WO2004006904A1

WO2004006904A1 - Oral controlled-release dosage forms containing acetaminophen

Info

Publication number: WO2004006904A1
Application number: PCT/KR2003/001036
Authority: WO
Inventors: Beom-Jin Lee; Qing-Ri Cao; Youn-Woong Choi
Original assignee: Seoul Pharm. Co., Ltd.
Priority date: 2002-07-16
Filing date: 2003-05-27
Publication date: 2004-01-22
Also published as: AU2003232652A1; KR20040006887A; KR100522239B1

Abstract

The present invention relates to oral dosage forms containing acetaminophen. More particularly, the present invention relates to oral dosage forms containing acetaminophen as a model drug, polymer base, disintegrants and lubricant, where the water-soluble additives further are contained in the said preparations. The dosage forms of the present invention are formulated to various formulations such as tablet, compressed pellet, granule and capsule. Upon exposure to the various dissolution media, the oral dosage forms of the present invention absorb water and form a gel structure, showing rapidly release of 50 % drug within a few minutes like a commercial two-layered tablet followed by the extended release thereafter. The release rate of drug is mainly governed by the swelling and erosion rate of the polymer base together with additives incorporated in matrix tablet. Unlike the two-layered commercial tablet, the new heterodisperse and single-layered HPMC matrix tablet could be easily prepared by using conventional tablet machine. The dosage forms also provide an economical and unique preparation method.

Description

ORAL CONTROLLED-RELEASE DOSAGE FORMS CONTAINING ACETAMINOPHEN

Technical Field

The present invention relates to oral controlled- release dosage forms containing acetaminophen. More particularly, the present invention relates to oral controlled-release dosage forms containing acetaminophen as a drug, polymer base, disintegrants and lubricant, where the water-soluble additives are further contained in the dosage forms. Upon oral administration, the dosage forms of the present invention absorb water and rapidly release about 50% of loading dose within a few minute in some acidic condition of stomach. Thereafter, the oral dosage forms form a gel structure by polymer base and slowly release the residual amount of acetaminophen in a controlled fashion. As a result, the oral dosage forms show immediate and extended release profiles by controlling release rate of acetaminophen.

The dosage forms of the present invention are formulated to various formulations such as tablet, compressed pellet, granule and capsule. Also, the oral dosage forms of the present invention have the same release as commercial tablet in various dissolution media, could be easily prepared by using conventional tablet machine. And the oral dosage forms could be prepared by economical and unique method, to use as substitute of commercial tablet. Background Art

Acetaminophen is an analgestic and antipyretic drug as non-steroidal agent. Acetaminophen had a short half-life in body. Therefore, it was out of question to administer acetaminophen for pain-killing. However, it gets into trouble to frequently administer acetaminophen for pain-killing of chronic disease.

Therefore, the researchers developed the dosage forms showing rapid release of drug for immediate effect of a medicine, showing slow release of acetaminophen for lasting treatment of analgesia, or showing both rapid and slow release of acetaminophen so-called controlled release.

International Pat. No. US 6,217,907 discloses the dosage forms showing rapid release of acetaminophen, which contain sodium starch glycolate and microcrystalline cellulose as erosion-accelerating agent and wicking agent and are prepared by direct tableting.

International Pat. No. US 4,439,453 discloses the dosage forms showing rapid release of drug, which are obtained by preparing wet granule by using disintegrant such as pregelatinized Starch and cross-linked SCMC, integrants and tableting the resulting granules. Also, the dosage forms showing rapidly release of drug, which are obtained by preparing wet granule by using Polyvinylpyrrolidone (Povidone, PVP, Kollidon) and Croscarmellose Sodium as integrant and disintegrants, respectively and tableting the resulting granules [International Pat. No. US 6,264,983]. The oral dosage forms is useful for rapid treatment of analgesia, however the dosage forms leave much to be desired for lasting effect of a drug

The dosage forms showing slow release of drug, which are obtained by preparing wet granule by using hydroxypropyl methylcellulose and tableting the resulting granules [International Pat. No. US 4,695,591].

International Pat. No. US 6,210,714 discloses the dosage forms showing rapid release of drug, which are obtained by preparing core tablet by using polyvinylpyrrolidone and Lactose and then coated the core tablet with Aquacoat ECD-30 and Methocel E5 preminum.

However, the method for preparing the said dosage forms showing slowly release of drug was known in the art. Also, the dosage forms had demerits that it takes long time to have an immediate effect of a medicine. Therefore, the researches for developing the dosage forms showing both rapid and slow release of drug were recently progressed or reported by those skilled in the art.

International Pat. No. US 6,254,891 discloses the dosage forms prepared by using sugar/starch seeds, which are obtained by mixing the pellet showing rapidly release of drug and coated with drug and strong disintegrant, and the pellet showing slowly release of drug and coated with drug and lubricant .

Also, the tablet showing slow release of drug was prepared by simultaneously adding microcrystalline cellulose and strong disintegrant to acetaminophen microparticles, coating the resulting tablet, and further coating the resulting tablet with hydroxypropylmethyl cellulose (HPMC)

[International Pat. No. US 6,126,969].

However, two moieties of the tablets, i.e. moieties showing rapid release of drug and slow release of drug, are separately prepared in the said method. Also, the method was known in the art . Further process is needed to control release of drug from the tablet . Therefore the tablets are prepared by uneconomical preparation method. The dosage forms (Tylenol ER) showing both rapid and slow release of drug are commercially sold by JANSSEN [International Pat. No. US 4,820,522]. The Tylenol ER is two- layered tablet, which drug is contained in drug layers showing rapid and slow release in constant weight . More particularly, Tylenol ER is two-layered tablet containing 650 mg of acetaminophen. 325 mg of acetaminophen, the half of total drug is released for immediate effect from drug layer showing rapid release. Thus 325 mg of acetaminophen, the residue of total drug is released for lasting effect from drug layer showing slow release. Particularly, the effect is lasted for 8 hours. Therefore, the Tylenol ER is film-coating tablet showing broadly release. Wicking agent and erosion- accelerating agent are contained in drug layer showing rapid release, activated matrix integrant (hydroxylethyl cellulose) and wicking agent (microcrystalline cellulose) are contained in drug layer showing slow release. The Tylenol ER is two- layered tablets prepared by tableting the powder with specific tableter.

Many-layered tablets are reported to have an immediate effect on body and maintain the effect lastingly by simultaneously controlling drug layer showing both rapid and slow release. However, the method for preparing the two- layered tablet was known in the art and required the specific machine. And the method is incongruent to the mass-production.

Therefore, the present inventors developed the oral dosage forms showing both rapid and slow release of drug. The oral dosage forms contain acetaminophen as a model drug, where the water-soluble additives further are contained in the said oral dosage forms. Unlike the two-layered commercial tablet, the oral dosage forms of the present invention, i.e. the heterodisperse and single-layered tablet are prepared by simply mixing the content. Also, the oral dosage forms had the same dissolution as commercial tablet in various dissolution media such as artificial gastric juice, artificial intestinal juice, acetic acid-buffer solution and water.

Disclosure of invention

It is an object of the present invention to provide the oral dosage forms containing acetaminophen as a model drug, polymer base, disintegrants and lubricant, where the water-soluble additives are further contained in the dosage forms .

It is another object of the present invention to provide the oral dosage forms containing acetaminophen, which is the heterodisperse and single-layered tablet and is prepared by an economical and unique method, showing rapid and slow release .

It is still another object of the present invention to provide the method for preparing the oral dosage forms containing acetaminophen.

Best Mode for Carrying Out the Invention

The present invention provides oral dosage forms containing acetaminophen as a model drug, polymer base, disintegrants, surfactant and lubricant. Also, the present invention provides oral dosage forms containing acetaminophen as a model drug, where the water- soluble additives are further contained in the said oral dosage forms .

Polymer base used in the oral dosage forms according to the present invention is material absorbing water to control and delay release of drug. In the present invention, release of drug is controlled and delayed by using the said polymer base in the oral dosage forms containing acetaminophen.

All of the pharmaceutically acceptable polymer bases are used as the said polymer base. More particularly, the said polymer base is selected from the cellulose derivatives consisting hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxyprolpymethylcellulose acetylsuccinate and sodium carboxymethylcellulose ; polyethylene oxide and its derivatives ; polyvinylpyrrolidone (commercially Kollidon) ;polyethylene glycol (commercially carbowax) and polyvinyl alcohol; polyvinylacetate, polyvinylacetate phthalate, polymethacrylate and its copolymers (commercially Eudragit) ; polyacrylic acid and its derivatives (typically carbamer) ; glycerol monostearate and poloxamer, sodium alginate, guar gum, chitosan, sodium pectinate, gelatin and gum tragacanth.

Preferably, the said cellulose derivatives are used as the said polymer base. Hydroxypropyl methylcellulose gives the most ideal result as polymer base. The said hydroxypropyl methylcellulose had pharmaceutically various uses as its molecular weight. {Handbook of Pharmaceutical Excipients, Edited by Arthur H. Kibbe, 2000, 3rd edition, APHA) .

Hydroxypropyl methylcellulose as polymer base in the example of the present invention is preferably used in amount of 10-90 parts by weight, more preferably in amount of 20-50 parts by weight, most preferably in amount of 30-40 parts by weight .

Disintegrant used in the oral dosage forms according to the present invention absorbs water, to accelerate the initial disintegration. The said disintegrant is selected one or more from the group consisting Croscarmellose Sodium, Sodium Starch Glycolate (Primojel) , Pregelatinized Starch (Starch 1500 or Prejel) , microcrystalline cellulose (Avicel) , Crospovidone (cross-linked povidone, Polyplasdone , Kollidon CL) and the commercially used Polyvinylpyrrolidone (PVP, Povidone, Kollidon), low substituted hydroxypropylcellulose, alginic acid, Carboxymethylcellulose (Ac-Di-Sol) calcium salt and its sodium salt, colloidal silica(fumed silica, Aerosil, Cab-0-Sil) , guar gum, magnesium aluminium silicate, methylcellulose, powder cellulose, starch and sodium alginate.

Preferably, Croscarmellose Sodium, Sodium Starch Glycolate, Pregelatinized Starch, microcrystalline cellulose, Crospovidone or the commercially used Polyvinylpyrrolidone are used as the said disintegrant .

Most preferably, Pregelatinized Starch, Sodium Starch Glycolate or microcrystalline cellulose are used as the disintegrant. Particularly, disintegrants over two kinds of them had most efficient effect. Preferably, the said disintegrant is used in amount of 5 ~ 100 parts by weight, most preferably in amount of 10 — 30 parts by weight. Also, the said disintegrant is further added in formulating the drug to the pharmaceutically acceptable formulations such as ■ compressed pellet, pellet, granule and capsule. Also, the secondary disintegrant is further added to the oral dosage forms to release the drug more rapidly.

Surfactant used in the oral dosage forms according to the present invention enhances the permeability of water to powder and improves solubility of the drug. Surfactant used in the oral dosage forms according to the present invention is in the condition such as hydrophilic state, lipophilic state or balance state between this and that, by dint of polar group or non polar group existed in the surfactant molecule. Surfactant functions to lower the surface tension between two surfaces such as distilled water-oil, and thus is used as emulsifying agent, surface adsorbent, wetting agent and dispersing agent. Particularly, the surfactants are used as auxiliary dissolving agent when being present at a concentration higher than critical micelle concentration (CMC) , thereby being widely utilized in increasing solubility and bioavailability of poorly soluble drugs. Examples of the surfactants useful in the present invention include, but are not limited to, sodium lauryl sulfate (SLS) and its derivatives, poloxamer and its derivatives, medium chain triglyceride (MCT) , labrasol, transcutol, labrafil, labrafac, various polysorbate[which are exemplified as polyoxyethylene sorbitan monolaurate( ereinafter, abbreviated to "Tween 20"), polyoxyethylene sorbitan monopalmitate( hereinafter, abbreviated to "Tween 40"), polyoxyethylene sorbitan monostearate (hereinafter, abbreviated to "Tween 60") and polyoxyethylene sorbitan monooleate (hereinafter, abbreviated to "Tween 80")], Sorbitan Esters [which are exemplified as sorbitan monolaurate (hereinafter, abbreviated to "Span 20"), sorbitan monopaImitate (hereinafter, abbreviated to "Span 40"), sorbitan monostearate (hereinafter, abbreviated to "Span 60"), sorbitan monooleate (hereinafter, "Span 80"), sorbitan trilaurate (hereinafter, abbreviated to "Span 25"), sorbitan trioleate (hereinafter, abbreviated to "Span 85"), sorbitan tristearate (hereinafter, abbreviated to "Span 65")], Cremophor, PEG-60 hydrogenated castor oil, PEG-40 hydrogenated castor oil, sodium lauryl glutamate, disodium cocoamphodiacetate, Polyoxyl 23 lauryl ester (hereinafter, Brij 35) or their mixtures.

Preferred surfactants are anionic surfactants such as sodium lauryl sulfate (SLS) and its derivatives, nonionic surfactants such as Tween 20, Tween 40, Tween 60 or Tween 80 and sorbitan esters such as Span 20, Span 40, Span 60, Span 80, Span 25, Span 85 or Span 65. SLS and Tween 80 are most preferable surfactants. In oral dosage forms of the present invention, the surfactant is used in amount of 0.01~100 parts by weight, preferably in amount of 0.1 —10 parts by weight, most preferably in amount of 1 —3 parts by weight.

Also, examples of the lubricant, which improves reformation of oral dosage forms according to the present invention include, but are not limited to, magnesium stearate, Si0₂ or fumed silica (Aerosil, colloidal silica, Cab-O-Sil) or talc. Particularly, to use mixture of two or more lubricants gives the most ideal effect in the preparation of oral dosage forms. The lubricant is preferably used in amount of 0.1 —20 part by weight, more preferably in amount of 1 —10 part by weight, most preferably in amount 3~6 part by weight.

Also, to improve the water-absorptivity of the drug and consequently increase the initial release of the drugs, water -soluble additives, i.e. additives which are dissolved in water, are further used in the preparation of the oral dosage forms according to the present invention. Inorganic additives and organic additives are used as the water-soluble additives. The additives include, but are not limited to, examples stated in the following. Examples of inorganic additives are NaH₂P0₄ and KH₂P0 . Examples of organic additives are water-soluble polymolecules selected from the group consisting Polyvinylpyrrolidone (hereinafter, abbreviated to "PVP") or Polyethylene glycol (hereinafter, abbreviated to "PEG" ) _/further additives such as gelatin, gum, carbohydrate, cellulose and its derivatives, polyethylene oxide and its derivatives, polyvinyl alcohol, poly acrylic acid and its derivatives (typically carbamer) , polymethylacrylate and their mixtures.

The PVP of the water-soluble polymolecules is broadly used as the same terminology as Kollidon, plasdone or povidone. And the PVP is synthetic polymolecules, containing linear l-vinyl-2-pyrrolidinone . And medium molecular weight of PVP is in the broad range such as 2,500 —3,000,000. The PEG as another water-soluble polymolecule is broadly used as the same terminology as macrogol or carbowax. The PEG is synthetic polymolecule, containing oxyethylene group. The medium molecular weight of PEG is in the broad range such as

300-35,000.

Water-soluble additives used in the oral dosage forms according to the present invention are preferably selected from the group consisting NaH₂P0 , KH₂P0₄, polyvinylpyrrolidone and polyethyleneglycol . Particularly, NaH₂P0₄ is most effective as water-soluble additive. NaH₂P0₄ is used in amount of 1~80 part by weight, most preferably in amount of 1 — 10 part by weight.

In addition to, the oral dosage forms according to the present invention further include various pharmaceutically acceptable agents such as antioxidant which prevent the oral dosage forms from being oxidized, secondary disintegrant which assists faster release of the dosage forms, or foaming agents which improves foaming of the dosage forms, within an amount not negatively affecting efficacy thereof. Examples of the foaming agent include, but are not limited to, sodium bicarbonate (NaHC0₃) and sodium carbonate (Na₂C0₃) .

The oral dosage forms according to the present invention preferably contain acetaminophen as drug in amount of 300 —900 parts by weight; polymer base in amount of 10 ~90 parts by weight; disintegrant in amount of 5 —100 parts by weight; surfactant in amount of 0.01—100 parts by weight; lubricant in amount of 0.1 —20 parts by weight; and water- soluble additives in amount of 1~80 parts by weight.

More preferably, the oral dosage forms according to the present invention preferably contain acetaminophen as drug in amount of 300—900 parts by weight; polymer base in amount of 20 —50 parts by weight; disintegrant in amount of 10 —30 parts by weight; surfactant in amount of 0.1 —10 parts by weight; lubricant in amount of 1~10 parts by weight; and water-soluble additives in amount of 1~10 parts by weight.

Most preferably, the oral dosage forms according to the present invention preferably contain acetaminophen as drug in amount of 300 —900 parts by weight; polymer base in amount of 30—40 parts by weight; disintegrant in amount of 10 —30 parts by weight; surfactant in amount of 1~3 parts by weight; lubricant in amount of 3~6 parts by weight; and water-soluble additives in amount of 1—10 parts by weight.

Content of acetaminophen contained in the oral dosage forms according to the present invention is selected in a proper amount, taking consideration of economy and stability. Acetaminophen is preferably contained in amount of 300-900 mg

(once per day, for controlled release) , most preferably in amount of 650 mg.

The oral dosage forms may be formulated into the various formulations such as tablets, compressed pellets, granules and capsules.

Upon exposure of the dosage forms of the present invention and one of the conservatively commercial dosage forms to the various dissolution media such as pH 1.2, pH 4.0, pH 6.8 and water, the present inventors measured the dissolution of the drug. The result is that the dosage forms of the present invention show the same release types as the commercially dosage forms do. Also, in the tablet as one of the dosage forms of the present invention, some drug is rapidly released and the other drug is slowly released for minimal 4 hours. In other words, as the oral dosage form of the present invention is administered, it absorbs water in the acidic condition of gastrointestinal tract and rapidly releases the drug. Also, the oral dosage form of the present invention, containing the water by said process, forms a gel structure by polymer base and slowly releases the drug in constant weight, to control the release of the drug.

Also, the present invention provides the method for preparing the oral dosage forms containing acetaminophen as a model drug. Particularly, the oral dosage forms of the present invention are prepared by homogeneously mixing acetaminophen as a drug, polymer base, disintegrant, surfactant, lubricant and water-soluble additive, adding liquid solvent to the mixture in a small amount, mixing the resulting mixture to prepare wet granules, drying and milling the dried granules, and then tableting the resulting granules by general tablet machine (direct compression tableting) . The liquid solvent, which is added to the powder mixture in the preparation of the oral dosage forms according to the present invention, is one or more selected from the group consisting water, ethanol, glycerine, propyleneglycol and polyethyleneglycol . Preferably, water or mixture of water and ethanol is used as the liquid solvent. When water or mixture of water and ethanol is used as the liquid solvent, it is added to the mixture in amount of 5~50% to drug, more preferably in an amount of 10 ~30% to drug, and most preferably in an amount of 20 ~25% to drug. Thereafter, unlike the two-layered commercial tablet such as Tyrenol ER, the oral dosage forms of the present invention prepared by simple mixing method is heterodisperse and single-layered tablet. The oral dosage forms of the present invention are prepared by economical method. Particularly, the oral dosage forms are prepared by conventional machine, to lower their manufacturing expenses. The oral dosage forms are prepared by simple method, to be favorable to the mass-production. Also, tablets as one formulation of the oral dosage forms according to the present invention are crushed to compressed pellet or granule, thereafter are further filled in commercially available hard- gelatin capsule.

The present invention will be explained in more detail with reference to the following examples. However, the following examples are provided only to illustrate the present invention, and the present invention is not limited to them. Therefore, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. <Example 1>

650 mg of acetaminophen as drug and 6 mg of colloidal silicon dioxide (Cab-O-Sil) as lubricant were homogeneously mixed in powder mixer, to increase fluidity of the drug. Also, 50 mg of hydroxypropylmethylcellulose (HPMC) as polymer base, 30 mg of sodium starch glycolate (primoj el) as disintegrant, and 10 mg of sodium lauryl sulfate (SLS) as surfactant were further added to the powder mixer. The resulting mixture was homogeneously mixed and sprayed with water, to prepare wet granule .

3 ml of water was used to prepare 20 tablets from the mixture. If necessary, a polymer base was dissolved in water, alcohol, and mixture of water and alcohol, thereafter the resulting solution was used to granulize the powder. The prepared granule was completely dried in oven at 60 °C for 12 hours, thereafter was homogeneously milled. 4 mg of magnesium stearate as lubricant which has the resulting granule formulated, was further added to the granule. Using rotary tableter(12 stations), the present inventors prepared the tablet containing 650 mg of acetaminophen of which hardness is about 65 N (Length direction) .

<Example 2> The tablet containing 650 mg of acetaminophen of which hardness is about 65 N (Length direction) , was prepared by the same method as one of example 1, except that 10 mg of poloxamer 470 was used as surfactant.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N (Length direction), was prepared by the same method as one of example 1, except that 10 mg of Polyoxyl 23 lauryl ester (Brij 35) was used as surfactant.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 1, except that 20 mg of sodium lauryl sulfate was used as surfactant .

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 1, except that 30 mg of sodium lauryl sulfate was used as surfactant.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 1, except that 50 mg of sodium lauryl sulfate was used as surfactant .

<Exa ple 7> The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 1, except that 60 mg of HPMC was used as polymer base .

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 1, except that 70 mg of HPMC was used as polymer base .

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 1, except that 60 mg of HPMC, 40 mg of sodium starch glycolate and 10 mg of sodium lauryl sulfate were used as polymer base, disintegrant and surfactant, respectively.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 1, except that 60 mg of HPMC, 50 mg of sodium starch glycolate and 10 mg of sodium lauryl sulfate were used as polymer base, disintegrant and surfactant, respectively.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 10, except that 5 mg of NaHC0₃ was further added.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 10, except that 10 mg of NaHC0₃ was further added.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 10, except that 15 mg of NaHC0₃ was further added.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 7, except that 60 mg of sodium starch glycolate was used as disintegrant.

<Example 15> The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 7, except that 70 mg of sodium starch glycolate was used as disintegrant.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 1, except that 30 mg of HPMC, 6 mg of collidal silica and 4 mg of magnesium stearate were used as polymer base, and 50 mg of pregelatinized Starch, 5 mg of sodium lauryl sulfate and 20 mg of microcrystalline cellulose were used as disintegrant, surfactant and secondary disintegrant, respectively.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 16, except that 2.5 mg of sodium lauryl sulfate was used as surfactant. <Example 18 >

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 1, except that 6 mg of colloidal silica and 4 mg of magnesium stearate were used as lubricant, and 30 mg of HPMC, 45 mg of pregelatinized starch, 2.5 mg of sodium lauryl sulfate, 25 mg of microcrystalline cellulose were used as polymer base, disintegrant, surfactant and secondary disintegrant, respectively.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 18, except that 40 mg of pregelatinized starch was used as disintegrant.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 18, except that 25 mg of pregelatinized starch was used as disintegrant.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 1, except that 6 mg of colloidal silica and 4 mg of magnesium stearate were used as lubricant, and 30 mg of HPMC, 25 mg of pregelatinized starch, 2.5 mg of sodium lauryl sulfate, 25 mg of microcrystalline cellulose and 10 mg of NaH₂P0₄ were used as polymer base, disintegrant, surfactant, secondary disintegrant and water-soluble additive, respectively.

<Example 22> The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 21, except that 40 mg of NaH₂P0₄ was used as water-soluble addditive.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 21, except that 80 mg of NaH₂P0₄ was used as water-soluble addditive.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 21, except that 5 mg of NaH₂P0₄ was used as water-soluble addditive. <Example 25>

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 1, except that 6 mg of colloidal silica and 4 mg of magnesium stearate were used as lubricant, and 40 mg of HPMC, 25 mg of pregelatinized starch, 2.5 mg of sodium lauryl sulfate, 25 mg of microcrystalline cellulose and 5 mg of NaH₂P0₄ were used as polymer base, disintegrant, surfactant, secondary disintegrant and water-soluble additive, respectively.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 1, except that 6 mg of colloidal silica and 4 mg of magnesium stearate were used as lubricant, and 35 mg of HPMC, 25 mg of pregelatinized starch, 1.0 mg of sodium lauryl sulfate, 20 mg of microcrystalline cellulose and 2.5 mg of NaH₂P0₄ were used as polymer base, disintegrant, surfactant, secondary disintegrant and water-soluble additive, respectively.

<Example 27> The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 26, except that 37.5 mg of HPMC was used as polymer base.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 21, except that 36.5 mg of HPMC was used as polymer base .

The compositions of the oral dosage forms prepared in the above examples were shown in table 1. [Table l]

The composition of the oral dosage forms prepared in the above examples

The tablet containing 650 mg of acetaminophen of which hardness is about 150 N, was prepared by the same method as one of example 1, except that 6 mg of colloidal silica and 4 mg of magnesium stearate were used as lubricants and tableting pressure of tableter was controlled.

The tablet containing 650 mg of acetaminophen of which hardness is about 80 N, was prepared by the same method as one of example 1, except that 6 mg of colloidal silica and 4 mg of magnesium stearate were used as lubricants and tableting pressure of tableter was controlled.

To confirm whether release of drug is influenced by viscosity of polymer base (particularly, HPMC) , the oral dosage form containing acetaminophen as a drug was prepared by following method.

Micro-granules were prepared by the same method as example 17, wherein HPMC (viscosity 4000 cps) and HPMC (viscosity 100,000 cps) was used as polymer base, respectively. Two sorts of the granules were mixed in the ratio of 1:1. 6 mg of colloidal silica and 4 mg of magnesium stearate as lubricant were homogeneously mixed with the mixture. Thereafter, the direct tablet was prepared by using rotary tableter (12 stations) . <Exaιnple 32>

To confirm whether release of drug is influenced by particle size of drug, the present inventors prepared the oral dosage forms with drug powder (60-100 mesh) , which is prepared by crushing acetaminophen as a drug. 6 mg of colloidal silica and 4 mg of magnesium stearate as lubricant were homogeneously mixed with the drug powder. Thereafter, the direct tablets were prepared by the same method as example 1.

The tablet containing 650 mg of acetaminophen of which hardness is about 65 N, was prepared by the same method as one of example 1, except that 50 mg of sodium lauryl sulfate was not used as surfactant .

The tablet containing 650 mg of acetaminophen was prepared by the same method as one of comparative example 1, except that 30 mg of carboxymethylcellulose (Ac-Di-Sol) as disintegrant was used in place of sodium starch glycolate.

<Comparative example 3> The tablet containing 650 mg of acetaminophen of which hardness was about 65 N, was prepared by the same method as one of comparative example 1, except that 30 mg of corn starch as disintegrant was used in place of sodium starch glycolate.

The tablet containing 650 mg of acetaminophen of which hardness was about 65 N, was prepared by the same method as one of comparative example 1, except that 70 mg of HPMC was used as polymer base.

The tablet containing 650 mg of acetaminophen of which hardness was about 65 N, was prepared by the same method as one of comparative example 1, except that 90 mg of HPMC was used as polymer base.

The tablet containing 650 mg of acetaminophen of which hardness was about 65 N, was prepared by the same method as one of comparative example 1, except that 40 mg of sodium starch glycolate was used as disintegrant.

<Comparative example 7> The tablet containing 650 mg of acetaminophen of which hardness was about 65 N, was prepared by the same method as one of comparative example 1, except that 50 mg of sodium starch glycolate was used as disintegrant.

The tablet containing 650 mg of acetaminophen of which hardness was about 65 N, was prepared by the same method as one of comparative example 1, except that 6 mg of colloidal silica and 4 mg of magnesium stearate were used as lubricant, and 30 mg of HPMC and 70 mg of pregelatinized starch (Prej el) were used as polymer base and disintegrant, respectively.

The tablet containing 650 mg of acetaminophen of which hardness was about 65 N, was prepared by the same method as one of comparative example 1, except that 6 mg of colloidal silica and 4 mg of magnesium stearate were used as lubricant, and 30 mg of HPMC, 50 mg of pregelatinized starch (Prejel) and 20 mg of avicel were used as polymer base, disintegrant and secondary disintegrant, respectively.

The tablet containing 650 mg of acetaminophen of which hardness was about 65 N was prepared by the same method as one of comparative example 9, except that 30 mg of pregelatinized starch (Prejel) were used as disintegrant.

<Comparative example ll>(Tyrenol ER commercial tablet)

Tyrenol ER commercial tablet containing 650 mg of acetaminophen was used as comparative sample.

<Comparative example 12> (capsule containing milled pellet)

Milled pellet was obtained by milling the oral dosage form containing 650 mg of acetaminophen and having the composition represented in example 26. Thereafter, the milled pellet containing 650 mg of acetaminophen was filled in hard- gelatin empty capsule, to obtain solid capsule.

<Comparative example 13> (Capsule containing granule) The wet granule containing 650 mg of acetaminophen and having the composition represented in example 26, was prepared by the method represented by comparative example 1. Thereafter, granule containing 650 mg of acetaminophen was filled in hard-gelatin empty capsule, to obtain solid capsule.

Experimental example 1> Solubility of drug

The present inventors measured solubility of acetaminophen in an additive of the group consisting various oils, fatty acids or surfactants, to select. one favorable to initial release of acetaminophen. The results were shown in table 2. [table 2]

Solubility of acetaminophen

As shown in table 2 , acetaminophen had the largest solubility in poloxamer 407 as surfactant. In addition, acetaminophen had large solubility in polyoxyl 23 lauryl ester (Brij35) , sodium lauryl sulfate, cremophor, labrasol, tween 20 and tween 80, respectively.

Also, solubilities of acetaminophen in additives were maximum twice as large as one in water. Increase of solubility accelerates the intial release of drug. Therefore, the present inventors selected surfactant as preferable additive. More preferably, the surfactant is selected from the group consisting poloxamer, sodium lauryl sulfate, labrasol, transcutol, labrafil, labrafac, polysorbate containing Tween 20, Tween 40, Tween 60, and Tween 80, PEG-60 hydrogenated castor oil, PEG-40 hydrogenated castor oil, Polyoxyl 23 lauryl ester (Brij35) . Most preferably, the surfactant is selected from the group consisting poloxamer, sodium lauryl sulfate and Tween 80.

Experimental example 2> hardness of the tablets and content of acetaminophen

To measure the hardness of the tablets, the present inventors used the commercial tablet and the oral dosage forms prepared in the examples . The present inventors used hardness measurer [Erweka, Germany] to measure the hardness of the tablets. The results were shown in table 3.

Also, the present inventors transformed the commercial tablets (6 tablets) to drug powder by using pestle and mortar. 100 mg of the powder was dissolved in 100 ml of distilled water, thereafter the solution was filtered to prepare a filtrate. The filtrate was diluted as forty times. Content of acetaminophen from the diluted filtrate was measured by UV spectrophotometer in range of 254 nm. And content of acetaminophen contained in the oral dosage forms (6 tablets) prepared in the example was measured by the same method. The results were shown in table 3. [table 3]

Hardness of the tablets and content of acetaminophen

Table 3 shows that the tablets prepared in the examples had higher hardness than the commercial tablets, which hardness of the tablets had tendency to increase with increasing content of HPMC as polymer base. Also, hardness of the tablets had tendency to decrease with decreasing content of HPMC. However, in addition to HPMC, hardness of the tablets was influenced in other additives used in preparation of the tablets. The oral dosage forms according to the present invention were formulated into preparation such as compressed pellet, granule or hard-gelatin capsule through milling, as well as tablets. Therefore, . for favorable hardness with preparation, polymer base is preferably used in amount of 10-90 parts by weight, more preferably in amount of 20-50 parts by weight, most preferably in amount of 30-40 parts by weight.

Also, as shown in table 3, the tablets prepared in examples according to the present invention contain acetaminophen to be 80% above on the average. Compared with commercial tablet, the tablets of the present invention had no significant difference in the content of acetaminophen as well as the hardness.

Experimental example 4> dissolution rate of drug in various dissolution media

The present inventors measured dissolution rate of commercial tablets and the tablets prepared in the example in various dissolution, using the following method.

Dissolution rate of acetaminophen was measured according to the dissolution test method disclosed in a guidebook "Korea Pharmacopeia (7^th revision) " . Particularly, commercial tablets (6 tablets) and the tablets (6 tablets) of the present invention were weighted in the same amounts, respectively. Dissolution solution was selected from the group consisting artificial gastric juice (pH 1.2), artificial intestinal juice (pH 6.8), acetic acid buffer- solution (pH 4.0) and water. Dissolution was performed according to the paddle method at a stirring rate of 50 rpm, a dissolution temperature of 37 ± 1 °C and a dissolution time of 8 hours, using 900 ml of the selected dissolution solution. 1 ml samples were collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 hours, at which point the same dissolution solution was supplemented with an equivalent amount of the collected sample. The collected sample was diluted for forty times after being centrifuged. Thereafter, the content of acetaminophen from the diluted samples was measured by using the UV spectrophotometer in the range of 254 nm. Concentration of acetaminophen was determined by a standard curve, which was converted to dissolution rate (%) . The method for measurement of dissolution rate was decided by the preliminary experiment, which is measurement of dissolution rate in artificial intestinal juice (pH 6.8). The present inventors measured dissolution rate of tablets, particularly commercial tablet and the tablet of the present invention, in artificial gastric juice (pH 1.2) and artificial intestinal juice (pH 6.8) . The results were shown in table 4 - 6. [table 4 ]

Dissolution rate of the oral tablets containing acetaminophen in artificial gastric juice (%)

[table 5]

Dissolution rate of the oral tablets containing acetaminophen in artificial intestinal juice (%)

[table 6]

Dissolution rate of the oral tablets containing acetaminophen in water (%)

step 1 : Effect of HPMC as polymer base

The present inventors used the oral tablets prepared in the comparative example 1, comparative example 4, comparative example 5, example 7, example 8 and example 30 to observe the dissolution of acetaminophen as the fraction of HPMC as polymer base. The oral tablets prepared without sodium lauryl sulfate as surfactant, in comparative example 1, comparative example 4 and comparative example 5, had no difference in intial dissolution rate, with fraction of HPMC as polymer base increasing. Also, at 2 hours, dissolution rate of drug was decreased with concentration of HPMC increasing.

However, the oral tablets prepared with sodium lauryl sulfate as surfactant, in example 7, example 8 and example 30, had remarkable decreasement in intial dissolution rate, with fraction of HPMC as polymer base increasing.

Dissolution rate in the oral tablets prepared in example 10 and example 31 showed that viscosity of HPMC as polymer base had effect on the release of acetaminophen. Particularly, dissolution rate of acetaminophen in artificial gastric juice (pH 1.2) had decreased with the fraction of HPMC (high viscosity) increasing.

Also, dissolution rate in the oral tablets prepared in example 26, example 27 and example 28 showed that in presence of water-soluble inorganic additives, concentration of HPMC had effect on the release of acetaminophen. Particularly, in presence of water-soluble inorganic additives, dissolution rate of acetaminophen in artificial intestinal juice (pH 6.8) and water was largely changed with concentration of HPMC (concentration of HPMC was slightly changed form 35.0 to 37.5) . Therefore, the acetaminophen of the oral tablets had a tendency to slowly release with fraction of HPMC increasing.

Therefore, to rapidly release acetaminophen in steady amount, in artificial gastric juice (pH 1.2), the oral tablets have to ^' be prepared by using polymer base in an amount 30-40 parts by weight in the presence of surfactant, which viscosity of the surfactant is not high. Also, to accelerate release of drug in artificial intestinal juice (pH 6.8) and water, water-soluble inorganic additives preferably have to be contained in the oral tablets .

step 2 : Effect of disintegrant

The present inventors observed disintegration effect of various disintegrant such as sodium starch glycolate, pregelatinized starch, carboxymethyl cellulose and corn starch.

Pregelatinized starch had better disintegration effect than sodium starch glycolate and carboxymethyl cellulose. Also, corn starch had slighter disintegration effect than other disintegrants.

Sodium starch glycolate was used as disintegrant in the comparative example 1, 6, 7, example 7, 9, 10, 14 and 15. The present inventors measured dissolution of acetaminophen from the prepared oral dosage forms, to observe effect of release of acetaminophen as fraction of sodium starch glycolate.

Dissolution of acetaminophen in the oral dosage forms prepared in comparative example 1, 6 and 7, without sodium lauryl sulfate as surfactant was decreased with fraction of sodium starch glycolate increasing. Also, intial dissolution of acetaminophen was not influenced by fraction of sodium starch glycolate.

However, the oral dosage forms prepared in example 7, 9,

19, 14 and 15 in the presence of sodium lauryl sulfate as surfactant had no difference in initial dissolution in artificial gastric juice. Also, dissolution in 2 hours was decreased with fraction of sodium starch glycolate increasing.

The present inventors measured dissolution rate in the oral dosage forms prepared by using pregelatinized starch and Avicel as other dusintegrant and secondary disintegrant, respectively, in comparative example 8 and example 20, to observe dissolution of acetaminophen as fraction of pregelatinized starch and Avicel. The results showed that further addition of Avicel increased initial dissolution of acetaminophen in artificial gastric juice. Also, reproducible dissolution was caused by control the fraction of pregelatinized starch and Avicel.

step 3 : Effect of surfactant

Sodium lauryl sulfate, poloxamer and Brij35 were used as surfactant in example 1, 2 and 3, respectively. The present inventors measured dissolution rate of acetaminophen from the oral dosage forms, to observe solublization of surfactant. Sodium lauryl sulfate gave better solubilization effect than poloxamer and Brij35 as surfactant, which is different from the result obtained in solubility in experimental example .

However, sodium lauryl sulfate was used in different fraction in example 1, example 4 to 6. the present inventors measured dissolution rate from the oral tablets, to observe dissolution of acetaminophen as concentration of sodium lauryl sulfate. Dissolution of acetaminophen was decreased with the fraction of sodium lauryl sulfate increasing. step 4 : Effect of hardness of the tablet

The oral tablets prepared in example 1, example 29 and example 30 have different hardness. The present inventors measured dissolution rate from the oral tablets, to observe the effect of hardness on the dissolution rate of acetaminophen. Hardness of the tablets caused difference in initial dissolution of acetaminophen. Dissolution of acetaminophen was decreased with hardness of the tablets increasing. Therefore, dissolution of acetaminophen was influenced by difference of hardness of the tablets.

step 5: Effect of foaming agent (NaHCQ₃)

The oral tablets were prepared by using NaHC0₃ as foaming agent in example 11 to 14. The present inventors measured dissolution rate from the oral tablets, to observe dissolution of acetaminophen as use of foaming agent.

The oral tablets prepared in example 12 were rapidly disintegrated by means of small hardness. However, the oral tablets prepared in example 11 and example 13, with different fraction of foaming agent (NaHC0₃) had similar dissolution. The foaming agent established excellent results in formulation of tablet. However, the foaming agent lowered mobility of powder and had the powder discolored to brown. Therefore, the foaming agent was not favorable as additives. step 6: Effect of water-soluble additive (NaH₂PQ₄)

The oral tablets were prepared by using NaH₂P0₄ as water-soluble additives in example 20 to 24. The present inventors measured dissolution rate from the oral tablets, to observe dissolution of acetaminophen as use of NaH₂P0₄ as water-soluble inorganic additives.

Dissolution of acetaminophen was increased with the fraction of water-soluble additives increasing. 90% of acetaminophen was released within 30 min in the oral tablets containing NaH₂P0₄ in an amount of 10 mg per pellet, therefore the oral tablets had no slowly-releasing effect. Also, the oral tablets containing NaH₂P0₄ in an amount of 5 mg per pellet by controlling other additives in example 25 to 28 had favorable releasing type.

Dissolution rates from commercial tablet and the tablet prepared in example 38, in artificial gastric juice, artificial intestinal juice and water were measured by the method represented in the experimental example 4. The results were shown in table 7.

[table 7]

Dissolution rate in artificial gastric juice, artificial intestinal juice and water (%)

As shown in table 7, the oral tablets prepared in example 28 had equivalent had the same dissolution rate as commercial tablets in various condition such as artificial gastric juice, artificial intestinal juice, acetate acid- buffered solution and water. Therefore, the oral dosage forms prepared in example 28 had the same release, particularly rapidly-releasing and slowly-releasing, as commercial tablets. And the dosage forms of the present invention are prepared by unique and economical preparation method. Therefore, the oral dosage forms can be used as substitutes of commercial tablets.

Industrial Applicability

As described hereinbefore, the present inventors provided the oral dosage forms containing acetaminophen as a model drug, polymer base, disintegrants, lubricant and water- soluble additives. Upon oral administration, the dosage forms of the present invention absorb water and rapidly release about 50% of loading dose within a few minute in some acidic condition of stomach. Thereafter, the oral dosage forms form a gel structure by polymer base and slowly release the residual amount of acetaminophen in a controlled fashion. As a result, the oral dosage forms show immediate and extended release profiles by controlling release rate of acetaminophen.

The dosage forms of the present invention are formulated to various formulations such as tablet, compressed pellet, granule and capsule. Also, the oral dosage forms of the present invention have the same release as commercial tablet in various dissolution media, could be easily prepared by using conventional tablet machine. And the oral dosage forms could be prepared by economical and unique method, to use as substitute of commercial tablet.

Claims

What is claimed is:

1. Oral dosage forms containing acetaminophen, wherein the oral dosage forms contain acetaminophen as a drug; polymer base; disintegrant; surfactant; and lubricant.

2. The oral dosage forms containing acetaminophen according to claim 1, wherein the oral dosage forms further contain water-soluble additives.

3. The oral dosage forms containing acetaminophen according to claim 1, wherein the oral dosage forms are formulated to tablet, compressed pellet, granule or capsule containing the granule .

4. The oral dosage forms containing acetaminophen according to claim 1, wherein the polymer base is selected from the group consisting the cellulose derivative; propylene oxide and its derivatives; polyvinylpyrrolidone; polyethylene glycol and polyvinyl alcohol; polyvinylacetate, polyvinylacetate phthalate, polymethacrylate and its copolymer; polyacrylic acid and its derivatives; glycerol monostearate, poloxamer, sodium alginate, guar gum, chitosan, sodium pectinate, gelatin and gum tragacanth.

5. The oral dosage forms containing acetaminophen according to claim 4, wherein the cellulose derivative is selected from the group consisting hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose , hydroxypropylmethylcellulose phthalate, hydroxyprolpymethylcellulose acetylsuccinate and sodium carboxymethylcellulose.

6. The oral dosage forms containing acetaminophen according to claim 5, wherein the cellulose derivative is hydroxypropylmethylcellulose.

7. The oral dosage forms containing acetaminophen according to claim 1, wherein the disintegrant is selected from the group consisting Croscarmellose Sodium, Sodium Starch Glycolate, Pregelatinized Starch, microcrystalline cellulose, Crospovidone and the commercially used Polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, alginic acid, Carboxymethylcellulose calcium salt and its sodium salt, colloidal silica, guar gum, magnesium aluminium silicate, methylcellulose, powder cellulose, starch, sodium alginate and their mixture.

8. The oral dosage forms containing acetaminophen according to claim 7, wherein the disintegrant is selected from the group consisting Croscarmellose Sodium, Sodium Starch Glycolate, Pregelatinized Starch, microcrystalline cellulose and Crospovidone.

9. The oral dosage forms containing acetaminophen according to claim 1, wherein the surfactant is selected from the group consisting sodium lauryl sulfate and its derivatives, poloxamer and its derivatives, medium chain triglyceride, labrasol, transcutol, labrafil, labrafac, polysorbate, sorbitan Esters, cremophor, PEG-60 hydrogenated castor oil, PEG-40 hydrogenated castor oil, sodium lauryl glutamate, disodium cocoamphodiacetate, Polyoxyl 23 lauryl ester and their mixtures.

10. The oral dosage forms containing acetaminophen according to claim 9, wherein the surfactant is selected from the group consisting sodium lauryl sulfate and its derivatives, polysorbate, Sorbitan Esters and their mixtures.

11. The oral dosage forms containing acetaminophen according to claim 1, wherein the lubricant is selected from the group consisting magnesium stearate, Si0₂, colloidal silica, talc and their mixture.

12. The oral dosage forms containing acetaminophen according to claim 2, wherein the water-soluble additive is selected from the group consisting NaH₂P0₄, KH₂P0₄, polyvinylpyrrolidone, polyethylene glycol, gelatin, gum, carbohydrate, cellulose and its derivatives, polyethylene oxide and its derivatives, polyvinyl alcohol, poly acrylic acid and its derivatives, polymethylacrylate and their mixtures .

13. The oral dosage forms containing acetaminophen according to claim 12, wherein the water-soluble additive is selected from the group consisting NaH₂P0₄, KH₂P0₄, polyvinylpyrrolidone and polyethylene glycol.

14. The oral dosage forms containing acetaminophen according to claim 1 or 2 , wherein the oral dosage forms further contain antioxidant, secondary disintegrant or foaming agent .

15. The oral dosage forms containing acetaminophen according to claim 14, wherein the foaming agent is sodium bicarbonate or sodium carbonate .

16. The oral dosage forms containing acetaminophen according to claim 1, wherein the oral dosage forms contain acetaminophen as drug in amount of 300 —900 parts by weight; polymer base in amount of 10 ~90 parts by weight; disintegrant in amount of 5~100 parts by weight; surfactant in amount of 0.01—100 parts by weight; lubricant in amount of 0.1—20 parts by weight; and water-soluble additives in amount of 1~80 parts by weight.

17. The oral dosage forms containing acetaminophen according to claim 1, wherein the oral dosage forms contain acetaminophen as drug in amount of 300 ~900 parts by weight; polymer base in amount of 20 —50 parts by weight; disintegrant in amount of 10~30 parts by weight; surfactant in amount of 0.1—10 parts by weight; lubricant in amount of 1~10 parts by weight; and water-soluble additives in amount of 1 —10 parts by weight.

18. The oral dosage forms containing acetaminophen according to claim 1, wherein the oral dosage forms contain acetaminophen as drug in amount of 300—900 parts by weight; polymer base in amount of 30—40 parts by weight; disintegrant in amount of 10 ~30 parts by weight; surfactant in amount of 1~3 parts by weight; lubricant in amount of 3~6 parts by weight; and water-soluble additives in amount of 1 —10 parts by weight.

19. The oral dosage forms containing acetaminophen according to claim 1, wherein the oral dosage forms contain 650 mg of acetaminophen.

20. The oral dosage forms containing acetaminophen, wherein the oral dosage forms contain acetaminophen as a drug; hydroxypropylmethyl cellulose as polymer base; Pregelatinized Starch, sodium starch glycolate or their mixture as disintegrant; sodium lauryl sulfate and Tween 80 as surfactant; and colloidal silica or magnesium stearate as lubricant .

21. The oral dosage forms containing acetaminophen, wherein the oral dosage forms contain acetaminophen as a drug; hydroxypropylmethyl cellulose as polymer base; Pregelatinized Starch, sodium starch glycolate or their mixture as disintegrant; sodium lauryl sulfate as surfactant; colloidal silica or magnesium stearate as lubricant; NaH₂P0₄ as water-soluble additive; and microcrystalline cellulose as secondary disintegrant.

22. The oral dosage forms containing acetaminophen claim 20 or 21, wherein the oral dosage forms are formulated to tablet, compressed pellet, granule or capsule containing the said granule.

23. A method for preparing the oral dosage forms containing acetaminophen, wherein the method is comprised; homogeneously mixing acetaminophen as a drug, polymer base, disintegrant, surfactant, lubricant and water-soluble additive, preparing wet granule by adding liquid solvent to the mixture, drying and milling the wet granule and tableting the resulting granule by general tablet machine (direct tableting) .

24. The method for preparing the oral dosage forms containing acetaminophen according to claim 23, wherein the liquid solvent is one or more selected from the group consisting water, ethanol, glycerine, propyleneglycol and polyethyleneglycol .

25. The method for preparing the oral dosage forms containing acetaminophen according to claim 24, wherein the liquid solvent is water or mixture of water and ethanol.

26. The method for preparing the oral dosage forms containing acetaminophen according to claim 25, wherein the water or mixture of water and ethanol is used in amount of 5-50% to drug.

27. The method for preparing the oral dosage forms containing acetaminophen according to claim 25, wherein the water or mixture of water and ethanol is used in amount of 20-30% to drug.