KR20040011087A - A process for preparing roxythromycin granules having masked taste and smell - Google Patents

Abstract

PURPOSE: Provided is a process for preparing controlled release roxithromycin granules having masked taste and flavor, thereby completely masking unpleasant taste and flavor and selectively releasing drugs in the stomach. CONSTITUTION: A process for preparing controlled release roxithromycin granules having masked taste and flavor is characterized by granulating roxithromycin and coating the roxithromycin granule with a coating material and a plasticizer at low temperature.

Description

A process for preparing roxythromycin granules having masked taste and smell}

The present invention relates to a method for preparing a release-controlled roxithromycin-coated granule, which is microcoated after granulation of roxithromycin, which is difficult to be orally administered due to unpleasant taste and aroma. More specifically, the present invention relates to a method for producing a release-controlled roxithromycin coated granule, which is prepared by adding a sweetening agent and an excipient to roxithromycin and mixing the mixture, and then using the seed and a coating agent and a plasticizer at low temperature. .

Roxismycin, a drug of the present invention, has an antimicrobial effect mainly on streptococci, pneumococci, gonococci, diphtheria bacteria, cholera bacteria, staphylococci, and especially has a therapeutic effect against infections of the respiratory system such as sore throats, acute bronchitis and bacterial pneumonia. It is an excellent macrolide antibiotic. In addition, the blood half-life is long, and the absorption rate in the gastrointestinal tract is high, and thus usually shows sufficient effect for twice daily use. These advantages are widely used in children as well as adults.

However, when applied to children, tablets or capsules, which are conventional formulations, are administered in a powdered form, and the drug's unique taste and aroma cause a problem that children's medication compliance falls. In general, tablets or capsules may have the effect of blocking the taste and aroma of the drug due to the disintegration time delay (drug release delay) effect of the formulation itself and the time the film is broken on the surface, but in the case of powder, the drug is immediately released and tasted. Is passed to.

In order to solve such low medication compliance, the conventional administration method is to prepare the granules or powders after mixing the drug with a suitable sweetener, but this method also does not completely mask the unique taste and aroma.

In this case, it is preferable to formulate the powder or granule after fine coating the drug to mask the taste and aroma.

U. S. Patent No. 5707646 describes a method of formulating a dry syrup by concealing bitter taste by mixing macrolide antibiotics with Eudragit egg (R) and tooth (E). In this case, Eudragit eggs (E) and (E) are used to dissolve in weak acidity, but in neutral to alkaline liquids, the film-coated film swells slightly, penetrates water, releases drugs, and the shielding time is too short. It should be used immediately after manufacturing as a syrup and has a disadvantage that the bitter taste is immediately delivered when it remains in the mouth.

U.S. Patent 5728403 describes a shielding system consisting of a three-component system of metronidazole and triglyceride mixtures and cationic copolymers. This invention has the disadvantage that the shielding efficiency is inferior in contact with water, ie in saliva or syrup.

Kolon Pharmaceutical's patented method of Korean Patent Publication No. 1999-0086232 discloses that the drug is not crushed and formulated by dissolving or melting together using fatty acids, waxes or various polymers, rather than masking taste and aroma by coating. It is not a coating of the drug particles one by one because it is a kind of matrix in which the drug particles are present on the surface of the particles. Therefore, there is a problem that the drug on the surface of the particle does not completely mask the bitter taste and aroma, and the particle is large, and there is a problem that there is a foreign body feeling and residual feeling in the mouth when the dose is taken, and the remaining particles are broken and the bitter taste appears.

Shielding technology consisting of a conventional granulation step and coating step, unlike other drugs in the case of roxithromycin, due to the nature of the coating treatment is not dense there is a problem that the efficiency of the shielding is leaked due to the leaked drug ingredients.

The particle size of the coating granules of roxithromycin according to the conventional technology is 20 mesh or more, in which case, the particles are large, so that a residual feeling remains in the mouth and the coating layer is physically broken by the chewing action.

Therefore, it is small enough to be stored or distributed when orally administering roxysomycin drug as well as added to a liquid syrup or not to be broken by chewing when the drug is applied alone, and the coating of the coating granules on saliva, ambient humidity, water, etc. It is necessary to select and finely coat a film-forming polymer whose film is broken at the low pH of the stomach when taking without breaking. Accordingly, the present inventors have developed a stable microcoating technology that rapidly disintegrates and releases only in the gastric environment based on the development of various polymers and natural product extraction materials as a coating base. Therefore, the present inventors make fine granules using suitable sweeteners and excipients, and then use a coating base and a plasticizer using the developed polymer and natural extract material to completely coat the film at low temperature, thereby completely masking the taste and aroma and promptly only in the stomach environment. A method of preparing controlled release roxysomycin coated granules was studied.

Accordingly, it is an object of the present invention to provide a method for preparing a release-controlled roxithromycin coated granule that can mask the unpleasant taste and aroma of roxithromycin.

The above object of the present invention is to granulate the main component of roxythromycin difficult to orally administered due to the unpleasant taste and aroma, and finely coated the prepared granules using a coating agent and a plasticizer at low temperature to completely mask the taste and aroma. Achieved by providing a method of making controlled granules.

1 is a scanning electron microscopy (SEM) of the coating granules of roxithromycin prepared according to Example 1.

The present invention is prepared by spraying a coating solution containing a coating agent and a plasticizer at high speed while floating the prepared granules at a low temperature of 25 to 60 ° C. after preparing granules by adding roxisthromycin as a main ingredient and adding and mixing sweeteners and excipients. It is a method of manufacturing a controlled release roxysomycin coating granules.

In the present invention, the content of roxithromycin is preferably 1 to 95% by weight of the total coated granules.

In the present invention, the sweetener may be used by mixing any one or two or more selected from synthetic sweeteners and natural sweeteners such as steviosides, aspartame, saccharin, white sugar, mannitol, xylitol, sorbitol, trihalose, and the amount of the sweetener used 1 to 95% by weight of the total weight of the coated granules, preferably 1 to 60% by weight.

In the present invention, the coating liquid is prepared by dissolving the coating base and the plasticizer in a suitable solvent. Coating bases used for coating include methacrylic acid-ethyl acrylate copolymers (Eudragit® E-100, Eudragit L 30D; Rohm & Hass, Germany), corn protein Extracts (Zein-DP®) and artificially processed analogs thereof, sodium alginate, alginic acid, shellac, carbopols (carbomer®, carboxyvinyl polymer), hydroxypropylmethyl Cellulose phthalates, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl acetate succinate, carboxymethyl cellulose, cellulose acetate phthalates, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, polyvinylacetate phthalate, soybean Protein, wheat protein, soy protein or wheat protein, chitin, chitin, chitin or chitin, agar, carrageenan (Carra geenan, pectin, guar gum, locust bean gum, xanthan gum, gellan gum, arabic gum, colicoat Kollicoat) MAE 30 DP (BASF Corporation), any one or two or more selected from heavy chain fatty acids having 6 to 12 carbon atoms can be used in combination. The amount of the coating base used for preparing the coating liquid is preferably 1 to 50% by weight based on the total coating granules.

Plasticizer used in the coating of controlled release coating granules of the present invention any one selected from polyethylene glycols, glycerin fatty acid esters, sorbitan fatty acid esters, propylene glycol, glycerin, triethyl citrate, triacetin, cetyl alcohol, stearyl alcohol Alternatively, the mixture may be used in combination of two or more, and the amount of the plasticizer is preferably 0.5 to 50% by weight based on the total coating granules. When the amount of the coating base and the plasticizer is out of the range of use, the disintegration of the coating granules is delayed, thereby providing rapid drug efficacy. Unexpected or stable coatings cannot be obtained.

Solvents used in the coating include water, ethanol, alcohol (methanol, isopropyl alcohol), acetone, acetonitrile, methylene chloride, ether, hexane, chloroform, 1,4-dioxane, tetrahydrofuran, dimethylsulfoxide, Either one selected from ethyl acetate, methyl acetate or two or more may be mixed.

Excipients other than the sweetener used in the present invention include starch, lactose, microcrystalline cellulose, light anhydrous silicic acid, calcium phosphate dibasic, Ac-di-sol (), PVP (polyvinylpyrolidon) K-30, etc. Preference is given to 0.5 to 90% by weight of the coated granules.

In the preparation of granules, a fluidized bed granulator, a high speed mixer and a cylindrical granulator are used.

The apparatus used for coating is a so-called "Fluid bed coater" or CF-granulator, or a similar apparatus, and in the present invention, the fluidized bed granulator Granulex-40 (Fundund Co., Japan) is used. Similar preparations are also possible with similar devices.

The temperature conditions of the apparatus for the production of controlled release coated granules of the present invention ranges from 35 ° C to 70 ° C. In addition, it is preferable that the granule temperature in the apparatus of all processes maintains 25 degreeC-60 degreeC. Because the granules or raw material mixture in the step-by-step device can not prevent the aggregation of the moisture-absorbed granules at 25 ℃ or less, and granules before the in-process or granules formed in the device may be broken at a temperature of 60 ℃ or more Because. At this time, the temperature is adjusted according to the season, depending on the season is adjusted accordingly, for example, during the rainy season or winter, a somewhat higher temperature is suitable for coating, in the summer it is possible to coat even at a lower temperature of the temperature range.

In the following examples, the composition of the coating granules of roxithromycin according to the present invention, and a manufacturing process thereof are specifically illustrated.

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

Example 1

Granulation process Seed Roxysomycin 1,500 g Mannitol 1,150 g Avicel PH 101 180 g Calcium-phosphate debasic 170 g Binder Hydroxypropyl Methyl Cellulose 200 g water 1,000 mL ethanol 1,000 mL Coating process Seed Granules 3,000 g Coating solution Zein-DP 250 g Shellac 350 g 80% ethanol 1,800 mL

Granulation process

The granulation was prepared by spraying the binding solution while the roxysomycin and the excipient were suspended in a fluidized bed granulator. The temperature of the loxithromycin and excipient in the device was kept within the range of 25-60 ° C. The process was carried out in the range of inlet air and exhaust temperature in the range of 35 to 70 ° C., and the rotation speed of the rotor in the range of 100 to 350 rpm.

Coating process

The granules prepared in the granulation process were coated by spraying the coating solution while floating in a fluidized bed granulator as a seed.

The temperature of the product in the apparatus of the fluid bed granulator was kept within the range of 25 ° C to 60 ° C. The inflow air and exhaust temperature were 35 ° C. to 70 ° C., and the rotation speed of the rotor was in the range of 100 rpm to 350 rpm.

As a result of observing the prepared coating granules with a scanning electron microscope, it can be seen that the coating granules surface is completely covered with a polymer material without a pin hole as shown in FIG. 1.

Example 2

Granulation process Seed Roxysomycin 1,500 g Mannitol 500 g Starch 500 g Lactose 500 g Granule water 1,500 mL Coating process Seed Granules 3,000 g Coating solution Ethyl Cellulose 500 g Acetone 3,000 mL ethanol 2,000 mL

Coating granules were prepared using the ingredients in Table 2 in the same manner as described in Example 1.

Example 3

Granulation process Seed Roxysomycin 1,500 g glucose 350 g PVP K-30 350 g Avicel 800 g water 80 mL Coating process Seed Granules 3,000 g Coating solution HPMC 2910 650 g 80% ethanol 1,800 mL PEG6000 65 g

Coating granules were prepared using the ingredients in Table 3 in the same manner as described in Example 1.

Example 4

Granulation process Seed Roxysomycin 1,500 g Lactose 700 g Mannitol 700 g Ac-di-sol 100 g Granule Hydroxypropyl cellulose 300 g 70% Ethanol 2,000 mL Coating process Seed Granules 3,000 g Coating solution Polyvinylacetate phthalate 700 g 90% ethanol 5,000 mL Propylene glycol 70 g

Coating granules were prepared using the ingredients of Table 4 in the same manner as described in Example 1.

Example 5

Granulation process Seed Roxysomycin 1,500 g Starch: Lactose (1: 2) 1,500 g Sodium alginate 100 g water 2,500 mL Coating process Seed Granules 3,000 g Coating solution HPMCP (hydroxypropylmethylcellulose phthalate) 550 g Ethanol: Acetone (1: 1) 5,000 mL Glycerin Fatty Acid Ester 50 g

Coating granules were prepared using the ingredients in Table 5 in the same manner as described in Example 1.

Example 6

Granulation process Seed Roxysomycin 1,500 g Mannitol: White sugar (1: 1) 1,500 g 10% Mannitol 2,500 mL Coating process Seed Granules 3,000 g Coating solution Eudragit L 30D 1650 ml (500 g as a solid) water 300 mL Triethyl citrate 50 g

Coating granules were prepared using the ingredients in Table 6 in the same manner as described in Example 1.

Example 7

Coating granules were prepared in the same manner as described in Example 1 using the same ingredients as in Example 6 except that Colicoat MAE 30 DP was used instead of Eudragit L 30D as the coating base.

Example 8

Double coated granules were prepared by recoating the coated granules of Example 1 with the coating liquid composition of Example 2.

Experimental Example 1

The particle size distribution of the coated granules prepared in Examples 1 to 8 was measured, and the results are shown in Table 7 below.

Particle size distribution of roxysomycin coated granules Particle size distribution of each example (%) Mesh size (mm) 20 (0.84) 30 (0.59) 40 (0.42) 50 (0.297) Particle Size Distribution of 1 (%) 7.4 50.5 38.6 3.5 Particle Size Distribution of 2 (%) 9.5 47.6 34.4 8.5 Particle Size Distribution of 3 (%) 9.3 45.8 37.3 7.6 Particle size distribution of 4 (%) 11.7 44.1 40.0 4.2 Particle Size Distribution of 5 (%) 4.8 52.2 38.6 4.4 Particle Size Distribution of 6 (%) 9.0 54.7 30.5 5.8 7 particle size distribution (%) 8.9 57.7 23.0 10.4 Particle Size Distribution of 8 (%) 14.2 60.0 21.5 4.3

As shown in Table 7, the homogeneous coating granules in which the coating granules of 30 to 40 mesh are distributed by 80% or more were obtained. The particle size of the coating granules of roxithromycin according to the prior art is 20 mesh or more. In this case, the particles are large and remain in the mouth, and it is inevitable that the coating layer is physically broken by chewing. The coating granules of the above can solve the problems of the existing technology because a homogeneous coating granules in which the coating granules of 30 to 40 mesh is distributed by 80% or more as described above.

Experimental Example 2

In order to examine the improvement of medication compliance, the ultimate goal of the present invention, the dissolution rate in gastric juice, artificial intestinal fluid, and water was observed. The measurement method was calculated as the time at which the release rate of loxithromycin reached more than 30% in each dissolution medium. Samples were taken for 1 hour every 15 minutes, and samples were taken every 30 minutes thereafter. The eluate was 900 mL and 100 mg of roxysomycin was used for the analysis. The rotational speed was 50 times / min, and a certain amount of protease and lipase were added to the gastric juice and intestinal fluid. The dissolution test results are shown in Table 8.

Roxismycin Release Rate> 30% Reach Time (min) Example number Emission rate 30% or more Reach time (minutes) Artificial gastric juice Artificial serous water Roxis romycin free coating granule 15 15 15 One 30 90 90 2 45 45 60 3 30 30 30 4 90 30 90 5 90 30 60 6 90 30 60 7 90 30 30 8 45 90 90

From the results shown in Table 8, even when taking the granules themselves, it was found that the bitter taste of the drug was not eluted for a certain period of time even in the mouth without feeling enough bitter taste.

Experimental Example 3

The prepared roxysomycin coated granules were added to commercially available ibuprofen syrup (S) and synthetic cold syrup (H) at a concentration of 5 mg / mL as roxysomycin and samples were taken at the time intervals of Test Example 2 above. The elution reaching time of more than 30% of the roxysomycin was observed, and the results are shown in Table 9.

Reach-over 30% release time for roxysomycin release in ibuprofen syrup and cold syrup Example number Emission rate 30% or more Arrival time (hours) Ibuprofen syrup Synthetic Cold Syrup Remarks Roxis romycin free coating granule 0.25 0.25 One 39.0 30.5 Easy redispersion 2 37.5 35.0 Easy redispersion 3 3.0 2.5 Easy redispersion after settling 4 7.5 5.5 Easy redispersion 5 8.0 6.5 Easy redispersion 6 9.0 8.5 Easy redispersion 7 7.5 7.0 Easy redispersion 8 42.0 40.5 Easy redispersion

As a result of the above Table 9, when the roxithromycin coated granules were added to the commercially available syrups, the release of the drug was significantly delayed due to the absence of stirring or digestive enzymes, unlike the conditions of Experiment 2. In all cases except Example 3, it was easy to redistribute when gently shaken. In addition, it can be seen that it can be applied to liquid oral solutions such as oral or syrup.

Experimental Example 4

The prepared roxisthromycin coated granules were subjected to sensory experiments in adults (10 persons) as general granules and in liquid formulations. The aesthetics of the raw material of roxysomycin was set to 0, and the shielding degree was quantified as 1 (bitter), 2 (slightly bitter), 3 (not bitter), 4 (good taste), or the like. The final formulation was prepared by adding an appropriate amount of sweetener, copulation agent, and flavor to the roxysomycin coated granules.

50 mg of roxysomycin, the main ingredient in 1 g of granules, was taken at a concentration of 5 mg / mL in commercial ibuprofen syrup (S) and 1 g and 10 mL respectively. Syrup was taken after 24 hours. The results of the experiments are shown in Table 10.

Sensory Sensory Studies of Roxisthromycin Coated Granules Example number Sensory test score Granule Syrup Additives Remarks Roxis romycin free coating granule 0 0 One 4 3 2 4 3 3 3 2 Granules adhere slightly in the mouth 4 4 3 5 4 2 6 3 3 7 4 3 8 4 3

Looking at the results of Table 10, when the sensory experiments were performed by adding a sweetener, a copulation agent, a flavor, etc. to the loci romycin coating granules prepared in the above-mentioned examples, the remarkable improvement of the bitter taste of roxithromycin as well as various It can be seen that the application to the formulation is possible.

The roxithromycin coated granules prepared by the preparation method of the present invention have the effect of completely masking the unpleasant taste and aroma of the roxithromycin drug inherent, and are small enough to not be broken by chewing, and are not released from water or saliva. In addition to the superior effect of selectively released only in a low pH of the gastric environment, the formulations prepared in various forms are useful inventions in the pharmaceutical manufacturing industry because they have an excellent effect of significantly improving medication compliance upon oral administration.

Claims (1)

In the method for producing a release-controlled roxithromycin coated granule comprising the steps of preparing granules by adding and mixing sweeteners and excipients to roxysomycin and coating the granules with a coating solution in which a coating agent and a plasticizer are dissolved in a solvent. , The coating base may be a methacrylic acid-ethyl acrylate copolymer, corn protein extract, corn protein extract processed material, sodium alginate, alginic acid, shellac, carbopol, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate. Nate, hydroxypropylmethyl acetate succinate, carboxymethyl cellulose, cellulose acetate phthalates, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, polyvinylacetate phthalate, soy protein, wheat protein, soy protein or wheat protein Processed materials, chitin, chitin, chitin or processed materials of chitin, agar, carrageenan, pectin, guar gum, low-cursor gum, xanthan gum, gellan gum, gum arabic, collicoat MAE 30 DP, carbon number 6-12 Any one or more selected from the heavy chain fatty acids of the whole coated granules 1 Not used 50% by weight, and The plasticizer is 0.5 to 50% by weight of any one or more selected from polyethylene glycol, glycerin fatty acid esters, propylene glycol, sorbitan fatty acid esters, glycerin, triethyl citrate, triacetin, cetyl alcohol or stearyl alcohol , The granulation step and the coating step is carried out at 25 ~ 60 ° C to be prepared.