KR19990086232A - Oral drug composition oral preparation method for hiding the bitter taste - Google Patents

Abstract

The present invention relates to a pharmaceutical composition capable of effectively concealing the bitter taste of roxithromycin, a macrolide antibiotic having an unpleasant taste, and a method for preparing the same, wherein the roxithromycin is dissolved or suspended together with a taste masking powder. It is manufactured by the method of chemistry. A water-soluble or water-insoluble conventional excipient as a dispersing medium for dissolving roxysomycin and fatty acid esters or waxes having a melting point in the range of 40-120 ° C. and one or more water-soluble or water-insoluble high molecular materials, and then dissolving them. Drug composition for masking the taste and a method for manufacturing the same, the drug composition of the present invention can effectively shield the unpleasant taste of the drug, as well as limit the application to the liquid because the shielding system is maintained even when suspended in liquid There is no advantage. The drug compositions according to the invention can be formulated as powders, granules, capsules, chewable tablets or dry syrups or suspensions.

Description

Oral drug composition oral preparation method for hiding the bitter taste

The present invention is a drug composition for increasing the convenience of the drug by concealing the bitter taste of roxithromycin (macrolide-based antibiotic) is very bitter taste uncomfortable to take or easy to reject the drug and its preparation It is about a method.

Roxithromycin used in the present invention is an antibiotic of macrolide series, and mainly exhibits antibacterial effects on streptococci, pneumococci, gonococci, diphtheria, cholera, 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 commercially available in various formulations such as tablets, capsules, powders, granules, solutions, 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 polymer used 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. 5156842 describes a method for suspending antibiotics such as penicillin, erythromycin, loxromycin and amoxicillin with a nonaqueous 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. This method is applied only to water-soluble drugs, and the used polymer is also water-soluble, which has a problem in that the taste masking effect is reduced when applied to a liquid formulation.

In order to solve the above problems, the present invention melts fatty acid esters and waxes having low melting points alone or dissolves or disperses water-soluble or non-aqueous polymer materials in the molten liquid as a method for using as little organic solvent as possible. After dissolution or dissolution of roxysomycin is insufficient, it is intended to provide a method of adding an appropriate amount of an organic solvent to dissolve the drug and then solidifying the powder as it is or by spraying or coalescing with a suitable excipient to solidify it.

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 the above circumstances, the present invention is a taste masking system of a roxysomycin preparation which does not change the formulation even when it is mixed with a general syrup or a liquid, and improves the bitter taste of roxythromycin, which has a stimulating taste, and is used in tablets, capsules, powders, It is an object of the present invention to provide a pharmaceutical composition and a preparation method which can be formulated into a conventional oral solid dosage form such as granules.

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, methylcellulose, ethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, phthalic acid hydroxypropylmethyl. Cellulose derivatives such as cellulose, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate butyrate or polyethylene glycols having a molecular weight of 6000 or more, polyvinylacetate phthalate, polyvinylpyrrolidone, polymethacrylate [eudragit Lee (E), Eudragit L (L), Eudragit S (S), Eudragit AL (RL), Eudragit RS (RS)], Betacyclodextrin, Methylbetacyclocyclodextrin, Hydroxy Cycling such as profile 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 roxithromycin.

When the above fatty acid esters or waxes and water-soluble or water-insoluble high molecular materials are used as a composition for concealing the bitter taste of roxithromycin, the total amount used alone or as a mixture may be 0.1% by weight or more relative to roxithromycin. Is 0.5 to 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, It is possible to select one or more kinds from aspartame, etc. It is used to properly process by mixing necessary things according to the formulation such as powder, granule, capsule, tablet, dry syrup, syrup and liquid which can be manufactured.

The present invention will be described in more detail by the following examples and experimental examples, but the technical scope of the present invention is not limited thereto.

<Example 1>

Taste shielding drug composition prepared by using at least one fatty acid ester or wax

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.

If roxysomycin does not completely dissolve, add 10 ml of acetone to dissolve completely and maintain the temperature, mix excipients such as microcrystalline cellulose, lactose, starch, mannitol, and light anhydrous silicic acid, take 200 g in total, and then use fatty acid esters, waxes and roxysomycin The mixture is added to the melt mixture and cooled while being combined. Once cooled to room temperature, it is ground to a suitable size using a grinder to complete the powdery taste masking composition.

Prescription Fatty acid ester Waxes Roxysomycin Raw material name Usage (g) Raw material name Usage (g) Prescription 1 Stearic acid 100 100 g Prescription 2 Palmitic acid 100 Prescription 3 Stearyl stearate 100 Prescription 4 Cetostearyl alcohol 100 Prescription 5 Stearyl alcohol 100 Prescription 6 Glyceryl Behenate 100 Prescription 7 Glyceryl Monostearate 100 Prescription 8 Glyceryl Palmitostearate 100 Prescription 9 Cetyl alcohol 100 Prescription 10 Biswax 100 Prescription 11 Carnauba wax 100 Prescription 12 Cetyl palmitate 50 Paraffin wax 50 Prescription 13 Stearic acid 50 Biswax 50 Prescription 14 Stearyl alcohol 50 Caster wax 50 Prescription 15 Glyceryl Behenate 50 Biswax 50 Prescription 16 Glyceryl Monostearate 50 Caster wax 50

Experimental Example 1

For the taste masking composition prepared above, a sensory experiment was conducted 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.

Prescription One 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 evaluation +3 +4 +3 +4 +2 +3 +4 +4 +3 +4 +4 +4 +4 +4 +4 +4

As the result of the evaluation, it can be seen that the taste masking composition prepared by mixing fatty acid esters or waxes alone or in combination can significantly improve the bitter taste of roxithromycin.

<Example 2>

Taste shielding drug composition prepared by using at least one water-soluble or water-insoluble high molecular material

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 following table, excipients such as microcrystalline cellulose, lactose, starch, mannitol, calcium dihydrogen phosphate, and hard silicic anhydride were prepared by coating a solution of 50 ml of ethanol, acetone, and methylene chloride and completely dissolving the solution. To 200 g of the total amount was added to the fluidized bed coater and spray granulated coating according to the following conditions to prepare a taste masking drug composition.

Fluid Bed Coating Machine Operating Conditions

Inlet air temperature 50 ℃

Process temperature 35 ℃

Air temperature 30 ℃

Spray rate 2 ml / min

Air pressure 2kg / ㎠

Prescription Polymer Quality Roxysomycin Raw material name Usage (g) Raw material name Usage (g) Prescription 17 Phthalate Hydroxypropyl Methyl Cellulose 100 100 g Prescription 18 Eudragit S 100 Prescription 19 Ethyl Cellulose 100 Prescription 20 Polyethylene Glycol 20000 100 Prescription 21 Betacyclodextrin 100 Prescription 22 Polyvinyl alcohol 100 Prescription 23 Cellulose Acetate Succinate 100 Prescription 24 Polyvinylacetate phthalate 100 Prescription 25 Aluminum silicate 100 Prescription 26 Eudragit Yi (E) 50 Phthalate Hydroxypropyl Methyl Cellulose 50 Prescription 27 Hydroxypropyl Methyl Cellulose 50 Cellulose acetate phthalate 50 Prescription 28 Polyvinylpyrrolidone 50 Eudragit S 50 Prescription 29 Hydroxypropyl cellulose 50 Aluminum silicate 50 Prescription 30 Polyethylene Glycol 20000 50 Light anhydrous silicic acid 50 Prescription 31 Polyvinylacetate phthalate 50 Aluminum silicate 50

Experimental Example 2

For the taste masking composition prepared above, a sensory experiment was conducted 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.

Prescription 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 evaluation +4 +4 +4 +3 +3 +4 +3 +3 +2 +3 +3 +4 +3 +4 +3

As a result of the evaluation, it can be seen that the taste-masking drug composition prepared by using alone or mixed with a water-soluble or water-insoluble high molecular material can significantly improve the bitter taste of roxithromycin.

<Example 3>

Taste shielding drug composition 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 substance is not completely dissolved, add 10 ml of ethanol, acetone, and methylene chloride to completely dissolve, and then mix with excipients such as microcrystalline cellulose, lactose, starch, mannitol, calcium dihydrogen phosphate, and hard silicic anhydride. To a fluidized bed coater spray spray coating according to the following conditions to prepare a taste masking drug composition.

Fluid Bed Coating Machine Operating Conditions

Inlet air temperature 50 ℃

Process temperature 35 ℃

Air temperature 30 ℃

Spray rate 2 ml / min

Air pressure 2kg / ㎠

Prescription Polymer Fatty acid esters or waxes Roxysomycin Raw material name Usage (g) Raw material name Usage (g) Prescription 32 Cellulose acetate phthalate 50 Polyoxyethylene stearate 50 100 g Prescription 33 Phthalate Hydroxypropyl Methyl Cellulose 50 Stearic acid 50 Prescription 34 Ethyl Cellulose 50 Stearyl alcohol 50 Prescription 35 Eudragit Yi (E) 50 Glyceryl Behenate 50 Prescription 36 Polyethylene Glycol 20000 50 Glyceryl Monostearate 50 Prescription 37 Betacyclodextrin 50 Biswax 50 Prescription 38 Carbomer 50 Caster wax 50 Prescription 39 Eudragit Yi (E) 50 Cetyl palmitate 50 Prescription 40 Polyvinyl alcohol 50 Paraffin wax 50

Experimental Example 3

For the taste masking composition prepared above, a sensory experiment was conducted 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 This indicated little.

Prescription 32 33 34 35 36 37 38 39 40 evaluation +4 +4 +4 +4 +3 +4 +3 +4 +4

As a result of the evaluation, it can be seen that the taste masking composition prepared by mixing fatty acid esters or waxes with a water-soluble or water-insoluble high molecular substance can significantly improve the bitter taste of roxithromycin.

Experimental Example 4

The elution experiment of roxisthromycin was performed on the taste masking composition of the above-mentioned roxismycin. The test method was a rotary sample method, which was the 1st method of the dissolution test method of the Korean Pharmacopoeia, and the eluate was composed of pH 6.0 artificial intestinal fluid [0.2 mol (M) potassium dihydrogen phosphate solution. 50 ml of 0.2 mole (M) 5.6 ml of sodium hydroxide solution and 200 milliliters of water] was used in the drug composition mixed with fatty acid esters or waxes. One artificial intestine solution was used. Specimen was treated with 150 milligrams of each drug composition as roxithromycin, and the eluent 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.

Prescription number Dissolution Rate (%) 30 minutes 1 hours 2 hours Roxysomycin raw material 78 ± 1.7 85 ± 2.5 97 ± 3.1 One 40 ± 1.3 63 ± 0.5 84 ± 0.7 5 32 ± 1.2 56 ± 0.4 83 ± 0.2 10 35 ± 0.6 46 ± 1.8 75 ± 1.2 15 45 ± 0.9 67 ± 0.5 89 ± 0.4 20 56 ± 0.8 78 ± 1.2 94 ± 0.5 25 62 ± 0.7 83 ± 0.9 98 ± 1.4 30 37 ± 0.7 59 ± 1.1 76 ± 0.8 35 41 ± 0.6 65 ± 0.8 88 ± 0.5 40 39 ± 0.7 52 ± 0.8 74 ± 1.3

In the above results, it can be seen that the drug composition that masks the bitter taste of roxithromycin does not show a large dissolution rate reduction phenomenon that may affect the efficacy of roxithromycin.

<Test Example 5>

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

Prescription Evaluation of bitter taste over time 24 hours 36 hours 48 hours 5 +3 +2 +2 26 +4 +4 +4 35 +3 +4 +3

In the experiments described above, the drug composition for masking the taste of roxithromycin prepared by using alone or mixed fatty acid esters or waxes or water-soluble or water-insoluble high molecular materials does not affect the drug efficacy while effectively concealing the bitter taste of roxithromycin. It can be seen that. Roxisomycin prepared by the composition and method described above may be formulated into tablets, capsules, dry syrups or suspension syrups such as powders, granules and suspension tablets or effervescent tablets, and chewable tablets by adding conventional excipients.

By the method of the present invention can be prepared a pharmaceutical composition that can effectively hide the bitter taste of the macrolide antibiotic roxisthromycin having an unpleasant taste, it is limited to the application to the liquid because the shielding system is maintained even when suspended in liquid There is no advantage to this. The drug compositions according to the invention can also be formulated in powders, granules, capsules, chewable tablets or dry syrups or suspensions.

Claims (8)

It is a water-soluble or dispersing medium for solidifying it after dissolving a macrolide antibiotic, roxithromycin, a fatty acid ester or wax having a melting point in the range of 40 to 120 ° C, and one or more water-soluble or water-insoluble high molecular materials. Bitter Taste Concealed Roxithromycin Oral Drug Composition Composed of Water-insoluble Excipients The method of claim 1, wherein the fatty acid esters are stearic acid, palmitic acid, stearyl stearate, cetostearyl alcohol, stearyl alcohol, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, cetyl alcohol, poly Oxyethylene stearate, sorbitan monostearate, sorbitan monopalmitate and waxes are biswax, carnauba wax, castor wax, paraffin wax or cetyl laurate, cetyl myristate, cetyl palmitate, cetyl stearate alone Or a cetyl ester wax composed of a mixture, wherein the oral drug composition for which the bitterness is concealed, characterized in that one or two or more are used. The method of claim 2 wherein the fatty acid esters or waxes are used alone or mixed in two or more kinds of oral drug composition for the bitter taste concealed roxithromycin characterized in that used in more than 0.1% by weight relative to the roxithromycin. 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 and cellulose acetate butyrate or polyethylene glycols having a molecular weight of 6000 or more, polyvinylacetate phthalate, polyvinylpyrrolidone, polymethacrylate copolymers [Euradgit E (E), Eudragit L (L), Eudragit S (S), Eudragit AL (RL), Eudragit RS (RS)], Betacyclodextrin, Methylbetacyclocyclodextrin, Hydroxypropylbetacyclodextrin, etc. To cyclodextrins, carbomers, polyvinyl alcohol Alone or the drug composition characterized by used a hydroxy-throw cover bitterness oral azithromycin The method of claim 4, wherein the water-soluble or non-aqueous polymer material is used alone or mixed in two or more kinds by weight at least 0.1% by weight relative to the roxithromycin oral drug composition oral roxysomycin oral The method of claim 1, wherein the excipients are starch, lactose, white sugar, granular white sugar, microcrystalline cellulose, mannitol, sorbitol, dextrin, light silicic anhydride, calcium dihydrogen phosphate, sodium starch glycolate, talc, magnesium stearate, aspartame, Oral drug composition with a bitter taste concealed roxithromycin, characterized in that at least one of stevioside is used in combination The method of claim 1, wherein the oral drug composition of the bitter concealed roxithromycin oral use of the drug composition as a formulation for oral administration such as formulated powder, granules, capsules, suspension tablets, effervescent tablets, dry syrups or suspension syrups Fatty acid esters or waxes or water-soluble or non-aqueous polymers are heated to melt, or dissolved or suspended in a solvent, suspended or dissolved in roxithromycin, and then solidified by the addition of conventional excipients, spray-assembled using a fluidized bed coater, or by roxis. Method for preparing oral drug composition for roximamycin with bitter taste concealed by cooling and solidifying the solution in which the mycin and fatty acid ester, wax or polymer substance are suspended or dissolved as it is, and then powdered and mixed with conventional excipients