WO2004112746A1 - Controlled release-drug delivery system for oral administration - Google Patents

Controlled release-drug delivery system for oral administration Download PDF

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Publication number
WO2004112746A1
WO2004112746A1 PCT/KR2004/001437 KR2004001437W WO2004112746A1 WO 2004112746 A1 WO2004112746 A1 WO 2004112746A1 KR 2004001437 W KR2004001437 W KR 2004001437W WO 2004112746 A1 WO2004112746 A1 WO 2004112746A1
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Patent type
Prior art keywords
controlled
release
oral administration
delivery system
drug delivery
Prior art date
Application number
PCT/KR2004/001437
Other languages
French (fr)
Inventor
Hai Bang Lee
Sun Hang Cho
Gilson Khang
Sang Young Jeong
Bok Ki Kang
Kwang Su Seo
Moon Suk Kim
Se Kang Chon
Original Assignee
Korea Research Institute Of Chemical Technology
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5026Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Abstract

The present invention relates to a controlled-release drug delivery system for oral administration and a composition for forming a controlled-release porous membrane employed in the system. The controlled-release drug delivery system for oral administration of the present invention comprises a core containing a pharmaceutically active ingredient; and a controlled-release porous membrane coated on the outer surface of the core comprising at least one film formation material selected from the group consisting of a cellulose based compound, polymethacrylate, an acetate based compound, polyamide, polyurethane and sulfonated polystyrene. The controlled-release drug delivery system for oral administration according to the present invention can provide an effective and consistent drug release in gastrointestinal tracts because the release rate of the drugs can be controlled. Also, the timing of drug release can be controlled by varying the thickness of the porous membrane, composition of the membrane material, amount of the plasticizer and amount of the vehicles. And, preparation of the controlled-release formulation becomes simple and cost-effective because a small amount of the porous membrane is coated on a conventional tablet or granule. In addition, since the membrane is highly stable, a controlled-release formulation for oral administration not affected by temperature or humidity can be produced in large quantities.

Description

DESCRIPTION

Invention Title

CONTROLLED RELEASE-DRUG DELIVERY SYSTEM

FOR ORAL ADMINISTRATION

Technical Field

The present invention relates to a controlled-release drug delivery system

for oral administration and a composition for forming a controlled-release porous

membrane used in the system, and more particularly to a controlled-release drug

delivery system for oral administration capable of controlling release rate of the

drug without being affected by external conditions, so that the drug can be

released in the gastrointestinal tracts effectively and consistently.

Background Art

The dug delivery rate into the body should be controlled when a drug is

absorbed too slowly and bioavailability of the drug is low or when the drug is

absorbed too quickly and is lost out of the body. For this purpose, mechanical

systems, osmosis pumps, membranous diffusion systems, systems utilizing

polymer materials that are degradable or nondegradable in the body, and so forth,

are employed alone or in combination.

U.S. Patent No. 4,752,470 discloses a controlled-release formulation

comprising a pellet coated with indomethacin as a diffusion-controlled osmosis

control system using an osmotiά membrane. The pellet comprises a non-pareil

bead supporting indomethacin and a binder and is coated with a water-insoluble

film comprising a mixture of hydroxypropyl cellulose, ethyl cellulose and a plasticizer. In this patent, drug release is controlled by the proportion of ethyl

cellulose to hydroxypropyl cellulose, that is, by adding water-soluble polymer

materials to the water-insoluble film.

U.S. Patent No. 4,892,741 discloses a medicament preparation

comprising a core which contains a dihydropyridine in rapid-release form, for

example nifedipine, nitrendipine, nimodipine or nisoldipine, which has low

aqueous solubility, and a coat containing a dihydropyridine in sustained-release

form. When this preparation is put in an aqueous environment, the swelling

layer swells and the drug is released rapidly. As a result, the release amount

becomes relatively excessive at the beginning and decreases with time, so that it

is difficult to obtain a consistent zero-order release rate.

U.S. Patent No. 4,971 ,790 discloses an osmotic administration system

using a semi-permeable membrane. The semi-permeable membrane has at

least one outlet path penetrating the membrane and surrounds a core containing

an osmotic agent, a neutral hydrogel, an ionic hydrogel and a drug. Because the

membrane is permeable to water, water transfers to the core through the semi¬

permeable membrane. The water dissolves the hydrogel and the internal

pressure increases because of ionization of the osmotic agent. As a result, the

drug is released out of the dissolved ionic hydrogel containing the drug, the

hydrogel and other constituents by the pressure through the path.

U.S. Patent No. 6,046,177 discloses a drug delivery system for oral

administration comprising a core, in which two layers aiding release of the drug

are positioned above and below a layer containing therapeutic ingredients, and a semi-permeable membrane. This system is limited in that the rapid-release

layer and the sustained-release layer of the drug layer should be prepared

separately. Also, the core and the drug layer surrounding it should be prepared

separately.

U.S. Patent Nos. 6,110,500 and 6,126,956 disclose a system comprising

a core having a donut-like configuration with a cylindrical hole extending through

the center of the core. The core is prepared by mixing a water-soluble

pharmaceutical ingredient, a water-soluble polymeric carrier, etc. and is coated

with an inactive material covering the entire core except that which is defined by

the cylindrical hole. In this system, the water-soluble drug is released

consistently through the cylindrical hole when exposed to an aqueous

environment. Although this system provides an effective zero-order, linear drug

release, it is applicable only to water-soluble drugs.

U.S. Patent No. 6,030,641 discloses a sustained-release capsule in

which an outer surface of a hard gelatin capsule is coated with a polymer material

enabling sustained release. However, while the capsule is coated with the

polymer material, incomplete coating at the cap part or curved part of the capsule

may cause excessive release of drug. As a result, a particular care should be

taken in the coating process.

U.S. Patent No. 6,190,692 discloses a time-specific drug delivery system.

This drug delivery system comprises a core including a pharmaceutically active

agent and a swellable polymeric coating layer surrounding the core. In the drug

delivery system, the drug is released as the surface of the swellable coating layer is eroded. However, because the degree of erosion of the swellable polymer

varies greatly depending on the pH, the drug delivery tends not to be attained at

the right time.

Korean Laid-Open Publication No. 1997-032869 discloses a diltiazem-

containing pellet formulation for daily administration, which has a multiple

membrane structure comprising multiple membranes in which the drug is

contained and a pseudo matrix membrane, and a preparation method thereof. In

this patent, a pseudo matrix membrane comprising a diltiazem-containing layer

and a water-soluble or water-insoluble polymer is formed on a core or a granule.

The membrane is present at 5 to 30 %. If the portion of the membrane is below

5 %, controlled release of the drug is impossible. Otherwise, if it exceeds 30 %,

the drug is not released.

Korean Laid-Open Publication No. 2000-69800 discloses a method of

preparing a porous matrix type controlled-release formulation by the emulsion

method. That is, after a drug-containing aqueous solution is dispersed in an

organic solvent dissolving a polymer compound and a surfactant, the solution is

stirred to obtain an emulsion. Then, the emulsion is prepared into a wanted

matrix form and dried at room temperature or lyophilized to obtain a porous matrix.

This method has disadvantages in uniformity of the membrane, stability of the

resultant polymer membrane or enlarged pore size.

Disclosure

Technical Problem

It is an aspect of the present invention to provide a controlled-release drug delivery system for oral administration capable of effectively and consistently

controlling drug release and a composition for forming a controlled-release porous

membrane used in the system.

Technical Solution

To attain the aspect, the present invention provides a controlled-release

drug delivery system for oral administration comprising a core containing a

pharmaceutically active ingredient; and a controlled-release porous membrane

coated on the outer surface of the core and containing at least one film formation

material selected from the group consisting of a cellulose based compound,

polymethacryiate or a derivative thereof, polyamide, polyurethane and sulfonated

polystyrene.

Advantageous Effects

The controlled-release drug delivery system for oral administration

according to the present invention can provide effective and consistent drug

release in gastrointestinal tracts because the release rate of the drugs can be

controlled. Also, the timing of drug release can be controlled by varying the

thickness of the porous membrane, composition of the membrane material,

amount of the plasticizer and amount of the vehicles. And, preparation of the

controlled-release formulation becomes simple and cost-effective because a

small amount of the porous membrane is coated on a conventional tablet or

granule. In addition, since the membrane is highly stable, a controlled-release

formulation for oral administration that is not affected by temperature or humidity

can be produced in large quantity. Brief Description of Drawings

FIG. 1 is a schematic diagram illustrating the controlled-release drug

delivery system for oral administration of the present invention.

FIG. 2 shows the tendency of drug release with time of the controlled-

release drug delivery system for oral administration of the present invention

containing nifedipine, a hardly soluble drug, prepared according to Examples 1 to

4.

FIG. 3 shows the tendency of drug release with time of the controlled-

release drug delivery system for oral administration of the present invention

containing doxazosin mesylate, a water-soluble drug, prepared according to

Examples 5 to 8.

FIG. 4 shows the tendency of drug release with time of the nifedipine-

containing controlled-release drug delivery system for oral administration of the

present invention prepared according to Example 9 at different releaser paddle

speeds.

FIG. 5 shows the tendency of drug release with time of the nifedipine-

containing controlled-release drug delivery system for oral administration of the

present invention prepared according to Example 10 at different releaser paddle

speeds.

FIG. 6 shows the tendency of drug release with time of the nifedipine-

containing controlled-release drug delivery system for oral administration of the

present invention prepared according to Example 11 at different releaser paddle

speeds. FIG. 7 compares the tendency of drug release with time of the nifedipine-

containing controlled-release drug delivery system for oral administration of the

present invention prepared according to Examples 9 to 11 with that of

Comparative Example 1.

Best Mode

As illustrated in FIG. 1 , which shows an embodiment of the present

invention, the core of the controlled-release drug delivery system for oral

administration of the present invention 1 may comprise a crystalline core material

a; a moisture absorption promoting layer b coated on the outer surface of the

crystalline core material and containing a pharmaceutically available moisture

absorption promoting material; and an active ingredient layer c coated on the

outer surface of the moisture absorption promoting layer and containing a

pharmaceutically active ingredient.

For the crystalline core material, a crystalline material such as sugar and

non-pareil prepared from sugar may be used. The pellet size may be

determined according to the size of the crystalline core material. Preferably, the

crystalline core material has a diameter ranging from 50 to 825 μm. If the

diameter of the crystalline core material is smaller than 50 μm, the core materials

may coagulate during coating, so that it is difficult to obtain a uniform coat.

Otherwise, if it is larger than 825 μm, the resultant system may become larger

than wanted and the fluidity problem may occur.

The pharmaceutically available moisture absorption promoting material

increases the rate of absorption of the aqueous solution. Any material known for performing such role can be used as the pharmaceutically available moisture

absorption promoting material. Typical examples are salts, saccharides, urea

and tartaric acid. The salts may include sodium chloride, potassium chloride,

magnesium chloride, potassium sulfate, sodium sulfate, magnesium sulfate,

calcium bicarbonate, etc. and the saccharides may include mannitol, glucose,

lactose, fructose, sucrose, etc.

The drug release rate may be controlled by the amount of the

pharmaceutically available moisture absorption promoting material or by the kind

and composition of the moisture absorption promoting material. This is possible

due to the difference in the rate of moisture absorption. The moisture absorption

promoting layer is formed on the crystalline core material using a coater. The

pellet form is maintained after the moisture absorption promoting layer has been

formed. Preferably, the resultant pellet has a diameter ranging from 70 to 1500

μm. If the pellet size falls outside the range, filling may become difficult or fluidity

of the granule may decrease during coating.

For the pharmaceutically active ingredient, doxazosin mesylate, ambroxol

hydrochloride, albuterol hydrochloride, theophylline, acetoaminophen,

methylphenidate, hydromorphon, glipizide, nifedipine, simvastatin, nitrendipine,

lovastatin, prazocin, isradipine, metoprolol, oxybutynin, diltiazem, enalapril,

verapamil, etc. may be used.

The pharmaceutically active ingredient is comprised in 0.1 to 90 wt% per

100 wt% of the controlled-release drug delivery system for oral administration of

the present invention. If the content of the pharmaceutically active ingredient is below 0.1 wt%, the amount of the pellet should be increased because the

concentration of the active ingredient is too low. Otherwise, if it exceeds 90 wt%,

control of sustained release becomes difficult.

The active ingredient layer may further comprise a binder. For the

binder, at least one member selected from the group consisting of a cellulose

derivative containing water-swellable and/or water-soluble

hydroxypropyimethylcellulose and polyvinylpyrrolidone may be used. The binder

is comprised in 50 wt% or less per 100 wt% of the pharmaceutically active

ingredient. If the content exceeds 50 wt%, the coating solution becomes so

viscous that it is not transferred well and drying becomes incomplete so that the

granules may coagulate.

The active ingredient layer may further comprise a pharmaceutically

available water-soluble polymer. For the water-soluble polymer, at least one

member selected from the group consisting of polyvinylpyrrolidone, polyethylene

glycol, hydroxypropyimethylcellulose and hydroxypropylcellulose may be used.

The water-soluble polymer is comprised in 50 wt% or less per 100 wt% of the

pharmaceutically active ingredient.

The active ingredient layer may further comprise a pharmaceutically

available additive. For the additive, a vehicle, a lubricant such as talc, a pigment,

a sweetener, etc. may be used, as required. Also, a disperser, an emulsifier, a

wetting agent or a dye may be added. For example, lactose, magnesium

stearate, microcrystalline cellulose, starch, stearic acid, calcium phosphate,

glycerol monostearate, sucrose, polyvinylpyrrolidone, gelatin, methyl cellulose, sodium carboxymethyl cellulose, sorbitol, mannitol, polyethylene glycol or other

ingredients used as stabilizer or commonly used in drug formulations may be

added. The additive may be comprised in 0 to 80 wt%, as required.

Preferably, the core on which the active ingredient layer has been formed

has a pellet form and the pellet has a diameter ranging from 90 to 2,000 μm.

The controlled-release porous membrane formed on the outer surface of

the active ingredient layer comprises at least one film formation material selected

from the group consisting of a cellulose based compound, polymethacryiate, an

acetate based compound, polyamide, polyurethane and sulfonated polystyrene.

For the cellulose based compound, a member selected from the group

consisting of unplasticized cellulose acetate, plasticized cellulose triacetate,

triacetate cellulose, acetate ethyl cabamate, cellulose acetate phthalate, cellulose

acetate methyl cabamate, cellulose acetate succinate, cellulose acetate dimethyl

aminoacetate, cellulose acetate ethyl carbonate, cellulose acetate methyl

sulfonate, cellulose acetate butyl sulfonate, cellulose ether, cellulose acetate

propionate, cellulose acetate octate, cellulose acetate laurate and cellulose

acetate having methyl cellulose and acetylated hydroxyethyl cellulose may be

used.

Preferably, the film formation material is comprised in 0.1 to 50 parts by

weight, more preferably in 0.1 to 30 parts by weight, and most preferably in 0.1 to

1 part by weight, per 100 parts by weight of the core. If the content of the film

formation material is below 0.1 part by weight per 100 parts by weight of the core,

the membrane is not obtained because the film is not formed. Otherwise, if it exceeds 50 parts by weight, the drug is not released.

The film formation material comprises cellulose acetate and

polymethacryiate in 9 to 1 :1 to 9 by weight.

For the polymethacryiate, commercially available Eudragit E, Eudragit L,

Eudragit S, Eudragit RL, Eudragit RS, Eudragit NE30D, Eudragit FS, Eudragit FD,

etc. may be used.

For the acetate based compound, agar acetate, amylose triacetate, β-

glucan acetate, etc. may be used.

The film formation material may further comprise a plasticizer and/or a

disintegrant.

For the plasticizer, polyethylene glycol, glycerol, a glycerol derivative, a

fatty acid citrate derivative, etc. may be used. And, for the disintegrant, sodium

starch glycolide, calcium-carboxylmethylcellulose, a fatty acid glycol derivative,

etc. may be used.

Preferably, the system maintains a pellet form after the controlled-release

porous membrane has been formed, and the pellet has a diameter ranging from

100 to 2,200 μm.

The plasticizer and the disintegrant comprising the controlled-release

drug delivery system for oral administration of the present invention are released

from the membrane in an aqueous solution or a body fluid (gastric juice, intestinal

juice, etc.) to form pores at the sustained-release layer. Then, the drug is

released by passing through the pores by diffusion.

In the controlled-release drug delivery system for oral administration of the present invention, the process of preparing the core containing the

pharmaceutically active ingredient into the controlled-release porous membrane

may be performed by a general coating method using a commonly used solvent.

For the solvent, at least one of the groups consisting of ethanol, acetone, water,

etc. may be used.

The present invention also provides a composition for forming a

controlled-release porous membrane for preparing the controlled-release drug

delivery system for oral administration.

The composition for forming a controlled-release porous membrane

comprises at least one film formation material selected from the group consisting

of a cellulose based compound, polymethacryiate, an acetate based compound,

polyamide, polyurethane and sulfonated polystyrene.

For the cellulose based compound, a member selected from the group

consisting of unplasticized cellulose acetate, plasticized cellulose triacetate,

triacetate cellulose, acetate ethyl cabamate, cellulose acetate phthalate, cellulose

acetate methyl cabamate, cellulose acetate succinate, cellulose acetate dimethyl

aminoacetate, cellulose acetate ethyl carbonate, cellulose acetate methyl

sulfonate, cellulose acetate butyl sulfonate, cellulose ether, cellulose acetate

propionate, cellulose acetate octate, cellulose acetate laurate and cellulose

acetate having methyl cellulose and acetylated hydroxyethyl cellulose may be

used.

The film formation material comprises cellulose acetate and

polymethacryiate in 9 to 1 :1 to 9 by weight. For the polymethacryiate, commercially available Eudragit E, Eudragit L,

Eudragit S, Eudragit RL, Eudragit RS, Eudragit NE30D, Eudragit FS, Eudragit FD,

etc. may be used.

For the acetate based compound, agar acetate, amylose triacetate, β-

glucan acetate, etc. may be used.

The composition for forming a controlled-release porous membrane of

the present invention may further comprise a plasticizer and/or a disintegrant.

For the plasticizer, polyethylene glycol, glycerol, a glycerol derivative, a

fatty acid citrate derivative, etc. may be used. Preferably, the plasticizer is

comprised in 1 to 40 parts by weight per 100 parts by weight of the composition

for forming a controlled-release porous membrane.

For the disintegrant, sodium starch glycolide, calcium-

carboxylmethylcellulose, a fatty acid glycol derivative, etc. may be used.

Preferably, the disintegration agent is comprised in 0.1 to 10 parts by weight per

100 parts by weight of the composition for forming a controlled-release porous

membrane.

Mode for Invention

Hereinafter, the present invention is described in more detail through

examples. However, the following examples are only for the understanding of

the present invention and they do not limit the present invention.

1. Single-layered coating

<Example 1>

0.61 wt% of cellulose acetate, 0.41 wt% of Eudragit RL, 0.41 wt% of polyethylene glycol, 0.41 wt% of glycerol, 0.41 wt% of

hydroxypropyimethylcellulose, 0.51 wt% of water, 5.12 wt% of ethanol, 51.2 wt%

of acetone, 0.06 wt% of triethylcitrate and 0.2 wt% of sodium starch glycolide

were mixed to prepare a composition for forming a controlled-release porous

membrane.

40.66 wt% of a pellet core containing hardly soluble nifedipine was

coated with the composition using a fluid bed coater to prepare a controlled-

release drug delivery system for oral administration. The coating condition was:

spray air pressure = 1.65 psi, outlet air temperature = 28 °C , inlet air temperature

= 38 °C, flow rate = 12 and outlet air ratio = 37 %.

<Example 2>

3 wt% of cellulose acetate, 2 wt% of Eudragit RL, 0.4 wt% of

polyethylene glycol, 0.4 wt% of glycerol, 0.4 wt% of hydroxypropyimethylcellulose,

0.51 wt% of water, 4.1 wt% of ethanol, 48.1 wt% of acetone, 0.09 wt% of

triethylcitrate and 0.2 wt% of sodium starch glycolide were mixed to prepare a

composition for forming a controlled-release porous membrane.

40.66 wt% of a pellet core containing hardly soluble nifedipine was

coated with the composition using a fluid bed coater to prepare a controlled-

release drug delivery system for oral administration, as in Example 1.

<Example 3>

6 wt% of cellulose acetate, 4 wt% of Eudragit RL, 0.41 wt% of

polyethylene glycol, 0.4 wt% of glycerol, 0.41 wt% of

hydroxypropyimethylcellulose, 0.2 wt% of water, 3.12 wt% of ethanol, 45.2 wt% of acetone, 0.06 wt% of triethylcitrate and 0.2 wt% of sodium starch glycolide were

mixed to prepare a composition for forming a controlled-release porous

membrane.

40.66 wt% of a pellet core containing hardly soluble nifedipine was

coated with the composition using a fluid bed coater to prepare a controlled-

release drug delivery system for oral administration, as in Example 1.

<Example 4>

0.3 wt% of cellulose acetate, 0.2 wt% of Eudragit RL, 0.41 wt% of

polyethylene glycol, 0.41 wt% of glycerol, 0.41 wt% of

hydroxypropyimethylcellulose, 0.51 wt% of water, 5.22 wt% of ethanol, 51.6 wt%

of acetone, 0.06 wt% of triethylcitrate and 0.2 wt% of sodium starch glycolide

were mixed to prepare a composition for forming a controlled-release porous

membrane.

40.66 wt% of a pellet core containing hardly soluble nifedipine was

coated with the composition using a fluid bed coater to prepare a controlled-

release drug delivery system for oral administration, as in Example 1.

<Example 5>

0.3 wt% of cellulose acetate, 0.2 wt% of Eudragit RL, 0.41 wt% of

polyethylene glycol, 0.41 wt% of glycerol, 0.41 wt% of

hydroxypropyimethylcellulose, 0.51 wt% of water, 5.22 wt% of ethanol, 51.6 wt%

of acetone, 0.06 wt% of triethylcitrate and 0.2 wt% of sodium starch glycolide

were mixed to prepare a composition for forming a controlled-release porous

membrane. 40.66 wt% of a pellet core containing water-soluble doxazosin mesylate

was coated with the composition using a fluid bed coater to prepare a controlled-

release drug delivery system for oral administration, as in Example 1.

<Example 6>

A controlled-release drug delivery system for oral administration was

prepared as in Example 1 , except for using a pellet core containing water-soluble

doxazosin mesylate as the pharmaceutically active ingredient.

<Example 7>

A controlled-release drug delivery system for oral administration was

prepared as in Example 2, except for using a pellet core containing water-soluble

doxazosin mesylate as the pharmaceutically active ingredient.

<Example 8>

A controlled-release drug delivery system for oral administration was

prepared as in Example 3, except for using a pellet core containing water-soluble

doxazosin mesylate as the pharmaceutically active ingredient.

2. Multi-layered coating

<Example 9>

1) First coating of moisture absorption promoting layer

A moisture absorption promoting layer composition was added to a fluid

bed coater containing 3.96 wt% of sugar. A first moisture absorption promoting

layer was formed on the outer surface of sugar. The moisture absorption

promoting composition was prepared by dissolving and dispersing 17.96 wt% of

lactose, 3.56 wt% of hydroxypropyimethylcellulose, which is a binder, and 0.32 wt% of polyethylene glycol, which is a plasticizer, in a solvent comprising 20.8

wt% of distilled water, 29.7 wt% of acetone and 23.7 wt% of ethanol. The

coating condition was: spray air pressure = 1.45 psi, outlet air temperature =

29 °C , inlet air temperature = 38 °C , flow rate = 10 and outlet air ratio = 35 %.

2) Second coating of active ingredient layer

10.2 wt% of the pellet on which the moisture absorption promoting layer

had been formed was put in a fluid bed coater and the second coating was

performed with an active ingredient layer composition. The active ingredient

layer composition was prepared by mixing 13.67 wt% of lactose, 3.58 wt% of

nifedipine, 0.7 wt% of hydroxypropyimethylcellulose, which is a binder, 3.58 wt%

of fructose, 0.05 wt% of polyethylene glycol, 19.1 wt% of distilled water, 34.82

wt% of acetone and 14.3 wt% of ethanol. The coating condition was: spray air

pressure = 1.55 psi, outlet air temperature = 35.9 °C, inlet air temperature = 53 °C,

flow rate = 12 and outlet air ratio = 37 %.

3) Third coating of controlled-release porous membrane

40.8 wt% of the pellet on which the second coat had been coated was

coated with a controlled-release porous membrane composition. The sustained-

release composition was prepared by mixing 0.61 wt% of cellulose acetate, 0.41

wt% of Eudragit RL, 0.41 wt% of polyethylene glycol, 0.41 wt% of glycerol, 0.41

wt% of hydroxypropyimethylcellulose, 0.51 wt% of water, 5.1 wt% of ethanol,

51.08 wt% of acetone, 0.06 wt% of triethylcitrate and 0.2 wt% of sodium starch

glycolide. The coating condition was: spray air pressure = 1.65 psi, outlet air

temperature = 28 °C, inlet air temperature = 38 °C , flow rate = 12 and outlet air ratio = 37 %.

<Example 10>

A moisture absorption promoting layer and an active ingredient layer

were formed in the same manner as in Example 9. The third coating of

controlled-release porous membrane was performed by coating a controlled-

release porous composition prepared by mixing 0.495 wt% of cellulose acetate,

0.495 wt% of Eudragit RL, 0.41 wt% of polyethylene glycol, 0.41 wt% of glycerol,

0.41 wt% of hydroxypropyimethylcellulose, 0.51 wt% of water, 5.1 wt% of ethanol,

51.08 wt% of acetone, 0.09 wt% of triethylcitrate and 0.2 wt% of sodium starch

glycolide on 40.8 wt% of the coated pellet.

<Example 11>

A moisture absorption promoting layer and an active ingredient layer

were formed in the same manner as in Example 9. The third coating of

controlled-release porous membrane was performed by coating a controlled-

release porous composition prepared by mixing 0.87 wt% of cellulose acetate,

0.87 wt% of Eudragit RL, 0.4 wt% of polyethylene glycol, 0.4 wt% of glycerol, 0.4

wt% of hydroxypropyimethylcellulose, 0.51 wt% of water, 11.67 wt% of isopropyl

alcohol, 43.75 wt% of acetone, 0.13 wt% of triethylcitrate and 0.2 wt% of sodium

starch glycolide on 40.8 wt% of the coated pellet.

Experimental Example 1 >

Each controlled-release drug delivery system for oral administration

prepared according to Examples 1 to 8 was analyzed with HPLC under the

following conditions. The results are shown in FIGs. 2 and 3. Mobile phase: water/methanol/methyl cyanide = 1/1/1 by volume

Column: ODS-C18, 250 x 4.6 mm, 5 μm

Flow rate: 1.0 mL/min

Detector: 235 nm

Eluting condition: 1 %-SDS (sodium lauryl sulfate) solution, 900mL

As seen in FIGs. 2 and 3, the drug release rate could be controlled by

varying the content of the film formation material. That is, the drug release rate

decreased with time as the content of the film formation material increased to give

a linear graph.

Experimental Example 2>

Each nifedipine-containing multi-layered granule prepared according to

Examples 9 to 11 was analyzed under the same condition of Experimental

Example 1. Because activity in the stomach and the intestine is dependent on

the patient, the release rate was determined by varying the paddle stirring rate of

the releaser to 50 rpm, 100 rpm and 150 rpm. The result for Example 9 is shown

in FIG. 4, that of Example 10 in FIG. 5 and that of Example 11 in FIG. 6. As

seen in FIGs. 4 to 6, the granules prepared according to Example 9 to 11 showed

superior drug release efficiency without regard to the stirring rate.

The drug release rate for the conventional commercially available tablet

(Adalat, Comparative Example 1) was compared with those of Examples 9 to 11

in FIG. 7. As seen in FIG. 7, the initial release for the first two hours was

superior in Example 9, but there was little initial drug release in Comparative

Example 1. And, although the drug release was almost linear with time for Comparative Example 1 , the initial drug release could not be controlled.

However, the drug release pattern for Examples 10 and 1 1 could be controlled.

As described in detail above, the controlled-release drug delivery system

for oral administration prepared using the composition for forming a controlled-

release porous membrane according to the present invention can provide

effective and consistent drug release in gastrointestinal tracts because the

release rate of drugs can be controlled. Also, the timing of drug release can be

controlled by varying the thickness of the porous membrane, composition of the

membrane material, amount of the plasticizer and amount of the vehicle. And,

preparation of the controlled-release formulation becomes simple and cost-

effective because a small amount of the porous membrane is coated on a

conventional tablet or granule. In addition, since the membrane is highly stable,

a controlled-release formulation for oral administration not affected by

temperature or humidity can be produced in large quantities.

Industrial Applicability

The present invention relates to a controlled-release drug delivery system

for oral administration and a composition for forming a controlled-release porous

membrane employed in the system. The controlled-release drug delivery system

for oral administration of the present invention comprises a core containing a

pharmaceutically active ingredient; and a controlled-release porous membrane

coated on the outer surface of the core comprising at least one film formation

material selected from the group consisting of a cellulose based compound,

polymethacryiate, an acetate based compound, polyamide, polyurethane and sulfonated polystyrene. The controlled-release drug delivery system for oral

administration prepared using the composition for forming a controlled-release

porous membrane according to the present invention can provide effective and

consistent drug release in gastrointestinal tracts because the release rate of

drugs can be controlled. Also, the timing of drug release can be controlled by

varying the thickness of the porous membrane, composition of the membrane

material, amount of the plasticizer and amount of the vehicle. And, preparation

of the controlled-release formulation becomes simple and cost-effective because

a small amount of the porous membrane is coated on a conventional tablet or

granule. In addition, since the membrane is highly stable, a controlled-release

formulation for oral administration not affected by temperature or humidity can be

produced in large quantities.

While the present invention has been described in detail with reference to

the preferred embodiments, those skilled in the art will appreciate that various

modifications and substitutions can be made thereto without departing from the

spirit and scope of the present invention as set forth in the appended claims.

Claims

1. A controlled-release drug delivery system for oral administration
comprising a core containing a pharmaceutically active ingredient; and a
controlled-release porous membrane coated on the outer surface of the core and
comprising at least one film formation material selected from the group consisting
of a cellulose based compound, polymethacryiate, an acetate based compound,
semi-permeable polyamide, semi-permeable polyurethane and semi-permeable
sulfonated polystyrene.
2. The controlled-release drug delivery system for oral administration of
claim 1 , wherein the core comprises a crystalline core material; a moisture
absorption promoting layer coated on the outer surface of the crystalline core
material and containing a pharmaceutically available moisture absorption
promoting material; and an active ingredient layer coated on the outer surface of
the moisture absorption promoting layer and containing a pharmaceutically active
ingredient.
3. The controlled-release drug delivery system for oral administration of
claim 2, wherein the crystalline core material is sugar or non-pareil prepared
using sugar.
4. The controlled-release drug delivery system for oral administration of
claim 2, wherein the moisture absorption promoting material is selected from the
group consisting of a salt, a saccharide, urea and tartaric acid.
5. The controlled-release drug delivery system for oral administration of
claim 4, wherein the salt is selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, potassium sulfate, sodium sulfate,
magnesium sulfate and calcium bicarbonate.
6. The controlled-release drug delivery system for oral administration of
claim 4, wherein the saccharide is selected from the group consisting of mannitol,
lactose, fructose, glucose and sucrose.
7. The controlled-release drug delivery system for oral administration of
claim 2, wherein the active ingredient layer further comprises a pharmaceutically
available water-soluble polymer.
8. The controlled-release drug delivery system for oral administration of
claim 7, wherein the water-soluble polymer is selected from the group consisting
of polyvinylpyrrolidone, polyethylene glycol, hydroxypropyimethylcellulose and
hydroxypropylcellulose.
9. The controlled-release drug delivery system for oral administration of
claim 1 or claim 2, wherein the pharmaceutically active ingredient is selected from
the group consisting of doxazosin mesylate, ambroxol hydrochloride, albuterol
hydrochloride, theophylline, acetoaminophen, methylphenidate, hydromorphon,
glipizide, nifedipine, simvastatin, nitrendipine, lovastatin, prazocin, isradipine,
metoprolol, oxybutynin, diltiazem, enalapril and verapamil.
10. The controlled-release drug delivery system for oral administration of
claim 1, wherein the cellulose based compound is selected from the group
consisting of unplasticized cellulose acetate, plasticized cellulose triacetate,
triacetate cellulose acetate ethyl cabamate, cellulose acetate phthalate, cellulose
acetate methyl cabamate, cellulose acetate succinate, cellulose acetate dimethyl aminoacetate, cellulose acetate ethyl carbonate, cellulose acetate methyl
sulfonate, cellulose acetate butyl sulfonate, cellulose ether, cellulose acetate
propionate, cellulose acetate octate, cellulose acetate laurate, and cellulose
acetate having methyl cellulose and acetylated hydroxyethyl cellulose.
11. The controlled-release drug delivery system for oral administration of
claim 1, wherein the film formation material is comprised in 0.1 to 50 parts by
weight per 100 parts by weight of the core.
12. The controlled-release drug delivery system for oral administration of
claim 1 or claim 1 1 , wherein the film formation material comprises cellulose
acetate and polymethacryiate.
13. The controlled-release drug delivery system for oral administration of
claim 12, wherein the film formation material comprises 9 to 1 :1 to 9 of cellulose
acetate and polymethacryiate by weight.
14. The controlled-release drug delivery system for oral administration of
claim 12, wherein the film formation material further comprises a plasticizer and/or
a disintegrant.
15. The controlled-release drug delivery system for oral administration of
claim 14, wherein the plasticizer is selected from the group consisting of
polyethylene glycol, glycerol, a glycerol derivative and a fatty acid citrate
derivative.
16. The controlled-release drug delivery system for oral administration of
claim 14, wherein the disintegrant is selected from the group consisting of sodium
starch glycolide, calcium-carboxylmethylcellulose and a fatty acid glycol derivative.
17. A composition for forming a controlled-release porous membrane for
a drug delivery system for oral administration comprising at least one film
formation material selected from the group consisting of a cellulose based
compound, polymethacryiate, an acetate based compound, semi-permeable
polyamide, semi-permeable polyurethane and semi-permeable sulfonated
polystyrene.
18. The composition for forming a controlled-release porous membrane
for a drug delivery system for oral administration of claim 17, wherein the
cellulose based compound is selected from the group consisting of unplasticized
cellulose acetate, plasticized cellulose triacetate, triacetate cellulose acetate ethyl
cabamate, cellulose acetate phthalate, cellulose acetate methyl cabamate,
cellulose acetate succinate, cellulose acetate dimethyl aminoacetate, cellulose
acetate ethyl carbonate, cellulose acetate methyl sulfonate, cellulose acetate
butyl sulfonate, cellulose ether, cellulose acetate propionate, cellulose acetate
octate, cellulose acetate laurate, and cellulose acetate having methyl cellulose
and acetylated hydroxyethyl cellulose.
19. The composition for forming a controlled-release porous membrane
for a drug delivery system for oral administration of claim 17, wherein the film
formation material comprises cellulose acetate and polymethylmethacrylate.
20. The composition for forming a controlled-release porous membrane
for a drug delivery system for oral administration of claim 19, wherein the film
formation material comprises 9 to 1:1 to 9 of cellulose acetate and
polymethylmethacrylate by weight.
21. The composition for forming a controlled-release porous membrane
for a drug delivery system for oral administration of claim 19, which further
comprises a plasticizer and/or a disintegrant.
22. The composition for forming a controlled-release porous membrane
for a drug delivery system for oral administration of claim 21 , wherein the
plasticizer is selected from the group consisting of polyethylene glycol, glycerol, a
glycerol derivative and a fatty acid citrate derivative.
23. The composition for forming a controlled-release porous membrane
for a drug delivery system for oral administration of claim 21, wherein the
disintegrant is selected from the group consisting of sodium starch glycolide,
calcium-carboxylmethylcellulose and a fatty acid glycol derivative.
PCT/KR2004/001437 2003-06-26 2004-06-16 Controlled release-drug delivery system for oral administration WO2004112746A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
KR20030042015A KR100527335B1 (en) 2003-06-26 2003-06-26 Sustained release drug delivery system
KR10-2003-0042015 2003-06-26
KR20030057918A KR100601249B1 (en) 2003-08-21 2003-08-21 Composition for producing controllable porous membrane of oral drug delivery system
KR10-2003-0057918 2003-08-21

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2006515340T JP2007520421A (en) 2003-06-26 2004-06-16 Controlled release drug delivery systems for oral administration

Publications (1)

Publication Number Publication Date
WO2004112746A1 true true WO2004112746A1 (en) 2004-12-29

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Country Status (2)

Country Link
JP (1) JP2007520421A (en)
WO (1) WO2004112746A1 (en)

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EP2057984A1 (en) * 2007-11-09 2009-05-13 Acino Pharma AG Retard tablets with hydromorphon
US7833548B2 (en) * 2002-06-18 2010-11-16 Surmodics, Inc. Bioactive agent release coating and controlled humidity method
US8795730B2 (en) 2006-01-31 2014-08-05 David John Vachon Compositions and methods for promoting the healing of tissue of multicellular organisms
US9446226B2 (en) 2005-12-07 2016-09-20 Ramot At Tel-Aviv University Ltd. Drug-delivering composite structures

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7833548B2 (en) * 2002-06-18 2010-11-16 Surmodics, Inc. Bioactive agent release coating and controlled humidity method
US9446226B2 (en) 2005-12-07 2016-09-20 Ramot At Tel-Aviv University Ltd. Drug-delivering composite structures
WO2007072060A2 (en) * 2005-12-23 2007-06-28 Cipla Limited Particles comprising a core containing a hmg-coa reductase inhibitor and coated with a film
WO2007072060A3 (en) * 2005-12-23 2008-03-27 Cipla Ltd Particles comprising a core containing a hmg-coa reductase inhibitor and coated with a film
US8795730B2 (en) 2006-01-31 2014-08-05 David John Vachon Compositions and methods for promoting the healing of tissue of multicellular organisms
EP2057984A1 (en) * 2007-11-09 2009-05-13 Acino Pharma AG Retard tablets with hydromorphon
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