WO2004050064A1

WO2004050064A1 - Method of manufacturing controlled release formulation using pelletizer

Info

Publication number: WO2004050064A1
Application number: PCT/KR2003/000660
Authority: WO
Inventors: Ung Kil Jee; Sung Joo Hwang; Jin Kyu Park; Kyung Lae Park; Young Girl Moon; Si Beum Lee; Yong Jin Kwon
Original assignee: Centurion Inc
Current assignee: Centurion Inc
Priority date: 2002-11-29
Filing date: 2003-04-02
Publication date: 2004-06-17
Anticipated expiration: 2005-05-29
Also published as: KR20040047347A; KR100510270B1; AU2003219575A1

Abstract

Disclosed is a method of manufacturing a controlled release formulation by use of a pelletizer, including the steps of extruding a drug-containing combination to a filament, and molding the filament to a pellet. The combination having suitable ductility is obtained by dissolving at least a drug and a hydrophilic polymer or a surfactant for use in assisting dissolution of the drug in a solvent, to form a mixture, and combining the mixture with an inert diluent and/or a dissolution inhibitor. The method is advantageous in that drug loss during production of the formulation is prevented, whereby the formulation having a uniform amount of the drug can be produced.

Description

METHOD OF IVTANUFACTURING CONTROLLED RELEASE FORMULATION

USING PELLETIZER

Technical Field

The present invention relates, in general, to methods of manufacturing a controlled release formulation using a pelletizer, and more specifically, to a preparation method of a pellet-shaped controlled release formulation containing a drug, characterized in that a pellet having a desired size can be produced using an extruding process and a pelletizing process, whereby an amount of the drug in the formulation is maintained at a predetermined level or more, and as well release properties of the drug can be controlled. Generally, the drug may be widely used in various amounts according to purposes.

In the present invention, since the drug should be accurately administered in a very small amount to humans, drug loss should be minimized during preparation of the formulation. Meanwhile, the drug may be administered in a large amount in some cases.

Background Art

Hereinafter, problems related to conventional controlled release formulations are discussed with the use of tamsulosin hydrochloride as a representative drug requiring minimal drug loss.

As well known to those skilled in the art, tamsulosin was firstly disclosed in

Japanese Patent Laid-open Publication No. Sho. 56-110665, together with pharmaceutically acceptable salts thereof. The chemical name of tamsulosin represented by the following

Formula 1 is (R)(-)-5-[2-[[2-(o-ethoxyphenoxy)ethyl]amino]propyl]-2- methoxyberizenesulfoneamide: Formula 1

Only males are afflicted with benign prostatic hyperplasia due to prostatomegaly.

That is, the prostate gland is enlarged and the bladder outlet is obstructed, and an amount of coi receptor increases in the enlarged prostate gland, whereby prostate smooth muscle is extraordinarily contracted and bladder muscle becomes hypertrophic upon discharging urine. Internal bladder pressure is increased attributable to intense bladder constriction, and mucosa between hypertrophic muscle fibers is subjected to pressure. Thus, upon evacuation, patients suffer from obstruction of a urinary stream, urgency of voiding, and frequent urination [UROLOGY 51 (Suppl 4A): 1-7, 1998].

Tamsulosin or salts thereof are known to be an antagonist of α adrenoceptors. In particular, tamsulosin hydrochloride (tamsulosin HC1) functions as an on receptor blocker in the urethra and the prostate region, and also decreases pressure of prostate regions in urethra inner pressure curves, to improve benign prostatic hyperplasia due to prostatomegaly [UROLOGY 58 (Suppl 6A): 42-48, 2001].

Korean Patent Laid-open Publication No. 02-0016944 discloses a therapeutic agent of lower urinary tract diseases comprising tamsulosin or pharmaceutically acceptable salts thereof as an effective ingredient. Lower urinary tract disease is regarded as a kind of benign prostatic hyperplasia symptom caused by functional obstruction of lower urinary tracts of males as well as females. As such, it is noted, that disorders of nerves controlling lower urinary tract and organic obstruction of the urethra are not included in the above urinary tract disease category. Females are often afflicted with lower urinary tract diseases. Lower urinary tract disease is caused by dysuria, sclerosis or obstruction of neck of the urinary bladder, urethra syndrome, detrusor-sphincter coordinated insufficiency, unstable bladder, chronic prostatitis, chronic cystitis, prostatalgia, Hinman's syndrome, Fowler's syndrome, psychogenic benign prostatic hyperplasia, benign prostatic hyperplasia due to drug and aging, etc.

Further, tamsulosin hydrochloride for treatment of benign prostatic hyperplasia is orally administered in the amount of 0.2-0.4 mg/day [UROLOGY 58 (Suppl 6A) : 42-48, 2001], and preferable administration form is a controlled release formulation which is continuously released. Commercially available Harnal^® capsule (containing 0.2 mg of tamsulosin HC1) sold by Yamanouchi Pharmaceutical Co., Ltd., and FLOMAX™ capsule (containing 0.4 mg of tamsulosin HC1) sold by Boeringer Ingelheim are known as a controlled release dosage form administered once per day. In Korean Patent Laid-open Publication Nos. 86-0006984 and 02-0016944 and

Japanese Patent Laid-open Publication No. Sho. 62-9, there is disclosed a method of preparing a controlled release formulation of tamsulosin hydrochloride, in which crystalline cellulose and water-insoluble polymer are used as a unit forming material and a dissolution controlling agent, respectively. The above water-insoluble polymer is used in the form of aqueous dispersion, aqueous emulsion or water-containing organic solvent, and examples thereof include acrylate polymers or copolymers, or cellulose derivatives [e.g., commercially available Eudragit L30D-55 (methacrylic acid copolymer LD), Eudragit E30D (ethylacrylate methylmethacrylate copolymer emulsion), Aquacoat ECD-30 (aqueous ethyl cellulose dispersion)]. Then, a granular formulation is prepared from the above materials by use of a centrifugal fluid granulating machine, after which such granules are filled into capsules.

The above method is advantageous in terms of preparation of dense spherical granules, but is disadvantageous in light of use of very expensive fluid granulating machines, and high product drug price. In addition, in case of using a base drug such as tamsulosin hydrochloride in a very small amount (0.2 mg), a base drug solution, which is sprayed through a spray nozzle, is not mixed with an excipient by air circulating in the granulating machine and is lost, whereby the amount of the drug contained in the formulation may not reach a desired level.

Disclosure of the Invention

Accordingly, the present invention has been made keeping in mind the above problems related to conventional drug release systems in the prior art, and an object of the present invention is to provide a method of manufacturing a controlled release formulation using a pelletizer, which is advantageous in terms of preventing drug loss during production of the formulation, and containing a uniform amount of a drug. Another object of the present invention is to provide a method of manufacturing a controlled release formulation using, a pelletizer, characterized in that a pellet to be prepared can be molded to have desired various sizes or multiple layers by adjusting an inner diameter of holes in an extruder and of semicircular grooves between neighboring protruded portions which are formed along rolling surfaces of molding rollers equipped to the pelletizer, therefore resulting in that control of release rates of the drug can be achieved.

Brief Description of the Drawings The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

FIG. 1 is a view schematically illustrating a structure of an extruder used in the present invention;

FIG. 2a is a perspective view of a pelletizer used in the present invention;

FIG. 2b is a left side view of the pelletizer of FIG. 2a;

FIG. 2c is a sectional view taken along A-A line shown in FIG. 2b;

FIG. 3 is a graph illustrating an amount of tamsulosin HC1 in a controlled release formulation prepared by the method of the present invention;

FIG. 4 is a graph illustrating the results of dissolution test for the controlled release formulation of the present invention (drug: tamsulosin HC1) and a commercially available product (D ontrolled release formulation of the present invention as a test formulation, O*: commercially available product as a control formulation); and FIG. 5 is a graph illustrating the results of dissolution test for the controlled release formulation of the present invention (drug: phenylpropanolamine hydrochloride).

Best Mode for Carrying Out the Invention

The present invention concerns a method of manufacturing a controlled release formulation comprising the steps of extruding a drag-containing combination to a filament and molding the filament to a pellet.

The term 'combination' means a mixture including the drug and various assistant components to have strength and ductility suitable for extrusion. Although strength and ductility required to extrude the combination to the filament may be experimentally determined, cohesion of the combination amounts to 3.0-45 N when the combination is extruded under a pressure of 1000-4000 N.

The assistant components contained in the combination are selected from among a dissolution assisting agent (hydrophilic polymer, surfactant) when release of the drug is incomplete, inert diluent, binder, a dissolution inhibitor (this component may function as the binder when the binder is not contained) when controlled release is required; or mixtures thereof.

According to a first embodiment of the present mvention, the manufacturing method of the controlled release formulation comprises the following steps: (a) dissolving at least an effective amount of a drug, and a hydrophilic polymer or a surfactant for use in assisting dissolution of the drug in a suitable solvent, to prepare a mixture;

(b) combining the mixture with an inert diluent and/or a dissolution inhibitor, to form a combination having suitable ductility; and (c) extruding the combination to a filament, followed by molding the filament to a pellet.

The drag contained in the controlled release formulation is not specifically limited so long as it may be administered in trace amounts to humans as water-insoluble materials.

Such a drag is illustrated as follows. Antiphlogistics and antipyretic analgesics: pentazocine, mefenamic acid, naproxen, indomethacin, phenacetin, acetaminophen, aspirin, sodium salicilate, antipyrine, aminopyrine, diclofenac sodium, ibuprofen, piroxicam, nimesulide, etc.;

Stenocardia therapeutic agents: amyl nitrate, glyceryl trinitrate, isoso bid dinitrate and mononitrate, pentaei thritol tetranitrate, etc.; Hypertension therapeutic agents: enalapril, captopril, amlodipine, clonidine, diltiazem, felodipine, nifedipine, prazocine hydrochloride, etc.;

Adrenergic agonists: salbutamol sulfate, terbutalin, ephedrine hydrochloride, naphazoline hydrochloride, phenylpropanolamine hydrochloride, etc.;

Hyperhpidemia therapeutic agents: lovastatin, clofibrate, gemfibrozil, benzafibrate, simfibrate, etc.;

H2-receptor antagonists for treating gastro-enteropathy: cimetidine, ranitidine, famotidine, cisapride, domperidone, omeprazole, loperamide, mesalazine, etc.;

Antibiotics: ampicillin, amoxicillin, gentamicin, erythromicin, rifampicin, chloramphenicol, tetracycline, cefalexin, cefazolin sodium, etc.; and Diabetes therapeutic agents for oral administration: tolbutamide, chlorpropamide, acetohexamide, glibenclamide, metformin hydrochloride, phenformin hydrochloride, etc..

The hydrophilic polymer or surfactant used to assist dissolution of the above drag is not specifically limited so long as it may function to dissolve the above drug in a suitable solvent, for example, water, ethanol or a mixture of water and ethanol to control release properties of the drug.

In addition, the hydrophilic polymer is pharmaceutically acceptable, and is available in cases where the amount of the drag is very small or solubility thereof is considerably low. The hydrophilic polymer is exemplified by polyvinylpyrrolidone, polyvmyl alcohol, cellulose derivatives such as hydroxypropylmethylcellulose, or polyethylene oxide.

The surfactant is pharmaceutically acceptable and includes any material so long as it may function to assist dissolution of the drag. Such a surfactant is exemplified by polyethyleneglycol, poloxamers, sodium lauryl sulfate (SLS), etc.

The weight ratio of the hydrophilic polymer or surfactant to the drug is 0.5 :1~100:1, depending on release profiles of the drug. When release of the drag is slow or incomplete, the amount of the used hydrophilic polymer or surfactant increases. Alternatively, a bioavailabihty enhancer is used alone or together with the above surfactant.

The term 'bioavailabihty enhancer' means a material assisting dissolution and absorption of the drug in the body to enhance bioavailabihty of the drug. The bioavailabihty enhancer is selected from the group consisting of lauroyl macrogol-32 glyceride, stearoyl macrogol-32 glyceride, propylene glycol monocaprylate, oleoyl macrogol-6 glyceride, linoleoyl macrogol-6 glyceride, caprylocaproyl macrogol-8 glyceride, propylene glycol monolaurate, polyglyceryl-6 dioleate, or mixtures thereof. On the other hand, when release of the drug is fast, the amount of the used hydrophilic polymer or surfactant decreases. Preferably, with the intention of extending release of the drag, a fatty acid component is used in the state of being warmed and melt- mixed, or a binder is used alone or used together with the above surfactant.

The fatty acid is pharmaceutically acceptable, and is not specifically limited so long as it may function to extend release of the drug. Such a fatty acid includes glyceryl behenate, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, or mixtures thereof.

The fatty acid is preferably added 0.5-50 times to the weight of the drag when being dissolved together with the drug. The binder comprises water-soluble polymers, which are exemplified by cellulose derivatives mcluding methyl cellulose, ethyl cellulose, hydroxypropyl cellulose or hydroxypropylmethylcellulose, alginic acid, sodium alginate, acacia, guar gum, polymethacrylate, or mixtures thereof.

The binder may simultaneously function as a dissolution inhibitor. In such a case, it is used in 10-45 wt%. Otherwise, the binder may be used in 5-10 wt%. The controlled release formulation of the present invention comprises a pharmaceutically acceptable diluent, which is exemplified by microcrystalline cellulose, cellulose powders, cellulose acetate, calcium phosphate, calcium sulfate, corn starch, lactose, mannitol, polyvinylpyrrolidone, talc, dexrrate and dextrin, glucose, fructose, maltose, sucrose, kaolin, magnesium carbonate, magnesium oxide, polymethacrylate, or mixtures thereof.

The diluent is preferably used in about 25wt% or more on the basis of the whole weight of the controlled release formulation.

As for the method according to the first embodiment of the present invention, the order of the above steps (a) and (b) may be variably performed. That is, the step (a) is firstly performed and then the step (b) may be performed or vice versa. Any case is included in the scope of the present invention, and in particular, operation of the step (a) following the step (b) is described in Example 2, later.

In the present invention, the controlled release formulation should be obtained in the pellet form using a pelletizer. For this, the mixture of the drug and the dissolution assisting agent should have suitable strength and ductility. Thus, the dissolution inhibitor, functioning as the binder at the same time, is suitably added to the mixture.

The dissolution inhibitor includes the above mentioned fatty acids, cellulose derivatives, gelatin, guar gum, xanthan gum, acrylate homopolymers or copolymers, or mixtures thereof.

More particular examples of the dissolution inhibitor are as follows.

As commercially available fatty acids, there are exemplified Compritol 888 ATO (glyceryl behenate), Precirol ATO 5 (glycerylpalmitostearate), etc.

The cullulose derivative includes AnyCoat (cellulose derivative), or Surelease (25 wt% aqueous ethyl cellulose dispersion added with plasticizer). The acrylate copolymers include Eudragit L30D-55 (copolymer of methacrylic acid and ethyl acrylate), Eudragit RL30D (copolymer of ethyl acrylate and methylmethacrylate introduced with trimethylammomoethyl methacrylate chloride), Eudragit RS30D (copolymer of ethyl acrylate and methyl methacrylate introduced with trimethylammomoethyl methacrylate chloride), Eudragit NE30D (copolymer of ethylacrylate and methyl methacrylate), etc.

The dissolution inhibitor may be used in the form of powders, aqueous dispersion, aqueous emulsion, or water-containing organic solvent.

The dissolution inhibitor in the form of powders is used in the amount of 10-45 wt%, and includes at least one component. When being in the form of aqueous liquid, the inhibitor is used in the amount of 50-150 wt%.

When the dissolution inhibitor is in the form of aqueous dispersion, it may further include 2-5 wt% of a plasticizer selected from among polyethylene glycol, propylene glycol, glycerol, dimethylphthalate, dibutylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, triethylacetylcitrate, triacetin, castor oil, etc.

In addition, a filler or a colorant may be contained in the controlled release formulation of the present invention.

The combination obtained from the above step (b) should have strength and ductility required to perform a filament molding process by extrusion and a pellet molding process. Although strength and ductility required to extrude the combination to the filament may be experimentally determined, cohesion of the combination reaches 3.0 to 45

N when the combination is extruded under a pressure of 1000-4000 N.

Referring to FIG. 1, there is shown a schematic structure of an extruder used in the present invention. An extruding process is performed by use of a hydraulic extruder 1 having a „.„„,-,,

PCT/KR2003/000660

plurality of holes 2, in which the holes 2 have a predetermined inner diameter and are formed at a bottom of the extrader 1. The combination having suitable strength and ductility is introduced into the extruder 1 and molded to a cylindrical filament.

FIGs. 2a and 2b are a perspective view and a left side view of a pelletizer used to mold the extruded filament to the pellet, respectively. Further, FIG. 2c is a sectional view of A- A line shown in FIG.2b.

The pelletizer is equipped with a pair of molding rollers 4 and 5 useful to mold the filament to the pellet. The molding rollers 4 and 5 are composed of semicircular grooves 6 and protruded portions 7 along each rolling surface, in which the grooves 6 having a predetermined inner diameter are formed perpendicular to a rotation shaft and also are disposed between neighboring protruded portions 7 functioning to cut an extradate. The molding rollers 4 and 5 are rotated in opposite directions while the top roller 4 comes into mutual contact with the bottom roller 5. As such, the protruded portions 7 of the top and bottom rollers 4 and 5 are brought into mutual contact. A long cylindrical filament 3 is placed parallel to the rotation shaft between the contact surfaces of the two rollers 4 and 5. The extradate is cut by the protruded portions 7 of the rollers 4 and 5 and compressed by the semicircular grooves 6 while being rotated by the two rollers respectively rotating at different speeds, thereby preparing the pellet having a predetermined diameter.

The size of the final pellet obtained from the step (c) as mentioned above is controlled by adjusting an inner diameter of the plurality of holes 2 in the extrader 1 or a size of the grooves 6 between adjacent protruded portions 7 of the molding rollers 4 and 5 provided to the pelletizer.

Thusly prepared pellet has a size of l-5mm, preferably 1.5-2.5mm, and consists of the controlled release formulation. According to a second embodiment of the present invention, the step (b) of forming the combination as mentioned above comprises the steps of:

(bl) combining the mixture of the drug and the dissolution assistant component with the inert diluent and/or the dissolution inhibitor, followed by granulating a combination, to prepare granules; and (b2) further combining the granules with the inert diluent and/or the dissolution inhibitor, to prepare a desired combination having suitable strength and ductility.

The inert diluent and the dissolution inhibitor used at the steps (bl) and (b2) are as defined above.

The granulating operation of the step (bl) accords to general methods using a cylindrical granulating machine, or oscillator granulating machine.

According to a third embodiment of the present invention, the present invention further comprises the step (d) of coating the pellet with a coating agent for controlled release, after the step (c) of preparing the pellet.

The coating agent for controlled release includes enteric coating materials or non- enteric coating materials. The enteric coating material is exemplified by cellulose acetate phthalate (CAP), Eudragit L and S types of acrylate copolymers, hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PNAP), etc. In addition, examples of the non-enteric coating material include hydroxypropyl methylcellulose (HPMC), methylhydroxy ethylcellulose (MHEC), ethylcellulose (EC), hydroxypropylcellulose (HPC), povidone (PNP), sodium carboxymethylcellulose (Sod. CMC), propylene glycols (PEGs), acrylate copolymers (Eudragit E, RL and RS types).

The coating agent for controlled release is not specifically limited so long as it may be dissolved in or diluted with an organic solvent, such as alcohol, acetone, methylene chloride, or a mixture of water and the organic solvent. This component is used in the amount of 1.5-30wt% according to various viscosities. It is preferred that the coating agent is added with 2-5 wt% of a plasticizer, which is exemplified by polyethyleneglycol, propyleneglycol, glycerol, dimethylphthalate, dibutylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, triethylacetylcitrate, triacetin, castor oil, etc. On the other hand, commercially available Eudragit L30D-55, NE30D, RS30D and RL30D are in the state of 30 wt% aqueous dispersion, while commercially available Surelease is in the state of 25 wt% aqueous ethyl cellulose dispersion. As necessary, the above commercially available material may be used in the state of being diluted with a suitable solvent. A coating process using the above coating agent may be performed by means of a known system. In this regard, there is a spray pan coating system under operation conditions of pan temperatures of 35-40°C, rotation speeds of 55-60 rpm, and spray speeds of the coating agent of to be sprayed through a nozzle of 2-5 ml/min. In addition, a fluid bed coating process may be used. According .to a fourth embodiment of the present invention, the method of the prevent invention further comprises, after the step (c) of preparing the pellet, the steps of:

(e) combining the pellet with a diluent and/or a dissolution inhibitor, to prepare a combination having suitable ductility; and

(f) extruding the combination to a filament, which is then molded to a final pellet. The diluent and the dissolution inhibitor of the step (e) are defined as in the above step (b).

As such, an extrader and a pelletizer used in the above steps (e) and (f) comprise holes and grooves having inner diameters 1.5-2.5 times larger than the holes of the extruder and the grooves between neighboring protruded portions of the molding rollers equipped to the pelletizer used in the above step (c) of preparing the primary pellet. In case where dissolution inhibition is further required, pellets having at least double layers may be prepared.

A better understanding of the present invention may be obtained through the following examples using tamsulosin hydrochloride as an effective ingredient for treatment of benign prostatic hyperplasia and phenylpropanolamine hydrochloride as an effective ingredient of adrenergic agonists, which are set forth to illustrate, but are not to be construed as the limit of the present invention.

Examples 1-8

According to a composition shown in the following Table 1, tamsulosin hydrochloride was dissolved in a proper amount of ethanol, together with polyvinylpyrrolidone (PNP K-30) or poloxamer (Lutrol F 127). The solution was combined with microcrystalhne cellulose (Avicel PHI 02) and granulated by use of a cylindrical granulating machine having a 20 mesh (850 μm) sieve, to form primary granules, which were then dried at 50 °C for 6 hours. The primary granules were further combined with microcrystalline cellulose

(Avicel PH102), Eudragit L30D-55, ΝE30D, RS30D and RL30D each comprising 30wt% aqueous dispersion as an acrylate copolymer, and a small amount of water. The resultant combination was introduced into an extruder having a plurality of holes with an inner diameter of 2.0 mm, and molded to a long cylindrical filament, which was then finally molded to a pellet using a pelletizer.

TABLE 1

Examples 9-12

According to a composition shown in the following Table 2, tamsulosin hydrochloride and poloxamer (Lutrol F 127) were dissolved in ethanol. The solution was combined with microcrystalline cellulose (Avicel PHI 02) and granulated by use of a cylindrical granulating machine having a 20 mesh (850 μm) sieve, to form primary granules, which were then dried at 50 °C for 6 hours.

The primary granules were further combined with microcrystalline cellulose (Avicel PH102), and Eudragit L30D-55, NE30D, RS30D and RL30D each comprising 30wt% aqueous dispersion as an acrylate copolymer, added with 5 wt% of triethylcitrate.

A molding process of thusly obtained combination to a filament and a pellet was performed in the same manner as in the above examples 1-8.

TABLE 2

Examples 13-16

According to a composition shown in the following Table 3, a solution of tamsulosin hydrochloride and poloxamer (Lutrol F 127) in ethanol was mixed with warmed glyceryl behenate (Compritol 888 ATO) for use in retarding dissolution. This solution was combined with a mixture powder of microcrystalline cellulose (Avicel PHI 02), glyceryl behenate (Compritol 888 ATO) and hydroxypropyl methylcellulose (60SH 50, 60SH 4,000), along with water. The combination was granulated by use of a cylindrical granulating machine having a 20 mesh (850 μm) sieve, to form primary granules, which were then dried at 50 °C for 6 hours.

Thereafter, the primary granules were uniformly mixed with microcrystalline cellulose (Avicel PH102) and hydroxypropyl methylcellulose (60SH 50, 90SH 4,000, 90SH 100,000), and further combined with Eudragit RS30D comprising 30wt% aqueous dispersion, or Surelease comprising 25wt% aqueous ethyl cellulose dispersion added with a plasticizer, or water-diluted Surelease.

As such, the prepared pellet had a particle size of 1.0-5.0 mm, and a large percentage of the pellet were 1.5-2.5 mm in size. TABLE 3

Examples 17-22

According to a composition shown in the following Table 4, an ethanol solution of tamsulosin hydrochloride and poloxamer (Lutrol F 127) or an ethanol/water solution of tamsulosin hydrochloride, poloxamer (Lutrol F 127) and hydroxypropyl methylcellulose (90SH 4,000) was uniformly mixed with microcrystalline cellulose (Avicel PHI 02) and hydroxypropyl methylcellulose (90SH 4,000, 90SH 100,000), and then combined with a proper amount of water or Eudragit RS30D.

The combination was granulated by use of a cylindrical granulating machine having a 20 mesh (850 μm) sieve, to form primary granules, which were then dried at 50°C for 6 hours. The primary granules were uniformly mixed with microcrystalline cellulose (Avicel PHI 02) and hydroxypropyl methylcellulose (60SH 50, 90SH 4,000, 90SH 100,000), and further combined with Surelease comprising 25wt% aqueous etliyl cellulose dispersion added with a plasticizer, or Eudragit L30D-55.

As such, the prepared pellet had a particle size of 1.0-5.0 mm, and a large percentage of the pellet were 1.5-2.5 mm in size.

TABLE 4

Example 23

0.02g of tamsulosin hydrochloride and 0.05g of poloxamer (Lutrol F 127) were dissolved in ethanol. The ethanol solution was uniformly mixed with 4.0g of microcrystalline cellulose (Avicel PHI 02), and 4.0g of magnesium stearate. The combination was granulated by use of a cylindrical granulating machine having a 20 mesh (850 μm) sieve, to form primary granules, which were then dried at 50 °C for 6 hours. 5 The primary granules were uniformly mixed with 4.0g of microcrystalline cellulose (Avicel PHI 02) and 4.0g of magnesium stearate, and further combined with 3.6g of Eudragit RS30D and Eudragit L30D-55 each comprising 30wt% aqueous dispersion, added with about 3wt% of triacetin as a plasticizer.

A molding process of thusly obtained combination to a filament and a pellet was ^' 10 performed in the same manner as in the above examples 1-8.

Example 24

0.02g of tamsulosin hydrochloride and 0.05g of poloxamer (Lutrol F 127) were 15 dissolved in ethanol. The ethanol solution was uniformly mixed with lO.Og of microcrystalline cellulose (Avicel PH102) and 4.0g of ethyl cellulose (EC N50), and further combined with 15.0 g of Surelease comprising 25wt% aqueous ethyl cellulose dispersion.

The combination was formulated into granules by use of a hydraulic extrader having a plurality of holes with an inner diameter 2.0 mm, and formulated to long

20 cylindrical filament, which was then pelletized using a pelletizer. As such, the prepared pellet had a particle size of 1.0-5.0 mm, and a large percentage of the pellet were 1.5-2.5 mm size. Example 25

0.1 g of hydroxypropyl cellulose (HPC-M) was dissolved in 4.0 g of Surelease comprising 25wt% aqueous ethyl cellulose dispersion, to which a solution of 0.02g of tamsulosin hydrochloride and 0.15g of poloxamer (Lutrol F 127) in ethanol was added. The mixture was uniformly mixed with 6.0g of corn starch, 6.0g of microcrystalline cellulose, 0.5 g of magnesium stearate, and 1.0 g of talc, and combined with 13.0g of 20wt% Surelease obtained by diluting 25wt% Surelease with water.

A molding process of thusly obtained combination to a filament and a pellet was performed in the same manner as in the above examples 1-8. As such, the prepared pellet had a particle size of 1.0-5.0 mm, and a large percentage of the pellet were 1.5-2.5 mm in size.

Example 26

0.02g of tamsulosin hydrochloride and O.lg of sodium alginate (NSPLL) were dissolved in a proper amount of water. The solution was uniformly mixed with lO.Og of microcrystalline cellulose (Avicel PH102), 0.5 g of magnesium stearate, and 1.0 g of talc, and combined with 5.5g of Surelease comprising 25wt% aqueous ethyl cellulose dispersion, and a proper amount of ethanol.

Example 27

0.02g of tamsulosin hydrochloride, 0.05g of poloxamer (Lutrol F 127) and O.lg of sodium alginate (NAPH) were dissolved in water. The solution was uniformly mixed with 5.0g of microcrystalhne cellulose (Avicel PH102), 5.0g of sodium alginate (NSPH), 5.0g of magnesium trisilicate, 0.5g of magnesium stearate and 1.0 g of talc, and combined with 16.6g of Surelease comprising 25wt% aqueous ethyl cellulose dispersion, and a proper amount of ethanol.

Examples 28-31

According to a composition shown in the following Table 5, an aqueous, solution of tamsulosin hydrochloride and poloxamer (Lutrol F 127), or a solution of sodium alginate dissolved in the above aqueous solution, was uniformly mixed with microcrystalline cellulose (Avicel PHI 02), sodium alginate, alginic acid, and magnesium trisilicate, and further combined with Surelease comprising 25wt% aqueous ethyl cellulose dispersion, or water-diluted Surelease.

A molding process of thusly obtained combination to a filament and a pellet was performed in the same manner as in the above examples 1-8. The prepared pellet was dried at 50°C for 6 hours, each of which was coated with Surelease diluted to 15wt% with water using a spray coater.

TABLE 5

Example 32

An aqueous solution of 0.02g of tamsulosin hydrochloride and 0.05g of poloxamer (Lutrol F 127) was uniformly mixed with 12.0g of corn starch, l.Og of hydroxypropyl methylcellulose (90SH 4,000) and a proper amount of water, and further combined with 4.0g of Surelease comprising 25wt% aqueous ethyl cellulose dispersion.

A molding process of thusly obtained combination to a filament and a pellet was performed in the same manner as in the above examples 1-8. The prepared pellets were dried at 50°C for 6 hours, each of which was coated with 30.0g of 25wt% water/ethanol solution of hydroxypropyl methylcellulose (90SH 4,000) using a spray coater.

Experimental Example 1

Amount Measurement

500 mg of each of the pellets obtained from the above examples 1 through 32 was added to 1000 ml of phosphate buffer, pH 7.2, as necessary, containing ethanol or 0.1N sodium hydroxide, and sonicated at 37.5°C for 3 hours, and strongly stirred for 3 hours. Thereafter, 15 ml of the above solution was centrifuged at 25°C at 3,000 rp , and

10 ml of a supernatant was collected, to which 2 ml of an internal standard solution was further added. Thusly treated eluate was filtered with a 0.45 μm filter, and this filtrate was used as a test liquid. Under detection conditions shown in the following Table 6, tamsulosin hydrochloride was isolated by liquid chromatography and measured for absorption at 225 nm, to determine concentrations of tamsulosin hydrochloride. The results are shown in the attached FIG. 3.

TABLE 6

*A liquid: 1 ml of perchloric acid added to 450 ml of water is controlled by sodium hydroxide to be 2.0 in pH, and then is further added with water to have a total volume of 500 ml.

RSD (relative standard deviation) was calculated based on the results shown in FIG. 3, and its value was found to be 2.2. From this result, it can be confirmed that the amount of the tamsulosin component is uniformly contained in the formulation.

Experimental Example 2

Comparison Dissolution Test

The pellet containing 0.2 mg of tamsulosin HC1 obtained from the above example

30 was filled in a void-capsule. As a control, a commercially available formulation containing an equal amount of the above drug component (Harnal^® capsule (161.4 mg), sold by Yamanouchi Pharmaceutical Co., Ltd.) was used. These two formulations were subjected to comparison dissolution test. The dissolution test was performed at 150 rpm at 37±0.5°C based on the 2^nd Method of Dissolution Test of General Test Methods defined in Korean Pharmacopeia. As such, 1 ml of Polysorbate 80 (Tween 80) [3->200] added to 500 ml of a first liquid of Disintegration Test defined in the same was used as a dissolution medium. 2 hours immediately after the test was initiated, the dissolution medium was replaced with 500 ml of phosphate buffer, pH 7.2, and the test was further performed at 37+0.5°C. 10 ml of respective eluate was collected at predetermined time intervals, after which 10 ml of an additional dissolution medium was replenished in place of the collected eluate. The eluate collected after the dissolution test was performed for 2 hours was directly added with exactly 2.0 ml of the internal standard solution. 3 and 5 hours after the test was initiated, each of two collected eluates was added with exactly 1 ml of 0.5N hydrochloric acid and then 2 ml of the internal standard solution.

Thusly treated eluates were filtered with a 0.45 μm filter. Thusly obtained each filtrate was used as a test liquid. Under the same detection conditions as in the above experimental example 1, tamsulosin hydrochloride was isolated by liquid chromatography, and measured for absorption at 225 nm, thereby determining concentrations of tamsulosin hydrochloride. Such concentrations were calculated to dissolution rates. The results are shown in the attached FIG. 4.

As shown in FIG. 4, it can be seen that the formulation prepared by the method of the present invention has similar release properties to the commercially available formulation but 100% release of the inventive formulation can be realized within 24 hours, compared to the commercially available formulation.

Examples 35-40 lOg of phenylpropanolamine hydrochloride and 2 g of PNP K-30 were completely dissolved in lOg of ethanol. This solution was mixed with 82g of lactose, 5 g of corn starch and 1 g of magnesium stearate as a lubricant, and combined with an excipient.

The combination was extruded by use of a hydraulic extrader to a cylindrical filament, which was then introduced into a pelletizer having two rollers rotating in opposite directions, to prepare a pellet having a diameter of 3 mm. Such pellet was dried at 50°C for 6 hours. Of the prepared pellets, pellets of 6-7 mesh were collected and coated with a coating agent having a composition shown in the following Table 7 by use of a spray coater.

TABLE 7

Examples 41-44

1 g of Eudragit RS100 was completely dissolved in lOg of 50% ethanol. 2g of hydroxypropyl methylcellulose (HPMC 606) was dissolved in lOg of 50% ethanol, to which lOg of phenylpropanolamine hydrochloride was added and dissolved. 30 g of lactose was added to the alcohol solution of hydroxypropyl methylcellulose and phenylpropanolamine hydrochloride to prepare gel solution, to which the ethanol solution containing Eudragit RS 100 was added and uniformly mixed. This mixture was combined with 57g of lactose, to afford a combination. The combination was introduced into an extruder, and extruded by use of the hydraulic extrader to a cylindrical filament, which was then introduced into a pelletizer having two rollers rotating in opposite directions, to prepare a pellet having a diameter of 3mm. Such pellet was dried at 50°C for 6 hours. Of the prepared pellets, pellets of 6-7 mesh were collected and coated with a coating agent having a composition shown in the following Table 8 by use of a spray coater.

TABLE 8

Experimental Example 3 Dissolution Test

The sample obtained from the above example 44 was subjected to dissolution test. The dissolution test was performed at 100 rpm at 37±0.5°C according to the 1^st

Method, Rotating-Basket Method, of Dissolution Test of General Test Methods defined in Korean Pharmacopeia. As such, 900 ml of an artificial gastric juice, pH 1.2, was used as a dissolution medium. The coated pellet was placed into a rotating basket, and the basket was disposed in a container containing the dissolution medium, after which the test was initiated. The collected eluate was passed through a 0.70 μm filter, and placed into a cell of UN-1201 spectrometer and measured for absorption at 257 run at predetermined time intervals, after which the measured eluate was again withdrawn to the container. 75 mg of phenylpropanolamine hydrochloride was accurately weighed and used as a test material.

Through the above procedure, dissolution rates of the test material were determined and the results are shown in the attached FIG. 5. From this graph, it can be seen that controlled release of the test material is realized. Industrial Apphcability

As described above, the present invention provides a method of manufacturing a controlled release formulation using a pelletizer, which is advantageous in terms of remarkably decreased drag loss during a production process of the formulation, and production of the formulation having a uniform amount of a drug. ha addition, a pellet having various sizes can be molded by adjusting an inner diameter of holes formed in an extruder and of semicircular grooves between neighboring protruded portions formed along each rolling surface of molding rollers provided to the pelletizer. As necessary, a multi-layered pellet can be manufactured, thereby realizing various release controls.

Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.

Claims

1. A method of manufacturing a controlled release formulation using a pelletizer, comprising the following steps of: extruding a drug-containing combination to a filament; and molding the filament to a pellet.

2. The method as defined in claim 1, wherein the combination is obtained by:

(a) dissolving at least a drug and a hydrophilic polymer or a surfactant for use in assisting dissolution of the drug in a solvent, to form a mixture; and (b) combining the mixture with an inert diluent and/or a dissolution inhibitor, to prepare the combination with suitable ductility.

3. The method as defined in claim 2, wherein the mixture of the step (a) further comprises a fatty acid or a binder to extend drug release.

4. The method as defined in claim 3, wherein the fatty acid is selected from the group consisting of glyceryl behenate, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, or mixtures thereof.

5. The method as defined in claim 3, wherein the binder is selected from the group consisting of cellulose derivatives, alginic acid, sodium alginate, acacia, guar gum, polymethacrylate, or mixtures thereof.

6. The method as defined in claim 2, wherein the mixture of the step (a) further comprises a bioavailabihty enhancer.

7. The method as defined in claim 6, wherein the bioavailabihty enhancer is selected from the group consisting of lauroyl macrogol-32 glyceride, stearoyl macrogol-32 glyceride, propylene glycol monocaprylate, oleoyl macrogol-6 glyceride, linoleoyl macrogol-6 glyceride, caprylocaproyl macrogol-8 glyceride, propylene glycol monolaurate, polyglyceryl-6 dioleate, or mixtures thereof.

8. The method as defined in claim 2, wherein the diluent of the step (b) is selected from the group consisting of microcrystalline cellulose, cellulose powders, cellulose acetate, calcium phosphate, calcium sulfate, corn starch, lactose, mannitol, polyvinylpyrrolidone, talc, dextrate and dextrin, glucose, fructose, maltose, sucrose, kaolin, magnesium carbonate, magnesium oxide, polymethacrylate, or mixtures thereof.

9. The method as defined in claim 2, wherein the dissolution inhibitor of the step

(b) is selected from the group consisting of fatty acids, cellulose derivatives, gelatin, guar gum, xanthan gum, acrylate homopolymers or copolymers, or mixtures thereof.

10. The method as defined in claim 2, wherein the dissolution inhibitor is used in the form of powders, aqueous dispersion, aqueous emulsion, or water-containing organic solvent.

11. The method as defined in claim 1, wherein the pellet has a size of 1.5-2.5 mm.

12. The method as defined in claim 2, wherein the step (b) comprises the steps of: (bl) combining the mixture with the inert diluent and/or the dissolution inhibitor, followed by granulating a combination, to prepare granules; and

(b2) further combining the granules with the inert diluent and/or the dissolution inhibitor, to prepare a final combination having suitable ductility.

13. The method as defined in claim 1 or 2, further comprising the step of coating the pellet with a coating agent for controlled release.

14. The method as defined in claim 1 or 2, further comprising the steps of: combining the pellet with a binder and/or a dissolution inhibitor to prepare a combination having suitable ductility; and extruding the combination to a filament, followed by molding the filament to a final pellet.