Pharmaceutical composition and method using the same

Abstract

To provide a stable pharmaceutical composition comprising Nintedanib.SOLUTION: Provided is a pharmaceutical composition comprising Nintedanib or a pharmaceutically acceptable salt thereof and a stabilizer. The stabilizer comprises polyoxylglyceride. Also provided is a method for preventing, ameliorating, or treating fibrotic disease and / or lung cancer. The method comprises administering an effective amount of the pharmaceutical composition to a subject in need thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to pharmaceutical compositions, and more particularly to pharmaceutical compositions for preventing, ameliorating, or treating fibrotic diseases and / or lung cancer. [Background technology]

[0002] Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia that primarily affects elderly people and is limited to the lungs. The pathological mechanism of IPF remains unclear. Potential risk factors include smoking, viral infections, environmental pollution, genetic factors, and drugs. Current research indicates that the pathogenesis of IPF involves repeated damage to alveolar epithelial cells, which may lead to tissue fibrosis. Damaged epithelial cells secrete large amounts of growth factors, which activate fibroblasts and promote their activation, proliferation, and differentiation. This results in the formation of fibroblastic foci containing activated fibroblasts and myofibroblasts.

[0003] Antifibrotic drugs, including nintedanib, have been developed that inhibit intracellular signaling, inhibit fibroblast proliferation, migration, and transformation, and reduce the progression of the fibrotic process and the decline in lung function.

[0004] Ofev® (active substance: nintedanib), developed by Boehringer Ingelheim, is a soft capsule formulation recommended for administration twice daily after meals. However, according to the Japanese Pharmaceutical Interview Form (IF), Ofev® does not meet the required dissolution rate in accelerated stability testing. If the drug's dissolution rate does not meet the requirements of accelerated stability testing, intermediate and long-term stability data must be provided to demonstrate the drug's shelf life. Furthermore, previous studies have reported that Ofev® must be stored below 25°C, which increases transportation and storage costs, especially in tropical regions such as Southeast Asia.

[0005] It is known that U.S. Patent No. 9,907,756 discloses a soft capsule containing nintedanib. However, U.S. Patent No. 9,907,756 does not disclose a method for maintaining or improving the stability and dissolution property of the soft capsule for a long period of time.

[0006] Therefore, there is an unmet need in the art to overcome the drawback of inconsistent dissolution properties of pharmaceutical products containing nintedanib in accelerated stability tests. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent No. 9,907,756 Summary of the Invention [Means for solving the problem]

[0008] In view of the above, the present disclosure provides a pharmaceutical composition comprising nintedanib or a pharmaceutically acceptable salt thereof; and a stabilizer comprising a polyoxylglyceride.

[0009] The present disclosure also provides a method for preventing, ameliorating, or treating a fibrotic disease and / or lung cancer, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition of the present disclosure.

[0010] In at least one embodiment of the present disclosure, a stabilizer containing a polyoxylglyceride can provide superior effects in increasing the stability of a pharmaceutical composition for a longer period of time and improving its dissolution properties compared to commercially available drugs.

[0011] The objectives of the present disclosure will be understood by those skilled in the art after reading the following detailed description of the embodiments that are illustrated in the various figures and drawings. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows the dissolution profiles of the comparative group (Ofev®) and experimental group 1 according to an embodiment of the present disclosure. [Figure 2] FIG. 2 shows the dissolution profiles of the comparative group (Ofev®) and experimental group 2 according to an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0013] The following embodiments are provided to explain the present disclosure in detail. Those skilled in the art can easily understand the advantages and effects of the present disclosure by reading the disclosure of this specification, and can implement or apply it in other different embodiments. Therefore, without departing from the scope of different aspects and applications, the following embodiments for implementing the present disclosure can be modified and / or changed, and any element or method within the scope of the present disclosure disclosed herein can be combined with any other element or method disclosed in any embodiment of the present disclosure.

[0014] In order that this disclosure may be more readily understood, certain terms are first defined. Furthermore, it should be noted that whenever a value or range of values for a parameter is listed, it is intended that values and ranges intermediate to the listed values are also part of this disclosure.

[0015] As used herein, the singular forms "a," "an," and "the" include plural referents unless expressly and unambiguously limited to one referent. For example, "an active ingredient" means one active ingredient or more than one active ingredient, e.g., a plurality of active ingredients. The term "or" is used interchangeably with the term "and / or" unless the context clearly dictates otherwise.

[0016] As used herein, the terms "comprising," "comprises," "include," "including," "have," "having," "contain," "containing," and other variations thereof, are intended to cover non-exclusive inclusions. For example, when a subject matter expresses that it "comprises" a limitation, unless otherwise specified, it may further include other components, elements, constituents, parts, steps, or relationships, and should not exclude other limitations.

[0017] As used herein, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from one or more elements in the list of elements, but not necessarily including at least one of each element listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows that elements other than those identified in the list of elements to which the phrase "at least one" refers may optionally be present, whether related or not to those identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") can indicate, in one embodiment, at least one, optionally more than one A, and no B (and optionally including elements other than B); in another embodiment, at least one, optionally more than one B, and no A (and optionally including elements other than A); and in yet another embodiment, at least one, optionally more than one A, and at least one, optionally more than one B (and optionally including other elements).

[0018] The numerical ranges used herein are inclusive and combinable, and any numerical value within a numerical range herein can be considered as a maximum or minimum value, from which a subrange can be derived. For example, the numerical range "0.5% to 5%" includes any subrange between the minimum of 0.5% and the maximum of 5%, such as 0.5% to 3%, 0.7% to 5%, 3% to 4%, etc. Furthermore, multiple numerical values used herein can be arbitrarily selected as maximum and minimum values to derive a numerical range. For example, the numerical ranges 0.5% to 5%, 0.7% to 5%, and 0.5% to 0.7% can be derived from the numerical values 0.5%, 0.7%, and 5%.

[0019] The term "subject" refers to a human or other animal. In at least one embodiment of the present disclosure, the subject may be a mammal, such as, but not limited to, a human, a non-human primate, a dog, a cat, a mouse, a cow, a horse, a pig, a sheep, a deer, a wolf, a fox, and a rabbit.

[0020] As used herein, the term "carrier" refers to a pharmaceutically acceptable material, vehicle, or composition, such as a solid or liquid filler, binder, diluent, preservative, biocompatible solvent, disintegrant, lubricant, suspending agent, flavoring agent, encapsulating material, thickener / viscosifying agent, acid, surfactant, complexing agent, wetting agent, or any combination thereof. In some embodiments, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation and suitable for use in contact with the organs or tissues of a subject without undue toxicity, allergic response, irritation, immunogenicity, or other complication or problem. See, for example, Remington: The Science and Practice of Pharmacy, 22nd ed.; Allen ed.; Philadelphia, PA, 2012; Handbook of Pharmaceutical Excipients, 7th ed.; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2012; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson eds. Ed.); CRC Press LLC: Boca Raton, FL, 2009.

[0021] As used herein, the term "effective amount" refers to an amount of an active agent or pharmaceutical composition sufficient to treat, prevent, or improve a disorder, disease, or condition in a subject in need thereof. The effective amount may vary depending on the use of excipients, the route of administration, the possibility of co-administration with other therapeutic treatments, or the condition being treated, and the present disclosure is not limited thereto.

[0022] As used herein, the terms "administer," "administering," or "administration" refer to the placement of an active ingredient into a subject by a method or route that results in at least partial localization of the active ingredient at a desired site to produce a desired effect. For example, but not limited to, the active ingredients of the present invention can be administered to a subject by oral administration, injection, subcutaneous administration, intramuscular administration, topical administration, or intranasal administration.

[0023] As used herein, the terms "treat," "treating," or "treatment" refer to obtaining a desired pharmacological and / or physiological effect. This effect may be prophylactic, in that it completely or partially prevents a disease or its symptoms or conditions, or therapeutic, in that it completely or partially cures, alleviates, relieves, remedyes, or ameliorates the disease or the adverse effects caused by the disease or its symptoms or conditions.

[0024] As used herein, the terms "prevent," "preventing," or "prevention" do not require that a disease state be completely prevented. Rather, as used herein, the terms "prevent," "preventing," or "prevention" refer to the ability of a skilled artisan to identify a population susceptible to a disease so that administration of the extracellular vesicles of the present disclosure occurs before the onset of the disease. This term does not imply that the disease state is completely avoided.

[0025] The terms "ameliorate" and "ameliorating" refer to alleviating or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. These terms can also refer to reducing side effects associated with the active ingredient. In some embodiments, the beneficial effects a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.

[0026] In at least one embodiment of the present disclosure, the stabilizer can include a polyoxylglyceride, including at least one selected from the group consisting of lauroyl polyoxylglyceride, caprylocaproyl polyoxylglyceride, stearoyl polyoxylglyceride, and linoleoyl polyoxylglyceride, but the present disclosure is not limited thereto. In some embodiments, the lauroyl polyoxylglyceride can be lauroyl polyoxyl-32 glyceride. In some embodiments, the caprylocaproyl polyoxylglyceride can be caprylocaproyl polyoxyl-8 glyceride. In some embodiments, the stearoyl polyoxylglyceride can be stearoyl polyoxyl-32 glyceride. In some embodiments, the linoleoyl polyoxylglyceride can be linoleoyl polyoxyl-6 glyceride.

[0027] In at least one embodiment of the present disclosure, the stabilizer can be present in an amount of 0.5% to 5.0% by weight of the pharmaceutical composition, such as, but not limited to, 0.5% to 4.0% by weight, 0.9% to 3.0% by weight, 0.9% to 2% by weight, or 1.3% to 2.0% by weight of the pharmaceutical composition. In some embodiments, the stabilizer can be present in an amount of 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, 2%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, or 5.0% by weight of the pharmaceutical composition, but the present disclosure is not limited thereto.

[0028] In at least one embodiment of the present disclosure, the stabilizer can have a hydrophilic-lipophilic balance (HLB) value of 11.0 to 14.0, for example, but not limited to, 11.0 to 13.5, 11.5 to 13.0, or 12 to 13.5. In some embodiments, the stabilizer can have an HLB value of 11, 11.5, 12, 12.5, 13, 13.5, or 14, although the present disclosure is not limited thereto.

[0029] In at least one embodiment of the present disclosure, the pharmaceutically acceptable salt of nintedanib is selected from the group consisting of nintedanib methanesulfonate, nintedanib esylate, nintedanib ethanedisulfonate, nintedanib isethionate, nintedanib tosylate, nintedanib sulfate, nintedanib phosphate, nintedanib benzenesulfonate, nintedanib camphorsulfonate, nintedanib citrate, nintedanib bromide, nintedanib chloride, nintedanib benzoate, nintedanib saccharinate, nintedanib L-lactate, nintedanib The present disclosure is not limited to at least one selected from the group consisting of L-malate, nintedanib D-malate, nintedanib gentisinate, nintedanib glycolate, nintedanib naphthalene-1,5-disulfonate, nintedanib L-tartrate, nintedanib D-tartrate, nintedanib glycinate, nintedanib malonate, nintedanib oxalate, nintedanib camphorate, nintedanib mandelate, nintedanib salicylate, nintedanib ascorbate, and nintedanib xinafoate. In some embodiments, the pharmaceutically acceptable salt may be nintedanib esylate.

[0030] In at least one embodiment of the present disclosure, nintedanib or a pharmaceutically acceptable salt thereof may be present in an amount of 20% to 50% by weight of the pharmaceutical composition, for example, but not limited to, 20% to 45%, 30% to 45%, or 35% to 50% by weight of the pharmaceutical composition. In some embodiments, nintedanib or a pharmaceutically acceptable salt thereof may be present in an amount of 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight of the pharmaceutical composition, but the present disclosure is not limited thereto.

[0031] In at least one embodiment of the present disclosure, the pharmaceutical composition may further comprise a carrier and / or a surfactant.

[0032] In at least one embodiment of the present disclosure, the carrier may comprise a lipophilic substance. In some embodiments, the lipophilic substance may be at least one selected from the group consisting of vegetable oil, medium-chain triglyceride, medium-chain partial glyceride, animal-derived oil, sorbitan monostearate, ethyl oleate, corn oil glyceride, acetylated monoglyceride, caprylic / capric triglyceride, caprylic / capric / succinic triglyceride, caprylic / capric / linoleic triglyceride, oleic acid, glycerol monooleate, macrogolglycerol caprylocaprate, propylene glycol dicaprylate, and glycerol monolinoleate. In some embodiments, the lipophilic substance may be vegetable oil, medium-chain triglyceride, or a combination thereof, and the vegetable oil may be soybean oil, coconut oil, castor oil, or a combination thereof.

[0033] In at least one embodiment of the present disclosure, the carrier has a hydrophilic-lipophilic balance (HLB) value of 1 to 3.

[0034] In at least one embodiment of the present disclosure, the carrier may be present in an amount of 30% to 70% by weight of the pharmaceutical composition, for example, but not limited to, 30% to 60%, 35% to 55%, or 40% to 60% by weight of the pharmaceutical composition. In some embodiments, the carrier may be present in an amount of 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70% by weight of the pharmaceutical composition, but the present disclosure is not limited thereto.

[0035] In at least one embodiment of the present disclosure, the surfactant can include at least one selected from the group consisting of propylene glycol monolaurate, polyglycerol-3 dioleate, propylene glycol monocaprylate, propylene glycol dicaprylate, lecithin, polyethylene glycol sorbitan monolaurate, polyethylene glycol sorbitan monooleate, macrogolglycerol hydroxystearate, macrogolglycerol ricinoleate, macrogolglycerol linoleate, polyglycerol-6 dioleate, and D-α-tocopherol polyethylene glycol succinate, but the present disclosure is not limited thereto. In some embodiments, the surfactant can include propylene glycol monolaurate, lecithin, or a combination thereof.

[0036] In at least one embodiment of the present disclosure, the surfactant can have an HLB value of 3 to 6, such as, but not limited to, 3 to 5, 4 to 6, or 4 to 5. In some embodiments, the surfactant can have an HLB value of 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, or 6.0, although the present disclosure is not limited thereto.

[0037] In at least one embodiment of the present disclosure, the surfactant can be present in an amount of 0.3% to 25% by weight of the pharmaceutical composition, such as, but not limited to, 0.3% to 20% by weight, 5.0% to 15% by weight, or 10.0% to 25% by weight of the pharmaceutical composition. In some embodiments, the surfactant can be present in an amount of 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, or 25% by weight of the pharmaceutical composition, but the present disclosure is not limited thereto.

[0038] In at least one embodiment of the present disclosure, the pharmaceutical composition may comprise nintedanib or a pharmaceutically acceptable salt thereof in an amount of 20% to 69.2% by weight of the pharmaceutical composition, a stabilizer in an amount of 0.5% to 5% by weight of the pharmaceutical composition, a carrier in an amount of 30% to 55% by weight of the pharmaceutical composition, and a surfactant in an amount of 0.3% to 20% by weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition may comprise nintedanib or a pharmaceutically acceptable salt thereof in an amount of 20% to 59.2% by weight of the pharmaceutical composition; the stabilizer in an amount of 0.5% to 5% by weight of the pharmaceutical composition; the carrier in an amount of 40% to 50% by weight of the pharmaceutical composition; and the surfactant in an amount of 0.3% to 15% by weight of the pharmaceutical composition.

[0039] In at least one embodiment of the present disclosure, the stabilizer may have an HLB value of 11 to 14, the carrier may have an HLB value of 1 to 3, and the surfactant may have an HLB value of 3 to 6.

[0040] At least one embodiment of the present disclosure may provide a capsule containing a pharmaceutical composition of the present disclosure. In some embodiments, the capsule may be a soft capsule or a hard capsule. In some embodiments, the soft capsule or hard capsule may include a capsule shell enclosing the pharmaceutical composition of the present disclosure. In some embodiments, the capsule shell may include gelatin, solvents, emollients, opacifiers, plasticizers, sweeteners, dyes, pigments, flavorings, sugars, oligosaccharides or polysaccharides, adjuvants, preservatives, and / or one or more active ingredients, although the present disclosure is not limited thereto. In some embodiments, the soft capsule may have a capsule shell containing gelatin 160, glycerin, titanium dioxide, iron oxide red, iron oxide yellow, and / or purified water.

[0041] At least one embodiment of the present disclosure may provide a tablet comprising the pharmaceutical composition of the present disclosure. In some embodiments, the tablet may be a chewable tablet, a film-coated tablet, an orally disintegrating tablet, or an enteric-coated tablet. In some embodiments, the tablet may comprise a tablet shell that encapsulates the pharmaceutical composition of the present disclosure.

[0042] In some embodiments, the pharmaceutical compositions of the present disclosure may be, but are not limited to, an injectable formulation, a dry powder, a tablet, an oral liquid, a wafer, a film, a lozenge, a capsule, a granule, or a pill.

[0043] At least one embodiment of the present disclosure provides use of nintedanib or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for preventing, ameliorating, or treating fibrotic diseases and / or lung cancer, the pharmaceutical composition comprising a stabilizer containing a polyoxylglyceride.

[0044] At least one embodiment of the present disclosure provides a pharmaceutical composition for use in the prevention, amelioration, or treatment of fibrotic diseases and / or lung cancer, the pharmaceutical composition comprising nintedanib or a pharmaceutically acceptable salt thereof; and a stabilizer comprising a polyoxylglyceride.

[0045] In at least one embodiment of the present disclosure, the fibrotic disease can be idiopathic pulmonary fibrosis and the lung cancer can be non-small cell lung cancer.

[0046] In some embodiments, the fibrotic disease can be, but is not limited to, fibrosis and remodeling of lung tissue in chronic obstructive pulmonary disease, fibrosis and remodeling of lung tissue in chronic bronchitis, fibrosis and remodeling of lung tissue in emphysema, pulmonary fibrosis and lung diseases with a fibrotic component, fibrosis and remodeling in asthma, fibrosis in rheumatoid arthritis, viral-induced liver cirrhosis, radiation-induced fibrosis, post-angioplasty restenosis, chronic glomerulonephritis, renal fibrosis, skin diseases with a fibrotic component, and / or excessive scarring.

[0047] In some embodiments, the lung cancer can be, but is not limited to, non-small cell lung cancer, squamous cell lung carcinoma, small cell lung carcinoma, and / or lung adenocarcinoma.

[0048] In at least one embodiment of the present disclosure, the operating process for the dissolution test may include using the paddle method; a speed of 70 rpm to 150 rpm; and a dissolution medium of 700 ml to 1000 ml of 0.1 N HCl.

[0049] In at least one embodiment of the present disclosure, the paddle speed can be 70 rpm to 150 rpm, for example, but not limited to, 80 rpm to 120 rpm, 80 rpm to 150 rpm, or 90 rpm to 120 rpm. In some embodiments, the speed can be 70 rpm, 80 rpm, 90 rpm, 100 rpm, 110 rpm, 120 rpm, 130 rpm, 140 rpm, or 150 rpm, although the present disclosure is not limited thereto.

[0050] In at least one embodiment of the present disclosure, the dissolution medium can be 700 ml to 1000 ml of 0.1 N HCl, for example, but not limited to, 700 ml to 950 ml, 800 ml to 950 ml, or 850 ml to 1000 ml of 0.1 N HCl. In some embodiments, the dissolution medium can be 700 ml, 750 ml, 800 ml, 850 ml, 900 ml, 950 ml, or 1000 ml, although the present disclosure is not limited thereto.

[0051] In at least one embodiment of the present disclosure, the dissolution rate of the pharmaceutical composition of the present disclosure may be greater than 75% in 45 minutes, for example, but not limited to, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99% in 45 minutes. In some embodiments, the dissolution rate of the pharmaceutical composition of the present disclosure may be greater than 85% in 45 minutes after storage for 1 month, 3 months, or 6 months. In some embodiments, the pharmaceutical composition of the present disclosure exhibits superior dissolution rates in accelerated stability tests compared to commercially available drugs, such as, but not limited to, Ofev®.

[0052] In at least one embodiment of the present disclosure, the pharmaceutical composition of the present disclosure and the marketed drug, such as, but not limited to, Ofev®, share similar dissolution profiles in in vitro dissolution tests, indicating pharmaceutical identity and performance between the pharmaceutical composition and the marketed drug.

[0053] In at least one embodiment of the present disclosure, the pharmaceutical composition of the present disclosure and marketed drugs such as, but not limited to, Ofev® may be bioequivalent according to the results of in vivo pharmacokinetic studies. [Example]

[0054] Exemplary embodiments of the present disclosure are further described in the following examples, which should not be construed as limiting the scope of the disclosure.

[0055] Example 1: Preparation of soft capsules containing nintedanib

[0056] First, referring to the capsule shell compositions in Tables 1 and 2, gelatin 160, glycerin, and purified water were prepared and mixed at 65±5°C to remove dissolved gases from the mixture. Next, pigment, iron oxide red, iron oxide yellow, and titanium dioxide were added to the mixture to obtain a capsule shell solution.

[0057] Next, referring to the compositions of the pharmaceutical suspensions in Tables 1 and 2, heat and mix each substance (except nintedanib esilate) to prepare a solution. Next, add nintedanib esilate to the solution and mix evenly to prepare a pharmaceutical suspension.

[0058] Finally, the nintedanib-containing soft capsules are prepared by filling the drug suspension into the capsule shell solution using a softgel encapsulation machine. The final nintedanib-containing soft capsule formulation is obtained by drying at a temperature of 15°C to 25°C and a relative humidity of 15% to 30%.

[0059] [Table 1]

[0060] [Table 2]

[0061] Example 2: In vitro dissolution test of nintedanib-containing soft capsules (pharmaceutical composition (experimental group 1))

[0062] Since the absorption of a pharmaceutical composition depends on the dissolution profile of the pharmaceutical composition, in vitro dissolution testing can determine the rate and extent of release of the pharmaceutical composition. Furthermore, in vitro dissolution testing can be used to ensure the quality of the pharmaceutical product of the pharmaceutical composition.

[0063] The comparative group (i.e., Ofev®) and the pharmaceutical composition (experimental group 1) were subjected to in vitro dissolution test, and the operation process was as follows: In vitro dissolution testing: sinker paddle method Speed: 100rpm; Dissolution medium: 900 ml of 0.1 N HCl; and Sampling times: 0, 10, 15, 20, 30, 45, and 60 min.

[0064] Figure 1 and Table 3 show the results of the in vitro dissolution test, which indicate that the comparative group (i.e., Ofev®) and the pharmaceutical composition (experimental group 1) share similar dissolution profiles, ensuring the pharmaceutical identity and performance between the comparative group (i.e., Ofev®) and the pharmaceutical composition (experimental group 1).

[0065] [Table 3]

[0066] Example 3: In vitro dissolution test of nintedanib-containing soft capsules (pharmaceutical composition (experimental group 2))

[0067] The comparative group (i.e., Ofev®) and the pharmaceutical composition (experimental group 2) were subjected to in vitro dissolution test, and the operation process was as follows: In vitro dissolution testing: sinker paddle method Speed: 100rpm; Dissolution medium: 900 ml of 0.1 N HCl; and Sampling times: 0, 10, 15, 20, 30, 45, and 60 min.

[0068] Figure 2 and Table 4 show the results of the in vitro dissolution test, which indicate that the comparative group (i.e., Ofev®) and the pharmaceutical composition (experimental group 2) share similar dissolution profiles, ensuring the pharmaceutical identity and performance between the comparative group (i.e., Ofev®) and the pharmaceutical composition (experimental group 2).

[0069] [Table 4]

[0070] Example 4: Accelerated stability test of nintedanib-containing soft capsules (pharmaceutical compositions (experimental groups 1 and 2))

[0071] Stability testing provides information about changes in the quality of a drug over time under the influence of various environmental factors such as temperature, humidity, and light, and may establish expiration dates and recommended storage conditions for the drug. Furthermore, to accelerate the rate of physical and performance change of a drug product, Example 4 uses accelerated stability testing (40°C / 75% RH) in place of formal stability testing.

[0072] With reference to Tables 5 to 7, the comparative group (Ofev®), experimental group 1, and experimental group 2 are evaluated for changes in analytical sample values, dissolution tests, and impurity tests. The test frequency under accelerated storage conditions includes four time points (e.g., 0, 1, 3, and 6 months), including the initial and final time points. The acceptance criteria for each test are described in the "Specifications" column. Each evaluation item in the accelerated stability tests for experimental group 1 and experimental group 2 is within the specification range throughout the four time points. However, the dissolution of the comparative group (Ofev®) does not meet the specification criteria of more than 75% in 45 minutes at 1 month and 3 months.

[0073] [Table 5]

[0074] [Table 6]

[0075] [Table 7]

[0076] Example 5: In vivo pharmacokinetics of experimental group 2

[0077] Pharmacokinetic parameters are assessed by monitoring the variation in drug concentration in physiological fluids (e.g., plasma or urine) at different time points after administration to investigate the drug's absorption, distribution, biotransformation, and excretion in subjects. According to the European CPMP and FDA bioequivalence guidance, drugs are considered bioequivalent if the 90% confidence interval is completely within the range of 80% to 125%. The pharmacokinetic parameters shown in Table 8 indicate the behavior of a drug in the subject's body.

[0078] Referring to Table 8, plasma concentrations of 21 subjects were measured at multiple time points (0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 24, 48, and 72 hours) after administration of the pharmaceutical composition (i.e., experimental group 2 after a meal). Statistical analysis included 90% confidence intervals (CIs). The ratios between experimental group 2 and the control group for each pharmacokinetic parameter fell within the 80% to 125% limits of the European CPMP and FDA bioequivalence guidance with 90% confidence, demonstrating bioequivalence between the control group and experimental group 2.

[0079] [Table 8]

[0080] Those skilled in the art will readily appreciate that numerous modifications and variations can be made to the embodiments while retaining the teachings of the present disclosure. Accordingly, the above disclosure should be construed as limited only by the metes and bounds of the appended claims.

Claims

1. Nintedanib or a pharmaceutically acceptable salt thereof; and Stabilizers including polyoxylglycerides A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition of claim 1, wherein the polyoxylglyceride comprises at least one selected from the group consisting of lauroyl polyoxylglyceride, caprylocaproyl polyoxylglyceride, stearoyl polyoxylglyceride, and linoleoyl polyoxylglyceride.

3. 10. The pharmaceutical composition of claim 1, wherein the stabilizer is in an amount of 0.5% to 5% by weight of the pharmaceutical composition.

4. 2. The pharmaceutical composition of claim 1, wherein the stabilizer has a hydrophilic-lipophilic balance value of 11 to 14.

5. 2. The pharmaceutical composition of claim 1, wherein the nintedanib or a pharmaceutically acceptable salt thereof is in an amount of 20% to 50% by weight of the pharmaceutical composition.

6. The pharmaceutical composition of claim 1 , further comprising a carrier and / or a surfactant.

7. The pharmaceutical composition of claim 6 , wherein the carrier comprises a lipophilic substance.

8. 8. The pharmaceutical composition of claim 7, wherein the lipophilic substance is at least one selected from the group consisting of vegetable oils, medium-chain triglycerides, medium-chain partial glycerides, animal-derived oils, sorbitan monostearate, ethyl oleate, corn oil glycerides, acetylated monoglycerides, caprylic / capric triglyceride, caprylic / capric / succinic triglyceride, caprylic / capric / linoleic triglyceride, oleic acid, glycerol monooleate, macrogolglycerol caprylocaprate, propylene glycol dicaprylate, and glycerol monolinoleate.

9. 9. The pharmaceutical composition of claim 8, wherein the lipophilic substance is a vegetable oil, a medium chain triglyceride, or a combination thereof, and the vegetable oil is soybean oil, coconut oil, castor oil, or a combination thereof.

10. 7. The pharmaceutical composition of claim 6, wherein the carrier is in an amount of 30% to 70% by weight of the pharmaceutical composition.

11. 7. The pharmaceutical composition of claim 6, wherein the carrier has a hydrophilic-lipophilic balance value of 1 to 3.

12. 7. The pharmaceutical composition of claim 6, wherein the surfactant comprises at least one selected from the group consisting of propylene glycol monolaurate, polyglycerol-3 dioleate, propylene glycol monocaprylate, propylene glycol dicaprylate, lecithin, polyethylene glycol sorbitan monolaurate, polyethylene glycol sorbitan monooleate, macrogolglycerol hydroxystearate, macrogolglycerol ricinoleate, macrogolglycerol linoleate, polyglycerol-6 dioleate, and D-α-tocopherol polyethylene glycol succinate.

13. 7. The pharmaceutical composition of claim 6, wherein the surfactant comprises propylene glycol monolaurate, lecithin, or a combination thereof.

14. 7. The pharmaceutical composition of claim 6, wherein the surfactant is in an amount of 0.3% to 25% by weight of the pharmaceutical composition.

15. 7. The pharmaceutical composition of claim 6, wherein the surfactant has a hydrophilic-lipophilic balance value of 3 to 6.

16. nintedanib or a pharmaceutically acceptable salt thereof in an amount of 20% to 69.2% by weight of the pharmaceutical composition; the stabilizer in an amount of 0.5% to 5% by weight of the pharmaceutical composition; the carrier in an amount of 30% to 55% by weight of the pharmaceutical composition; and the surfactant in an amount of 0.3% to 20% by weight of the pharmaceutical composition 7. The pharmaceutical composition of claim 6, comprising:

17. the nintedanib or a pharmaceutically acceptable salt thereof is in an amount of 20% to 59.2% by weight of the pharmaceutical composition; the stabilizer is in an amount of 0.5% to 5% by weight of the pharmaceutical composition; the carrier is in an amount of 40% to 50% by weight of the pharmaceutical composition; and The surfactant is present in an amount of 0.3% to 15% by weight of the pharmaceutical composition.

17. The pharmaceutical composition of claim 16.

18. 10. A method for preventing, ameliorating or treating fibrotic diseases and / or lung cancer, comprising administering an effective amount of the pharmaceutical composition of claim 1 to a subject in need thereof.

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