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WO2018160011A1 - Composition pharmaceutique présentant des caractéristiques améliorées de formation de comprimés selon le contrôle de taille des particules de pirfénidone, et son procédé de préparation - Google Patents

Composition pharmaceutique présentant des caractéristiques améliorées de formation de comprimés selon le contrôle de taille des particules de pirfénidone, et son procédé de préparation Download PDF

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Publication number
WO2018160011A1
WO2018160011A1 PCT/KR2018/002484 KR2018002484W WO2018160011A1 WO 2018160011 A1 WO2018160011 A1 WO 2018160011A1 KR 2018002484 W KR2018002484 W KR 2018002484W WO 2018160011 A1 WO2018160011 A1 WO 2018160011A1
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WO
WIPO (PCT)
Prior art keywords
pirfenidone
composition
tablet
particle size
weight
Prior art date
Application number
PCT/KR2018/002484
Other languages
English (en)
Korean (ko)
Inventor
윤양노
김정필
최용환
Original Assignee
영진약품 주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 영진약품 주식회사 filed Critical 영진약품 주식회사
Priority to JP2019547670A priority Critical patent/JP2020509053A/ja
Priority to CN201880018876.5A priority patent/CN110430871A/zh
Publication of WO2018160011A1 publication Critical patent/WO2018160011A1/fr
Priority to JP2021213391A priority patent/JP2022031527A/ja

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating

Definitions

  • the present invention relates to pirfenidone oral preparations with improved tabletting properties. More specifically, the present invention relates to a pharmaceutical composition comprising pirfenidone having an average particle size in a specific range as an active ingredient, and to a method for preparing an oral dosage form having improved tabletting including the composition.
  • Pirfenidone is an antifibrotic drug that is useful for the treatment of idiopathic pulmonary fibrosis. It suppresses the production of inflammatory cytokines (TNF- ⁇ , IL-1, IL-6) and the anti-inflammatory cytokines (IL-10). Production of proliferative factors (TGF- ⁇ 1, b-FGF, PDGF), which are involved in fibrosis formation, which show increased production, show inhibition of IFN- ⁇ levels leading to improved Th2 type deflection (Th1 and Th2 balance modification). It has a production control action on various cytokines and proliferation factors, such as showing inhibition.
  • TGF- ⁇ 1, b-FGF, PDGF proliferative factors
  • Th1 and Th2 balance modification Th1 and Th2 balance modification
  • Idiopathic pulmonary fibrosis is a disease that causes fibrosis in the alveolar wall due to an unidentified cause, which gradually decreases lung function such as lung activity and eventually leads to respiratory distress. About 50% of patients die after 5 years of prognosis. Is not a good disease in Korea is prescribed as a rare intractable disease.
  • 10-0777169 discloses a method for refining using a fluidized bed granulation process in order to solve the low tableting properties of pirfenidone itself, but in general, the granules prepared in the fluidized bed have a high speed It is known that tableting properties are lowered due to a lower bulk density than granules produced by a mixer), and thus, such a patent method is merely a general tableting method. Furthermore, in the above patent, the tableting pressure is specified, but the hardness of the tablet finally obtained is not specified, so a more preferable and specific manufacturing method is required.
  • pirfenidone was orally administered 1 tablet 3 times a day at an initial dose after meals, and increased by 1 tablet once every 2 weeks depending on the patient's response and tolerability. Since it is possible to increase the amount of tablets (600mg once, 1800mg per day), it is cumbersome and inconvenient to take it. Therefore, it is necessary to develop 600mg tablets with improved medication compliance.
  • the present inventors have diligently studied to prepare pirfenidone tablets, which improve the low compressibility of pirfenidone itself, which is the biggest problem in formulating pirfenidone into oral preparations, especially tablets, Even if the same process has a significant effect on the tableting according to the particle size of the main component, when the specific particle size range has been confirmed that it is possible to develop an oral dosage agent of pirfenidone with excellent tableting properties have been completed to complete the present invention It was.
  • one object of the present invention is a pharmaceutical for preventing or treating inflammation of pulmonary fibrosis, liver failure, arteriosclerosis, respiratory tract or skin, comprising pirfenidone having a specific particle size range and improving tabletting as an active ingredient.
  • pirfenidone having a specific particle size range and improving tabletting as an active ingredient.
  • the present invention comprises a pirfenidone (average idiopathic pulmonary fibrosis), atherosclerosis, respiratory tract or skin inflammation comprising a pirfenidone having an average particle size of 20 to 100 ⁇ m as an active ingredient, And it provides a method for preventing or treating inflammation of pulmonary fibrosis, arteriosclerosis, respiratory tract or skin comprising the step of administering it.
  • Pirfenidone included as an 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 having a molecular weight of 185.23 daltons.
  • the chemical formula is C 12 H 11 NO, the structure is the same as the formula (1).
  • Pirfenidone is clinically evaluated as a broad spectrum anti-fibrotic drug. Pirfenidone is known to have anti-fibrotic and anti-inflammatory pharmacological activity that is reflected in its expression of TGF- ⁇ 1, TNF- ⁇ , PDGF and most importantly its activity of lowering the expression of different types of collagen.
  • the pirfenidone may be prepared according to known methods, for example, US Pat. No. 3,839,346, US Pat. No. 3,974,281, US Pat. No. 4,042,699, US Pat. No. 4,052,509, or the like.
  • the pirfenidone is characterized in that the average particle size is 20 to 100 ⁇ m as the volume mean diameter (VMD). According to the present invention, when pirfenidone has such an average particle size range, the compressibility is remarkably increased, and the tableting property is excellently improved when prepared as an oral administration agent, especially a tablet.
  • VMD volume mean diameter
  • the content of pirfenidone having the specific average particle size range can be appropriately controlled according to the use form and purpose, patient condition, type of symptom and severity, and the total weight of the pharmaceutical composition. It may be 10 to 90% by weight on the basis. However, this may be increased or decreased in accordance with the needs of the doser, and may be appropriately increased or decreased depending on various factors such as diet, nutritional status, progression of pathological symptoms, and the like, but is not limited to the above range.
  • the dosage of the pharmaceutical composition of the present invention may be determined by a specialist according to various factors such as the patient's condition, age, weight, degree of cartilage damage, disease progression, and the like. In addition, it is intended to contain a daily dose or 1/2, 1/3 or 1/4 dose thereof of the pharmaceutical composition per unit dosage form, and may be administered 1 to 6 times a day.
  • the composition according to the present invention when formulating the composition according to the present invention, as an active ingredient per unit dosage form, it may include 1 to 1000 mg, preferably 200 to 600 mg of pirfenidone having the specific average particle size range. have. More preferably, when formulating the composition according to the present invention, as an active ingredient per unit formulation, it may include 200 mg or 600 mg of pirfenidone having the specific average particle size range.
  • the pharmaceutical composition according to the present invention is an average according to the present invention per unit dosage form so that it can be administered according to the general frequency of pirfenidone administration (that is, 200 mg 1 tablet three times a day at an initial dose).
  • Pirfenidone according to the present invention may be included to include 200 mg of pirfenidone having a particle size range, and to improve low medication compliance due to inconvenience caused by an increase in the number and dosage of unit dosages administered at a later dose. You can also include 600mg of money.
  • a high dose of pirfenidone per unit formulation is included by excellent tableting due to the remarkable compressibility In this way, it is possible to prepare high dose formulations that have been difficult to manufacture in the past, which has the advantage of excellently improving the low medication compliance caused by administration of pirfenidone.
  • composition according to the invention can be administered to a mammal, including humans, by various routes.
  • the mode of administration can be any of the routinely used methods, for example, can be administered orally or parenterally (eg, skin, vein, intramuscular, subcutaneous), etc., but for the purposes of the present invention is preferred. It can be administered orally.
  • the oral preparations include, but are not limited to, for example, tablets, capsules, granules, powders, pills, and the like, but may be preferably formulated in the form of tablets for the purposes of the present invention. Tablets may be prepared according to common tablet manufacturing methods (e.g., grinding, mixing, granulating, drying, tableting and coating, if necessary).
  • the formulation into tablets in the present invention, it can be prepared according to the wet granulation method, dry granulation method or direct stroke method.
  • the wet granulation method includes, for example, a mixing step of weighing an active ingredient (main ingredient), a diluent, an excipient, and a disintegrant and mixing until homogeneous with a mixer, an association step of adding and mixing a binder thereto, and sieving to prepare granules.
  • Dry granulation also includes, for example, weighing and mixing the components, crushing or compressing them, preparing them into flat tablets or pellets, crushing the tablets or pellets, sieving processes and tableting the same. Tablets are manufactured according to the process of slugging through a process or by mixing the components weighed in a roller to produce a compressed product, roller compaction method of breaking the compressed product, sizing, lubricating and tableting to produce tablets. It is.
  • the direct hit method means a method of compressing at once after mixing the components necessary for the manufacture of tablets.
  • the present invention can be formulated in tablet form by wet granulation.
  • composition of the present invention for formulation, adjuvants such as pharmaceutically suitable and physiologically acceptable carriers, excipients and diluents, in addition to pirfenidone having an average particle size of the volume average diameter of 20 to 100 ⁇ m as an active ingredient It may further contain.
  • adjuvants such as pharmaceutically suitable and physiologically acceptable carriers, excipients and diluents, in addition to pirfenidone having an average particle size of the volume average diameter of 20 to 100 ⁇ m as an active ingredient It may further contain.
  • an excipient a binder, a disintegrant, a lubricant, a solubilizer, a suspending agent, a preservative, an extender, or the like may be formulated.
  • the excipients include, but are not limited to, lactose hydrate, mannitol, corn starch, microcrystalline cellulose, sucrose, dextrose, sorbitol, and more preferably lactose hydrate.
  • the excipient content may be included in 5 to 80% by weight of the total weight of the tablet to be prepared, but is not limited thereto.
  • the binder may be, but is not limited to, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinylpyrrolidone, and more preferably hydroxypropyl cellulose.
  • the binder content may be included in 0.5 to 30% by weight of the total weight of the tablet prepared, but is not limited thereto.
  • disintegrant examples include, but are not limited to, corn starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, carmellose sodium, low substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl starch sodium, crosslinked polyvinyl Pyrrolidine is preferred, and more preferably may contain croscarmellose sodium.
  • the content of the disintegrant may be included in 0.1 to 30% by weight of the total weight of the tablet produced, but is not limited thereto.
  • the lubricant is, but is not limited to, calcium stearate, sodium stearate, magnesium stearate, hard silicic anhydride, more preferably magnesium stearate.
  • the amount of the lubricant may be included in 0.1 to 5% by weight of the total weight of the tablet produced, but is not limited thereto.
  • the pharmaceutical composition according to the present invention when the pirfenidone content of the active ingredient is 200 mg, 55 mg of lactohydrate as excipient, 20 mg of croscarmellose sodium as a disintegrant, hydroxypropyl cellulose as a binder It may be in the form of a tablet containing 8 mg, uncoated tablet containing 2 mg of magnesium stearate as a lubricant, and the tablet may have a hardness of 8 to 18 kp after tableting.
  • the pharmaceutical composition according to the present invention has a pirfenidone content of 600 mg as an active ingredient, 165 mg of lactose hydrate as an excipient, 60 mg of croscarmellose sodium as a disintegrant, 24 mg of hydroxypropyl cellulose as a binder, a lubricant It may be in the form of a tablet containing uncoated tablet containing 6 mg of magnesium stearate, and the tablet may have a hardness of 8 to 30 kp after tableting.
  • the pharmaceutical composition according to the invention may further comprise a coating layer on the outside thereof.
  • the coating layer may be formed through a generally known coating method (for example, film coating, sugar coating, etc.) using a coating agent used for coating of tablets.
  • the pharmaceutical composition according to the present invention was formulated into tablets (coated tablets) and then coated with Opadry 03F620043 yellow containing hydroxypropylmethylcellulose, titanium oxide, polyethylene glycol, to prepare a tablet.
  • the present invention relates to a method for producing a tablet containing the pirfenidone as an active ingredient comprising the following steps:
  • step b) mixing the pirfenidone prepared in step a) with an excipient and a disintegrant;
  • step b) adding a binder to the mixture prepared in step b) and obtaining granules;
  • step d) mixing and tableting the granules and the lubricant prepared in step c) to prepare a tablet.
  • the method may further comprise coating a tablet prepared in step d).
  • a pirfenidone having a volume average diameter of 20 to 100 ⁇ m is prepared, and a lactose and croscarmellose sodium are added thereto to prepare a mixture, and to the mixture, Hydroxypropylcellulose solution was sprayed using a fluidized bed granulator to obtain granules, and the obtained granules were compressed to prepare tablets in uncoated form. Then, coated with Opadry 03F620043 yellow containing hydroxypropylmethylcellulose, titanium oxide, polyethylene glycol to prepare a coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablet containing 200 mg of pirfenidone (coated tablet weight 285 mg / tablet).
  • Particle size was measured by SYMPATEC HELOS particle size analyzer.
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 10 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablet containing 200 mg of pirfenidone (coated tablet weight 285 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 10 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone with an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablet containing 200 mg of pirfenidone (coated tablet weight 285 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 10 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablet containing 200 mg of pirfenidone (coated tablet weight 285 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 10 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone with an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablet containing 200 mg of pirfenidone (coated tablet weight 285 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 10 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablet containing 200 mg of pirfenidone (coated tablet weight 285 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 10 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablet containing 200 mg of pirfenidone (coated tablet weight 285 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 10 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablet containing 200 mg of pirfenidone (coated tablet weight 285 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 10 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablet containing 200 mg of pirfenidone (coated tablet weight 285 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 10 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablets containing 200 mg of pirfenidone (coated tablet weight 285 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 10 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablets containing 600 mg of pirfenidone (uncoated tablet weight 855 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 30 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablets containing 600 mg of pirfenidone (uncoated tablet weight 855 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 30 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone with an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablets containing 600 mg of pirfenidone (uncoated tablet weight 855 mg / tablet).
  • An aqueous solution of about 15 (w / w)% concentration of party Opadry 03F620043 was prepared and sprayed using a * 137 fan coater to coat 30 mg of uncoated tablet to obtain the desired pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablets containing 600 mg of pirfenidone (uncoated tablet weight 855 mg / tablet).
  • An aqueous solution of about 15 (w / w)% concentration of party Opadry 03F620043 was prepared and sprayed using a * 144 fan coater to coat 30 mg of uncoated tablet to obtain the desired pirfenidone coated tablet.
  • Pirfenidone with an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablets containing 600 mg of pirfenidone (uncoated tablet weight 855 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 30 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablets containing 600 mg of pirfenidone (uncoated tablet weight 855 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 30 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablets containing 600 mg of pirfenidone (uncoated tablet weight 855 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 30 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablets containing 600 mg of pirfenidone (uncoated tablet weight 855 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 30 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablets containing 600 mg of pirfenidone (uncoated tablet weight 855 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 30 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Pirfenidone having an average particle size as the volume average diameter was mixed with lactose and croscarmellose sodium.
  • Granules are made by preparing and spraying an aqueous solution of about 5 (w / w)% concentration of hydroxypropylcellulose using a fluid bed granulator. Sodium croscarmellose is added to the granules and mixed, followed by lubrication with magnesium stearate. The final mixture was pressed with a force of 15 kN to obtain uncoated tablets containing 600 mg of pirfenidone (uncoated tablet weight 855 mg / tablet).
  • An aqueous solution having a concentration of about 15 (w / w)% of party Opadry 03F620043 was prepared and sprayed using a pan coater to coat 30 mg of uncoated tablet to obtain a target pirfenidone coated tablet.
  • Hardness and Compressibility Index (CI) of tablets containing pirfenidone prepared according to Examples 1 to 10 and Comparative Examples 1 to 10 of the present invention were measured. Hardness was measured by ERWEKA TBH-200 hardness tester, CI was measured using the bulk density and tap density of the final mixture.

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Abstract

La présente invention concerne une préparation à administration par voie orale de pirfénidone, présentant des caractéristiques améliorées de formation de comprimés. Plus précisément, la présente invention concerne une composition pharmaceutique contenant, comme principe actif, de la pirfénidone ayant une taille moyenne de particule située dans une plage spécifique, et un procédé de préparation d'une préparation à administration par voie orale comprenant la composition et présentant des caractéristiques améliorées de formation de comprimés. Lors de la préparation d'une dose unitaire en utilisant la composition pharmaceutique contenant la pirfénidone ayant une plage de tailles moyennes de particule, selon la présente invention, une dose élevée de pirfénidone peut être comprise par dose unitaire du fait des excellentes caractéristiques de formation de comprimés dues à l'aptitude remarquable à la compression, une préparation à dose élevée, qui de manière classique a été difficile à préparer, peut être préparée, et une faible conformité de prise du médicament provoquée par l'administration de pirfénidone peut être considérablement améliorée, et ainsi la présente invention est très utile dans le développement d'une préparation à administration par voie orale de pirfénidone.
PCT/KR2018/002484 2017-03-02 2018-02-28 Composition pharmaceutique présentant des caractéristiques améliorées de formation de comprimés selon le contrôle de taille des particules de pirfénidone, et son procédé de préparation WO2018160011A1 (fr)

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JP2019547670A JP2020509053A (ja) 2017-03-02 2018-02-28 ピルフェニドンの粒子の大きさ調節による打錠性が改善された薬剤学的組成物およびその製造方法
CN201880018876.5A CN110430871A (zh) 2017-03-02 2018-02-28 可压缩性改善的粒度受控的吡非尼酮的药物组合物及其制备方法
JP2021213391A JP2022031527A (ja) 2017-03-02 2021-12-27 ピルフェニドンの粒子の大きさ調節による打錠性が改善された薬剤学的組成物およびその製造方法

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CN115666533B (zh) * 2020-04-22 2024-08-09 永进药品工业株式会社 具有改善的安全性和稳定性的含吡非尼酮的肠溶包衣制剂及其制备方法

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