KR100771426B1 - Pharmaceutical composition using the micro-pellet and the preparation thereof - Google Patents

Abstract

The micropellets according to the present invention are spherical particles having a diameter of 150 to 500 µm and contain fluconazole as an active ingredient. Michaelo pellets prepared using a fluidized bed coater is easy to fill into hard capsules and contains an active ingredient in a micro pellet of a certain size, uniform drug release and excellent stability. In addition, it can be applied in various forms, such as absorption of uniform drugs, securing the stability of high or hygroscopic active ingredients, solubilization of poorly soluble drugs, and is easy to manufacture.

Micro Pellets, Fluconazole, Fluid Bed Coating Machine

Description

 Pharmaceutical composition using the micro-pellet and the preparation

1A, 1B and 1C show electron scanning micrographs of micropellets prepared according to the present invention.

2A and 2B show the dissolution graphs of Comparative Example 1 and Example 3, respectively, and the micropellets prepared according to the present invention showed uniform dissolution results compared to the case of Comparative Example 1, and were not affected by pH. Instead, the uniform elution tendency is shown.

The present invention relates to a method for producing a micropellet having a size of 150 ~ 500㎛ diameter containing an active ingredient using a fluidized bed coater, specifically, as a seed material for determining the overall size of the particles, refined sugar or lactose ( Fluidized bed coater after dissolving the film material of cellulose, polymethacrylic, polyvinylacetate-vinylpyrrolidone-based as fluconazole as an active ingredient to crystalline particles of 100 ~ 300㎛ crystalline particles such as FlowLac 100, MicroceLac 100) It relates to a method for producing a micropellet using.

Fluconazole is an antifungal agent of triazoles, which is administered in the form of tablets, capsules or intravenous injections. However, in the case of tablets or capsules, the particles are in the form of finely divided crystalline particles, which are difficult to prepare due to the compressibility and fluidity of the tablets, and in particular, in the case of capsules, it is cumbersome to fill together with fluid particles. In addition, triazoles are poorly soluble drugs and are known to be poorly absorbed by the gastrointestinal tract and have severe liver toxicity.

As a method of solving such a problem, Korean Patent No. 10-0395320 discloses a fine powder manufactured by an air spraying method and a manufacturing method thereof. This is a method of preparing a fine powder by air spraying method to prepare a fine powder by mixing the bioactive material and the coating material in a solution state and then supplying the mixed solution to the solution inlet of the air spraying device at a constant speed. This has the problem that not only the flowable surface but also the particles grow again to form crystalline particles. This is a water-soluble drug in the process of spraying the possible production have a special device, In the case of the sodium alginate one coating material injection I for insoluble drugs has possible application, however, water-soluble drugs, calcium chloride (CaCl ₂₎ solution also There is a disadvantage in that the content of the drug is very small in the melt.

In addition, Korean Patent Laid-Open Publication No. 2001-0054823 discloses a method of spray-drying itraconazole together with a water-soluble polymer and a solubilizing agent to improve the solubility of water in itracosol in water and to exhibit uniform solubility under a wide range of acidification conditions. As a method of preparing a uniform fine powder by simple spray drying, this method also grows the crystals of the drug during long-term storage, thereby reducing the uniformity of the bioavailability, and the filling into the capsule is also poor.

Korean Patent Laid-Open Publication No. 2001-0040727 also discloses a pharmaceutical composition in the form of polymeric microparticles obtained by extrusion and spheronization. This discloses a process for the preparation of a pharmaceutical composition comprising at least one polymer and at least one drug selected from the amphipathic polymer group by extrusion and spheronization techniques. Compared with this method, the production method of the present invention is better in terms of ease of preparation and filling.

In addition, International Patent Application Publication No. WO93 / 005768 discloses a drug carrier consisting of solid lipid particles-soiled lipid nanospheres (SLN), which is a drug carrier consisting of lipids or lipid-like particles, and a preparation method and a drug. The absorption mechanism relates to a method for improving drug absorption, which is completely different from the present invention. Also water-soluble, such as enteric coating bases such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, methylcellulose, sodium alginate, hydroxypropylmethylcellulose phthalate, polyethylene glycol-polypropylene glycol copolymers, etc. A method of preparing a solid dispersion after dissolving a polymer material and an effective drug is introduced as a method of solubilizing an effective drug by preparing a crystalline drug in an amorphous state, but this is to be reduced to crystalline particles in a long-term stability test. There is a possibility of growing into crystalline particles again depending on the property, which causes a decrease in the absorption rate.

In one aspect of the present invention, the crystalline particles form a network of water-soluble and water-insoluble polymers, thereby allowing effective drugs to enter the polymer network, thereby delaying and stabilizing the growth of the particles.

In order to solve the problems of the prior art as described above, an object of the present invention is to provide a micropellet and a method for producing the same, which can be easily filled into hard capsules and can be prepared into tablets by constant compression.

Another object of the present invention can be applied to various forms such as uniform absorption of drugs, securing stability of high or high hygroscopic active ingredients, solubilization of poorly soluble drugs, as well as easy to manufacture and efficient micropellets. And to provide a method for producing the same.

According to a preferred embodiment of the present invention, a micropellet composition comprising an inert core, a binder, a plasticizer and an effective drug, wherein the size of the inert core is 150 to 300 µm, and the effective drug fluconazole is 20 to 65 based on the total pellet weight. Monolayer or multilayer coated micropellets containing weight percent are provided.

According to another suitable embodiment of the present invention, the inert core may use at least one compound selected from the group consisting of white sugar, lactose, microcrystalline cellulose, lactose-microcrystalline cellulose and dextrin, and may be 10 to 10% by weight of the total pellet. 60 wt%.

According to another suitable embodiment of the present invention, the binder for coating the effective drug on the inert core may include cellulose derivatives such as hydroxymethylpropyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose and hydroxyethyl cellulose; Cured polyacrylate, polyethylene glycol, polyethylene glycol-polypropylene glycol copolymer, polyvinylpyrrolidone-vinylacetate copolymer, polymethacrylate, sodium alginate, polyvinyl alcohol, partially hydrated polyvinyl alcohol, enteric At least one compound selected from the group consisting of hydroxymethylpropyl cellulose phthalate, hydroxymethylpropyl cellulose acetylsuccinate, shellac, cellulose acetate phthalate and methacrylic copolymer (eudragit) can be used, and the whole pellet It may be included as 0.01 to 40% by weight relative to the weight.

According to another suitable embodiment of the present invention, the plasticizer may use a compound selected from the group consisting of trialkyl citrate, glycerol fatty acid derivatives, dialkyl sebacate, oleate, di, triacetin, dialkyl phthalate and castor oil. And, it may be included as 0.05 to 5% by weight relative to the total pellet weight.

According to another suitable embodiment of the present invention, the pharmaceutical composition using the prepared fluconazole-containing micropellets may be provided in the form of tablets or hard capsules.

The micropellets prepared according to the present invention are in the form of spherical particles having a diameter of 100 to 500 μm, specifically, particle sizes 150 to lactose (FlowLac 100), nonpareil, lactose crystalline cellulose (MicroceLac 80, 100), and the like. It is coated with fluconazole, an active ingredient, on a 300 µm microinert core.

Hereinafter, the present invention will be described in more detail.

In the micropellet of the present invention, the inert core is fluidized in a fluidized bed coater, and then the active ingredient fluconazole, a binder, a plasticizer, and the like are dissolved in an organic solvent and coated on the inert core.

The binder is a cellulose derivative which is a water-soluble polymer such as hydroxymethylpropyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose and hydroxyethyl cellulose, cured polyacrylate (trade name carbopol ^® ), polyethylene glycol (MW 1,500 to 8,000 ), Polyethylene glycol-polypropylene glycol copolymer (trade name poloxamer ^® ), polyvinylpyrrolidone-vinylacetate copolymer, polymethacrylate (trade name Eudragit E 100 ^® ), sodium alginate, and the like. In addition, polyvinyl alcohol or partially hydrated polyvinyl alcohol (opadry AMB ^® ) may be used to prevent the growth of the drug into crystalline particles during long-term stability testing. In addition, hydroxymethylpropyl cellulose phthalate, hydroxymethylpropyl cellulose acetylsuccinate, shellac, cellulose acetate phthalate, methacrylic copolymers (eudragit), and the like may also be used as enteric coatings.

In addition, as the plasticizers added together with the high molecular material, one or two or more selected from trialkyl citrate, glycerol fatty acid derivative, dialkyl sebacate, oleate, di or triacetin, dialkyl phthalate and castor oil, etc. are mixed. Can be used. By using a plasticizer together, the film strength of the polymer material used as the binder can be controlled to control the release rate and stability of the drug.

The micropellets prepared according to the present invention can be administered in the form of hard capsules due to their fluidity and compressibility, and can also be applied as tablets.

Fluconazole-containing micropellet formulations for oral administration of the present invention may be monolayer or optionally multi-layer coated.

Fluconazole coating as active drug on inert core

The micropellet formulation of the present invention is 20 to 50% by weight of the inert core (150 to 300㎛), 20 to 60% by weight of fluconazole, 0.3 to 30% by weight of the binder, and 0.05 to 3.5% by weight of the plasticizer. It is characterized by containing.

In the present invention, the inert core can be prepared using white sugar, lactose, microcrystalline cellulose, lactose-crystalline cellulose (MicroceLac 100), dextrin and the like.

The size of the inert core is preferably 150 to 300 µm, more preferably 150 to 200 µm. When the size of the inert core is 150 μm or less, the amount of coating is weak due to the large loss of solids in the coating solution. When the size of the inert core is 300 μm or more, the size of the finally prepared pellet is large and it is not easy to fill the hard capsule. In addition, the surface area of the pellets increases, affecting the dissolution and absorption of the effective drug.

When the binder is used in an amount of 0.5 wt% or less, the viscosity of the coating solution is low, so that the amount of coating is small and the crystallinity of the active drug is increased. When the binder is used in an amount of 30% by weight or more, the viscosity is increased, so that pellets are stuck in the middle of the coating. Thus, the amount of the solvent used to reduce the viscosity is increased, thereby lengthening the coating process.

The plasticizer has a correlation with the strength of the polymer material used, and it was observed that the degree of crystallinity varies depending on its degree. Increasing the hydrophilicity of the plasticizer increases the dissolution rate of the effective drug, the opposite was observed when the lipophilic increases. The plasticizer used is 0.05 to 3.5% by weight, and when it is 0.05% by weight or less, the pellets break during coating, which is considered to be too high. And when the plasticizer is more than 3.5% by weight, the plasticizer is excessively used, making film formation difficult.

The micropellets of the present invention may be a secondary coating to prevent moisture absorption in some cases, enteric coating is also possible.

In the coating process of the present invention, a peristaltic pump having a silicone tube (inner diameter: 6.0 mm) was used by using a fluidized coating machine of GPCG type, and a coating liquid of about 5 g was sprayed every minute, and the injection pressure was 1.2 bar. Adjusted. A, B or C type was used as the type of air spray plate, and the amount of air sprayed was adjusted to 15%. The chamber to be sprayed along the air stream was preheated. An inert core was added thereto to allow fluidization, and then the prepared coating solution was coated. The temperature of each process product was about 34-36 degreeC, and the flow rate at the time of coating was adjusted to be 5 m / sec.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples.

Example  One

Primary coating: manufacture of effective drug layer

First, 150 to 300 µm of FlowLac 100 or MicroceLac 100, 100 g as an inert core was fluidized in a fluidized bed coater, and then 150 g of fluconazole, 60 g of hydroxypropylmethylcellulose, and 6 g of polyethylene glycol 6000 were added to methylene chloride: ethanol = 1: 1 Completely dissolve in 1,200 g of mixed solvent and spray to coat the effective drug layer. However, operating conditions of the fluidized bed coater are shown in Table 1 below.

Inlet air temperature 60 ℃ Product bed temperature 35 ℃ Feeding rate 5 g / min Air flap 10% Spray nozzle pressure 1.2 bar Spray nozzle diameter 0.8mm Dispersion plate type B type

Secondary coating: Jang Sung  coating

30 g of methacryl copolymer (Eudragit) L 100 as an enteric polymer and 3 g of triethyl citrate (TEC) as a plasticizer were completely dissolved in 600 g of methylene chloride: ethanol = 1: 1 mixed solvent, 300 g of primary coated pellets were sprayed to obtain secondary coated pellets. However, the operating conditions of the fluidized bed coater follows the conditions of Table 1.

Example  2

Effective drug layer manufacturing

FlowLac 100 or MicroceLac 100, 100 g of 150 to 300 μm as an inert core was fluidized in a fluidized bed coater, and then 150 g of fluconazole, 60 g of hydroxypropyl cellulose, and 6 g of polyethylene glycol 8000 were mixed with methylene chloride: ethanol = 1: 1. It was completely dissolved in 1,200 g of solvent and then sprayed to coat the effective drug layer. However, operating conditions of the fluidized bed coater are shown in Table 1 above.

Example  3 to 10

FlowLac 100 or MicroceLac 100, 100 g of 150-300 μm as an inert core was fluidized in a fluidized bed coater, and the effective drug was then coated using the compositions and amounts shown in Table 2. The operating conditions of the fluidized bed coater are shown in Table 3 below.

Ingredient Name Example 3 4 5 6 7 8 9 10 Fluconazole 150 g 150 g 150 g 150 g 150 g 150 g 150 g 150 g Hydroxypropyl cellulose 60 g - 60 g 60 g - - - - Methylcellulose - 60 g - - - - - - Eudragit E 100 - - - - - - 30 g - Eudragit L 100 - - - - - - - 20 g Polyethylene Glycol 6000 6 g 6 g - - 20 g - - - Phloxamer F 127 - - - - - 35 g - - Triethyl citrate - - - - - - 3 g 2 g Diethyl sebacate - - 6 g - Castor Oil 4 g

Inlet air temperature 36 ℃ Product bed temperature 28 ℃ Feeding rate 5 g / min Air flap 20% Spray nozzle pressure 1.3 bar Spray nozzle diameter 0.8mm Dispersion plate type C type

Example  11

FlowLac 100 or MicroceLac 100, 100g of 150 to 300㎛ as an inert core was fluidized in a fluidized bed coater, and then 150g of fluconazole as a main component was completely dissolved in 700g of methylene chloride: ethanol = 1: 1 mixed solvent, followed by 20g of sodium alginate. After dispersing, 2 g of polyethylene glycol 6000 was dissolved to coat the effective drug layer. However, operating conditions of the fluidized bed coater are shown in Table 4 below.

Example  12

FlowLac 100 or MicroceLac 100, 100g of 150 to 300㎛ as an inert core was fluidized in a fluidized bed coater, and 150g of fluconazole as a main component was completely dissolved in 700g of methylene chloride: ethanol = 1: 1 mixed solvent, followed by Carboful 971 P After dispersing 20 g, 2 g of polyethylene glycol 6000 was dissolved to coat the effective drug layer. However, operating conditions of the fluidized bed coater are shown in Table 4 below.

Inlet air temperature 52 ℃ Product bed temperature 35 ℃ Feeding rate 4.5 g / min Air flap 20% Spray nozzle pressure 1.3 bar Spray nozzle diameter 0.8mm Dispersion plate type C type

Comparative example  One

In Comparative Example 1, 50 mg of fluconazole (Flucan Capsule, Korea United Pharmaceutical Co., Ltd.) currently produced herein was used as a control.

Experimental Example 1

The experimental example was compared with the comparative example 1 and the example in the eluent pH 1.2, 4.0, 6.8, water, the rpm was 50 and the temperature of the eluent was 37.5 ℃ by the method of the Korean Pharmacopoeia 2 method. The dissolution test results of Comparative Example 1 and Example 3 are shown in FIGS. 2A and 2B. The micropellets prepared according to the present invention showed a uniform dissolution result compared to the case of Comparative Example 1, and showed a uniform dissolution tendency without being affected by pH.

The micropellets of the present invention are manufactured by modifying various polymer materials, plasticizers, lubricants, and coating conditions used as binders by using a fluidized bed coater, thereby solving the problems of the conventional fine pellet coating.

In addition, the micropellets prepared according to the present invention are spherical particles having a diameter of 150 to 500 µm, and contain fluconazole as an active ingredient. Michaelo pellets prepared according to the present invention is prepared by a fluidized bed coater, it is easy to fill in hard capsules and contains an active ingredient in a micro pellet of a certain size, uniform drug release and excellent stability. In addition, it can be applied in various forms, such as absorption of uniform drugs, securing the stability of high or hygroscopic active ingredients, solubilization of poorly soluble drugs, and is easy to manufacture.

Claims (5)

In the fluconazole-containing micropellet composition, The composition is an inert core of 150 ~ 300㎛ size, consisting of lactose, An effective drug layer comprising 20 to 65% by weight of micropellet by weight of fluconazole, hydroxypropylmethylcellulose and polyethylene glycol, and Fluconazole-containing micropellet composition comprising an enteric coating layer comprising triethyl citrate and methacrylic copolymer. According to claim 1, wherein the inert core lactose is a micropellet composition, characterized in that it comprises 10 to 60% by weight relative to the total pellet weight. The method of claim 1, wherein the hydroxypropyl methyl cellulose, polyethylene glycol and methacrylic copolymer is a micropellet composition, characterized in that it comprises 0.01 to 40% by weight relative to the total pellet weight. According to claim 1, wherein the triethyl citrate is a micropellet composition, characterized in that 0.05 to 5% by weight relative to the total pellet weight. A pharmaceutical formulation containing fluconazole-containing micropellets prepared according to any one of claims 1 to 4.

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