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WO2018105943A1 - Composition pharmaceutique pour le traitement ou le soulagement de la fibrose pulmonaire et de l'asthme - Google Patents

Composition pharmaceutique pour le traitement ou le soulagement de la fibrose pulmonaire et de l'asthme Download PDF

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Publication number
WO2018105943A1
WO2018105943A1 PCT/KR2017/013799 KR2017013799W WO2018105943A1 WO 2018105943 A1 WO2018105943 A1 WO 2018105943A1 KR 2017013799 W KR2017013799 W KR 2017013799W WO 2018105943 A1 WO2018105943 A1 WO 2018105943A1
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WIPO (PCT)
Prior art keywords
asthma
formula
treatment
pharmaceutically acceptable
paquinimod
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2017/013799
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English (en)
Korean (ko)
Inventor
박춘식
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Industry Academy Cooperation Foundation of Soonchunhyang University
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Industry Academy Cooperation Foundation of Soonchunhyang University
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
Priority claimed from KR1020160165762A external-priority patent/KR20180065224A/ko
Priority claimed from KR1020160165761A external-priority patent/KR20180065223A/ko
Application filed by Industry Academy Cooperation Foundation of Soonchunhyang University filed Critical Industry Academy Cooperation Foundation of Soonchunhyang University
Publication of WO2018105943A1 publication Critical patent/WO2018105943A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • polymorph means a solid crystalline form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound show different physical, chemical and / or spectral properties. Differences in physical properties include, but are not limited to, stability (eg, thermal or light stability), compressibility and density (important for formulation and product manufacture), and dissolution rate (which may affect bioavailability). Not.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising paquinimod, laquinimod, tasquinimod, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the active ingredient according to the invention is paquinimod or a salt thereof for pulmonary fibrosis use, and tasquinimod or a salt thereof for asthma, in particular neutrophil asthma use.
  • the present invention provides a method for treating pulmonary fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of paquinimod, laquinimod, tasquinimod, or a pharmaceutically acceptable salt thereof. (Neutrophils) Methods are provided for treating or alleviating their symptoms.
  • the subject is a human.
  • the quinimod compound of the present invention is administered in a therapeutically effective amount.
  • the quinimod compound of the present invention may be administered by any suitable route in the form of a pharmaceutical composition suitable for this route, and in dosages effective for the intended treatment. Effective dosages are generally from about 0.0001 to about 10 mg / kg body weight / day in single or divided doses, preferably from about 0.001 to about 1 mg / kg / day, more preferably from about 0.001 to about 0.1 mg / kg / day.
  • dosage levels below the lower limit of this range may be appropriate, depending on age, species, and disease or condition to be treated. In other cases, larger doses can still be used without deleterious side effects. Larger doses may be divided into several smaller doses for administration throughout the day. Methods for determining appropriate dosages are well known in the art, and for example, Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000 can be used.
  • the quinimod compound of the present invention may be administered orally, and the oral cavity is a concept including swallowing.
  • oral administration the compounds of the present invention may enter the gastrointestinal tract or be absorbed directly from the mouth into the bloodstream, such as, for example, buccal or sublingual administration.
  • the amount of drug that is the active ingredient may be present from about 0.05% to about 95% by weight, more generally from about 2% to about 50% by weight of the formulation.
  • tablets may contain a disintegrant comprising from about 0.5% to about 35%, more generally from about 2% to about 25% by weight of the formulation.
  • disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.
  • Parenteral formulations can also be prepared in dried form (eg, lyophilized) or as sterile non-aqueous solutions. These formulations can be used with a suitable vehicle, such as sterile water. Solubility-enhancing agents can also be used to prepare parenteral solutions.
  • compositions for inhalation administration are administered to the respiratory tract by a pressurized pump or inhaler such as a reservoir dry powder inhaler, a single-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a pressurized aerosol inhaler, a nebulizer or a pulverizer.
  • a pressurized pump or inhaler such as a reservoir dry powder inhaler, a single-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a pressurized aerosol inhaler, a nebulizer or a pulverizer.
  • a pressurized pump or inhaler such as a reservoir dry powder inhaler, a single-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a pressurized aerosol inhaler, a nebulizer or a pulverizer.
  • the quinimod compounds of the present invention may be used alone or in combination with other pharmaceutically active compounds to treat or alleviate pulmonary fibrosis or (neutrophil) asthma.
  • the quinimod compound (s) and other pharmaceutically active compound (s) of the invention may be administered simultaneously (in the same or in separate formulations) or sequentially.
  • the present invention provides a subject with a therapeutically effective amount of one or more quinimod compounds of the invention and one or more additional pharmaceutically active compounds to prevent pulmonary fibrosis or (neutrophil) asthma. Methods for treatment or alleviation.
  • a pharmaceutical composition comprising one or more quinimod compounds of the invention, one or more additional pharmaceutically active compounds, and a pharmaceutically acceptable carrier.
  • the pulmonary fibrosis therapeutic agent for example, the following drugs may be used, but the present invention is not limited to the specific kind of the second active ingredient.
  • -(Inhalation) steroids beclomethasone dipropionate, budesonide, ciclesonide, fluticasone, mometasone furoate, triamcinolone acetonide Etc)
  • ipratropium ipratropium bromide, etc.
  • oxytropium oxitropium bromide, etc.
  • chromoline agent cromolyn sodium, nedocromil sodium
  • one of the therapeutic agents is given in multiple doses, or both are given in multiple doses. If not simultaneous, the timing between multiple doses can optionally vary from more than zero weeks to less than twenty weeks.
  • compositions that constitute the combination therapy disclosed herein are optionally combined formulations or predominantly separate formulations for co-administration.
  • the pharmaceutical agents that make up the combination treatment may also be administered sequentially to any of the agents administered by a therapy requiring two stages of administration.
  • Two-step dosage regimens may require sequential administration of the active agent or separate administration of separate active agents.
  • the time period between the multiple administration steps can vary from several minutes depending on the nature of each pharmaceutical agent, such as potency, solubility, bioavailability, plasma half-life, and the kinetic profile of the pharmaceutical agent. Up to several hours. Circadian variation in target molecule concentration is used to determine the optimal dosing interval.
  • Figure 2 is the result of measuring the ratio of macrophages, neutrophils, eosinophils and lymphocytes among 500 random cells in bronchoalveolar lavage of Silica induced IPF model mice.
  • the experimental animals used in this study were 6-week-old C57BL / 6 male mice purchased from Orient bio (Seongnam, Gyeonggi-do, Korea). The breeding conditions of these animals were kept in a constant temperature and humidity chamber at 22 ° C. and 50% RH humidity.
  • the cage was a transparent plastic cage (4 mice / cage) with a stainless wire lid.
  • Anesthesia diluted with SiO 2 in 1.05x PBS was injected into the lungs through the airways of anesthetized C57BL / 6 mice, and then bred in a thermohygrostat for 2 weeks.
  • the bronchoalveolar lavage fluid of this experiment was performed by drip infusion with 1.05x Phosphated buffered saline. After gently washing the lung, the obtained sample was centrifuged at 1000 rpm for 15 minutes. Subsequently, the supernatant was stored at -80 ° C, and pellets of the formed cells were added to 1 ml of 1.05x PBS to measure immune cells and determine the total number of cells.
  • the total number of inflammatory cells was measured by a hematocytometer.
  • Silicotic nodule was measured by light microscopy.
  • the Image J program was used to compare the Silicotic nodules between groups 1, 2, 3, 4 and 5.
  • the overall cross-sectional area of the lung tissue subjected to H & E staining was measured by Image J program, and the cross-sectional area of the silicotic nodule was measured to express the percentage of silicotic nodule in the total cross-sectional area.
  • the inflammatory response induced by Silica was analyzed. The results are shown in FIG.
  • the second, third and fifth groups were more than the first group, but the third group was focused on whole cells, macrophages and neutrophils.
  • paquinimod treatment significantly reduced dose-dependent treatment.
  • the fifth group was significantly decreased than the second group.
  • FIG. 2 The results of observing the proportion of inflammatory cells through Diff-quik staining are shown in FIG. 2. As shown in Figure 2, dose-dependently the number of neutrophils was significantly reduced, it was observed that the ratio is increased so that the specific gravity of the macrophages similar to the first group.
  • Silicotic nodule evaluation results are shown in FIG. 3. When comparing the size of Silicotic nodule of Group 2 and Silcotic nodule of Group 3 and 4, significant efficacy of Paquinimod was observed, and the size of Silicotic nodule of Group 3 and 4 was compared. The decrease of Silicotic nodule in the fourth group was observed.
  • mice were purchased from Orient Bio (Seongnam, Korea) and maintained aseptic.
  • CFA / OVA model six-week-old C57BL / 6 females were used. 20 ⁇ g of grade V chicken egg OVA (Sigma-Aldrich, ST Lousi, MO, USA) was mixed with endotoxin-free phosphate buffer saline (PBS), and CFA (Sigma-Aldrich). , ST Louis, USA) were added intraperitoneally at 0, 7, and 14 days with addition of 75 ⁇ l. On days 21 and 22, all mice were dosed nasal with 0.1% grade III OVA dissolved in 50 ⁇ l of saline.
  • Paquinimod, Laquinimod, or Tasquinimod were purchased from J & H Korea, AdooQ Bioscience, or MedChem Expres, respectively. After dissolving 20 mg of each compound in 200 ⁇ l of endotoxin free water (stock concentration: 100 ⁇ g / ⁇ l), aliquots of 20 ⁇ l were stored. In order to administer 0.1 ⁇ g per mouse weight (g) per day, assuming that the mouse weighs 20g, vortex the stock, and then add 1 ⁇ l (including 100 ⁇ g of test drug) to 135ml of purified water and provide 2.7ml per mouse. Intake 2 ⁇ g per day.
  • mice 24 hours after the last OVA nasal administration, mice were anesthetized with zoletil and lumpoon. The tracheotomy was then performed and connected to Flexi-Vent (SCIREQ, Flexivent Scireq Inc., Montreal, Canada) to measure mechanical respiration. Airway resistance was measured using various concentrations of methacholine (0,20,100 mg / ml, Sigma-Aldrich, ST. Louis, USA) dissolved in PBS.
  • Alveolar lavage fluid was extracted immediately after measuring airway resistance. 4 ml infusion was performed with phosphate buffered saline using a 1 ml syringe. The alveolar lavage fluid was gently extracted, and the extracted alveolar lavage fluid was centrifuged at 500 g for 5 minutes and the supernatant was stored at -80 ° C. The remaining cell layer pellet was released using PBS 1ml and the total cell number was measured using a hemocytometer.
  • Cells were adhered to the slides with a cytocentrifuge and subjected to Diff-Quick staining (Scientific Products, Gibbstown, NJ, USA.). Differentiation of inflammatory cells was performed under a 400x microscope. After reading 500, fractions of macrophages, neutrophils, eosinophils, and lymphocytes were determined.
  • PAS stain was performed as follows. After the re-hydrolyzed process, the tissue was dyed with Periodic Acid Solution for 7 minutes and then washed with distilled water. After dyeing with Schiff's solution for 30 minutes, wipe with hot water and then again with distilled water. Stained with hematoxylin for 2 minutes and dyed with Bluing Reagent solution for 30 seconds, then washed with distilled water and dried. After mounting with balsam solution was observed under a microscope.
  • FIGS. 5 and 6 Comparison results of bronchoalveolar lavage fluid are shown in FIGS. 5 and 6. Compared with the Sham group, the total cell number and the number of macrophages, neutrophils, eosinophils, and lymphocytes were significantly increased in the CFA / OVA group (p ⁇ 0.05) (FIG. 5).
  • laquinimod and tasquinimod showed significant differences in total cell count and decrease in macrophages, neutrophils, eosinophils, and lymphocytes compared to paquinimod. (p ⁇ 0.05).
  • laquinimod and tasquinimod showed more significant inhibition on total cell number and macrophages, neutrophils, eosinophils and lymphocytes than laquinimod (p ⁇ 0.05) (see FIG. 6).
  • FIG. 10 The result of measuring the goblet cell through PAS stain is shown in FIG. 10.
  • the CFA / OVA group significantly increased than the Sham group (p ⁇ 0.05).
  • the Paquinimod, Laquinimod, and Tasquinimod groups all significantly decreased (p ⁇ 0.05).
  • the Tasquinimod group was significantly reduced compared to the Paquinimod group (p ⁇ 0.05).
  • goblet cells which are mucus-secreting cells, increase, and bronchial smooth muscle increases.
  • Administration of the quinimod compound according to the present invention was found to be effective in improving asthma in this respect.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique pour le traitement de la fibrose pulmonaire ou de l'asthme neutrophile ou le soulagement de leurs symptômes, comprenant ou utilisant, à titre de principes actifs, du laquinimod, du paquinimod et du tasquinimod ou des sels pharmaceutiquement acceptables de ceux-ci, et de préférence du paquinimod ou un sel pharmaceutiquement acceptable de celui-ci pour une utilisation dans le traitement ou le soulagement de la fibrose pulmonaire, et du tasquinimod ou un sel pharmaceutiquement acceptable de celui-ci pour une utilisation dans le traitement ou le soulagement de l'asthme neutrophile. À savoir, la présente invention concerne une nouvelle utilisation médicale du laquinimod, du paquinimod, du tasquinimod ou des sels pharmaceutiquement acceptables de ceux-ci.
PCT/KR2017/013799 2016-12-07 2017-11-29 Composition pharmaceutique pour le traitement ou le soulagement de la fibrose pulmonaire et de l'asthme Ceased WO2018105943A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR1020160165762A KR20180065224A (ko) 2016-12-07 2016-12-07 폐섬유증의 치료 또는 완화용 약학 조성물
KR10-2016-0165761 2016-12-07
KR1020160165761A KR20180065223A (ko) 2016-12-07 2016-12-07 천식의 치료 또는 완화용 약학 조성물
KR10-2016-0165762 2016-12-07

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WO2018105943A1 true WO2018105943A1 (fr) 2018-06-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12485095B2 (en) 2021-05-25 2025-12-02 Active Biotech Ab Plurality of tasquinimod particles and use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010043066A (ko) * 1998-04-27 2001-05-25 액티브 바이오테크 에이비 퀴놀린 유도체
KR20010053115A (ko) * 1998-07-15 2001-06-25 액티브 바이오테크 에이비 퀴놀린 유도체
JP2013177351A (ja) * 2012-02-29 2013-09-09 Shionogi & Co Ltd Ｐｇｄ２拮抗剤及びロイコトリエン拮抗剤からなる喘息治療剤
KR20140035493A (ko) * 2011-06-22 2014-03-21 액티브 바이오테크 에이비 중수소 농축된 4-하이드록시-5-메톡시-ｎ,1-다이메틸-2-옥소-ｎ-[(4-트리플루오로-메틸)페닐]-1,2-다이하이드로퀴놀린-3-카르복사미드

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010043066A (ko) * 1998-04-27 2001-05-25 액티브 바이오테크 에이비 퀴놀린 유도체
KR20010053115A (ko) * 1998-07-15 2001-06-25 액티브 바이오테크 에이비 퀴놀린 유도체
KR20140035493A (ko) * 2011-06-22 2014-03-21 액티브 바이오테크 에이비 중수소 농축된 4-하이드록시-5-메톡시-ｎ,1-다이메틸-2-옥소-ｎ-[(4-트리플루오로-메틸)페닐]-1,2-다이하이드로퀴놀린-3-카르복사미드
JP2013177351A (ja) * 2012-02-29 2013-09-09 Shionogi & Co Ltd Ｐｇｄ２拮抗剤及びロイコトリエン拮抗剤からなる喘息治療剤

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Title
STENSTROM, M. ET AL.: "Paquinimod Reduces Skin Fibrosis in Tight Skin 1 Mice, an Experimental Model of Systemic Sclerosis", JOURNAL OF DERMATOLOGICAL SCIENCE, vol. 83, no. 1, July 2016 (2016-07-01), pages 52 - 59, XP029569709 *
XAUBET, A. ET AL.: "Pirfenidone for the Treatment of Idiopathic Pulmonary Fibrosis", EXPERT OPINION ON PHARMACOTHERAPY, vol. 15, no. 2, 2014, pages 275 - 281, XP055515933 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12485095B2 (en) 2021-05-25 2025-12-02 Active Biotech Ab Plurality of tasquinimod particles and use thereof

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