HK1180583A - Drug-containing film-coated particles in which unpleasant taste is masked - Google Patents

Description

Pharmaceutical film-coated particles with masked unpleasant taste

Technical Field

The present invention relates to a drug-containing film-coated granule with masked unpleasant taste, which can be used in a granular preparation called powder or granule in the field of medicine, and can also be used in a rapidly disintegrating tablet having a rapid disintegration even with little or no water in the oral cavity.

Background

In modern society in which aging progresses, as the number of elderly people who have to take a variety of medicines on a daily basis due to various diseases is increasing, patients who have difficulty in the "behavior of taking medicine" due to the decline of swallowing function accompanying the increase in age are also increasing. Such a situation causes a decrease in the compliance with the drug. For such patients with decreased swallowing function, granules such as granules and fine granules or orally disintegrating tablets which are rapidly disintegrated in the oral cavity by a small amount of water or saliva are more desirable than tablets and capsules. However, since all formulations are dispersed in the oral cavity, when masking of the unpleasant taste is insufficient, it is difficult to take the formulation due to the unpleasant taste diffused in the oral cavity.

As a method for masking the unpleasant taste of a drug, a method of adding a flavor, a sweetener, or the like, and a method of using a polymer base are known. The method of adding a flavor or a sweetener is a simple method, but the masking effect is weak, and thus the kinds of drugs to be applied are limited. On the other hand, as methods of using a polymer base, a matrix (matrix) method of dispersing a drug mainly in a polymer carrier and a coating method of coating a drug with a film comprising a polymer are known. In general, in this base method, a part of the drug is exposed on the surface of the preparation, and therefore, a desired effect may not be obtained in a drug having a strong unpleasant taste. In addition, although the coating method has an excellent masking effect of the unpleasant taste, the quick release property is often insufficient.

In order to solve the above-mentioned problems, various preparations have been developed. For example, patent document 1 discloses a preparation in which a core containing an unpleasant-tasting drug and a water-swellable substance is coated with a coating layer containing ethylcellulose and a water-soluble substance. However, when such a preparation is used as an orally disintegrating tablet, the masking time of the unpleasant taste is insufficient.

Patent document 2 discloses a fine granule in which a water-soluble coating agent such as hydroxypropyl cellulose and a saliva-insoluble coating agent such as carboxymethyl ethyl cellulose are double-coated on core particles containing a pharmaceutical active ingredient having a bitter taste. When a water-insoluble coating agent such as ethyl cellulose is used as the coating agent, a large amount of the water-insoluble coating agent is required to sufficiently exhibit the bitterness-masking effect, and therefore, a good therapeutic effect cannot be obtained. However, saliva-insoluble coating agents exhibit solubility depending on pH, and therefore may affect the in vivo kinetics of the drug.

Patent document 3 discloses a core particle coated with a powder-form dispersion agent in which a main drug and low-substituted hydroxypropyl cellulose are blended. However, the present nucleated particles are characterized in that the main drug powder and the low-substituted hydroxypropylcellulose are dispersed while the binder liquid is sprayed onto the nucleated particles, but in such a production method, aggregates are easily formed, and therefore, the present nucleated particles cannot be applied unless they are relatively large particles. Further, there is no detailed description about masking of bitterness. Patent document 4 also discloses similar nucleated particles, but in order to achieve a good balance between drug-eluting properties and bitterness-masking effects, the amount of low-substituted hydroxypropylcellulose to be added has to be practically limited, and there is still room for improvement.

Patent document 5 discloses a nucleated powder obtained by coating at least 1 physiologically active substance with a water-soluble polymer. However, since the dissolution property of the drug is controlled only by the viscosity grade, content, etc. of the water-soluble polymer, such a nucleated powder may not sufficiently suppress the dissolution of the drug from the viewpoint of masking the bitterness.

Documents of the prior art

Patent document

Patent document 1: japanese patent No. 3317444

Patent document 2: japanese laid-open patent publication No. 63-258809

Patent document 3: japanese laid-open patent publication No. 63-301816

Patent document 4: japanese laid-open patent publication No. 2-174931

Patent document 5: japanese laid-open patent publication No. 5-92918

Disclosure of Invention

Problems to be solved by the invention

The present invention provides drug-containing particles which effectively mask the unpleasant taste of a drug, can be used in granular preparations called powders or granules in the field of medicine, and can also be used in orally disintegrating tablets.

Means for solving the problems

The present inventors have conducted various studies to solve the above problems, and as a result, have found that drug-containing particles which can rapidly release a drug after masking the unpleasant taste of the drug for a certain period of time by forming a film layer using a specific pharmaceutical additive at a specific ratio have been obtained, and have completed the present invention.

That is, the present invention provides a particle coated with a drug-containing film, which is characterized in that a multi-film layer comprising a film layer (a) and a film layer (B) is formed on the surface of a core particle (P) containing no unpleasant drug and no water-swellable polymer, the film layer (a) contains the unpleasant drug and the water-swellable polymer, the film layer (B) contains a water-insoluble polymer, a water-soluble substance and an inorganic compound, the multi-film layer is characterized in that the film layer (a) is an innermost film layer, the mass ratio of the core particle (P) is 30 mass% or less, the drug content is 40 mass% or less, the water-swellable polymer content is 13 to 30 mass%, the water-insoluble polymer content is 7 to 11 mass%, and the water-soluble substance content in the film layer (B) is 0.4 to 0.6 times the water-insoluble polymer content, based on 100 mass% of the total amount of the particles coated with the drug-containing film, and the content of the inorganic compound is 25 to 35% by mass in 100% by mass of the film layer (B).

ADVANTAGEOUS EFFECTS OF INVENTION

The particles coated with the drug-containing film of the present invention have an excellent balance between the masking property of the unpleasant taste of the drug and the dissolution property. Therefore, there is no fear of a decrease in drug compliance, and since the drug is released rapidly after administration, the biological availability and biological equivalence to a normal preparation can be secured.

Further, the rapidly disintegrating tablet does not feel unpleasant taste in the oral cavity, and can be easily taken even with a small amount of water or without water.

Detailed Description

The present invention will be described in detail below.

In the present specification, the term "coated" includes not only a case where the entire surface of the core particle is coated with a film but also a case where the core particle is partially coated.

The drug-containing film-coated particles of the present invention are formed by forming a plurality of layers on the surface of the core particle (P), and these layers coat the core particle. In such a multi-layer film, at least 1 film layer contains a drug, and the core particle (P) does not contain an unpleasant drug or a water-swellable polymer. That is, the multi-layer film includes at least 2 layers including a film layer (a) containing an unpleasant drug and a water-swellable polymer and a film layer (B) containing at least a water-insoluble polymer, a water-soluble substance, and an inorganic compound, and the film layer (a) containing the unpleasant drug and the water-swellable polymer is formed on the surface of the core particle (P) as an innermost film layer.

In this way, since the particle coated with a drug-containing film of the present invention uses the core particle (P) not containing both the unpleasant-tasting drug and the water-swellable polymer and forms the film layer containing the unpleasant-tasting drug and the water-swellable polymer on the surface of the core particle, the water-swellable polymer can be uniformly arranged in the vicinity of the drug, and the masking property and the elution property of the unpleasant taste of the drug can be balanced and both the unpleasant taste can be sufficiently suppressed and the desired drug effect can be effectively exhibited. Therefore, the composition is completely different from the preparation described in patent document 1. That is, as described in patent document 1, even in the case of a preparation in which a film layer is formed on a core containing an unpleasant drug and a water-swellable polymer, it is difficult to maintain a good balance between the masking property and the dissolution property of the unpleasant taste of the drug as compared with the present invention as shown in comparative example 5 described later. The reason for this is that when a drug having an unpleasant taste and a core of a water-swellable polymer are used, it is difficult to say that the water-swellable polymer is uniformly present in the vicinity of the drug. In addition, it is considered that a part of the water-swellable polymer is exposed from the core to the outer film layer, and the outer film layer becomes uneven and fragile. Therefore, the initial dissolution rate of the preparation becomes high. Even if the amount of the water-swellable polymer added is the same, the distribution is not uniform, but the swelling power is weaker than that in the case of uniform distribution, and it is estimated that the dissolution rate of the preparation at the later stage is reduced.

The unpleasant taste drug is not particularly limited as long as it exhibits an unpleasant taste such as a bitter taste in the oral cavity and can exert its efficacy as a pharmaceutically active ingredient in the treatment and prevention of diseases when taken. As such a drug, 1 or 2 or more components selected from drugs for the central nervous system, drugs for the peripheral nervous system, drugs for the sensory organs, drugs for the circulatory organs, drugs for the respiratory organs, drugs for the digestive organs, hormones, drugs for the urogenital organs and the anus, vitamins, tonic drugs, blood-body fluids, other metabolic drugs, drugs for cell activation, drugs for tumors, drugs for allergy, crude drugs, chinese medicinal preparations, antibiotic preparations, chemotherapeutic preparations, drugs for parasitic animals, alkaloid anesthetics, non-alkaloid anesthetics, and the like can be used, but the drug is not limited thereto. Among these drugs, from the viewpoint of the administration frequency, digestive organ drugs are preferred, and antiulcer agents are more preferred. Examples of such an antiulcer agent include ranitidine hydrochloride, cimetidine, famotidine and lafutidine, and among them, lafutidine is more preferable. Lafutidine is (. + -.) -2- (furfurylsulfinyl) -N- [ 4- [ 4- (1-piperidinylmethyl) -2-pyridyl ] oxy- (Z) -butenyl ] acetamide, and in the present invention, includes the stereoisomers and optical isomers, and also includes salts and derivatives that can be easily derived therefrom by those skilled in the art, and is synthesized, for example, according to the method described in Japanese patent application laid-open No. Sho 63-225371.

The content of the unpleasant-tasting drug is 40 mass% or less, preferably 5 to 35 mass%, more preferably 10 to 30 mass% based on 100 mass% of the total amount of the particles coated with the drug-containing film. When the content is within the above range, the unpleasant taste can be sufficiently suppressed and the desired medicinal effect can be effectively exhibited.

The water-swellable polymer to be included in the film layer (a) together with the drug is not particularly limited as long as it is practically insoluble in water (solubility is evaluated from the extent of being soluble in water within 30 minutes when the water-swellable polymer is added to water at 25 ± 5 ℃ and mixed with vigorous shaking for 30 seconds every 5 minutes as defined in the general regulations of the japanese pharmacopoeia of the sixteenth modification, "practically insoluble in water" means that the amount of water required to dissolve 1g of the water-swellable polymer is 10000mL or more), and the polymer material is a polymer material that swells with water and is other than a water-insoluble polymer, and examples thereof include low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, carboxymethylcellulose or a salt thereof, croscarmellose sodium, and crospovidone. Among them, low-substituted hydroxypropylcellulose is preferable. Here, the low-substituted hydroxypropylcellulose has a degree of substitution (%) of hydroxypropoxyl groups of 5.0 to 16.0%, preferably 10 to 13%. The low-substituted hydroxypropylcellulose having a hydroxypropoxyl group substitution degree of less than 5.0% is poor in swelling power, and when it is more than 16.0%, it tends to become sticky when containing water, and therefore, it tends to feel sticky when taken.

The substitution degree of hydroxypropylcellulose is an amount (%) of hydroxypropoxy group substituted with hydroxyl group of pyranose ring of cellulose, specifically, a value measured by gas chromatography according to the method for determining low-substitution degree hydroxypropylcellulose defined in the japanese pharmacopoeia of the sixteenth modification.

The content of the water-swellable polymer in the particles coated with the drug-containing film in an amount of 100% by mass in total is 13 to 30% by mass, preferably 15 to 25% by mass, and more preferably 17 to 22% by mass. When the content is within the above range, the other film layer formed can be sufficiently destroyed, and therefore, the drug contained in the film layer (a) can be effectively released. Further, as described later, by efficiently disposing the water-swellable polymer on the surface of the core particle (P), it is considered that a force necessary for breaking the film layer can be obtained even if the amount is small. When the content is larger than a desired value, the proportion of the other coating agent in the entire particle coated with the drug-containing film decreases, and therefore, the dissolution property becomes too fast, and the balance between the dissolution property and the bitterness-masking effect tends to deteriorate.

The thickness of the film layer (A) is preferably 70 μm or less, more preferably 20 to 50 μm. When the thickness is within the above range, the size of the particles coated with the drug-containing film can be reduced as much as possible, and therefore, the feeling of roughness is not felt upon administration.

In the film layer (a), hydroxypropyl cellulose (hereinafter, unless particularly referred to as "low-substitution hydroxypropyl cellulose", and also referred to as "hydroxypropyl cellulose", it means a binder such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, and Povidone (Povidone) included in japanese pharmacopoeia), various flavors such as orange and lemon, and flavors such as l-menthol, peppermint oil, Neotame (Neotame), Thaumatin (Thaumatin), aspartame, steviosin (Stevia), sucralose, saccharin sodium, sodium glutamate, and acesulfame potassium may be used alone or in combination of 2 or more, as necessary.

The core particle (P) is a particle serving as a core to be coated, and is not particularly limited as long as the film layer (a) can be formed as an innermost layer on the surface thereof, and commercially available spherical granules and commercially available spray granules can be exemplified. These core particles can also be produced by a known pulverization method or granulation method and used. These core particles may be used as they are or may be prepared by sieving to give particles having a desired particle size. Examples of such core particles include core particles comprising a combination of 1 or 2 or more selected from mannitol, crystalline cellulose, lactose, refined white sugar, corn starch, and the like. The core particle (P) does not contain a drug or a water-swellable polymer.

The shape of the core particle (P) is preferably a spherical particle from the viewpoint of obtaining a particle having uniform physical properties and from the viewpoint of more efficiently disposing the water-swellable polymer on the surface of the core particle (P). When the film is amorphous, the thickness of the formed film layer tends to become uneven, and the masking effect of the unpleasant taste may become insufficient. The average particle diameter of the core particle (P) may be a size such that when the drug-containing film-coated particles are prepared using the particles, rough and astringent feeling is not felt in the oral cavity. Specifically, the average particle diameter is preferably 10 to 200. mu.m, more preferably 50 to 170. mu.m, and still more preferably 100 to 150. mu.m. In the case of such a size, the size of the particles coated with the resulting drug-containing film is sufficiently small, and coarse and astringent feeling is not felt in the oral cavity.

As such core particles (P), commercially available spray granulated products such as "Nonpareil-108 (100)" (manufactured by FREUND industries, Ltd), "Celphere CP-102", "CelphereSCP-100" (both manufactured by Asahi Kasei Chemicals Corporation), "FlowLac 90", "FlowLac 100", "Cellactose 80", "MicroceLac 100", "StarLac 100" (both manufactured by MEGGLE Corporation), "SuperTab 11 SD" and SuperTab14SD "(both manufactured by DMV-Fonterra Excipients) can be used.

The mass ratio of the core particles (P) is 30 mass% or less, and more preferably 14 to 20 mass% with respect to 100 mass% of the total amount of the particles coated with the drug-containing film.

The water-insoluble polymer contained in the film layer (B) is not particularly limited as long as it is practically insoluble in water (solubility is evaluated from the extent of being soluble within 30 minutes when the water-insoluble polymer is added to water at 25 ± 5 ℃ and mixed with vigorous shaking for 30 seconds every 5 minutes as defined in the general rules of the japanese pharmacopoeia of the sixteenth modification, "practically insoluble in water" means that the amount of water required to dissolve 1g of the water-insoluble polymer is 10000mL or more), and a polymer substance which hardly swells even if it contains water, that is, a polymer substance other than the water-swellable polymer is generally used as an additive for pharmaceuticals, and is generally used as a coating agent. Examples of the water-insoluble polymer include ethyl cellulose, aminoalkyl methacrylate copolymer RS, and ethyl acrylate-methyl methacrylate copolymer, among which ethyl cellulose is preferred. The ethylcellulose used in the present invention is preferably ethylcellulose in accordance with the japanese pharmaceutical additives specifications, that is, ethylcellulose having an ethoxy content of 46.5 to 51.0%, preferably a 5% ethylcellulose/toluene-ethanol solution viscosity of about 4 to about 100cps at 25 ± 0.1 ℃, more preferably, ethylcellulose having a viscosity of about 7 to about 20 cps.

The content of the water-insoluble polymer is 7 to 11 mass%, preferably 8 to 10 mass% based on 100 mass% of the total amount of the drug-containing film-coated particles. If the content is less than the lower limit, masking of the unpleasant taste may become insufficient, and if the content is greater than the upper limit, the release of the drug may be delayed by a necessary time or more.

The water-soluble substance contained in the film layer (B) together with the water-insoluble polymer is not particularly limited as long as it dissolves in water to a certain extent (solubility is evaluated from the extent that it can be dissolved in water within 30 minutes when the water-soluble polymer is added to water at 25 ± 5 ℃ and mixed with vigorous shaking for 30 seconds every 5 minutes as defined in the general regulations of the japanese pharmacopoeia of the sixteenth modification, "dissolve to a certain extent in water", and specifically, the water-soluble substance is a viscous colloidal dispersion liquid corresponding to the state expressed by the wording "extremely easily dissolve" or "easily dissolve" and the amount of water required to dissolve 1g of the water-soluble substance is less than 10 mL), and the water-soluble substance is generally used as an additive for pharmaceuticals and is usually used as a coating agent. Examples of such water-soluble substances include refined white sugar, D-sorbitol, D-mannitol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, methylcellulose, and sodium carboxymethylcellulose.

The content of the water-soluble substance contained in the film layer (B) based on 100 mass% of the total amount of the particles coated with the drug-containing film can vary depending on the content of the water-insoluble polymer in 100 mass% of the total amount of the particles coated with the drug-containing film, and is 0.4 to 0.6 times, preferably 0.45 to 0.55 times, and most preferably 0.5 times the content of such water-insoluble polymer.

As the inorganic compound that may be contained in the film layer (B), an inorganic compound effective for preventing aggregation and adhesion of particles coated with a drug-containing film is preferable. Examples of such inorganic compounds include talc, titanium oxide, magnesium stearate, and light silica. Among them, titanium oxide is preferable.

The content of the inorganic compound is 25 to 35% by mass, preferably 27 to 32% by mass, based on 100% by mass of the film layer (B). If the amount is less than the lower limit, there is a possibility that a sufficient effect of preventing aggregation and adhesion of particles coated with the obtained drug-containing film cannot be obtained, and if the amount is more than the upper limit, there is a possibility that film formation becomes difficult. In addition, when the amount is within the above range, more favorable dissolution properties and favorable storage stability of the preparation under exposure can be imparted.

In addition, in 100 mass% of the film layer (B), the mass ratio of the content of the water-insoluble polymer, the content of the water-soluble substance and the content of the inorganic compound is preferably 1: 0.4-0.6: 0.5-0.7, and more preferably 1: 0.5: 0.6. When the content thereof is in the above range, the resulting drug-containing film-coated particles can be effectively prevented from aggregation and adhesion, and an excellent balance of unpleasant taste masking property and drug dissolution property can be maintained.

The multi-layer film formed on the surface of the core particle (P) may further include an intermediate film layer. Such an intermediate film layer may be a single layer or a plurality of layers, and may be formed between the film layer (a) as the innermost film layer and the film layer (B). That is, the film layer (B) containing a water-insoluble polymer, a water-soluble substance and an inorganic compound may be the outermost film layer. In this way, by forming the intermediate film layer between the innermost film layer and the outermost film layer, storage stability, taste, and the like can be improved.

The component contained in the intermediate film layer is not limited as long as it does not interfere with the effect of the drug-containing film-coated particles of the present invention, and specific examples thereof include, but are not limited to, D-sorbitol, D-mannitol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, methylcellulose, and sodium carboxymethyl cellulose. These can be used alone in 1 kind, also can combine more than 2 kinds to use. Among these components, D-mannitol and hydroxypropylmethylcellulose are preferable, and hydroxypropylmethylcellulose is more preferable, from the viewpoint of ease of coating. In addition, talc, magnesium stearate, light silica, and the like may be added as necessary for the purpose of reducing adhesiveness when coating the intermediate film layer.

The mass of the intermediate film layer is not limited as long as the effect of the drug-containing film-coated particles of the present invention is not impaired, and may vary depending on the size of the core particles (P), but is preferably 15 to 25 parts by mass, and more preferably 18 to 22 parts by mass, relative to 100 parts by mass of the total of the core particles (P) and the film layer (a).

The drug-film-coated particle of the present invention can be produced by spraying a coating liquid containing each film component onto the core particle (P). Specifically, using a fluidized bed granulator or the like, (1) first, a spray liquid prepared by dissolving or dispersing an unpleasant drug and a water-swellable polymer as innermost layer components in an organic solvent such as ethanol or methanol is sprayed onto the core particles (P). The content of the film component in the spray liquid is preferably at most 30 mass%. When the amount is more than 30% by mass, the spray gun may be clogged and the spraying becomes difficult.

(2) Next, in forming the intermediate film layer, a spray solution is prepared by dissolving a desired film component in water or the like, and the particles obtained in (1) are sprayed. The content of the film component in the spray liquid is preferably 5 to 15 mass%, more preferably 8 to 12 mass%. If the content is less than the lower limit, the efficiency of film formation may be deteriorated, and the productivity may be lowered, and if the content is more than the upper limit, the coated particles may aggregate and become aggregates.

(3) Finally, a spray liquid prepared by dissolving or dispersing a water-insoluble polymer, a water-soluble substance, and an inorganic compound in a mixed liquid containing an organic solvent such as ethanol or methanol and water is sprayed onto the particles obtained in (2), thereby obtaining particles coated with a drug-containing film with reduced unpleasant taste. The content of the film component in the spray liquid is preferably 3 to 7% by mass, more preferably 4 to 6% by mass. If the content is less than the lower limit, the efficiency of film formation may be deteriorated and the productivity may be lowered, and if the content is more than the upper limit, the coated particles may aggregate and become aggregates.

As the coating method, various methods such as an upper spray type, a side spray type, and a lower spray type can be selected, but the side spray method is preferable from the viewpoint of being able to effectively obtain particles coated with a drug-containing film in which each film layer is densely formed and particles are not aggregated and have a narrow particle size distribution.

The average particle diameter of the particles coated with the drug-containing film obtained is preferably 250 μm or less, more preferably 150 to 250 μm, and still more preferably 150 to 200 μm. Thus, it is possible to obtain finer particles than conventional ones, and the tablets obtained therefrom greatly contribute to an excellent feeling of taking.

The drug-film-coated granule of the present invention has an ideal dissolution profile (profile) with an excellent balance between unpleasant taste masking properties and drug dissolution properties, in which the dissolution of the drug is suppressed as much as possible during the retention period in the oral cavity immediately after the granule is taken, and the drug is rapidly dissolved until the granule disintegrates and moves from the oral cavity into the body. Therefore, the drug is released quickly as a proper time elapses without feeling an unpleasant taste in the oral cavity when the drug is taken, and thus the biological usability and biological equivalence to a normal preparation can be secured. The ideal dissolution profile is specifically such that when the particles coated with the drug-containing film of the present invention are tableted by the method described below and tested by the 2 nd method (50 rpm) using 900mL of the dissolution test solution 2 described in the japanese pharmacopoeia general test method acceptance dissolution test method, the dissolution rate after 2 minutes is 5% or less, preferably 2% or less, and the dissolution rate after 30 minutes is 85% or more, preferably the dissolution rate after 15 minutes is 85% or more.

The masking time of the unpleasant taste in the particles coated with the drug-containing film may vary depending on the type of the drug, but is preferably 30 to 300 seconds, and more preferably 120 to 300 seconds.

The tablet obtained using the particles coated with the drug-containing film according to the present invention has appropriate hardness and disintegration time, can effectively mask an unpleasant taste, and exhibits excellent rapid disintegration properties. The hardness of the tablet varies depending on the shape of the tablet, and is usually 30 to 70N, preferably 40 to 60N. The intraoral disintegration time of the tablet containing the granules coated with the drug-containing film is usually 15 to 60 seconds, preferably 20 to 40 seconds. Thus, a tablet which can be easily taken without chewing and without unpleasant taste can be obtained.

Examples

The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[ reference example 1 ]: production of spherical mannitol

The production method is described in International publication No. 2010/021300. That is, a spray dryer (ODT-20 type, manufactured by Dachuan Processingequipment Co., Ltd.) was used as a sample manufacturing apparatus. A spray device equipped with a product recovery tank at the lower part of the device and an M-pin type disk (a disk having a diameter of 84mm, manufactured by Dachuan Processingequipment Co., Ltd.) attached to the upper part of the device was used to introduce a mannitol aqueous solution into the spray device through 2 tubes (6 mm in outside diameter and 4mm in inside diameter) made of Teflon (registered trademark). The hot air is introduced from the upper part of the apparatus and discharged from the lower part of the apparatus in a parallel flow type in which air is jetted in the same direction as the sprayed liquid to form a vortex.

As mannitol, 20 parts by mass of a commercially available crystalline product (manufactured by manit P, mitsubishi shodtech corporation) was added to 80 parts by mass of pure water, and the mixture was dissolved while heating until the solid was completely dissolved to obtain a clear solution, and a mannitol aqueous solution having a solid content concentration of 20% by mass at a temperature of 70 ℃ was obtained and used for spray drying.

The rotational speed of the atomizer was 15000rpm, the temperature of hot air introduced into the spray dryer was 100 ℃ at the inlet, and the amount of hot air supplied was 7m 3/min. The amount of mannitol aqueous solution introduced was set to 6.5 kg/hr. After introducing 30kg of a previously prepared mannitol aqueous solution into the apparatus, the powder accumulated in the product tank at the lower part of the spray dryer was collected and dried at 80 ℃ for 10 minutes using a fluidized bed dryer (FLO-5, manufactured by Okawa Kagaku Co., Ltd.) to obtain the desired spherical mannitol.

The bulk density was determined by the method described in International publication No. 2010/021300. That is, the spherical mannitol was lightly packed in a cup (mass Wa) having a volume of 100mL and scraped off, and the weighed mass Wb was obtained from the following formula (I) and the average value of 3 to 5 measurements was used.

Bulk Density (g/mL) = (Wb-Wa)/100 … … (I)

The aspect ratio is determined as follows: the length of the major axis (major axis) and the length of the minor axis (minor axis) perpendicularly drawn from the midpoint of the major axis were measured for 30 spherical particles by photographing with a scanning electron microscope (S-2600N, manufactured by Hitachi, Ltd.) at a non-vapor deposition accelerating voltage of 20kV, a vacuum degree of 50Pa and a magnification of 1500 times, and the ratio of the major axis to the minor axis was determined and determined from the average of 30 particles.

The oil absorption was determined as follows: 30g of medium-chain fatty acid triglyceride (Coconad MT, manufactured by Kao corporation) and 15g of mannitol as a sample were added to a 100mL glass beaker, stirring and mixing the oil and powder sample with scraper smoothly without breaking powder, placing into vacuum constant temperature dryer (produced by VOS-300D, EYELA), the pressure was reduced to 0.67Pa at room temperature, the oil was impregnated for 3 hours, the mixture was transferred into a centrifugal separation tube (having a hole at the bottom) having a 325 mesh (45 μm pore) filter cloth laid thereon, and a centrifugal separator (H-500R, manufactured by Nippon national center Co., Ltd.) was used, the mass (Wc) of the powder sample remaining in the centrifugal separation tube after the centrifugal separation was obtained from the measured values of the mass of the centrifugal separation tube with the sample and the tare weight of the centrifugal separation tube after the centrifugal separation by centrifugation at about 1300G for 10 minutes, and the value calculated by the following formula (II) was obtained as the oil absorption 1.

Oil absorption 1 (%) = [ (Wc-15)/15 ]. times.100 100 … … (II)

Further, a centrifuged sample-attached centrifugal separation tube was placed in a 100mL glass beaker, 20G of n-hexane was added to the powder sample, the mixture was centrifuged at about 1300G for 10 minutes by a centrifugal separator, the mass (Wd) of the powder sample remaining in the centrifugal separation tube after the centrifugation was determined from the mass of the centrifuged sample-attached centrifugal separation tube and the measured value of the tare mass of the centrifugal separation tube, and the value calculated from the following formula (III) was determined as the oil absorption 2.

Oil absorption 2 (%) = [ (Wd-15)/15 ]. times.100 100 … … (III)

The average particle diameter was determined as follows: the sample was added to a display part until an "appropriate amount" was displayed using a laser diffraction particle size distribution measuring instrument (MT-3000, manufactured by Nikkiso K.K.) and 2-propanol (reagent grade, purity 99.0% or more, and manufactured by Wako pure chemical industries, Ltd.) as a dispersion solvent, and ultrasonic treatment was performed for 30 seconds at an ultrasonic output of 40W, and then the average particle size was measured and determined from the average value of 2 measurements.

The angle of repose is determined as follows: the sample fed into the sample hopper was dropped onto a circular plate of an angle of repose sample table through a vibrating bar, a mesh (opening 1000 μm), a discharge funnel, and a nozzle (inner diameter 1 cm) using an a.b.d. powder characteristic measuring instrument (manufactured by cylindrical well physico-chemical instruments co., ltd.) to form a mountain shape, the angle of the mountain was measured at 3 points in different directions with a goniometer, and the average value was obtained by repeating the operation 3 times and using the average value obtained by 3 measurements.

As a result, the obtained spherical mannitol had a bulk density: 0.46g/mL, aspect ratio: 1.07, average particle diameter 44 μm, oil absorption 1 by test method A: 31.0%, oil absorption 2 by test method a: 20.1%, angle of repose: and 39 degrees.

[ example 1 ]

(1) Formation of innermost layer containing drug

90g of hydroxypropyl cellulose "HPC-SSL" (manufactured by Nippon Caoda Co., Ltd.) was dissolved in 1610g of ethanol (95), and 300g of lafutidine (manufactured by Central Nitro Co., Ltd., Ltd.) and 300g of low-substitution hydroxypropyl cellulose "L-HPC (LH-31)" (manufactured by shin-Etsu chemical Co., Ltd.) were added to prepare a suspension (1) -1. 250g of Nonpareil-108 (100) as core particles (P: core particles containing no drug or water-swellable polymer) was added to a fluidized bed granulation coating apparatus (apparatus name "Multiplex MP-01", manufactured by Powrex corporation), 1916.7g of the suspension (1) -1 was sprayed at a set temperature of 60 to 65 ℃ and a spraying speed of 5.0g/min, and after drying, the particles were sieved through a sieve having openings of 355 μm to obtain particles coated with a lafutidine-containing film.

Further, when the particle size distribution was measured by a dry-single shot (one-shot) measurement using a laser diffraction-scattering particle size distribution measuring instrument (LMS-30, produced by Seishin Enterprise co., Ltd.), the average particle size of the Nonpareil-108 (100) was 100 μm.

The average particle size of the core particles and the average particle size of the particles coated with the lafutidine-containing film obtained are also determined in the same manner as described below.

(2) Formation of interlayer film

To the purified water were added 50g of hydroxypropylmethylcellulose "TC-5E" (manufactured by shin-Etsu chemical Co., Ltd.) and 50g of talc "PKP-81" (manufactured by Fuji talc Industrial Co., Ltd., LTD.) to prepare 1000g of suspension (2) -1. 350g of the lafutidine membrane-coated granules prepared in (1) above were charged into a fluidized bed granulation coater "Multiplex MP-01", and 20% of suspension (2) -1 added as a solid component was sprayed at a set temperature of 70 ℃ and a spraying speed of 3.8g/min, and after drying, 2.1g of the above talc was added. Sieving with a sieve with 500 μm openings to obtain the lafutidine-containing film-coated granules coated with the intermediate layer.

(3) Formation of the outermost film layer

60g of hydroxypropylmethylcellulose "TC-5E" (as solution A) was dissolved in a mixed solution of 140g of purified water and 400g of ethanol (95). 50g of ethyl cellulose "ETHOCEL STD7 Premium" (manufactured by The Dow Chemical Company) was dissolved in 950g of ethanol (95), and 250g of solution A (as solution B) was added. 32.2g of TITANIUM oxide "NA 65" (manufactured by Toho TITANIUM CO., LTD.) was dispersed in 200g of purified water, and added to the solution B to prepare a suspension (3) -1. 300g of the lafutidine film-coated granules prepared in (2) above were charged into a fluidized bed granulation coater "MultiplexMP-01", and a 30% suspension (3) -1 added as a solid component was sprayed at a set temperature of 60 ℃ and a spraying speed of 5.2g/min, and after drying, the lafutidine film-coated granules coated with an outermost layer containing ethylcellulose (average particle size 200 μm) were obtained by sieving the resultant mixture through a sieve having openings of 355 μm.

[ example 2 ]

(1) Formation of innermost layer containing drug

920g of hydroxypropyl cellulose "HPC-SSL" was dissolved in 12.88kg of ethanol (95), and 2.3kg of lafutidine and 2.3kg of low-substitution hydroxypropyl cellulose "L-HPC (LH-31)" were added to prepare a suspension (1) -2. 2kg of lactose "FlowLac 90" (produced by MEGGLE) (average particle diameter 120 μm) was added as core particles (P) to a fluidized granulation coating apparatus (apparatus name "Flow coater NFLO-5 (2) SJ", produced by FREUND industries, 16kg of the suspension (1) -2 was sprayed at an air suction temperature of 54 to 67 ℃ and a spraying speed of 20.9g/min, and after drying, the resultant was sieved through a sieve having openings of 355 μm to obtain particles coated with a lafutidine-containing film.

(2) Formation of interlayer film

To the purified water were added 700g of hydroxypropylmethylcellulose "TC-5E" and 700g of talc "PKP-81" to prepare 14kg of suspension (2) -2. 6.3kg of the particles coated with the lafutidine-containing film prepared in (1) above was charged into a fluidized granulation coating apparatus "Flow coaterNFLO-5 (2) SJ", 12.6kg of the suspension (2) -2 was sprayed at a suction temperature of 76 to 82 ℃ and a spraying speed of 17.2g/min, and after drying, 76g of the talc was added. Sieving with a sieve with 500 μm openings to obtain Lafutidine-containing film-coated granules coated with the intermediate layer.

(3) Formation of the outermost film layer

468g of hydroxypropylmethylcellulose "TC-5E" and 938.1g of ethylcellulose "ETHOCEL STD7 Premium" were dissolved in a mixed solution of 2.145kg of purified water and 33.069kg of ethanol (95) (as solution C). 602.7g of titanium oxide "NA 65" was dispersed in 2.9472kg of purified water, and added to the solution C to prepare a suspension (3) -2. 7.2kg of the lafutidine-containing film-coated granules prepared in (2) above were added to a fluidized bed granulation and coating apparatus "Flow coater NFLO-5 (2) SJ", 36kg of the suspension (3) -2 was sprayed at a suction temperature of 62 to 68 ℃ and a spraying speed of 24.0g/min, and after drying, the particles were sieved through a sieve having an opening of 355 μm to obtain lafutidine-containing film-coated granules (average particle size of 180 μm) coated with an outermost layer containing ethylcellulose.

Comparative example 1

(1) Formation of innermost layer containing drug

57g of hydroxypropyl cellulose "HPC-SSL" was dissolved in 1019.7g of ethanol (95), and 380g of lafutidine was added to prepare a suspension (1) -3. 350g of sodium carboxymethyl starch "Primojel" (average particle diameter 40 μm) as a water-swellable polymer was added as core particles to a fluidized bed granulation coating apparatus "MultiplexMP-01", 1341.7g of suspension (1) -3 was sprayed at a set temperature of 60 ℃ and a spraying speed of 5.1g/min, and after drying, the particles were sieved through a sieve having openings of 355 μm to obtain particles coated with a Lafutidine-containing film.

(2) Formation of interlayer film

In the same manner as in example 1 (2), a film-coated pellet containing lafutidine in which an intermediate layer was coated was obtained.

(3) Formation of the outermost film layer

In the same manner as in example 1 (3), lafutidine-containing film-coated particles (average particle diameter 210 μm) coated with an outermost layer containing ethylcellulose were obtained.

Comparative example 2

(1) Formation of innermost layer containing drug

64g of hydroxypropyl cellulose "HPC-SSL" was dissolved in 800g of ethanol (95), and 320g of lafutidine and 160g of low-substituted hydroxypropyl cellulose "L-HPC (LH-31)" were added to prepare a suspension (1) -4. 300g of Nonpareil-108 (100) is added into a fluidized bed granulation coating device, namely 'Multiplex MP-01', to be used as core particles (P), 1700g of suspension (1) -4 is sprayed at a set temperature of 60-65 ℃ and a spraying speed of 5.6g/min, and after drying, the particles are sieved by a sieve with openings of 355 mu m to obtain the particles coated with the Lafutidine film.

(2) Formation of interlayer film

In the same manner as in example 1 (2), a film-coated pellet containing lafutidine in which an intermediate layer was coated was obtained.

(3) Formation of the outermost film layer

In the same manner as in example 1 (3), lafutidine-containing film-coated particles (average particle diameter 230 μm) coated with an outermost layer containing ethylcellulose were obtained.

Comparative example 3

(1) Formation of innermost layer containing drug

In the same manner as in example 1 (1), particles coated with a lafutidine-containing film were obtained.

(2) Formation of interlayer film

In the same manner as in example 1 (2), a film-coated pellet containing lafutidine in which an intermediate layer was coated was obtained.

(3) Formation of the outermost film layer

30g of hydroxypropylmethylcellulose "TC-5E" (as solution D) was dissolved in a mixed solution of 70g of purified water and 200g of ethanol (95). To 1488.8g of ethanol (95), 78.4g of ethyl cellulose "ETHOCEL STD7 Premium" was dissolved, and 196.2g of D solution (as E solution) was added. 260.9g of purified water was dispersed with 42g of titanium oxide "NA 65" and the resultant mixture was added to the solution E to prepare a suspension (3) -4. 300g of the lafutidine film-coated granules prepared in (2) above were charged into a fluidized bed granulation coater "Multiplex MP-01", and 30% of the suspension (3) -4 added as a solid component was sprayed at a set temperature of 60 ℃ and a spraying speed of 5.4g/min, and after drying, the lafutidine film-coated granules coated with an outermost layer containing ethylcellulose (average particle size 210 μm) were obtained by sieving the resultant mixture through a sieve having openings of 355 μm.

Comparative example 4

(1) Formation of innermost layer containing drug

In the same manner as in example 1 (1), particles coated with a lafutidine-containing film were obtained.

(2) Formation of interlayer film

In the same manner as in example 1 (2), a film-coated pellet containing lafutidine in which an intermediate layer was coated was obtained.

(3) Formation of the outermost film layer

40g of hydroxypropylmethylcellulose "TC-5E" (as solution F) was dissolved in a mixed solution of 93.3g of purified water and 266.7g of ethanol (95). 74.6G of ethyl cellulose "ETHOCEL STD7 Premium" was dissolved in 1417.4G of ethanol (95), and 196.2G of F solution (as solution G) was added. 28G of titanium oxide "NA 65" was dispersed in 173.9G of purified water, and added to solution G to prepare a suspension (3) -5. 300g of the lafutidine film-coated granules prepared in (2) above were charged into a fluidized bed granulation coater "Multiplex MP-01", and 30% of the suspension (3) -5 added as a solid component was sprayed at a set temperature of 60 ℃ and a spraying speed of 5.3g/min, and after drying, the lafutidine film-coated granules coated with an outermost layer containing ethylcellulose (average particle size 220 μm) were obtained by sieving the resultant mixture through a sieve having openings of 355 μm.

Comparative example 5

(1) Formation of drug-containing prilled core particles

82.4g of hydroxypropyl cellulose "HPC-SSL", 205.9g of lafutidine, 205.9g of low-substituted hydroxypropyl cellulose "L-HPC (LH-31)" and 205.9g of lactose hydrate "Lactochem" (manufactured by Powrex corporation) were charged into a high-speed stirring GRANULATOR (apparatus name "VERTICAL GRANULATOR VG-05", manufactured by TOYOBO Co., Ltd.), mixed for 2 minutes, and granulated by adding 127.2g of ethanol (95), dried by a fluidized bed granulation coating apparatus "Multiplex MP-01", and sieved through a sieve having an opening of 355 μm to obtain granulated core granules containing lafutidine.

(2) Formation of interlayer film

In the same manner as in example 1 (2), a film-coated particle containing lafutidine coated with an intermediate layer (no innermost layer) was obtained. Thereafter, the lafutidine-containing granulated core particles were used in place of the lafutidine-containing film-coated particles obtained in example 1 (2).

(3) Formation of the outermost film layer

Particles coated with a lafutidine-containing membrane having an outermost layer containing ethylcellulose were obtained (average particle diameter: 189 μm) in the same manner as in example 1 (3) except that the amount of sprayed suspension (3) -1 was changed to 25% of the amount added as a solid content.

These results are shown in table 1.

[ Table 1 ]

[ evaluation of dissolution Rate ]

Using the particles coated with the lafutidine-containing film obtained in examples 1 to 2 and comparative examples 1 to 5, samples were prepared in the following manner, and the dissolution rate (%) was evaluated under the following measurement conditions according to the dissolution test method loaded in the general test method formulation test method of the japan bureau of medicine. The results are shown in Table 2.

Preparation of samples

An amount of each of the lafutidine-containing film-coated granules corresponding to 10mg of lafutidine was weighed and mixed with 169mg of a mixture obtained by mixing 160/8/1 spherical mannitol/low-substituted hydroxypropylcellulose "L-HPC (LH-21)"/sodium stearyl fumarate "PRUV (manufactured by JRS)" manufactured in referential example 1. Each sample was obtained by compression molding the powder preparation at 250kgf using a punch of diameter 8mm and R12mm and a hydraulic press (available from Milliki Co., Ltd.).

Conditions for measurement

Dissolution test method: method 2 (50 rpm)

Test solution: dissolution test solution 2 (900 mL)

Measuring wavelength: λ =271nm

[ Table 2 ]

As is clear from the results in table 2, the particles coated with the lafutidine-containing film of examples 1 and 2 exhibited a dissolution rate of not less than 5% after 2 minutes, but not less than 85% after 15 minutes. On the other hand, in comparative example 1 and comparative example 5 using the drug-containing granulation core particles containing no water-swellable polymer in the drug layer, although the dissolution rate was 85% or more after 15 minutes, the dissolution rate after 2 minutes was more than 5%, and masking of the unpleasant taste was insufficient. In comparative example 2 in which the total amount of the particles is insufficient in the water-swellable high molecular weight, comparative example 3 in which the amount of the water-soluble substance is small relative to the amount of the water-insoluble polymer (ethyl cellulose), and comparative example 4 in which the amount of the inorganic compound in the outermost layer is insufficient, the dissolution rate after 2 minutes is 5% or less, but the dissolution rate after 30 minutes is 85% or less, and as a result, the biological usability is reduced and the biological equivalent to that of a normal preparation may not be ensured.

[ examples 3 to 11 ]

In the same manner as in example 1, lafutidine-containing film-coated granules coated with an outermost layer containing ethylcellulose were obtained according to the formulation shown in table 3. Table 4 shows the values of the predetermined content (% by mass) and ratio. In all of the examples, the dissolution rate was low after 2 minutes as in example 1, and it was found that the masking property of the unpleasant taste was sufficient. Further, the dissolution property was thereafter exhibited rapidly.

[ Table 3 ]

[ Table 4 ]

[ evaluation of unpleasant taste masking Property ]

The taste of the lafutidine-film-coated granules obtained in example 2 and comparative example 1 and the taste of lafutidine-containing raw material powder were evaluated according to the following evaluation methods and evaluation criteria. The results are shown in Table 5.

Evaluation method

After the oral administration of lafutidine-containing film-coated granules or lafutidine raw material powder in an amount of 10mg of lafutidine for 30 seconds, 3 healthy adult men released the lafutidine, and evaluated for unpleasant taste after 30 seconds.

Evaluation criteria for unpleasant taste

-: no unpleasant taste is felt

+ -: slightly taste, but acceptable

+ is as follows: an unpleasant taste is felt

+ of: strongly felt the unpleasant taste

[ Table 5 ]

As is clear from the results in table 5, lafutidine raw material powder is a drug strongly showing an unpleasant taste, but the coated particles of example 2 do not feel an unpleasant taste or an acceptable range not only immediately after being contained in the oral cavity but also after 1 minute. On the other hand, the coated particles of comparative example 1 were perceived to have an unpleasant taste.

[ measurement of hardness and disintegration time in tablet ]

51.51mg of the lafutidine-containing film-coated particles produced in example 2 were weighed out and mixed with 169mg of a mixture mixed with spherical mannitol/low-substitution hydroxypropylcellulose "L-HPC (LH-21)"/sodium stearyl fumarate "PRUV (produced by JRS)" =160/8/1 (mass ratio) produced in reference example 1. The powder was compression-molded at 250kgf using a punch of Φ 8mm and R12mm and a hydraulic press (available from Milliki Co., Ltd.) to obtain a tablet.

The hardness of the obtained tablet was measured in the diametrical direction using a tablet hardness tester (manufactured by 6D, Schleuniger) and was determined from the average value of 3 tablets.

Intraoral disintegration time, the time until complete disintegration of the tablet with saliva alone was measured without chewing by placing the tablet on the tongue of 1 healthy adult male. The time is shown in table 6.

[ Table 6 ]

Hardness (N) of the tablets	Intraoral disintegration time (second)
		41.0	33

Claims (13)

1. A film-coated particle comprising:

the film layer (A) contains an unpleasant drug and a water-swellable polymer, and the film layer (B) contains a water-insoluble polymer, a water-soluble substance and an inorganic compound, wherein the film layer (A) is an innermost film layer, the mass ratio of the core particles (P) is 30 mass% or less, the drug content is 40 mass% or less, the water-swellable polymer content is 13 to 30 mass%, the water-insoluble polymer content is 7 to 11 mass%, the water-soluble substance content in the film layer (B) is 0.4 to 0.6 times the water-insoluble polymer content, and the film layer (B) is 100 mass% of the total mass of the particles coated with the drug-containing film, the content of the inorganic compound is 25 to 35% by mass.

2. The drug-containing film coated particle of claim 1, wherein:

the average particle diameter of the particles coated by the medicine-containing film is below 250 mu m.

3. The drug-containing film coated particle of claim 1 or 2, wherein:

the average particle diameter of the core particle (P) is 10 to 200 [ mu ] m.

4. The film-coated particle comprising according to any one of claims 1 to 3, wherein: in the multi-film layer, the film layer (B) is the outermost film layer.

5. The film-coated particle comprising any one of claims 1 to 4, wherein:

the drug-containing film comprises 5 to 35 mass% of the total 100 mass% of the particles coated with the drug-containing film, 15 to 25 mass% of a water-swellable polymer, and 8 to 10 mass% of a water-insoluble polymer, and the film layer (B) comprises 27 to 32 mass% of an inorganic compound in 100 mass%.

6. The film-coated particle comprising any one of claims 1 to 5, wherein:

the drug-containing film comprises 10 to 30 mass% of the drug, 17 to 22 mass% of the water-swellable polymer, and the film layer (B) contains 0.5 times the amount of the water-insoluble polymer, based on 100 mass% of the total amount of the drug-containing film-coated particles.

7. The film-coated particle comprising any one of claims 1 to 6, wherein: the unpleasant tasting drug is an antiulcer agent.

8. The drug-containing film coated particle of claim 7, wherein:

the anti-ulcer agent is lafutidine.

9. The film-coated particle comprising any one of claims 1 to 8, wherein: the water-insoluble polymer is ethyl cellulose.

10. The film-coated particle comprising any one of claims 1 to 9, wherein: the water-swellable polymer is low-substitution-degree hydroxypropyl cellulose.

11. The film-coated particle comprising any one of claims 1 to 10, wherein: the inorganic compound is titanium oxide.

12. The film-coated particle comprising any one of claims 1 to 11, wherein: in 100 mass% of the film layer (B), the mass ratio of the water-insoluble polymer content to the water-soluble substance content to the inorganic compound content is 1: 0.4-0.6: 0.5-0.7.

13. A method for producing the drug-containing film-coated particle according to claim 1, comprising:

a step (X) of spraying a spray solution containing an unpleasant drug and a water-swellable polymer onto the surface of core particles (P) that do not contain the unpleasant drug and the water-swellable polymer; and

and (Y) spraying a spray solution containing a water-insoluble polymer, a water-soluble substance and an inorganic compound onto the particles obtained in the step (X).