JP2001172430A - Spherical granules - Google Patents

Abstract

(57) [Summary] [Problem] A well-balanced property such as average particle diameter, sphericity, strength, and water absorption, and suppressed the reactivity with a drug.
Provides spherical nuclei useful as nuclei for spherical granules. SOLUTION: A spherical core containing 0 to 95% by weight of a cellulose powder and 5 to 100% by weight of trehalose.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a spherical nucleus and a spherical granule produced using the spherical nucleus.

[0002]

2. Description of the Related Art Film-coated preparations of pharmaceuticals are effective in terms of bioavailability, so-called drug delivery for selectively delivering drugs to specific sites, and feeling of ingestion. It is applied to enteric and bitter masking preparations. When applying film coating to the granules, a nucleus that is as spherical as possible is desirable in order to improve coating efficiency and reproducibility. Examples of such core particles for coating include spherical nuclei of sucrose or sucrose / starch disclosed in JP-A-61-1614,
JP-A 1-213201, spherical cellulose nuclei composed of crystalline cellulose disclosed in JP-A-63-301816, Japanese Patent No. 2542122, spherical nuclei containing 50% or more of crystalline cellulose, JP-A-4-2835
A spherical nucleus containing 10 to 70% of crystalline cellulose and 10 to 90% of a water-soluble additive disclosed in JP-A-20 is known.

[0003] However, when a sucrose or a sucrose / starch nucleus disclosed in JP-A-61-1614 is used as the nucleus,
In a formulation method in which the core is coated with a powder containing a drug using a binding solution, and further coated with a film,
Because sucrose, which is the main component of the nucleus, is dissolved in the binding solution and the surface becomes sticky, and the nucleus has a high degree of friability, the granules aggregate, the granules adhere to the coating machine wall,
There was a problem that the yield and the coating efficiency deteriorated. Furthermore, since sucrose is mixed into the coating film, there is a problem that desired elution characteristics cannot be obtained with good reproducibility. In addition, when the granules are administered to the body, sucrose, which is the main component of the nucleus, gradually dissolves and the strength decreases, so that when stress is applied by intestinal motility, the coating film is broken and it is difficult to obtain desired dissolution characteristics. Was. JP-A-61-213201, JP-A-63-3018
The spherical nucleus made of crystalline cellulose disclosed in Japanese Patent No. 16 has the advantage that the friability is reduced and the nucleus strength is improved, but the water absorption of the nucleus increases, and a large amount of a binding solution is required during coating, and the coating time is increased. However, there was a disadvantage that it required The crystalline cellulose disclosed in Japanese Patent No.
% Of the nucleus has high strength without disintegration in a solution and has a high water absorption of the nucleus to improve coating properties. Uses a large amount of coating liquid when coating the body, weak powder adhesion to the nucleus, time-consuming powder coating, and use for drugs that are reactive with crystalline cellulose There were drawbacks such as the inability to do so. The crystalline cellulose disclosed in Japanese Patent Application Laid-Open No.
The spherical nucleus containing 0% and 10 to 90% of the water-soluble additive suppresses the water absorption of the nucleus and improves the adhesion of the powder to the nucleus by blending the water-soluble additive. When lactose, sucrose, D-mannitol, and glucose, which are listed as water-soluble additives, are used, when the blending amount of these saccharides increases, the friability of the granules increases and the strength decreases. Due to the high water solubility, the adhesion of the powder to the nucleus is too strong, and there is a problem that agglomeration of the granules easily occurs. Further, there is no description about the use of trehalose as a water-soluble additive and its effectiveness, particularly reducing the reactivity of a drug with crystalline cellulose. Among the water-soluble additives, D-mannitol is a low-reactive substance and is good in reducing the reactivity of crystalline cellulose, but has the disadvantage that the strength of the nucleus is low and the core is easily worn. Japanese Patent No. 2934436 discloses 99 to 10 parts by weight of a cellulose powder and 1 to 90 parts by weight of a water-soluble substance.
It discloses an oral composition comprising 0.2 to 20% by weight of spherical granules consisting of parts by weight and having an average particle diameter of 50 μm to 2000 μm, and trehalose is described as a water-soluble substance. The oral composition is intended for removal of plaque, and when the spherical core of the present invention is used for carrying a drug, the coating properties of the core become good, and the release of pharmaceuticals, control of enteric acid, and masking of bitterness can be effectively imparted. The purpose is different from that of the invention of this publication.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a spherical nucleus containing trehalose, in particular, an average particle size, sphericity, strength,
It is an object of the present invention to provide a spherical nucleus in which properties such as water absorption are balanced and reactivity with a drug is suppressed. Further, by using the spherical nucleus as a nucleus, powder coating, film coating can be easily performed, the objective is to provide a high commercial value sphere element granules, spherical granules in which the reaction of the drug over time was suppressed. I do.

[0005]

Means for Solving the Problems As a result of intensive studies, the present inventors have solved the above problems by using a spherical core containing 0 to 95% by weight of cellulose powder and 5 to 100% by weight of trehalose as a core. We have found that we can do this and completed the present invention.

That is, the present invention provides (1) cellulose powder in an amount of 0 to 95% by weight and trehalose in an amount of 5 to 100% by weight.
(2) Spherical particles having a powder layer containing a drug around the spherical nucleus of (1), (3) Spherical particles having a coating layer around the sphere particles of (2) Granules.

The spherical nucleus of the present invention has a high strength and can be easily coated to impart desired elution characteristics. The spherical nucleus has a particularly excellent balance of strength, water absorption and adhesion, so that the coating time can be shortened. Since reactivity with a drug is reduced, there are advantages such as being suitable as core particles when coating a basic drug or the like.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. The spherical nucleus referred to in the present invention is obtained by adding cellulose powder from 0 to 95.
Pharmaceutically containing 10% by weight, preferably 10-80% by weight, more preferably 20-60% by weight, and trehalose 5-100% by weight, preferably 20-90% by weight, more preferably 40-80% by weight. Inactive spherical nuclei. From the viewpoint of suppressing reactivity with a drug or the like, it is preferable that the amount of trehalose is large, and from the viewpoint of coating properties,
It is preferable to mix an appropriate amount of cellulose. The average particle size of the spherical nuclei is preferably 50 to 2000 μm, more preferably 50 to 1000 μm, particularly preferably 100 to 2000 μm.
700 μm. The tapping apparent density is preferably 0.60 g / cm ³ or more, more preferably 0.70 g.
/ Cm ³ or more, particularly preferably 0.80 g / cm ³ or more. The sphericity is preferably 0.7 or more, and more preferably 0.8 or more. The water absorption is preferably 2 to 15%, more preferably 5 to 15%,
The friability is preferably 1.0% or less, more preferably 0.8% or less.

If the content of the cellulose powder exceeds 95% by weight (if the content of trehalose is less than 5% by weight), the water absorption of the core becomes too large, so that a large amount of the binding solution is required and the powder containing the drug is required. It is not preferable because it takes time to coat the body. In addition, the spherical nuclei remaining in the mouth may cause roughness, or may enter the denture gap, causing pain.

The average particle size of the spherical nucleus is determined by the amount of the powder containing the drug, the coating amount, the target spheroidal granules, and the particle size of the spheroidal granules. Aggregation is likely to occur. If the average particle size of the spherical nuclei exceeds 2000 μm, the amount of the drug to be coated is undesirably limited. Tapping apparent density is 0.60g
If it is less than / cm ³ , the flowability of nuclei at the time of coating the powder becomes poor, and uniform coating becomes difficult, which is not preferable. If the sphericity is less than 0.7, the finished sphere element granules and spherical granules have poor sphericity, which is not preferable in terms of product aesthetics and drug elution control. When the water absorption of the spherical nucleus is less than 2%, when the binding liquid or the coating liquid is sprayed, the aggregation of particles and the adhesion to the machine wall increase, and when the water absorption is more than 15%, the liquid which the nucleus absorbs. The disadvantage is that the coating rate of the powder is slowed down due to the large amount.
On the other hand, if the friability is more than 1%, abrasion occurs at the time of coating, and the yield and coating efficiency deteriorate.

The components of the spherical nucleus of the present invention will be described. The cellulose powder used in the present invention is a β-1,4 glucan powder such as crystalline cellulose and powdered cellulose.
It is preferably of a quality compatible with the thirteenth revised Japanese Pharmacopoeia, and among them, crystalline cellulose is preferred.

Crystalline cellulose is a water-soluble cellulose obtained by depolymerizing a cellulosic material such as wood pulp, refined linters and regenerated fibers by acid hydrolysis, alkali oxidative decomposition, enzymatic decomposition, steam explosion decomposition, or the like.
And obtained by performing a mechanical treatment such as pulverization after drying the cellulose or the chemical treatment,
The average degree of polymerization is preferably from 60 to 350. Particularly preferably, it is 100 to 300. The term “crystalline cellulose” as used herein means that the crystallinity measured by the X-ray diffraction method is 10%.
The above refers to cellulose. It is preferably at least 40%. Water absorption is 1.0 to 2.8 ml / g, 75 μm
It is preferable that the ratio of the above particles is 80% or less.
When the average degree of polymerization is less than 60, the entanglement of the cellulose molecules is reduced, so that the friability of the spherical nucleus is increased.
If the value is larger than 0, fibrous properties appear, and it is difficult to form a sphere, which is not preferable.

The trehalose used in the present invention is α,
α-trehalose, α, β-trehalose and β, β-trehalose, and naturally occurring α, α-trehalose is preferred. Trehalose has two types of anhydride and dihydrate in a solid state, but dihydrate is more preferable because it does not absorb moisture over time. Especially in crystalline state 2
Water is preferred. The heat of fusion peak by DSC measurement is 10
It can be determined by appearing at around 0 ° C.

The trehalose used in the present invention is obtained by enzymatically treating a starch decomposition product having a degree of polymerization of glucose of 3 or more, and is, for example, a commercially available product ("Trehaose").
(Manufactured by Hayashibara Biological Research Institute)) and JP-A-7-143876
Manufactured by a method using an enzyme from a starch hydrolyzate described in Japanese Patent Application Laid-Open Publication No. H10-209 (A solution containing one or two or more reductive starch partial hydrolysates selected from a glucose polymerization degree of 3 or more, A non-reducing saccharide-forming enzyme having a trehalose structure at the terminal thereof is acted on from one or more kinds of partially decomposed starches having a degree of polymerization of 3 or more, and then glucoamylase or α-glucosidase is acted on, A solution containing trehalose and contaminating saccharides, which is obtained by column chromatography using a strongly acidic cation exchange resin, and which has an improved content of trehalose) as a raw material, which is obtained through further purification, pulverization, particle size adjustment, etc. However, from the viewpoint of cost, it is preferable for industrial use.

The purity of trehalose is 98.0% or more.
Preferably, the glucose content as an impurity is less than 1.0%. The purity of trehalose is less than 98.0%,
Alternatively, when the glucose content is 1.0% or more, the reactivity with the medicinal component tends to increase. Trehalose is expected to reduce the reactivity of the drug, but the presence of glucose as an impurity impairs the stability of the drug. More preferably, the purity of trehalose is 99.0%
That is all. Preferably, the glucose content is 0.5
% Or less. Particularly preferably, the glucose content is 0.1.
3% or less. Whenever possible, the purity of trehalose should be 1
It is preferable that the glucose content is close to 00% and the glucose content is close to 0%. However, since the yield is deteriorated and the cost is increased, the purification may be performed in view of the required labor and the effect.

The average particle size of trehalose is 10 to 350 μm.
m is preferred. When it is less than 10 μm, the cohesiveness of the powder is increased, and it is difficult to make the powder spherical. When it exceeds 350 μm, the mixing property with crystalline cellulose is deteriorated, and at the same time, it is not suitable for producing a spherical core having a small average particle size. More preferably, 20 to 250 μm, and still more preferably, 30 to 150 μm.
μm, particularly preferably 30 to 120 μm.

In the particle size of trehalose, 75 μm
The proportion of particles having a particle size of m or more is preferably 2 to 90% by weight. If it is less than 2% by weight, spheroidization is difficult. Also 90
If it exceeds the weight, the miscibility with the crystalline cellulose becomes poor. More preferably, it is 5 to 80% by weight, and still more preferably 10 to 70% by weight.

The apparent specific volume of trehalose is from 1.3 to
3.5 cm ³ / g is preferred. If it is less than 1.3 cm ³ / g, the miscibility with other additives will be poor. Also, 3.
If it exceeds 5 cm ³ / g, the fluidity of the powder is remarkably deteriorated, and the handling property is deteriorated, which is not practical. More preferably, it is 1.5 to 3.0 cm < ³ > / g, particularly preferably 1.6 to 2.5 cm < ³ > / g. Further, the whiteness of trehalose is preferably 90% or more. In a formulation, the color of appearance is often considered to be higher as the color becomes whiter, and even in the case of coloring, the higher the whiteness of the additive, the more beautiful the color. It is more preferably at least 93%.

As the components of the spherical core of the present invention, in addition to cellulose powder and trehalose, they are pharmaceutically inert as long as they do not impair the balance of strength, water absorption, tackiness and low reactivity characteristic of the spherical core. Various additives can be used. For example, excipients, disintegrants, binders, flow agents, lubricants, flavoring agents, flavors, colorants, sweeteners, surfactants and the like can be mentioned. As excipients, sugars such as lactose and sucrose, sugar alcohols such as mannitol, xylitol, maltitol, erythritol, sorbitol, rice starch, wheat starch, corn starch, starches such as potato starch, calcium hydrogen phosphate, Examples include inorganics such as calcium carbonate, silicic acid anhydride, hydrous silicic acid, aluminum silicate, calcium silicate, and magnesium aluminate silicate. As a disintegrant, croscarmellose sodium,
Cellulose such as carmellose calcium, carmellose, low-substituted hydroxypropylcellulose and the like; starches such as sodium carboxymethyl starch, hydroxypropyl starch and partially pregelatinized starch; crospovidone; As binders, gelatin, pullulan, carrageenan, locust bean gum,
Agar, konjac mannan, xanthan gum, tamarind gum, pectin, sodium alginate, water-soluble polysaccharides such as gum arabic, hydroxypropyl cellulose,
Examples include celluloses such as hydroxypropylmethylcellulose and methylcellulose; starches such as pregelatinized starch and starch paste; and synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer, and polyvinyl alcohol. Examples of the fluidizing agent include hydrous silicon dioxide and light anhydrous silicic acid. As a lubricant,
Magnesium stearate, calcium stearate,
Stearic acid, sucrose fatty acid esters, talc, and the like. Examples of the flavoring agent include glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, 1-menthol, and the like. Flavors include orange, vanilla, strawberry, yogurt, menthol and the like.
Examples of the coloring agent include food colors such as Food Red No. 3, Food Yellow No. 5, and Food Blue No. 1, and riboflavin. Sweetening agents include aspartame, saccharin, dipotassium glycyrrhizinate, stevia and the like. Examples of the surfactant include phospholipids, glycerin fatty acid esters, polyethylene glycol fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene hydrogenated castor oil.

The method for producing a spherical core according to the present invention will be described. Extrusion of raw material powder into kneaders, planetary mixers, colloid mills, ribbon blenders and other general-purpose kneading machines, grinding machines, fluidized bed granulators, high-speed stirring granulators, oscillating granulators, extruders, etc. It can be produced by processing one or a combination of two or more of granulators, dryers such as drum dry and spray dry, and spherical granulators such as marmellaizers. For example, it is manufactured by the following method. A powder containing 0 to 95% by weight of cellulose powder and 5 to 100% by weight of trehalose is put into a mixing and stirring granulator, and kneaded by adding distilled water. An aqueous solution of hydroxypropylcellulose, starch paste, polyvinylpyrrolidone, or the like may be used as the binding liquid instead of distilled water. Thereafter, the kneaded material is extruded and granulated by using an extruder. Thereafter, the extrudate is transferred to a rolling type coating apparatus, spheroidized, dried, and sieved as necessary to obtain a spherical core. In this method, the kneaded material is strongly compacted during extrusion granulation, so that there is an advantage that a spherical nucleus having a small friability can be formed even when the content of the cellulose powder is small. Trehalose also functions as a lubricant for smoothly performing extrusion during extrusion granulation.
It is also possible to put the powder in a mixing and stirring granulator, add distilled water, knead the mixture, and then directly transfer the granulated product to a rolling type coating apparatus to perform spheroidization. It is also possible to obtain a spherical core by dispersing and dissolving the powder in water, spray drying and, if necessary, sieving. As described above, the spherical nucleus of the present invention has an advantage that it can be manufactured by combining inexpensive equipment conventionally used without using expensive equipment.

The spherical granules and the method for producing the spherical granules of the present invention will be described. In the past, coating and film coating of powder layers containing drugs were often performed with organic solvent systems, but due to environmental, cost, and residual solvent problems, gradually switching to aqueous solutions and aqueous suspension systems Is planned. Therefore, it is preferable to carry out the reaction in an aqueous solution system or an aqueous suspension system as described below, and the effect of the spherical nucleus of the present invention is more remarkably exhibited in an aqueous system.

The coating of the powder layer and the film coating are carried out by conventional methods, for example, a tumbling fluidized bed coating machine, a fluidized bed coating machine, a Wurster type fluidized bed coating machine, a rolling type coating machine, a centrifugal rolling type coating. Can be carried out by a machine, a pan-type coating machine or the like. For example, while rolling the spherical nuclei in a centrifugal flow type coating apparatus, continuously spraying an aqueous solution containing a binding solution,
At the same time, a powder comprising a drug and, if necessary, an excipient is supplied, and the spherical core is coated with the powder to obtain spherical granules. Alternatively, while flowing the spherical core in a fluidized bed coating machine,
A solution in which a drug is dissolved or suspended in a binding aqueous solution is sprayed, and a spherical nucleus is coated with a powder containing the drug to form spheroidal granules. After drying the sphere element granules if necessary, spray an aqueous solution of the coating agent or an aqueous suspension of the coating agent,
It is dried to form a coating layer for the purpose of moisture proofing, bitterness masking, enteric coating, sustained release, etc., to obtain spherical granules. When coating the powder containing the drug, an aqueous solution of the coating agent or an aqueous suspension of the coating agent may be simultaneously sprayed.

The particle size of the spherical elementary granules and the spherical granules is determined by the particle size of the spherical core used and the weight of the powder layer containing the drug.
Powders defined by the Japanese Pharmacopoeia, such as fine granules and granules, can be freely manufactured in the range of about 50 to 2000 μm. Further, depending on the spherical nucleus used, by using a spherical nucleus having a narrow particle size distribution, the particle size distribution of the sphere elementary granules and the spherical granules can be narrowed.

The amount of the powder used for coating varies depending on the amount of the drug to be administered, the size of the final preparation, and the like, but is about 1 to 300% of the spherical core. However, more can be used if necessary. The powder coated on the spherical nucleus of the present invention includes pharmaceutical active ingredient powder, agricultural chemical ingredient powder, fertilizer ingredient powder, feed ingredient powder, food ingredient powder, cosmetic ingredient powder, pigment powder, flavor powder, metal powder, ceramic powder, catalyst Powders, surfactant powders and the like may be included. Furthermore, if necessary, other excipients, disintegrants, binders, lubricants, sweeteners and the like can be freely contained as additives. Pharmaceutical medicinal ingredients include, for example, antibiotics, chemotherapeutics, absorption enhancers, sedatives, anxiolytics, antiepileptics, antiparkinson agents, agents for psychiatric nerves, skeletal muscle relaxants,
Agents for autonomic nerves, antispasmodics, circulation / metabolic improvers, inotropic agents, antiarrhythmic agents, antihypertensive agents, vasodilators, vascular reinforcing agents, vasoconstrictors, anticoagulants, antilipidemic agents, diuretics, antipyretic analgesics Anti-inflammatory,
Antitoxicants, antivirals, antiulcers, gastrointestinals, antacids, healthy digestives, intestinals, cholestics, agents for liver diseases, gouts, diabetes, osteoporosis, antihistamines, antitussives and expectorants Orally administered drugs, herbal medicines, antiasthmatics, pollakiuria, nutrient tonics, vitamins, etc. The effect of using the spherical nucleus of the present invention becomes more remarkable since the water-soluble drug dissolves in the aqueous binder solution and becomes tacky, and tends to cause adhesion and aggregation of core particles. As excipients, crystalline cellulose, low-substituted hydroxypropylcellulose, celluloses such as powdered cellulose, sucrose,
Sugars such as glucose, lactose, fructose, maltose, sugar alcohols such as mannitol, xylitol, maltitol, erythritol, sorbitol, rice starch, wheat starch, corn starch (CS), potato starch, pregelatinized starch, partially pregelatinized starch, etc. Starch, calcium hydrogen phosphate, calcium carbonate, silicic anhydride, hydrous silicic acid, aluminum silicate, calcium silicate,
Inorganic compounds such as magnesium aluminate silicate are exemplified. As a disintegrant, croscarmellose sodium,
Cellulose such as carmellose calcium, carmellose, low-substituted hydroxypropylcellulose and the like; starches such as sodium carboxymethyl starch, hydroxypropyl starch and partially pregelatinized starch; crospovidone; Examples of binders include hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose, cellulose derivatives such as sodium carboxymethylcellulose, starch paste, processed starch products such as pregelatinized starch, polysaccharides such as gum arabic and pullulan, Aqueous solutions of synthetic polymers such as polyvinylpyrrolidone (PVP) and sugars such as sugar syrup are preferred. When the drug is water-soluble, the drug aqueous solution itself may be used as the binder aqueous solution. When an organic solvent is used, PVP, HP
C and the like may be dissolved in an organic solvent and used. Examples of the fluidizing agent include hydrous silicon dioxide and light anhydrous silicic acid. Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, talc and the like. Examples of the flavoring agent include glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, 1-menthol, and the like. Flavors include orange, vanilla, strawberry, yogurt, menthol and the like. Edible red No. 3 as coloring agent,
Food dyes such as Food Yellow No. 5 and Food Blue No. 1, riboflavin and the like. Aspartame as a sweetener,
Saccharin, dipotassium glycyrrhizinate, stevia and the like. Examples of the surfactant include phospholipids, glycerin fatty acid esters, polyethylene glycol fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene hydrogenated castor oil. As the coating machine, a conventional coating machine such as a rolling coating machine, a centrifugal fluidized coating machine, a fluidized bed coating machine, a Wurster type fluidized bed coating machine, a rolling fluidized bed coating machine, and a pan coating machine can be used. As the aqueous solution of the coating agent, HPMC, HPC, PVP,
Aqueous solutions such as polyvinyl alcohol and polyethylene glycol are mentioned. The aqueous suspension of the coating agent is a suspension of a water-insoluble coating agent, and includes ethylcellulose (EC), hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, cellulose acetate, and cellulose acetate butyrate. rate,
Examples include aqueous suspensions of celluloses such as hydroxypropylmethylcellulose acetate succinate, acrylic copolymers, vinyl copolymers, shellac, and silicone resins. As a commercially available product, for example, TC-5
(HPMC, manufactured by Shin-Etsu Chemical Co., Ltd.), fine powder EC (EC, manufactured by Dow Chemical, USA), Aquacoat (aqueous suspension of EC, manufactured by FMC, USA), Eudragit L-30D
-55 and NE30D (both are aqueous suspensions of acrylic copolymer, manufactured by Reem, Germany). These coating agents may be used alone or in combination of two or more. When an organic solvent is used, a solvent system in which the above-mentioned coating agent is dissolved is used. A mixed solution of water and an organic solvent miscible with water such as ethanol or acetone may be used. Further, a water-soluble substance, a plasticizer, a stabilizer, a coloring agent, a drug and the like for adjusting the dissolution rate may be added as required. The amount of the coating layer varies depending on the purpose of coating, the particle size of the granules, and the like.
About 100% is preferable. When aiming for sustained release,
It is preferably about 5 to 50%, and it is preferable to coat about 2 to 30% for the purpose of masking bitterness and preventing moisture. A powder layer and a coating layer of a coating agent may be further formed on the obtained spherical granules. The obtained spherical element granules and spherical granules may be filled into capsules by a known method, or may be mixed with a suitable additive such as crystalline cellulose and then compressed into tablets.

Now, the present invention will be described in further detail with reference to Examples. In addition, crystalline cellulose, trehalose,
The methods for evaluating the physical properties of the spherical nuclei and the spherical granules are as follows. Here, the cellulose powder has a crystallinity of 10%.
The above crystalline cellulose was used.

Crystalline Cellulose-Average Polymerization Degree The 13th revised edition of the Japanese Pharmacopoeia, "Crystalline Cellulose" Confirmation Test (3) According to the average polymerization degree measurement method.

Water absorption According to the method for measuring oil absorption described in JIS K5101, distilled water is used instead of oil. The end point is the point where the water starts to separate after the whole has become one lump.

Ratio of particles having a particle size of 75 μm or more It is a residue on a sieve after 30 g of a sample is sieved for 30 minutes using a JIS standard sieve having a mesh size of 75 μm (200 mesh) with a low tap sieve.

Trehalose Purity, glucose content In the following method, water of crystallization is not taken into account, but saccharides are determined as those converted to anhydrides. (A) 1.0 g of a sample is accurately weighed and dissolved in water to make exactly 100 cm ³ . (B) 20 μL of this solution is analyzed by liquid chromatography under the following operating conditions. (C) Peaks appear in the order of oligosaccharide, trehalose, and glucose. (D) The ratio of the trehalose or glucose peak area to the total peak area is determined by the automatic integration method.

Trehalose purity (%) = (A2 / (A1)
+ A2 + A3)) × 100 Glucose content (%) = (A3 / (A1 + A2 + A)
3)) × 100 A1: Peak area of oligosaccharide A2: Peak area of trehalose A3: Peak area of glucose

Operating conditions Detector: Differential refractometer (ERC-7515B) Column: MCI-GEL CK04SS (Mitsubishi Chemical Corporation) Column temperature: 85 ° C. Mobile phase: water Flow rate: 0.4 cm ³ / min

Whiteness: Trehalose powder was analyzed using a color analyzer (TC-18).
00MKII, manufactured by Tokyo Denshoku Co., Ltd.), the values of L, a, and b were obtained and calculated by the following equations. Whiteness = 100 − [(100−L) 2+ (a2 + b)
2)] 0.5

・ Ratio of particles of 75 μm or more Take 5 g of trehalose on a sieve having an opening of 75 μm, and air jet sieve (200LS type, manufactured by ALPINE)
Weight percentage of the total weight of the particles remaining on the sieve when sieved for 5 minutes.

Average particle size 5 g of trehalose is sieve-opened 500 μm, 300 μm,
Sieve using a 250 μm sieve, and sieve opening 150 μm
m, 75 μm, 45 μm, 38 μm, and 32 μm sieves were sieved with an air jet sieve, the on-screen weight percentage [%] of each sieve was determined, and expressed as the particle diameter when the cumulative weight percentage was 50%.

Apparent specific volume 10 g of powder was gently poured into a 100 cm ³ graduated cylinder without giving an impact (at this time, a cylinder smaller than the inner diameter of the graduated cylinder was charged, and after the powder was poured, the cylinder was slowly poured). Lifted) and the volume read was divided by the weight of the powder.

Spherical nucleus ・ Average particle size Sample 3 using a JIS standard sieve with a low tap sieve
0 g is sieved for 10 minutes, and the particle size of 50% by weight is defined as the average particle size.

Tapping apparent density 30 g of a sample was filled in a 100 cm ³ graduated cylinder,
Approximately tapping about 0 times. The number of repetitions is 3, and the average value is taken.

Sphericity The major and minor diameters of each of the 100 particles were determined by an image analyzer (Imagehyper, Interquest), and the sphericity was calculated by the following equation. Sphericity = minor diameter of particle / major diameter of particle

Water absorption rate While rotating 400 g of spherical cores (in terms of solid content) in a centrifugal flow type coating apparatus (CF-360, manufactured by Freund Corporation), 6 g of a 3% HPC (low viscosity type) aqueous solution was rotated. Spray at a speed of min. The process is performed until the nuclei start to adhere to each other, and the end point is obtained, and the required liquid weight (g) is obtained. The water absorption is represented by the following equation. The water content in the formula is the water content originally contained in the spherical nucleus (excluding two water contents in the trehalose crystal). Water absorption (%) = (liquid weight / 400) × 100 + water content (%)

Abrasion degree A friability degree tester was charged with 10 g of a sample and subjected to 15 rpm at 25 rpm.
Rotate for a minute and express the weight loss due to powdering as a percentage by weight. The number of repetitions is 3, and the average value is taken.

Reactivity Reactive spherical nuclei and arginine are mixed in equal amounts and placed in a sealed bottle.
The degree of coloring when left for 2 weeks under humidification at 75 ° C. and 75% RH was visually observed.

Explanation of symbols ◎: White color ○: Almost white, but slightly yellowish. △: slightly yellowing ×: yellowing

Spherical Granules Coating Efficiency (%) The recovered amount of spherical granules is expressed as a percentage by weight divided by the total amount of raw materials used.

Agglomeration degree (%) Spherical granules are dispersed on paper, the number of agglomerated particles is counted, and expressed as a percentage when divided by the total number. This is performed at n = 1000.

Example 1 400 g of crystalline cellulose (a) shown in Table 1 and 600 g of trehalose A shown in Table 2 were mixed in a plastic bag, and then placed in a planetary mixer 5DM-R (manufactured by Shinagawa Seisakusho), and 0.3 kg of distilled water was added. And knead for 5 minutes. Thereafter, an extruder granulator Dome Gran (manufactured by Fuji Paudal Co., Ltd .;
(5 mmφ). 0.6 kg of the extrudate is taken and transferred to a marmalizer Q-230 (manufactured by Fuji Paudal Co., Ltd.), and tumbled at 500 rpm for 20 minutes while spraying distilled water little by little to form a sphere. The wet sphere was subjected to multiplex MP-01 (manufactured by Powrex Corporation) at an inlet temperature of 75.
After fluidized drying at ℃, 30 mesh (mesh size 0.50mm)
And sieved so as to remain on a 60 mesh (aperture 0.25 mm) to obtain a spherical core (A). Table 3 shows the physical properties of the obtained spherical nuclei.

Example 2 A spherical nucleus (B) was obtained in the same manner as in Example 1 except that the crystalline cellulose (a) shown in Table 1 and trehalose B shown in Table 2 were used. Table 3 shows the physical properties of the obtained spherical nucleus (B).

Example 3 Spherical nuclei (C) were obtained in the same manner as in Example 1 except that the amount of water was reduced using crystalline cellulose (b) shown in Table 1. Table 3 shows the physical properties of the obtained spherical nucleus (C).

Example 4 A spherical nucleus (D) was obtained in the same manner as in Example 1 except that the amount of water was reduced using crystalline cellulose (c) shown in Table 1. Table 3 shows the physical properties of the spherical nucleus (D) obtained.

Example 5 Using crystalline cellulose (d) shown in Table 1, the amount of water added was increased, and 70 mesh (opening 0.212 mm) was used instead of 60 mesh (opening 0.25 mm). Except for this, a spherical nucleus (E) was obtained in the same manner as in Example 1. Table 3 shows the physical properties of the spherical nucleus (E) obtained.

Example 6 The amount of water added was reduced using the crystalline cellulose (a) shown in Table 1, and 50 meshes (mesh size 0.3 mm) instead of 30 meshes (mesh size 0.5 mm) were used. Example 1 except that a 150 mesh (aperture 0.105 mm) was used instead of a mesh (aperture 0.25 mm).
A spherical nucleus (F) was obtained in the same manner as described above. Table 3 shows the physical properties of the obtained spherical nucleus (F).

Example 7 Using crystalline cellulose (a) shown in Table 1 and increasing the amount of water added, 24 meshes (aperture 0.71 mm) instead of 30 meshes (aperture 0.5 mm), 60 A spherical nucleus (G) was obtained in the same manner as in Example 1 except that a 50 mesh (aperture 0.3 mm) was used instead of the mesh (aperture 0.25 mm). Obtained spherical nucleus (G)
The physical properties of are shown in Table 3.

Example 8 Using crystalline cellulose (a) shown in Table 1, the amount of water added was increased. Instead of 30 mesh (mesh 0.5 mm), 16 mesh (mesh 1.0 mm), 60 mesh A spherical nucleus (H) was obtained in the same manner as in Example 1 except that 30 meshes (mesh 0.5 mm) were used instead of the mesh (mesh 0.25 mm). Table 3 shows the physical properties of the obtained spherical nucleus (H).

Example 9 Spherical nuclei (I) were obtained in the same manner as in Example 1 except that the amount of water was reduced using crystalline cellulose (e) shown in Table 1. Table 3 shows the physical properties of the obtained spherical nucleus (I).

Example 10 Spherical nuclei (J) were obtained in the same manner as in Example 5 except that the amount of water was increased using crystalline cellulose (f) shown in Table 1. Table 3 shows the physical properties of the obtained spherical nucleus (J).

[0055]

[Table 1]

[0056]

[Table 2]

[0057]

[Table 3]

Example 11 400 g of the spherical nucleus (A) of Example 1 was placed in a centrifugal flow type coating apparatus (CF-360, manufactured by Freund Corporation) at an air temperature of 40 ° C. and a rotor rotation speed of 160 rpm. While spraying an aqueous solution of cellulose [HPC (low viscosity type)] (3% W / V) at a rate of 10 ml / min, the following composition powder is supplied while observing a granulated state, and powder coating is performed. Then take out the granules 40 ℃
For 16 hours. Next, the fine powder was cut with a sieve having openings of 106 μm to obtain spheroid granules. The sphere element granules had a very small degree of agglomeration and had good appearance.

Powder composition Theophylline (manufactured by Wako Pure Chemical Industries, Ltd.) 50 g White sugar (manufactured by Kyushu Seiyaku Co., Ltd.) 100 g CS (manufactured by Nisseki Chemical Co., Ltd.) 50 g

Next, the spherical granules were put into a CF-360 apparatus, the air temperature was set to 60 ° C., the rotor speed was set to 200 rpm, and an aqueous suspension having the following composition was sprayed at a rate of 20 ml / min to perform sustained release coating. .

Aqueous suspension Aquacoat 400 g (EC aqueous suspension, 30% W / V, manufactured by FMC USA) Triethyl citrate (Tokyo Kasei Co., Ltd.) 25 g

After coating is completed, 1
After a period of time, spherical granules were obtained. Table 4 shows the measurement results of the time (T (minutes)) required from the start of the supply of the binding liquid to the end of the powder coating, the degree of aggregation of the obtained spherical granules, and the coating efficiency.

Examples 12 to 14 Except that the spherical nuclei (C), (D) and (E) were used, the same operation as in Example 11 was carried out to obtain spherical granules. Table 4 shows the measurement results of T (minute), the degree of aggregation of the spherical granules, and the coating efficiency.

[0064]

[Table 4]

Example 15 A spherical nucleus (K) was obtained in the same manner as in Example 1 except that the formulation (k) shown in Table 5 was used and the amount of water added was increased. Table 6 shows the physical properties of the obtained spherical nucleus (K).

Example 16 Using the formulation (1) shown in Table 5, the amount of water added was reduced, and 50 was used instead of 30 mesh (aperture 0.5 mm).
Instead of a mesh (aperture 0.3 mm) and a 60 mesh (aperture 0.25 mm), a 100 mesh (aperture 0.2 mm) is used.
A spherical nucleus (L) was obtained in the same manner as in Example 1 except that 15 mm) was used. Table 6 shows the physical properties of the obtained spherical nucleus (L).

Example 17 A spherical nucleus (M) was obtained in the same manner as in Example 1 using the formulation (m) shown in Table 5. Table 6 shows the physical properties of the obtained spherical nucleus (M).

Example 18 A 30% strength aqueous solution was prepared using the formulation (n) shown in Table 5, and the inlet temperature was 150 ° C., the exhaust air temperature was 70 ° C., and the aqueous solution flow rate was 5 L / min. The spray drying was performed at a disk rotation speed of 10,000 rpm. Furthermore, 60 mesh (aperture 0.25
mm), and passed through a 200 mesh (opening 0.075 m).
m) The mixture was sieved so as to remain on top, and spherical nuclei (n) were obtained. Table 6 shows the physical properties of the obtained spherical nucleus (N).

Comparative Example 1 A spherical nucleus (O) was obtained in the same manner as in Example 1 except that the formulation (o) shown in Table 5 was used and the amount of water added was increased. Table 6 shows the physical properties of the obtained spherical nucleus (O).

Comparative Example 2 Nonpareil-101 (commercially available, Freund Corporation)
Manufacture: 75% by weight of white sugar, 25% by weight of corn starch) 42
The spherical nucleus (P) was obtained in the same manner as in Example 1 except that meshes to 32 meshes were changed to spherical nuclei (P). The composition is shown in Table 5 and the physical properties are shown in Table 6.

Comparative Example 3 Nonpareil-103 (commercially available, Freund Corporation)
Manufacture: 100% by weight of sugar) The spherical nucleus (Q) was obtained in the same manner as in Example 1 except that 42 to 32 mesh was used as the spherical nucleus (Q). The composition is shown in Table 5 and the physical properties are shown in Table 6.
Shown in

[0072]

[Table 5]

[0073]

[Table 6]

Examples 19 to 21 Spherical granules were obtained in the same manner as in Example 11, except that the spherical nuclei (K), (L) and (M) shown in Table 6 were used. T
Table 7 shows the measurement results of (minutes), the degree of aggregation of the spherical granules, and the coating efficiency.

Comparative Examples 4 to 6 Spherical granules were obtained in the same manner as in Example 11 except that spherical nuclei (O), (P) and (Q) shown in Table 6 were used. T
Table 7 shows the measurement results of (minutes), the degree of aggregation of the spherical granules, and the coating efficiency.

[0076]

[Table 7]

Example 22 500 g of the spherical nucleus (A) shown in Table 3 was
Charged into a P-01 fluidized bed coating machine and set the inlet temperature to 6
While flowing at 0 ° C., the following drug aqueous solution was
The drug was coated by spraying at a rate of 1 / min to obtain spheroid granules. The sphere element granules had a very small degree of agglomeration and had good appearance.

Composition of drug solution Sulpyrine (manufactured by Hoei Pharmaceutical Co., Ltd.) 100 g HPC (low viscosity type) 5 g Distilled water 145 g

Next, for masking bitterness, 150 ml of an aqueous solution of TC-5 (manufactured by Shin-Etsu Chemical Co., Ltd.) (10% W / V) is sprayed at a rate of 10 ml / min. Thereafter, the granules are taken out and dried at 40 ° C. for 16 hours. Next, for granules passing through 24 mesh, 150 mesh (opening 106
μm) to cut fine powder to obtain spherical granules. Table 8 shows the measurement results of the cohesion and the coating efficiency of the spherical granules. Although the spherical granules were contained in the mouth for a while, the bitter taste of sulpyrine was hardly felt even after the film was dissolved due to the presence of trehalose. In addition, roughness in the mouth was not felt, and the feel was smooth.

Example 23 Using spherical nuclei (N), sieving 50 mesh and 20 mesh
Except using 0 mesh, it carried out similarly to Example 22 and obtained the spherical granule. Table 8 shows the measurement results of the cohesion and the coating efficiency of the spherical granules. Similar to Example 22, the granules were contained in the mouth for a while, but the bitterness of sulpyrine was hardly felt even after the film was dissolved due to the presence of trehalose. In addition, roughness in the mouth was not felt, and the feel was smooth.

Comparative Example 7 Spherical granules were obtained in the same manner as in Example 22 except that spherical nuclei (O) were used. Table 8 shows the measurement results of the cohesion and the coating efficiency of the spherical granules. As in Example 22, the spherical granules were included in the mouth for a while, but after the film was dissolved, the bitter taste of sulpyrine was felt. In addition, roughness due to the spherical nucleus was felt in the mouth.

Comparative Example 8 Spherical granules were obtained in the same manner as in Example 22 except that the spherical core (P) was used. Table 8 shows the measurement results of the cohesion and the coating efficiency of the spherical granules. As in Example 22, the spherical granules were included in the mouth for a while, but after the film was dissolved, the bitter taste of sulpyrine was felt.

[0083]

[Table 8]

Example 24 400 g of spherical nuclei (M) shown in Table 6 were placed in a centrifugal flow type coating apparatus (CF-360, manufactured by Freund Corporation) at an air temperature of 40 ° C., a rotor rotation number of 160 rpm, and polyvinylpyrrolidone. (K-30, manufactured by BASF)
While spraying 100 ml of an aqueous solution (6% W / V), powder having the following composition is supplied to perform powder coating. The granules are then removed and dried at 40 ° C. for up to 16 hours. Next, the fine powder was cut through a sieve having openings of 106 μm to obtain spheroidal granules.

Powder composition Riboflavin (Wako Pure Chemical Industries, Ltd.) 20 g Lactose (DMV, 200 mesh) 60 g CS (Nisseki Chemical Co., Ltd.) 20 g

Next, the spherical granules are placed in a CF-360 apparatus, and the coating is performed by spraying an aqueous suspension having the following composition at a rate of 15 ml / min at an air temperature of 60 ° C. and a rotor rotation speed of 200 rpm.

Aqueous suspension composition Eudragit L-30D-55 300 g (30% W / V, manufactured by Laem Pharma Co., Ltd.) Talc (manufactured by Wako Pure Chemical Industries, Ltd.) 15 g Triethyl citrate (Wako Pure Chemical Industries, Ltd.) 9g distilled water 136g

After completion of the coating, the coating was dried at 40 ° C. for 16 hours to obtain enteric spherical granules. Table 9 shows the measurement results of the degree of aggregation and the coating efficiency of the obtained enteric spherical granules.

Comparative Example 9 Spherical grains were obtained in the same manner as in Example 24 except that spherical nuclei (Q) were used. Table 9 shows the measurement results of the cohesion of the spherical particles and the coating efficiency.

[0090]

[Table 9]

[0091]

According to the present invention, since the core has an appropriate solubility and water absorption, the coating of the powder layer is improved, and the coating properties such as being able to impart desired dissolution characteristics are excellent. Core particles can be provided. Further, since the core particles of the present invention have low reactivity to a drug or the like, they also have the effect of reducing the restrictions on the drugs that can be used. By using the spherical nucleus of the present invention in which properties such as average particle diameter, sphericity, strength, and water absorption are balanced, the nucleus is coated with a powder containing a drug, and further coated with a coating agent to form a sphere. In the case of making granules, the aggregation between granules was remarkably reduced to about 1/10, the coating efficiency was about 5% higher, and the reactivity with the drug was suppressed as compared with the conventional nucleus mainly composed of sucrose. Spherical granules with high commercial value can be easily produced. Further, the spherical nucleus of the present invention, compared with the conventional spherical nucleus mainly composed of crystalline cellulose, the water absorption is suppressed, and because the adhesion of the powder to the nucleus is strong, the powder coating speed is high,
Further, the amount of the binding solution may be small. Further, there is no rough feeling in the mouth and the feel is good.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C076 AA31 AA61 CC01 DD47 DD67 EE31 EE32 EE38 FF21 FF70 4J002 AB01W AB05X EL086 FA08X FA086 FD020 FD090 FD170 FD200 FD310 GB04

Claims (3)

[Claims] 1. A spherical core containing 0 to 95% by weight of cellulose powder and 5 to 100% by weight of trehalose. 2. Spherical granules having a drug-containing powder layer around the spherical nucleus according to claim 1. 3. A spherical granule having a coating layer around the spherical granule according to claim 2.