JP6915956B2 - Treatment of pulmonary fibrosis once daily - Google Patents

Description

37 C. F. Statement on Prior Disclosure by Co-Inventor Based on R § 1.77 (b) (6) An overview of Phase Ia data is provided by Specto Biotech AB, BioCenter, on-line Review, week of March, p. 16, Shown in BioCenter. A copy of the summary of the relevant Phase Ia data is available at 78 Fed. Reg. Submitted in the Information Disclosure Statement in accordance with 11076 (February 14, 2013).

The present invention relates to compounds of formula (I) for use in methods for the treatment of human pulmonary fibrosis such as idiopathic pulmonary fibrosis. The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) for use in methods for the treatment of human pulmonary fibrosis. The present invention further relates to methods for the treatment of human pulmonary fibrosis. Furthermore, the present invention relates to a dry powder inhaler device for administering the compound of formula (I) to the narrowest portion of human lung tissue once daily.

Idiopathic pulmonary fibrosis (IPF) has become a significant health burden on a global scale. This is a chronic condition of unknown cause, with repeated acute lung injuries causing gradual fibrosis, resulting in destruction of lung structure and diminished lung function, which is associated with respiratory failure and death. .. Idiopathic pulmonary fibrosis (IPF) is a typical and most common cause of pulmonary fibrosis, many respiratory diseases can progress from pulmonary fibrosis, and the prognosis for pulmonary fibrosis is usually relatively poor. The median time from diagnosis to death is 2.5 years, and the incidence and prevalence of IPF continue to rise. It continues to be one of several respiratory medical conditions for which there is no effective treatment and no reliable biomarker to predict disease progression. The mechanism by which it occurs in pulmonary fibrosis is unknown, but is currently focused on abnormal wound healing as a result of recurrent epithelial injury of unknown cause. IPF is characterized by a growth foci of fibroblasts, including fibroblasts / myofibroblasts, that show a high activation response to fibroblasting cytokines such as transforming growth factor-β1 (TGF-β1). Demand for drugs for the treatment of idiopathic pulmonary fibrosis is high and has not yet been achieved.

The compound of formula (I) is a novel dry powder inhalation therapy for the treatment of IPF. Based on the results of a first-in-human study with single dose escalation, the compounds of formula (I) are safe and well tolerated in humans, and the favorable PK parameters are in a specific volume range. It was concluded that once-daily administration was supported in.

In a first aspect, the invention is of formula (I) for use in methods for the treatment of human pulmonary fibrosis.

With respect to the compounds of, the method comprises administering an effective amount of the compound of formula (I) to treat the pulmonary fibrosis to the narrowest portion of human lung tissue once daily.

In a further aspect, the invention is of formula (I) for use in methods for the treatment of human pulmonary fibrosis.

With respect to the pharmaceutical composition comprising the compound of, the method comprises applying the composition comprising an amount of formula (I) effective for treating pulmonary fibrosis to the narrowest portion of human lung tissue once daily. Including administration.

In a further aspect, the present invention relates to a method for the treatment of human pulmonary fibrosis, wherein the method is an effective amount of formula (I) for treating the pulmonary fibrosis.

の化合物をヒトの肺組織の最も狭い部分に１日１回投与することを含む。

Compound is administered once daily to the narrowest portion of human lung tissue.

In a further aspect, the present invention relates to formula (I).

With respect to the dry powder inhaler device comprising the compound of the above, the dry powder inhaler device provides an amount of the compound of formula (I) effective in treating pulmonary fibrosis in the narrowest part of human lung tissue. It is intended to be administered once a day.

The compound of formula (I) is a chemical called bis (3-deoxy-3- (3-fluorophenyl-1H-1,2,3-triazole-1-yl) -β-D-galactopyranosyl) -sulfan. It has the name (IUPAC) and is intended to include compounds of formula (I) in any possible form, such as solid or liquid, salt, solvate or free form, as used in this application. Is. Compounds of formula (I) may be prepared as described in US Patent Application Publication No. 2014/0121179 or International Publication No. 2014/0678996.

In certain embodiments, the compound of formula (I) is in free form bis (3-deoxy-3- (3-fluorophenyl-1H-1,2,3-triazole-1-yl) -β-D- Galacopyranosyl) -Sulfan.

In a further embodiment, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

In a further embodiment, administration is performed by a dry powder inhaler. Typically, a single or multiple dose DPI inhaler is used. In certain embodiments, the dry powder inhaler is an RS01 Monodose Dry Powder Inhaler (Plastiape).

When the compound of formula (I) is formulated as a dry powder, it has a mass average of aerodynamic diameter (MMAD) of 0.1 to 20 μm, eg, MMAD of 0.50 to 10 μm, 1 to 5 μm. , Typically present in a suitable particle size selected from particles of 2-3 μm. In the tests described in the experimental section below, MMAD was measured up to 2.5 μm. The selected range does not preclude the presence of particle sizes outside these ranges, but the selected range is a range that provides the desired effect as described herein.

In a further embodiment, the narrowest part of the lung tissue is the bronchioles and alveoli.

In a further embodiment, the daily dose is 0.15-50 mg, eg 0.15-1.5 mg, 1.5-3 mg, 3-5 mg, 5-7 mg, 7-8 mg, 8-10 mg, 10 ~ 20 mg, 20-50 mg. In particular, a once-daily dose of 1.5-2.0 mg leads to a concentration of the active compound of formula (I) in 1 nM-100 μM BAL solution and / or macrophages. Concentrations of preferably 10 nM to 10 μM, or more preferably 100 nM to 1 μM, can be provided by a once-daily dose of 3 to 10 mg. Based on the results and tests herein, for example, 2-7 mg, 1.5-10 mg once-daily doses to suppress galectin-3 and provide a safe and effective treatment for pulmonary fibrosis. It is expected to provide a sufficient local concentration of the compound of formula (I) in the human lung.

In a further embodiment, the treatment is a long-term treatment.

As used herein, the terms "treatment" and "treating" mean the management and protection of a patient for the purpose of combating a condition such as a disease or disorder. The term is used to alleviate a symptom or complication, to slow the progression of a disease, disorder or condition, to alleviate or alleviate a symptom or complication, and / or to cure or eliminate a disease, disorder or condition. , And, as well as the administration of active compounds to prevent such conditions, are intended to include all aspects of treatment for a given condition suffering by a patient, and prevention is a disease, condition or. It should be understood as the management and protection of patients for the purpose of combating the disorder and also includes the administration of active compounds to prevent the development of symptoms or complications. Treatment is carried out in a long-term manner. Patients to be treated are human subjects diagnosed with pulmonary fibrosis or other types of pulmonary fibrosis.

The term used herein, the compound of formula (I) of the present invention, "an amount effective to treat pulmonary fibrosis" refers to pulmonary fibrosis and its complications. Means an amount sufficient to cure, alleviate or partially prevent the clinical signs of. The amount effective for each purpose will depend on the severity of the disease or wound and the weight and general condition of the subject. Appropriate dose determination can be achieved using conventional experimental methods by constructing a matrix of multiple values and testing various points within this matrix, all of which are made by a seasoned physician or veterinarian. It is within the scope of normal technology.

In a further aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) and optionally a pharmaceutically acceptable additive such as a carrier or excipient.

As used herein, "pharmaceutically acceptable additives" are formulated, but not limited to, the compounds of the invention to make pharmaceutical compositions. It is intended to include carriers, excipients, diluents, auxiliaries, colorants, fragrances, preservatives, etc. that one of ordinary skill in the art will consider using.

Auxiliary agents, diluents, excipients and / or carriers that may be used in the compositions of the present invention are in the sense that they are compatible with the compounds of formula (I) and other components of the pharmaceutical composition. It must be pharmaceutically acceptable and not harmful to the recipient. The composition preferably does not contain any material that can cause an unfavorable reaction such as an allergic reaction. Auxiliary agents, diluents, excipients and / or carriers that can be used in the compositions of the present invention are known to those of skill in the art.

As mentioned above, the compositions disclosed herein and in particular pharmaceutical compositions are, in addition to the compounds disclosed herein, at least one pharmaceutically acceptable adjunct, diluent, additive. The form and / or carrier may be further included. In certain embodiments, the pharmaceutical composition comprises a net compound of formula (I). In some embodiments, the pharmaceutical composition comprises 1-99% by weight of at least one pharmaceutically acceptable auxiliary agent, diluent, excipient and / or carrier described above, as well as herein. Contains 1 to 99% by weight of the compound. The total amount of active ingredient and pharmaceutically acceptable adjuncts, diluents, excipients and / or carriers constitutes more than 100% by weight (100% w / w) of the composition, in particular the pharmaceutical composition. I can't. According to the present invention, the pharmaceutical composition may consist of a net compound of formula (I) (ie, a compound of formula (I) of 100% w / w) or, for example, a compound of formula (I) 3 It may contain a 1-90% w / w mixture of compounds of formula (I), such as 2-20% w / w which is a% w / w mixture. Typically, the 3% w / w mixture is a pharmaceutical composition containing 3% w / w of the compound of formula (I) and 97% w / w of the lactose carrier. For clinical trials, a 10% w / w mixture is used, which consists of a pharmaceutical composition containing 10% w / w of the compound of formula (I) and 90% w / w of the lactose carrier.

It is known to those skilled in the art that particles with an aerodynamic diameter mass average (MMAD) of 0.1 to 20 μm (micrometers) are more likely to deposit in the terminal regions of the bronchi and alveoli. This particle size range has many requirements for pulmonary drug delivery, as some of the material also deposits in the upper part of the airways (see Controlled Pulmonary Drag Delivery, Smith and Hickey, Springer, 2011, Chapter 13). Ideal for.

One of ordinary skill in the art will obtain a method of prescribing compounds such as compounds of formula (I) for pulmonary drug delivery in accordance with Controlled Pulmonary Drug Delivery, Smith and Hickey ed., Springer, 2011 especially in Chapters 13, 14, and 15. be able to.

Dry powder inhalers (DPIs), such as metered dose inhalers, are known for delivering the drug to the lungs of the patient. Some conventional inhalers include a pressurized aerosol distribution container, the aerosol containing a gas propellant in which a powdered drug is suspended. When the inhaler is activated, the aerosol content is expelled into the patient's lungs through the metering valve. A preferred DIP for use in the present invention is a Monodose dry powder inhaler manufactured by Plastape (Headquarters, Osnago, Italy), in particular the RS01 Monodose Dry Powder Inhaler.

Current designs include pre-weighing DPI or device weighing DPI, both of which can be driven solely by patient inspiration or with some form of power assist. Pre-weighed DPI is a pre-weighed dose or portion of a dose that is later inserted into the device by the patient during production or prior to use, such as a single or single unit within a blister, capsule or other cavity. It is contained in multiple forms). Thus, the dose can be inhaled directly from the pre-weighing unit or the dose can be transferred from the chamber by the time the patient inhales. Device Weighing DPI has an internal reservoir containing sufficient formulation for multiple doses weighed by the device itself while being activated by the patient. Many of the various DPI designs have their own unique characteristics, which presents a challenge in developing information that supports a given application. Regardless of the DPI design, the most important attributes are the reproducibility of dose and particle size distribution. Maintaining the above quality for the entire life of use and guaranteeing the function of the device for the entire life of the device under the conditions used by the patient will probably present the most difficult problem to solve.

A pressurized metered-dose inhaler (pMDI) can also be a suitable delivery device for the compounds of the invention of formula (I), Controlled Pulmonary Drug Delivery, Smith and Hickey, 20 years, Spring, 20 years. It is described in Chapter 8 of.

Therefore, several types of non-aerosol breath-actuated dry powder inhalers are provided. For example, US Pat. No. 5,503144 by Bacon refers to a breath-actuated dry powder inhaler. The device passes a dry powder reservoir containing the dry powdered drug, a metering chamber for removing the powdered drug from the reservoir in separate amounts, and the removed powdered drug through a mouthpiece. Includes an air inlet for inclusion in the patient's inhalation.

U.S. Pat. No. 5,458,135 discloses a method and apparatus for producing an aerosolized single dose of drug for subsequent patient inhalation. The method first involves dispersing a preselected amount of the drug in a predetermined volume of gas, which is usually air. This dispersion may be formed from a liquid or dry powder. This method is accomplished by the influx of nearly all of the aerosolized dose into a chamber that is initially filled with air and opens to the surroundings through the mouthpiece. After the aerosolized drug has been transferred into the chamber, the patient will inhale the entire dose in a single breath.

US Pat. No. 6,065,472 has a housing containing a pharmacologically active compound and a conduit having an outlet extending into the housing (through this outlet the user can inhale and generate an air flow through this conduit). And a powder comprising a dose dividing unit for delivering one dose of the compound to the conduit and a baffle disposed within the conduit to assist the disintegration of the powder aggregates contained in the air stream. Discloses body inhalation devices.

Most importantly, whether using an aerosol inhaler or a non-aerosol inhaler, the distributed dry powder drug particles have a sufficient amount of drug in the bronchial region of the patient's lungs during inhalation. It should be small enough to ensure that it fits in. However, since dry powder drugs consist of very small particles and are sometimes provided as compositions containing carriers such as lactose, undefined drug aggregates or aggregates are randomly formed prior to distribution. NS. Therefore, it has been found that it is preferable to provide a breath-actuated dry powder inhaler with means for disintegrating the drug or drug and carrier aggregates prior to inhalation of the drug.

Further embodiments of the process are described in the Experimental Sections herein, where each individual process and each starting material constitutes an embodiment, and these embodiments may form part of an embodiment.

The above embodiments are described herein in a plurality of embodiments (“methods for treatment”, unless it is specified that an embodiment relates to one or more particular embodiments of the invention. , "Pharmaceutical composition", "Compound for use as a drug" or "Compound for use in a method"), and any of the plurality of embodiments described herein. Please be understood as referring to one.

All citations cited herein, including publications, patent applications and patents, each citation is individually and specifically incorporated herein by reference, and which is incorporated herein by reference. Incorporated herein by reference to the same extent as described in its entirety.

All headings and subtitles are used herein solely for convenience and should not be construed as limiting the invention in any way.

Any combination of any of the above elements in any possible variation is included herein unless otherwise indicated herein or is not apparent from the context.

The terms "a, an", "that, the above" and equivalent referents used in the context of describing the invention are used unless otherwise indicated herein. Unless it is clear from the context that this is not the case, it should be interpreted as including both singular and plural.

The enumeration of the range of values herein is used as a method that omits the independent reference to each of the distinct values within that range, unless otherwise indicated herein. , Each of the above distinct values is incorporated herein by reference as if it were independently listed in the favorite document. All exact values provided herein are representative of the corresponding approximations (eg, given for a particular factor or measurement, unless indicated herein otherwise. All the exact exemplary values given can be considered to provide corresponding approximations modified with "about", if desired).

All methods described herein can be performed in any preferred order unless otherwise indicated herein or is not apparent from the context.

The use of all examples, or the phrase meaning an example as used herein (eg, "... etc. (Such as)", is merely intended to make the present invention clearer and is intended herein. Unless otherwise indicated in the document, the scope of the invention is not limited. Interpret as indicating that the element is required.

References and references to patent documents herein are made solely for convenience and do not reflect any opinion regarding the validity, patentability and / or enforcement power of these patent documents.

Any aspect of the invention that uses terms such as "comprising," "having," "inclusion," or "contining" with respect to one or more elements. Alternatively, the description herein of an embodiment comprises one or more of the above elements "consists of" unless otherwise indicated herein or is not apparent from the context. , "Consistently of" or "substantially complies" is intended to provide a basis for similar embodiments or embodiments of the invention (eg,). A composition described herein as comprising a particular element is a composition comprising the above elements unless otherwise indicated herein or is not apparent from the context. It shall be understood as explaining).

The present invention includes all modifications and equivalents of the subject matter presented herein or in the claims to the extent permitted by applicable law.

The following examples further demonstrate the invention, but these examples should not be construed as limiting the scope of protection. The features disclosed in the above description and the features disclosed in the following examples can be materials for realizing the present invention in various forms separately or in any combination.

The compound of empirical formula (I) is a novel inhalation, dry powder, anti-galectin-3 small molecule drug therapy developed for the treatment of IPF. The results of the First in Human (FIH) study in healthy male applicants are listed here.

METHODS: This study was randomized to assess the safety, tolerability, PK (pharmacodynamics), and PD (pharmacodynamics) of compounds of formula (I) in 36 healthy male volunteers (HVs). Randomization, double-blind, single-center, placebo-controlled, single-dose dose escalation (SAD), phase I trial. Six dosing cohorts of six subjects were evaluated using a 4: 2 ratio (active: placebo). The compound of formula (I) was delivered to the lungs of HV using RS01 Monodose Dry Powder Inhaler (Plastiape) at the following six doses: 0.15 mg, 1.5 mg, 3 mg, 10 mg, 20 mg, 50 mg. The doses of 0.15 mg, 1.5 mg and 3 mg were 3% w / w lactose mixtures, and the doses of 10 mg, 20 mg and 50 mg were prescribed as net ingredients. The specific capsule filling weight was 5 mg for a dose of 0.15 mg, 50 mg for a dose of 1.5 mg, 5 mg for a dose of 10 mg, and 50 mg for a dose of 50 mg. The HV was housed overnight and continued with vital signs, EKG, physical examination, urinalysis, and laboratory blood tests for 14 days. PK blood was taken periodically before and up to 48 hours after administration. Plasma samples for drug concentration measurements were analyzed by Bioanalytic Unit of Simbec (UK). PK variables were determined using the non-compartment analysis option of the software WinNONLIN 6.3 from Certara (www. Certara.com) based in 08540, NJ, Princeton.

Results Administration of the compound of formula (I) was extremely well tolerated at all six doses. The adverse events were only mild in nature and included headache, cough and dose-related dysphoria (net mixture only), all of which were self-limiting. There were no significant changes from baseline in any of the following parameters: EKG, vital signs, blood and urine analysis up to 2 weeks post-dose. The compound of formula (I) was rapidly absorbed and the average tmax value was 0.8-3 hours regardless of dose. The drug concentration increased with increasing dose based on Cmax and AUC, indicating dose proportionality. t1 / 2 is 12 hours. Clearance (CL / F) is high (~ 50,000 mL / hr or 900 mL / min), i.e. several times higher than renal filtration. Given these findings and findings consistent with the GLP toxicokinetics study (~ 90% of compounds of formula (I) after intravenous administration in mice are found in excretion), the liver (via bile excretion) ) Is considered to be the main route of excretion in humans. Radioisotope test of pulmonary deposition of compound of formula (I) in mice, along with Cmax data from administration of 3 mg at inhalation concentrations used in humans (concentration of compound of formula (I) in the lungs from the circulatory organs Based on the fact that the local concentration of the compound of formula (I) in the human lung is based on the ex-vivo data of the suppression of galectin-3 in human-derived macrophages, in lung target cells. It is more than twice the local concentration required to suppress galectin-3.

Conclusion The compound of formula (I) is a novel dry powder inhalation therapy for the treatment of IPF. The results of this FIH-SAD study show that the compound of formula (I) is safe and well tolerated in the human body, and favorable PK parameters support once-daily administration. The second part of this study is underway, which formulates a once-daily escalating dose (0.15 mg, 1.5 mg, 3 mg, 10 mg, 20 mg, 50 mg) to 24 patients with IPF. It is continuously administered for 2 weeks by inhalation of the compound (I). Based on these data, compounds of formula (I) could provide useful and safe treatment options for patients with IPF in the future.

Claims (13)

Formula (I) for use in methods for the treatment of human pulmonary fibrosis

It is a drug containing the compound of
An effective amount of the drug to treat the pulmonary fibrosis is administered once daily to the narrowest part of human lung tissue by a dry powder inhaler.
The daily dose of the compound is 0.15 to 50 mg, for example 0.15 to 1.5 mg, 1.5 to 3 mg, 3 to 5 mg, 5 to 7 mg, 7 to 8 mg, 8 to 10 mg, 10 to 20 mg. A drug that is 20-50 mg. The compound of the formula (I) is a bis (3-deoxy-3- (3-fluorophenyl-1H-1,2,3-triazole-1-yl) -β-D-galactopyranosyl) as a free form. ) The agent according to claim 1, which is sulfan. The agent according to claim 1 or 2, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). The administration can, RS01 Monodose Dry Powder Inhaler performed by the unit-dose dry powder inhaler, such as (Plastiape), agent according to any one of claims 1-3. The agent according to any one of claims 1 to 4 , wherein the narrowest portion of the lung tissue is a bronchiole and an alveoli. The agent according to claim 1, wherein the daily dose is 1.5 to 10 mg, for example, 3 to 7 mg. A pharmaceutical composition comprising the agent according to any one of claims 1 to 6 and an optionally pharmaceutically acceptable additive. Equation (I)

With respect to a dry powder inhaler device comprising a drug containing a compound of
The agent is for administering an effective amount of the compound of the formula (I) to the narrowest part of human lung tissue once a day to treat pulmonary fibrosis.
The daily dose of the compound is 0.15 to 50 mg, for example 0.15 to 1.5 mg, 1.5 to 3 mg, 3 to 5 mg, 5 to 7 mg, 7 to 8 mg, 8 to 10 mg, 10 to 20 mg. A dry powder inhaler device that is 20-50 mg. The compound of the formula (I) is a bis (3-deoxy-3- (3-fluorophenyl-1H-1,2,3-triazole-1-yl) -β-D-galactopyranosyl) as a free form. ) The dry powder inhaler device according to claim 8 , which is sulfan. The dry powder inhaler device according to claim 8 or 9 , wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). The dry powder inhaler device according to any one of claims 8 to 10 , wherein the device is a single-dose dry powder inhaler such as RS01 Monodose Dry Powder Inhaler (Plastiape). The dry powder inhaler device according to claim 8 , wherein the once-daily dose is 1.5 to 10 mg, for example 3 to 7 mg. The dry powder inhaler device according to any one of claims 8 to 12 , wherein the narrowest portion of the lung tissue is the bronchioles and alveoli.