WO2022007743A1 - Forme posologique pour administration par les muqueuses et son utilisation - Google Patents

Forme posologique pour administration par les muqueuses et son utilisation Download PDF

Info

Publication number
WO2022007743A1
WO2022007743A1 PCT/CN2021/104474 CN2021104474W WO2022007743A1 WO 2022007743 A1 WO2022007743 A1 WO 2022007743A1 CN 2021104474 W CN2021104474 W CN 2021104474W WO 2022007743 A1 WO2022007743 A1 WO 2022007743A1
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
sodium
mucosal administration
ccr4
asthma
Prior art date
Application number
PCT/CN2021/104474
Other languages
English (en)
Chinese (zh)
Inventor
赵海峰
Original Assignee
迈德欣国际有限公司
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 迈德欣国际有限公司 filed Critical 迈德欣国际有限公司
Publication of WO2022007743A1 publication Critical patent/WO2022007743A1/fr

Links

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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medicine, and relates to a mucosal administration dosage form containing a CCR4 inhibitor, and the use of the medicine for treating diseases mediated by CCR4.
  • CCR4 (Chemokine Receptor 4, Chemokine Receptor 4) was first discovered by Christine A.Power in 1995 (Christine AP et al. J.Biol.Chem.1995,270(8):19495-19500), belonging to chemotaxis A member of the factor receptor (CCR) family, it is a seven-transmembrane G-protein coupled receptor.
  • CCR4 is expressed in peripheral blood leukocytes, thymocytes, basophils, monocytes, macrophages, platelets, IL-activated NK cells, spleen and brain, and can play an important role in a variety of diseases.
  • PBMCs peripheral blood mononuclear cells
  • TARC peripheral blood mononuclear cells
  • the drugs used to treat allergic dermatitis mainly include antihistamines and bronchodilators, but they can only improve symptoms, but have no effect on the development of the disease.
  • corticosteroids also have a certain effect on allergic dermatitis, but there are potential safety hazards. Studies have shown that antagonism of MDC or TARC can reduce the accumulation of T cells at the site of inflammation, and CCR4 antagonists may be very effective in the treatment of allergic inflammation including but not limited to allergic rhinitis and allergic dermatitis.
  • CCR4 has also been found to be strongly associated with lung diseases such as chronic obstructive pneumonia, chronic bronchitis and asthma.
  • CCR4 can be restrictedly expressed in the cells involved in the asthma response, and is considered to be a good target for the treatment of asthma. Therefore, the development of CCR4 antagonist drugs has good application prospects.
  • CN101370793A discloses compounds of formula and their use as CCR4 antagonists, including for CCR4-mediated diseases
  • CN102388039A discloses indazole compounds of the following formula (I) and their use as CCR4 antagonists, including their use in treatments associated with CCR4 antagonists:
  • the invention provides a technology for improving the bioavailability of GSK2239633 through mucosal administration route and a usable pharmaceutical preparation, which solves the problems of low solubility of CCR4 inhibitors in the prior art, difficulty in preparation, and excessive bioavailability of the prepared preparations. Low, unable to reach the expected effective plasma concentration in the body.
  • the CCR4 inhibitor pharmaceutical preparation provided by the present invention also has the advantages of no local irritation and safe use.
  • the present invention provides a dosage form for mucosal administration, which contains a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof:
  • the CAS number of the compound of formula I is 1240516-71-5, its preparation is disclosed in Example 57 of CN102388039A, and its chemical name is N-[(3- ⁇ [3- ⁇ [(5-chloro-2-thienyl) Sulfonyl]amino ⁇ -4-(methoxy)-1H-indazol-1-yl]methyl ⁇ phenyl)methyl]-2-hydroxy-2-methylpropanamide.
  • the common name for the compound of formula I is GSK2239633.
  • the compounds of formula I may be administered in the form of prodrugs, which are compounds that are cleaved in humans or animals to release the compounds of the present invention.
  • prodrugs include in vivo cleavable ester derivatives and in vivo cleavable amide derivatives, which may be formed at the carboxyl or hydroxyl group of the compound of formula I, which amide derivatives may be formed at the carboxyl group of the compound of formula I or on the amino group.
  • compositions of formula I are, for example, their in vivo cleavable esters or ethers.
  • In vivo cleavable esters or ethers of hydroxyl-containing compounds of formula I are, for example, pharmaceutically acceptable esters or ethers that are cleaved in humans and animals to yield the parent hydroxy compound.
  • suitable pharmaceutically acceptable ester-forming groups include inorganic esters such as phosphates (including phosphoramidates).
  • suitable pharmaceutically acceptable ester-forming groups also include (1-10C) alkanoyl groups (such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl), (1-10C) alkanoyl groups 10C) Alkoxycarbonyl (eg ethoxycarbonyl, N,N-[di-(1-4C)alkyl]carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl).
  • (1-10C) alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl
  • 1-10C alkanoyl groups 10C) Alkoxycarbonyl (eg ethoxycarbonyl, N,N-[di-(1-4C)alkyl]carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl).
  • ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(1-4C)alkylpiperazin-1-ylmethyl.
  • suitable pharmaceutically acceptable ether-forming groups include alpha-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.
  • the compounds of formula I of the present invention or pharmaceutically acceptable salts, solvates or prodrugs thereof, have CCR4 inhibitory activity.
  • a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof can be used for the treatment of CCR4 mediated diseases or for the manufacture of a medicament for the treatment of CCR4 mediated diseases.
  • the dosage form for mucosal administration is a dosage form for nasal administration.
  • the dosage form for mucosal administration is nasal administration and is a solution composition containing the compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • Dosage forms for nasal administration can be administered by inhalation of the composition using a suitable delivery device such as a nebulizer (eg, a spray pump, aerosol, nebulizer, or metered-dose nebulizer) or a dropper container (eg, a dropper or nasal dropper). It is dropped or applied in the nasal cavity to adhere to the nasal mucosa, whereby the active ingredient is absorbed through the nasal mucosa.
  • the compound of formula I above is substantially completely dissolved in the solution.
  • the dosage form for mucosal administration is in the presence of a partially suspended compound of formula I.
  • the dosage form for mucosal administration particularly a dosage form for transnasal mucosal administration, eg, a solution for spraying, comprises a cosolvent.
  • the cosolvent facilitates the dissolution of the compound of formula I in solution.
  • the cosolvent is selected from sodium hydroxide, sodium methoxide, potassium hydroxide, sodium bicarbonate, sodium dihydrogen phosphate, sodium citrate, ⁇ -, ⁇ - or ⁇ -cyclodextrin any one or more of them.
  • the co-solvent is sodium hydroxide and/or ⁇ -cyclodextrin.
  • the co-solvent is sodium hydroxide.
  • the content of the cosolvent contained in the mucosal administration dosage form is about 0.25-1.5 mol/L, preferably 0.5-1.0 mol/L.
  • the dosage form for mucosal administration comprises a pH adjusting agent.
  • the mucosal administration dosage form comprises a pH adjusting agent selected from the group consisting of phosphoric acid, hydrochloric acid, citric acid, tartaric acid, acetic acid, maleic acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, citric acid Any one or more of sodium, phosphate buffer, acetate buffer, and citrate buffer.
  • the dosage form for mucosal administration comprises a pH adjusting agent phosphate and/or citrate buffer.
  • the dosage form for mucosal administration particularly a dosage form for transnasal mucosal administration, eg, a solution for spraying, comprises a cosolvent and a pH adjuster.
  • the mucosal administration dosage form has a pH of about 6.5-9.5; preferably about 7.0-8.5, such as 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9 , 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5, and a range of pH values formed by any two of these specific pH values.
  • the mucosal administration dosage form comprises a preservative, for example selected from methylparaben, ethylparaben, propylparaben, butylparaben, Sodium Methylparaben, Sodium Ethylparaben, Sodium Propylparaben, Sodium Butylparaben, Sorbic Acid, Sodium Sorbate, Benzoic Acid, Sodium Benzoate, Benzyl Alcohol, Benzalkonium Any one or more of ammonium bromide, benzalkonium chloride, chlorobutanol, resorcinol and sodium edetate, preferably, the preservative is sodium methylparaben.
  • a preservative for example selected from methylparaben, ethylparaben, propylparaben, butylparaben, Sodium Methylparaben, Sodium Ethylparaben, Sodium Propylparaben, Sodium Butylparaben
  • the dosage form for mucosal administration is an isotonic formulation. Since the nasal environment is capable of self-regulating, in yet another aspect of the present invention, the formulation is free of osmotic pressure regulators.
  • the mucosal administration dosage form comprises an osmotic pressure regulator, such as any one or more selected from sodium chloride, potassium nitrate, boric acid and glucose, preferably sodium chloride.
  • an osmotic pressure regulator such as any one or more selected from sodium chloride, potassium nitrate, boric acid and glucose, preferably sodium chloride.
  • the mucosal administration dosage form does not contain a penetration enhancer.
  • the compound of formula I has a molecular weight of about 550, and the formulation may be free of penetration enhancers.
  • the mucosal administration dosage form spray solution dosage form has a spray particle size of about 5-200 ⁇ m, preferably about 10-150 ⁇ m.
  • the dosage form for mucosal administration (especially the dosage form for transnasal mucosal administration, such as a solution for spraying) is present in an amount of the compound of formula I or a pharmaceutically acceptable form thereof per 100 ml of the dosage form.
  • the amount of salt, solvate or prodrug is about
  • the dosage form for mucosal administration (especially the dosage form for transnasal mucosal administration, eg, a solution for spraying) is a dosage form for single-dose or multiple-dose administration, wherein the The amount of the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is about 2.5 ⁇ g to 10.0 mg, preferably about 5.0 ⁇ g to 1.0 mg.
  • the mucosal administration dosage form is used to treat a CCR4 mediated disease.
  • a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof has CCR4 inhibitory activity.
  • the compounds of formula I of the present invention or pharmaceutically acceptable salts, solvates or prodrugs thereof can be used for the treatment of CCR4 mediated diseases or for the preparation of medicaments for the treatment of CCR4 mediated diseases.
  • the compounds of formula I of the present invention, or pharmaceutically acceptable salts, solvates or prodrugs thereof can be used to treat diseases in which modulation of CCR4 (eg, inhibition of CCR4 activity) is beneficial to patients.
  • the CCR4-mediated diseases are, for example: (1) respiratory diseases, such as airway obstructive diseases, including asthma, including bronchial asthma, allergic asthma, endogenous asthma, extrinsic asthma, exercise-induced asthma, Drug-induced (including aspirin and NSAID-induced) asthma and dust-induced asthma, intermittent and persistent asthma; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; pulmonary gas Bronchiectasis; cystic fibrosis; hypersensitivity pneumonitis; pulmonary fibrosis, including cryptogenic fibrotic alveolitis, idiopathic interstitial pneumonia, fibrosis complicated by antineoplastic therapy and chronic infection; pulmonary vascular Vasculitis and thrombotic disease and pulmonary hypertension; rhinitis: acute and chronic rhinitis, including drug-induced rhinitis and vasomotor rhinitis; perennial and seasonal allergic rhinitis, including
  • a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for use in a method for the treatment or prevention of CCR4 mediated diseases by mucosal route of administration, in particular Methods of treating or preventing CCR4-mediated diseases by the nasal mucosal route of administration.
  • the compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered in the form of a spray solution.
  • the present invention also provides a method of preparing a dosage form for mucosal administration of the present invention as previously defined, wherein the mucosal dosage form comprises a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the dosage form for mucosal administration is a dosage form for nasal administration, eg, a solution composition.
  • the method includes the step of mixing a compound of formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, with a co-solvent and/or pH adjusting agent.
  • the method includes the step of adjusting the pH to about 6.5-9.5; preferably about 7.0-8.5.
  • the method further includes the step of adding one or more of preservatives, osmotic pressure regulators, and penetration enhancers.
  • preservatives osmotic pressure regulators
  • penetration enhancers the cosolvent, pH adjuster, preservative, osmotic pressure adjuster, and penetration enhancer are as defined above.
  • the method for preparing the nasal dosage form of the present invention, especially the spray comprises the following steps:
  • the volume of the cosolvent added therein is about 0.5-3 parts by volume, preferably about 1-2 parts by volume, for example, about 1.5 parts by volume;
  • the cosolvent added in step 1 of the preparation method is selected from sodium hydroxide, sodium methoxide, potassium hydroxide, sodium bicarbonate, sodium dihydrogen phosphate, sodium citrate, ⁇ -, ⁇ - or any one or more of ⁇ -cyclodextrin, preferably, the co-solvent it contains is sodium hydroxide/or ⁇ -cyclodextrin, more preferably, the co-solvent it contains is sodium hydroxide and .
  • the formulation for mucosal administration of the compound of formula I is prepared by first dissolving the compound of formula I in a smaller volume of co-solvent (eg, sodium hydroxide), and then adding the other components or water to the working volume.
  • co-solvent eg, sodium hydroxide
  • the concentration of the cosolvent added in the mucosal administration dosage form is about 0.1-3.0 mol/L, preferably about 0.2-2.0 mol/L, more preferably about 0.3-1.0 mol/L L, for example, is about 0.5 mol/L, and contains about 0.5-3.0 parts by volume, preferably about 1.0-2.0 parts by volume, such as about 1.5 parts by volume, of cosolvent per 100 parts by volume of the dosage form for mucosal administration.
  • co-solvents such as sodium hydroxide can promote the dissolution of the compound of formula I, but when the amount of sodium hydroxide is low or the concentration of sodium hydroxide in the formulation is low, it is not enough to dissolve the CCR4 inhibitor .
  • co-solvents such as sodium hydroxide
  • more pH adjusters such as sodium dihydrogen phosphate and sodium bicarbonate need to be used.
  • the amount of sodium hydroxide added is calculated at a concentration of about 0.5mol/L, and the volume is about 0.5ml-3ml , preferably about 1ml-2.0ml, more preferably 1.5ml.
  • sodium hydroxide may also be used so long as the amount of sodium hydroxide falls within or is equivalent to the above ranges.
  • the compound of formula I has good solubility and high solubility in the formulation of the present invention, the nasal ciliary toxicity is small and reversible, and the pH value of the formulation is suitable for the nasal cavity.
  • the nasal spray provided by the present invention has the advantages of quick-acting, avoiding the first-pass effect, high bioavailability, convenient use, safety and good compliance.
  • GSK2239633, CAS number 1240516-71-5 was purchased from MCE China, catalog number: HY-100183.
  • the reagents or instruments used in the examples without the manufacturer's indication are conventional products that can be obtained from the market. If the specific conditions are not indicated in the examples, it is carried out according to the conventional conditions or the conditions suggested by the manufacturer.
  • This experiment evaluated the nasal ciliary toxicity of the previously prepared formulations with different concentrations of CCR4 inhibitor.
  • sodium deoxycholate which is recognized in the literature as having severe ciliary toxicity, was used as a positive control, and normal saline was used as a blank control.
  • Blank control normal saline
  • Lasting time of eilliary movement was measured by in vitro method of cilia on toad palate.
  • the blank control was normal saline.
  • the toad was fixed in the supine position, the mouth was opened, and 0.5 ml of the drug solution was dripped on the upper palate mucosa to completely immerse the upper palate. After contacting for 30 minutes, the drug was washed with normal saline, and the upper palate mucosa was separated for microscope observation of ciliary movement. The mucosa was washed immediately after separation, flattened on a glass slide, dripped with normal saline on the surface of the mucosa, covered with a cover glass, and observed and recorded the duration of ciliary movement as described above.
  • the ciliary toxicity of the CCR4 inhibitor nasal spray prepared in Examples 1-9 was evaluated by the in vivo method. It was found that the ciliary toxicity of each preparation was lower than that in the in vitro experiment, and the continuous movement time of the cilia was longer than that in the in vitro method.
  • the preparations of the above examples all have good ciliary safety and are suitable for nasal administration.
  • CCR4 inhibitor injection in a 100ml volumetric bottle, add an appropriate amount of water for injection, then add 250mg of GSK2239633, add an appropriate amount of sodium hydroxide (1.5ml, 0.5mol/L), shake to dissolve, shake well, and adjust with sodium bicarbonate The pH value was adjusted to 8.5, water for injection was added to the scale, shaken well, and the liquid was filtered with a 0.22 ⁇ m microporous membrane to prepare a CCR4 inhibitor injection liquid.
  • Preparation of oral preparation of CCR4 inhibitor in a 100ml measuring bottle, add an appropriate amount of water for injection, then add GSK2239633 250mg, add an appropriate amount of sodium hydroxide (1.5ml, 0.5mol/L), shake to dissolve, shake well, and use sodium bicarbonate Adjust the pH value to 10, add water for injection to the scale, shake well, and filter the medicinal solution with a 0.22 ⁇ m microporous membrane to prepare an oral medicinal solution of CCR4 inhibitor.
  • Route of administration nasal spray, oral, injection.
  • Dosage oral 5mg/kg, nasal spray, injection 1mg/kg.
  • the experiment adopted a three-period, self-controlled crossover design.
  • 27 male beagle dogs were randomly divided into 9 groups.
  • CCR4 inhibitors were administered orally, by injection, and by nasal spray, respectively. relative bioavailability.
  • 0min before administration and 0.033, 0.083, 0.167, 0.5, 1, 2, 3, 4, 6, and 8 hours after administration about 1ml of blood was alternately collected from the veins of the limbs, and transferred to a 1.5ml EP tube at 3000 rpm/ minutes, centrifuged for 15 minutes, and separated about 100 ⁇ L of plasma.
  • the present invention overcomes the defects of poor solubility and bioavailability of the CCR4 inhibitor GSK2239633, and is the first in the field to prepare and provide a CCR4 inhibitor preparation that is more suitable for clinical applications.
  • the present invention provides a technique for improving the bioavailability of GSK2239633 through mucosal administration routes such as nasal mucosal administration and a usable pharmaceutical preparation, which solves the problem that the CCR4 inhibitor in the prior art has low solubility and affects the bioavailability of active pharmaceutical ingredients. Release, resulting in too low bioavailability, there is a problem that the expected effective plasma concentration cannot be achieved in the body at the maximum safe dose.
  • the CCR4 inhibitor pharmaceutical preparation provided by the present invention also has the advantages of no local irritation and safe use.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pulmonology (AREA)
  • Virology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Otolaryngology (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Inorganic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une forme posologique pour administration par les muqueuses, en particulier une forme posologique pour administration nasale, contenant un composé de formule (I) ou un sel pharmaceutiquement acceptable, un solvate ou un promédicament correspondant. La forme posologique pour administration par les muqueuses décrite dans la présente invention peut être utilisée pour traiter des maladies médiées par CCR4, en particulier l'asthme, la BPCO et la rhinite. La forme posologique pour administration par voie nasale selon la présente invention présente les avantages d'être d'action rapide, d'éviter l'effet de premier passage et de présenter une biodisponibilité élevée, et est pratique à utiliser, sûre et bonne en termes d'observance.
PCT/CN2021/104474 2020-07-07 2021-07-05 Forme posologique pour administration par les muqueuses et son utilisation WO2022007743A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010646239.1 2020-07-07
CN202010646239 2020-07-07

Publications (1)

Publication Number Publication Date
WO2022007743A1 true WO2022007743A1 (fr) 2022-01-13

Family

ID=79187560

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/104474 WO2022007743A1 (fr) 2020-07-07 2021-07-05 Forme posologique pour administration par les muqueuses et son utilisation

Country Status (2)

Country Link
CN (1) CN113893220A (fr)
WO (1) WO2022007743A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101273993A (zh) * 2007-03-27 2008-10-01 北京亚欣保诚医药科技有限公司 糠酸莫米松溶液型液体制剂
CN102388039A (zh) * 2009-02-26 2012-03-21 葛兰素集团有限公司 用作ccr4受体拮抗剂的吡唑衍生物
CN104606136A (zh) * 2015-01-06 2015-05-13 中国人民解放军军事医学科学院毒物药物研究所 甲氧氯普胺鼻腔喷雾剂、其制备方法及用途
CN110028501A (zh) * 2018-01-12 2019-07-19 迈德欣国际有限公司 化合物及其制备方法和用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200730512A (en) * 2005-12-12 2007-08-16 Astrazeneca Ab Novel compounds
GB201401904D0 (en) * 2014-02-04 2014-03-19 Ziarco Pharma Ltd Pharmaceutical composition for topical administration

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101273993A (zh) * 2007-03-27 2008-10-01 北京亚欣保诚医药科技有限公司 糠酸莫米松溶液型液体制剂
CN102388039A (zh) * 2009-02-26 2012-03-21 葛兰素集团有限公司 用作ccr4受体拮抗剂的吡唑衍生物
CN104606136A (zh) * 2015-01-06 2015-05-13 中国人民解放军军事医学科学院毒物药物研究所 甲氧氯普胺鼻腔喷雾剂、其制备方法及用途
CN110028501A (zh) * 2018-01-12 2019-07-19 迈德欣国际有限公司 化合物及其制备方法和用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANTHONY CAHN;SIMON HODGSON;ROBERT WILSON;JONATHAN ROBERTSON;JOANNA WATSON;MISBA BEERAHEE;STEVE C HUGHES;GRAEME YOUNG;REBECCA GRAVE: "Safety, tolerability, pharmacokinetics and pharmacodynamics of GSK2239633, a CC-chemokine receptor 4 antagonist, in healthy male subjects: results from an open-label and from a randomised study", BMC PHARMACOLOGY AND TOXICOLOGY, BIOMED CENTRAL LTD, LONDON, UK, vol. 14, no. 1, 28 February 2013 (2013-02-28), London, UK , pages 14, XP021143639, ISSN: 2050-6511, DOI: 10.1186/2050-6511-14-14 *

Also Published As

Publication number Publication date
CN113893220A (zh) 2022-01-07

Similar Documents

Publication Publication Date Title
US10945950B2 (en) Liquid inhalation formulation comprising RPL554
US10736841B2 (en) Bepotastine compositions
JP2023520229A (ja) 製剤
US11844823B2 (en) Beta-hairpin peptidomimetic with elastase inhibitory activity and aerosol dosage forms thereof
CA2827299A1 (fr) Formulation sans propulseur liquide comprenant un medicament antimuscarinique
WO2022007743A1 (fr) Forme posologique pour administration par les muqueuses et son utilisation
US20240082203A1 (en) Pharmaceutical composition for inhalation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21838376

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21838376

Country of ref document: EP

Kind code of ref document: A1