KR100370870B1 - Bitter taste-masked roxithromycin granule and production thereof - Google Patents

Abstract

PURPOSE: A method of making a roxithromycin granule by dissolving roxithromycin as macrolide antibiotics in a compound having a melting point in the range of 40 to 120deg.C and then adding aqueous or non-aqueous excipients as a dispersion medium for solidification is provided. It effectively masks the bitter taste of the roxithromycin while producing granules suitable for children and infants with ease. CONSTITUTION: The roxithromycin granule is prepared by the following process consisting of: thoroughly dissolving roxithromycin as macrolide antibiotics in 0.1 parts by weight of a compound having a melting point in the range of 40 to 120deg.C to mask the bitterness, based on roxithromycin; and then adding aqueous or non-aqueous excipients as a dispersion medium for solidification. The compound is at least one selected from the group consisting of fatty acid ester, wax, an aqueous and non-aqueous polymer material.

Description

Loxysomycin granules concealing bitterness and preparation method thereof

The present invention is a granule for increasing the convenience of taking the bitter taste of roxithromycin, a macrolide antibiotic (roxithromycin), which is very inconvenient to take or has a strong feeling of rejection of the drug. And a method for producing the same.

Roxithromycin used in the present invention is an antibiotic of the macrolide family and mainly exhibits antimicrobial effects on streptococci, pneumococci, gonococci, diphtheria bacteria, cholera bacteria, staphylococci, and especially of the respiratory system such as pharyngitis, acute bronchitis and bacterial pneumonia. It is characterized by an excellent therapeutic effect against infection. Unlike other macrolide antibiotics, roxysomycin has high gastrointestinal absorption and high blood levels and a long half-life. Due to these advantages, it is widely used in bacterial infections in children, but the bitterness is very strong, such as problems with other macrolide antibiotics, and there is a problem in that it is difficult to administer due to the objection of the drug when the powder is administered. Thus, the present invention provides a method that can overcome this disadvantage of loxithromycin.

In general, the formulation of the drug is prepared to be suitable for application to the human body. In particular, orally administered drugs are marketed in various formulations such as tablets, capsules, powders, granules, liquids, etc., which are designed to overcome the disadvantages of drugs and to be suitable for administration. However, in some cases, it is necessary to change the properties of the drug due to the constraints of the formulation, there is a limit in the selection of the formulation to overcome the disadvantages of the drug. For example, children or elderly people who have difficulty taking tablets or capsules may be easier to take with granules or powders, but if the taste of the drug is very irritating, powders or granules prepared by the usual methods may be It does not form a proper formulation because it exposes the taste as it is. In such cases, it is desirable to mask the irritating taste of the drug and then formulate it as a powder or granules.

U.S. Patent No. 5707646 discloses a method of formulating a dry syrup by concealing bitter taste by mixing it with Eudragit egg (R) and tooth (E), which have a very strong bitterness, and macrolide antibiotics having a melting point of 40-120 ° C. Described. Eudragit eggs (R) and (E) are soluble in acidic or weakly acidic conditions and water is permeable in neutral to alkaline acids. Suspending dry syrup in water causes the drug's bitter taste to elapse. As a result, the bitterness shielding effect disappears. Dry syrup prepared by this method can be said to have the effect of bitterness only when suspended immediately after suspension in water because of this disadvantage.

US Pat. No. 5728403 describes a bitterness masking system consisting of a three-component system of metronidazole and triglyceride mixtures and cationic copolymers. In the present invention, the melting point of the triglyceride mixture is low, so that it melts at body temperature and the used polymer is dissolved at low acidity, so that the drug is eluted from acidic gastric juice. In the case of the present invention, the shielding effect is excellent in the solid state, but there is a problem that the bitterness shielding effect is significantly reduced when dissolved in syrup or taken in water.

US Pat. No. 5405617 mentions a technique for masking the bitter taste of drugs using stearyl stearate, a fatty acid ester. This method uses a method in which a drug is dissolved or suspended in molten stearyl stearate and solidified without using an organic solvent. However, if the organic solvent is not used, it is difficult to completely dissolve the drug, and if it is manufactured under conditions that are not completely dissolved, there is a disadvantage in that the masking effect of the bitter taste is lowered. have. In addition, the scope of drugs applied is limited to antihistamines, anti-inflammatory analgesics, anti-diarrheal agents, etc., and the shielding substance is limited to stearyl stearate, so it is difficult to expect the same effect in all drugs.

U.S. Patent No. 5,684,684 describes a method of suspending antibiotics such as penicillin, erythromycin, roxithromycin and amoxicillin with a non-aqueous oil as a carrier. The purpose of this technique is to increase the bioavailability of the antibiotics used and to control the release of the drug, which is different from the object of the present invention.

British Patent Publication No. 2081092 introduces a drug composition and a manufacturing method prepared by mixing waxes, fatty acid esters and various water-soluble polymers to mask the taste of water-soluble drugs such as talampicillin hydrochloride, indenolol hydrochloride, and hydralazine hydrochloride. have. If this method is limited to water-soluble drugs, the used polymer is also water-soluble, and thus has a problem in that the taste masking effect is reduced upon adaptation to inhibition.

In order to solve the above problems, in the present invention, as a method for using as little organic solvent as possible, low melting point of fatty acid esters and waxes are used alone or after dissolving a water-soluble or non-aqueous polymer in a molten liquid. When roxysomycin is dissolved or not sufficiently dissolved, an appropriate amount of an organic solvent is added to completely dissolve the drug, and then a method of assembling by adding an appropriate excipient is provided.

In addition, in the case of children, in order to increase the convenience of taking the drug, oral solids, which are generally provided, may be powdered and suspended or dissolved in tasty syrups. In this case, even if the formulation masks the unpleasant taste of the drug, there is an example in which the modification of the formulation occurs in the syrup and the original unpleasant taste is reproduced as it is. In view of such a case, the present invention is a taste masking system of a roxisthromycin preparation which does not change the formulation even when mixed with a general syrup or a liquid preparation, and improves the bitter taste of the irritating roxithromycin to improve tablets, capsules, dry syrups, and syrups. It is an object to provide a granule that can be formulated in a conventional oral dosage form and the like and a preparation method thereof.

The roxithromycin granules of the present invention may be selected from the group consisting of macrolide antibiotics, roxithromycin, selected from the group consisting of fatty acid esters, waxes, water-soluble and water-insoluble high molecular materials in the melting point of 40 to 120 ° C. for masking bitter taste. It is characterized in that the matrix-type bitter taste concealed roxysomycin granules, which are completely dissolved in one compound and then assembled by adding a water-soluble or water-insoluble excipient as a dispersion medium for solidification.

As the shielding material used in the present invention, the fatty acid ester has stearic acid, palmitic acid, stearyl stearate, cetostearyl alcohol, cetyl ester wax, stearyl alcohol, glyceryl behenate and glyceryl having a melting point in the range of 40 to 120 ° C. Monostearate, glyceryl palmitostearate and waxes such as cetyl alcohol, biswax, carnauba wax, castor wax, paraffin wax, polyoxyethylene stearate, sorbitan monostearate, sorbitan monopalmitate and cetyl laurate One or two or more selected from cetyl ester wax composed of a single or a mixture of latex, cetyl myristate, cetyl palmitate and cetyl stearate may be used. If necessary, fatty acid esters or waxes can be mixed with water-soluble or water-insoluble high molecular materials, and methylcellulose, ethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, and phthalic acid hydroxy. Cellulose derivatives such as propyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate or polyethylene glycols having a molecular weight of 6,000 or more, polyvinylacetate phthalate, polyvinylpyrrolidone, polymethacrylate Eudragit E, Eudragit L, Eudragit S, Eudragit AL, Eudragit RS, Betacyclodextrin, and Methylbetacyclo Cycles such as dextrin and hydroxypropyl beta cyclodextrin The dextrin acids, carbomer, polyvinyl alcohol, aluminum silicate, one or two or more in the light anhydrous silicic acid may be mixed.

The above water-soluble or water-insoluble high molecular material can be used for the purpose of improving the dissolution of roxithromycin while being effective in masking the bitter taste of roxithromycin, and even when used alone, it is effective in masking the bitter taste of cexithromycin.

When the fatty acid esters or waxes, water-soluble or water-insoluble high molecular materials are used to conceal the bitter taste of roxithromycin, the total amount used may be used in an amount of 0.1 weight or more relative to roxithromycin alone or as a mixture, preferably 0.5 Can be used in more than ~ 2 weight ratio.

Conventional excipients used in the present invention include starch, lactose, granular white sugar, microcrystalline cellulose, mannitol, sorbitol, dextrin, hard silicic anhydride, calcium dihydrogen phosphate, sodium starch glycolate, talc, magnesium stearate, stevioside, At least one selected from aspartame and the like.

Formulations that can be made include capsules, tablets, dry syrups, syrups, and liquids.

The present invention also includes a method for preparing the granulomycin granules in which the bitter taste of the matrix type is concealed.

The method for preparing the roxithromycin granules of the present invention comprises the following steps.

(a) heating a fatty acid ester or wax or a water-soluble or non-aqueous polymer material to melt or dissolve it in a solvent; (b) dissolving roxysomycin in the molten or dissolved liquid obtained by the electrical process; (c) adding a water-soluble or non-aqueous excipient as a dispersion medium for solidification to the mixed solution obtained by the electrical process, followed by spray granulation coating using a fluidized bed coater.

The manufacturing method in another aspect of the present invention comprises the following steps.

(a) heating a fatty acid ester or wax or a water-soluble or non-aqueous polymer material to melt or dissolve it in a solvent; (b) dissolving roxysomycin in the molten or dissolved liquid obtained by the electrical process; (c) cooling the mixed solution obtained by the electrical process and solidifying by adding a water-soluble or non-aqueous excipient with a dispersion medium for solidification and then powdering.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples, but the technical scope of the present invention is not limited thereto.

<Example 1>

Taste masking drug granules prepared using one or more fatty acid esters or waxes

In the fatty acid esters or waxes, only one substance or a mixture of the two was used to mask the bitter taste of roxithromycin. The components shown in the table below are weighed, mixed and warmed to fully melt the fatty acid esters and waxes while maintaining 70 ° C. and completely dissolve the roxysomycin. Add 10 ml of acetone, which does not completely dissolve roxysomycin, completely dissolve and maintain the temperature, mix with excipients such as microcrystalline cellulose, lactose, starch, mannitol, light anhydrous silicic acid, and take 200 g in total. It is put into the molten mixture of thromycin and cooled by association. Once cooled to room temperature, the mill is milled to a suitable size using a grinder to complete the taste masking granules.

<Example 1>

The taste masking granules prepared above were subjected to sensory experiments to evaluate taste in 10 adults. The control group was made of non-taste-closing loxrommycin raw material, and the bitterness of the loxromycin raw material was 0, resulting in +1 slightly improved taste, +2 improved, +3 very improved, and +4 Almost no bitterness was indicated.

The evaluation results showed that the taste masking granules prepared alone or in combination with fatty acid esters or waxes significantly improved the bitter taste of roxithromycin.

<Example 2>

Taste masking granules prepared using at least one water-soluble or non-water-soluble polymer

An example is shown in which the bitter taste of loxithromycin is masked by alone or by mixing a water-soluble or water-insoluble high molecular material. After weighing and mixing the components shown in the table below, 50 ml of ethanol, acetone, and methylene chloride were added and completely dissolved to form a coating solution, such as microcrystalline cellulose, lactose, starch, mannitol, calcium dihydrogen phosphate, and hard silicic anhydride. A total amount of 200 g was added to the fluidized bed coater by mixing excipients, and spray granulation coating was carried out according to the following conditions to prepare a granule for masking taste.

Experimental Example 2

The taste masking granules prepared above were subjected to sensory experiments to evaluate taste in 10 adults. The control group was made of non-taste-closing loxrommycin raw material, and the bitterness of the loxromycin raw material was 0, resulting in +1 slightly improved taste, +2 improved, +3 very improved, and +4 bitter taste. Almost none was indicated.

The evaluation results showed that the taste masking drug granules prepared alone or in combination with water-soluble or water-insoluble high molecular materials significantly improved the bitter taste of roxithromycin.

<Example 3>

Taste masking granules prepared by mixing fatty acid esters or waxes with water-soluble or water-insoluble high molecular materials

The components shown in the table below are weighed and mixed and then warmed to 70 ° C. to melt the fatty acid esters or waxes and dissolve the roxysomycin and the polymeric material. If roxysomycin or polymer is not completely dissolved, add 10 ml of ethanol, acetone, or methylene chloride to completely dissolve it, and then mix the excipients such as microcrystalline cellulose, lactose, starch, mannitol, calcium dihydrogen phosphate, and hard silicic anhydride. 200 g was placed in a fluidized bed coater and spray granulated coating was prepared according to the following conditions to prepare a granule for masking taste.

The taste masking granules prepared above were subjected to sensory experiments to evaluate taste in 10 adults. The control group was made from non-taste-closing loxysis mycin, and the bitterness of the roxysomycin ingredient was 0, resulting in +1 slightly improved taste, +2 improved, +3 highly improved, +4 bitter taste It is shown that there is almost no.

As the results of the evaluation, it can be seen that the taste-blocking granules prepared by mixing fatty acid esters or waxes with water-soluble or water-insoluble high molecular materials can significantly improve the bitter taste of roxithromycin.

Experimental Example 4

The elution test of roxithromycin was performed with respect to the taste masking granules of the roxithromycin prepared above. The test method was a rotational sample method, which was the first method of the dissolution test of the Korean Pharmacopoeia, and the granules without fatty acid or wax were used in 50 ml of pH 6.0 artificial intestinal fluid [0.2 mol (M) potassium dihydrogen phosphate solution. 5.6 ml of 0.2 mol (M) sodium hydroxide solution, and 200 milliliters of water] was used, and granules mixed with fatty acid esters or waxes were used to add lipase, a lipolytic enzyme, to at least 10,000 epi (EP) units. Serum was used. Specimen was used as granulosine of 150 milligrams as roxisthromycin, and the eluator was operated at 50 revolutions per minute, the eluent at 500 milliliters, and the temperature at 37 ° C. The eluate was taken for 30 minutes, 1 hour, and 2 hours after the start of the elution, and the amount of the elution was analyzed by high performance liquid chromatography. The dissolution test results are as follows.

In the above results, it can be seen that the granules masking the bitter taste of roxithromycin do not exhibit a significant dissolution rate drop that may affect the efficacy of roxithromycin.

Experimental Example 5

The taste masking granules of No. 5, No. 26 and No. 35 of the above-mentioned roxithromycin prepared as a commercially available syrup was suspended in ibuprofen syrup or water to evaluate the bitter taste after time passed. Suspension concentration was 50 mg / 10 ml as loxithromycin.

In the above experiments, the taste masking granules of roxithromycin prepared solely or in combination with fatty acid esters or waxes or water-soluble or water-insoluble high molecular substances do not affect the drug efficacy while effectively concealing the bitter taste of roxisomycin. appear. The roxithromycin granules prepared by the above method may be formulated into tablets such as suspension tablets, effervescent tablets, chewable tablets, capsules, dry syrups or suspension syrups by adding conventional excipients.

The method of the present invention can produce a granule that can effectively conceal the bitter taste of the macrolide antibiotic roxisthromycin having an unpleasant taste, the granules of the present invention is suspended even in the liquid formulation or crushed after tableting, Since it is maintained, there is no restriction on the application to the liquid, and there is an advantage that it is suitable as a pediatric medicament to be administered by powdering. The granules according to the invention can also be formulated into various formulations such as capsules, chewable tablets or dry syrups or suspensions.

Claims (8)

Loxilomycin, a macrolide antibiotic, is completely dissolved in at least one compound selected from the group consisting of fatty acid esters, waxes, water-soluble and water-insoluble high molecular materials in the melting point of 40 to 120 ° C. for masking bitter taste. , A matrix-type bitter taste concealed roxysomycin granules prepared by adding a water-soluble or water-insoluble excipient as a dispersion medium for solidification. The method of claim 1, The fatty acid ester is stearic acid, palmitic acid, stearyl stearate, cetostearyl alcohol, stearyl alcohol, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, cetyl alcohol, polyoxyethylene stearate, sorb At least one member selected from the group consisting of non-monostearate and sorbitan monopalmitate, The wax is at least one selected from the group consisting of biswax, carnauba wax, castor wax, paraffin wax and cetyllaurate, cetyl myristate, cetyl palmitate, and cetyl ester wax composed of a mixture of cetyl stearate alone and a mixture. Granules characterized by. The method according to claim 1 or 2, wherein the at least one compound selected from fatty acid esters, waxes, water-soluble and non-water-soluble high molecular materials in the range of 40 to 120 ° C for the bitter taste masking is at least 0.1% by weight relative to roxithromycin. Granules, characterized in that used as. The method of claim 1, wherein the water-soluble or water-insoluble high molecular material is methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose Cellulose derivatives such as acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate or polyethylene glycols having a molecular weight of 6,000 or more, polyvinylacetate phthalate, polyvinylpyrrolidone, polymethacrylate copolymers [Euragit E (E), Eudragit L (L), Eudragit S (S), Eudragit AL (RL), Eudragit RS (RS)], Betacyclodextrin, Methylbetacyclocyclodextrin, Hydroxypropylbetacyclodextrin, etc. Cyclodextrins, carbomers, polyvinyl alcohols, al Granules, characterized in that one or two or more selected from the group consisting of aluminum silicate and light anhydrous silicic acid. The method of claim 1, wherein the excipient is starch, lactose, white sugar, granular white sugar, microcrystalline cellulose, mannitol, sorbitol, dextrin, hard silicic anhydride, calcium dihydrogen phosphate, sodium starch glycolate, talc, magnesium stearate, aspartame And at least one selected from the group consisting of steviosides. A formulation comprising the granules of claim 1 formulated in a conventional pharmaceutical method, wherein the formulation comprises one formulation selected from capsules, tablets, dry syrups, syrups and liquids. (a) heating and melting or dissolving in at least one compound selected from the group consisting of fatty acid esters, waxes, water-soluble and water-insoluble high molecular materials in the melting point of 40 to 120 ℃; (b) dissolving loxithromycin in the melt or solution obtained in (a); (c) A matrix-type bitter taste-clogged roximamycin granule comprising the step of adding a water-soluble or non-aqueous excipient as a dispersion medium for solidification to the mixed solution obtained in (b) followed by spray granulation coating using a fluidized bed coater. Manufacturing method. (a) heating and melting or dissolving in at least one compound selected from the group consisting of fatty acid esters, waxes, water-soluble and water-insoluble high molecular materials in the melting point of 40 to 120 ℃; (b) dissolving loxithromycin in the melt or solution obtained in (a); (c) cooling the mixed solution obtained in (b) and solidifying by adding a water-soluble or non-aqueous excipient with a dispersion medium for solidification and then pulverizing the powdered bitterness of the matrix-type bitter taste-locked roxithromycin granules. Manufacturing method.