as measured in the "procedure of preparing a drug-containing suspension" (2).

Comparative example 1

This example shows a method for preparing a compound omeprazole dry suspension.

1. Prescription composition

The composition of the prescription of this comparative example is shown in Table 4.

Table 4 prescription composition in comparative example 1

Prescription composition	Mg/bag	Percent (mass ratio)
			Omeprazole	20	0.34
Sodium bicarbonate	1680	28.97
			Carboxymethylcellulose sodium 7LF	6	0.10
Sucrose	2054	35.41
			Xylitol	1950	33.62
Sucralose	40	0.69
			Xanthan gum	20	0.34
Honey peach powder essence	30	0.52
			Totals to	5800	100.00
Purified water	400	/

2. Preparation method

The procedure is as in example 1, except for the "procedure for preparing a drug-containing suspension" (2). In this comparative example "(2) the procedure for preparing the drug-containing suspension" was as follows:

adding sodium carboxymethylcellulose into purified water under stirring, stirring to dissolve, adding omeprazole, stirring to disperse uniformly to obtain medicinal suspension, and measuring pH of the medicinal suspension to 6.84. Wherein stirring is maintained during granulation.

Comparative example 2

This example shows a method for preparing a compound omeprazole dry suspension.

1. Prescription composition

The composition of the prescription of this comparative example is shown in Table 5.

Table 5 prescription composition in comparative example 2

Prescription composition	Mg/bag	Percent (mass ratio)
			Omeprazole	20	0.34
Sodium bicarbonate	1680	28.97
			Carboxymethylcellulose sodium 7LF	6	0.10
Anhydrous disodium hydrogen phosphate	2	0.03
			Sucrose	2052	35.38
Xylitol	1950	33.62
			Sucralose	40	0.69
Xanthan gum	20	0.34
			Honey peach powder essence	30	0.52
Totals to	5800	100.00
			Purified water	400	/

2. Preparation method

The procedure of example 1 is followed except that the pH of the drug-containing suspension is 7.86 as measured in the "procedure of preparing a drug-containing suspension" (2).

Comparative example 3

This example shows a method for preparing a compound omeprazole dry suspension.

1. Prescription composition

The composition of the prescription in this comparative example is shown in Table 6.

Table 6 prescription composition in comparative example 3

2. Preparation method

adding anhydrous disodium hydrogen phosphate into purified water, stirring until the anhydrous disodium hydrogen phosphate is dissolved, adding omeprazole, stirring to uniformly disperse the mixture, obtaining a drug-containing suspension, and measuring the pH value of the drug-containing suspension to be 9.08. Wherein stirring is maintained during granulation.

Comparative example 4

This example shows a method for preparing a compound omeprazole dry suspension.

1. Prescription composition

The composition of the prescription in this comparative example is shown in Table 7.

Table 7 prescription composition in comparative example 4

Prescription composition	Mg/bag	Percent (mass ratio)
			Omeprazole	20	0.34
Sodium bicarbonate	1680	28.97
			Povidone K30	40	0.69
Anhydrous disodium hydrogen phosphate	15	0.26
			Sucrose	2005	34.57
Xylitol	1950	33.62
			Sucralose	40	0.69
Xanthan gum	20	0.34
			Honey peach powder essence	30	0.52
Totals to	5800	100.00
			Purified water	400	/

2. Preparation method

Adding anhydrous disodium hydrogen phosphate into purified water, and stirring until the anhydrous disodium hydrogen phosphate is dissolved; continuing to add povidone K30 under stirring, and stirring until the povidone K30 is dissolved; and adding omeprazole and stirring to uniformly disperse to obtain a drug-containing suspension, wherein the pH value of the drug-containing suspension is measured to be 8.98. Wherein stirring is maintained during granulation.

Comparative example 5

This example shows a method for preparing a compound omeprazole dry suspension.

1. Prescription composition

The composition of the prescription in this comparative example is shown in Table 8.

Table 8 prescription composition in comparative example 5

Wherein, the swelling adhesive is respectively two types of sodium carboxymethylcellulose 7MF (viscosity value 415-770cP,2% aqueous solution) and 7HF (viscosity value 1500-2500cP,2% aqueous solution) manufactured by Nanjing chemical industry Co., ltd.

2. Preparation method

When the preparation method of the example 1 is used for preparing the drug-containing suspension, the drug-containing suspension prepared by the prescription 1 is found to be in a semi-fluid gel state, and the drug-containing suspension prepared by the prescription 2 is found to be in a viscous gel state and is difficult to flow; therefore, both formulations are not suitable for fluid bed granulation.

And the sodium carboxymethylcellulose 7LF type used in examples 1-3, the prepared drug-containing suspension can flow freely and can meet the requirements of fluid bed granulation.

Comparative example 6

1. Prescription composition

The composition of the prescription in this comparative example is shown in Table 9.

Table 9 prescription composition in comparative example 6

Wherein, the swelling adhesive is respectively two types of sodium carboxymethylcellulose SH-SJJ-800 (viscosity value 600-1120cP,2% aqueous solution) and SH-7HF (viscosity value 1500-2800cP,1% aqueous solution) manufactured by Anhui Shanhe pharmaceutical excipients Co., ltd.

2. Preparation method

Similarly, when the drug-containing suspension was prepared by the preparation method of example 1, it was found that the drug-containing suspension prepared in the formulation 3 was in a gel state with poor fluidity, and the drug-containing suspension prepared in the formulation 4 was in a viscous gel state with little flow. Therefore, both of these formulations are also unsuitable for fluid bed granulation.

And the drug-containing suspension prepared by using the sodium carboxymethylcellulose 7LF model of the methylene blue in the examples 1-3 can flow freely and can meet the granulating requirement of a fluidized bed.

Test examples

1. Drug adsorption experiments

The omeprazole content of inventive examples 1-3 was measured separately from a reference formulation (20 mg/1680mg gauge, lot number: 0061R, underwriter: salix) by taking 5 bags. Referring to the method for treating the sample for content uniformity, 1 bag was poured into a suitable volumetric flask, but the remaining contents in the bag were not rinsed with solvent, and the content measurement results are shown in Table 10.

Table 10 comparison of omeprazole content measurement results

Sample of	Omeprazole content (%)	RSD(％)
			Reference formulation (0061R batch)	94.2	3.0
Example 1	99.5	0.3
			Example 2	99.8	0.1
Example 3	99.6	0.2

From the results shown in table 10, the dosage form of the reference formulation was simulated when the reference formulation was used by the general population, and the content of the reference formulation was 94.2% and 5.8% of the drug remained in the pouch, which affected the accuracy of the dosage. The samples prepared in the embodiments 1-3 of the invention have the measured content close to 100%, ensure the accuracy of the dosage and have better content uniformity.

The results show that the prepared sample can obviously reduce the adsorption of the raw material medicine in the package, thereby ensuring the accuracy of the medicine dosage and having better content uniformity.

2. Dispersibility experiment

Taking 3 bags of each of the inventive examples 1-3, comparative examples 3-4 and reference preparation (20 mg/1680mg specification, batch number: 0061R, manufacturer: salix), simulating a clinical dispensing mode, pouring the contents into a volumetric flask, and placing into a shaking table to ensure that the intensity and time of sample shaking are the same; then, 10ml and 20ml of warm water at about 50℃were added, respectively, and the behavior of the solution in the bottle was observed with time.

TABLE 11 comparison of solution Properties over time

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Further, 1 bag of each of the inventive examples 1 to 3, comparative examples 3 to 4 and the reference preparation was taken, 20ml of hot water (about 25 ℃) was added to each of them according to the above-mentioned dispensing method, and the time-dependent change of the properties of the solution in the bottle was observed.

TABLE 12 comparison of solution Properties over time

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As can be seen from the results in Table 12 above, the samples prepared in examples 1-3 formed a fully dispersed homogeneous suspension with minimal time and minimal water addition under the same shaking intensity and water addition temperature conditions, followed by the sample prepared in comparative example 4 and finally the reference formulation. The reason for this may be that sodium carboxymethylcellulose is used in the formulation of examples 1-3, and has a suitable binding and suspending effect, and swells after absorbing water. In addition, the invention adopts the fluidized bed granulation process, and the formed fine particles have high porosity (the porosity can be determined by adopting a particle porosity measuring method known in the art), which is favorable for moisture infiltration, thereby promoting the dispersion and dissolution of the particles.

The dissolution rate of the sodium carboxymethylcellulose in the formulation of comparative example 3 is affected only by the dissolution rate of the hydrophilic auxiliary material, and the dissolution rate is affected somewhat because the particle size of the prepared granules is finer without using a binder, so that the dissolution rate is slightly slower than the dispersion dissolution time of the samples prepared in examples 1 to 3.

The formulation of comparative example 4, which uses povidone K30 as the binder (viscosity less than 10 cP) and typically at a concentration of 10-30%, uses a concentration of about 10% but the prepared sample was dispersed and dissolved for a slower time than the samples prepared in examples 1-3, probably due to the binding effect alone.

The reference preparation is filled with powder, and poured into a bottle to form a powder pile, and the powder contacted with the bottom of the bottle is adhered to the bottom of the bottle quickly after meeting water due to the existence of a large amount of hydrophilic auxiliary materials and suspending agent xanthan gum in the prescription, and the powder at the outer layer of the powder pile delays the penetration and dissolution of water into the interior due to quick dissolution and adhesion, so that the dissolution and dispersion time is longest.

The results show that when the sample prepared by the invention is used, a small amount of water (warm water or normal temperature water) can be used for preparing a completely and uniformly dispersed suspension in a short time, and the sample is convenient to take.

3. Stability test

Stability studies were performed on inventive examples 1-3, comparative examples 1-4 and reference formulations (20 mg/1680mg gauge, lot number: 0061R, underwriter: salix) under accelerated test (40 ℃ C./75% RH), and the 0-month and 6-month properties and degradation impurities were examined, with the results shown in Table 13 below.

Table 13 results of stability investigation in acceleration test

Table 14 stability investigation 0 month-6 month accelerated degradation impurity growth level comparison

From the results in Table 14 above, it can be seen that the samples prepared in examples 1-3 have the same tendency to grow as the reference formulation under accelerated test conditions, indicating comparable stability. Since the reference formulation only remained half the effective period when tested for 0 month related substances, its 0 month degradation impurity level was slightly higher than that of the samples prepared in examples 1-3.

In the stabilizers of examples 1-3, anhydrous disodium hydrogen phosphate is used as a pH regulator, and the pH value of the drug-containing suspension is controlled within 8.4-9.6, so that the omeprazole is kept suspended in an adhesive solution and is prevented from being degraded, and the stability of a sample is ensured.

In comparative example 1, sodium carboxymethylcellulose was used as the binder, but no pH adjuster was used, and the pH of the formulated drug-containing suspension was 6.84, and compared with examples 1-3, the maximum known and unknown degradation impurities, and the total impurities, were both significantly increased, and the sample stability was significantly reduced.

The stabilizer of comparative example 2 uses sodium carboxymethylcellulose as binder, but reduces the dosage of anhydrous disodium hydrogen phosphate, the pH value of the prepared drug-containing suspension is 7.86, compared with examples 1-3, the maximum known and unknown degradation impurities and total impurities are also obviously increased, and the stability of the sample is reduced, but compared with comparative example 1, the stability is advantageous, and the pH value is favorably improved by using anhydrous disodium hydrogen phosphate to adjust.

The stabilizer of comparative example 3 was formulated with no binder and only anhydrous disodium hydrogen phosphate to give a drug-containing suspension having a pH of 9.08, with no significant difference in stability compared to examples 1-3.

The stabilizer of comparative example 4 was prepared as a drug-containing suspension having a pH of 8.98 using anhydrous disodium hydrogen phosphate as the pH adjuster and povidone K30 as the binder, and the maximum known degradation impurity increased slightly, but the maximum unknown degradation impurity increased significantly, and the total impurity increased significantly, as compared to examples 1-3, resulting in reduced stability.

In conclusion, compared with a reference preparation, the omeprazole sodium bicarbonate dry suspension prepared by the invention has almost consistent stability, in addition, the invention effectively solves the problem of raw material medicine adsorption, improves medicine dosage accuracy and safety, and simultaneously improves medicine dispersing speed, and is more convenient to use.

Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art will understand that: the technical scheme described in the foregoing embodiments can be modified or some of the technical features thereof can be replaced by equivalents. Such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. The compound omeprazole dry suspension is characterized by being prepared from raw materials containing an active ingredient, a diluent, a stabilizer and auxiliary materials, wherein the active ingredient comprises omeprazole and sodium bicarbonate, the stabilizer comprises a swelling adhesive and a pH regulator, and the omeprazole and the stabilizer are coated on the outer surface of the diluent after being mixed so as to form dry particles with loose porous structures on the surface.

2. The compound omeprazole dry suspension according to claim 1, wherein the pH adjustor comprises at least one of disodium hydrogen phosphate, sodium bicarbonate, sodium acetate, sodium citrate, sodium tartrate and sodium glycinate; the swellable binder comprises carboxymethyl cellulose or a salt thereof, preferably carboxymethyl cellulose, sodium carboxymethyl cellulose and/or calcium carboxymethyl cellulose, having a viscosity number of 10-200 cP; the auxiliary materials comprise at least one of suspending agents, sweetening agents and flavoring agents.

3. The compound omeprazole dry suspension according to claim 2, wherein the compound omeprazole dry suspension comprises 20-40 parts by weight of the active ingredient, 50-75 parts by weight of a diluent, 0.05-0.5 parts by weight of a stabilizer, 0.1-1 parts by weight of a suspending agent, 0.1-1 parts by weight of a sweetener and 0.1-1 parts by weight of a flavoring agent.

4. The compound omeprazole dry suspension according to claim 1, wherein the weight ratio of the binder to the pH adjuster is (1-5): 1 or the weight ratio of the omeprazole to the sodium bicarbonate is (20-100).

5. The compound omeprazole dry suspension according to claim 1, wherein the diluent comprises at least one of sucrose, xylitol, lactose, glucose, fructose, maltose, mannitol, sorbitol, microcrystalline cellulose, starch, dextrin, calcium phosphate and calcium sulfate.

6. The preparation method of the compound omeprazole dry suspension is characterized by comprising the following steps:

7. The method for preparing a compound omeprazole dry suspension according to claim 6, wherein the pH adjustor comprises at least one of disodium hydrogen phosphate, sodium bicarbonate, sodium acetate, sodium citrate, sodium tartrate and sodium glycinate;

The swellable binder comprises carboxymethyl cellulose or a salt thereof, preferably carboxymethyl cellulose, sodium carboxymethyl cellulose and/or calcium carboxymethyl cellulose, having a viscosity number of 10-200 cP;

The auxiliary materials comprise suspending agents, sweetening agents and flavoring agents;

The diluent comprises at least one of sucrose, xylitol, lactose, glucose, fructose, maltose, mannitol, sorbitol, microcrystalline cellulose, starch, dextrin, calcium phosphate and calcium sulfate.

8. The method for preparing the compound omeprazole dry suspension according to claim 6, wherein the preparation of the drug-containing suspension comprises the following steps: adding the pH regulator into water, stirring until the pH regulator is dissolved, continuously adding the swelling adhesive under stirring, stirring until the pH regulator is dissolved, adding the omeprazole, stirring and dispersing uniformly to obtain the drug-containing suspension.

9. The method for preparing a compound omeprazole dry suspension according to claim 6, wherein the fluid bed granulation comprises: the diluent is put into a fluidized bed, the air inlet temperature is set at 60-80 ℃, the air quantity is adjusted to enable the materials to be in a fluidized state, after the materials are preheated, the materials are sprayed into the medicine-containing suspension, the temperature of the materials is kept at 35-45 ℃ in the granulating process, the materials continue to be dried after the medicine-containing suspension is sprayed, the moisture of the particles is controlled to be less than 1.0%, and the obtained particles are sieved to obtain dry particles.

10. The method for preparing a compound omeprazole dry suspension according to claim 6, wherein the suspending agent comprises xanthan gum and the sweetener comprises sucralose.