WO2018105943A1 - Pharmaceutical composition for treatment or alleviation of pulmonary fibrosis and asthma - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treatment of pulmonary fibrosis or neutrophilic asthma or alleviation of symptoms thereof, comprising or using, as active ingredients, laquinimod, paquinimod, and tasquinimod or pharmaceutically acceptable salts thereof, and preferably paquinimod or a pharmaceutically acceptable salt thereof for use in treatment or alleviation of pulmonary fibrosis, and tasquinimod or a pharmaceutically acceptable salt thereof for use in treatment or alleviation of neutrophilic asthma. That is, the present invention relates to a new medicinal use of laquinimod, paquinimod, tasquinimod or pharmaceutically acceptable salts thereof.

Description

Pharmaceutical compositions for the treatment or alleviation of pulmonary fibrosis or asthma

The present invention relates to pharmaceutical compositions for the treatment of various pulmonary fibrosis or asthma (especially neutrophil asthma) including idiopathic pulmonary fibrosis or for the relief of these symptoms. That is, the present invention relates to new medicinal uses of the compounds of the present invention and the present invention also relates to the treatment of pulmonary fibrosis or asthma (in particular neutrophil asthma) or a method for alleviating these symptoms.

Pulmonary fibrosis refers to a condition in which fibrous connective tissue proliferates in the lungs, leading to destruction of normal lung structure and hardening and deterioration of lung tissues.

In particular, idiopathic pulmonary fibrosis is a disease in which chronic inflammatory cells penetrate into the alveolar (lungary) walls, causing various changes to harden the lung, causing severe structural changes in the lung tissue, and gradually deteriorating lung function. There is no effective treatment so far, usually when symptoms appear and the diagnosis is a very bad disease with a median survival of 3 to 5 years.

To date, Roche's Esbriet (primary component pirfenidone) and Boehringer Ingelheim's Ofev (primary component nintedanib) are known to treat or improve these pulmonary fibrosis, but these drugs only slow the reduction of pulmonary function. There is difficulty to satisfy.

Asthma, on the other hand, is a generic name for a broad spectrum of diseases characterized by various inflammatory responses in the trachea, bronchus, bronchioles, and alveoli, resulting in damage and changes in airway tissue (Wardlaw A et al., Clin Exp Allergy 2005; 35: 1254-62). More specifically, asthma is a general name for a condition in which the bronchus in the lungs is very sensitive, sometimes the narrowing of the bronchus causes severe coughing as the breathing and crotching sounds are heard. Typical symptoms of asthma include difficulty breathing, coughing, and wheezing. Asthma can also be seen as an allergic disease caused by an allergic inflammatory response in the bronchus. When allergic inflammation occurs in the bronchus, the air flow path due to exposure to irritants, the bronchial mucosa is swollen and the surrounding muscles convuls, causing the bronchial blockage to become short and short, causing shortness of breath. This increases the frequency and severity of seizures. Asthma is a chronic and recurrent disease that controls symptoms and normalizes lung function to maintain daily life, while minimizing side effects from long-term treatments.

Drugs for treating or relieving asthma symptoms include bronchodilators (beta-2 agonist, theophylline, anticholinergic agents, etc.), which are symptomatic agents, and steroidal anti-inflammatory agents, which are disease modifying agents. The leukotriene modulator is being used, and the symptom relieving agent and the disease control therapeutic agent are used together appropriately according to the symptom which changes by stage.

Although many asthma patients are currently receiving adequate treatment through these existing therapies, 5-10% of the patients are severely refractory asthma patients who do not respond well to existing therapies, and it is time to develop new treatments for these patients. Severe refractory asthma is found in approximately 5-10% of all patients, with both airway inflammation and remodeling findings, and neutrophil inflammation in contrast to normal eosinophilic inflammation. In addition, the damage and recovery of the tissue is repeated, and the growth and recovery process is caused by various growth factors in the connective tissue, resulting in resistance to airway remodeling and poor response to steroids. At the present time, these severe refractory asthma patients were treated with theophylline or leukotriene inhibitors in addition to steroids, but these treatments had little effect on inflammatory diseases due to neutrophil infiltration and only limited effects were obtained.

Studies related to neutrophil asthma include Clin Exp Allergy 2012; 42: IL-4, IL-5, and IL-13 secreted from Th2-biased lymphocytes at 625-37 are involved in eosinophilic airways in asthmatic patients, IL-8, TNF-α, interferon secreted from Th1 lymphocytes IL-17 secreted from (INF) -γ and Th17 is predicted to be involved in neutrophil inflammation. However, studies related to the pathological or pharmacological mechanisms of neutrophil asthma are still insufficient.

Accordingly, an object of the present invention is to provide a pharmaceutical composition capable of treating pulmonary fibrosis and / or asthma (preferably neutrophil asthma) including idiopathic pulmonary fibrosis and / or alleviating their symptoms.

That is, the problem to be solved by the present invention is a compound useful for the treatment and / or alleviation of pulmonary fibrosis and / or (neutrophil) asthma and the use of medicaments for the treatment and / or alleviation of pulmonary fibrosis and / or (neutrophil) asthma. To provide.

Another problem to be solved by the present invention is a compound useful for the treatment of pulmonary fibrosis and / or (neutrophil) asthma in patients in need of treatment, alleviation or prevention of pulmonary fibrosis and / or (neutrophil) asthma, including idiopathic pulmonary fibrosis. It is to provide a method for the treatment and / or alleviation of pulmonary fibrosis and / or (neutrophil) asthma characterized in that the administration of.

Another object of the present invention is to provide a pharmaceutical composition comprising as an active ingredient a compound capable of producing a synergistic effect by co-administration with other therapeutic agents for asthma, and a medicinal use thereof for treating and / or alleviating neutrophils. .

Another problem to be solved by the present invention is the simultaneous or sequential treatment of compounds useful for the treatment and / or alleviation of neutrophil asthma according to the present invention and asthma therapeutic agents having mechanisms different from these compounds to patients in need of treatment, alleviation or prevention of asthma. To provide a method for treating or alleviating neutrophil asthma, characterized in that the administration.

summary

In order to achieve the above object, in one aspect, the present invention is paquinimod of the following formula (1), laquinimod of the following formula (2), tasquinimod of the following formula (3), Or a pharmaceutical composition for the treatment of pulmonary fibrosis and / or asthma (preferably, neutrophil asthma) and / or alleviation of these symptoms, comprising pharmaceutically acceptable salts thereof as an active ingredient. to provide.

[Formula 1]

[Formula 2]

[Formula 3]

Preferably, the active ingredient according to the invention is paquinimod or a pharmaceutically acceptable salt thereof, wherein the medicinal use is the treatment or amelioration of pulmonary fibrosis. In other embodiments, such pharmaceutical compositions may further comprise one or more additional pulmonary fibrosis therapeutics.

Preferably, the active ingredient according to the invention is tasquinimod or a pharmaceutically acceptable salt thereof, wherein the medicinal use is the treatment or amelioration of asthma, preferably neutrophils asthma. In other embodiments, such pharmaceutical compositions may further comprise one or more additional asthma therapeutics.

In another aspect, the invention provides pulmonary fibrosis and / or (neutrophil) comprising administering to a subject a therapeutically effective amount of paquinimod, laquinimod, tasquinimod, or a pharmaceutically acceptable salt thereof. Configuration) A method of treating and / or alleviating asthma is provided. That is, the present invention provides a medicinal use for treating and / or alleviating pulmonary fibrosis and / or (neutrophil) asthma of paquinimod, laquinimod, tasquinimod, or a pharmaceutically acceptable salt thereof. In such medicinal uses, paquinimod or a pharmaceutically acceptable salt thereof is more preferred for the treatment or improvement of pulmonary fibrosis, and tasquinimod or its pharmaceutically acceptable for the treatment or improvement of (neutrophil) asthma. Possible salts are more preferred.

In another embodiment, the method comprises administering a combination of paquinimod, laquinimod, tasquinimod, or a pharmaceutically acceptable salt thereof with at least one other pulmonary fibrosis or (neutrophil) asthma treatment Steps. That is, the present invention is a combination comprising (a) paquinimod, laquinimod, tasquinimod, or a pharmaceutically acceptable salt thereof and (b) another pulmonary fibrosis or (neutrophil) asthma treatment Provided is a medicinal use for the treatment and / or alleviation of pulmonary fibrosis or (neutrophil) asthma.

That is, the present invention unexpectedly finds that paquinimod, laquinimod, tasquinimod, or pharmaceutically acceptable salts thereof are useful for the treatment of pulmonary fibrosis and (neutrophil) asthma and alleviating their symptoms. Based on. In particular, it is based on the unexpected surprising finding that among these quinimod compounds, tasquinimod or salts thereof are more desirable for the treatment and / or alleviation of neutrophils asthma. In particular, it is based on the unexpected surprising finding that among these quinimod compounds, paquinimod or salts thereof are more desirable for the treatment and / or alleviation of pulmonary fibrosis.

details

The following description is merely exemplary and is not intended to limit the invention, application, or use.

Justice

As used herein, the following terms are defined as follows.

As used herein, the term "quinimod compound" means laquinimod, paquinimod, tasquinimod, or a pharmaceutically acceptable salt thereof.

"Pharmaceutically acceptable salts" in the present invention include salts of quinimod compounds prepared by reacting the free base form of the quinimod compound with a relatively non-toxic acid or base. When the quinimod compounds of the present invention comprise relatively acidic functionality, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base and a pure or suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention comprise relatively basic functionality, acidic addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid with a pure or suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include acetic acid, propionic acid, isobutyl acid, oxalic acid, maleic, malonic, benzoate, succinic acid, suberic, fumaric ( relatively, including fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric acid, tartaric acid, methanesulfonic, and the like In addition to salts derived from non-toxic organic acids, hydrogen chloride, hydrogen bromide, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogenphosphate, sulfuric acid, monohydrosulfuric acid, hydrogen iodide or phosphorous acid ( phosphorous acid) and analogs thereof. Also included are salts of amino acids such as arginate and the like and analogs of glucuronic or galactunoric acids and organic acids such as the like (eg, Berge et al. (1977). J. Pharm. Sci. 66: 1-19). Other examples of salts include those known in the art, such as Remington's Pharmaceutical Sciences , l8 ^th eds., Mack Publishing, Easton PA (1990) or Remington : The Science and Practice of Pharmacy , 19 ^th eds., Mack Publishing, Easton PA (1995).

For pulmonary fibrosis related applications, the "effective amount" as used herein treats, delays, ameliorates or alleviates the symptoms of pulmonary fibrosis in which soft and elastic normal lung tissue hardens and becomes hard to breathe, or pulmonary fibrosis Amounts of the quinimod compound of the invention sufficient to provide a therapeutic benefit in the treatment or management of

For asthma related applications, the "effective amount" as used herein reduces the therapeutic benefit in treating or managing asthma, such as reducing the typical symptoms of asthma, shortness of breath, cough, wheezing, or neutrophil control. Refers to an amount of the quinimod compound of the present invention sufficient to provide.

As used herein, "treatment" includes eradication, alleviation, or control of pulmonary fibrosis or asthma symptoms and is intended to minimize or delay the individual's suffering from pulmonary fibrosis or asthma.

As used herein, the terms "quinimod compound", "laquinimod", "paquinimod" and "tasquinimod" refer to compounds of each of the laquinimod, paquinimod and tasquinimod as well. Rather, it is meant to include their clathrates, hydrates, solvates, or polymorphs (crystal polymorphs). The terms "quinimod compound", "laquinimod", "paquinimod" and "tasquinimod" also include pharmaceutically acceptable salts of the compounds of the present invention when no pharmaceutically acceptable salt thereof is mentioned. It means. In one embodiment the compound of the invention is a stereoisomerically pure compound (eg, substantially free of other stereoisomers (eg, at least 85% ee, at least 90% ee, at least 95% ee, 97%) ee or greater, or 99% ee or greater)). That is, if the compounds according to the invention or salts thereof are tautomeric and / or stereoisomers (e.g., geometrical isomers and conformalal isomers), their isolated isomers and mixtures, respectively Also included within the scope of the compounds of the present invention.

As used herein, the term "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. Differences in stability may be due to chemical reactivity changes (e.g., differential oxidation, such as discoloration faster when composed of one polymorphism than that of another polymorphism) or mechanical characteristics (e.g., kinetics Tablet fragments stored as preferred polymorphs convert into thermodynamically more stable polymorphisms) or both (purification of one polymorph is more susceptible to degradation at higher humidity). Other physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form a solvate, for example due to its shape or the size distribution of particles, or may be more difficult to filter or wash, compared to another.

As used herein, the term "solvent compound" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof that includes a stoichiometric or non-stoichiometric amount of solvent bound by noncovalent intermolecular forces. Preferred solvents are volatile, non-toxic and can be administered in very small amounts to humans.

As used herein, the term “hydrate” means a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of water bound by force between non-covalent molecules. .

The term "clathrate" as used herein refers to a compound of the present invention in the form of a crystal lattice comprising a space (e.g., a channel) that traps a guest molecule (e.g., a solvent or water). Or salts thereof.

If any compound (prodrug) is separated in the body to produce the quinimod compound of the present invention or a salt thereof, such compound is also included in the scope of the present invention. Unless otherwise used and indicated herein, the term “prodrug” is hydrolyzed, oxidized, and other reactions under biological conditions (in vitro or in vivo) to supply the active compound, in particular the compound of the present invention. It means the compound of the present invention that can be. Examples of prodrugs include biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, and biohydrolyzable ureides. ureides), and compounds that can be biohydrolyzed to produce the compounds of the present invention, including but not limited to this specific aspect, including biohydrolyzable moieties such as biohydrolyzable phosphate analogs. Prodrugs are Burger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abrahamed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed ., 1985, Harwood Academic Publishers Gmfh) can be readily prepared using well known methods.

As used herein, the term "purified" means that when separated, the separator is at least 90% pure, in one embodiment at least 95% pure, in other embodiments at least 99% pure, and In another embodiment, 99.9% or more pure.

The term "pharmaceutically acceptable" means suitable for use as a pharmaceutical preparation and is generally considered safe for such use and is officially approved by the national control authority for such use or has been obtained from the Korean Pharmacopoeia or the United States. It means being on the list of pharmacopoeias.

All documents mentioned in this specification are incorporated herein by reference as if the contents were set forth herein. When introducing elements of the invention or its preferred aspect (s), the articles "a", "an", "the" and "said" are one or more elements. It is intended to mean that there is. That is, as used herein, the singular forms “a,” “an,” and “an” may include the plural forms unless the context clearly dictates otherwise. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements. Although the present invention has been described in terms of particular aspects or aspects, it should not be construed as limiting the details of these aspects.

Active Ingredients of the Invention

The present invention provides a pharmaceutical composition comprising paquinimod, laquinimod, tasquinimod, or a pharmaceutically acceptable salt thereof as an active ingredient. Preferably, 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.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of paquinimod, laquinimod, tasquinimod, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another embodiment, the invention provides paquinimod, laquinimod, tasquinimod, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and pulmonary fibrosis other than the quinimod compound of the invention, or Provided is a pharmaceutical composition comprising a therapeutically effective amount of an asthma therapeutic agent.

In another embodiment, 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. In another embodiment, the subject is a human.

That is, the present invention provides a medicinal use comprising using paquinimod, laquinimod, tasquinimod, or a pharmaceutically acceptable salt thereof as an active ingredient.

Pharmaceutical Uses and Methods of Treatment of Compounds of the Invention

The present invention relates to an individual or a disease diagnosed with pulmonary fibrosis or (neutrophil) asthma by administering to the subject a therapeutically effective amount of paquinimod, laquinimod, tasquinimod, or a pharmaceutically acceptable salt thereof. Further provided are methods for treating and / or alleviating pulmonary fibrosis and / or (neutrophil) asthma in a subject at risk. In one aspect, the treatment is preventive treatment. In another embodiment, the treatment is a palliative treatment.

Suitable subjects to be treated in accordance with the invention include mammalian subjects. Preferably, the mammal according to the invention 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. In another embodiment, the effective dosage of the quinimod compound of the present invention may be from 0.01 to 100 mg in total daily dosage, preferably from 0.05 to 50 mg, more preferably from 0.1 to 30 mg, even more preferably Is 0.5 to 10 mg, most preferably 0.5 to 3 mg. Such daily dosages may be administered in single or divided doses.

In determining effective dosages, 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.

Pharmaceutical Compositions, Formulations, and Routes of Administration

For the treatment or alleviation of pulmonary fibrosis or (neutrophil) asthma, the quinimod compound described herein or a pharmaceutically acceptable salt thereof can be administered as follows.

Oral administration

The quinimod compound of the present invention may be administered orally, and the oral cavity is a concept including swallowing. By 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.

Suitable compositions for oral administration may be in solid, liquid, gel or powder form and may have formulations such as tablets, lozenges, capsules, granules, powders and the like. .

Compositions for oral administration may optionally be enteric coated and may exhibit delayed or sustained release through the enteric coating. In other words, the composition for oral administration according to the present invention may be a formulation with an immediate or modified release pattern.

Liquid formulations may include solutions, syrups and suspensions, and such liquid compositions may be in forms contained in soft or hard capsules. Such formulations may include pharmaceutically acceptable carriers such as water, ethanol, polyethylene glycol, cellulose, or oils. The formulation may also include one or more emulsifiers and / or suspending agents.

In tablet formulations, 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. In addition, 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. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

Suitable glidants included for the manufacture of tablets may be present in amounts from about 0.1% to about 5% by weight and include talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like. It can be used as a lubricant, but the present invention is not limited to these kinds of additives.

As a binder for preparing tablets, gelatin, polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and the like may be used. Suitable diluents for preparing tablets may include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc., but the present invention is not limited to these types of additives. .

Optionally, the solubilizer that may be included in the tablet may be used in an amount of about 0.1% to about 3% by weight based on the total weight of the tablet, for example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, Diethylene glycol monoethyl ether, dimethylisosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR ^™ (Nikkol), oleyl ester, Gelucire ^™ , caprylic / caprylic acid mono / Diglycerides, sorbitan fatty acid esters, Solutol HS ^TM and the like can be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to these specific types of solubilizers.

Parenteral Administration

The quinimod compounds of the invention can be administered directly into the bloodstream, muscle, or intestines. Suitable methods for parenteral administration include intravenous, intra-muscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial injection, and the like. Include. Suitable devices for parenteral administration include injectors (including needles and needleless syringes) and infusion methods.

Compositions for parenteral administration can be formulations with immediate or modified release patterns, and modified release patterns can be delayed or sustained release patterns.

Most parenteral formulations are liquid compositions, which are aqueous solutions comprising the active ingredient, salts, buffers, isotonic agents and the like according to the invention.

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.

Inhalational administration

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. Aqueous, organic or aqueous / organic mixtures, dry powders, or crystalline compositions. Suitable compositions contain water as a diluent or carrier for this purpose, and conventional excipients such as buffers, osmotic pressure regulators and the like can be provided. Aqueous compositions can also be administered to other areas of the airways by nebulization. Such compositions may be aqueous solutions or suspensions or aerosols derived from pressurized packs, such as metered dose inhalers, with the use of suitable liquefied propellants.

As a representative suction device, DISKHALER ^TM , DISKUS ^TM , TURBUHALER ^TM , TWISTHALER ^TM , CLICKHALER ^TM , ROTAHALER ^TM , HANDIHALER ^TM and the like can be used, and the present invention is not limited to this specific type of suction device.

Pressurized aerosol compositions for inhalation may be suspensions or solutions, and the quinimod compounds according to the invention, and suitable propellants, for example fluorocarbons or hydrogen containing chlorofluorocarbons or mixtures thereof, in particular hydrofluoroalkanes, In particular 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane, or mixtures thereof. The aerosol composition optionally comprises additional composition excipients well known in the art, for example surfactants such as oleic acid, lecithin or oligolactic acid or derivatives thereof, for example International Patent Application Publication Nos. WO 94/21229 and WO 98 / Surfactants described in 34596, and auxiliary solvents such as ethanol. The pressurized composition will generally be held in a canister (eg, aluminum canister) that is closed by a valve (eg, a metering valve) and mounted to an actuator provided with a mouthpiece.

References for the Preparation of Pharmaceutical Compositions

Methods of preparing pharmaceutical compositions for the proper treatment or prevention of a disease or condition are well known to those of ordinary skill in the art. For example, Handbook of Pharmaceutical Excipients (7 ^th ed.), Remington : The Science and Practice of Pharmacy (20 ^th ed.), Encyclopedia of Pharmaceutical Technology (3 ^rd ed.), Sustained and Controlled Release Drug Delivery Systems (1978 As described above, pharmaceutically acceptable carriers, carriers, additives and the like may be mixed with the compounds according to the present invention to prepare pharmaceutical compositions for the purposes of the present invention.

Combinations and Combination Therapy

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. Thus, in one aspect, 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.

In another aspect, there is provided a pharmaceutical composition comprising one or more quinimod compounds of the invention, one or more additional pharmaceutically active compounds, and a pharmaceutically acceptable carrier.

In another embodiment, the one or more additional pharmaceutically active compounds is a pulmonary fibrosis or asthma treatment.

As 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.

-pirfenidone

-nintedanib

As the asthma treatment agent, for example, the following drugs may be used, but the present invention is not limited to this specific kind of the second active ingredient.

-(Inhalation) steroids: beclomethasone dipropionate, budesonide, ciclesonide, fluticasone, mometasone furoate, triamcinolone acetonide Etc)

(Oral) steroids: systemic glucocorticoids

-(Inhalation) airway dilators: ipratropium (ipratropium bromide, etc.), oxytropium (oxitropium bromide, etc.)

Leukotriene receptor antagonists: montelukast, franlukast, zafirlukast

Leukotriene Synthetic Inhibitor: zileuton

-(Inhalation) airway dilators: beta2 agonists: salmeterol, formoterol, salbutamol, terbutaline, bambuterol, phenoterol

(Oral) bronchodilators: theophylline (including sustained release theophylline)

-Stamina cell stabilizer: chromoline agent: cromolyn sodium, nedocromil sodium

Anti-IgE Antibody: Omalizumab

When the quinimod compound of the present invention is used as one active ingredient in the combination, the therapeutically effective dosage may vary. The combination treatment may further include periodic treatments that start and stop at various times to assist the clinical management of the patient. In any case, multiple therapeutic agents, one of which is a quinimod compound as described herein, are administered in any order, or simultaneously. At the same time, multiple therapeutic agents are optionally provided in a single, unified form, or in multiple forms (eg, as one pill or two separate pills).

In one aspect, 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.

In addition, the combination methods, compositions and formulations are not limited to the use of only two agents, and multiple therapeutic combinations are envisioned. Dosage regimens for treating, preventing, or alleviating pathological condition (s) can be varied arbitrarily depending on various factors. These elements include the age, weight, sex, diet, and medical condition of the individual, as well as the disorder that the individual suffers from.

Pharmaceutical formulations 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.

The active ingredients according to the present invention can effectively suppress pulmonary fibrosis disease by improving neutrophil infiltration, tissue inflammation, tissue fibrosis, etc. in the pulmonary fibrosis model. In addition, the active ingredients according to the present invention can effectively suppress asthma diseases such as neutrophil infiltration, tissue inflammation, airway resistance, and inflammatory cytokine secretion in the neutrophil asthma model, and also with other asthma treatment agents such as budesonide, montelukast, dexamethasone, etc. It can be used together efficiently. The active ingredients according to the invention are also useful for these uses as they are well distributed in airway tissues upon oral administration. Therefore, the active ingredients according to the present invention can be usefully used for the treatment of pulmonary fibrosis or neutrophil asthma or alleviation of these symptoms.

Paquinimod or a pharmaceutically acceptable salt thereof is preferred for the treatment or amelioration of pulmonary fibrosis, and tasquinimod or a pharmaceutically acceptable salt thereof is preferred for the treatment or amelioration of neutrophils. This difference in effect is presumed to be due to chemical structural differences of the compounds and / or physical and chemical property differences caused by such structural differences.

The following drawings, which are attached to this specification, illustrate preferred embodiments of the present invention, and together with the contents of the present invention serve to further understand the technical spirit of the present invention, the present invention is limited to the matters described in such drawings. It should not be construed as limited.

Figure 1 is an experimental result of measuring the total cell number, macrophage number, neutrophil count, eosinophil count and lymphocyte count in bronchial alveolar lavage fluid of Silica induced IPF model mice.

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.

3 is a measurement result of the silica nodule area located in the lung tissue of Silica induced IPF model mice.

Figure 4 shows the results of Hydroxyproline assay using Silica induced IPF model mice.

5 and 6 are the results of measuring the number of various cells in the BAL solution (bronchoalveolar lavage) of the neutrophil-induced asthma mouse model induced by CFA / OVA (mann-whitney test). *: p <0.05, compared with Sham group; †: p <0.05, compared to CFA / OVA group; #: p <0.05, compared with paquinimod group; @: p <0.05, compared with laquinimod administration group.

7 and 8 show the results of measuring changes in airway resistance due to the administration of quinimod compound in neutrophil-induced asthma mouse model induced by CFA / OVA (using Flexivent). *: p <0.05, compared with Sham group; †: p <0.05, compared to CFA / OVA group; #: p <0.05, compared with paquinimod group; @: p <0.05, compared with laquinimod administration group.

9 is a result of H & E staining analysis to evaluate the histological changes appearing by administering the quinimod compound according to the present invention.

10 is a result of evaluating the change in goblet cells appearing by administering a quinimod compound according to the present invention.

11 is a result of evaluating the change in the smooth muscle thickness appeared by administering the quinimod compound according to the present invention.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

[Evaluation of Pulmonary Fibrosis Treatment or Palliative Effect]

Materials and methods

material

Laboratory animal classification, SiO ₂ administration and paquinimod treatment

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.

The SiO ₂ and Endotoxin-free water will Sigma Aldrich 1.05x Phosphate buffered saline (hereinafter 1.05x PBS) was purchased from (St. Louis, MO, USA ), made of Endotoxin-free water used in this study SiO ₂ Was dissolved (10mg / 100μl) and used as an inducer of idiopathic pulmonary fibrosis.

Paquinimod was prepared as mentioned below according to mouse weight and administered with Drinking water.

Way

SiO ₂ implantation into C57BL / 6 mice

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.

Experimental group

For this experiment, the experimental group was divided into five groups as follows.

1st group: 1.05x Phosphate buffered saline (100μl) injection group (n = 12)

2nd group: SiO ₂ (10mg), 1.05x Phosphate buffered saline (100μl) injection group (n = 15)

Group 3: Paquinimod 0.1mg / kg with drinking water in SiO ₂ (10mg), 1.05x Phosphate buffered saline (100μl) injection group (n = 9)

Group 4: Paquinimod 1mg / kg with drinking water in SiO ₂ (10mg), 1.05x Phosphate buffered saline (100μl) injection group (n = 9)

Group 5: Paquinimod 10mg / kg Drinking water treated with SiO ₂ (10mg), 1.05x Phosphate buffered saline (100μl) injection group (n = 15)

After injecting SiO ₂ into the lungs, the second to fifth groups were administered with drinking water every day from 4 days after dissection to the day of dissection.

Paquinimod  Dosage

The actual dose of paquinimod was shown in Table 1 below.

Groups dosage D.W. volume Third group 0.002mg 2.7 ml 4th group 0.02mg 2.7 ml Fifth group 0.2mg 2.7 ml

Bronchial Alveolar Lavage Analysis

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.

Inflammatory cell rate measurement and total immune cell count

In the present study, the immune cell ratio was measured by bronchoalveolar lavage (BAL) of C57BL / 6, followed by cyto-centrifugation. Diff-Quik (scientific Products, Gibbstown, NJ, USA) staining was performed after attaching the inflammatory cells to the slide glass. We then randomly counted 500 cells to determine the ratio of macrophages, neutrophils, eosinophils, and lymphocytes.

The total number of inflammatory cells was measured by a hematocytometer.

Anatomical Analysis and Silicotic Nodule Measurement

A portion of the left lung tissue was cut and fixed in 4% Paraformaldehyde, and then planted in paraffin. The tissue was cut to 4μm thickness and then subjected to Hematoxylin & eosin stain. A portion of the right lung tissue was cut out and used to extract RNA and protein.

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.

Hydroxyproline  assay

Hydroxyproline assay was performed to quantitatively measure collagen formation, a representative symptom of IPF, through silica. First, the lung tissue was subjected to Vacuum dry out, and then treated with 500 μl of 6N HCl. After heating at 120 ° C. for 16 hours, centrifuge was performed at 13000 rpm for 15 minutes. After the evaporated amount of 6N HCl was filled, the pH was adjusted to 7 by adding 500 μl of 6N NaOH. 100 μl of the supernatant of the obtained sample was transferred to a 2 ml tube, followed by 12.5 μl of 7% choloramine T (Sigma, St Louis, MO, USA) and 50 μl of acetate / citrate buffer (57 g sodium acetate, 37.5 g Trisodium citrate · 2H ₂ O ₂ , 5.5g citric acid.H ₂ O, 385ml Isopropanol, and adjust the final volume to 1L with distilled water). Thereafter, 375 μl of Ehrlich's solution (2 g p-dimethylamino-benzaldehyde (sigma), 3 ml 60% HClO ₄ (Sigma), 9 ml isopanol) was added and then reacted for 60 to 35 minutes. Since absorbance was measured at 560nm. The amount of Hydroxyproline in the tissue measured for normalization was divided by the weight of the dried tissue.

statistics

Statistical analysis and analysis were performed using the Kruskal-wallis test and Mann-Whitney U-Wilcoxon Rank Sum W test, with a confidence interval of 95%.

result

SiO2  Through inflammatory responses and the formation of silicotic nodule Paquinimod  effect

First, the inflammatory response induced by Silica was analyzed. The results are shown in FIG. In assessing the number of whole cells, macrophages, neutrophils, eosinophils and lymphocytes of inflammatory cells obtained through BAL, the second, third and fifth groups were more than the first group, but the third group was focused on whole cells, macrophages and neutrophils. In comparison with the second group, paquinimod treatment significantly reduced dose-dependent treatment. In eosinophils and lymphocytes, the fifth group was significantly decreased than the second group.

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.

Effect of Paquinimod on Inhibition of Collagen Formation

The results of measuring the amount of hydroxylproline are shown in FIG. 4. When comparing the amount of collagen formed by measuring the amount of hydroxyproline, it was observed that the amount of hydroxyproline in the 4th and 5th groups was significantly reduced than the 2nd group.

[Evaluation of Treatment or Palliative Effect of Neutrophil Asthma]

Samples and Methods

Neutrophil asthma animal model

Experimental mice were purchased from Orient Bio (Seongnam, Korea) and maintained aseptic. For the CFA / OVA model, six-week-old C57BL / 6 females were used. 20 μg 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 μl. On days 21 and 22, all mice were dosed nasal with 0.1% grade III OVA dissolved in 50 μl of saline.

CFA / OVA in sensitized / challenged Animal Models Quinimod  Treatment of Compounds (Paquinimod, Laquinimod, Tasquinimod)

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 μl of endotoxin free water (stock concentration: 100 μg / μl), aliquots of 20 μl were stored. In order to administer 0.1μg per mouse weight (g) per day, assuming that the mouse weighs 20g, vortex the stock, and then add 1μl (including 100μg of test drug) to 135ml of purified water and provide 2.7ml per mouse. Intake 2 μg per day.

Airway Resistance Measurement

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.

Analysis of bronchoalveolar lavage fluid as an indicator of inflammation

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.

Histological analysis

After measuring airway resistance, rat lung tissue was fixed with 4% paraformaldehyde and planted in paraffin, and paraffin tissue was made into slides with a thickness of 4 μm. After the re-hydrolyzed process, the tissue was stained for 1 minute with diluted hematoxylin solution and washed with water. After staining with eosin solution again, washed and dried. Mounted with balsam solution and observed under a microscope.

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.

result

Inflammation Changes and Inhibition of Inflammation by Quinimod Compounds in Asthma Models

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).

When laquinimod, tasquinimod or paquinimod was administered at 0.1 mg / kg / day compared to the CFA / OVA group, total cell numbers and macrophages, neutrophils, eosinophils, and lymphocytes were significantly decreased (p <0.05) (FIG. 5).

When comparing laquinimod, tasquinimod, and paquinimod, laquinimod and tasquinimod showed significant differences in total cell count and decrease in macrophages, neutrophils, eosinophils, and lymphocytes compared to paquinimod. (p <0.05). Among laquinimod and tasquinimod, tasquinimod showed more significant inhibition on total cell number and macrophages, neutrophils, eosinophils and lymphocytes than laquinimod (p <0.05) (see FIG. 6).

Airway resistance measurement result

Airway resistance measurement results are shown in FIGS. 7 and 8. The CFA / OVA group significantly increased (p <0.05) at all concentrations of methacholine 0, 20, and 100 mg / ml compared to the Sham group. Airway resistance by 100 mg / mL methacholine inhalation was significantly decreased in the laquinimod and tasquinimod groups (p <0.05) compared with the CFA / OVA group, but not in the paquinimod group. The laquinimod and tasquinimod groups decreased significantly compared to the paquinimod group (p <0.05), and the tasquinimod group significantly decreased than the laquinimod group (p <0.05). Results of the same trend were observed for airway resistance by 20 mg / mL methacholine inhalation.

Histological Analysis

The results of H & E stain analysis are shown in FIG. 9. As shown in Figure 9, compared with the Sham group, it was confirmed that the inflammatory cells are expressed in the CFA / OVA group, when the Paquinimod, Laquinimod, or Tasquinimod in water to the CFA / OVA was confirmed to decrease the inflammatory cells.

The result of measuring the goblet cell through PAS stain is shown in FIG. 10. As shown in FIG. 10, the CFA / OVA group significantly increased than the Sham group (p <0.05). Compared with the CFA / OVA group, 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).

Smooth muscle thickness measurement results are shown in FIG. 11. As shown in FIG. 11, as a result of the smooth muscle thickness measurement, the Sham group and the CFA / OVA group showed a significant increase (p <0.05), and the Lauqinimod and Tasquinimod groups significantly decreased as compared to the CFA / OVA group. However, the Paquinimod group was not significant (p <0.05). Tasquinimod group was significantly decreased compared with Paquinimod group (p <0.05).

In asthmatic patients, 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.

Claims (12)

Paquinimod of formula (1), laquinimod of formula (2), Tasquinimod of formula (3), or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition for treating or alleviating pulmonary fibrosis or asthma. [Formula 1]

[Formula 2]

[Formula 3]

The pharmaceutical composition of claim 1, wherein the composition comprises paquinimod or a pharmaceutically acceptable salt thereof as an active ingredient, and is used for the treatment or alleviation of pulmonary fibrosis. The pharmaceutical composition of claim 2, wherein the composition further comprises pirfenidone, nintedanib, or a mixture thereof as an active ingredient. The pharmaceutical composition of claim 1, wherein the asthma is neutrophil asthma. The pharmaceutical composition according to claim 4, wherein the composition comprises tasquinimod or a pharmaceutically acceptable salt thereof as an active ingredient, and is used for the treatment or alleviation of neutrophil asthma. 6. The composition of claim 4, wherein the composition is a steroid, a leukotriene receptor antagonist, a leukotriene modulator, a leukotriene synthetase, a beta2 agonist, an airway dilator, a bronchodilator, a blast cell stabilizer, a chromoline agent, and an anti-IgE antibody. Pharmaceutical composition, characterized in that it further comprises any one or more active ingredients selected from the group consisting of. Treatment or alleviation of pulmonary fibrosis or asthma of paquinimod of formula 1, laquinimod of formula 2, tasquinimod of formula 3, or a pharmaceutically acceptable salt thereof Medicinal uses for. [Formula 1]

[Formula 2]

[Formula 3]

The pharmaceutical use according to claim 7, wherein the active ingredient is paquinimod or a pharmaceutically acceptable salt thereof, and the pharmaceutical use is for the treatment or alleviation of pulmonary fibrosis. The pharmaceutical use according to claim 7, wherein the active ingredient in the pharmaceutical use is tasquinimod or a pharmaceutically acceptable salt thereof, and the pharmaceutical use is for the treatment or alleviation of neutrophil asthma. A therapeutically effective amount of paquinimod of formula 1, laquinimod of formula 2, tasquinimod of formula 3, or a pharmaceutically acceptable salt thereof is pulmonary fibrosis Or administering to an individual in need of treatment or alleviation of asthma. [Formula 1]

[Formula 2]

[Formula 3]

The method of claim 10, wherein the method is administered paquinimod or a pharmaceutically acceptable salt thereof. The method of claim 10, wherein the method is administered tasquinimod or a pharmaceutically acceptable salt thereof.

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