CN107625754B - Cefpodoxime proxetil taste masking particles and preparation method thereof - Google Patents

Abstract

The invention relates to the field of pharmaceutical preparations, and particularly discloses cefpodoxime proxetil taste masking granules and a preparation method thereof. The taste masking particles are prepared by mixing cefpodoxime proxetil coated pellets and taste modifying particles, the coated pellets are provided with three-layer structures of a pill carrying layer, an isolating layer and a smooth layer from inside to outside, the invention mainly solves the problems that cefpodoxime proxetil products on the market are unpleasant in taste immediately after being taken by a child, the mouth feeling is extremely poor, the drug compliance of the child is poor and the drug taking is inconvenient because the child needs to take water, completely masks the bitter taste of the drug in order to improve the drug compliance of the child, adds components such as sweetening agents suitable for the child to take, removes the bitter taste of chemical drugs and increases aromatic odor, the child is easy to accept and feels pleasant to the aromatic odor, and thus the drug taking compliance of the child is improved. Besides improving the compliance of children in taking medicine, special auxiliary materials which can be directly swallowed without water when children in taking medicine are added into the prescription, so that the problem that children in patients are inconvenient to take medicine is solved.

Description

Cefpodoxime proxetil taste masking particles and preparation method thereof

Technical Field

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

Background

Cefpodoxime Proxetil (Cefpodoxime Proxetil) is a third generation oral broad spectrum cephalosporin, a beta-lactam antibiotic, developed by san congo japan, first marketed in japan in 1990 under the trade name: borna, schbo, gabor, lianbo, bovoxin, banan, Cepodem, Vantin, chemical name (6R,7R) -7- [2- (2-aminothiazol-4-yl) -2- (Z) - (methoxyimino) -acetamido ] -3-methoxymethyl-8-oxo-5-thio-1-azabicyclo- [4,2,0] oct-2-ene-2-carboxylic acid isopropoxycarbonyloxyethyl ester.

Cefpodoxime proxetil is a prodrug of cefpodoxime proxetil, has no antibacterial activity, is absorbed by intestinal tracts after being taken orally, is hydrolyzed into cefpodoxime proxetil by nonspecific esterase on the intestinal wall, can inhibit the membrane transpeptidase of a bacterial cell wall system, ensures that the transpeptidase forming cross-linking can not be carried out, prevents the synthesis of sticky peptide of the bacterial cell wall, causes the defect of the cell wall of a cell, leads the bacterial cell to lose a protective barrier, leads the bacteria to swell, deform and break to die, and realizes the bactericidal action by inhibiting the biosynthesis of the microbial cell wall. The antibacterial spectrum of the cefpodoxime proxetil comprises staphylococcus, streptococcus, gram-positive bacteria and gram-negative bacteria, and the cefpodoxime proxetil is mainly used for treating urinary tract infection, gonorrhea, skin infection and upper respiratory tract and lower respiratory tract infection clinically. Moreover, many penicillin and cephalosporin resistant beta-lactamase-producing microorganisms are still sensitive to this product because cefpodoxime proxetil is highly stable against beta-lactamase.

The cefpodoxime proxetil products in the market are mainly tablets, capsules and dry suspensions, but the cefpodoxime proxetil is cephalosporins, so that the medicines are unstable to water and acid, and the main medicines have the characteristics of bitter taste, peculiar smell and the like, so that the application of the cefpodoxime proxetil is limited, and particularly for children, the cefpodoxime proxetil has low medication compliance.

Chinese patent No. CN103230367B discloses a cefpodoxime proxetil composition dry suspension and a preparation method thereof, the method obtains the cefpodoxime proxetil dry suspension with high dissolution rate and good stability under the premise of omitting the addition of a suspending agent through the combined action of sucrose, mannitol and starch slurry, but a large amount of flavoring agents are added in the method to not completely cover the peculiar smell of the medicine, the taste remained in the oral cavity after the administration is still remarkable, and the administration of the cefpodoxime proxetil composition dry suspension by adding water is inconvenient for children.

The Chinese patent application with publication number CN103919734A discloses a cefpodoxime proxetil pellet, a microcapsule and a preparation method thereof, which are composed of a base pill and a protective coating coated on the surface of the base pill, but the product solves the problem of bitter taste of the medicament to a certain extent, but the product is swallowed by water when in use, has poor smooth mouthfeel and does not solve the defect of poor medicament administration compliance.

Disclosure of Invention

The invention mainly solves the problems that the cefpodoxime proxetil product on the market immediately generates unpleasant bitter taste after being taken by a child, the taking taste is extremely poor, the drug compliance of the child is poor and the drug taking is inconvenient because the child needs to take the drug by water, completely covers the bitter taste of the drug for improving the drug taking compliance of the child, adds sweetening agents and other components suitable for the child to take so as to remove the bitter taste of chemical drugs and increase aromatic odor, is easy to be accepted by the child and is pleasant to the aromatic odor, thereby improving the drug taking compliance of the child. Besides improving the compliance of children in taking medicine, special auxiliary materials which can be directly swallowed without water when children in taking medicine are added into the prescription, so that the problem that children in patients are inconvenient to take medicine is solved.

The invention aims to provide a cefpodoxime proxetil coated pellet which is provided with a three-layer structure of a pill carrier, an isolating layer and a smooth layer from inside to outside.

The cefpodoxime proxetil coated pellet comprises a drug-loaded pellet at the innermost layer, an active ingredient cefpodoxime proxetil and optional auxiliary materials selected from one or more of the following materials: the pellet core comprises a pellet core matrix, an adhesive, an anti-sticking agent, a plasticizer, a surfactant, a filler, a flavoring agent, a wetting agent, a disintegrating agent and the like, and preferably, the pellet core matrix contains auxiliary materials, an adhesive and a cosolvent.

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

Preferably, the pill-carrying components and the content percentages thereof are as follows:

wherein the content of the cefpodoxime proxetil is preferably 15-30%, more preferably 15-25%, and more preferably 15-20%.

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

Wherein the content of the cosolvent is preferably 0.1-9%, more preferably 0.2-5%, and more preferably 0.3-2%.

The content of the binder is preferably 2% to 9%, more preferably 2.5% to 8%, and still more preferably 3% to 6%.

The cefpodoxime proxetil coated pellet provided by the invention is characterized in that the smooth layer comprises one or more of the following components: film forming material, anti-sticking agent, plasticizer, surfactant, filler, correctant, wetting agent, disintegrant, gel, pH regulator, etc. Preferably contains component adhesive, anti-adhesive agent, gel agent, and pH regulator.

The binder is selected from one or more of the following: yutex, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, and the like; the anti-adhesive agent is selected from one or more of the following substances: talcum powder, stearic acid, magnesium stearate, superfine silica gel powder, glyceryl stearate and the like; the gelling agent is selected from one or more of the following substances: carbomer, gelatin, carrageenan, xanthan gum, agar, and the like. The pH regulator is selected from one or more of the following substances: sodium bicarbonate, sodium dihydrogen phosphate, sodium carbonate, sodium sesquicarbonate, etc. . The smooth layer is added with a film forming material and a gel, the film forming material is a taste masking component in the taste masking layer, and the taste masking layer is formed after coating, so that the peculiar smell and the bitter taste of the main medicine can be effectively isolated, and a good taste masking effect is achieved; the gel can form gel after meeting water, so that the surface of the drug-loaded pill is very smooth, the oral taste is improved, and the effect of swallowing without water can be achieved.

Preferably, the taste-masking smooth layer comprises the following components in percentage by weight:

the content of the film forming material is preferably 20% to 35%, more preferably 25% to 35%, and still more preferably 30% to 35%.

The content of the anti-adhesive agent is preferably 20% to 35%, more preferably 25% to 35%, and still more preferably 30% to 35%.

The content of the gel is preferably 10-20%, more preferably 12-18%, and more preferably 14-16%.

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

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

The cefpodoxime proxetil coated pellet of the present invention has the isolating layer of material selected from pharmaceutically acceptable compounds, such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and other components, used alone or in mixture. Additives such as plasticizers, anti-sticking agents and antistatic agents, such as magnesium stearate, titanium dioxide, talc and other additives may also be included in the barrier layer. The gel in the taste-masking smooth layer is contacted with the cefpodoxime proxetil, so that impurities in the cefpodoxime proxetil are unstable, acceleration and long-term stability of the cefpodoxime proxetil are reduced, and the isolation layer can prevent the main drug cefpodoxime proxetil from being contacted with the gel and other auxiliary materials, so that the stability of a sample is enhanced.

In a preferred embodiment of the present invention, the isolating layer coating composition comprises: hydroxypropyl methylcellulose, polyethylene glycol, and pulvis Talci.

The cefpodoxime proxetil coated pellet can be mixed with taste-modifying particles to prepare taste-masking granules with better taste-masking effect. The taste-masking effect of the cefpodoxime proxetil coated pellet can be further enhanced by the taste-masking particles, the taste and compliance of patients, especially children patients, in taking medicine are increased, and the taste-masking particles can be any pharmaceutical auxiliary material or mixture thereof which can cover the peculiar smell of cefpodoxime proxetil and is easily accepted by patients, especially children patients, for example, one or more of the following components are contained: aromatic, sweetener, sour agent, diluent, gel, and lubricant.

The aromatic is selected from one or more of artificial essence or natural essence, the natural essence comprises lemon oil, anise oil, peppermint oil, etc., and the artificial essence comprises sweet orange essence, strawberry essence, vanilla essence, peppermint essence, lemon essence, banana essence, etc.; the sweetener is one or more selected from aspartame, sucralose, acesulfame potassium, sodium cyclamate, mannitol and sorbitol; the sour agent is selected from one or more of citric acid, sodium citrate, potassium citrate, monosodium citrate, malic acid and tartaric acid; the diluent is selected from one or more of sorbitol, mannitol and sucrose; the adhesive is selected from one or more of sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose; the lubricant is not particularly limited, and may be one or more of pharmaceutically commonly used lubricants, such as talc, magnesium stearate, stearic acid, aerosil, titanium dioxide, and magnesium oxide; the taste-modifying granule can further remove the bitter taste of chemical drugs and increase aromatic smell, so that children patients can easily accept the granules and feel pleasurable to the aromatic smell, and the compliance of children in taking the granules is improved.

More preferably, the flavoring material comprises the following components in percentage by weight:

wherein the content of the diluent is preferably 55-90%, more preferably 60-85%; the content of the adhesive is preferably 2 to 8 percent, and more preferably 3 to 7 percent; the content of the lubricant is preferably 0.2-8%, and more preferably 0.5-6%; the content of the sweetener is preferably 0.2 to 8 percent, and more preferably 0.5 to 6 percent; the fragrance content is preferably from 0.2% to 8%, more preferably from 0.5% to 6%; the content of the sour agent is preferably 0.5% to 8%, more preferably 2% to 6%.

Another object of the present invention is to provide a method for preparing a stable cefpodoxime proxetil coated pellet, which comprises the steps of preparing a pellet carrier, coating an isolation layer, and coating a taste-masking smooth layer.

The medicine carrying pill is prepared by spraying medicine coating on the pill core substrate by adopting a fluidized bed method, and then an isolating layer and a taste masking smooth layer are sequentially coated outside the medicine carrying pill, and each layer is coated by adopting a fluidized bed.

In the invention, preferably, in order to achieve the effect of smooth swallowing of patients and excellent taste after taking medicines, the particle size range of the medicine-containing pellets can be controlled to be 0.4-0.7 μm, after taking medicines with the particle size smaller than 0.3 μm, the individual medicine-containing pellets are easy to block the teeth gaps, and the medicine-taking taste is seriously reduced by the particle size larger than 0.8 μm.

Specifically, the method comprises the following steps:

preparing the pill: adding the components except the pill core matrix into an ethanol solution, dissolving to form a medicine-applying solution, and coating the sucrose pill core with the medicine-applying solution by adopting a fluidized bed to prepare a pill-carrying pill;

and (3) coating of an isolation layer: adding the components of each isolation layer into purified water for dissolving or dispersing, fully stirring to form an isolation layer solution, and performing encapsulation of the isolation layer by adopting a fluidized bed.

And (3) coating a smooth layer: and (3) preparing the components of the smooth layer into ethanol to prepare ethanol suspension, and then coating the taste masking layer by adopting a fluidized bed.

It should be noted that the cefpodoxime proxetil coated pellet of the present invention can be mixed with other taste-masking particles to prepare a cefpodoxime proxetil taste-masking particle with a better taste-masking effect. The taste-modifying material can be prepared by wet granulation, and the finished product can be prepared by uniformly mixing the coated drug-loaded pellets and the taste-modifying material.

The taste-modifying granules can be prepared by a wet granulation process, for example, as follows: putting the materials into a wet granulator, starting the granulator to mix the materials, adding a proper amount of ethanol into the materials in an atomized form under the stirring state, granulating for a certain time, and performing wet granulation; drying by a fluidized bed and then performing dry granulation; and adding sodium carboxymethylcellulose and magnesium stearate into the granules according to the formula ratio according to the yield of the materials, and uniformly mixing to form the flavoring component.

The cefpodoxime proxetil coated drug-loaded pellet completely covers the peculiar smell of the drug, in order to realize the anhydrous swallowing effect, the outermost layer of the pellet needs to be coated with a smooth layer, the smooth layer is added with a taste masking component capable of masking the peculiar smell of the main drug, and a special auxiliary material gel which can be directly swallowed without water when a child takes the drug is also added, the gel can form gel after meeting water, so that the surface of the pellet is very smooth, and the problem of inconvenience in taking the drug by the child is solved. Most of the gel is pH sensitive auxiliary materials, so that impurities in the cefpodoxime proxetil are unstable after the gel is contacted with the cefpodoxime proxetil, the risk of acceleration and unqualified long-term sample stability exists, an isolation layer needs to be wrapped outside the drug-loaded pill, the pH sensitive auxiliary materials are prevented from being directly contacted with the cefpodoxime proxetil, and the stability of the sample is greatly enhanced. Thus, the cefpodoxime proxetil coated pellet of the present invention has been completed. In addition, flavoring particles containing essence and sweetener suitable for children can be added, bitter taste and peculiar smell of chemical medicines are further removed, aromatic smell is increased, children patients can easily accept the flavoring, and the flavor of the aromatic smell is pleasant, so that the compliance of children in taking medicine is improved.

Detailed Description

The cefpodoxime proxetil taste masking particles of the present invention are further illustrated by the following examples, but the present invention is not limited to the following examples. Therefore, simple modifications to the present invention in the context of the method of the present invention are within the scope of the claimed invention.

Example 1

The preparation process comprises the following steps:

1. preparation of pellet-carrying pill

Dissolving PEG6000 in a certain amount of purified water, mixing an aqueous solution containing PEG6000 with absolute ethanol to prepare an 80% ethanol solution, dissolving hydroxypropyl cellulose in the 80% ethanol solution, adding a main drug cefpodoxime proxetil after the hydroxypropyl cellulose is completely dissolved, forming a drug solution after the main drug is completely dissolved, and coating a drug-containing layer on a sucrose pellet core by adopting a fluidized bed, wherein the material is controlled at 30-35 ℃ in the coating process. The water content of the pill is controlled below 3%.

2. Wrapping of barrier layers

Adding the polyethylene glycol 6000 and the hydroxypropyl methylcellulose 603 in the prescription amount into the purified water in the stirring process, and after the polyethylene glycol 6000 and the hydroxypropyl methylcellulose 603 are completely dissolved, adding the talcum powder in the prescription amount and stirring until the talcum powder is fully dispersed in the solution to form the final solution. The fluidized bed is adopted for coating the isolating layer, and the material is controlled to be 40 +/-2 ℃ in the coating process.

3. Smooth layer wrapping

The Eudragit E100 and other components in the prescription are prepared into ethanol suspension with fixed concentration, a fluidized bed is adopted for coating a taste masking layer, and the material temperature is controlled to be 30 +/-5 ℃ in the coating process according to the properties of the coating material.

4. Preparation of taste-modifying granules

Putting sorbitol, essence, aspartame and anhydrous citric acid into a wet granulator, starting a bottom paddle and a side paddle of the granulator, mixing the materials, adding a proper amount of ethanol into the materials in an atomized manner under the stirring state, granulating for a certain time, and performing wet granulation by adopting a 20-mesh screen. Drying with fluidized bed, controlling material temperature at 50 deg.C in the drying process, reaching drying end point when the water content of the granule is less than 3%, and drying and grading with 20 mesh sieve. And adding sodium carboxymethylcellulose and magnesium stearate into the granules according to the formula ratio according to the yield of the materials, and uniformly mixing to form the flavoring component.

5. Mixing the pellets with the taste-modifying granules:

and mixing the coated pellets with the taste-modifying particles to obtain the cefpodoxime proxetil taste-masking particles.

Example 2

Example 2 the process of preparation is as described in example 1, except that the flavor-modifying particles are removed from the product of example 1.

Example 3

Example 4

Examples 3-4 preparation of samples reference example 1.

Detection indexes and results are as follows:

1. evaluation of the effect of water-free swallowing:

after 10 volunteers had tried to take the samples orally, the samples were scored. The 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

	Has satisfactory mouthfeel	Has good taste	Has good taste, but is acceptable
				Example 1	7 persons	3 persons	0 person
Example 2	6 persons	3 persons	1 person
				Example 3	5 persons	5 persons	0 person
Example 4	8 persons	2 persons	0 person

2. The results of the release rate measurements were as follows:

the release rate of the cefpodoxime proxetil taste-masking particles in the medium with the pH of 3.0 is determined under the following conditions: medium ph3.0, slurry, 75 rev, release medium 900 ml.

Table 2: results of the degree of release of the sample in acidic media

The results show that: the active ingredients meet the requirement of quick release in acid, also meet the effect of quick release in stomach and realize quick effect.

Claims (9)

1. The cefpodoxime proxetil odor masking particle is characterized by comprising a cefpodoxime proxetil coated pellet and a taste-modifying particle,

wherein the cefpodoxime proxetil coated pellet comprises three layers of structures of a pill carrier, an isolating layer and a smooth layer from inside to outside,

wherein the drug-loaded pill contains an auxiliary material pill core matrix, an adhesive and a cosolvent,

wherein the pill-carrying components and the content percentage thereof are as follows:

wherein the cosolvent is polyethylene glycol, and the pellet core matrix is a sucrose pellet core; the adhesive is hydroxypropyl cellulose;

wherein the isolating layer is made of polyethylene glycol and hydroxypropyl methyl cellulose;

wherein the smooth layer comprises the following components in percentage by weight:

wherein the film-forming material is Ewing; the anti-adhesive agent is selected from one or more of the following substances: talcum powder, stearic acid, magnesium stearate, superfine silica gel powder and glyceryl stearate; the gel is carbomer; the pH regulator is selected from one or more of the following substances: sodium bicarbonate, sodium dihydrogen phosphate, sodium carbonate, sodium sesquicarbonate;

wherein the flavoring particles comprise a flavoring agent, a sweetener, an acidulant, a diluent, a lubricant, and a binder,

wherein the content of the diluent is 55 to 90 percent, the content of the adhesive is 2 to 8 percent, the content of the lubricant is 0.2 to 8 percent, the content of the sweetening agent is 0.2 to 8 percent, the content of the aromatic agent is 0.2 to 8 percent, the content of the sour agent is 0.5 to 8 percent,

wherein the diluent is sorbitol, the binder is sodium carboxymethylcellulose, the aromatic is one or more of artificial essence and natural essence, the natural essence comprises lemon oil, anise oil and peppermint oil, and the artificial essence comprises sweet orange essence, strawberry essence, vanilla essence, peppermint essence, lemon essence and banana essence; the sweetener is one or more selected from aspartame, mannitol, sorbitol, sucralose, acesulfame potassium and sodium cyclamate; the sour agent is one or more selected from citric acid, sodium citrate, potassium citrate, monosodium citrate, malic acid and tartaric acid; the lubricant is selected from one or more of magnesium stearate, talcum powder, stearic acid, superfine silica gel powder, titanium dioxide and magnesium oxide.

2. The cefpodoxime proxetil taste-masking granule of claim 1 wherein the pellet further comprises an adjuvant selected from one or more of the following: anti-sticking agent, plasticizer, surfactant, filler, correctant, wetting agent, and disintegrating agent.

3. The cefpodoxime proxetil taste-masking particle according to claim 1 wherein the slip layer further comprises one or more ingredients selected from the group consisting of: plasticizer, surfactant, filler, correctant, wetting agent, and disintegrating agent.

4. The cefpodoxime proxetil taste-masking granule according to claim 1 wherein the isolation layer further comprises one or more additional additives selected from the group consisting of magnesium stearate, titanium dioxide, talc, aerosil, stearic acid.

5. The method for preparing cefpodoxime proxetil odor-masking granules according to any one of claims 1 to 4, wherein the inner drug-loaded pellets are prepared by a fluidized bed method by spraying a drug coating on a pellet core substrate, the isolation layer and the smooth layer are sequentially coated by the fluidized bed method, the odor-modifying granules are prepared by a wet granulation process, and finally the prepared coated pellets are mixed with the odor-modifying granules.

6. The method for preparing cefpodoxime proxetil taste-masking granules according to claim 5, wherein the method for preparing the pill-carrying layer, the isolating layer and the smoothing layer comprises the following steps:

preparing the pill: adding the components except the pill core matrix into an ethanol solution, dissolving to form a medicine-applying solution, and coating the sucrose pill core with the medicine-applying solution by adopting a fluidized bed to prepare a pill-carrying pill;

and (3) coating of an isolation layer: adding the components of each isolation layer into purified water for dissolving or dispersing, fully stirring to form an isolation layer solution, and wrapping the isolation layers by adopting a fluidized bed;

and (3) coating a smooth layer: and (3) preparing the components of the smooth layer into ethanol to prepare ethanol suspension, and then coating the taste masking layer by adopting a fluidized bed.

7. Cefpodoxime proxetil taste masking granules, the unit dose of which is formulated as follows:

8. cefpodoxime proxetil taste masking granules, the unit dose of which is formulated as follows:

9. cefpodoxime proxetil taste masking granules, the unit dose of which is formulated as follows: