JP2013241451A - Production method of physiologically active substance-containing particle - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a granulated product that masks a physiologically active substance having a bitter taste, improves administration property for a patient, has stability against light and controls dissolution property, through a simple process with high productivity.SOLUTION: A method for producing minute particles (fine granule) comprises: charging a spouted fluid-bed granulating device with additive powder particles having a high liquid retaining ability; adding by spraying a liquid, which is prepared by dispersing, suspending or partially dissolving a physiologically active drug in water, an aqueous solution of a water-soluble polymer, a dispersion liquid of a water-insoluble substance or a mixture liquid of these, to prepare a granulated product, while maintaining a fluidized condition in the device; and coating the granulated product with a water-soluble polymer, sugar or sugar alcohol, a water-insoluble substance, or a mixture of these to ensure stability against light and to mask a bitter taste. By compounding the obtained minute particles with other additives, a solid preparation with high qualities and superior administrating property can be produced.

Description

  The present invention relates to a method for producing bioactive substance-containing particles.

With regard to recently handled drugs, bitterness and unpleasant odor masks and formulation measures for elution control are important points for improving patient compliance.
The most common production method that has been widely used conventionally masks bitterness by coating the tablet surface after granulation and tableting.
Recently, there are many demands for orally disintegrating tablets that can be taken without water. However, when the tablet surface is coated with a bitterness mask, disintegration is delayed due to the strength of the film and does not become a quick disintegrating tablet. .
Therefore, recently, a technique has been adopted in which smooth additive core particles having a surface shape that have been granulated in advance are used, and after the drug is coated in a layered manner, particles with bitterness masking or elution control are produced. As additive particles pre-granulated, for example, nonparrel (Freund Sangyo), crystalline cellulose spherical core particle SELFIA (Asahi Kasei Chemicals), D-mannitol spherical particles (manufactured by Mitsubishi Corporation Foodtech), etc. are commercially available. The core particle surface of the drug is coated with a drug, and the particle surface is coated with a film agent to process the bitterness mask and elution-suppressing particles, and the resulting particles are blended with other additives or re-granulated. And tableting. However, all of these additive core particles have an average particle size larger than 100 μm, and D-mannitol spherical particles have high solubility, and the surface is dissolved by the addition of an aqueous spray solution, and the particles are adhered and aggregated. This is likely to occur, and the spray speed must be reduced to suppress aggregation, so there is a problem that the spray time becomes longer.
In addition, when pre-granulated core particles are used, the particle size increases in proportion to the amount of drug coating. Therefore, in consideration of ingestion such as rough feeling in the oral cavity, a high content of the drug is added. It is difficult. When the drug-coated particles are coated with a bitterness masking or elution control coating using a polymer film or the like, the drug content is further reduced. When producing orally disintegrating tablets using these particles, The problem is that the size of the tablet is increased and the dosage is reduced.

  Recently, in order to improve patient compliance, improvement of ingestion is required, and a smoother surface shape is required with a small particle size in terms of formulation, such as a rough feeling at the time of taking, bitterness mask, elution control, etc. became. In general, the particle size that does not feel rough is set to 150 μm or less. As a standard for evaluating the shape of the particle surface, in powder engineering, the number of fractal dimensions (Non-Patent Document-1) and the geometric standard deviation (Non-patent) Reference-2) is often used.

Michitaka Suzuki, Journal of Powder Engineering, Vol. 27, 693-699 (1990) Introduction to Powder Engineering, edited by Japan Powder Industrial Technology Association, published on April 10, 1995, pages 3 to 5 (1.1.3 Particle size distribution) Kenji Nishimura et al., Pharmacology, Vol. 38, 1978, P117-P195

  An object of the present invention is to provide a method for producing a drug-containing particle having an average particle size of 150 μm or less, which is masked or shielded by a simple method in terms of formulation operation. Another object of the present invention is to provide a granulated product for a solid preparation which has a high property and is easy to control the bitterness mask of a physiologically active substance and the dissolution rate.

Against this background, the present invention was completed as a result of intensive studies using core particles having a high liquid holding capacity (water absorption capacity) and an average particle diameter of 80 μm or less.
More specifically, the average particle size is 80 μm or less, and the liquid holding capacity (water absorption capacity) is higher than 1.5 mL / g (the capacity of 1 g of additive particles to hold a liquid of 1.5 mL or more). Further, additive particles having a major axis / minor axis ratio of 3.0 or less are introduced into a fluidized bed apparatus, a rolling fluidized bed apparatus, or a spouted fluidized bed apparatus to be fluidized, and water, a water-soluble polymer are contained therein. Sprayed with a dispersion, suspension, partial dissolution, or total dissolution of a bioactive drug finely pulverized to 5 μm or less in an aqueous solution or a dispersion of a water-insoluble substance or a mixture thereof. By penetrating and adsorbing inside the agent, adhesion and aggregation between particles are suppressed, and as a result, a high content of drug-containing particles (core particles A) having an average particle size of 120 μm or less is obtained. Further, the surface of the obtained particle (core particle A) is coated with one or more layers of a water-soluble polymer, sugar or sugar alcohol, water-insoluble substance, etc., so that a bitterness mask having an average particle diameter of 150 μm or less or light shielding It was found that particles B with controlled elution were obtained. The particles obtained by the present invention are extremely important for companies because they can improve patient compliance, improve content uniformity during production, reduce loss, scattering, and device wall adhesion, and improve yield. Think. Moreover, automation is easy by adopting a liquid feed pump, etc., and there is a great merit in terms of quality control.
For example, calcium silicate (1 g of additive particles holds 6.5 to 7.0 ml of liquid) as an additive particle having a high liquid holding capacity (water absorption capacity) is described as calcium silicate in a fluid state. When a drug solution is added by spraying, it penetrates and adsorbs from the pores on the surface of the calcium silicate particles, so that there are few drugs and binders on the additive particle surface. Since the resulting adhesion and aggregation are suppressed, the spray rate can be increased and the productivity is improved.
Moreover, it is the outstanding technique which can mix | blend the obtained particle | grains with another additive as it is, or re-granulate, and can manufacture the powder, tablet, orally disintegrating tablet masked with a bitter taste.

That is, the present invention relates to the following (1) to (4).
(1) A) Spouted fluidized bed containing additive particles having a liquid holding capacity (water absorption) of 1.5 mL / g or more, an average particle diameter of 80 μm or less, and a major axis / minor axis ratio of 3.0 or less. B) In a dispersion of a water-insoluble substance or a mixture of a water-soluble polymer or a bioactive drug finely pulverized to an average particle size (D50) of 5 μm or less while maintaining a fluidized state in a granulator In addition, a dispersion, suspension, partial dissolution, or total dissolution and spray addition are performed, and one layer of water-soluble polymer, sugar or sugar alcohol, water-insoluble substance or a mixture thereof is formed on the surface of the obtained granulated particles. By coating multiple layers, the average particle diameter is 150 μm or less, the geometric standard deviation (σg: D84.1 / D50) is 1.1 to 1.4, and the fractal dimension is 1.0 to 1.2. Smooth surface, light stabilization, bitter mass Or elution control process for the preparation of biologically active drug-containing particles.
(2) Additive particles are calcium silicate, partially pregelatinized starch, pregelatinized starch, crystalline cellulose, synthetic aluminum silicate, synthetic hydrotalcite, magnesium metasilicate aluminate, sodium carboxymethyl starch and low substituted hydroxypropyl The granulation method of the particle | grains shown to (1) which is 1 type, or 2 or more types chosen from the group which consists of cellulose.
(3) The water-soluble polymer is one or more selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. method for producing a granulated product according to (1) or (2).
(4) Water-insoluble substance is aminoalkyl methacrylate copolymer (E, RL, RS), methacrylic acid copolymer (L, LD, S), ethyl acrylate / methyl methacrylate copolymer dispersion, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate The manufacturing method of the granulated material in any one of (1)- (3) which is 1 type, or 2 or more types chosen from the group which consists of a succinate, an ethyl cellulose, a talc, and a titanium oxide.

  According to the present invention, a physiologically active substance having a bitter taste is masked or shielded by a simple method in terms of formulation operation, and further blended with other additives to provide a powder, tablet, orally disintegrating that is excellent in dosage. A method for producing a lock or the like can be provided.

In carrying out the present invention, while confirming the proper flow state (especially avoiding excessive air volume) according to the particle size and particle properties of the additive powder particles charged in the spouted fluidized bed apparatus, The spray mist diameter and the viscosity of the liquid were selected according to the shape and solubility. When the discharge speed of the gas body (generally compressed air) at the nozzle tip is 400 m / sec or more and the discharge liquid speed is 1 m / sec or less, the adhesion and aggregation of large particles are suppressed and the inner surface of the apparatus is suppressed. By operating the exhaust temperature to be higher than the adiabatic saturation temperature so that condensation does not occur, and by operating to promote the adhesion and aggregation of the fine particles (the main factor is adjusting the mist diameter), the granulated product The geometrical standard deviation (σg: D84.1 / D50) is 1.1 to 1.5, more preferably 1.1 to 1.4.
In other words, if the size of the adhering binder droplet is larger than the size of the jet flowing particle, it adheres to nearby particles. This is due to the separation force caused by the kinetic energy of the particles and the combination of spray droplets Determined by balance with power. That is, when separation force> bonding force, particle adhesion / aggregation is suppressed, and when separation force <bonding force, particles adhere / aggregate. However, even with the same droplet size, when the initial particle size is small, even if it contributes to adhesion / aggregation, if the particle size grows to a certain size, the separation force due to particle movement increases as the mass increases. Therefore, particle growth is suppressed, and as a result, a granulated product having a sharp particle size distribution is obtained (Non-patent Document 3).
As described above, the geometric standard deviation (σg: D84.1 / D50) can be controlled by controlling the droplet diameter, although it depends on the viscosity and adhesion force of the liquid to be sprayed.
In the present invention, the spray-added mist penetrates and is adsorbed from the pores on the surface of the additive particle having a high liquid holding ability, so that the binding force due to the wetting of the particle surface is relaxed, and as a result, the separation force> It becomes a binding force, and adhesion and aggregation between particles are suppressed.

  Particles obtained by coating the drug-coated particles obtained in the present invention with a water-soluble polymer, sugar, sugar alcohol, water-insoluble polymer, or the like have an average particle diameter of 150 μm or less, less irregularities on the granulated surface, and a fractal dimension of 1 A granulated product having a smooth particle surface of .0 to 1.2 is obtained, and a granulated product having a sharp particle size distribution having a geometric standard deviation (σg: D84.1 / D50) in the range of 1.1 to 1.4. It is a grain.

Examples of the water-soluble polymer used in the present invention include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, etc. Examples thereof include a film agent and a binder, and among them, hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer are preferable. Furthermore, by blending water-insoluble additive fine particles such as talc, titanium oxide, and zeolite having an average particle size of 20 μm or less, particle growth of fine powder can be promoted while suppressing the binding force.
In addition, as additives on the preparation that can be used, commonly used excipients, disintegrants, binders, flavoring agents, coloring agents, tonicity agents, and other additives can be appropriately used.

  Examples of the film agent for elution control include aminoalkyl methacrylate copolymer (E, RS), methacrylic acid copolymer (L, LD, S), ethyl acrylate / methyl methacrylate copolymer dispersion, hydroxypropyl methylcellulose phthalate, hydroxypropyl Well-known elution control film | membrane agents, such as methylcellulose acetate succinate and an ethylcellulose type | system | group aqueous dispersion, can be mentioned. These film agents may be used alone or in combination.

  Additives include lactose, crystalline cellulose, corn starch, potato starch, partially pregelatinized starch, pregelatinized starch, D-mannitol, sucrose, sucrose, glucose, low-substituted hydroxypropylcellulose, light anhydrous silicic acid, silicic acid The additive used for pharmaceutical solid preparations, such as calcium or carboxymethyl starch sodium, is mentioned. A part or all of these excipients may be dissolved, dispersed, or suspended in the binder solution.

  Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropyl cellulose, and partially pregelatinized starch.

A) Partially pregelatinized starch having an average particle size of 70 μm (Asahi Kasei Chemicals: PCS) 317.0 g was charged into a spouted fluidized bed granulator (manufactured by POWREC: MP-01-SPC type), and allowed to flow. Disperse and suspend 100.0 g of donepezil hydrochloride pulverized to an average particle size of about 5 μm in 500.0 g of a solution of 3.0 g of acrylic acid / methyl methacrylate copolymer (manufactured by Daido Kasei Kogyo: POVACOAT) in purified water. -Partially dissolved liquid was added by spraying to obtain particles having an average particle size of about 73 μm and a geometric standard deviation (σg) of 1.3 (core particle-1).
B) The obtained core particle-1 was put into a jet fluidized bed granulator and fluidized, and averaged in 720.0 g of a solution obtained by dissolving 8.0 g of polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer in purified water. A liquid in which 72.0 g of talc wet-pulverized to a particle size of 0.5 μm was dispersed was sprayed to obtain particles having an average particle size of 78 μm and a geometric standard deviation (σg) of 1.3 (core particle-2).
C) The obtained core particle-2 was introduced into a jet fluidized bed granulator and allowed to flow, and methacrylic acid copolymer LD (Evonik Degussa Japan: Eudragit L30D-55) 600.0 g, D-mannitol 50.0 g, citric acid Purified water was added to 20.0 g of triethyl and 50.0 g of talc wet-pulverized to 0.5 μm, and 1500.0 g of a uniformly dispersed solution (solid content 20%) was spray-added, with an average particle size of 88 μm, geometric standard deviation Particles with masked bitterness of (σg) 1.3 and fractal dimension 1.1 were obtained (nuclear particle-3).

A) 56.0 g of calcium silicate having an average particle size of 31.0 μm (manufactured by Tokuyama: Fluorite RE) was charged into a spouted fluidized bed granulator (manufactured by POWREC: MP-01-SPC type), and sodium hydroxide A solution obtained by dissolving 800.0 g of rabeprazole sodium (solid content concentration: 28.9 wt%) in a solution obtained by dissolving 80.0 g in 2160 g of purified water was sprayed, and the average particle size was about 96 μm, geometric standard deviation (σg) 1 .3 particles (nuclear particle-4) were obtained.
B) 468.0 g of the obtained core particle-4 was put into a spouted fluidized bed granulator, and 75.52 g of talc was added to a solution obtained by dissolving 0.24 g of sodium hydroxide and 25.2 g of HPC-L in 1430.0 g of purified water. A liquid in which 151.04 g of titanium oxide was dispersed and suspended was sprayed to obtain a granulated product (core particle-5).
C) To 720.0 g of the obtained core particle-5, 853.3 g (solid content: 256.0 g) of ethyl acrylate / methyl methacrylate copolymer dispersion (manufactured by Evonik Degussa Japan: Eudragit NE30D), ethylcellulose aqueous dispersion 426 A solution obtained by adding 1024.0 g of purified water to 0.7 g (solid content: 128.0 g) and mixing and stirring, and further adding 96.0 g of light anhydrous silicic acid, mixing, stirring and dispersing (solid content concentration: 20% by weight) ) Was added by spraying to obtain a granulated product (core particle-6).
D) 180.0 g of the obtained core particle-6 was charged into a jet fluidized bed, 670.4 g (solid content: 201.12 g) of methacrylic acid copolymer LD (Evonik Degussa Japan: Eudragit L30D-55), and ethyl acrylate A solution obtained by adding 861.44 g of purified water to 670.4 g of methyl methacrylate copolymer dispersion (solid content: 201.12 g), gently mixing and stirring, and further adding 47.76 g of glycerin monostearate (solid content concentration: 20.1% by weight) was added by spraying to obtain particles having an average particle size of 135 μm, a geometric standard deviation (σg) of 1.2, and a fractal dimension of 1.1 (nuclear particles-7).
The obtained core particle-7 was mixed with other additives and tableted to obtain an orally disintegrating tablet having an oral disintegration time of about 50 seconds.

A) 114.5 g of sodium carboxymethyl starch having an average particle size of 45 μm (manufactured by Rocket Japan: Glicolis) is charged into a spouted fluidized bed granulator (manufactured by Pauleck Co., Ltd .: MP-01-SPC type) and fluidized, and loxoprofen sodium 340 A solution obtained by dissolving 0.5 g in 859.5 g of purified water was added by spraying to obtain particles having an average particle diameter of about 65 μm, a fractal dimension of 1.2, and a geometric standard deviation (σg) of 1.3 (core particle-8).
B) The obtained core particle-8 was put into a jet fluidized bed granulator and allowed to flow, and 650.0 g of ethylcellulose aqueous dispersion, 50.0 g of triacetin, 50.0 g of D-mannitol and 1050 g of purified water were uniformly suspended. The dispersed liquid was added by spraying to obtain particles having an average particle diameter of 84 μm, a geometric standard deviation (σg) of 1.2, and a masked bitterness of a fractal dimension of 1.2 (core particle-9).
C) 300.0 g of the obtained core particles-9, 540.0 g of D-mannitol and 100.0 g of corn starch were charged into a spouted fluidized bed granulator and allowed to flow, and 50.0 g of hydroxypropyl cellulose was added to 950.0 g of purified water. The solution dissolved in was sprayed to obtain a powder having an average particle size of 275 μm and good dosing properties.

  ADVANTAGE OF THE INVENTION According to this invention, the method of manufacturing the granular material which improved the patient's ingestibility can be provided by the simple method on formulation operation of a physiologically active substance. It is suitable for the production of granules for solid preparations, and can be used for the production of powders of pharmaceuticals and orally disintegrating tablets.

Claims (4)

A) A spouted fluidized bed granulator for adding additive particles having a liquid holding capacity (water absorption capacity) of 1.5 mL / g or more, an average particle diameter of 80 μm or less, and a major axis / minor axis ratio of 3.0 or less. B) Disperse a bioactive drug finely pulverized to an average particle size (D50) of 5 μm or less in water, an aqueous solution of a water-soluble polymer, a dispersion of a water-insoluble substance or a mixture thereof while maintaining the fluid state.・ Suspension, partial dissolution, or total dissolution and spray addition. The surface of the resulting granulated particles is coated with one or more layers of water-soluble polymer, sugar or sugar alcohol, water-insoluble substance, or a mixture thereof. As a result, a surface having an average particle diameter of 150 μm or less, a geometric standard deviation (σg: D84.1 / D50) of 1.1 to 1.4, and a fractal dimension of 1.0 to 1.2 is obtained. Smooth, light stabilization, bitterness mask or Method of manufacturing output controlled bioactive drug-containing particles. The additive particles consist of calcium silicate, partially pregelatinized starch, pregelatinized starch, crystalline cellulose, synthetic aluminum silicate, synthetic hydrotalcite, magnesium metasilicate aluminate, sodium carboxymethyl starch and low substituted hydroxypropylcellulose The method for granulating particles according to claim 1, which is one or more selected from the group. The water-soluble polymer is one or more selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. Or the manufacturing method of the granulated material of 2. Water-insoluble substances are aminoalkyl methacrylate copolymer (E, RL, RS), methacrylic acid copolymer (L, LD, S), ethyl acrylate / methyl methacrylate copolymer dispersion, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, The method for producing a granulated product according to any one of claims 1 to 3 , which is one or more selected from the group consisting of ethyl cellulose, talc and titanium oxide.