KR101168189B1 - Process for producing coated preparation having relieved unpleasantness - Google Patents

Abstract

It is unpleasant by heat-processing to the microparticles | fine-particles containing a pharmaceutical compound and a waxy substance, adding a powdery waxy substance under the temperature which made the waxy substance wetted the surface, and performing hot melt coating on the surface of the microparticles | fine-particles. Coating formulations with improved beauty can be prepared. Moreover, the sweetness fine grain obtained by granulating by the wet method using the binder liquid which melt | dissolved or disperse | distributed the sweetening agent and the binder can be mixed with the coating formulation, and a dose can be improved further.

Small particles, unpleasant

Description

Production method of coating formulation which improved unpleasant taste {PROCESS FOR PRODUCING COATED PREPARATION HAVING RELIEVED UNPLEASANTNESS}

The present invention relates to a method for producing a coating formulation, in particular a method for producing a coating formulation containing a medicinal compound having discomfort.

When a medicine is accompanied by unpleasant taste, such as bitterness, it is remarkably difficult for a patient to take it as an oral preparation (especially powder and granules). Therefore, in order to mask the unpleasant taste in the mouth at the time of taking, it can be considered to process a coating | cover etc. Although a film coating method for masking bitterness by forming a film such as white sugar on the surface is known, this sugar process is very complicated. In addition, in these cases, it is common to apply | coat a chemical | medical agent after shape | molding into particle | grains, a tablet, etc., but it becomes easy to grind | pulverize as particle diameter becomes small, and it is also difficult to prevent the leakage of unpleasant taste. Although the method of adding a mating agent (refer patent document 1) also exists, the effect is inadequate depending on the kind of chemical | medical agent.

Generally, as a manufacturing method of the coating formulation most commonly used, there exists a method (refer patent document 2 or 3) which coats the granular object surface with coating agents which are not melt | dissolved in a mouth, such as a waxy substance and a water-insoluble polymer. Conventionally, especially when water-insoluble polymer is used as a coating agent (refer patent document 3), the method of spray coating by dissolving a coating agent in an organic solvent, etc. has been used. However, the use of organic solvents has many problems such as adverse sanitary effects on workers, environmental pollution and residual in the formulation. Even when a water-insoluble high molecular material such as methyl methacrylate-methacrylate trimethylammonium is used as a binder at the time of granulation before coating (see Patent Document 4), a large amount of organic solvent is not used in the granulation. You must. Therefore, similarly to spray coating, there remain a problem regarding safety, such as explosion during granulation operation and residual organic solvent during taking and taking.

As a manufacturing method of the coating agent which does not use an organic solvent, the manufacturing method of the coating agent which heat-processes wax to the solid drug at the temperature more than melting | fusing point of wax is disclosed (refer patent document 2). Moreover, the method of granulating the mixture containing a waxy substance by the wet method using water, and heat-processing at the temperature more than melting | fusing point of a waxy substance (refer patent document 5) is also disclosed. By these methods, although a masking effect becomes high, a granule is easy to fully coat by melt | dissolving a waxy substance completely. In particular, a drug having low solubility and a fat-soluble property has a low elution property and becomes an obstacle when the drug is absorbed in the body. In addition, there is a method in which a mixture containing a waxy substance is heat-treated at a melting point of the waxy substance or more and granulated, and a melt coating is performed on the powder of the water-insoluble high molecular compound at a melting point or more of the waxy substance as a coating agent (patent See Document 6). However, when using a powdery water-insoluble high molecular compound as a coating agent, it is difficult to make it adhere to a granular material uniformly.

There is also disclosed a coating formulation obtained by mixing a waxy substance, such as an original medicine, granulated by a dry method, and then heating the waxy substance so as to cover at least the surface thereof (see Patent Document 7). However, since this coating formulation is incompletely masked, it is pointed out that a raw drug is expressed on the surface of a particle | grain, and a bitter taste is felt.

Patent Document 1: Japanese Patent Application Laid-Open No. 2-56416

Patent Document 2: Japanese Patent Application Laid-Open No. 1-287021

Patent document 3: Unexamined-Japanese-Patent No. 3-83922

Patent Document 4: Japanese Patent Application Laid-Open No. 2-96516

Patent Document 5: Japanese Patent Application Laid-Open No. 7-188058

Patent Document 6: Japanese Patent Application Laid-Open No. 9-506543

Patent Document 7: Japanese Patent Application Laid-Open No. 4-300821

Problems to be solved by the invention

The objective of this invention is providing the manufacturing method of the coating formulation which improved the unpleasant taste, without accompanying the expression of the medicinal effect of an active ingredient, and the reduction of a therapeutic effect.

Means for solving the problem

In order to satisfy the requirements on the above formulations, intensive studies and studies were conducted. As a result, heat-treatment is carried out to the small particle containing a pharmaceutical compound and a waxy substance, the powdery waxy substance is added under the temperature which made the wax wet the surface, and it is made to the surface of the small particle. By performing hot melt coating, it was found that a coating formulation in which elution was secured and unpleasantness was suppressed can be obtained. That is, the coating formulation by the manufacturing method of this invention is suitably coat | covered from the exterior with a waxy substance, and the unpleasant taste is suppressed and the elution property is ensured further.

Moreover, when manufacturing the sweet granules taken with the coating formulation, it was found that the sweetness of the sweet granules obtained was enhanced by granulation using a binder solution in which a sweetener and a binder were dissolved or dispersed in an aqueous solution. The production of sweet fine grains by this method facilitates the elution of the sweetener in the oral cavity, thereby enhancing the sweetness. By taking this sweet fine grain in admixture with said coating formulation, discomfort can be improved further.

That is, the present invention,

(1) A heat treatment is performed on a small particle containing a pharmaceutical compound and a waxy substance, a powdery waxy substance is added at a temperature at which the waxy substance wets the surface, and the surface of the small particle is subjected to hot melt coating. Method for producing a coating formulation, characterized in that

(2) The average particle diameter of this powdery waxy substance is smaller than the average particle diameter of the small particle, The manufacturing method of the coating formulation as described in (1),

(3) The manufacturing method of the coating agent as described in (2) whose powdery waxy substance is at least 1 sort (s) of powdery waxy substance chosen from the group which consists of hardened oil, stearyl alcohol, stearic acid, and polyethyleneglycol,

(4) About 40% by weight or less of the pharmaceutical compound, about 5-25% by weight of the waxy substance, about 5% to about 35% by weight of the water-swellable substance, and about 5% to about the powdery waxy substance, based on the weight of the coating formulation. A process for preparing the coating formulation according to (3), which is 25% by weight,

(5) The method for producing a coating formulation according to any one of (1) to (4), wherein the pharmaceutical compound has an unpleasant taste;

(6) The pharmaceutical compound is (+)-(6R, 7R) -7-[(Z) -2- (2-amino-4-thiazolyl) -2-pentenamide] -3-carbamoyloxymethyl- 8-oxo-5-thia-1-azabicyclo [4.2.0] octo-2-ene-2-carboxylic acid pivaloyloxymethyl ester hydrochloride, in any one of (1) to (4) A process for preparing the described coating formulations,

(7) The method for producing a coating preparation according to (6), wherein the leakage concentration of the pharmaceutical compound after 60 seconds is 70 µg / mL or less, and the dissolution rate of the pharmaceutical compound after 30 minutes is 75% or more.

(8) Coating preparation manufactured by the manufacturing method in any one of (1)-(7),

(9) It relates to the coating formulation as described in (8) which further mix | blended the sweet granules obtained by granulating by the wet method using the binder liquid which melt | dissolved or disperse | distributed the sweetener and the binder.

Effects of the Invention

The coating formulation of the present invention temporarily delays the elution of the pharmaceutical compound as a main drug and enables the suppression of unpleasant taste in the mouth. As for the coating formulation, the delay of an elution rate is hardly recognized. Moreover, the unpleasant taste can be improved further by taking the sweet fine grain which accelerated the dissolution rate by mixing with the coating formulation.

1 is a leak concentration of the pharmaceutical compound of Examples and Reference Examples.

2 is a dissolution rate of the pharmaceutical compound of Examples and Reference Examples.

Carrying out the invention  Best form for

In the present specification, the term "unpleasant taste" refers to feeling unpleasant due to taste and smell when the user puts it into the mouth, and includes, for example, bitterness, spicy taste, astringent taste, and unpleasant smell.

A "pharmaceutical compound" is a pharmaceutically acceptable compound, its salts, or hydrates thereof. As a pharmaceutical compound which can be applied to the coating formulation according to the present invention, in particular, a pharmaceutical compound having an unpleasant taste, for example, penicillin-based fluorocloxacillin sodium, deampicillin hydrochloride, tosyl sulfate sulfacillin and baccampiline hydrochloride, Antibiotics such as cefecrolol, cefepodoxime proxetyl, ceftiamhcetyl, ceproxac axetyl, cefecapfenpixyl and cefterapixyl, or macrolide erythromycin; Quinolone antibacterial agents, such as romefloxacin, nofloxacin, opfloxacin, enoxacin, and pipemic acid; Antitussive antimicrobial agents such as dextromethorphan hydrobromide, isoaminyl citrate and dimemorphane phosphate; Antipyretic analgesic anti-inflammatory drugs such as acetaminophen, ketoprofen and tolphenamic acid; Antihistamines such as dihydramine hydrochloride and promethadiline hydrochloride; In addition, a dicethiamine hydrochloride is mentioned. In particular, when using a low solubility pharmaceutical compound, it is possible to obtain an excellent effect of suppressing discomfort while ensuring elution. Thus, a poorly soluble pharmaceutical compound such as (+)-(6R, 7R) -7-[(Z) -2- (2-amino-4-thiazolyl) -2-pentenamide] -3- Carbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] octo-2-ene-2-carboxylic acid pivaloyl oxymethyl ester hydrochloride monohydrate is preferable.

Although the waxy substance is solid in the vicinity of room temperature, if it is softened and melt | dissolved easily by heating, a pharmaceutically acceptable thing can be used widely. For example, hardened oils (cured castor oil, hardened soybean oil, hardened soybean oil, etc.), higher alcohols (stearyl alcohol, cetanol, etc.), higher fatty acids (stearic acid, palmitic acid, etc.), vegetable or animal fats (Uji, Carr) Nava wax), beeswax, polyethylene glycol (PEG: macrogol 4000, macrogol 6000, etc.) and the like. In terms of industrial practice, the melting point is preferably in the range of about 40 ° C to about 100 ° C. Especially preferably, it is hardening oil. For reference, the melting point (° C.) of each waxy substance is exemplified by stearyl alcohol (about 59), cetanol (about 49), stearic acid (about 71), palmitic acid (about 63), carnauba wax (About 78 to 84), hydrogenated oil (palm oil: about 43 to 45, palm oil: about 56 to 58, cottonseed oil: about 62 to 63, soybean oil: about 69 to 71, castor oil: about 86 to 90), PEG6000 (about 58 65).

As a waxy substance (Hereinafter, it may be called a "internally-added waxy substance.") Used before manufacture of an elementary particle | grain, what can melt | dissolve easily by heating is preferable. Cured oil, stearyl alcohol, stearic acid, polyethylene glycol, etc. are mentioned.

As the powdered waxy substance (hereinafter sometimes referred to as "externally added waxy substance") used for the outer coating of the obtained small particle, it is preferable to be hydrophobic in order to suppress discomfort. Cured oil, stearyl alcohol, stearic acid, polyethylene glycol, etc. are mentioned. In the case where a waxy substance having a large particle diameter is used, the molten waxy substance becomes a nucleus and coarse particles are produced, so that the shape of the externally added waxy substance is preferably a powder form smaller than the small particles to be coated. It is preferable that the average particle diameter of this powdery waxy substance is smaller than the average particle diameter of the small particle. Regarding the average particle diameter of the powdery waxy material, those of about 100 μm or less are usually used, and preferably about 50 μm or less.

Until now, when coating with a waxy material using a fluidized bed, since wax particles are scattered in the flow, it has been considered that the shape of the waxy material must be larger than the particles to be coated. 1-287021). However, in the method of the present invention, the waxy material is blended into the small particles, and the wax is formed by acting as a binder of the small particle and the external powdery waxy material in a state where the internal waxy material is melted during the hot melt coating. The problem of particles scattering during flow can be solved.

As the internally added waxy substance and the externally added waxy substance, the same waxy substance may be used or different waxy substance may be used.

In the case where different waxy substances are used, the internally added waxy substance is preferably equal to or lower in melting point than the externally added waxy substance. In this case, the heat treatment of the small particle is performed near the melting point of the internally added waxy substance, the temperature is increased during the hot melt coating process after the addition of the externally added waxy substance, and at the end of the melting point of the externally added waxy substance. Adjust to the vicinity. As a combination of different waxy materials, a combination in which the internally added waxy material is hydrophilic and powdery, and the externally added waxy material is hydrophobic and powdery is preferable. In particular, a combination of polyethylene glycol (PEG6000 powder) in the internally added waxy material and hardened castor oil in the externally added waxy material is preferable.

"Wetting the surface" of "under the temperature which the wax-like substance wetted the surface" shows the state which the internal addition wax-like substance softens by heating and is expressed on the surface of a small particle. The internally added waxy material in this state can act as a binder of the small particle and the external powdery waxy material.

In addition, the water-swellable substance is almost insoluble in water, but expands while absorbing while maintaining its shape to form a matrix structure. Examples of the water swellable substance include cellulose derivatives such as carboxymethyl cellulose calcium, croscarmellose sodium (crosslinked CMC · Na), and low-substituted hydroxypropyl cellulose (L-HPC); Various starches such as partially alpha starch (PCS) and carboxymethyl starch sodium (CMS-Na); Synthetic high molecular compounds, such as a crospopidon, are mentioned.

As the waxy substance, when using cured oil, stearyl alcohol, stearic acid or polyethylene glycol, the small particle used in the present invention is about 40% by weight or less, preferably about about the pharmaceutical compound to which the present invention can be applied. 25 weight% or less, about 5 to about 25 weight% of waxy material, preferably about 5 to about 15 weight%, about 5 to about 35 weight% of water swellable material, preferably about 20 to about 35 weight% It is obtained by assembling a mixture. In addition, the coating formulation of the present invention is obtained by heating the above-mentioned small particles, and then adding about 5 to about 25% by weight of the powdered waxy substance, preferably about 5 to about 15% by weight, and then hot-melt coating. Lose. In addition, each weight% means the ratio with respect to the total weight of a coating formulation.

When the total addition amount which adds the internal addition amount and the external addition amount of a waxy substance is excessive, it will become difficult to disintegrate granules in a body, and the elution property of a containing component will fall. On the contrary, when too little, the suppression of leakage in the oral cavity becomes insufficient. In addition, the internal addition amount and external addition amount of a waxy substance mean the quantity of an internal addition waxy substance and an external addition waxy substance, respectively. The total addition amount of the waxy substance is preferably about 10 to about 50% by weight based on the total weight of the coating formulation.

The external addition amount (external addition rate) with respect to the total addition amount of a waxy substance changes with kinds of waxy substance.

In the case of using a waxy substance having a low hydrophobicity, leakage can be suppressed while maintaining elution even if the external addition rate is high, but when the external addition rate is low, suppression of leakage in the oral cavity is insufficient. Therefore, when using a waxy substance with low hydrophobicity, it is preferable that the amount of external addition is large. For example, in the case of polyethylene glycol, the external addition rate is 50 to 80%, especially 70% is preferable. In addition, when using a waxy substance with low hydrophobicity, it is more preferable that the total addition amount of a waxy substance is large. For example, it is preferable that the total amount of the waxy substance is about 20 to 50% by weight relative to the total weight of the coating formulation. As such a waxy substance, polyethyleneglycol etc. are mentioned, for example.

In contrast, in the case of using a waxy substance having high hydrophobicity, a high external addition rate makes it difficult to disintegrate granules in the body, so that the elution property of the inclusion component is lowered. However, even when the external addition rate is low, the elution property can be maintained while suppressing leakage. Therefore, when using a waxy substance with high hydrophobicity, it is preferable that the amount of external addition is small. For example, in the case of hardened castor oil, the external addition rate is about 20 to 60%, particularly preferably 50%. Moreover, when using a waxy substance with high hydrophobicity, it is preferable that the total addition amount of a waxy substance is small. For example, it is preferable that the total amount of the waxy substance is about 10 to 30% by weight based on the total weight of the coating formulation. As such a waxy substance, hardening oil etc. are mentioned, for example.

In addition, when the water-swellable disintegrating agent is too small, the granules are less likely to collapse in the body and the elution property of the inclusion component is lowered. On the contrary, when the water swellable disintegrant is excessive, the suppression of leakage in the oral cavity becomes insufficient.

The coating formulation of the present invention includes coating granules, coating granules and preparations in which sweet granules such as white sugar are added to the granules, for example, children's dry syrup, tablets tableted using the coating granules of the present invention, and the like. Included.

There are two methods for producing granules or tablets: wet and dry. The wet method refers to a method of producing by adding water or / and an organic solvent and using a binder. The dry method means a method of manufacturing by compacting the powder without using water or an organic solvent. What is necessary is just to perform drying, upsetting, classification operation, etc. of granulated material in accordance with a conventional method. If the manufacturing method of the coating formulation of this invention includes the process of masking with a waxy substance, you may use any of the wet method and the dry method. When using the manufacturing method of the coating formulation of this invention when manufacturing the formulation containing the pharmaceutical compound which is unstable in water, it is preferable to use a dry method.

When using the wet method, it is preferable to use water as the solvent. Moreover, as a water-soluble binder, celluloses (hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose), starch (potato starch, alpha starch, corn starch), polyvinylpyrrolidone ( PVP) and the like. The use ratio is about 1 to about 5 weight% with respect to the granulation mixture.

The coating formulation of the present invention is, for example, about 40% by weight or less of a pharmaceutical compound, particularly a drug compound having an unpleasant taste, about 5 to about 25% by weight of a waxy substance, and about 5 to about 35% by weight of a water swellable substance, as required On the other hand, a mixed powder composed of other additives such as a binder, a lubricant, a copper, a colorant, and the like is granulated and granulated by a wet method or a dry method, adjusted to an arbitrary particle diameter, and then heat-treated to act as a binder. And it can be manufactured easily by the manufacturing method characterized by adding about 5 to about 25 weight% of powdery waxy substances, and carrying out hot melt coating.

Mixing, granulating and sizing of each powder component can be used according to a conventional method. For example, in the case of using a dry method, the granulation of powder is compression-molded into slug and flake at a pressure of 50 to 100 MPa by a press such as a tablet press or a roll compressor, followed by 350 by a crushing type granulator. It carries out by adjusting to arbitrary particle sizes, such as-1410 micrometers (grains) and 75-500 micrometers (fine granules). The small particle obtained by this manufacturing method (it means the granulation before a heat processing. The same is the same below) is a wax-like substance and a water swellable substance of a component uniformly disperse | distribute, and a part of a wax-like substance spread | extends by expansion. Iii) presumably.

Subsequently, after heat-processing this small particle, a powdery waxy substance is added, and the hot melt coating granules (The granules after wax-coating process with heating are called. The same applies below) are prepared.

In the hot melt coating process, heating before and during addition of the powdered waxy material is carried out for a sufficient time at a temperature sufficient to soften the internally added waxy material. Heating temperature is about 40 degreeC or more normally, and below melting | fusing point of an internal addition waxy substance is preferable. That is, heating temperature should just be a temperature more than the internal additive waxy substance which can make the surface of a small particle wet during the process. The internally added waxy substance melted by this treatment acts as a binder of the externally added waxy substance on the surface of the small particle. Thus, the heating temperature is varied by the melting point of the internally added waxy material. The internally added waxy material is preferably softened at about 40 to about 90 ° C, particularly preferably at about 50 to about 85 ° C.

The heating after the addition of the powdered waxy material is carried out for a sufficient time at a temperature sufficient for the externally added waxy material to soften. Heating temperature is about 40 degreeC or more normally, and below melting | fusing point of an external addition waxy substance is preferable. Thus, the heating temperature varies with the melting point of the externally added waxy material. The externally added waxy material is preferably softened at about 40 to about 90 ° C, particularly preferably at about 50 to about 85 ° C.

In the hot melt coating process, when the heating temperature is high, the internally added waxy substance and the externally added waxy substance are completely melted, and the coating of the granules by the waxy substance is completed, which makes it difficult for the granules to collapse in the body. And elution of the inclusion component is lowered. On the contrary, when the heating temperature is too low, the coating of the granules is excessive because the internally added waxy substance does not act as a binder of the externally added waxy substance and the externally added waxy substance is not sufficiently inverted on the surface of the small particle. This reduces the leakage in the oral cavity.

When the heating temperature reaches the appropriate temperature, the powdered waxy substance is added and hot melt coated on the surface of the small particle. The coating time is preferably about 10 to about 90 minutes, particularly preferably about 20 to about 60 minutes. As a preferable apparatus for hot melt coating, a fluidized bed drying apparatus is mentioned.

Usually, when powder coating is performed in a fluidized bed, it is very difficult to coat uniformly. However, by using the method of the present invention, the waxy substance is softened by flowing with heating by a fluidized bed drying apparatus (flow coater FLO · 5 type; Okawara Corporation) even if it is uneven when the powdery waxy substance is added, It extends on the surface of the small particle and becomes uniform. In this respect, the method of the present invention provides a very simple outer coating method.

Hereinafter, the manufacturing method of the coating formulation which concerns on this invention is demonstrated in detail. In the present specification, unless otherwise indicated, formulation processes known in the art are employed.

Firstly, about 40% by weight or less of a pharmaceutical compound, especially a drug compound having an unpleasant taste, about 5 to about 25% by weight of a waxy substance and about 5 to about 35% by weight of a water swellable substance, if necessary, a binder, a lubricant, and a mating agent And other additives such as colorants. This mixed powder is compacted and shaped into flakes and then crushed. Thereafter, the particles are classified with a particle separator and adjusted to an arbitrary particle diameter to obtain a small particle (assembly step).

Next, the small particle is heated so that the waxy material wets the surface, and under this condition, a powdery waxy material (about 5 to about 25% by weight) is added. Thereafter, under a heated state, a hot melt coating granule is obtained by flowing for a predetermined time (hot melt coating step).

Moreover, in order to improve the discomfort in the oral cavity, the coating formulation containing a sweetening agent can be granulated. Alternatively, the sweet granules can be granulated and mixed with the coating formulation. As the sweetener, for example, lactose, white sugar, powdered reduced maltose syrup, glucose, xylitol, mannitol, sorbitol, maltose, erythritol, aspartame, saccharin, sodium saccharin, acesulpam potassium or dipotassium glycylate, etc. are used. do.

When sweet granules are mixed with the coating formulation, sweet granules prepared by conventional methods can be used. For example, it can be obtained by mixing a sweetener, adding an appropriate amount of water to coalesce, extruding the coalesced to produce granules, and drying.

The present invention provides a sweet granule having an increased sweetness from the sweet granules described above. That is, in order to improve the elution property of a sweetener, the sweet granule in this invention dissolves or disperse | distributes some sweetener in water with the binder which has a solubilizing effect as a binder liquid, when a sweetener is granulated, It can be obtained by adding and associating with sweeteners and assembling and drying the association.

By taking this sweet fine grain in admixture with said coating formulation, discomfort can be improved further.

The sweet granules in this invention are granulated by the wet method using the sweetener and the binder liquid which melt | dissolved or disperse | distributed the sweetener with the binder in water. As a sweetener, said sweetener can be used. As the binder, the water-soluble binder described above can be used. In particular, binders having a surfactant activity, for example, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP) and the like are preferable.

Test Example  One

(Preliminary examination)

In order to pursue the manufacturing method of the granule which can achieve the objective of this invention, the threshold of bitterness was calculated | required by the sensory test first.

(Sensory test of the taste of Sefkafen hydrochloride)

The powder of Sefkafenfichyl hydrochloride was dissolved, and 100 mL (liquid temperature 36-38 degreeC) of 8 levels of test liquids were prepared for 6 servings. First, the panelist put 10 mL of the lowest concentration test solution in the mouth for about 30 seconds and spit it out for sensory evaluation. This about 30 seconds is the maximum expected residence time in the mouth.

Subsequently, the mouth was rinsed with water, and the sensory evaluation was similarly performed on the high concentration liquid sequentially.

density
(Μg / mL) Panelist One 2 3 4 5 6 33 ± ± - ± - ± 40 ± ± ± ± ± ± 56 + ± ± ± ± ± 60 + + ± ± ± + 70 + + + + + + 80 + + + + + + 90 +++ + + + +++ + 100 +++ + + +++ +++ +

? Not feeling bitter at all

± hardly felt bitter

+ Feels a bitter bitter taste

++ Feel strong bitterness

＋＋＋ Feeling very strong bitter taste

From the results of the test, it was found that the elution concentration in the mouth should be able to be suppressed to less than 70 µg / mL, which is the concentration at which all panelists feel bitter taste.

Example  One

(1) small particles (assembly process)

The small particle components of two compositions shown in the following table are mixed for 15 minutes in a V-type mixer (50L). The mixed powder was molded into a flake shape by a roller compactor (Roller Compactor Turbo Industries, Ltd.), and then pulverized and assembled by a roll granulator (Nippon Granulator Co., Ltd.), filled with a vibrating separator, and classified. A particle size of ˜100 mesh is obtained.

(2) hot melt coating process

After putting a small particle into a fluidized-bed drying apparatus (flow coater FLO type 5; Okawara Corporation), and heating it to the temperature of 80-85 degreeC, hardening castor oil is thrown in a fluidized bed according to the composition of the following table | surface. do. After flowing 10-30 minutes at the temperature of 80-85 degreeC, it passes through a 30 mesh net and obtains a hot melt coating granule.

Example  2

It carried out similarly to Example 1. The compositions of Examples 1 and 2 are shown in Table 2.

Example 1 Example 2 Small particles Hydrochloric acid Sepcapen coat 140.0 mg 25.0 wt% 140.0 mg 25.0 wt% Cured Castor Oil 69.0mg 12.3 wt% 57.5 mg 10.3 wt% Low Substitution Hydroxypropyl Cellulose 140.0 mg 25.0 wt% 140.0 mg 25.0 wt% Powdered reduced maltose syrup 132.0mg 23.6 wt% 132.0mg 23.6 wt% D-mannitol 15.0mg 2.7 wt% 15.0mg 2.7 wt% Magnesium stearate 18.0mg 3.2 wt% 18.0mg 3.2 wt% Coating agent Cured Castor Oil 46.0 mg 8.2 wt% 57.5 mg 10.3 wt% Total amount 560.0mg 100 wt% 560.0mg 100 wt%

Reference Example  One

Reference Example 1 Hydrochloric acid Sepcapen coat 140.0 mg 25.0 wt% Cured Castor Oil 115.0mg 20.5 wt% Low substitution degree
Hydroxypropyl cellulose 140.0 mg 25.0 wt% Powdered reduced maltose syrup 132.0mg 23.6 wt% D-mannitol 15.0mg 2.7 wt% Magnesium stearate 18.0mg 3.2 wt% Total amount 560.0mg 100 wt%

(1) small particles (assembly process)

The component of Table 3 is mixed for 15 minutes in V-type mixer (50L). The mixed powder is shaped into flakes by a roller compactor, and then pulverized by a roll granulator, filled with a vibrating separator, and classified to obtain a granule of 30 to 100 mesh.

(2) Hot Melting (Heating) Process

After a small particle is put into a fluidized bed drying apparatus, it is made to flow for 30 to 40 minutes at the temperature of 80-85 degreeC, and it passes through 30 mesh nets, and obtains a hot melt granule.

Reference Example  2

The small particle of Example 1 and the hardened castor oil of Table 2 are mixed for 5 minutes in V-type mixer 50L, and a mixture is thrown into a fluidized bed drying apparatus (flow coater FLO * 5 type: Okawara Corporation). After heating at 80-85 degreeC and flowing for 10-30 minutes, it passes through a 30 mesh net and obtains a hot melt granule.

Test Example  2

(Leak test)

Leak tests were carried out for the hot melt coated granules obtained in Examples 1 and 2, the small particles obtained in Reference Example 1, and the hot melt granules. After measuring a certain amount of sample in a static test tube with a balance, 30 mL of water was added, and then the sample shaken for 30 seconds with a vibrator (50 revolutions / minute) was filtered, and the filtrate was prepared in a cephacappenic hydrochloride solution. The concentration was measured by absorbance method. The results are shown in Fig. The leakage concentration of the thermal melting granules of Reference Examples 1 and 2 was lower than that of the small particles, but after 60 seconds from the start of the test, all panels exceeded 70 µg / mL for detecting the bitter taste in the sensory test. On the other hand, it was found that the leakage concentrations after 60 seconds of the heat-melt-coated granules of Examples 1 and 2 were 46 and 39 µg / mL, and all panelists were suppressed to a concentration that hardly detects bitter taste.

Test Example  3

(Dissolution test)

The elution test was performed with the paddle method (100 rpm) using the Japanese Pharmacopoeia 2nd liquid about the hot melt coating granules (coating preparation) obtained in Examples 1 and 2 and the hot melt granules obtained by the reference example 1. The results are shown in FIG. Although Examples 1 and 2 increased the masking effect of the unpleasant taste of a chemical | medical agent than Reference Example 1, the delay of an elution rate was hardly recognized. Although the coating formulations of Examples 1 and 2 were coated, the dissolution rates of the pharmaceutical compounds after 30 minutes were 77.1% and 75.4%, respectively, and were 75% or more similarly to the thermal melting granules (80.0%) obtained in Reference Example 1.

Example  3

(1) sweetness

After mixing five components of aspartame, xylitol, D. mannitol, hydroxypropyl cellulose, and alpha starch shown in Table 4 with a stirring granulator (25L) for 2 minutes, aspartame and hydroxypropyl cellulose were dissolved or dispersed. The liquid (420 g of water) was added and associated. The coalescence was extruded and granulated in a cylindrical granulator and dried in a fluidized bed drying apparatus (flow coater FLO · 5 type: Okawara Corporation). The dry granules were temporarily granulated with a roll granulator (Japan Granulator Co., Ltd.), filled with a vibrating separator, and classified to obtain 5000 g of a granule of 30 to 100 mesh.

Aspartame 90 g (1.5 wt%) Xylitol 3000 g (50% by weight) D-mannitol 2400 g (40 wt%) Hydroxypropylcellulose 240 g (4 wt%) Alpha Starch 120 g (2% by weight) Aspartame 90 g (1.5 wt%) Hydroxypropylcellulose 60 g (1 wt%) Total amount 6000 g (100% by weight)

Reference Example  3

(1) sweetness

After mixing five components of Table 5 in a stirring granulator (25L) for 2 minutes, 420g of water was added and it combined. The coalescence was extruded into a cylindrical granulator, granulated, and dried in a fluidized bed drying apparatus (flow coater FLO · 5 type; Okawara Corporation). The dry granules were temporarily granulated with a roll granulator (Japan Granulator Co., Ltd.), filled with a vibrating separator, and classified to obtain 5000 g of a granule of 30 to 100 mesh.

Aspartame 180 g (3% by weight) Xylitol 3000 g (50% by weight) D? Mannitol 2400 g (40 wt%) Hydroxypropylcellulose 300 g (5% by weight) Alpha Starch 120 g (2% by weight) Total amount 6000 g (100% by weight)

Test Example  4

(Sensory sensory test)

The sweet granules of Example 3 and Reference Example 3 were mixed with the hot melt coated granules of Example 1 at a ratio of 1: 1, respectively, and the taste sensory test was performed.

1 g of each composite granule was prepared for 6 servings. Of the six panelists, three half of them took A (complex granulation of the sweet granule of Example 3 and the hot melt coating granules of Example 1), followed by rinsing their mouths with water and B (sweet granulating granule of Example 3 and Examples). 1) a composite granule of hot melt coated granules). The other three were taken in the order of B and A. Panelists conducted sensory evaluation on which granules they felt strongly.

The number of people who felt strong bitterness of A 0 The number of people who felt strong bitterness of B 6

Although the granulation of A and B was the same in composition, as shown above, all six panelists felt the bitter taste of B strongly. This is a result of enhanced sweetness because aspartame, a sweetening agent, was dispersed in the binding liquid together with a small amount of hydroxypropyl cellulose.

According to this invention, the manufacturing method of the coating formulation which improved the unpleasant taste is provided. In detail, in the formulation for oral administration containing the chemical | medical agent which has unpleasant taste, the manufacturing method of the easy to take formulation which suppressed the leak in the oral cavity and reduced the discomfort at the time of taking is provided.

Claims (15)

A small particle containing a pharmaceutical compound and a waxy substance is heat-treated, and a powdery waxy substance having an average particle diameter smaller than the average particle diameter of the small particle is added at a temperature at which the waxy substance wets the surface, A method for producing a coating formulation, wherein the surface of the small particle is hot melt coated. delete The method of claim 1, A method for producing a coating formulation, wherein the powdery waxy material is at least one powdery waxy material selected from the group consisting of cured oil, stearyl alcohol, stearic acid, and polyethylene glycol. The method of claim 3, wherein The weight of the coating formulation is 40% by weight or less of the pharmaceutical compound, 5-25% by weight of the waxy substance, 5-25% by weight of the water-swellable substance, 5-25% by weight of the powdery waxy substance, and other additives. A method of making a coating formulation that is 100% by weight in total, with or without. The method according to any one of claims 1, 3 or 4, The manufacturing method of the coating formulation in which a pharmaceutical compound has unpleasant taste. The method according to any one of claims 1, 3 or 4, The pharmaceutical compound is (+)-(6R, 7R) -7-[(Z) -2- (2-amino-4-thiazolyl) -2-pentenamide] -3-carbamoyloxymethyl-8-oxo -5-thia-1-azabicyclo [4.2.0] octo-2-ene-2-carboxylic acid pivaloyloxymethylester hydrochloride, the manufacturing method of the coating agent which is monohydrate. The method of claim 6, In the coating formulation shaken for 30 seconds after the addition of 30 mL of water, the dissolution concentration of the pharmaceutical compound after 60 seconds from the start of the leak test was 70 µg / mL or less, and the dissolution test started by the paddle method using the Japanese Pharmacopoeia 2nd liquid. The manufacturing method of the coating formulation whose dissolution rate of the pharmaceutical compound after 30 minutes from is 75% or more. Coating formulation manufactured by the manufacturing method of any one of Claims 1, 3, or 4. 9. The method of claim 8, The coating formulation which further mix | blended the sweet granules obtained by granulating by the wet method using the binder liquid which melt | dissolved or disperse | distributed the sweetener and the binder. Coating formulation manufactured by the manufacturing method of Claim 5. Coating formulation manufactured by the manufacturing method of Claim 6. Coating formulation manufactured by the manufacturing method of Claim 7. 11. The method of claim 10, The coating formulation which further mix | blended the sweet granules obtained by granulating by the wet method using the binder liquid which melt | dissolved or disperse | distributed the sweetener and the binder. The method of claim 11, wherein The coating formulation which further mix | blended the sweet granules obtained by granulating by the wet method using the binder liquid which melt | dissolved or disperse | distributed the sweetener and the binder. 13. The method of claim 12, The coating formulation which further mix | blended the sweet granules obtained by granulating by the wet method using the binder liquid which melt | dissolved or disperse | distributed the sweetener and the binder.

Images