KR20180100869A - Pharmaceutical composition of particle size controlled pirfenidone with improved compressibility and method for preparing the same - Google Patents

Abstract

The present invention relates to an oral preparation of pirfenidone with enhanced stability. More specifically, the present invention relates to a pharmaceutical composition comprising the pirfenidone having an average particle size in a specific range as an active ingredient, and a method for manufacturing an oral preparation having enhanced tablet compressibility comprising the composition. When manufacturing a unit formulation using the pharmaceutical composition comprising pirfenidone having an average particle size range according to the present invention, a high dosage of pirfenidone per unit preparation can be included due to excellent tablet compressibility due to remarkable compressibility. Thus, a high-dose preparation which is difficult to be manufactured can be manufactured to remarkably improve the low drug compliance caused by administration of pirfenidone, thereby being very useful for development of oral preparation of pirfenidone.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a pharmaceutical composition having improved titability according to particle size control of pirfenidone and a method for preparing the same,

The present invention relates to an oral preparation of pyrifnidone with improved stability. More particularly, the present invention relates to a pharmaceutical composition comprising as an active ingredient, pypenidone having an average particle size in a specific range, and a method for preparing an improved oral dosage form containing the composition.

Pirfenidone is an antifibrotic drug that is useful for the treatment of idiopathic pulmonary fibrosis. It inhibits the production of inflammatory cytokines (TNF-α, IL-1, IL-6) and the production of anti-inflammatory cytokines (IL-10) (TGF-β1, b-FGF, PDGF), which is involved in the formation of fibrosis, and suppresses the decrease of IFN-γ level, which is linked to Th2-type deficiency improvement (Th1 · Th2 balance correction) Suppression of various cytokines and proliferative factors. It also has a fibroblast proliferation inhibitory action and collagen production inhibitory action, and exhibits anti-fibrosis action based on this complex action. With respect to various effects of pypenidone, therapeutic effects on pulmonary fibrosis and arteriosclerotic lesions are described in Japanese Patent Laid-Open No. H02-215719, and the utility for treating inflammation of the respiratory tract or skin is disclosed in U.S. Patent No. 3,974,281, 4,042,699 and 4,052,509, and the synthesis and release inhibition effects of TNF-? Are disclosed in Japanese Patent Laid-Open Publication No. H11-512699. Idiopathic pulmonary fibrosis is a disease in which pulmonary fibrosis progresses due to an unidentified cause and progressively reduces pulmonary function such as pulmonary function, resulting in dyspnea. Approximately 50% of patients will die within 5 years Is considered to be a rare disease.

The greatest problem in formulating such pypenidone with oral preparations, especially tablets, is the low compressibility of pypenidone. When compressibility is low, it is important to improve such precision in the production of pyflnidone tablets because the important qualities in the production of tablets are lowered. In this regard, Japanese Patent Application Laid-Open No. H02-215719 discloses capsules, tablets, powders, granules, syrups, injections, creams, ointments, inhalants and the like as the dosage form of pyperidone, It is not. Korean Patent No. 10-0777169 discloses a preparation method for purification using a fluidized bed granulation process to solve the low titration property of pyperpinidone itself. Generally, granules prepared in a fluidized bed are mixed with a high speed mixer it is known that the bulk density is lower than that of the granules prepared by the mixer, so that the stability is increased. Thus, the above-mentioned method is merely a general improvement method. Further, in the above patent, although the tableting pressure is specified, the hardness of the tablet obtained finally is not specified, and a more preferable and specific preparation method is required.

In addition, pyupenidone was administered orally three times a day, once per day, with an initial dose of 3 times a day, followed by 3 times a day, once every 3 weeks, once every 2 weeks, depending on the patient's response and tolerability (600mg once a day, 1800mg a day) can be increased, so it is cumbersome and uncomfortable to take a 600mg tablets developed to improve compliance.

The inventors of the present invention have conducted intensive studies to prepare pyrpennidone tablets having improved dissolution rate and improved low compressibility of pyperpinidone itself, which is the biggest problem in formulating pypernidone into oral formulations, especially tablets. As a result, It has been confirmed that it is possible to develop an orally-administered formulation of pypennidone, which has remarkable effect on the qualities depending on the particle size of the main component even if the same process is used, Respectively.

Accordingly, one object of the present invention is to provide a pharmaceutical composition for preventing or treating pulmonary fibrosis, hepatic dysfunction, arteriosclerosis, respiratory tract or skin inflammation, comprising pyripenoid having improved specificity, And a method for producing the same.

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

The present invention provides a pharmaceutical composition for preventing or treating pulmonary fibrosis, arteriosclerosis, respiratory tract or skin inflammation comprising pypenidone having an average particle size of 20 to 100 占 퐉 as an active ingredient.

The pyrennidone contained in the active ingredient (main component) of the present invention is a drug composed of small molecules, and its chemical name is 5-methyl-1-phenyl-2- (1H) -pyridone. It is a synthetic molecule of non-peptides with a molecular weight of 185.23 daltons. Its chemical formula is C ₁₂ H ₁₁ NO, and its structure is shown in the following formula (1).

[Chemical Formula 1]

Currently, pyrenendin is clinically evaluated as a broad spectrum anti-fibrosis drug. Furfenidone is known to have anti-fibrosis and anti-inflammatory pharmacological activity reflected in its activity of lowering the expression of TGF-? 1, TNF-a, PDGF and, most importantly, the different types of collagen. The pypiranidone may be manufactured according to a known production method, for example, the methods disclosed in U.S. Patent No. 3,839,346, U.S. Patent No. 3,974,281, U.S. Patent No. 4,042,699, U.S. Patent No. 4,052,509, or the like, or a commercially available product may be used.

In the pharmaceutical composition according to the present invention, the pyrennidone has an average particle size of 20 to 100 탆 as a volume mean diameter (VMD). According to the present invention, compressibility increases markedly when pypenidone has an average particle size range as described above, which shows an excellent effect of improving the stability in the preparation of oral administration, particularly tablets.

As the active ingredient in the composition according to the present invention, the content of pypernidone having the specific average particle size range can be appropriately controlled by the type and purpose of use, the patient condition, the type of symptoms and the severity, and the total weight of the pharmaceutical composition Based on the total weight of the composition. However, this is not limited to the above range, as it may be increased or decreased according to the needs of the medicinal person, and may be appropriately increased or decreased according to various factors such as diet, nutritional status,

The dose of the pharmaceutical composition of the present invention can be determined by a specialist according to various factors such as the condition of the patient, age, body weight, degree of cartilage damage, progress of disease, and the like. Also, the daily dosage of the pharmaceutical composition per unit dosage form, or a half, 1/3 or 1/4 dose thereof, may be contained, and may be administered 1 to 6 times per day.

In a preferred embodiment, when formulating the composition according to the present invention, as an active ingredient per unit dosage form, it may contain 1 to 1000 mg, preferably 200 to 600 mg of pyperpinidone having the specified average particle size range have. More preferably, when formulating the composition according to the present invention, as an active ingredient per unit dosage form, 200 mg or 600 mg of pypernidone having the specified average particle size range may be included. Specifically, the pharmaceutical composition according to the present invention may be formulated so as to be administered according to the number of times of administration of general pyperidone (i.e., three times a day as an initial dose, 200 mg per tablet) In order to improve the low medication adherence due to the inconvenience caused by the increase in the number and the number of dosage forms of the unit dosage form to be administered at the future dose, You can also include 600mg of money. In particular, when a unit dosage form is prepared using a pharmaceutical composition comprising pypernidone having an average particle size range according to the present invention, pyripenis per unit dosage form is contained at a high dose due to the excellent solubility due to the remarkable compressibility This makes it possible to produce a high-dose preparation which has been difficult to manufacture in the past, and has an advantage that it can remarkably improve the low-level compliance of the patient caused by the administration of pypnidone.

The compositions according to the present invention can be administered to mammals, including humans, in a variety of routes. The mode of administration may be any mode conventionally used and may be administered, for example, by oral or parenteral routes (e. G., Skin, intravenous, intramuscular, subcutaneous), etc., but for the purposes of the present invention, Orally. Examples of the pharmaceutical composition for oral administration include tablets, capsules, granules, powders, pills and the like, but they can be formulated into tablets for the purpose of the present invention, Tablets may be prepared according to the general method of tablet preparation (e.g., milling, mixing, granulating, drying, tableting and coating if necessary). Specifically, in the formulation into tablets, the present invention can be produced by a wet granulation method, a dry granulation method, or a direct method. The wet granulation method can be carried out, for example, by mixing the active ingredient (main ingredient), the diluent, the excipient and the disintegrant in a mixing process until they are homogenized with a mixer, a combined process in which the binder is additionally mixed, A granulating step for extruding the granules, a step for drying the prepared granules, a sizing step for arranging the granules using a small lake body, a step for adding a lubricant to the granulated granules, Can be manufactured. The dry granulation method can be carried out by, for example, a process of weighing and mixing the components, a process of striking or compressing the components, a process of producing the tablets or pellets, a process of crushing the tablets or pellets, a sieving process, Slugging through the process, mixing the weighed components with the roller to produce a compact, preparing the tablet according to the roller compacting method of forming the compact by excavating the compacted product, . In addition, the direct method refers to a method of mixing the components necessary for manufacturing the tablet and compressing them at once. In a preferred embodiment, the present invention can be formulated in tablet form by a wet granulation method.

For formulation, the composition of the present invention may contain pharmaceutically acceptable and physiologically acceptable carriers, excipients and diluents as well as pyperidone having an average particle size of 20 to 100 mu m, And the like. For example, in the case of oral preparations, formulations can be prepared using excipients, binders, disintegrants, lubricants, solubilizers, suspending agents, preservatives or extenders.

Examples of the excipient include, but are not limited to, lactose hydrate, mannitol, corn starch, microcrystalline cellulose, sucrose, dextrose and sorbitol, and more preferably lactose hydrate. Preferably, the content of the excipient may be 5 to 80% by weight of the total weight of the tablet to be prepared, but is not limited thereto.

Examples of the binder include, but are not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and polyvinylpyrrolidone, and more preferably, hydroxypropylcellulose. Preferably, the content of the binder may be in the range of 0.5 to 30% by weight based on the total weight of the tablet to be prepared, but is not limited thereto.

Such disintegrants include, but are not limited to, corn starch, carboxymethylcellulose, carboxymethylcellulose calcium, carmellose sodium, low substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium, crosslinked polyvinyl Pyrrolidine is preferred, and more preferred may include croscarmellose sodium. Preferably, the content of the disintegrant may be in the range of 0.1 to 30% by weight based on the total weight of the tablet to be prepared, but is not limited thereto.

The lubricant is preferably calcium stearate, sodium stearate, magnesium stearate, and light anhydrous silicic acid, and more preferably magnesium stearate. Preferably, the content of the lubricant may be 0.1 to 5% by weight based on the total weight of the tablets to be produced, but is not limited thereto.

In one specific embodiment, the pharmaceutical composition according to the present invention contains 55mg of lactose hydrate as an excipient, 20mg of croscarmellose sodium as a disintegrant, 20mg of hydroxypropylcellulose as a binding agent, 8 mg of magnesium stearate and 2 mg of magnesium stearate as a lubricant, and the tablet may have a hardness of 8 to 18 kp after tableting.

In addition, the pharmaceutical composition according to the present invention contains 165 mg of lactose hydrate as an excipient, 60 mg of croscarmellose sodium as a disintegrant, 24 mg of hydroxypropyl cellulose as a binding agent, Magnesium stearate, and the tablet may have a hardness of 8 to 30 kp after tableting.

In a further aspect, the pharmaceutical composition according to the present invention may further comprise a coating layer on the outside. The coating layer may be formed through coating methods generally known in the art (e.g., film coating, sugar coating, etc.) using coatings used for coating tablets. In one specific embodiment, the pharmaceutical composition according to the present invention was formulated into tablets by coating with Opadry 03F620043 Yellow containing hydroxypropylmethylcellulose, titanium oxide, and polyethylene glycol after being formulated into tablets (untreated).

In another aspect, the present invention relates to a method for producing a tablet comprising the pypnidone as an active ingredient, comprising the steps of:

comprising the steps of: a) milling pyrinidone having a volume average diameter of 5 to 100 占 퐉;

b) mixing the pyrepenidone prepared in step a) with excipients and disintegrants;

c) adding a binder to the mixture prepared in step b) and obtaining granules; And

d) mixing the tablets prepared in step c) with a lubricant and tabletting to prepare tablets.

The matters relating to pyflnidone, excipient, disintegrant, binder and lubricant used in each of the above steps may be applied as described in the above pharmaceutical composition and tablet. In a further embodiment, the method may further comprise the step of coating the tablets prepared in step d).

As a concrete example, to prepare tablets according to the present invention, pypenidone having a volume average diameter of 20 to 100 탆 is prepared, a lactose hydrate thereof, croscarmellose sodium is added to prepare a mixture, A hydroxypropylcellulose aqueous solution was sprayed using a fluidized bed granulator to obtain granules, and the obtained granules were tableted to prepare tablets in the form of tablets. Thereafter, coated tablets were prepared by coating with Opadry 03F620043 Yellow containing hydroxypropylmethylcellulose, titanium oxide, and polyethylene glycol.

When preparing a unit dosage form using a pharmaceutical composition comprising pypnnidone having an average particle size range according to the present invention, it is possible to incorporate a high dose of pyphenidone per unit dosage form due to the excellent titratability due to the remarkable compressibility Thus, it is possible to produce a high-dose preparation which has been difficult to manufacture conventionally, and it is possible to remarkably improve the low-level compliance of the patient caused by administration of pypnidone, which is very useful for the development of an oral dosage form of pypnidone .

Hereinafter, the present invention will be described in more detail with reference to the following examples, which should not be construed as limiting the scope of the present invention.

Comparative Example  One: Pypennidone  Preparation of 200 mg tablets

About 10 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain an adhe- sion containing 200 mg of pyperidone (lozenge weight 285 mg / tablet).

Particle size was measured with a SYMPATEC HELOS particle size analyzer.

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 10 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 1 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 200 Particle size: VMD * About 10㎛ Excipient Lactose baggage 55 Disintegration Croscarmellose sodium 20 Binder Hydroxypropylcellulose 8 Lubricant Magnesium stearate 2 Tread weight 285 Coater Opa Dry 03F620043 Yellow 10 Coated tablet weight 295

(*: VMD means volume mean diameter)

Example  One: Pypennidone  Preparation of 200 mg tablets

About 20 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain an adhe- sion containing 200 mg of pyperidone (lozenge weight 285 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 10 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 2 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 200 Particle size: VMD * About 20㎛ Excipient Lactose baggage 55 Disintegration Croscarmellose sodium 20 Binder Hydroxypropylcellulose 8 Lubricant Magnesium stearate 2 Tread weight 285 Coater Opa Dry 03F620043 Yellow 10 Coated tablet weight 295

(*: VMD means volume mean diameter)

Example  2: Pypennidone  Preparation of 200 mg tablets

About 30 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain an adhe- sion containing 200 mg of pyperidone (lozenge weight 285 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 10 mg of the solution was coated on the bottom of the flask to obtain the intended pyphenidon-coated tablets.

The components of the pyrimidon coating definition are shown in Table 3 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 200 Particle size: VMD * About 30㎛ Excipient Lactose baggage 55 Disintegration Croscarmellose sodium 20 Binder Hydroxypropylcellulose 8 Lubricant Magnesium stearate 2 Tread weight 285 Coater Opa Dry 03F620043 Yellow 10 Coated tablet weight 295

(*: VMD means volume mean diameter)

Example  3: Pypennidone  Preparation of 200 mg tablets

About 50 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain an adhe- sion containing 200 mg of pyperidone (lozenge weight 285 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 10 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 4 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 200 Particle size: VMD * About 50㎛ Excipient Lactose baggage 55 Disintegration Croscarmellose sodium 20 Binder Hydroxypropylcellulose 8 Lubricant Magnesium stearate 2 Tread weight 285 Coater Opa Dry 03F620043 Yellow 10 Coated tablet weight 295

(*: VMD means volume mean diameter)

Example  4 : Pypennidone  Preparation of 200 mg tablets

About 80 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain an adhe- sion containing 200 mg of pyperidone (lozenge weight 285 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 10 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 5 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 200 Particle size: VMD * About 80㎛ Excipient Lactose baggage 55 Disintegration Croscarmellose sodium 20 Binder Hydroxypropylcellulose 8 Lubricant Magnesium stearate 2 Tread weight 285 Coater Opa Dry 03F620043 Yellow 10 Coated tablet weight 295

(*: VMD means volume mean diameter)

Example  5: Pypennidone  Preparation of 200 mg tablets

About 100 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and sodium croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain an adhe- sion containing 200 mg of pyperidone (lozenge weight 285 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 10 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 6 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 200 Particle size: VMD * About 100㎛ Excipient Lactose baggage 55 Disintegration Croscarmellose sodium 20 Binder Hydroxypropylcellulose 8 Lubricant Magnesium stearate 2 Tread weight 285 Coater Opa Dry 03F620043 Yellow 10 Coated tablet weight 295

(*: VMD means volume mean diameter)

Comparative Example  2 : Pypennidone  Preparation of 200 mg tablets

About 120 mu m in average particle size as a volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain an adhe- sion containing 200 mg of pyperidone (lozenge weight 285 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 10 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 7 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 200 Particle size: VMD * About 120㎛ Excipient Lactose baggage 55 Disintegration Croscarmellose sodium 20 Binder Hydroxypropylcellulose 8 Lubricant Magnesium stearate 2 Tread weight 285 Coater Opa Dry 03F620043 Yellow 10 Coated tablet weight 295

(*: VMD means volume mean diameter)

Comparative Example  3: Pypennidone  Preparation of 200 mg tablets

About 150 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain an adhe- sion containing 200 mg of pyperidone (lozenge weight 285 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 10 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 8 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 200 Particle size: VMD * About 150㎛ Excipient Lactose baggage 55 Disintegration Croscarmellose sodium 20 Binder Hydroxypropylcellulose 8 Lubricant Magnesium stearate 2 Tread weight 285 Coater Opa Dry 03F620043 Yellow 10 Coated tablet weight 295

(*: VMD means volume mean diameter)

Comparative Example  4 : Pypennidone  Preparation of 200 mg tablets

About 200 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain an adhe- sion containing 200 mg of pyperidone (lozenge weight 285 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 10 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 9 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 200 Particle size: VMD * About 200㎛ Excipient Lactose baggage 55 Disintegration Croscarmellose sodium 20 Binder Hydroxypropylcellulose 8 Lubricant Magnesium stearate 2 Tread weight 285 Coater Opa Dry 03F620043 Yellow 10 Coated tablet weight 295

(*: VMD means volume mean diameter)

Comparative Example  5: Pypennidone  Preparation of 200 mg tablets

About 300 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain an adhe- sion containing 200 mg of pyperidone (285 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 10 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 10 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 200 Particle size: VMD * About 300㎛ Excipient Lactose baggage 55 Disintegration Croscarmellose sodium 20 Binder Hydroxypropylcellulose 8 Lubricant Magnesium stearate 2 Tread weight 285 Coater Opa Dry 03F620043 Yellow 10 Coated tablet weight 295

(*: VMD means volume mean diameter)

Comparative Example  6: Pypennidone  Preparation of 600 mg tablets

About 10 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain a lozenge containing 600 mg of pyperidone (loose weight 855 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 30 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 11 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 600 Particle size: VMD * About 10㎛ Excipient Lactose baggage 165 Disintegration Croscarmellose sodium 60 Binder Hydroxypropylcellulose 24 Lubricant Magnesium stearate 6 Tread weight 855 Coater Opa Dry 03F620043 Yellow 30 Coated tablet weight 885

(*: VMD means volume mean diameter)

Example  6: Pypennidone  Preparation of 600 mg tablets

About 20 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain a lozenge containing 600 mg of pyperidone (loose weight 855 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 30 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 12 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 600 Particle size: VMD * About 20㎛ Excipient Lactose baggage 165 Disintegration Croscarmellose sodium 60 Binder Hydroxypropylcellulose 24 Lubricant Magnesium stearate 6 Tread weight 855 Coater Opa Dry 03F620043 Yellow 30 Coated tablet weight 885

(*: VMD means volume mean diameter)

Example  7: Pypennidone  Preparation of 600 mg tablets

About 30 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain an adhe- sion containing 600 mg of pyperidone (bed weight 855 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 30 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 13 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 600 Particle size: VMD Approx. 30㎛ Excipient Lactose baggage 165 Disintegration Croscarmellose sodium 60 Binder Hydroxypropylcellulose 24 Lubricant Magnesium stearate 6 Tread weight 855 Coater Opa Dry 03F620043 Yellow 30 Coated tablet weight 885

(*: VMD means volume mean diameter)

Example  8 : Pypennidone  Preparation of 600 mg tablets

About 50 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain an adhe- sion containing 600 mg of pyperidone (bed weight 855 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 30 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 14 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 600 Particle size: VMD * About 50㎛ Excipient Lactose baggage 165 Disintegration Croscarmellose sodium 60 Binder Hydroxypropylcellulose 24 Lubricant Magnesium stearate 6 Tread weight 855 Coater Opa Dry 03F620043 Yellow 30 Coated tablet weight 885

(*: VMD means volume mean diameter)

Example  9: Pypennidone  Preparation of 600 mg tablets

About 80 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain a lozenge containing 600 mg of pyperidone (loose weight 855 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 30 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 15 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 600 Particle size: VMD * About 80㎛ Excipient Lactose baggage 165 Disintegration Croscarmellose sodium 60 Binder Hydroxypropylcellulose 24 Lubricant Magnesium stearate 6 Tread weight 855 Coater Opa Dry 03F620043 Yellow 30 Coated tablet weight 885

(*: VMD means volume mean diameter)

Example  10: Pypennidone  Preparation of 600 mg tablets

About 100 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and sodium croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain a lozenge containing 600 mg of pyperidone (loose weight 855 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 30 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 16 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 600 Particle size: VMD * About 100㎛ Excipient Lactose baggage 165 Disintegration Croscarmellose sodium 60 Binder Hydroxypropylcellulose 24 Lubricant Magnesium stearate 6 Tread weight 855 Coater Opa Dry 03F620043 Yellow 30 Coated tablet weight 885

(*: VMD means volume mean diameter)

Comparative Example  7: Pypennidone  Preparation of 600 mg tablets

About 120 mu m in average particle size as a volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain a lozenge containing 600 mg of pyperidone (loose weight 855 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 30 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 17 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 600 Particle size: VMD * About 120㎛ Excipient Lactose baggage 165 Disintegration Croscarmellose sodium 60 Binder Hydroxypropylcellulose 24 Lubricant Magnesium stearate 6 Tread weight 855 Coater Opa Dry 03F620043 Yellow 30 Coated tablet weight 885

(*: VMD means volume mean diameter)

Comparative Example  8 : Pypennidone  Preparation of 600 mg tablets

About 150 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain a lozenge containing 600 mg of pyperidone (loose weight 855 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 30 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 18 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 600 Particle size: VMD * About 150㎛ Excipient Lactose baggage 165 Disintegration Croscarmellose sodium 60 Binder Hydroxypropylcellulose 24 Lubricant Magnesium stearate 6 Tread weight 855 Coater Opa Dry 03F620043 Yellow 30 Coated tablet weight 885

(*: VMD means volume mean diameter)

Comparative Example  9: Pypennidone  Preparation of 600 mg tablets

About 200 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain an adhe- sion containing 600 mg of pyperidone (bed weight 855 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 30 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 19 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 600 Particle size: VMD * About 200㎛ Excipient Lactose baggage 165 Disintegration Croscarmellose sodium 60 Binder Hydroxypropylcellulose 24 Lubricant Magnesium stearate 6 Tread weight 855 Coater Opa Dry 03F620043 Yellow 30 Coated tablet weight 885

(*: VMD means volume mean diameter)

Comparative Example  10: Pypennidone  Preparation of 600 mg tablets

About 300 mu m in average particle size as the volume average diameter was mixed with lactose hydrate and croscarmellose sodium. An aqueous solution having a concentration of about 5 (w / w)% of hydroxypropylcellulose was prepared and sprayed using a fluidized bed granulator to prepare granules. Add sodium croscarmellose sodium to the granules and mix them, then with magnesium stearate. The final mixture was squeezed with a force of 15 kN to obtain a lozenge containing 600 mg of pyperidone (loose weight 855 mg / tablet).

An aqueous solution having a concentration of about 15 (w / w)% of Opafra Dry 03F620043 was prepared by using a fan coater, and 30 mg of the solution was sprayed on the surface of the flask to obtain the desired pyrphenidone-coated tablets.

The components of the pyrimidon coating definition are shown in Table 20 below.

Purpose of blending Ingredients Amount (mg) Remarks chief ingredient Pypennidone 600 Particle size: VMD * About 300㎛ Excipient Lactose baggage 165 Disintegration Croscarmellose sodium 60 Binder Hydroxypropylcellulose 24 Lubricant Magnesium stearate 6 Tread weight 855 Coater Opa Dry 03F620043 Yellow 30 Coated tablet weight 885

(*: VMD means volume mean diameter)

Experimental Example  1: Measurement of hardness and compression index

The hardness and compressibility index (CI) of the tablets containing pypenidone prepared according to Examples 1 to 10 and Comparative Examples 1 to 10 of the present invention were measured. The hardness was measured with an ERWEKA TBH-200 hardness tester and the CI was measured using the bulk density and tap density of the final mixture.

CI (Carr's Index) was calculated according to the following formula.

Hardness and CI results according to the above measurement method are shown in Tables 21 and 22.

Hardness CI Comparative Example 1 16kp 37 Example 1 16kp 33 Example 2 16kp 29 Example 3 15kp 26 Example 4 13kp 22 Example 5 10kp 20 Comparative Example 2 8kp 17 Comparative Example 3 7kp 15 Comparative Example 4 6kp 13 Comparative Example 5 4kp 13

Hardness CI Comparative Example 6 29kp 38 Example 6 29kp 33 Example 7 29kp 30 Example 8 27kp 25 Example 9 21kp 22 Example 10 17kp 19 Comparative Example 7 15kp 17 Comparative Example 8 12kp 15 Comparative Example 9 10kp 13 Comparative Example 10 7kp 12

As can be seen in Tables 21 and 22, it was confirmed that the hardness of tablets obtained at the same pressure in the manufacture of pyrennidone tablets increased in hardness when the average particle size was 20 to 100 mu m. However, it was confirmed that the formulation having a mean particle size of pyrimpnidone of less than 20 탆 had a high CI value, which resulted in poor flowability during tableting, which unevenly filled the tablet die and posed a problem of mass deviation of tablets. A preparation having a particle size of more than 100 탆 can not be regarded as a suitable particle size because hardness is decreased as compared with an average particle size of 20 to 100 탆 and it is difficult to secure sufficient hardness in production process proceeding to coating. Thereby completing the invention of a production method for improving the stability of tablets containing pypypenidone.

Claims (21)

A pharmaceutical composition for preventing or treating pulmonary fibrosis, hepatic dysfunction, arteriosclerosis, respiratory tract or skin inflammation, comprising pypenidone having an average particle size of 20 to 100 占 퐉 or less as an active ingredient. 2. The composition of claim 1, wherein the pharmaceutical composition is in tablet form. 3. The composition of claim 1 or 2, wherein the composition comprises 200 to 600 mg of the pyrennidone. The composition of claim 1 or 2, wherein said pyrennidone comprises from 10 to 90% by weight of the total composition. The composition according to claim 1 or 2, further comprising at least one selected from the group consisting of excipients, binders, disintegrators, and glidants. The composition according to claim 5, wherein the excipient is at least one selected from the group consisting of lactose hydrate, mannitol, corn starch, microcrystalline cellulose, sucrose, dextrose and sorbitol. 6. The composition of claim 5, wherein the excipient comprises from 5 to 80% by weight of the total composition. The composition according to claim 5, wherein the excipient is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and polyvinylpyrrolidone. 6. The composition of claim 5, wherein the content of the binder comprises from 0.5 to 30% by weight of the total composition. 6. The composition of claim 5, wherein the disintegrant is selected from the group consisting of corn starch, carboxymethylcellulose, carboxymethylcellulose calcium, carmellose sodium, low substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl starch sodium and crosslinked polyvinylpyrrolidone And at least one member selected from the group consisting of gold, silver, and gold. 6. The composition of claim 5, wherein the content of the disintegrant comprises from 0.1 to 30% by weight relative to the weight of the total composition. The composition according to claim 5, wherein the lubricant is at least one selected from the group consisting of calcium stearate, sodium stearate, magnesium stearate, and light silicic anhydride. 6. The composition of claim 5, wherein the content of the lubricant comprises from 0.1 to 5% by weight relative to the weight of the total composition. The pharmaceutical composition according to claim 5, which comprises 200 mg of pyrenpidone having an average particle size of 20 to 100 탆 or less as an average volume diameter, 55 mg of lactose hydrate as an excipient, 20 mg of croscarmellose sodium as a disintegrant, 8 mg of hydroxypropylcellulose as a binder, ≪ / RTI > is in the form of a tablet comprising 2 mg of magnesium stearate. 15. The composition of claim 14, wherein the tablet has a hardness of between 8 and 18 kp after tableting. 6. The pharmaceutical composition according to claim 5, which comprises 600 mg of pyrenpidone having an average particle size of 20 to 100 탆 or less as an average particle size, 165 mg of lactose hydrate as an excipient, 60 mg of croscarmellose sodium as a disintegrant, 24 mg of hydroxypropylcellulose as a binder, ≪ / RTI > is in the form of a tablet comprising 6 mg of magnesium stearate. 17. The composition of claim 16, wherein the tablet has a hardness of between 8 and 30 kp after tableting. 3. The composition of claim 2, further comprising a coating layer on the outside of the tablet. comprising the steps of: a) milling pyrinidone having a volume average diameter of 20 to 100 占 퐉;
b) mixing the pyrepenidone prepared in step a) with excipients and disintegrants;
c) adding a binder to the mixture prepared in step b) and obtaining granules; And
d) mixing the granulate prepared in step c) with a lubricant and tabletting to prepare tablets. 20. The method of claim 19, further comprising coating the tablets prepared according to step d). The process according to claim 19, wherein in step c), the mixture prepared in step b) is sprayed with a binder in a liquid state using a fluidized bed granulator to obtain granules.