Methods for treating fibrosis

Abstract

This specification provides methods and compositions for treating fibrosis, particularly pulmonary fibrosis. Pulmonary fibrosis may be idiopathic or may occur after a lung infection. The lung infection may be caused by SARS-CoV-2. As a result of treatment, lung function is stabilized or improved. One aspect is a method for treating fibrosis that comprises the step of administering a Gli1 inhibitor. Inhibition of Gli1 may be indirect. In some embodiments, an SMO inhibitor is used to indirectly inhibit Gli1. In some embodiments, means for inhibiting SMO are used to indirectly inhibit Gli1.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit and priority of U.S. Patent Application No. 18 / 115,598, filed on February 28, 2023, the entire content of which is incorporated herein by reference.

Background Art

[0002] Background The treatment of fibrotic diseases has proven to be a challenge. Although there are some approved drugs for the treatment of certain fibrotic diseases (e.g., pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF)), these drugs only slightly slow down the progression of the above - mentioned diseases and do not stop or reverse it. The Hedgehog / GLI signaling pathway is an important regulator of normal embryonic development and is also involved in the development of fibrosis. However, inhibition of the standard Hh signaling pathway, for example, by inhibiting Smoothened (SMO) (a G - protein - coupled receptor in the Hedgehog (Hh) signaling pathway), has not led to clinically feasible treatments for pulmonary fibrosis, renal fibrosis, or myelofibrosis. In fact, cyclopamine and IPI - 926, which are inhibitors of SMO, have been found to be ineffective in treating renal fibrosis. Furthermore, the phase 2 clinical trial of IPI - 926 in myelofibrosis did not support the continuation of development. The phase 1b clinical trial of visimodegib (in combination with pirfenidone) for the treatment of IPF suggested some effectiveness, but many patients withdrew from the trial because they could not tolerate the drug, and the development of drugs for this indication was abandoned.

Summary of the Invention

Means for Solving the Problems

[0003] Abstract Methods and compositions for treating fibrotic diseases using an inhibitor of the hedgehog signaling pathway that is sufficiently potent and tolerable to warrant clinical use are disclosed herein.

[0004] One aspect is a method of treating fibrosis that includes administering an inhibitor of Gli1. Inhibition of Gli1 can be indirect. In some embodiments, an inhibitor of SMO is used to indirectly inhibit Gli1.

[0005] One aspect is a method of treating fibrosis that includes administering a means for inhibiting Gli1. Inhibition of Gli1 can be indirect. In some embodiments, a means for inhibiting SMO is used to indirectly inhibit Gli1. In various embodiments, one or another genus or species of SMO inhibitor is specifically excluded.

[0006] With respect to the above aspects, in some embodiments, the inhibitor of Gli1 or the means for inhibiting Gli1 is an inhibitor of SMO (or the means for inhibiting SMO). In some embodiments, the inhibitor of SMO, the inhibitor of Gli1, or the means for inhibiting Gli1 or SMO is a compound of Formula I:

Chemical formula

[0007] In relation to the above aspects, in some embodiments, the inhibitor of the SMO, the inhibitor of Gli1, or the means for inhibiting Gli1 or SMO is a compound of formula II: [ka] And here R 1 R is either hydrogen or methyl; 2 R is either hydrogen or methyl; 3 , R 4 , R 5 , R 6 , or R 7 These are independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, or trifluoromethylsulfonyl, provided that R 3 , R 4 , R 5 , R 6 , and R 7 A compound in which at least three of the atoms are hydrogen; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula II has the following structure: [ka] Compound L-4 has the following properties:

[0008] In relation to the above aspects, in some embodiments, the inhibitor of Gli1 or means for inhibiting Gli1 is administered to patients who require it, i.e., patients with fibrotic disease. In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrotic disease is post-infectious pulmonary fibrosis (including bacterial or viral infection). In most cases, the fibrosis occurs after a chronic infection of a length of several years in which the role of infection in causing the fibrosis cannot be definitively shown; therefore, such fibrosis is still classified as idiopathic. Covid-19 is a complete contrast in that the onset of fibrosis can be very rapid. In some embodiments, the pulmonary fibrosis occurs after infection with SARS-CoV-2. In some embodiments, the fibrotic disease is scleroderma. In some cases, the fibrous disease is systemic scleroderma (also known as systemic sclerosis), and in more cases, systemic scleroderma involving the lungs. In some embodiments, the fibrous disease is hepatic fibrosis (e.g., non-alcoholic steatohepatitis (NASH)). In some embodiments, the fibrous disease is renal fibrosis. In some embodiments, the fibrous disease is gastric fibrosis. In some embodiments, the patient is human.

[0009] With respect to the above aspects, in some embodiments, the inhibitor of Gli1 or means for inhibiting Gli1 is administered in an effective dose. In some embodiments, the effective dose is effective in reducing symptoms. In some embodiments, the effective dose is effective in slowing or stopping the progression of the disease. In some embodiments, the effective dose is effective in reducing the impairment caused by the disease. In some embodiments, the effective dose is effective in reversing (causing improvement) the impairment caused by the disease. With respect to IPF, impairment can be measured as a change in lung function, for example, by vital capacity measurement. Possible vital capacity measures to be used include forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and pulmonary carbon monoxide diffusion capacity (DL). CO ) are examples. The degree of fibrosis can also be assessed by imaging (e.g., high-resolution computed tomography (HRCT)). In some embodiments, the effective dose includes 50 to 200 mg of the Gli1 inhibitor or means for inhibiting the Gli1. In some embodiments, the effective dose includes 10 to 300 mg of the Gli1 inhibitor or means for inhibiting the Gli1.

[0010] One aspect is a pharmaceutically acceptable compound comprising an inhibitor of Gli1 or means for inhibiting Gli1. In some embodiments, the inhibitor of Gli1 or means for inhibiting Gli1 is a compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I is taladegib.

[0011] Further aspects include methods for producing the disclosed pharmaceutical composition. For example, the disclosed method may include removing the solvent component of a solution to produce a solid composition.

[0012] Further developments include kits containing the disclosed compositions. [Brief explanation of the drawing]

[0013] [Figure 1] Figure 1 shows a comparison of clinical trial results for four IPF treatments: pirfenidone, nintedanib, GLPG1690, and the Hh inhibitor bismodegib. The trials for pirfenidone, nintedanib, and GLPG1690 were placebo-controlled, while the bismodegib trial was open-label. Pirfenidone data are the average of three phase 3 trials over 24 weeks. Nintedanib data are the average of two phase 3 trials over 24 weeks. GLPG1690 data are phase 1b data over 12 weeks. Hh inhibitor (bismodegib) data are phase 1b data over 24 weeks.

[0014] [Figure 2] Figure 2 shows the percentage of Gli1 mRNA inhibition in skin samples from patients receiving various doses of taladegib.

[0015] [Figure 3] Figure 3 shows the drug-related discontinuation rates in clinical trials of four drugs investigated for the treatment of IPF.

[0016] [Figure 4] Figures 4A and 4B show α-SMA protein levels with and without taladegib treatment in a bleomycin-induced pulmonary fibrosis model. Figure 4A shows representative images of anti-α-SMA immunostained lung sections from sham control, vehicle-treated, and taladegib-treated mice. Figure 4B shows the percentage of α-SMA-positive areas from individual mice, as well as the mean and standard deviation of the treatment groups. [Modes for carrying out the invention]

[0017] explanation The general mechanism of fibrotic diseases is understood to involve initial tissue injury that triggers hedgehog upregulation and drives cell transdifferentiation into myofibroblasts (i.e., the conversion of differentiated cells (non-stem cells) into another type of differentiated cell (in this case, myofibroblasts)). The physiological function of myofibroblasts is to repair tissue by depositing extracellular matrix and contracting the tissue, as in wound closure. Fibrous diseases (including IPF) arise from dysregulated wound remodeling involving chronic matrix deposition and tissue contraction well after the initial tissue trauma has resolved. The methods and compositions disclosed herein treat fibrotic diseases by inhibiting the Hh signaling pathway so that upregulated hedgehog can no longer drive this pathology and halt the chronic remodeling that blocks myofibroblast generation and leads to fibrosis. Although this mechanism has been clinically validated, the prospect of Hh pathway inhibitors treating fibrosis has not been realized to date.

[0018] definition

[0019] "Administering" or "administering" means the process of giving (i.e., administering) a medical device, material, or drug to a subject. The formulations disclosed herein may be administered via several suitable routes.

[0020] "To dry" means to remove the solvent.

[0021] "Patient" refers to a human or non-human subject receiving medical or veterinary care.

[0022] "Pareral administration" and "administered parenterally" are terms known in the art and include, but are not limited to, modes of administration other than enteral and local administration, such as injection, including retroorbital, intraocular, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0023] "Pharmacologically acceptable" or "therapeutably acceptable" refers to a substance that does not interfere with the efficacy or biological activity of the active ingredient and is not toxic to the patient.

[0024] A “pharmaceutically acceptable carrier” includes, for example, a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which is publicly known in the art and is involved in transporting or delivering any subject composition from one organ or part of the body to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the subject composition and is not harmful to the patient. In certain embodiments, the pharmaceutically acceptable carrier is nonpyrogenic. Examples of materials that can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; excipients such as tragacanth powder, malt, gelatin, talc, cocoa butter, and suppository wax; oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; buffers such as agar, magnesium hydroxide, and aluminum hydroxide; alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, and other non-toxic, suitable substances used in pharmaceutical formulations.

[0025] The term "pharmaceutical composition" means a preparation containing an active ingredient. The term "preparation" means that, in addition to the active ingredient, the pharmaceutical composition contains at least one additional component (e.g., albumin [such as human serum albumin or recombinant human albumin] and / or sodium chloride, etc.). Therefore, a pharmaceutical composition is a preparation suitable for administration to subjects such as human patients for diagnostic, therapeutic, or cosmetic purposes. Pharmaceutical compositions may exist in a lyophilized or vacuum-dried state, in a solution formed after reconstituting a lyophilized or vacuum-dried pharmaceutical composition with, for example, physiological saline or water, or as a solution that does not require reconstitution. As mentioned above, pharmaceutical compositions may be liquid, semi-solid, or solid. Pharmaceutical compositions may not contain animal proteins.

[0026] "Reduce," "suppress," and "inhibit" all have the common understanding of reducing or decreasing something.

[0027] "Therapeutic preparations" means preparations that can be used to treat and thereby alleviate a disorder or disease and / or symptoms associated therewith.

[0028] "Therapeutic dose" refers to the level, amount, or concentration of a drug, material, or composition necessary to achieve a treatment objective.

[0029] composition

[0030] It is disclosed herein that certain 1,4-disubstituted phthalazines that are potent inhibitors of SMOs and the downstream transcription factors Gli1 and Gli2, and exhibit a desirable toxicological profile, satisfy this prospect. This embodiment refers to a compound of formula I: [ka]

[0031] And here R 1 R is either hydrogen or methyl; 2R is either hydrogen or methyl; 3 , R 4 , R 5 , R 6 , or R 7 These are independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, or trifluoromethylsulfonyl, provided that R 3 , R 4 , R 5 , R 6 , and R 7 The present invention provides a compound in which at least three of its atoms are hydrogen, or a method of treatment using a pharmaceutically acceptable salt thereof. Under the standard nomenclature used throughout this disclosure, the terminal portion of a given side chain is described first, followed by the functional group adjacent to the bond site. For example, a methylsulfonyl substituent is equivalent to CH3-SO2-. "pharmaceutically acceptable salt" means a relatively non-toxic inorganic salt or organic salt of the compound of the present invention.

[0032] Compounds of formula I and their synthesis are described in U.S. Patent No. 9,000,023, which is incorporated herein by reference in its entirety.

[0033] This embodiment also provides a pharmaceutical composition for use in a treatment method, comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable excipient, carrier, or diluent. “Pharmaceutically acceptable carrier, diluent, or excipient” means a medium generally accepted in the art for the delivery of a biologically active drug to a mammal, such as a human.

[0034] The series of compounds of formula I is 4-fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazole-5-yl)phthalazine-1-yl)piperidine-4-yl)-2-(trifluoromethyl)benzamide (CAS 1258861-20-9): [ka] (Also known as Talladegib). Talladegib (also known as LY2940680) is a potent, selective, and orally available Smo inhibitor with a favorable safety profile that can disrupt the Hh pathway. This molecule has been completed in over 192 human subjects and was initially developed to treat oncological indications, primarily lung cancer and basal cell carcinoma (BCC). Although primarily in cancer patients, these trials allowed for a preliminary understanding of dose and tolerability. Talladegib is orally available. In some embodiments, the mean oral bioavailability is approximately 72% to 91%.

[0035] M75, the major metabolite of taladegib, is an oxidative N-desmethylated product that retains activity as an inhibitor of SMO. M75 is R of formula I. 2 The methyl group is lost, and as a result, the position is understood to be hydrogen instead of methyl.

[0036] Taladegib is more suitable than bismodegib for targeting the lung. In animal models, taladegib is more than 20 times more potent than bismodegib in inhibiting Gli1 in the lung, a downstream effector molecule expressed when the Hh pathway is activated. The clinically established MTD for taladegib is 400 mg. At this dose, Gli1 mRNA inhibition was >85% in the skin, and approximately 9% discontinued treatment. Taladegib has been clinically evaluated at lower doses of around 50 mg (i.e., one-eighth of the clinically established MTD). At this dose, Gli1 mRNA inhibition was still higher than 80%. In contrast, bismodegib inhibits Gli1 mRNA by less than 50% at its MTD of 150 mg. Taladegib has a better clinical safety profile than bismodegib, with a substantially lower incidence of muscle cramps (40% vs. up to 80%). Therefore, bismodegib proved unsuitable for IPF, but clinical trials with bismodegib showed that inhibiting the Hh pathway may improve lung function in IPF patients.

[0037] The compound of formula I was measured in Daoy cells and, as described in U.S. Patent No. 9,000,023, generally increased Gli1 activity to <40 nM IC50. 50 It inhibits [the reaction]. Taladegib produced approximately 2.4 nM IC in this assay. 50 Such compounds constitute means for inhibiting Gli1 activity or means for inhibiting SMO.

[0038] Furthermore, U.S. Patent Application Publication No. 20200000784 A1 is incorporated herein by reference in all respects of teaching the use of taladegib in relation to the treatment of fibrosis, in particular idiopathic pulmonary fibrosis.

[0039] Certain analogs of the phthalazine described above are potent inhibitors of SMO and the downstream transcription factors Gli1 and Gli2, exhibiting a desirable toxicological profile. In some embodiments, the means for inhibiting the above SMO inhibitor, the above Gli1 inhibitor, or the above Gli1 or SMO is a compound of formula II: [ka]

[0040] And here R 1 R is either hydrogen or methyl; 2 R is either hydrogen or methyl; 3 , R 4 , R 5 , R 6 , or R 7 These are independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, or trifluoromethylsulfonyl, provided that R 3 , R 4 , R 5 , R 6 , and R 7A compound in which at least three of the atoms are hydrogen; or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula II has the following structure: [ka] It is N-(1-(4,5-dimethyl-6-(1-methyl-1H-pyrazole-5-yl)pyridazin-3-yl)piperidine-4-yl)-4-fluoro-2-(trifluoromethyl)benzamide (also known as L-4) having the following properties.

[0041] L-4 is described by Zhu et al. (L-4, a Well-Tolerated and Orally Active Inhibitor of Hedgehog Pathway, Exhibited Potent Anti-tumor Effects Against Medulloblastoma in vitro and in vivo, Frontiers in Pharmacology 10:89, 2019 (which is incorporated herein by reference in its entirety)). Zhu et al. describe L-4 as a promising anticancer agent. It has a similar ID for Hh inhibition as taladegib. 50 They are reported to have (2.33 nM vs. 2.26 nM, respectively).

[0042] Similar to taladegib and the compound of formula I, the L-4 and compound of formula II constitute means for inhibiting Gli1 activity or means for inhibiting SMO. Various embodiments specifically exclude the compound of formula I, the compound of formula II, or specific subgenera or species of formula I or formula II.

[0043] The compounds of the present invention can react with many inorganic and organic acids, for example, to form pharmaceutically acceptable acid addition salts. Such pharmaceutically acceptable salts and general methodologies for preparing them are well known in the art. See, for example, P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA / Wiley-VCH, 2002); SM Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol 66, No. 1, January 1977.

[0044] The compounds disclosed herein may be formulated as pharmaceutical compositions using pharmaceutically acceptable carriers, diluents, or excipients and administered by various routes. In certain embodiments, such compositions are intended for oral or intravenous administration. Such pharmaceutical compositions and processes for preparing them are well known in the art. For example, see REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al., 19th sup.th ed., Mack Publishing Co., 1995).

[0045] In some embodiments, the compounds disclosed herein may be formulated as tablets containing 50, 100, 150, 200, 250, 300, or 350 of the above compounds and common pharmaceutical ingredients: croscarmellose sodium, HPMCAS-H, mannitol, microcrystalline cellulose, silicon dioxide, and stearyl fumarate sodium. One particular embodiment contains 16.1% taladegib, 37.6% HPMCAS-H, 9.3% mannitol, 28.6% microcrystalline cellulose, 2.9% croscarmellose sodium, 1.0% silicon dioxide, 1.2% stearyl fumarate sodium, and 3.4% OPADRY® (film coating).

[0046] Further embodiments may include 5-25% active agents such as a Gli1 inhibitor, 20-50% HPMCAS-H, 15-45% mannitol, 15-45% microcrystalline cellulose, 1-5% croscarmellose sodium, 0.5-5% silicon dioxide, 0.5-5% stearyl fumarate sodium, and 1-10% OPADRY®.

[0047] How to use

[0048] IPF is a dysregulated wound healing process that leads to progressive fibrous pulmonary scarring. Targeting the Hedgehog pathway is a logical therapeutic approach to slow, halt, or reverse the progression of the disease. In the wound healing process, the Hh pathway regulates the activation of fibroblasts and their conversion to myofibroblasts, which, in dysregulated cases, is a major driving factor of fibrosis. In IPF, myofibroblasts infiltrate the lungs, where they produce extracellular matrix proteins such as collagen. Myofibroblasts adhere to the extracellular matrix and pull on the closed lung, similar to how they pull on a wound that is being closed. As a result of myofibroblast activity, lung function is progressively lost through fibrosis and tissue remodeling.

[0049] Targeting the Hh pathway via Smo inhibition has been validated both clinically and preclinically. In clinical settings, the FDA-approved Smo inhibitor bismodegiv (Erivedge for the treatment of adults with metastatic or locally advanced BCC) is used. (登録商標)Bismodegib (which is approved as such) was evaluated in combination with pirfenidone in a single-arm IPF trial. After 6 months of treatment, patients showed an average increase of approximately 100 mL in forced vital capacity (FVC). The increased FVC and lung capacity were not observed in any other clinical trials investigating any other targets considered for IPF. Smo inhibition, which disrupts the Hh pathway, was validated as a therapeutic target for IPF, but bismodegib was poorly tolerated by patients because severe muscle cramps were a major adverse event resulting in discontinuation in more than 40% of participants. This discontinuation rate is similar to the discontinuation rate experienced by patients with BCC who took bismodegib. All further development of bismodegib as an IPF treatment was discontinued.

[0050] Inhibition of Gli1 mRNA in the skin is similar to inhibition of Gli1 mRNA in the lung. Gli1 mRNA inhibition in skin biopsy material has been measured as a surrogate for Gli1 mRNA inhibition in the lung in clinical trials for lung cancer. Nonclinical in vivo models have shown that the kinetics and magnitude of Gli1 mRNA inhibition by orally administered taladegib are very similar in mouse skin and lung. Furthermore, the degree of Gli1 mRNA inhibition in mouse skin and lung was similar to the degree of Gli1 mRNA inhibition observed in skin biopsy material of human subjects treated with clinically relevant doses.

[0051] IPF patient samples showed elevated levels of Hh pathway components and myofibroblasts. Several studies examined tissue from IPF patient lung samples and compared them to lung samples from healthy subjects. The presence of significant increases in SHh (an activating ligand for the Hh pathway) and Gli1 was evident. Normal lungs showed no detectable levels of either SHh or Gli1, while IPF samples stained very strongly, indicating a significant presence. IPF lung samples also stained very strongly for α-smooth muscle actin 1 (α-SMA1), a marker defining myofibroblasts. Normal, healthy lung samples showed little to no staining for α-SMA1.

[0052] Disruption of the Hh pathway to inhibit fibrosis has been demonstrated in vitro and in numerous animal models using several Smo inhibitors. These animal models share similar characteristics, allowing fibroblast infiltration and transdifferentiation into myofibroblasts, which then drive progressive fibrosis. Inhibition of Smo has been observed to disrupt fibrosis and, in some cases, reverse the disease. Furthermore, inhibition of Smo has been shown to result in increased apoptosis of infiltrated myofibroblasts, decreased α-SMA1, decreased Gli1 and SHh, and decreased collagen.

[0053] Nonclinical toxicity findings for taladegib are similar to those of other approved drugs in this class, and the significant potential risks associated with the on-target effects of taladegib are considered to be liver damage, genital effects, rhabdomyolysis, reproductive toxicity, and bone effects. A class of effects not yet observed clinically or nonclinically with taladegib is amenorrhea.

[0054] Clinically, the mean half-life (t) across all doses is important. 1 / 2 Regarding taladegib, it was estimated that the median time was approximately 16 hours, allowing for once-daily administration. max It was 2 hours.

[0055] Taladegib has shown a favorable safety profile in six industry-funded trials, primarily conducted in patients with advanced cancer. As monotherapy in advanced cancer, the majority of commonly observed adverse events (AEs) were nausea, diarrhea, dysgeusia, fatigue, loss of appetite, alopecia, vomiting, muscle cramps, constipation, weight loss, and headache.

[0056] The relationship between the efficacy and toxicity of a drug is generally expressed in terms of the therapeutic window and therapeutic index. The therapeutic window is the dose range from the lowest dose that shows a detectable therapeutic effect to the maximum tolerated dose (MTD); the highest dose that produces the desired therapeutic effect without causing unacceptable toxicity. Most typically, the therapeutic index is the LD (Low Dose), based on animal studies. 50 :ED 50 As a ratio, and based on human studies, TD 50 :ED 50 It is calculated as a ratio of (however this calculation can also be derived from animal studies and is sometimes called the protective index). Here LD 50 , TD 50 , and ED 50 These are the lethal, toxic, and effective doses, respectively, in 50% of the population tested.

[0057] In various aspects of these embodiments, toxicity can be observable toxicity, substantial toxicity, severe toxicity, tolerable toxicity, or dose-limiting toxicity (e.g., not limited to MTD). Observable toxicity means that a change is observed, but its effects are negligible or mild. Substantial toxicity means that there is a negative impact on the patient's overall health or quality of life. In some cases, substantial toxicity can be mitigated or eliminated by other ongoing medical interventions. Severe toxicity means that its effects require acute medical intervention and / or dose reduction or temporary discontinuation of treatment. The tolerability of toxicity is influenced by the specific disease being treated, its severity, and the availability of mitigation of medical interventions.

[0058] Toxicity and adverse events are sometimes scored according to a 5-point scale. Grade 1 or mild toxicity induces no symptoms or very mild symptoms; may be characterized only by clinical or diagnostic observation; and no intervention is indicated. Grade 2 or moderate toxicity may impair activities of daily living (e.g., preparing meals, shopping, managing money, using the telephone), but minimal, local, or non-invasive intervention is indicated. Grade 3 toxicity is medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization is indicated; activities of daily living related to self-care (e.g., bathing, dressing, eating independently, using the toilet, taking medication, and avoiding bedriddenness) may be impaired. Grade 4 toxicity is life-threatening and requires immediate intervention. Grade 5 toxicity results in adverse event-related death. Accordingly, in various embodiments, the use of the drug in the regimens or dosages disclosed herein reduces the grade of toxicity associated with the treatment by at least one grade compared to the use of the drug in a different regimen. In other embodiments, the use of the drug in a specified regimen or dosage limits toxicity to grade 2 or less, grade 1 or less, or does not result in any observation of toxicity. In some embodiments, the therapeutic index of the inhibitors disclosed herein for Gli1 or SMO is greater than that of bismodegib (approximately 0.37). For comparison, the therapeutic index of taladegib is approximately 8. In some embodiments, the therapeutic index of the inhibitors disclosed herein for Gli1 or SMO is greater than 1, 2, 3, 4, 5, 6, or 7.

[0059] Aspects of this specification provide, in part, the process of administering an effective amount (or therapeutically effective amount) of a compound or composition disclosed herein. As used herein, the term “effective amount” is synonymous with “effective dose,” and when used in reference to the treatment of IPF, means at least the minimum dose of a compound or composition disclosed herein that is necessary to achieve the desired therapeutic effect. An effective dose or amount of a compound or composition disclosed herein can be readily determined by a person skilled in the art, taking into account all criteria (e.g., the elimination rate of the compound or composition used, the pharmacodynamics of the compound or composition used, the properties of other compounds that will be included in the composition, a particular route of administration, specific characteristics of the individual, medical history and risk factors (e.g., age, weight, general health status, etc.), the individual’s response to the treatment, or any combination thereof), and using the best judgment for the individual, in particular in light of the exemplary doses and other information disclosed herein. In some embodiments, the effective dose is 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg, or falls within a range delimited by any pair of the aforementioned values. In some embodiments, the effective dose is administered once daily.

[0060] In some embodiments, the dose of taladegib, L-4, or a related compound is started at 200 mg / day. In some embodiments, the above dose is provided as a single daily dose. If a grade 3 or higher AE is observed, the dose is reduced. In some embodiments, the above dose is reduced to approximately 50 mg / day, in increments of 50 mg / day, if necessary to avoid a grade 3 or higher AE. In some embodiments, the initial dose (before reduction) may be any dose higher than the minimum dose considered to be the effective dose. In some embodiments, the above initial dose is in the upper half of the effective dose range. In some embodiments, the above initial dose is at the top of the above effective dose range. For example, if the effective dose range is 50-200 mg, the initial dose may be >50 mg (e.g., 75 mg), 125-200 mg, or 200 mg. In some cases, the above initial dose is in the range of 100-300 mg / day. In some cases, the dosage may be reduced to 25 mg / day, 50 mg / day, or 100 mg / day.

[0061] In some embodiments, an effective dose of a Gli1 or SMO inhibitor, or a means for inhibiting Gli1 or SMO, results in stabilization or improvement of fibrosis (e.g., with respect to the physical degree of fibrosis, pulmonary function, or other measures as described herein). In further embodiments, stabilization or improvement of fibrosis is achieved without the patient experiencing any drug-related adverse events (toxicity). In certain cases, the avoided drug-related adverse event is grade 3 or higher toxicity. In some embodiments, drug-related adverse events that are absent are muscle spasms, QT prolongation, or hepatotoxicity.

[0062] Various aspects of fibrosis treatment involve administering inhibitors of Gli1 or SMO, or means for inhibiting Gli1 or SMO, to patients who require them, i.e., patients with fibrotic diseases. In some embodiments, the above-mentioned inhibitors of Gli1 or SMO, or means for inhibiting Gli1 or SMO, are used as monotherapy. In some embodiments, the above-mentioned inhibitors of Gli1 or SMO, or means for inhibiting Gli1 or SMO, are used in combination with another antifibrotic drug. In some embodiments, the other antifibrotic drug is not an Hh pathway inhibitor. In some cases, the above-mentioned non-Hh pathway inhibitor antifibrotic drugs are pirfenidone, nintedanib, GLPG4716, or PRM-151.

[0063] In some embodiments, the fibrous disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrous disease is pulmonary fibrosis following infection (including bacterial or viral infection). In most cases, the fibrosis occurs after a chronic infection of several years in which the role of infection in causing the fibrosis cannot be definitively shown; such fibrosis is therefore still classified as idiopathic. Covid-19 is a complete contrast in that the onset of fibrosis can be very rapid. In some embodiments, the pulmonary fibrosis occurs after infection with SARS-CoV-2. In some embodiments, the fibrous disease is scleroderma. In some cases, the fibrous disease is systemic scleroderma (also known as systemic sclerosis), and in even more cases, systemic scleroderma involving the lungs. In some embodiments, the fibrous disease is hepatic fibrosis (e.g., non-alcoholic steatohepatitis (NASH)). In some embodiments, the fibrous disease is renal fibrosis (e.g., interstitial fibrosis or allograft fibrosis). In some embodiments, the fibrous disease is gastric fibrosis (e.g., mucosal fibrosis, glandular stomach fibrosis, or retroperitoneal fibrosis). In some embodiments, the patient is human. In some embodiments, the patient is a non-human animal, such as a mammal.

[0064] With respect to each treatment method, there are corresponding embodiments that can be expressed as the use of the above-mentioned inhibitor of Gli1 or SMO in the treatment of fibrous diseases, or means for inhibiting Gli1 or SMO, or as a pharmaceutical for the treatment of fibrous diseases, or as a composition for use in treating fibrous diseases, or as the use thereof in the manufacture of a pharmaceutical composition.

[0065] The terms “treatment,” “treatment,” etc., refer to the medical management of a patient, intended to cure, improve, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, i.e., treatment directed specifically to improve the disease, pathological condition, or disorder, and also causal treatment, i.e., treatment directed to eliminate the cause of the associated disease, pathological condition, or disorder. Furthermore, this term includes palliative treatment, i.e., treatment designed to alleviate symptoms rather than cure the disease, pathological condition, or disorder; preventive treatment, i.e., treatment directed to minimize, or partially or completely inhibit, the occurrence of the associated disease, pathological condition, or disorder; and supportive treatment, i.e., treatment used to complement another specific treatment directed to improve the associated disease, pathological condition, or disorder. Various embodiments may specifically include or exclude one or more of these types of treatment.

[0066] Treatment activities include, in particular, the administration to a patient of the medicinal products, dosage forms, and pharmaceutical compositions described herein, whether by a healthcare professional, the patient themselves, or any other individual, in accordance with the various methods of treatment disclosed herein. Treatment activities include orders, instructions, and advice from a healthcare professional (e.g., a physician, physician's assistant, nurse practitioner, etc.) which are then carried out by any other individual, including other healthcare professionals or the patient themselves. This includes, for example, instructions to have a patient undergo a diagnostic procedure (e.g., imaging or assessment of lung function) or to have it performed by a clinical laboratory, so that the patient ultimately receives beneficial and appropriate treatment. In some embodiments, the command, instruction, and advice aspect of treatment activities may also include encouraging, inducing, or authorizing the selection—and actual use—of a particular medicine or combination of medicines for the treatment of a condition by approving insurance coverage for that medicine, denying coverage for alternative medicines (including including that medicine in a drug formulary, excluding alternative medicines from it, or providing a financial incentive to use that medicine), as may be done by an insurance company or a pharmacy benefits management company. In some embodiments, treatment activities may also include encouraging, inducing, or authorizing the selection—and actual use—of a particular medicine for the treatment of a condition—as may be established by a hospital, clinic, health maintenance organization, medical practice, or group of physicians, as well as by a policy or standard of practice. All such commands, instructions, and advice should be recognized as conditional on receiving the benefits of treatment in accordance with those instructions. In some cases, a financial benefit may also be received by the patient for complying with such commands, instructions, or advice. In some cases, financial compensation may also be received by healthcare professionals for complying with such orders, instructions, or advice.

[0067] The effectiveness or benefit of treatment for pulmonary fibrosis is generally assessed by changes in lung function, such as by measuring vital capacity. Possible vital capacity measures include forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and the pulmonary capacity to diffuse carbon monoxide (DL). CO Further vital capacity measurement parameters that may be considered include the FEV1 / FVC ratio, observed FVC as a percentage of predicted FVC (FVC % predicted), and observed FEV1 as a percentage of predicted FEV1 (FEV1% predicted). The predicted value of FVC (in liters) as published by the Association for Respiratory Technology and Physiology is 5.76 × height (in meters) - 0.026 × age (in years) - 4.34. The predicted value of FEV1 (in liters) as published by the Association for Respiratory Technology and Physiology is 4.30 × height (in meters) - 0.029 × age (in years) - 2.49.

[0068] Other evaluations include the following: i. Appearance of the lungs - the quantitative degree of fibrosis (including scarring or remodeling) in percentage and / or volume, as determined by CT scans, magnetic resonance imaging (MRI), etc.; ii. Appearance of the lungs - qualitative degree of fibrosis as determined by CT scan, magnetic resonance imaging (MRI), etc.: improvement, same, or worsening; iii. Number of respiratory hospitalizations; iv. The distance that can be walked in a set period of time (for example, the walking distance in 6 minutes); and v. Respiratory health questionnaire scores (e.g., St. George's Respiratory Questionnaire, UCSD Shortness of Breath Questionnaire, etc.)

[0069] evaluation Lung capacity measurements and other assessments can be performed at regular intervals (e.g., approximately every 24 weeks, four times a year, every six months, or once a year).

[0070] The effectiveness or benefit of a treatment may be observed as a reduction in disease progression, stabilization of the disease, or improvement in the patient's condition. In some embodiments, progression, stabilization, or improvement may be determined by comparison with the patient's previous measurements or a comparison of multiple measurements. In some embodiments, the previous measurements are baseline measurements before the initiation of the treatment. In some embodiments, progression, stabilization, or improvement is determined based on a comparison with other patients (actual or historical) who have not received treatment, are receiving a placebo, or are receiving an alternative treatment. Thus, in some embodiments, improvement or stabilization is determined by a comparison with what would be expected in an untreated patient. For example, in such embodiments, reduced scarring includes a smaller increase in scarring than would be expected in an untreated patient. Thus, stabilization of lung function does not implicitly mean that there will be no further decline in one or another measure of lung function, but rather that any decline will not exceed what would be expected with aging over a given period of time considered.

[0071] Manufacturing method

[0072] Further embodiments include methods for producing the disclosed pharmaceutical compositions.

[0073] In the pharmaceutical field, poorly soluble drugs are often known to exhibit insufficient bioavailability or irregular absorption, the degree of which is influenced by factors such as the dosage level, the patient's eating status, and the form of the drug.

[0074] It is generally known that using water-soluble polymers as matrix materials improves solubility. Examples of water-soluble polymers used to date include polyvinylpyrrolidone (PVP, povidone), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), sodium carboxymethylcellulose (NaCMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), ethylene oxide and propylene oxide block copolymer (PEO / PPO), and polyethylene glycol (PEG).

[0075] Talladegib is a Biopharmaceuticals Classification System (BCS) Class II (high permeability, low solubility) compound. Therefore, to improve the exposure and reproducibility of talladegib in humans, HPMCAS spray-dried solid dispersions are disclosed herein.

[0076] For example, the crystalline or amorphous forms of the disclosed embodiments can be prepared by one or more techniques such as spray drying, melt quenching, steam condensation, melt spinning, or sol-gel methods. The disclosed embodiments provide compositions comprising a spray-dried solid dispersion containing a water-insoluble drug (Talladegib or L-4) and HPMCAS. In the embodiments, the composition is preferably amorphous as much as possible. The disclosed embodiments may have an amorphous-to-crystalline form ratio of 80 / 20, an amorphous-to-crystalline form ratio of 85 / 15, an amorphous-to-crystalline form ratio of 90 / 10, an amorphous-to-crystalline form ratio of 95 / 5, and so on.

[0077] In a preferred embodiment, the drug / HPMCAS spray-dried dispersion itself contains a poorly soluble drug and HPMCAS.

[0078] Other components can be included in the dispersion as long as they are inactive in the sense that they do not adversely affect the maximum supersaturated concentration (MSSC) of the drug achievable in the dispersion under the usage environment. Components that affect the MSSC can also be included as long as they do not substantially adversely affect the MSSC (i.e., do not reduce the MSSC). In other words, all such components in the dispersion do not reduce the MSSC by more than 20% compared to a spray-dried dispersion that does not contain such components. Components that do not affect the MSSC, or actually improve the MSSC, can be included in any amount. In general, the amount of HPMCAS and the drug in the dispersion excluding residual solvent should exceed 75% by weight.

[0079] The main components present in the solid amorphous composition of the present invention are only the delivered drug and HPMCAS; however, the inclusion of other excipients in the dispersion is useful, and may even be preferable.

[0080] For example, polymers other than HPMCAS that are soluble in aqueous solutions in at least a portion of the pH range of 1.0 to 8.0 can be included in the dispersion together with HPMCAS. For example, it has been found that some drugs exhibit superior performance when amorphous dispersions of a drug with a conventional matrix material such as PVP, HPC, or HPMC are formed and then pulverized together with HPMCAS, compared to the same dispersion without HPMCAS. In such cases, whether the drug is crystalline or amorphous, HPMCAS is considered to have the main advantage of suppressing the precipitation or crystallization of the drug from a supersaturated solution. A preferred embodiment of the present disclosure is a dispersion obtained by co-spray drying of a drug, HPMCAS, and one or more additional polymers, in which case the drug and HPMCAS constitute, for example, 50%, 60%, or 75% or less of the dispersion.

[0081] In addition to the drug and HPMCAS, the compositions of the present invention may be used with other conventional pharmaceutical excipients, including excipients well known in the art. Generally, excipients such as fillers, disintegrants, dyes, binders, lubricants, fragrances, and flow enhancers may be used for conventional purposes and in typical amounts without affecting the properties of the composition. In embodiments, these excipients are used to formulate the dispersion into, for example, tablets or capsules after the HPMCAS / drug dispersion has been formed.

[0082] As used herein, spray drying refers to the process of atomizing a liquid mixture into small droplets and rapidly removing the solvent from the mixture within a container (spray dryer), where a strong driving force is at work to evaporate the solvent from the droplets. This strong driving force for solvent evaporation is generally achieved by maintaining the partial pressure of the solvent within the spray dryer well below the vapor pressure of the solvent at the temperature of the drying droplets. This is achieved by one of the following methods: i. Maintain the pressure inside the spray drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atmospheres). ii. Mix the droplets with a warm, dry gas, or iii. Both.

[0083] Solutions spray-dried to form HPMCAS / drug dispersions may contain only the drug and HPMCAS in the solvent. Typically, the ratio of drug to HPMCAS in the solution is in the range of 1:0.2 to 1:100, preferably in the range of 1:0.4 to 1:20. In the case of taladegib, the preferred ratio is 1:1 to 1:4. However, for small doses of the drug (less than 20 mg), the ratio of drug to HPMCAS may be even higher than 20. Basically, a solvent suitable for spray drying can be any organic compound in which the drug and HPMCAS are mutually soluble. Preferably, the solvent is volatile and has a boiling point of 150°C or less.

[0084] Preferred solvents include alcohols such as methanol, ethanol, n-propanol, isopropanol, and butanol; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate and propyl acetic acid; and various other solvents such as acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane. Low-volatility solvents such as dimethylacetamide or dimethyl sulfoxide can also be used. Mixtures of solvents can also be used, including mixtures with water, as long as the polymer and HPMCAS are sufficiently dissolved to make the spray-drying process practical.

[0085] In the spray drying embodiment, the temperature and flow rate of the drying gas are selected so that the droplets of HPMCAS / drug solution dry sufficiently and become substantially solid before reaching the walls of the apparatus, without forming a fine powder that adheres to the apparatus walls.

[0086] After solidification, the solid powder may remain in the spray drying chamber for 5 to 50 seconds to further evaporate the solvent from the solid powder. The final solvent content of the solid dispersion discharged from the dryer should be low to reduce the mobility of drug molecules in the dispersion and improve stability. Additional drying steps may be required to further reduce the amount of residual solvent. Generally, the residual solvent content of the dispersion should be less than 2 w / w%, preferably less than 0.2 w / w%.

[0087] The spray-dried dispersion can then be post-treated using methods known in the art, such as roller compression, fluidized bed agglomeration, or spray coating, to prepare it for administration or further processing.

[0088] The spray-dried solution and the resulting dispersion may also contain various additives that aid in the stability, dissolution, tableting, or processing of the dispersion. Examples of such additives may include surfactants, pH adjusters (e.g., acids, bases, buffers), fillers, disintegrants, flow enhancers, or binders. Such additives can be added directly to the spray-dried solution, thereby dissolving or suspending them in the solution as a slurry. Alternatively, such additives may be added after the spray-dried process to aid in the formation of the final dosage form.

[0089] Due to the amorphous nature of spray-dried dispersions, it is essential to protect tablets from moisture to prevent degradation of the active ingredient. This can be improved by coating tablets or capsules with known film coating materials such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, OPADRY®, or combinations thereof. In embodiments, the final oral dosage form may need to be stored in a low-permeability container, for example, with a desiccant, to further reduce the effects of moisture.

[0090] The disclosed embodiments may include fillers such as lactose, HPMCAS, kaolin, powdered cellulose, precipitated calcium carbonate, sorbitol, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, starch, or combinations thereof. For example, in the embodiments, the fillers may constitute 5, 10, 20, 30, or 45% of the disclosed formulation.

[0091] The disclosed embodiments may include disintegrants such as sodium starch glycolate, sodium alginate, alginic acid, amberlite, methylcellulose, croscarmellose sodium, or combinations thereof. For example, in the embodiments, the disintegrant may constitute 1, 5, 10, or 15% of the disclosed formulation.

[0092] The disclosed embodiments may include flow enhancers such as colloidal silica, corn starch, talc, or combinations thereof. For example, in the embodiments, the flow enhancer may constitute 0.5, 1, 5, or 10% of the disclosed formulation.

[0093] The disclosed embodiments may include lubricants such as magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, zinc stearate, or combinations thereof. For example, in the embodiments, the lubricant may constitute 1, 5, 10, or 15% of the disclosed formulation.

[0094] The disclosed embodiments may include film coatings such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, OPADRY®, or combinations thereof.

[0095] The disclosed embodiments may include binders such as acacia, alginic acid, methylcellulose, sodium carboxymethylcellulose, compressible sugar (Nu-Tab), microcrystalline cellulose, ethylcellulose, gelatin, povidone, starch, and gums such as guar gum, tragacanth, or combinations thereof. For example, in embodiments, the binder may constitute 5, 10, 15, 20, 25, 30, or 35% of the disclosed formulation.

[0096] The disclosed embodiments may include flavorings such as acacia syrup, aromatic elixirs, cherry syrup, cocoa syrup, orange syrup, or combinations thereof. For example, in the embodiments, the flavorings may constitute 1, 5, 10, or 15% of the disclosed formulation.

[0097] Commercially available products / kits

[0098] According to further embodiments, the disclosed composition may also be provided in the form of a kit combined with other components necessary for administration to a patient.

[0099] The kits are designed in various forms based on the specific defect being treated. [Examples]

[0100] Examples The following non-limiting examples are provided solely for illustrative purposes to facilitate a more complete understanding of the representative embodiments intended herein. These examples should not be construed as limiting any of the embodiments described herein.

[0101] Example 1 Talladegib's In Vitro Pharmacology Using an in vitro competitive binding assay, the 50% inhibitory concentration (IC) was determined. 50 ) and coupling constant (K i The ratio was calculated based on competitive substitution of the radioactive ligand. Talladegib binds to the hSMO receptor and to hSMO 3 The binding of H-2406189 (a known SMO agonist) to a K2 ion of 76.4±75.3 nM i and ICs with a frequency of 144±143nM 50 This inhibits the process (n=4, geometric mean ± standard error [SE]).

[0102] To determine the biological activity of taladegib in mouse cells, Gli-luciferase activity was measured in mouse mesenchymal C3H10T cells stimulated with sonic hedgehog-conditioned medium (SHh-CM). 1 / 2 Quantitative analysis was performed in cell lines. Taladegib hydrochloride was administered to mouse C3H10T cells. 1 / 2 In cells, IC50 was 11.2 ± 5.33 nM. 50 Hh signaling activity was inhibited (n=8, geometric mean ± SE). To determine the biological activity of taladegib in human cells, Gli1 transcript levels were quantified in human Daoy tumor cell lines stimulated with SHh-CM. Taladegib hydrochloride produced an IC50 of 2.22 ± 1.14 nM, as determined by Gli1 mRNA measurement using branched deoxyribonucleic acid (DNA) assay technology. 50This inhibited Hh signaling activity in human Daoy cells (n=8, geometric mean ± SE).

[0103] Example 2 Talladegib's In Vivo Pharmacology To understand PK / PD effects and guide dosing regimens for efficacy trials, key PK / PD trials involving dose response and time course are studied using Balb / c surrogate models and PTCH. - / + × p53 - / - This was performed after a single oral administration of taladegib in a tumor model. After a predetermined administration period, surrogate tissues (lungs, skin, and cerebellum) and Ptch derived from Balb / C mice were used. - / + × p53 - / - Tumors derived from transgenic tumor models were collected, processed, and quantitative reverse transcription polymerase chain reaction (TaqMan) was performed on Gli1 expression levels. (登録商標) The effects were evaluated using assays. As summarized in Table 1, taladegib inhibited Hh signaling as measured by mouse Gli1 expression levels in the tissues being evaluated. Time-course studies showed that sustained targeted inhibition could be maintained for at least 24 hours after a single oral dose of 8 mg / kg taladegib hydrochloride. Considering the corresponding PD effect, cutaneous Gli1 is a suitable PD surrogate to lung tissue Gli1. [Table 1]

[0104] Example 3 SMO inhibitors improve FVC in IPF patients. The results of various clinical trials for treatments for IPF were compared (Figure 1). The anti-inflammatory pirfenidone and the kinase inhibitor nintedanib could only slow the progression of FVC, whereas the SMO inhibitor bismodegib (in combination with pirfenidone) was able to produce a substantial increase in FVC (suggesting a reversal of pathology). The autotaxin inhibitor zirtaxestat (also known as GLPG1690) produced a small increase in FVC in a Phase 1b trial, but development of this drug was abandoned during a Phase 3 trial due to a risk-benefit profile that no longer supported its use, as assessed by an independent data monitoring committee. All development of zirtaxestat was discontinued. Development of bismodegib was also discontinued for IPF due to severe muscle spasms, but these data validate the use of Hh inhibitors in the treatment of IPF.

[0105] Example 4 Low-dose taladegib reduces the severity of muscle cramp adverse events but maintains the degree of Gli1 inhibition. Taladegib was administered to subjects at doses of 50 mg, 100 mg, 200 mg, 400 mg, and 600 mg. At these doses, most patients showed >80% inhibition of Gli, as measured in skin biopsy material (Figure 2). Some grade 3 toxicity was observed at 400 mg / day, but none was observed at 200 mg / day or 100 mg / day (Table 2). Given that the minimum bioeffective dose (BED) was defined in this study as the first dose level at which mGli1 inhibition was >50%, it was concluded that taladegib was pharmacologically active at all dose levels tested. [Table 2]

[0106] Example 5 Comparison of the main adverse events (AEs) of drugs tested in relation to IPF treatment. Taladegib, bismodegib, pirfenidone, and nintedanib have all been used in clinical trials to treat IPF and have been evaluated for their use. Except for taladegib, >20% of patients discontinued treatment for drug-related reasons (Figure 3). The main adverse events (AEs) leading to discontinuation were muscle cramps for bismodegib, nausea for pirfenidone, and diarrhea for nintedanib. There were no widespread AEs for taladegib, and <10% of patients discontinued treatment for drug-related reasons when the dose was ≤200 mg / day.

[0107] Example 6 Reduction of myofibroblasts in a bleomycin-induced pulmonary fibrosis model The bleomycin (BLM)-induced pulmonary fibrosis model is a standard IPF model and is widely used in pharmacological and basic research. Disease IPF is defined as progressive and irreversible limited lung injury. In IPF patients, loss of lung function is driven by the infiltration and proliferation of activated myofibroblasts. Intratracheal administration of bleomycin was performed using a Microsprayer® Aerosolizer. By administering bleomycin via the Microsprayer® Aerosolizer, it can be uniformly exposed to the lungs, thus generating a reproducible and homogeneous pathology. In this model, the presence of myofibroblasts is observed by immunohistochemistry when stained with anti-α-smooth muscle actin (α-SMA) antibody.

[0108] Animals were exposed to bleomycin and then treated with taladegib on day 7 when fibrosis developed. Pathology of the animals was examined on day 21 of the study. Treatment with 5 mg / kg of taladegib administered orally daily resulted in an approximately 40% reduction in α-SMA protein expression, which indicated a reduction in myofibroblasts (Figure 4A-B).

[0109] Example 7 A Phase 2 multicenter study evaluating the safety and efficacy of taladegib in subjects with IPF. American Thoracic Association, Japanese Respiratory Society, European Respiratory Patients diagnosed with IPF based on the Society and Latin American Thoracic Association guidelines, and confirmed by high-resolution computed tomography (HRCT) to have a percentage predicted FVC of >50% and a percentage predicted DLCO between 35% and 85%, will be randomized to either the taladegib group or the placebo group. Pulmonary function tests (FVC, FEV1, and DL) will be performed. CO Baseline results are obtained from ), HRCT, and the UCSD Shortness of Breath (SOB) questionnaire. Taladegib is administered daily for 12 weeks, starting at 200 mg / day. Patients are observed for an additional 6 weeks after completion of the planned treatment. If drug-related adverse events are experienced, the dose may be reduced to approximately 100 mg / day. Pulmonary function tests and the UCSD SOB questionnaire are repeated at weeks 6, 12, and 18 of the study. HRCT is repeated at 12 weeks. Efficacy is assessed by FVC, FEV1, FEV1 / FVC ratio, predicted FVC %, predicted FEV1%, and DL at weeks 6, 12, and 18. CO Furthermore, assessment will be made by changes from baseline in the UCSD SOB questionnaire. Quantitative (% and mL) and qualitative (improvement, same, exacerbation) assessments of pulmonary fibrosis by HRCT will be performed at screening and at 12 weeks. The screening HRCT will serve as the baseline for the study HRCT assessment. At 12 weeks, dose-limiting toxicities will be no or minimally observed. At 12 weeks, some efficacy endpoints will show stabilization or improvement. At 18 weeks, sustained responses will be observed. Patients will not experience any serious drug-related adverse events (if any, after sufficient dose reduction), including the absence of muscle cramps.

[0110] Example 8 COVID-19 Treatment Clinical Trials Patients who have recovered from SARS-CoV-2 infection and present with pulmonary fibrosis as determined by CT scan will be randomized to receive either standard care or taladegib monotherapy. Taladegib will be administered daily, starting at 200 mg. If a patient experiences a drug-related adverse event, the dose may be reduced in increments of 100 mg to reduce or eliminate the adverse event. Pharmacokinetic data will be collected. The primary efficacy endpoint is the change in FVC from baseline at 24 weeks. Secondary efficacy endpoints are the change in pulmonary fibrosis from baseline CT scan, the change from baseline in 6-minute walk distance, the number of respiratory hospitalizations, and the change from baseline in St. George's Respiratory Questionnaire. At 24 weeks, some efficacy endpoints will show stabilization or improvement. Patients will not experience any serious drug-related adverse events (if any, after sufficient dose reduction), including the absence of muscle cramps.

[0111] Example 9 Drug manufacturing The solution of the poorly soluble drug and HPMCAS in acetone is spray-dried by spraying it into a chamber maintained at a total pressure of 0.01–0.2 atmospheres, with the outlet connected to a vacuum pump, at a temperature of 50–70°C (the vapor pressure of acetone at 50°C is approximately 0.8 atmospheres). Alternatively, the acetone solution can be sprayed into a chamber mixed with nitrogen or another inert gas at a temperature of 110–150°C and a pressure of 1.0–1.2 atmospheres.

[0112] Next, the spray-dried composition is mixed with fillers, disintegrants, dyes, binders, lubricants, fragrances, flow promoters, etc., and the dispersion is formulated into, for example, tablets or capsules. The tablets or capsules may be coated with materials such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, or OPADRY®.

[0113] Example 10 Drug manufacturing Tablets containing 16.1% taladegib, 37.6% HPMCAS-H, 9.3% mannitol, 28.6% microcrystalline cellulose, 2.9% croscarmellose sodium, 1.0% silicon dioxide, 1.2% stearyl fumarate sodium, and 3.4% OPADRY® were prepared using the method of Example 9.

[0114] Example 11 Drug manufacturing Tablets containing 20% ​​L-4, 37.6% HPMCAS-H, 9.3% mannitol, 24.7% microcrystalline cellulose, 2.9% croscarmellose sodium, 1.0% silicon dioxide, 1.2% stearyl fumarate sodium, and 3.4% OPADRY® were prepared using the method of Example 9.

[0115] Finally, while aspects of this specification are emphasized by reference to specific embodiments, it should be understood that those skilled in the art will readily recognize that these disclosed embodiments are merely illustrative examples of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is by no means limited to the specific methodologies, protocols, and / or reagents, etc., described herein. Thus, various modifications or changes to alternative configurations of the disclosed subject matter may be made in accordance with the teachings herein without departing from the spirit of this specification. Finally, the terminology used herein is for the sole purpose of describing specific embodiments and is not intended to limit the scope of the invention as defined solely by the claims. Therefore, the invention is not limited to exactly what is shown and described herein.

[0116] Specific embodiments of the present invention are described herein, including the best modes known to the inventors for carrying out the invention. Naturally, variations to these described embodiments will be apparent to those skilled in the art by reading the preceding description. The inventors expect that those skilled in the art will adopt such variations where appropriate, and the inventors intend that the invention may be carried out in ways other than those specifically described herein. Thus, the invention includes all modifications and equivalents of the subject matter described in the claims appended herein, as permitted by applicable law. Furthermore, any combination of all conceivable variations of the above embodiments is encompassed by the invention unless otherwise indicated herein or unless it is clearly inconsistent with the context.

[0117] Any grouping of alternative embodiments, elements, or processes of the present invention should not be construed as limiting. Members of each group may be referred to and claimed individually or in any combination with members of other groups disclosed herein. It is acknowledged that one or more members of a group may be included in or removed from a group for convenience and / or patentability reasons. In the event of any such inclusion or removal, this specification shall be deemed to include the groups as modified and thus satisfy the written description of the Markush groups used in the appended claims.

[0118] Unless otherwise indicated, all figures used herein and in the claims to represent features, items, quantities, parameters, characteristics, periods, etc., should be understood in all cases to be modified by the term “about.” Where used herein, the term “about” means that the aforementioned feature, item, quantity, parameter, characteristic, or period, as thus modified, encompasses a range of ±10% above or below the stated value of that feature, item, quantity, parameter, characteristic, or period. Therefore, unless otherwise indicated, the numerical parameters expressed herein and in the appended claims are variable approximations. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the claims, each numerical representation should be interpreted in light of the reported significant figures and by applying common rounding techniques. Despite the approximations of the broad ranges and values ​​of the present invention, the numerical ranges and values ​​shown in their specific examples are reported as accurately as possible. However, any numerical range or value inherently contains certain errors that inevitably arise from the standard deviation found in their respective test measurements. The numerical ranges of values ​​described herein are intended solely as a means of convenience for referring individually to each distinct numerical value that falls within that range. Unless otherwise indicated herein, each individual value within a numerical range is incorporated herein as if it were described individually.

[0119] In the context describing this invention (in particular in the context of the following claims), the terms “a,” “an,” “the,” and similar references should be construed to encompass both singular and plural forms unless otherwise indicated herein or unless the context clearly contradicts it. All methods described herein may be performed in any appropriate order unless otherwise indicated herein or unless the context clearly contradicts it. The use of any and all examples or illustrative language provided herein (e.g., “for example, such as”) is intended only to better illustrate the invention and does not impose any limitation on the scope of the claimed invention. The language herein should not be construed to describe any unclaimed elements essential to the practice of this invention.

[0120] The specific embodiments disclosed herein may be further limited in the claims using the phrases "consisting of" or "essentially consisting of." When used in the claims, whether at the time of filing or added in accordance with amendments, the transitional phrase "consisting of" excludes any elements, processes, or components not specified in the claims. The transitional phrase "consisting essentially of" limits the scope of the claims to those that do not essentially affect the specified materials or processes and the basic and novel features. Embodiments of the invention as thus claimed are essentially or expressly described and made implementable herein.

[0121] All patents, patent publications, and other publications referred to and identified herein are incorporated herein individually and expressly by reference in whole, for example, for the purpose of describing and disclosing compositions and methodologies described in such publications that may be used in connection with the present invention. These publications are provided only in relation to their disclosures prior to the filing date of this application. In this regard, nothing should be construed as the inventors admitting that they do not have any rights prior to such disclosures, either by prior art or for any other reason. All statements relating to dates or indications relating to the contents of these documents are based on information available to the applicant and do not constitute any admission of the accuracy of the dates or contents of these documents.

Claims

1. A method for formulating a dry pharmaceutical composition containing an active agent, wherein the active agent has low water solubility, and the method comprises: mixing the agent with a polymer to form a solution or a homogeneous mixture; and drying the mixture to obtain a solid or a finely divided solid.

2. The method according to claim 1, wherein the drying includes spray drying, melt quenching, steam condensation, or melt spinning.

3. The method according to claim 2, wherein the drying includes spray drying.

4. The method according to claim 3, wherein the polymer comprises at least one of polyvinylpyrrolidone (PVP, povidone), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), sodium carboxymethylcellulose (NaCMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), ethylene oxide and propylene oxide block copolymer (PEO / PPO), and polyethylene glycol (PEG).

5. The method according to claim 4, wherein the dried pharmaceutical composition is at least 80% amorphous.

6. The method according to claim 5, wherein the dried pharmaceutical composition is at least 90% amorphous.

7. The method according to claim 6, wherein the dried pharmaceutical composition is at least 95% amorphous.

8. The method according to claim 5, wherein the active agent comprises a Gli1 inhibitor.

9. The Gli1 inhibitor is, 【Chemistry 9】 A compound wherein R １ is hydrogen or methyl; R ２ is hydrogen or methyl; R ３ , R ４ and R ５ and R ６ or R ７ is independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl or trifluoromethylsulfonyl, provided that at least three of R ３ and R ４ and R ５ and R ６ and R ７ are hydrogen; or a pharmaceutically acceptable salt thereof, The method according to claim 8, including the method described in claim 8.

10. The aforementioned Gli1 inhibitor is a compound of formula II: 【Chemistry 10】 And here R １ is hydrogen or methyl; R ２ is hydrogen or methyl; R ３ , R ４ , R ５ , R ６ , or R ７ These are independently hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, or trifluoromethylsulfonyl, provided that R ３ , R ４ , R ５ , R ６ , and R ７ A compound in which at least three of the atoms are hydrogen; or a pharmaceutically acceptable salt thereof, The method according to claim 8, including the method described in claim 8.

11. The Gli1 inhibitor is a compound of formula I, and R １ It is methyl, and R ２ It is methyl, and R ３ It is trifluoromethyl, and R ４ H is R ５ is fluoro, R ６ H is R ７ The method according to claim 9, wherein H is...

12. The method according to claim 10, wherein the Gli1 inhibitor in formula II is L-4.

13. The method according to claim 11, wherein the dried pharmaceutical composition contains 14.5 to 17.7% taladegib.

14. The method according to claim 13, wherein the dried pharmaceutical composition comprises 14.5 to 17.7% taladegib and 33.9 to 41.4% HPMCAS-H.

15. The method according to claim 14, wherein the dried pharmaceutical composition comprises 14.5 to 17.7% taladegib, 33.9 to 41.4% HPMCAS-H, and 8.4 to 10.2% mannitol.

16. The method according to claim 15, wherein the dried pharmaceutical composition comprises 14.5-17.7% taladegib, 33.9-41.4% HPMCAS-H, 8.4-10.2% mannitol, 25.7-31.5% microcrystalline cellulose, and 2.6-3.2% croscarmellose sodium.

17. The method according to claim 16, wherein the dried pharmaceutical composition comprises 14.5-17.7% taladegib, 33.9-41.4% HPMCAS-H, 8.4-10.2% mannitol, and 25.7-31.5% microcrystalline cellulose, 2.6-3.2% croscarmellose sodium, and 0.9-1.1% silicon dioxide.

18. The method according to claim 17, wherein the dried pharmaceutical composition comprises 14.5-17.7% taladegib, 33.9-41.4% HPMCAS-H, 8.4-10.2% mannitol, and 25.7-31.5% microcrystalline cellulose, 2.6-3.2% croscarmellose sodium, 0.9-1.1% silicon dioxide, and 1.1-1.3% stearyl fumarate sodium.

19. The method according to claim 18, wherein the dried pharmaceutical composition comprises 14.5-17.7% taladegib, 33.9-41.4% HPMCAS-H, 8.4-10.2% mannitol, 25.7-31.5% microcrystalline cellulose, 2.6-3.2% croscarmellose sodium, 0.9-1.1% silicon dioxide, 1.1-1.3% stearyl fumarate sodium, and 3.1-3.7% OPADRY®.

Images