KR20040006887A - Compositions for controlled release acetaminophen dosage forms - Google Patents

Abstract

PURPOSE: Provided is a release-controlled oral preparation which controls the release of drug by rapidly releasing a predetermined amount of drug by absorbing the moisture under the strong acid condition in the stomach, and slowly releasing the drug as formation of gel by the polymer. CONSTITUTION: An oral preparation comprises acetaminophen as a drug, a polymer material, a disintegrant, a surfactant, and a lubricant. The polymer material is selected from the group consisting of cellulose derivatives, polyethylene oxide and derivatives thereof, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polyvinylacetate, polyvinylacetate phthalate, polymethacrylate and derivatives thereof, glycerolmonostearate, poloxamer, sodium alginate, guar gum, chitosan, sodium pectinate, gelatin, and gum tragacanth.

Description

Compositional controlled release oral preparations containing acetaminophen {Compositions for controlled release acetaminophen dosage forms}

The present invention relates to oral preparations containing acetaminophen, more specifically, acetaminophen as a drug; Polymer bases; Disintegrants; Surfactants; And an oral formulation containing acetaminophen, which contains a lubricant and may further comprise a water-soluble additive. The preparation of the present invention may be provided in various forms of preparations, including tablets, compressed ingots, granules and capsule preparations, and upon oral administration of the oral preparations of the present invention, a certain amount of drug may be absorbed under conditions of strong acid in the gastrointestinal tract. It releases quickly and the gel is formed by the polymer base when water is contained, and by slowly releasing a certain amount of drug, the release property of the drug can be controlled, and the process itself is simple and can be mass-produced using existing equipment. It is a very economical oral preparation.

Acetaminophen is a type of nonsteroidal analgesic anti-inflammatory drug that has a short half-life and thus does not have a significant problem in the analgesic anti-inflammatory effect upon short-term administration, but has a problem that frequent administration is required for the treatment of analgesic and anti-inflammatory treatment of chronic diseases.

Therefore, in addition to a fast-release agent for expressing a quick medicinal effect, a sustained-release agent for the purpose of continuous analgesic and anti-inflammatory treatment, or acetaminophen containing both a fast-release and sustained-release property Research on formulations is actively underway.

According to US Pat. No. 6,217,907 as an example of a fast-release preparation, sodium starch glycolate and microcrystalline cellulose in the formulation are used as erosion accelerators and wicking agents and are used by the direct method. It is known about the fast-release tablet tableting. U.S. Patent No. 4,439,453 discloses wet granules using disintegrants and binders, such as pregelatinized starch, cross-linked sodium carboxymethyl cellulose (Cross-linked SCMC) and tablets for fast-release tablets. It is describing. In addition, another example in which the wet granules containing the binder and the disintegrant are prepared as fast-release tablets uses Povidone as a binder and Croscarmellose Sodium is referred to as a strong disintegrant [ US Patent No. 6,264,983].

However, the rapid-release preparations are useful as preparations for rapid analgesic and anti-inflammatory, but they are insufficient for sustaining the drug for a long time.

On the other hand, as a sustained-release preparation containing acetaminophen, sustained-release tablets prepared by wet granulation of hydroxypropyl methylcellulose (hydroxypropyl methylcellulose) have been reported (US Pat. No. 4,695,591). In addition, according to US Pat. No. 6,024,882, fast-release uncoated tablets containing polyvinyl pyrrolidone and lactose were converted into Aquacoat ECD-30 and Methocel E5 preminum. Reference is made to slow release tablets prepared by coating. However, the preparation method of the sustained release formulation is already known, and the sustained release formulation has a disadvantage in that it takes time to express an initial rapid drug effect.

Therefore, in recent years, studies on acetaminophen-containing preparations having both rapid release and sustained release have been conducted and reported.

According to US Pat. No. 6,254,891, a sustained release acetaminophen capsule using Sugar / starch seeds, a rapid release pellet coated with a drug and a strong disintegrant, and a mixture of a sustained release pellet coated with a drug and a lubricant are reported. Doing.

In addition, during the formulation, acetaminophen microparticles that are fast-release and drug-containing particles are simultaneously coated with microcrystalline cellulose and a strong disintegrant to prepare sustained-release tablets, and additionally, hydroxypropymethyl cellulose (HPMC). Has been reported for coating formulations (US Pat. No. 6,126,969).

However, these formulations have the disadvantage of separately preparing the fast-release portion and the sustained-release portion, and are not technically novel methods but also require relatively low economics because additional processes are required for the control of the release.

Representative formulations containing both rapid release and sustained release properties include Tylenol ER, which is currently marketed by Janssen [US Pat. No. 4,820,522], wherein the Tylenol ion contains a fixed amount of drug in the rapid release drug layer. It is a form of preparation containing a certain amount of drug at the same time in the over-release drug layer. More specifically, Tylenol IAL is a bilayer tablet containing 650 mg of acetaminophen, and the rapid-release drug layer containing 325 mg, which is half of the drug, first disintegrates rapidly and shows a quick effect, and contains the remaining 325 mg. The sustained release drug layer is a rectangular film-coated tablet that gradually disintegrates and lasts for up to 8 hours. The preparation contains a wicking agent and an erosion accelerator in the fast-release layer, and the sustained-release layer is a powder composition containing an active matrix binder (hydroxyethyl cellulose) and a wicking agent (microcrystalline cellulose). Bilayer tablets.

In general, the tablet in the form of a multi-layered tablet has been reported as a very useful dosage form to maintain the drug for rapid release and sustained for a long time by simultaneously controlling the fast-release and sustained-release drugs. In the preparation of the preparation, special equipment is required, and in particular, the mass productivity is relatively low and the unit price is high.

Accordingly, the present inventors have endeavored to obtain a more economical formulation while having a rapid-release and sustained-release release aspect containing acetaminophen, resulting in the drug acetaminophen; Polymer bases; Disintegrants; Surfactants; And an oral preparation containing acetaminophen, which contains a lubricant and may further include a water-soluble additive, wherein the oral preparation of the present invention can be obtained by simple mixing, not a bilayer structure of a commercially available formulation. As a heterogeneous dispersion of a single layer, the present invention was completed by confirming equivalence with commercially available formulations in various eluent compositions such as gastric juice, artificial intestinal fluid, acetate buffer, and water.

An object of the present invention is a drug that is a drug acetaminophen; Polymer bases; Disintegrants; Surfactants; And an oral formulation containing acetaminophen, which contains a lubricant and may further comprise a water-soluble additive.

Another object of the present invention is to provide an oral preparation containing acetaminophen which has improved economical efficiency in a single layer heterogeneous dispersible formulation having both rapid release and sustained release properties using a simple process.

Still another object of the present invention is to provide a method for preparing an oral preparation containing acetaminophen.

In order to achieve the above object, the present invention is a drug acetaminophen; Polymer bases; Disintegrants; Surfactants; And acetaminophen, which contains a lubricant and may further comprise a water-soluble additive.

The term "polymer base" of the present invention can absorb moisture to control and delay the release of the drug. Therefore, the release property of a drug can be controlled by using a polymeric base in the oral preparation containing the acetaminophen of this invention.

In this case, as the polymer base, any pharmaceutically acceptable polymer may be used, and examples thereof include hydropropylmethyl cellulose (hydroxypropymethylcellulose), methyl cellulose (methylcellulose), ethyl cellulose (ethylcellulose), hydropropyl cellulose (hydroxypropycellulose), Hydropropylmethylcellulose phthalate, hydroxypropymethylcellulose acetylsuccinate, and sodium carboxymethylcellulose cellulose derivatives composed of carboxymethylcellulose); Propylene oxide and its derivatives; Polyvinylpyrrolidone (commercially known as Kollidons); Polyethylene glycol (commercial carbowax) and polyvinyl alcohol; Polyvinylacetate, polyvinylacetate phthalate, polymethacrylate and polymers thereof (commercially Eudragit ; Polyacrylic acid and its derivatives (typically carbamers); Glycerol monostearate, and poloxamer can be selected and used.

In addition, sodium alginate, guar gum, chitosan, sodium pectinate, gelatin, and gum tra may absorb water to form gels. It may be selected from the group consisting of gum tragacanth.

Preferably, cellulose derivatives are used, and when using hydroxypropymethylcellulose, the most ideal effect can be obtained. The hydropropylmethyl cellulose is known to have a wide variety of purposes for pharmaceutical use according to its molecular weight [ Handbook of Pharmaceutical Excipients , Edited by Arthur H. Kibbe, 2000, 3rd edition, APHA].

The amount of hydropropylmethyl cellulose used as the polymer base in the embodiment of the present invention is preferably 10 to 90 parts by weight, more preferably 20 to 50 parts by weight, most preferably 30 to 40 parts by weight. will be.

Disintegrants are used to absorb water and promote early disintegration of the formulation. Examples of disintegrants that can be used as the formulation of the present invention include Croscarmellose Sodium and Sodium Starch Glycolate. Primojel, Pregelatinized Starch (Starch 1500 or Prejel), microcrystalline cellulose (Avicel), Crospovidone (Polyplasdone) and other commercially available products. Useful polyvinylpyrrolidone (Kollidon), low-substituted hydroxypropylcellulose, alginic acid, carboxymethylcellulose (Ac-Di-Sol) calcium salt and sodium salt, colloidal silicon dioxide , Guar gum, magnesium aluminum silicate, methylcellulose, powdered cellulose, starch There may be mentioned sodium alginate (sodium alginate).

Preferably, croscarmellose sodium, sodium starch glycolate, microcrystalline cellulose, crospovidone and commercially available polyvinylpyrrolidone (PVP) Is to use.

Most preferably in the above, it is effective when using sodium starch glycolate or microcrystalline cellulose, especially when using two or more disintegrants in combination. At this time, it is preferable to use 5-100 weight part of disintegrating agents, Most preferably, it uses 10-30 weight part.

The disintegrants may also be added in addition to oral solid preparations and also when molded into compressed ingots, pellets, granules, capsules and the like in a pharmaceutically acceptable manner. It is also possible to further use secondary disintegrants for the purpose of faster release of the formulation.

The surfactant used in the oral preparation of the present invention serves to increase the permeability with water or powder and to improve the solubility of the drug. Surfactants used in the formulations of the present invention are hydrophilic or lipophilic or in equilibrium between these two extremes in the presence of polar or nonpolar groups present in the molecule. Surfactants are used as emulsifiers, surface adsorbents, wetting agents, and diffusing agents by lowering the interfacial tension between two interfaces, such as water and oil. It is also widely used to increase. Examples of the surfactants include sodium lauryl sulfate and derivatives thereof, poloxamer and derivatives thereof, intermediate chain triglycerides (MCT), labrasol, transcutol, Labrafil, labrafac, poloxamer, various polysorbates (eg, polyoxyethylene sorbitan monolaurate (hereinafter “Tween 20”)), Polyoxyethylene sorbitan monopalmitate ("Tween 40"), polyoxyethylene sorbitan monostearate ("Tween 60") and polyoxyethylene sorbitan monooleate ("Tween 80")], Sorbitan Esters [for example, sorbitan monolaurate (hereinafter "Span 20"), sorbitan monopalmitate ("Span 40"), sorbitan monostearate ("Span 60") ), Sorbitan monooleate ("Span 80"), sorbitan trira Rate (hereinafter "Span 25") sorbitan trioleate (hereinafter "Span 85") sorbitan tristearate (hereafter "Span 65")], cremophor, PEG-60 hydrogenated castor oil (PEG-60 hydrogenated castor oil), PEG-40 hydrogenated castor oil, sodium lauryl glutamate, disodium cocoamphodiacetate, It is not limited to these. Among these, sodium lauryl sulfate and its derivatives which are anionic surfactants, Tween 20, 40, 60, 80 which are nonionic surfactants, and Span 20, 40, 60, 80, 25, 85, 65 which are sorbitan esters, etc. Preferred, most preferably sodium lauryl sulfate and Tween 80. The surfactant used in the oral preparation of the present invention uses 0.01 to 100 parts by weight, preferably 0.1 to 10 parts by weight, most preferably 1 to 3 parts by weight.

In addition, a pharmaceutically usable lubricant may be used to improve the moldability of the oral preparation according to the present invention. Examples thereof include magnesium stearate, silica oxide (SiO ₂ ), and amorphous silica ( Amorphous fumed silica (Cab-O-Sil) or talc may be added, but not limited thereto. Particularly, when the lubricant is used alone or in combination of two or more, it is most ideal. The use range of the lubricant is preferably 0.1 to 20 parts by weight, more preferably 1 to 10 parts by weight, most preferably 3 to 6 It is to use parts by weight.

In the preparation of the oral solvent of the present invention, water-soluble additives, that is, water-soluble additives, may be used to additionally improve water absorption to increase the initial release rate of the drug.

As the water-soluble additive, inorganic and organic materials may be used. Examples thereof include, but are not limited to. Inorganic additives include NaH ₂ PO ₄ and KH ₂ PO ₄ ; Water-soluble polymers including polyvinylpyrrolidone and polyethylene glycol; Other additives such as gelatin, gum, carbohydrates, cellulose and its derivatives, polyethylene oxide and its derivatives, polyvinyl alcohol, polyacrylic acid and its derivatives (typically carbamers), It may further comprise a poloxamer, polymethyl acrylate or an inorganic material.

In addition, PVP or PEG may be used as the organic additive. PVP, a water-soluble polymer, is widely used in the same terminology as Kollidon, Plasdone, or Povidone, and consists of linear 1-vinyl-2-pyrrolidinone groups. As synthetic polymers, the average molecular weight varies from as little as 2,500 to as much as 3,000,000. PEG, another water-soluble polymer, is widely used in the same terminology as macrogol or carbowax, and is a synthetic polymer composed of oxyethylene groups. Average molecular weights can vary from as little as 300 to as high as 35,000.

As the water-soluble additive that can be used as the oral solvent of the present invention, NaH ₂ PO ₄ and KH ₂ PO ₄ are preferably used. In particular, when NaH ₂ PO ₄ is used, it is very effective, and the amount used is 1 to 80 parts by weight, most preferably 1 to 10 parts by weight.

Oral formulations of the present invention can be used within the scope of not adversely affecting the medicament and also in various pharmaceutical commonly used substances, such as antioxidants to prevent the formulation from oxidizing, secondary to aid in the faster release of the formulation. Disintegrants can be used. In addition, it may further include a blowing agent and the like to improve the foaming of the formulation. Examples of blowing agents that can be used in the oral preparation of the present invention include, but are not limited to, sodium bicarbonate (NaHCO ₃ ), sodium carbonate (Na ₂ CO ₃ ), and the like.

In the preparation of the oral preparation of the present invention, it can be prepared by adding a liquid solvent to the mixed powder. In this case, a liquid solvent may be used alone or a mixed solvent thereof selected from the group consisting of water, ethanol, glycerin, propylene glycol and polyethylene glycol. Preferably, the liquid solvent uses water alone or a mixed solvent of water and ethanol. At this time, in the case of water alone or a mixed solvent of water and ethanol, the preferred amount of use is in the range of 5 to 50%, more preferably 10 to 30%, most preferably 20 to 25% with respect to the main weight ratio.

Oral preparations containing acetaminophen of the present invention include 300 to 900 parts by weight of acetaminophen as a drug; 10 to 90 parts by weight of the polymer base; 5 to 100 parts by weight of disintegrant; 0.01 to 100 parts by weight of surfactant; 0.1 to 20 parts by weight of lubricant; And 1 to 80 parts by weight of the water-soluble additive.

More preferably, 300 to 900 parts by weight of acetaminophen; 20 to 50 parts by weight of a polymer base; 10-30 weight part of disintegrants; 0.1-10 weight part of surfactant; 1 to 10 parts by weight of lubricant; And 1 to 10 parts by weight of the water-soluble additive.

Most preferably, 300 to 900 parts by weight of acetaminophen which is a drug; 30 to 40 parts by weight of a polymer base; 10-30 weight part of disintegrants; 1-3 parts by weight of surfactant; 3 to 6 parts by weight of lubricant; And 1 to 10 parts by weight of the water-soluble additive.

The amount of acetaminophen included in the oral preparation of the present invention may be appropriately selected in consideration of the economics and stability of the drug, but is usually 300 to 900 mg (once daily sustained release), most preferably 650 mg.

The novel oral preparation of the present invention shows a dissolution pattern equivalent to conventional commercial preparations when comparative elution with conventional commercial preparations in eluents of various compositions, such as pH 1.2, pH 4.0, pH 6.8, water, etc. Some are rapid release and some of the drugs are sustained release for at least 4 hours. That is, when oral administration of the oral preparation of the present invention, it absorbs moisture under the condition of strong acid in the gastrointestinal tract and rapidly releases a certain amount of drug, and when the water is contained, a gel is formed by the polymer base to gradually release a certain amount of the drug. Can control the release of.

In particular, the oral preparation of the present invention uniformly mixes acetaminophen, a polymer base, a disintegrant, a surfactant, a lubricant, and a water-soluble additive, adds a small amount of liquid solvent, and mixes again to prepare wet and dried wet granules. The wet granules may be dried and milled, and then prepared by tableting (direct tableting) using a general tablet machine. Therefore, the oral preparation of the present invention is a single-layer heterogeneous dispersion type obtained by simple mixing rather than a bilayer structure of a commercially available formulation, and it is possible to reduce the manufacturing cost by using existing equipment as well as to simplify the process itself. Advantageous in production, it is very economical. In addition, the tablets can be broken again to form compacted ingots or granules, and then filled into hard capsules that can be used commercially.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to these Examples, and various modifications and variations are possible within the protection scope of the present invention described in the claims. It will be apparent to those skilled in the art to which the invention pertains.

Example 1 Preparation of Tablets Containing Acetaminophen

650 mg of acetaminophen and 6 mg of colloidal silicon dioxide (Cab-O-Sil), a lubricant, were evenly mixed to increase fluidity of the drug. As a polymer base, 50 mg of hydroxypropymethylcellulose (hereinafter referred to as "HPMC") and 30 mg of sodium starch glycolate (primojel) as a disintegrating agent were mixed in a powder mixer and uniformly mixed. Then, the wet granules were prepared by spraying with distilled water. The drug of the given composition and the lubricant (Cab-O-Sil) were first mixed evenly to increase the fluidity of the medicine. A polymer base, a disintegrating agent, and a surfactant were added thereto, and the mixture was uniformly mixed in a powder mixer, followed by spraying distilled water to prepare wet granules. Typically, 3 ml of distilled water was used to prepare 20 tablets. If necessary, a small amount of the polymer base in the formulation may be dissolved in distilled water or a mixed solvent of distilled water / alcohol and used to granulate the powder. After the granules were sufficiently dried in an oven at 60 ° C. for 12 hours, milled evenly, 4 mg of glidant and magnesium stearate were further mixed to form the preparation. Tablet) containing 650 mg of acetaminophen having a hardness of about 65 N (Length direction) was prepared by tableting.

<Example 2>

Except for using 30 mg of carboxymethylcellulise (Ac-Di-Sol) as a disintegrant in the composition of Example 1, was carried out in the same manner as in Example 1, containing 650 mg of acetaminophen Tablets were prepared by tableting.

<Example 3>

A tablet containing 650 mg of acetaminophen having a hardness of 65 N was carried out in the same manner as in Example 1, except that 30 mg of corn starch was used as a disintegrant in the composition of Example 1. Prepared by.

<Example 4>

A tablet containing 650 mg of acetaminophen having a hardness of 65 N was prepared in the same manner as in Example 1, except that 70 mg of HPMC was used as the polymer base in the composition of Example 1.

Example 5

A tablet containing 650 mg of acetaminophen having a hardness of 65 N was prepared in the same manner as in Example 1, except that 90 mg of HPMC was used as the polymer base in the composition of Example 1.

<Example 6>

Except for using 40 mg of sodium starch glycorate (primojel) as a disintegrant in the composition of Example 1, was carried out in the same manner as in Example 1, containing 650 mg of acetaminophen having a hardness of 65 N Tablets were prepared by tableting.

<Example 7>

Except for using 50 mg of sodium starch glycorate (primojel) as a disintegrant in the composition of Example 1, was carried out in the same manner as in Example 1, containing 650 mg of acetaminophen having a hardness of 65 N Tablets were prepared by tableting.

<Example 8>

The above procedure was used except that 650 mg of acetaminophen, 50 mg of HPMC as polymer base, 30 mg of sodium starch glycorate as disintegrant, and 10 mg of sodium lauryl sulfate as surfactant were used. It carried out by the same method as Example 1, and prepared by tableting the tablet containing 650 mg of acetaminophen of hardness 65N.

Example 9

In the same manner as in Example 1, except that 650 mg of acetaminophen, 50 mg of HPMC as a polymer base, 30 mg of sodium starch glycorate as a disintegrant, and 10 mg of Ploxamer 470 as a surfactant were used. It carried out and prepared by tableting the tablet containing 650 mg of acetaminophen of 65N hardness.

<Example 10>

Acetaminophen 650 mg, HPMC 50 mg as polymer base, sodium starch glycorate 30 mg as disintegrant, and 10 mg polyoxyl 23 lauryl ether (Brij35) as surfactant A tablet containing 650 mg of acetaminophen having a hardness of 65 N was prepared by the same method as in Example 1, except that.

<Example 11>

Except that 20 mg of sodium lauryl sulfate was used as the surfactant in the composition of Example 8, the same procedure as in Example 1 was carried out to tablet tablets containing 650 mg of acetaminophen having a hardness of 65 N. Prepared.

<Example 12>

Except that 30 mg of sodium lauryl sulfate was used as the surfactant in the composition of Example 8, the same procedure as in Example 1 was carried out to tablet tablets containing 650 mg of acetaminophen having a hardness of 65 N. Prepared.

Example 13

Except that 50 mg of sodium lauryl sulfate was used as the surfactant in the composition of Example 8, the same procedure as in Example 1 was carried out to tablet tablets containing 650 mg of acetaminophen having a hardness of 65 N. Prepared.

<Example 14>

A tablet containing 650 mg of acetaminophen having a hardness of 65 N was prepared in the same manner as in Example 1, except that 60 mg of the polymer base HPMC was used in the composition of Example 8.

<Example 15>

A tablet containing 650 mg of acetaminophen having a hardness of 65 N was prepared in the same manner as in Example 1, except that 70 mg of the polymer base HPMC was used in the composition of Example 8.

<Example 16>

Same method as Example 1 above, except that 650 mg of acetaminophen, 60 mg of HPMC as the polymer base, 40 mg of sodium starch glycorate as the disintegrant, and 10 mg of sodium lauryl sulfate as the surfactant were used. It was prepared by tableting a tablet containing 650 mg of acetaminophen having a hardness of 65 N.

<Example 17>

Same method as Example 1 above, except that 650 mg of acetaminophen, 60 mg of HPMC as the polymer base, 50 mg of sodium starch glycorate as the disintegrant, and 10 mg of sodium lauryl sulfate as the surfactant were used. It was prepared by tableting a tablet containing 650 mg of acetaminophen having a hardness of 65 N.

Example 18

In the same manner as in Example 1, except that 5 mg of NaHCO ₃ as a blowing agent was additionally used in the composition of Example 17, the tablet was prepared by tableting a tablet containing 650 mg of acetaminophen having a hardness of 65 N. It was.

Example 19

In the same manner as in Example 1, except that 10 mg of NaHCO ₃ , a blowing agent, was additionally used in the composition of Example 17, the tablet was prepared by tableting a tablet containing 650 mg of acetaminophen having a hardness of 65 N. It was.

Example 20

In the same manner as in Example 1, except that 15 mg of NaHCO ₃ as a blowing agent was additionally used in the composition of Example 17, the tablet was prepared by tableting a tablet containing 650 mg of acetaminophen having a hardness of 65 N. It was.

Example 21

Except for using 60 mg of sodium starch glycorate (primojel) as a disintegrant in the composition of Example 16, was carried out in the same manner as in Example 1, containing 650 mg of acetaminophen having a hardness of 65 N Tablets were prepared by tableting.

<Example 22>

Except for using 70 mg of sodium starch glycorate (primojel) as a disintegrant in the composition of Example 16, was carried out in the same manner as in Example 1, containing 650 mg of acetaminophen having a hardness of 65 N Tablets were prepared by tableting.

<Example 23>

The hardness was 65, except that 650 mg of acetaminophen, HPMC 30 mg as the polymer base, and 70 mg of the pregelatinized starch (prejel) as the disintegrant were used. A tablet containing 650 mg of acetaminophen, N, was prepared by tableting.

<Example 24>

Same as Example 1, except that 650 mg of acetaminophen, 30 mg of HPMC as the polymer base, 50 mg of pregelatinized starch (prejel) as the disintegrant, and 20 mg of Avicel as the secondary disintegrant By the method, a tablet containing 650 mg of acetaminophen having a hardness of 65 N was prepared by tableting.

<Example 25>

A tablet containing 650 mg of acetaminophen having a hardness of 65 N was obtained in the same manner as in Example 1, except that 30 mg of pregelatinized starch (prejel) was used as the disintegrant in Example 24. Prepared by.

Example 26

Except for using 650 mg of acetaminophen, 30 mg of HPMC as polymer base, 50 mg of pregelatinized starch (prejel) as disintegrant, 5 mg of surfactant sodium lauryl sulfate and 20 mg of Avicel as secondary disintegrant Was prepared in the same manner as in Example 1, by tableting a tablet containing 650 mg of acetaminophen having a hardness of 65 N.

Example 27

In the composition of Example 26, except that 2.5 mg of the surfactant sodium lauryl sulfate was used, the same method as in Example 1 was carried out to tablet tablets containing 650 mg of acetaminophen having a hardness of 65 N. Prepared.

<Example 28>

Except that 650 mg of acetaminophen, 30 mg of HPMC as polymer base, 45 mg of pregelatinized starch (prejel) as disintegrant, 2.5 mg of surfactant sodium lauryl sulfate and 25 mg of Avicel as secondary disintegrant Was prepared in the same manner as in Example 1, by tableting a tablet containing 650 mg of acetaminophen having a hardness of 65 N.

<Example 29>

Tablets containing 650 mg of acetaminophen having a hardness of 65 N were carried out in the same manner as in Example 1, except that 40 mg of pregelatinized starch (prejel) was used as a disintegrant in the composition of Example 28. It was prepared by tableting.

<Example 30>

Tablets containing 650 mg of acetaminophen having a hardness of 65 N were carried out in the same manner as in Example 1, except that 25 mg of pregelatinized starch (prejel) was used as a disintegrant in the composition of Example 28. It was prepared by tableting.

<Example 31>

Acetaminophen 650 mg, HPMC 30 mg as polymer base, pregelatinized starch (prejel) as disintegrant, 2.5 mg surfactant sodium lauryl sulfate, 25 mg asavicel as secondary disintegrant, and water-soluble additives A tablet containing 650 mg of acetaminophen having a hardness of 65 N was prepared in the same manner as in Example 1, except that 10 mg of NaH ₂ PO ₄ was used as the tablet.

<Example 32>

A tablet containing 650 mg of acetaminophen having a hardness of 65 N was obtained in the same manner as in Example 1, except that 40 mg of NaH ₂ PO ₄ was used as the water-soluble additive in the composition of Example 31. Prepared by.

<Example 33>

A tablet containing 650 mg of acetaminophen having a hardness of 65 N was obtained in the same manner as in Example 1, except that 80 mg of NaH ₂ PO ₄ was used as the water-soluble additive in the composition of Example 31. Prepared by.

<Example 34>

A tablet containing 650 mg of acetaminophen having a hardness of 65 N was carried out in the same manner as in Example 1, except that 5 mg of NaH ₂ PO ₄ was used as the water-soluble additive in the composition of Example 31. Prepared by.

<Example 35>

650 mg acetaminophen, 40 mg HPMC as polymer base, 25 mg pregelatinized starch (prejel) as disintegrant, 2.5 mg surfactant sodium lauryl sulfate, 25 mg Avicel as secondary disintegrant, and water-soluble additives A tablet containing 650 mg of acetaminophen having a hardness of 65 N was prepared in the same manner as in Example 1, except that 5 mg of NaH ₂ PO ₄ was used as the tablet.

<Example 36>

Acetaminophen 650 mg, HPMC 35 mg as polymer base, pregelatinized starch as disintegrant 25 mg, 1.0 mg of surfactant sodium lauryl sulfate, 20 mg of avisel as secondary disintegrant, and water-soluble additives A tablet containing 650 mg of acetaminophen having a hardness of 65 N was prepared in the same manner as in Example 1, except that 2.5 mg of NaH ₂ PO ₄ was used as the tablet.

<Example 37>

A tablet containing 650 mg of acetaminophen having a hardness of 65 N was prepared in the same manner as in Example 1, except that 37.5 mg of HPMC was used as the polymer base in the composition of Example 36.

<Example 38>

A tablet containing 650 mg of acetaminophen having a hardness of 65 N was prepared in the same manner as in Example 1, except that 36.5 mg of HPMC was used as the polymer base in the composition of Example 36.

The composition for the oral preparation containing acetaminophen according to the above embodiment is summarized in Table 1 below.

Composition of oral formulations according to various embodiments (mg) APAP HPMC Cab-o-sil Mg-stea-rate Primojel Ac-Di-Sol Corn starch SLS Poloxa-mer407 Brij35 NaHCO ₃ Avicel NaH ₂ PO ₄ Example 1 650 50 6 4 30 - - - - - - - - Example 2 650 50 6 4 - 30 - - - - - - - Example 3 650 50 6 4 - - 30 - - - - - - Example 4 650 70 6 4 30 - - - - - - - - Example 5 650 90 6 4 30 - - - - - - - - Example 6 650 50 6 4 40 - - - - - - - - Example 7 650 50 6 4 50 - - - - - - - - Example 8 650 50 6 4 30 - - 10 - - - - - Example 9 650 50 6 4 30 - - - 10 - - - - Example 10 650 50 6 4 30 - - - - 10 - - - Example 11 650 50 6 4 30 - - 20 - - - - - Example 12 650 50 6 4 30 - - 30 - - - - - Example 13 650 50 6 4 30 - - 50 - - - - - Example 14 650 60 6 4 30 - - 10 - - - - - Example 15 650 70 6 4 30 - - 10 - - - - - Example 16 650 60 6 4 40 - - 10 - - - - - Example 17 650 60 6 4 50 - - 10 - - - - - Example 18 650 60 6 4 50 - - 10 - - 5 - - Example 19 650 60 6 4 50 - - 10 - - 10 - - Example 20 650 60 6 4 50 - - 10 - - 15 - -

(mg) APAP HPMC Cab-o-sil Mg-stearate Primo-jel Pre-jel Ac-Di-Sol Corn starch SLS Polox-amer407 Brij35 NaHCO ₃ Avicel NaH ₂ PO ₄ Example 21 650 60 6 4 60 - - - 10 - - - - Example 22 650 60 6 4 70 - - - 10 - - - - Example 23 650 30 6 4 - 70 - - - - - - - Example 24 650 30 6 4 - 50 - - - - - - 20 - Example 25 650 30 6 4 - 30 - - - - - - 20 - Example 26 650 30 6 4 - 50 - - 5 - - - 20 - Example 27 650 30 6 4 - 50 - - 2.5 - - - 20 - Example 28 650 30 6 4 - 45 - - 2.5 - - - 25 - Example 29 650 30 6 4 - 40 - - 2.5 - - - 25 - Example 30 650 30 6 4 - 25 - - 2.5 - - - 25 - Example 31 650 30 6 4 - 25 - - 2.5 - - - 25 10 Example 32 650 30 6 4 - 25 - - 2.5 - - - 25 40 Example 33 650 30 6 4 - 25 - - 2.5 - - - 25 80 Example 34 650 30 6 4 - 25 - - 2.5 - - - 25 5 Example 35 650 40 6 4 - 25 - - 2.5 - - - 25 5 Example 36 650 35 6 4 - 25 - - 1.0 - - - 20 2.5 Example 37 650 37.5 6 4 - 25 - - 1.0 - - - 20 2.5 Example 38 650 36.5 6 4 - 25 - - 1.0 - - - 20 2.5

<Example 39>

6 g of colloidal silicon dioxide (Cab-O-Sil) and 4 mg of magnesium stearate were used as a lubricant used for molding the formulation in the powder having the composition of Example 8. The mixture was uniformly mixed and carried out in the same manner as in Example 1 to prepare a tablet containing 650 mg of acetaminophen having a hardness of 150 N.

<Example 40>

6 g of colloidal silicon dioxide (Cab-O-Sil) and 4 mg of magnesium stearate were used as a lubricant used for molding the formulation in the powder having the composition of Example 8. The mixture was uniformly mixed and carried out in the same manner as in Example 1 to prepare a tablet containing 650 mg of acetaminophen having a hardness of 80 N.

<Example 41>

In order to observe the effect of drug release on the polymer-based HPMC viscosity, the fine granules containing HPMC (viscosity 4000cps) and HPMC (viscosity 100,000cps) in the composition of Example 17 was carried out in the same manner as in Example 1 Wet granules were prepared respectively and the granules were mixed in a proportion of 1: 1. As a lubricant used for shaping the formulation, 6 mg of colloidal silicon dioxide (Cab-O-Sil) and 4 mg of magnesium stearate were uniformly mixed and a rotary tablet (12 stations, Tablets were used to prepare tablets for direct stroke.

<Example 42>

In order to observe the effect of drug release on the particle size of the drug, acetaminophen, which is a drug, was ground to prepare a powder having a particle size of 60 to 100 mesh. As a glidant to the powder, 6 mg of colloidal silicon dioxide (Cab-O-Sil) and 4 mg of magnesium stearate were uniformly mixed and carried out in the same manner as in Example 1. , Was prepared for tablets.

<Comparative Example 1> (Tylenol YAL commercially available tablet)

Tylenol IAL commercial tablets containing 650 mg of acetaminophen were employed as comparative samples.

<Comparative Example 2> (Capsule containing a crushed mass)

After the oral tablet containing 650 mg of acetaminophen having the composition of Example 36 was crushed, the weight of drug amount 650 mg was filled into a hard gelatin cocapsule to obtain a solid capsule.

Experimental Example 1 Measurement of Solubility of Drug

In order to select an additive which is advantageous for the initial release of the drug, the solubility of acetaminophen was measured in the additives including various oils, fatty acids and surfactants, and the results are shown in Table 2 below.

Solubility of Acetaminophen in Various Additives Additives Solubility (mg / ml) water 10.60 pH 1.2 artificial gastric juice 10.73 pH 6.8 artificial intestinal fluid 10.73 Twin 20 16.42 Twin 80 16.97 Labrasol 16.89 Transcutol 14.90 PEG 400 14.82 PEG 6000 15.60 Sodium Lauryl Sulfate 17.38 Brij35 18.13 glycerin 11.69 Cremopher RH40 16.55 Poloxamer 407 20.05 Cremopher EL 17.93

As shown in Table 2, the solubility of acetaminophen is the highest in the phloxamer 407 surfactant, in addition to Brij35, sodium lauryl sulfate, Cremophor, Lasbrasol, Tween 20 and Tween 80 Appeared relatively large.

Depending on the composition of the additive, the solubility of acetaminophen, a drug, was increased by about two times compared to pure distilled water. Increasing solubility may promote the initial release of the drug, and therefore use surfactants as preferred additives. The surfactant may be polysorbate, cremopher, PEG-60 hydrogenated, including poloxamer, sodium lauryl sulfate, labrasol, transcutol, labrafil, labrapak, Tween 20, 40, 60, 80 and the like. More preferably, it is selected from the group consisting of castor oil, PEG-40 hydrogenated castor oil, and most preferably it is selected and used from floxamer, sodium lauryl sulfate and Tween 80.

Experimental Example 2 Hardness Test of Tablet

For oral tablets containing acetaminophen prepared in the above Examples, hardness was measured using a hardness measuring instrument [Erweka, Gemany], the results are shown in Table 3 below.

Experimental Example 3 Contents of Acetaminophen in the Formulation

Six tablets of the conventional commercial preparation and the tablets prepared in Examples of the present invention were taken to prepare fine powders in pestle and judo. 100 mg of the powder was accurately taken and diluted in 100 ml of distilled water. After filtration, the filtrate was diluted 40 times again and measured in the 254 nm region using a UV absorbance spectrometer.

The measured contents of the conventional commercially available tablets and the tablets prepared in the Examples of the present invention are shown in Table 3 below.

Hardness and content of conventional commercially available tablets and tablets prepared in Examples of the present invention Example Hardness (N) content (%) Comparative Example 1 198.6 85.6 Comparative Example 2 - 85.6 Example 1 126 84.9 Example 2 106 84.6 Example 3 229 87.9 Example 4 202 85.5 Example 5 220 84 Example 6 110 84 Example 7 121 83.2 Example 8 213 84.7 Example 9 146 85.2 Example 10 218 85.8 Example 11 141 83.1 Example 12 179 83.1 Example 13 161 81 Example 14 55 83.9 Example 15 61 82.5 Example 16 51 85.9 Example 17 55 83.1 Example 18 104 81.9 Example 19 70 81.2 Example 20 105 80.5 Example 21 51 81.5 Example 22 70 80.9 Example 23 53 85.9 Example 24 54 85.3 Example 25 49 87.5 Example 26 70 85.3 Example 27 73 85.4 Example 28 77 85.4 Example 29 76 86.2 Example 30 65 86.9 Example 31 70 86.5 Example 32 78 84.2 Example 33 82 80.1 Example 34 64 86.5 Example 35 73 85.3 Example 36 85 86.8 Example 37 80 87.6 Example 38 75 86.9 Example 39 156 84.7 Example 40 84 84.7 Example 41 60 83.1 Example 42 75 86.2

As shown in Table 3, the tablet prepared in the embodiment of the present invention had a tendency that the higher the content of the polymer base HPMC than the conventional commercial formulation tends to appear higher and the hardness is lower as the HPMC content is lower but Other additives used in the formulation also had a significant effect on hardness. Since the formulation of the present invention can be applied not only to tablets, but also to tablets, and then to compressed tablets, granules, or hard capsules, it is preferable to use 10 to 90 parts by weight of the polymer base to be used in order to obtain the desired hardness according to the formulation. It is preferred to use 20 to 50 parts by weight, most preferably 30 to 40 parts by weight.

In addition, the content of the drug contained in the oral tablet prepared in the embodiment of the present invention contains at least 80% acetaminophen, and confirmed the significant results with conventional commercial formulations.

Experimental Example 4 Comparative Dissolution Experiment According to Various Eluents

The dissolution rate of the tablets prepared in Examples of the present invention and the comparative examples of conventional commercially available tablets were tested in the following manner under various conditions of the solution.

A dissolution test was conducted for a formulation containing a certain amount of acetaminophen in accordance with the Korean Amendment 7 dissolution test method. Six tablets of the tablet prepared in the embodiment of the present invention and the conventional commercially available tablets were weighed at exactly the same weight, and then eluted with artificial gastric juice (pH 1.2), artificial intestinal fluid (pH 6.8), pH 4.0 acetate buffer, and water. The paddle method (50 rpm) was used in 900 ml of the solution, and the dissolution experiment was performed at an elution temperature of 37 ± 1 ° C. for 8 hours. After the start of elution, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 hours after each 1 ml of each eluate was taken and the same amount of the eluate was replenished. The collected sample was centrifuged filtered and diluted 40 times and measured in the 254 nm region using a UV absorbance spectrometer. From the standard calibration curve, the concentration of the main drug was first calculated and the release rate (%) was converted. In the dissolution test, the dissolution test was first performed on the artificial intestine solution of pH 6.8, and then the prescription of the embodiment was selected. The dissolution curves of were compared, and the results are shown in Tables 4 to 6 below.

Dissolution Rate of Oral Tablets Containing Acetaminophen in Artificial Gastric Fluid (%) Time (h) Example 0.25 0.5 0.75 One 1.5 2 3 4 6 8 Comparative Example 1 58.9 64.4 69.9 73.1 79.1 84.2 94.7 99.3 102.9 103 Comparative Example 2 81.5 85.4 89.2 93.7 97.8 100.3 102.4 101.5 100.6 100.1 Example 14 19.3 23.4 30.7 35 73.6 90.9 104.6 105 104.2 104.5 Example 16 23.6 39.4 69.4 76.8 85.8 89.6 96.9 98.1 98.5 98.3 Example 17 33.6 62.2 77.3 84.3 92.1 96 99.8 98.5 98.6 99.4 Example 18 26.6 32.5 39.3 50.1 66.8 71.7 76.4 100.6 100.5 99.9 Example 19 31.8 72.3 93.9 97.8 100.8 101.1 101.4 99.8 102.5 105.6 Example 20 22.8 38.5 48 64.3 70.5 74.5 74.1 102.6 103.6 102.6 Example 21 32.7 37.5 42 43.3 49.7 54.1 62.6 67.8 100.4 101 Example 22 23 27.9 31.2 32.8 39.8 54.6 69.9 76 98.6 99.9 Example 23 36.1 39.9 41.7 44.6 49.4 53.3 64.9 89.8 91.2 91.6 Example 24 48.9 51.5 53.9 56.7 60.6 67.3 78.9 95.3 97.3 Example 25 36.7 39.4 43.1 47 47.8 51.6 62.3 66.1 71.2 Example 26 44.9 79.3 86.8 89.3 93.2 96.8 102 Example 27 47.7 52.3 61.8 64.8 75.5 82.6 91.4 96.4 99.7 99.8 Example 28 50.4 65.7 67.4 74.2 76.1 88.6 95.3 99.5 101.4 99.4 Example 29 50.6 59.9 66.2 68.8 79.8 86.2 93.9 97.3 99 98.9 Example 38 60.2 70.1 75.0 80.0 86.3 89.7 96.0 100.0 100.2 Example 41 11.2 14.9 17.8 21.5 33.7 62.4 86.1 97.1 100.7 101.6 Example 42 51.9 67.6 74.4 77.4 82.3 87.3 94.9 96.3 99.4

Dissolution rate (%) in artificial intestinal fluid of oral tablets containing acetaminophen. Time (h) Example 0.25 0.5 0.75 One 1.5 2 3 4 6 8 Comparative Example 1 59.6 65.9 71.4 75.9 83.1 90.4 99.6 102.7 102.6 103.1 Comparative Example 2 83.4 87.6 90.2 94.5 99.8 100.9 101.5 99.7 100.9 101.5 Example 1 15.3 20.7 24.8 27.6 37.2 46.4 60.2 77.3 102.5 104.6 Example 2 17.5 22.4 26.8 30.2 37.5 50.1 62.3 75.2 106.5 106.6 Example 3 5.8 10 12.1 14.8 18.9 22.9 29.3 34.3 43.1 49.1 Example 4 19.9 24.3 27.8 31.9 35.9 40.3 48.8 58.4 71.5 86.4 Example 5 17.4 21.5 25.1 26.9 32 36.2 41.6 47.9 56.1 62.5 Example 6 16.5 22.2 26.5 29.8 37.8 55.3 83.6 95.7 100.8 104.5 Example 7 16.1 21.6 30 36.2 56.5 77.5 93 98.6 105.5 103.5 Example 8 31.7 49.6 59.7 68.9 89.7 96.1 97.1 97.4 96.9 98.5 Example 9 7.5 10.7 13.5 16.2 21.5 25.6 33 41.9 54.9 67.1 Example 10 7.5 10.4 12.9 15.3 19.3 22.7 29.5 32.9 44.1 51.3 Example 11 36.6 47.2 55.7 61.6 74.5 83.7 97.7 105.7 107.4 106.9 Example 12 11.2 21.3 26.3 31.9 44.7 51.3 65.9 75.6 82.1 90.4 Example 13 9.2 12.6 15.8 17.5 23.8 26.4 31.7 38.9 46.8 56.9 Example 14 46.1 61.5 70.9 78.9 90.9 98.6 99.7 101.5 100.1 100.5 Example 15 19.7 43 57.9 66.4 83.2 95.9 100.5 100.2 101.2 101.1 Example 16 39.3 58.9 72.6 80.9 92 94.5 98.6 97.1 98.6 98.9 Example 17 47.7 65.5 78.5 87.2 95.9 98.7 100.4 100 99 100 Example 21 72.7 85.4 90.6 95.6 99.9 101.9 101.4 100.2 101.2 99.5 Example 22 47.5 90.7 94.6 97.1 99.3 102.6 102.7 101.7 101.4 101.5 Example 23 39.7 41.5 42.2 44.3 49.6 56.7 84.6 100.3 100 98.6 Example 24 35.2 38.9 41.7 44.9 49.1 55.2 65.3 76.65 95.9 - Example 25 33.9 42.5 43.9 45.6 50.1 55 64.7 73.2 80.4 - Example 26 86.3 92.5 96.4 98.2 98.3 - - - - - Example 27 53.8 63 68.1 76.7 84.8 93.6 97.2 100.6 99.4 101.4 Example 28 53 75.8 81.7 88.7 92.7 97.7 99.2 99.8 99.7 102.5 Example 29 49 64.9 73.5 79.3 88.6 93.5 97.5 98.5 99.4 100.7 Example 34 89.9 97.1 97.8 98.4 99.1 99.9 - - - - Example 36 77.6 85.8 86.9 93.8 97.8 101.7 103.8 104.8 - - Example 37 52.8 57.5 61.8 65.3 74.5 76 90.9 102.3 - - Example 38 62.5 68.2 73.1 77.6 83.3 89.5 97.4 100.4 101.4 - Example 39 41.2 63.4 71.9 83.8 94.5 96.4 103.8 103.7 102.6 103.5 Example 40 49.8 66.7 82.2 87.7 100.3 103.4 102.3 103.6 102.3 103.7 Example 41 49.6 64.2 78.1 89.1 96.7 98.1 100.2 101.5 101.3 101.4 Example 42 78.3 92.3 95.1 95.9 97.8 97.9 98.6 98.3 100.4

Dissolution rate in water of oral tablets containing acetaminophen in water. Time (h) Example 0.25 0.5 0.75 One 1.5 2 3 4 6 8 Comparative Example 1 60.0 66.4 72.6 78 88 95.9 103.9 104.8 104.3 103.8 Comparative Example 2 82.6 86.8 88.6 92.3 98.1 101.2 101.9 102.3 100.7 100.6 Example 30 43.2 48.6 55 58.7 67.8 77.5 84.6 90.5 99.7 100.2 Example 31 85.2 90.9 97.5 98.3 100.2 100 - - - - Example 32 93.1 92.9 97.2 101.1 101.1 100.1 - - - - Example 33 95.5 97.8 97.8 100.9 100.7 101.1 - - - - Example 34 60.6 68.8 75.5 79.9 86.6 92.9 97.5 99.9 - - Example 35 42.8 52.8 53.9 56.9 60.1 65.3 72.4 77.7 85.6 92.4 Example 36 52.9 60.9 64.9 69.5 74.2 78.1 88.5 91.5 96.7 100.2 Example 37 46.9 52.9 58.6 63.9 70.8 77.5 84.7 92.7 98.2 - Example 38 53.1 59.7 65.7 73.2 79.4 88.1 95.4 99.4 100.1 -

Step 1: Influence of Polymer Base HPMC

In Examples 1, 4, 5, 14, 15, and 40 of the present invention, the results of the HPMC concentration of the polymer base were observed.

In Examples 1, 4 and 5, in which the sodium lauryl sulfate (SLS) was not present, the concentration of HPMC, which is a polymer base, was increased, but there was almost no change in the initial dissolution of the drug. Elution decreased with increasing HPMC concentration.

On the other hand, in Examples 14, 15, and 40, in which the sodium lauryl sulfate (SLS) surfactant is present, the initial dissolution of the drug was significantly decreased with increasing the HPMC concentration.

In Examples 17 and 41, the effect of the polymer-based HPMC viscosity on the drug dissolution was observed. The drug dissolution in the gastric juice (pH 1.2) was remarkably decreased as the fraction of the high viscosity HPMC in the composition increased.

In addition, in Examples 36 to 38, the effect of HPMC concentration on drug dissolution in the presence of water-soluble minerals was investigated.In the presence of soluble minerals, artificial intestinal fluid (pH) was observed even in the small change of HPMC concentration (35.0 to 37.5). 6.8) and the elution rate of the drug were significantly changed in both distilled water and the release rate was delayed as the amount of HPMC increased.

Therefore, when the oral preparation of the present invention is administered, in order to rapidly release a certain amount of drug in the gastric juice (pH 1.2), especially in the presence of a surfactant, the amount of the polymer base is used in a preferable range, that is, 30 to 40 parts by weight, The viscosity of the base should not be high. In addition, it was found that it is preferable to include a water-soluble additive in order to promote drug dissolution in artificial intestinal fluid (pH 6.8) and distilled water.

Step 2: Influence of Disintegrants

An embodiment of the present invention has investigated the disintegration effect of various disintegrants such as sodium starch gluconate (Primojel), pregelatinized starch (Prejel), carboxymethyl cellulose (Ac-Di-Sol), corn starch.

Pregelatinized starch (Prejel) showed better disintegration behavior than sodium starch gluconate (Primojel) or carboxymethyl cellulose (Ac-Di-Sol), and corn starch had a weaker disintegration effect than other disintegrants. .

Examples 1, 6, 7, 14, 16, 17, 21 and 22 as disintegrants, the effect of drug dissolution according to the concentration of sodium starch gluconate (Primojel) was considered. In Examples 1, 6 and 7 without the presence of the surfactant sodium lauryl sulfate (SLS), the drug dissolution rate decreased with increasing disintegrant concentration and had little effect on the initial dissolution of the tablet.

On the other hand, in Examples 14, 16, 17, 21, and 22 where SLS was present, the initial dissolution of the drug in the artificial gastric juice did not differ according to the concentration of the disintegrant, and the dissolution rate after 2 hours was rather increased with the increase of the disintegrant concentration. Reduced.

Examples 23-29 considered the effects of drug dissolution when using another type of disintegrant, pregelatinized starch (Prejel), and further configuring the secondary disintegrant, Avicel, as a composition. Due to the addition of Avicel, the initial dissolution of the preparation in artificial gastric juice was much increased, and the disintegration behavior of more reproducible tablets was observed by appropriately adjusting the ratio of pregelatinized starch (Prejel) and Avicel. Could.

Step 3: Influence of Surfactants

Example 8, Example 9, and Example 10, using a sodium lauryl sulphate, floxamer, Brij35 and the like as a surfactant, the solubilization effect was considered. Unlike the solubility experiment of Experimental Example 1, when sodium lauryl sulphate was used, a solubilization effect was better than that of floxamer or Brij35.

On the other hand, in Examples 8 and 11 to 13, the effect of sodium lauryl sulphate concentration on the drug dissolution was considered, drug dissolution was rather reduced as the concentration of sodium lauryl sulphate increased.

Step 4: Influence of Tablet Hardness

Considering the influence of the hardness of the tablets prepared in Examples 8, 39 and 40 on the drug dissolution, the initial dissolution of the drug was observed according to the hardness of the tablet. In other words, the greater the hardness of the tablet, the lower the drug dissolution. Therefore, it was found that the difference in hardness of tablets also affected drug release.

Step 5: blowing agent (NaHCO ₃ ) Impact

Examples 18 to 20 observed the drug dissolution according to the use of the blowing agent (NaHCO ₃ ).

In Example 19, rapid disintegration occurred due to the small hardness of the tablet, but Examples 18 and 20 showed different but almost identical dissolution patterns of the amount of the blowing agent (NaHCO ₃ ) contained. However, the molding of the tablets was excellent, but the flowability of the powder was much lower and it was not suitable for use as an excipient of acetaminophen due to the browning of the powder during preservation.

Step 6: Water Soluble Additive (NaH) ₂ PO ₄ ) Impact

In Examples 30 to 34, the effect of drug dissolution was observed using inorganic NaH ₂ PO ₄ as a hydrophobic additive.

As the concentration of the water-soluble additive used was increased, the drug dissolution was much increased.In the case of containing more than 10 mg of NaH ₂ PO ₄ , about 90% of the drug was eluted within 30 minutes, resulting in a slow release effect. In the case of Examples 35 to 38 containing less than 5 mg of NaH ₂ PO ₄ and adjusting the amount of the other composition, elution of the tablet showed the desired sustained release pattern.

Table 7 shows the results of comparing the dissolution rate of the tablet prepared in Example 38 of the present invention containing acetaminophen and conventional commercially available in artificial gastric juice, artificial intestinal fluid, acetate buffer and water.

Comparative dissolution rates in artificial gastric juice, artificial intestinal fluid, acetic acid buffer solution and water (%). Formulation Elution time 0.25 0.5 0.75 One 1.5 2 3 4 6 8 Commercial Tyreno Tablet Artificial gastric juice 58.9 64.4 69.9 73.1 79.1 84.2 94.7 99.3 102.9 103 Acetic acid buffer 57.5 63.4 68.8 73.1 80.7 86.6 95.5 100.2 101.9 102.6 Artificial serous 59.6 65.9 71.4 75.9 83.1 90.4 99.6 102.7 102.6 103.1 water 60 66.4 72.6 78 88 95.9 103.9 104.8 104.3 103.8 Example 38 Artificial gastric juice 60.2 70.1 75.0 80.0 86.3 89.7 96.0 100.0 100.2 - Acetic acid buffer 58.3 65.1 70.4 73.4 79.3 83.7 91.7 98.5 101.0 - Artificial serous 62.5 68.2 73.1 77.6 83.3 89.5 97.4 100.4 101.4 - water 53.1 59.7 65.7 73.2 79.4 88.1 95.4 99.4 100.1 -

As can be seen from the above results, oral tablets containing acetaminophen prepared in Example 38 of the present invention showed an equivalency with conventional commercially available tablets under various conditions of artificial gastric juice, artificial intestinal fluid, acetate buffer and water. Therefore, the oral preparation prepared in Example 38 of the present invention is an economical oral preparation that can be produced in a simple process while having the same release pattern as the rapid release and sustained release of conventional commercial preparations. It is a very effective agent that can be substituted.

As described above, the present invention prepared an oral preparation containing acetaminophen consisting of a drug acetaminophen, a polymer base, a disintegrant, a surfactant, a lubricant, and a water-soluble additive, the oral preparation of the present invention When orally administered, it absorbs water under conditions of strong acid in the gastrointestinal tract and rapidly releases a certain amount of drug, and when moisture is contained, a gel is formed by the polymer base to slowly release a certain amount of drug, thereby controlling the release property of the drug. Can be. The formulations of the present invention may be provided in various forms of formulations, including tablets, compressed ingots, granules and capsule formulations, and in particular the oral formulations of the present invention are comparable in various eluent compositions with conventional commercial formulations containing acetaminophen. It can be prepared using the existing equipment, the process itself is an economical oral preparation that can be mass-produced in a simple manner, it can be replaced with conventional commercial preparations.

Claims (23)

Acetaminophen, which is a drug; Polymer bases; Disintegrants; Surfactants; And oral formulations containing acetaminophen, containing a lubricant. The oral preparation of acetaminophen according to claim 1, wherein the oral preparation further contains a water-soluble additive. The oral preparation of acetaminophen according to claim 1, wherein the oral preparation is a tablet, a compressed mass, granules, and a capsule containing the granules. The method of claim 1, wherein the polymer base is a cellulose derivative; Propylene oxide and its derivatives; Polyvinylpyrrolidone; Polyethylene glycol and polyvinyl alcohols; Polyvinylacetate, polyvinylacetate phthalate, polymethacrylate and polymers thereof; Polyacrylic acid and derivatives thereof; An oral preparation containing acetaminophen, which is selected from the group consisting of glycerol monostearate, poloxamer, sodium alginate, guar gum, chitosan, sodium fetinate, gelatin, and gum tragacanth. 5. The cellulose derivative according to claim 4, wherein the cellulose derivative is selected from the group consisting of hydropropylmethyl cellulose, methyl cellulose, ethyl cellulose, hydropropyl cellulose, hydropropylmethyl cellulose phthalate, hydropropylmethyl cellulose acetylsuccinate, and sodium carboxymethyl cellulose. An oral preparation containing acetaminophen characterized by the above-mentioned. The oral preparation of acetaminophen according to claim 4, wherein the polymer base is hydropropylmethyl cellulose. The method of claim 1, wherein the disintegrant is croscarmellose sodium, sodium starch glycolate, pregelatinized pregelatinized starch, microcrystalline cellulose, crospovidone and other commercially available polyvinylpyrrolidone, Low-substituted hydroxypropylcellulose, alginic acid, carboxymethylcellulose calcium salt and sodium salt, colloidal silicon dioxide, guar gum, magnesium aluminum silicate, methylcellulose, powdered cellulose, starch and sodium alginate alone or mixtures thereof An oral preparation containing acetaminophen, characterized in that. 8. The oral preparation of acetaminophen according to claim 7, wherein the disintegrant is croscarmellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, crospovidone. The method of claim 1, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate and its derivatives, poloxamer and its derivatives, intermediate chain triglycerides, labrasol, transcutol, labrafil, labrapak, polysorbate; Sorbitan esters; Containing acetaminophen, characterized in that it is selected from the group consisting of cramopher, PEG-60 hydrogenated castor oil, PEG-40 hydrogenated castor oil, sodium lauryl glutamate, disodium cocoampodiacetate and mixtures thereof Oral preparations. 10. The oral preparation of acetaminophen according to claim 9, wherein the surfactant is selected from the group consisting of sodium lauryl sulfate and its derivatives, polysorbates, sorbitan esters, and mixtures thereof. The method of claim 2, wherein the water-soluble additive is NaH ₂ PO ₄ , KH ₂ PO ₄ , polyvinylpyrrolidine, polyethylene glycol, gelatin, gum, hydrocarbons, cellulose and derivatives thereof, polyethylene oxide and derivatives thereof Oral formulation containing acetaminophen, characterized in that selected from the group consisting of polyvinyl alcohol, polyacrylic acid and derivatives thereof, poloxamer, polymethylacrylate and mixtures thereof. The oral preparation of acetaminophen according to claim 2, wherein the water-soluble additive is NaH ₂ PO ₄ , KH ₂ PO ₄ , polyvinylpyrrolidine (PVP) or polyethylene glycol (PEG). . According to claim 1, wherein the oral preparation is a drug 300 to 900 parts by weight of acetaminophen; 10 to 90 parts by weight of the polymer base; 5 to 100 parts by weight of disintegrant; 0.01 to 100 parts by weight of surfactant; An oral preparation containing acetaminophen comprising 0.1 to 20 parts by weight of a lubricant and 1 to 80 parts by weight of a water-soluble additive. According to claim 1, wherein the oral preparation is a drug 300 to 900 parts by weight of acetaminophen; 20 to 50 parts by weight of a polymer base; 10-30 weight part of disintegrants; 0.1-10 weight part of surfactant; 1 to 10 parts by weight of lubricant; And acetaminophen, comprising 1 to 10 parts by weight of a water-soluble additive. According to claim 1, wherein the oral preparation is a drug 300 to 900 parts by weight of acetaminophen; 30 to 40 parts by weight of a polymer base; 10-30 weight part of disintegrants; 1-3 parts by weight of surfactant; 3 to 6 parts by weight of lubricant; And acetaminophen, comprising 1 to 10 parts by weight of a water-soluble additive. The oral preparation of claim 1, wherein the oral preparation contains 650 mg of acetaminophen. Acetaminophen, which is a drug; Polymer bases; Disintegrants; Surfactants; Oral solution containing acetaminophen, characterized in that the wet granules are uniformly mixed with a lubricating agent and a water-soluble additive to prepare a wet granule, the wet granules are dried and milled, and tableted directly using a general tableting machine. Method of Preparation of the Formulation. 18. The method of claim 17, further comprising a pharmaceutically acceptable antioxidant, secondary disintegrant, and blowing agent. The method of claim 18, wherein the blowing agent is sodium bicarbonate (NaHCO ₃ ) and sodium carbonate (Na ₂ CO ₃ ). 18. The method according to claim 17, wherein the liquid solvent is water, ethanol, glycerin, propylene glycol, polyethylene glycol alone or a mixture thereof. 18. The method of claim 17, wherein the liquid solvent is water or a mixed solvent of water and ethanol. 18. The method according to claim 17, wherein the amount of water or a mixed solvent of water and ethanol is 5 to 50% with respect to the main weight ratio. 18. The method according to claim 17, wherein the amount of water or a mixed solvent of water and ethanol is 20 to 30% with respect to the main weight ratio.