CN107625754A - A kind of Cefpodoxime Proxetil taste masked particle and preparation method thereof - Google Patents

Abstract

The invention relates to the field of pharmaceutical preparations, and specifically discloses a taste-masking granule of cefpodoxime axetil and a preparation method thereof. The taste-masking granules are prepared by mixing cefpodoxime-coated pellets and flavor-correcting granules. The coated pellets have a three-layer structure from the inside to the outside, including drug-loaded pellets, an isolation layer and a smooth layer. There are cefpodoxime axetil products on the market, which produce unpleasant bitter taste immediately after taking the children, and the taste is extremely bad when taking the medicine. The children's medication compliance is poor and the medicine needs to be washed with water, which leads to the inconvenience of taking the medicine. In order to improve the children's medication compliance Completely cover up the bitterness of the medicine itself, and add ingredients such as sweeteners suitable for children to remove the bitterness of chemical medicines and increase the aroma, which is easy for children to accept and feel happy about the aroma, thus improving children's medication compliance . In addition to improving children's compliance with medication, special excipients are added to the prescription to enable children to swallow the medicine without water, which solves the problem of inconvenient medication for children.

Description

A kind of cefpodoxime axetil taste-masking granules and preparation method thereof

technical field

The invention relates to the field of pharmaceutical preparations, in particular to a taste-masking granule of cefpodoxime axetil and a preparation method thereof.

Background technique

Cefpodoxime Proxetil (Cefpodoxime Proxetil) is a third-generation oral broad-spectrum cephalosporin, which belongs to the β-lactam antibiotics. It was developed by Sankyo Company of Japan and was first listed in Japan in 1990. The trade names are: Bona, Shibo , Jiabo, Liangbo, Bowoxin, banan, Cepodem, Vantin, the chemical name is (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-(form Oxyimino)-acetamido]-3-methoxymethyl-8-oxo-5-thio-1-azabicyclo-[4,2,0]oct-2-ene-2-carboxylic acid isopropyl Oxycarbonyloxyethyl ester.

Cefpodoxime axetil is the prodrug of cefpodoxime, which itself has no antibacterial activity. After oral administration, it is absorbed through the intestinal tract and is hydrolyzed into cefpodoxime by non-specific esterase in the intestinal wall. Cefpodoxime can inhibit the membrane boundary of the bacterial cell wall system. Transpeptidase, which prevents the transpeptidation that forms cross-links, blocks the synthesis of mucopeptides on the bacterial cell wall, causes cell wall defects, and bacterial cells lose their protective barrier, causing bacteria to swell, deform, rupture and die, that is, by inhibiting the biological activity of microbial cell walls Synthetic to achieve bactericidal effect. The antibacterial spectrum of cefpodoxil includes Staphylococcus, Streptococcus, Gram-positive bacteria and Gram-negative bacteria, and it is mainly used clinically for the treatment of urinary tract infections, gonorrhea, skin infections, and upper and lower respiratory tract infections. Moreover, because cefpodoxime is highly stable to β-lactamase, many β-lactamase-producing microorganisms resistant to penicillins and cephalosporins are still sensitive to this product.

The cefpodoxime products on the market are mainly tablets, capsules and dry suspensions, but because cefpodoxime is a cephalosporin, this type of medicine is unstable to water and acid, and the main drug has bitter taste, It has characteristics such as peculiar smell, so that its application is limited, especially for children, its medication compliance is not high.

The Chinese patent with the notification number CN103230367B discloses a dry suspension of a cefpodoxime ester composition and a preparation method thereof. The method, through the joint action of sucrose, mannitol, and starch slurry, under the premise of omitting the addition of a suspending agent, Obtained the dry suspension of cefpodoxime proxil with high dissolution rate and good stability, but this method adds a large amount of correctives and does not completely cover the peculiar smell of the medicine, and the residual taste in the oral cavity is still significant after taking, and adding water Swallowing is not convenient for children.

The Chinese patent application with publication number CN103919734A discloses a kind of cefpodoxime-exime pellets, microcapsules and preparation method thereof, which are composed of base pellets and the protective coating coated on the surface of the base pellets. The problem of bitter taste of the medicine is solved, but the mouthfeel is not good when swallowed with water during use, and the defect of poor compliance with taking medicine is not solved.

Contents of the invention

The present invention mainly solves the problem that the existing cefpodoxime axetil product on the market produces unpleasant bitter taste immediately after being taken by children, the mouthfeel is extremely bad, the children's medication compliance is poor, and the medicine needs to be washed with water, which leads to the inconvenience of taking the medicine. The compliance of children's medication completely covers the bitterness of the medicine itself, and adds ingredients such as sweeteners suitable for children to remove the bitterness of chemical medicines and increase the aroma, which is easy for children to accept and feel happy about the aroma, thus improving the quality of life. Medication adherence in children. In addition to improving children's compliance with medication, special excipients are added to the prescription to enable children to swallow the medicine without water, which solves the problem of inconvenient medication for children.

One of the objects of the present invention provides a kind of cefpodoxime-coated pellets, and the coated pellets have a three-layer structure of drug-loading pellets, isolation layer and smooth layer from the inside to the outside.

In the cefpodoxime axetil coated pellets of the present invention, the innermost drug-loaded pellets include the active ingredient cefpodoxime axetil and one or more auxiliary materials selected from the following: ball core matrix, adhesive, anti-adhesive Agents, plasticizers, surfactants, fillers, flavoring agents, wetting agents, disintegrants, etc., preferably containing auxiliary materials, pellet core matrix, binder, and cosolvent.

The co-solvent is selected from one or more of the following substances: polyethylene glycol, polysorbate, sodium lauryl sulfate, benzoic acid, sodium benzoate, salicylic acid, sodium salicylate, p-aminobenzoic acid etc.; the core matrix is selected from one or more of the following substances: sucrose cores, microcrystalline cellulose cores, mannitol cores, etc.; the binder is selected from one or more of the following substances : Hydroxypropyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, gelatin, etc.

Preferably, the ingredients of the pills and their content percentages are:

Wherein the content of cefpodoxime axetil is preferably 15%-30%, more preferably 15%-25%, more preferably 15%-20%.

Wherein the core matrix content is preferably 55%-85%, more preferably 65%-85%, more preferably 75%-80%.

Wherein the co-solvent content is preferably 0.1%-9%, more preferably 0.2%-5%, more preferably 0.3%-2%.

Wherein the binder content is preferably 2%-9%, more preferably 2.5%-8%, more preferably 3%-6%.

Cefpodoxime axetil coated pellets in the present invention, wherein said smooth layer comprises one or more selected from the following components: film-forming material, anti-sticking agent, plasticizer, surfactant, filler , flavoring agent, wetting agent, disintegrating agent, gelling agent, pH regulator, etc. It is preferable to contain the components binder, antisticking agent, gelling agent, pH adjusting agent therein.

The binder is selected from one or more of the following substances: Eudragit, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, etc.; The adhesive is selected from one or more of the following substances: talcum powder, stearic acid, magnesium stearate, micronized silica gel, glyceryl stearate, etc.; the gel is selected from one or more of the following substances Species: carbomer, gelatin, carrageenan, xanthan gum, agar, etc. The pH regulator is selected from one or more of the following substances: sodium bicarbonate, sodium dihydrogen phosphate, sodium carbonate, trisodium bicarbonate and the like. . The smooth layer is added with film-forming material and gel agent. The film-forming material is the taste-masking ingredient in the taste-masking layer. After coating, a taste-masking layer is formed, which can effectively isolate the peculiar smell and bitterness of the main drug and achieve good taste-masking. Effect: The gel can form a gel when it meets water, making the surface of the pills very smooth, improving the oral taste and achieving the effect of swallowing without water.

Preferably, the ingredients of the taste-masking smooth layer and their content percentages are:

Wherein the content of the film-forming material is preferably 20%-35%, more preferably 25%-35%, more preferably 30%-35%.

Wherein the content of the anti-sticking agent is preferably 20%-35%, more preferably 25%-35%, more preferably 30%-35%.

Wherein the gelling agent content is preferably 10%-20%, more preferably 12%-18%, more preferably 14%-16%.

Wherein the content of the pH regulator is preferably 20%-35%, more preferably 25%-35%, more preferably 30%-35%.

Preferably, the smooth layer comprises a gelling agent selected from carbomers.

Cefpodoxime axetil coated pellets of the present invention, wherein the material of the isolation layer is selected from pharmaceutically acceptable compounds, such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxyl Propyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and other ingredients, either alone or in admixture. Additives such as plasticizers, antiadhesive and antistatic agents such as magnesium stearate, titanium dioxide, talc and other additives may also be included in the release layer. Because the impurity in the cefpodoxime axetil will be destabilized after the gel in the taste-masking smooth layer contacts with cefpodoxime axetil, thereby reducing its acceleration and long-term stability, the isolation layer can avoid main drug cefpodoxime axetil Esters are in contact with gelling agents and other excipients to enhance sample stability.

In a preferred embodiment of the present invention, the coating components of the isolation layer include: hypromellose, polyethylene glycol, and talc.

The cefpodoxime axetil coated pellets of the present invention can be mixed with taste-correcting granules to prepare taste-masking granules with better taste-masking effects. The taste-correcting granules can further enhance the taste-masking effect of the cefpodoxime axetil-coated pellets, and increase the mouthfeel and compliance of patients, especially children, when taking medicine. Pharmaceutical excipients or mixtures thereof that have an unpleasant smell and are easily accepted by patients, especially children, for example, contain one or more of the following ingredients: fragrances, sweeteners, sour agents, diluents, gels, lubricant.

The fragrance is selected from one or more of artificial flavors or natural flavors, natural flavors include lemon oil, fennel oil, peppermint oil, etc., artificial flavors include sweet orange flavor, strawberry flavor, vanilla flavor, mint flavor, lemon flavor , banana essence, etc.; the sweetener is selected from one or more of aspartame, sucralose, acesulfame K, cyclamate, mannitol, sorbitol; the sour agent is selected from citric acid , one or more of sodium citrate, potassium citrate, monosodium citrate, malic acid, tartaric acid; the diluent is selected from one or more of sorbitol, mannitol, sucrose; the viscous The mixture is selected from one or more of sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose; the lubricant has no special Limitation, it can be a pharmaceutically commonly used lubricant, such as one or more selected from talcum powder, magnesium stearate, stearic acid, micronized silica gel, titanium dioxide, and magnesium oxide; flavoring particles can further remove chemical drugs The bitter taste and increase the aromatic smell, so that children are easy to accept and feel happy about the aromatic smell, and improve children's medication compliance.

More preferably, the flavoring material comprises the following ingredients in content percentage:

Wherein the diluent content is preferably 55% to 90%, more preferably 60% to 85%; the binder content is preferably 2% to 8%, more preferably 3% to 7%; the lubricant content is preferably 0.2% to 8%, more preferably 0.5% to 6%; sweetener content is preferably 0.2% to 8%, more preferably 0.5% to 6%; flavoring agent content is preferably 0.2% to 8%, more preferably 0.5% to 6%; the sour agent content is preferably 0.5% to 8%, more preferably 2% to 6%.

Another object of the present invention is to provide a preparation method of stable cefpodoxime axetil coated pellets, the method comprising the preparation of loaded pills, the encapsulation of the isolation layer and the encapsulation of the taste-masking smooth layer.

The drug-loaded pills of the present invention are prepared by spraying drug coating on the core matrix of the pills by using a fluidized bed method, and then sequentially wrap the drug-loaded pills with an isolation layer and a taste-masking smooth layer, and each layer is coated with a fluidized bed. cover.

In the present invention, as a preference, in order to achieve the effect of smooth swallowing and good taste after taking the medicine, the particle size range of the drug-containing pellets can be controlled to be between 0.4 and 0.7 μm, and individual drug-containing pellets with a particle size of less than 0.3 μm can be controlled. Pills are easy to clog the gap between the teeth, and when the particle size is greater than 0.8 μm, the taste of the medicine will be reduced and the gritty feeling will be serious.

Specifically, the inventive method comprises the steps:

Preparation of drug-loaded pills: add ingredients other than the core matrix to the ethanol solution, dissolve and form a drug-coating solution, and use a fluidized bed to coat the sucrose ball core with the drug-coating solution to prepare drug-loaded pills;

Packaging of the isolation layer: Add the components of the isolation layer to purified water to dissolve or disperse them, and form an isolation layer solution after fully stirring, and use a fluidized bed for the packaging of the isolation layer.

Encapsulation of the smooth layer: Divide the components of the smooth layer into ethanol to make an ethanol suspension, and then use a fluidized bed for encapsulation of the taste-masking layer.

It should be noted that the cefpodoxime axetil coated pellets of the present invention can be mixed with other taste-correcting granules to prepare cefpodoxime axetil taste-masking granules with better taste-masking effect. The flavoring material can be prepared by wet granulation, and the finished product can be obtained by mixing the coated drug-loaded pellets with the flavoring material evenly.

Flavor granules can be prepared by wet granulation process, for example, the method is as follows: put each material in a wet granulator, start the granulator to mix the materials, and add an appropriate amount of ethanol in the form of atomization while the materials are stirring, After granulation for a certain period of time, carry out wet sizing; use fluidized bed to dry and then carry out dry sizing; add prescription ratio carboxymethyl cellulose sodium and magnesium stearate to the granules according to the yield of materials, and mix them evenly to form corrected granules. flavor components.

The drug-loaded pellets coated with cefpodoxime axetil of the present invention completely cover up the peculiar smell of the drug itself. In order to realize the anhydrous swallowing effect, a smooth layer needs to be wrapped in the outermost layer of the pellets. In addition to the taste-masking ingredients that can mask the peculiar smell of the main drug, a special excipient gel is added so that children can swallow the medicine without water. The gel can form a gel when it meets water, making the surface of the pellets very It is smooth and smooth, which solves the problem of inconvenient medication for children. Since most of the gels are pH-sensitive excipients, the impurity in cefpodoxime axetil will be unstable after being in contact with cefpodoxime axetil, so there is a risk of accelerated and long-term sample stability unqualified, so it is necessary to A layer of isolation layer is wrapped to avoid direct contact between pH-sensitive excipients and cefpodoxime axetil, thereby greatly enhancing the stability of the sample. So far, the cefpodoxime axetil coated pellet of the present invention has been completed. In addition, it is also possible to increase the flavoring granules containing flavors and sweeteners suitable for children to further remove the bitterness and peculiar smell of chemical drugs and increase the aroma, so that children are easy to accept and feel happy about the aroma, thereby improving children's medication. of compliance.

detailed description

The taste-masking granules of cefpodoxime axetil of the present invention are further specifically described by the following examples, but the present invention is not limited to the following examples. Therefore, any simple improvement to the present invention under the premise of the method of the present invention belongs to the protection scope of the present invention.

Example 1

Preparation Process:

1. Preparation of Drug-Loaded Pills

First dissolve PEG6000 in a certain amount of purified water, then mix the aqueous solution containing PEG6000 with absolute ethanol to prepare an 80% ethanol solution, then dissolve hydroxypropyl cellulose in the above 80% ethanol solution, and wait for hydroxypropyl cellulose After the base cellulose is completely dissolved, add the main drug cefpodoxime axetil. After the main drug is completely dissolved, the drug solution is formed. The drug-containing layer is coated on the sucrose core by using a fluidized bed. The coating process controls the material at 30-35 ℃. The water content of the pills is controlled below 3%.

2. Packaging of the isolation layer

Add the prescribed amount of polyethylene glycol 6000 and hypromellose 603 into the prescribed amount of purified water being stirred, and after the polyethylene glycol 6000 and hypromellose 603 are completely dissolved, add the prescribed amount of talc The powder is stirred until the talc powder is fully dispersed in the solution to form a final solution. A fluidized bed is used for the coating of the isolation layer, and the coating process controls the material temperature at 40±2°C.

3. Packaging of smooth layer

The Eudragit E100 and other components in the prescription were prepared into a fixed concentration of ethanol suspension, and the taste-masking layer was coated by a fluidized bed. According to the properties of the coating material, the temperature of the material during the coating process was controlled at 30 ± 5°C.

4. Preparation of Flavoring Granules

Put sorbitol, essence, aspartame, and anhydrous citric acid in the wet granulator, turn on the bottom paddle and side paddle of the granulator, and mix the materials. The materials are in the form of atomization under stirring. Add an appropriate amount of ethanol, granulate for a certain period of time, and use a 20-mesh sieve for wet sizing. The fluidized bed is used for drying. During the drying process, the temperature of the material is controlled at 50°C, and the drying end point is reached when the moisture content of the particles is less than 3%. A 20-mesh sieve is used for dry sizing. According to the yield of materials, sodium carboxymethylcellulose and magnesium stearate are added into the granules according to the ratio of prescription, and mixed evenly to form flavoring components.

5. Mixing of pellets and flavoring granules:

The coated pellets are mixed with the taste-correcting granules to prepare the taste-masking granules of cefpodoxime axetil.

Example 2

The preparation method of Example 2 refers to Example 1, and the difference from the product of Example 1 is that the flavoring particles are removed.

Example 3

Example 4

Refer to Example 1 for the preparation method of the samples of Examples 3-4.

Test indicators and results:

1. Evaluation of the effect of swallowing without water:

After 10 volunteers tried the samples orally, the samples were scored and evaluated. Feedback from Table 1 can prove that the taste of the sample is good and is easily accepted by most people.

Table 1: Sample simulated mouthfeel results

satisfying taste good taste Average taste, but acceptable Example 1 7 people 3 people 0 people Example 2 6 people 3 people 1 person Example 3 5-people 5-people 0 people Example 4 8 people 2 people 0 people

2. The release test results are as follows:

The release measurement conditions of cefpodoxime axetil taste-masking granules in pH 3.0 medium are as follows: medium pH 3.0, paddle method, 75 revolutions, and 900 ml of release medium.

Table 2: Release results of samples in acidic media

The results showed that the active ingredients met the requirements of rapid drug release in acid, and also met the effect of rapid drug release in the stomach, achieving rapid onset of action.

Claims (14)

1. A cefpodoxime axetil coated pellet, the cefpodoxime axetil coated pellet comprises a three-layer structure of a drug-loaded pill, a barrier layer and a smooth layer from the inside to the outside. 2. cefpodoxime axetil coating pellet according to claim 1, described drug-loaded pill comprises active ingredient cefpodoxime axetil and is selected from following one or more adjuvants: pellet core matrix, binding agent, Anti-adhesive agent, plasticizer, surfactant, filler, flavoring agent, wetting agent, disintegrant, preferably containing auxiliary material pellet core matrix, binder, co-solvent. 3. cefpodoxime axetil coating pellet according to claim 2, described solubilizer is selected from one or more of following material: polyethylene glycol, polysorbate, sodium lauryl sulfate, benzene Formic acid, sodium benzoate, salicylic acid, sodium salicylate, p-aminobenzoic acid; the core matrix is selected from one or more of the following materials: sucrose core, microcrystalline cellulose core, mannitol core ; The binder is selected from one or more of the following substances: hydroxypropyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, gelatin. 4. according to claim 2 or 3 described cefpodoxime axetil coated pellets, wherein said loaded pill composition and content percentage thereof are: 5. The cefpodoxime axetil coated pellet according to any one of claims 1 to 4, wherein the smooth layer comprises one or more selected from the following components: binding agent, anti-sticking agent, Plasticizers, surfactants, fillers, flavoring agents, wetting agents, disintegrants, gelling agents, pH regulators; preferably contain film-forming materials, anti-sticking agents, gelling agents, pH regulators . 6. cefpodoxime axetil coating pellet according to claim 5, described film-forming material is selected from one or more of following material: Eudragit, polyvinylpyrrolidone, methyl cellulose, ethyl fiber hydroxypropyl cellulose, hypromellose; the anti-sticking agent is selected from one or more of the following substances: talcum powder, stearic acid, magnesium stearate, micro silica gel, glycerin stearate ester; the gelling agent is selected from one or more of the following substances: carbomer, gelatin, carrageenan, xanthan gum, agar; the pH regulator is selected from one or more of the following substances: carbonic acid Sodium hydrogen, sodium dihydrogen phosphate, sodium carbonate, trisodium bicarbonate. 7. The cefpodoxime axetil-coated pellets according to any one of claims 1 to 6, wherein the smooth layer comprises a gel selected from carbomer. 8. The cefpodoxime axetil coated pellets according to any one of claims 1 to 7, wherein the components of the smooth layer and their content percentages are: 9. The cefpodoxime axetil coated pellet according to any one of claims 1 to 8, wherein the material of the isolation layer is selected from one or more of the following pharmaceutically acceptable compounds: sugar, polyethylene glycol, Polyvinylpyrrolidone, Polyvinyl Alcohol, Polyvinyl Acetate, Hydroxypropyl Cellulose, Methyl Cellulose, Ethyl Cellulose, Hydroxypropyl Methyl Cellulose, Sodium Carboxymethyl Cellulose. 10. cefpodoxime axetil coating pellet according to claim 9, wherein said barrier layer also comprises one or more selected from magnesium stearate, titanium dioxide, talcum powder, micropowder silica gel, stearic acid other additives. 11. according to the preparation method of the cefpodoxime axetil coating pellet described in any one of claim 1～10, the drug-loaded pellet of wherein said inner layer adopts fluidized bed method, sprays medicine coating on ball core matrix The method is prepared, and the isolation layer and the smooth layer are sequentially coated by a fluidized bed method. 12. A taste-masking granule of cefpodoxime axetil, characterized in that it comprises the cefpodoxime axetil coated pellets and taste-correcting granules according to any one of claims 1-10. 13. cefpodoxime axetil taste-masking granules according to claim 12, wherein said taste-correcting granules comprise one or more of the following ingredients: fragrance, sweetener, sour agent, diluent, gel , lubricants, adhesives; wherein the flavoring agent is selected from one or more of artificial flavors or natural flavors, natural flavors include lemon oil, fennel oil, peppermint oil, artificial flavors include sweet orange flavor, strawberry flavor, Vanilla essence, mint essence, lemon essence, banana essence; the sweetener is selected from one or more of aspartame, mannitol, sorbitol, sucralose, acesulfame potassium, and cyclamate; the The sour agent is selected from one or more of citric acid, sodium citrate, potassium citrate, monosodium citrate, malic acid, tartaric acid; the diluent is selected from one or more of sorbitol, mannitol, sucrose Multiple; the binder is selected from one or more of sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose; The lubricant is selected from one or more of magnesium stearate, talcum powder, stearic acid, micronized silica gel, titanium dioxide, and magnesium oxide. 14. The preparation method of the cefpodoxime axetil taste-masking granules according to any one of claims 12 to 13, wherein the drug-loaded pellets of the inner layer adopt the fluidized bed method to spray the drug coating on the pellet core matrix For preparation, the isolation layer and the smooth layer are coated sequentially by a fluidized bed method, the taste-correcting granules are prepared by a wet granulation process, and finally the prepared coated pellets are mixed with the taste-correcting granules.