Ruxolitinib oral liquid formulation

Abstract

The present disclosure relates to oral formulations and dosage forms of ruxolitinib, or pharmaceutically acceptable salts thereof, that are useful in the treatment of Janus kinase (JAK)-associated diseases.

Description

Technical Field

[0001] Compositions and techniques related to oral liquid formulations or dosage forms of ruxolitinib.

Background Art

[0002] Ruxolitinib, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile, is a commercial product formulated as an oral immediate-release tablet administered twice daily (BID) at dosage strengths of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg for the treatment of Janus kinase (JAK)-related diseases such as myelofibrosis (MF), polycythemia vera (PV), and graft-versus-host disease (GvHD) in adult patients. The formulations of ruxolitinib addressed herein supplement existing products by providing dosage forms in liquid form.

[0003] GvHD is frequently seen in pediatric patients from 28 days to 18 years of age, and thus a dosage form suitable for age is desired. In addition to the pediatric population, there are adult patients who have difficulty swallowing the solid dosage form of ruxolitinib. Therefore, there is a need for novel and improved formulations of ruxolitinib at various dosages to improve safety and enhance patient compliance.

Summary of the Invention

[0004] One aspect of the present invention provides an oral liquid formulation comprising ruxolitinib, also known as (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile of formula I,

Chemical Formula

[0005] In one embodiment, the present invention provides (a) ruxolitinib or a pharmaceutically acceptable salt thereof, (b) a solvent, (c) Preservatives This relates to oral formulations including [specific formulations].

[0006] In one embodiment, the solvent in the oral formulation is water.

[0007] In one embodiment, the preservative in the oral formulation is a mixture of methylparaben and propylparaben.

[0008] In one embodiment, the oral formulation further comprises a co-solvent.

[0009] In one embodiment, the oral formulation further comprises a sweetener.

[0010] In one embodiment, the oral formulation further comprises a flavoring agent.

[0011] In one embodiment, the oral formulation further comprises a pH adjuster.

[0012] In one embodiment, the cosolvent is propylene glycol.

[0013] In one embodiment, the sweetener is sucralose.

[0014] In one embodiment, the flavor is strawberry.

[0015] In one embodiment, the pH adjusting agent is citric acid.

[0016] In one embodiment, the ruxolitinib (free base-based) concentration is approximately 1 mg / mL to 5 mg / mL.

[0017] Another aspect of the present invention provides a method for treating Janus kinase (JAK)-related disease, comprising the step of administering an oral formulation of the present disclosure comprising about 1 mg to about 65 mg of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis. [Brief explanation of the drawing]

[0018] [Figure 1] Summarize the study design of the pediatric acute GvHD trial. [Figure 2] Summarize the study design of the pediatric chronic GvHD trial.

Mode for Carrying Out the Invention

[0019] The commercially available formulation of Jakafi / Jakavi (trademark) (ruxolitinib) is an oral tablet administered twice daily (BID).

[0020] Ruxolitinib phosphate is designated as a Class 1 compound in the Biopharmaceutics Classification System (BCS). Ruxolitinib phosphate is a water-soluble drug that exhibits pH-dependent solubility, with higher solubility at lower pH. The drug substance in solution mainly shows degradation by oxidation. Temperature and oxygen induce an increase in oxidative decomposition. In an oral solution formulation, it is necessary to maintain the pH at 2.4 - 4.0 with an acidifying agent such as citric acid to keep the drug in solution. Nitrogen purging is carried out in the drug dispersion process during the manufacturing process to provide an inert environment with minimal oxygen. Together with an appropriate preservative system such as methylparaben and propylparaben, a taste masking agent such as sucralose, and a flavoring agent such as strawberry flavor, maintaining the pH of the solution at 2.4 - 4. and a simple mixing method are effective and have been found to result in a stable oral solution formulation with a good taste.

[0021] Based on chemical / physical stability, the formulation has a current shelf life of 12 months at room temperature (the shelf life is expected to be extended as additional stability data becomes available), and based on microbiological stability, it ensures stability with an optimal level of preservatives and a safe level of excipients.

[0022] This formulation can be stored at room temperature, in contrast to the low temperatures at which most liquid dosage forms are stored. It is a non-sugar, multi-use formulation that can be administered to pediatric patients for chronic use without concern for dental caries. It can also be administered to adult patients who have difficulty swallowing solid dosage forms.

[0023] The dosage of ruxolitinib administered to a patient depends on a number of factors, such as the patient's weight, the patient's body surface area, the severity of the symptoms, and the nature of other drugs being administered. Therefore, the therapeutic dosage is adjusted as appropriate to achieve equivalent pharmacokinetic profiles and similar therapeutic effects.

[0024] The formulation is an immediate-release formulation. It is usually administered twice a day (BID).

[0025] In the usage of this specification, the term "pharmaceutical composition" means a mixture (e.g., solid dispersion) and / or solution (e.g., liquid solution) containing a therapeutic compound administered to mammals, such as humans, to prevent, treat, or control a specific disease or medical condition that affects mammals. For example, in the usage of this specification, the term "pharmaceutical composition" also includes closely physical mixtures formed under high temperature and high pressure.

[0026] In the usage of this specification, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for contact with mammalian, especially human, tissues within the scope of sound medical judgment, with a reasonable benefit / risk ratio and without excessive toxicity, irritation, allergic responses, and other problem complications.

[0027] In the usage of this specification, the term "therapeutic compound" means any compound, substance, drug, agent, or active ingredient having a therapeutic or pharmacological effect in a composition suitable for oral administration, which is a composition particularly suitable for administration to mammals, such as humans. Particularly useful as therapeutic compounds in the present invention are ruxolitinib and its pharmaceutically acceptable salts.

[0028] In the usage of this specification, the term "ruxolitinib" refers to the free base of ruxolitinib or its pharmaceutically acceptable salts (e.g., ruxolitinib phosphate).

[0029] In an exemplary embodiment, the oral formulation contains ruxolitinib phosphate.

[0030] In another embodiment, the oral formulation comprises one or more preservatives. The preservatives may be antimicrobial preservatives, either alone or in combination. The preservatives may be selected from the group consisting of potassium sorbate, sodium benzoate, methylparaben, and propylparaben.

[0031] In one particular embodiment, the preservative is a mixture of methylparaben and propylparaben.

[0032] The ratio of methylparaben to propylparaben in the preservative mixture can vary from 3:1 to 1:9 (by weight).

[0033] The concentration range of preservatives in the formulation is approximately 0.1 mg / mL to 5 mg / mL. For example, the concentration of the preservative methylparaben is approximately 1.2 to 1.3 mg / mL, and the concentration of propylparaben is 0.3 to 0.5 mg / mL.

[0034] In another embodiment, the oral formulation comprises one or more cosolvents. The cosolvents may be selected from the group consisting of ethanol, glycerol, propylene glycol, and polyethylene glycol.

[0035] In one particular embodiment, the cosolvent is propylene glycol.

[0036] The concentration range of the co-solvent in the formulation is approximately 50 mg / mL to 300 mg / mL. For example, the co-solvent concentration is approximately 100 to 200 mg / mL, more specifically, 150 mg / mL.

[0037] In another embodiment, the oral formulation includes one or more sweeteners to mask the unpleasant sensory properties of the drug or excipient. The sweeteners may be selected from the group consisting of sucrose, sucralose, aspartame, acesulfame, potassium saccharin, and sodium saccharin.

[0038] In one particular embodiment, the sweetener is sucralose.

[0039] The concentration range of sweeteners in the formulation is approximately 0.5 mg / mL to 6 mg / mL. For example, the concentration of sweetener is approximately 1 to 3 mg / mL, more specifically 2 mg / mL.

[0040] In another embodiment, the oral formulation includes one or more flavorings to mask the unpleasant sensory properties of the drug or excipient. The flavorings may be selected from the group consisting of flavors such as banana, chocolate, orange, cherry, strawberry, blueberry, and tutti frutti.

[0041] In one particular embodiment, the flavoring agent is strawberry flavor.

[0042] The concentration range of flavorings in the formulation is approximately 0.5 mg / mL to 5 mg / mL. For example, the concentration of strawberry flavor is approximately 1 to 4 mg / mL, more specifically 2.5 mg / mL.

[0043] In another embodiment, the oral formulation comprises one or more pH adjusters. The pH adjusters may be selected from the group consisting of citric acid, fumaric acid, lactic acid, phosphoric acid, tartaric acid, and succinic acid.

[0044] In one particular embodiment, the pH adjusting agent is citric acid.

[0045] The concentration range of the pH adjusting agent in the formulation is approximately 2 mg / mL to 8 mg / mL. For example, the range of the pH adjusting agent is approximately 4 to 5 mg / mL, specifically about 4.27 mg / mL.

[0046] In another embodiment, the pH level of the oral formulation is in the range of approximately 2 to 4, specifically approximately 2.7 ± 0.5.

[0047] In another embodiment, the concentration of ruxolitinib (free base) in the oral formulation is about 0.1 mg / mL to about 10 mg / mL, preferably about 1 mg / mL to 6 mg / mL, and most preferably about 1 mg / mL to 5 mg / mL.

[0048] method Another aspect of the present invention relates to a method for treating a JAK-related disease or disorder in an individual (e.g., a patient) by administering an oral liquid formulation of the present invention to an individual requiring such treatment. JAK-related diseases may include any disease, disorder or condition that is directly or indirectly related to the expression or activity of JAK, including overexpression and / or abnormal activity levels. JAK-related diseases may also include any disease, disorder or condition that can be prevented, improved or cured by regulating JAK activity.

[0049] In further embodiments, JAK-related diseases are cancers characterized by solid tumors (e.g., prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman disease, uterine leiomyosarcoma, melanoma, etc.), hematological cancers (e.g., lymphoma; leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), etc.; or multiple myeloma), and skin cancers such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Examples of CTCL include Sézary syndrome and mycosis fungoides.

[0050] JAK-related disorders may further include myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), and systemic mastocytosis (SMCD). In some embodiments, the myeloproliferative disorder is myelofibrosis (e.g., primary myelofibrosis (PMF) or post-PV / ET MF). In some embodiments, the myeloproliferative disorder is post-ET MF. In some embodiments, the myeloproliferative disorder is post-PV MF.

[0051] JAK-related diseases may further include graft-versus-host diseases (GvHD), such as acute graft-versus-host disease (aGvHD) and chronic graft-versus-host disease (cGvHD). [Examples]

[0052] The following examples illustrate aspects of the present invention and do not limit it. Formulations for preparing oral solutions are described below.

[0053] Example 1: Stable pediatric oral solution formulation at a concentration of 5 mg / mL

[0054] [Table 1]

[0055] This stable oral solution for children (Table 1) has been developed, with a current shelf life of 12 months at room temperature, which may be extended as additional stability data becomes available. Ruxolitinibulinate tends to form cocrystals with the preservative sodium benzoate. The combination of methylparaben and propylparaben as preservatives has been found to be acceptable in this oral solution formulation. The manufacturing process is a simple mixing process with several mixing substeps to dissolve the components before mixing, and no special processes or techniques are required. The taste of the active pharmaceutical ingredient is largely masked by the use of the sweetener sucralose and a flavor such as strawberry flavor. The excipients in the formulation and their levels are acceptable from a safety standpoint for children from 1 month of age to 18 years of age.

[0056] Example 2: Key characteristic data demonstrating technological advantages and / or unexpected effects Developing a stable and palatable oral formulation of ruxolitinib is challenging due to the pH-dependent solubility of the active pharmaceutical ingredient (see Table 2), which is primarily accompanied by oxidative degradation products under high temperatures, high moisture content, and / or the presence of oxygen. As shown in Table 2 below, ruxolitinib phosphate exhibits pH-dependent solubility in aqueous media.

[0057] [Table 2]

[0058] To maintain the drug in solution (1 and 5 mg / mL), citric acid was selected as a palatable pH adjuster. To maintain the pH of the drug in the solution at 2.7 ± 0.3, 0.43% citric acid was selected as the pH adjuster.

[0059] The initial formulation was subjected to forced degradation, and the degradation profile of the solution was investigated. Forced degradation was carried out using acid (0.1N HCl), base (0.1N NaOH), high temperature such as 60°C, and oxidation (3% H2O2) as the main parameters. The levels of the two major degradation products, 521-11 and 536-11, increased (Table 3).

[0060] The structure of 521-11 is, [ka] That is the case.

[0061] The structure of 536-11 is, [ka] That is the case.

[0062] [Table 3]

[0063] Stability data was created for two different filling amounts of the 5 mg / mL oral solution formulation (60 mL filled in a 125 mL bottle and 140 mL filled in a 300 mL bottle), and it was confirmed to be acceptable (Table 4).

[0064] [Table 4]

[0065] The oral solution (5 mg / mL) was confirmed to have a simple manufacturing process, a safe taste level for the excipients, and stability at room temperature.

[0066] Example 3: A Phase I / II open-label, single-arm, multicenter trial of ruxolitinib in addition to corticosteroids in pediatric patients with Grade II-IV acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. the purpose: The pathophysiology of acute graft-versus-host disease (aGvHD) begins with the activation of host APCs, which then present host antigens to donor immune cells, leading to donor T cell proliferation and the production of inflammatory cytokines. These inflammatory cytokines then recruit additional immune effector cells to induce proliferation, thereby perpetuating a vicious cycle of alloreactive tissue damage and inflammation (Paczesny et al 2010). Ruxolitinib has been shown to reduce pro-inflammatory cytokines in MF patients. Furthermore, preclinical data support the following mechanisms of action of ruxolitinib in GvHD: i) impaired APC function, ii) inhibiting donor T cell proliferation, iii) suppressing the production of harmful cytokines, and iv) improving survival and disease manifestation in GvHD mouse models (Parampalli Yajnanarayana et al 2015, Heine et al 2013, Spoerl et al 2014). Furthermore, recently published data provide evidence of the clinical efficacy of adding ruxolitinib treatment to immunosuppressive therapy in patients with SR-aGvHD (Zeiser et al 2015; Spoerl et al 2014). Clinical studies using ruxolitinib alone or in comparison to the best available treatments are currently underway in SR-aGvHD settings in adult patients and some adolescents aged 12 years and older.

[0067] Although children have a lower risk of developing aGvHD than adults, this risk remains significant, especially when using alternative donor sources (Jacobsohn and Vogelsang 2007). Similar to adults, treatment options for grade II–IV aGvHD are limited, and systemic corticosteroids are used as the standard initial treatment for pediatric patients. Since only 30–50% of children respond to corticosteroids, there is a high unmet medical need for optimal initial and second-line treatments in the pediatric population. Recent data on ruxolitinib in pediatric patients with SR-aGvHD show a promising overall response rate compared to corticosteroids + / - CNI alone. Given this data (presented above) in the current context of a lack of effective first- or second-line treatments for pediatric aGvHD, this study aims to evaluate the safety, activity, and pharmacokinetics of ruxolitinib in combination with corticosteroids in untreated SR-aGvHD patients aged 28 days to under 18 years. Ruxolitinib is expected to provide a higher disease response rate compared to steroids + / - CNI monotherapy as a prior treatment for grade II–IV aGvHD. This response is further expected to persist during steroid tapering, representing a meaningful clinical benefit for patients.

[0068] Furthermore, untreated patients may benefit from steroid-saving effects due to the risks associated with long-term steroid exposure and the toxic effects of steroids observed in children. Considering that untreated patients have not received extensive prior treatment for their underlying condition compared to adults, the expected mechanism of action and safety profile of ruxolitinib are similar in both untreated patients and SR-aGvHD.

[0069] Expected significant clinical benefits in patients treated with ruxolitinib include its steroid-saving effect, a reduced rate of patients experiencing relapse during steroid tapering, a reduced rate and severity of infections, shorter hospital stays and fewer readmissions, maintenance of graft-versus-tumor efficacy, and a potential reduction in the rate of patients developing cGvHD.

[0070] Objectives and evaluation items

[0071] [Table 5]

[0072] [Table 6]

[0073] Research design This open-label, single-arm, phase I / II, multicenter study will investigate the pharmacokinetics, activity, and safety of adding ruxolitinib to the immunosuppressive regimen of infants, children, and adolescents aged 28 days or older but under 18 years with grade II-IV aGvHD or grade II-IV SR-aGvHD. The trial will utilize the following age groups: Group 1 (12 years or older but under 18 years), Group 2 (6 years or older but under 12 years), Group 3 (2 years or older but under 6 years), and Group 4 (28 days or older but under 2 years). Patients will remain in their age group based on their age at treatment initiation throughout the study. Enrollment in the youngest age group, Group 4 (phase I / II), will be decided by the sponsor after consultation with the Data Monitoring Committee (DMC) and the Pediatric Committee (PDCO), and after reviewing available pharmacokinetic, safety, and activity data.

[0074] All patients will be enrolled and treated for 24 weeks (approximately 6 months) or until early discontinuation. All patients will be followed for a further 18 months (total period = 2 years from enrollment). If treatment needs to be resumed due to aGvHD relapse, or if ruxolitinib is not discontinued by the end of 24 weeks due to prolonged tapering, patients may continue tapering ruxolitinib beyond 24 weeks for up to 48 weeks. Patients aged 12 to under 18 years (Group 1) have already been enrolled in the trial [CRUXOLITINIBC2301] and are being treated with 10 mg BID; therefore, this dose is the recommended dose for Phase II (RP2D) and will be used to treat all patients. In Phase II, all other age groups will be treated with the RP2D determined in Phase I. Therefore, all patients aged 12 to under 18 years will be automatically enrolled in Phase II. The first five patients treated in Group 1 are planned to undergo extensive PK sampling to inform the RP2D determination for the younger age groups in Phase I. If one or more of the initial five patients are unsuitable for evaluation, additional patients may undergo larger sampling.

[0075] Phase I Patients will be enrolled in four groups based on age, and appropriate medication will be prescribed based on the available data in Table 2. ●Phase I (Figure 1): For groups 2, 3, and 4, complete concentration-time course, safety, and activity data for ruxolitinib will be collected over 28 days. Groups 2 and 3 will be enrolled first, and the PK data generated from all patients (including group 1) will be used to provide information on the starting dose for group 4. Therefore, group 4 will only be opened after the RP2D for group 2 and the RP2D for group 3 have been defined. ●PK and safety data will be used to assess the appropriateness of the preliminary starting dose, which may be adjusted as needed (i.e., to take into account potential differences between expected ruxolitinib exposure and observed ruxolitinib exposure). ● If exposure in group 2, 3, or 4 is not confirmed after PK sampling in 5 evaluable patients, an additional 5 patients will be enrolled in that specific age group until dose / exposure is confirmed (i.e., selection of RP2D for age based on exposure and safety review by the DMC).

[0076] [Table 7]

[0077] Inclusion criteria To participate in this study, you must meet all of the following criteria: 1. Male or female patients who are 28 days old or older but under 18 years old at the time of informed consent. 2. Patients who have previously undergone alloSCT using bone marrow, peripheral blood stem cells, or umbilical cord blood from any donor source (compatible unrelated donor, sibling, haploidentical). Recipients of myeloablative or reduced-strength habituation are eligible. 3. Patients who have been clinically diagnosed with Grade II–IV aGvHD within 48 hours prior to the start of the investigational treatment. Patients may have one of the following: Untreated grade II-IV aGvHD according to Harris et al 2016. or Patients with aGvHD of grade II-IV steroid refractory according to facility standards, who are currently receiving systemic corticosteroid therapy. 4. Clear bone marrow engraftment with an absolute neutrophil count (ANC) exceeding 1,000 / μl and a platelet count exceeding 20,000 / μl. (Use of growth factor supplements and blood transfusion support is permitted). 5. The patient can swallow the investigational drug. 6. Written informed consent and / or acceptance from the patient, parent or guardian at the time of screening, i.e., when diagnosed with untreated aGvHD or steroid-refractory aGvHD.

[0078] Exclusion criteria Individuals who meet any of the following criteria are ineligible to participate in this study. 1. Have you received the following systemic therapies for aGvHD? a. Untreated aGvHD patients who have previously received systemic treatment for aGvHD, except for those who received up to 72 hours of methylprednisolone or equivalent systemic corticosteroid therapy after the onset of acute GvHD. Patients are permitted to have received prior GvHD prophylaxis that does not count as systemic treatment (as long as the prophylaxis was initiated before the diagnosis of aGvHD); or b. SR-aGvHD patients who have received two or more systemic treatments for aGvHD in addition to corticosteroids. 2. Clinical symptoms resembling novel chronic GvHD or GvHD duplication syndrome, possessing both acute and chronic GvHD characteristics (as defined by Jagasia et al 2015). 3. I have had a failed allo-SCT within the past 6 months. 4. The presence of a clinically active, poorly managed infection, including a significant bacterial, fungal, viral, or parasitic infection requiring treatment. If appropriate treatment is initiated and there are no signs of progression at the time of screening, the infection is considered controlled. Progression of an infection is defined as sepsis attributable to the infection, new symptoms, worsening of physical signs, or hemodynamic instability attributable to radiographic findings. Persistent fever without other signs or symptoms is not interpreted as an ongoing infection. 5. Evidence of poorly managed hepatitis B virus (HBV) or hepatitis C virus (HCV) is based on the attending physician's assessment. 6. Clinical evidence of active tuberculosis (clinical diagnosis by a local clinic; skin examination is not necessary as it is not informative due to anergy). 7. Known human immunodeficiency virus infections (HIV). 8. Individuals with a recurrent primary malignant tumor, or those who have received treatment for recurrence after allo-SCT, or those who require discontinuation of immunosuppression as a pre-treatment for early recurrence of malignant tumor. 9. Acute GvHD occurring after unplanned DLI administered for preemptive treatment of malignant tumor recurrence. Note: Patients who received planned DLI as part of a transplant procedure, rather than for the management of malignant tumor recurrence, are eligible. 10. Patients using mechanical ventilation, or patients with resting oxygen saturation levels below 90% as measured by pulse oximetry of indoor air, and other serious respiratory diseases. 11. The presence of severe renal impairment as defined below (confirmed within 72 hours prior to the start of the study treatment): ● Glomerular filtration rate (GFR) of less than 30 mL / min / 1.73 m2, using estimated creatinine clearance calculated at the bedside using the Schwartz or Cockroft-Gault formula. or ● The necessity of kidney dialysis 12. Clinically significant or poorly managed cardiac conditions, including any of the following: ● Acute myocardial infarction within 6 months from the first day of administration of the clinical trial treatment. ● Poorly managed hypertension ● New York Heart Association Class III or IV congestive heart failure ● Unstable angina within the past 6 months from the screening ● Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third-degree atrioventricular block without a pacemaker, circulatory collapse requiring support from vasopressors or inotropic agents, or arrhythmias requiring treatment). 13. Biliary stasis disorder, or unresolved sinusoidal obstruction syndrome / venous obstructive disease of the liver (defined as persistent bilirubin abnormalities and progressive organ dysfunction not attributable to aGvHD). 14. A history of bone disorders such as osteogenesis imperfecta, rickets, renal osteodystrophy, osteomyelitis, osteopenia, fibrous dysplasia, or osteomalacia, preceding the underlying diagnosis that led to allo-SCT. 15. A history of endocrine or renal-related growth retardation prior to the underlying diagnosis that led to alloSCT. 16. Corticosteroid therapy at doses exceeding 1 mg / kg / day (or equivalent prednisone dose of 1.25 mg / kg / day) for indications other than aGvHD within 7 days of screening. Routine corticosteroid administration during acclimatization or cell infusion is acceptable. 17. Current treatment with drugs that interfere with coagulation or platelet function, including but not limited to aspirin and related drugs, heparin, and warfarin (to minimize the risk of bleeding). Note: Heparin or low molecular weight heparin (LMWH) is acceptable when used at or below therapeutic doses, for example, for the prevention of sinusoidal obstructive syndrome / hepatic venous obstructive disease. 18. History of progressive multifocal leukoencephalopathy (PML). 19. Patients who have received JAK inhibitor therapy for any indication after the initiation of current allo-SCT habituation. 20. Investigational treatment within 30 days prior to the start of treatment or within 5 half-lives of the investigational drug, whichever is longer. 21. Any condition that, at the discretion of the principal investigator, prevents full participation in the study, including but not limited to, managing the trial treatment and participation in necessary trial sessions; posing a significant risk to the patient; or interfering with the interpretation of research data. 22. Known allergies, hypersensitivity, or intolerance to systemic immunosuppressive therapy or ruxolitinib (or any of its excipients). 23. Pregnant or breastfeeding female patients. 24. Female patients who do not consent to abstinence, or who do not consent to the use of contraception if they are sexually active, and who may be pregnant (e.g., during menstruation).

[0079] Clinical trial treatment The investigational treatment will be administered to all patients twice daily as a 5 mg tablet or as an oral pediatric formulation (taken in liquid form). ●Untreated aGvHD: In addition to ruxolitinib, treatment should include methylprednisolone (or equivalent prednisone) + / - cyclosporine or tacrolimus at a standard dose adjusted to the therapeutic trough level. ●SR-aGVHD: In addition to ruxolitinib, the concomitant use of corticosteroids + / - cyclosporine or tacrolimus at standard doses adjusted to therapeutic trough levels is acceptable.

[0080] In addition to the investigational treatment, patients may receive standard allo-SCT supportive care, including anti-infective drugs and fluid support. Continued use of systemic corticosteroids, CNIs (cyclosporine or tacrolimus), and topical corticosteroid therapy is permitted according to institutional guidelines. Other systemic medications used for the prevention of aGvHD may be continued beyond day 1, only if aGvHD has not yet been diagnosed. In SR-aGvHD patients, discontinuation of other systemic treatments for aGvHD, other than corticosteroids + / - CNIs, is required before initiating treatment.

[0081] [Table 8]

[0082] The principal investigator instructs the patient to receive the investigational treatment according to the protocol.

[0083] All dosages prescribed and dispensed to patients, as well as all dosage changes during the study, must be recorded in the medication management record (CRF) case report form.

[0084] Ruxolitinib is administered orally twice daily at an age-assigned starting dose, given as an equivalent dose in the form of a 5 mg tablet or oral pediatric formulation. Ruxolitinib (tablet or oral pediatric formulation) must be taken approximately 12 hours apart (morning and evening), regardless of meals. Ruxolitinib is administered by hospital staff in an inpatient setting or by the patient themselves in an outpatient setting.

[0085] Patients must be instructed not to take any investigational treatment at home on the scheduled date for pre-administration blood collection. Administration will be performed after pre-administration blood is collected during these visits.

[0086] Even if a patient moves to the next age group during the treatment period, the starting dose assigned on day 1 based on age will not increase.

[0087] Example 4: A Phase II open-label, single-arm, multicenter study in which ruxolitinib was added to corticosteroids in pediatric patients with moderate to severe chronic graft-versus-host disease after allogeneic stem cell transplantation. the purpose: The pathophysiology of chronic graft-versus-host disease (cGvHD) begins with the activation of host antigen-presenting cells (APCs) expressed by damaged tissue and / or pathogens (Dhir et al 2014). Activated host APCs present host antigens to donor immune cells, triggering donor T cell proliferation and inflammatory cytokine production. These inflammatory cytokines then recruit additional immune effector cells to promote proliferation, thereby perpetuating a vicious cycle of alloreactive tissue damage and inflammation (Paczesny et al 2010). This signaling cascade in cGvHD, as observed in mouse models and adult subjects with cGvHD, is expected to be the same in children under 12 years of age compared to subjects 12 years of age and older. Ruxolitinib has been shown to reduce pro-inflammatory cytokines in MF patients. Furthermore, preclinical data support the following mechanisms of action of ruxolitinib in GvHD: i) impaired APC function, ii) inhibiting donor T cell proliferation, iii) suppressing harmful cytokine production, and iv) improving survival and disease manifestation in GvHD mouse models (Parampalli Yajnanarayana et al 2015) (Heine et al 2013) (Spoerl et al 2014). Published data provide evidence of the clinical efficacy of adding ruxolitinib treatment to immunosuppressive therapy in subjects with SR-cGvHD (Zeiser et al 2015) (Boiko et al 2017).

[0088] Clinical studies using ruxolitinib alone or in comparison to the best available treatments are currently underway in SR-cGvHD settings in adults and adolescents aged 12 years and older. Despite children having a lower risk of developing cGvHD than adults (Baird et al 2010), the incidence of cGvHD in the pediatric population is substantial and has recently increased in connection with the expanded use of peripheral blood stem cells and unrelated donors (Zecca et al 2002). Treatment for moderate to severe cGvHD in pediatrics is highly diverse and largely extrapolated from adult experience. While there is no proven “standard of care,” corticosteroids and calcineurin inhibitors (CNIs) are commonly employed as frontline treatments.

[0089] Similar to adults, treatment options for moderate to severe cGvHD are limited, including systemic corticosteroids as the initial standard of care for pediatric patients. Since only 30%–50% of children respond to corticosteroid use, there is a high unmet medical need for optimal initial and second-line treatments in the pediatric population (Wolff et al 2011). Furthermore, children who respond to initial immunosuppressive therapy, which is almost always corticosteroids, require it for extended periods, resulting in debilitating, persistent, and irreversible effects on overall health and quality of life (Fraser et al 2006).

[0090] Based on the available data (above), and given the current lack of effective first-line or second-line treatments for pediatric cGvHD, this study aims to evaluate the pharmacokinetics, safety, and activity of ruxolitinib treatment in pediatric subjects (28 days of age or older to under 18 years of age) with untreated cGvHD or SR-cGvHD. Ruxolitinib is expected to provide a higher disease response rate compared to steroid-+ / - calcineurin inhibitors (CNIs) alone as a prior treatment for moderate to severe cGvHD. This response is further expected to persist during steroid tapering, representing a meaningful clinical benefit for pediatric subjects. Meaningful clinical benefits expected in patients treated with ruxolitinib include its steroid-saving effect, a reduced proportion of pediatric subjects experiencing relapse during steroid tapering, a reduced proportion and severity of infections, reduced length of hospital stay and need for readmission, and maintenance of graft-versus-malignancy efficacy.

[0091] Objectives and evaluation items

[0092] [Table 9]

[0093] [Table 10]

[0094] Research design This open-label, single-arm, phase II, multicenter study will investigate the activity, pharmacokinetics, and safety of ruxolitinib added to the immunosuppressive regimen of infants, children, and adolescents aged 28 days or older but under 18 years of age with moderate to severe, previously untreated cGvHD or SR-cGvHD. Approximately 42 subjects will be enrolled in this study. Subjects will be grouped by age as follows: Group 1, including subjects aged 12 to under 18 years; Group 2, including subjects aged 6 to under 12 years; Group 3, including subjects aged 2 to under 6 years; and Group 4, including subjects aged ≥28 days to under 2 years. Subjects will remain in their age group based on their age at treatment initiation throughout the study. Enrollment of the youngest age group, Group 4, will be initiated in consultation with the Data Monitoring Committee (DMC), after reviewing data available for this age group from Trial Example 3, as well as available PK, safety, and activity data generated from Groups 1-3 of this study, and subject to the final decision by the sponsor. For the primary analysis of groups 1, 2, and 3, at least five evaluable subjects are required per group. For group 4, there is no minimum number of evaluable subjects required.

[0095] After a screening period from day -28 to day -1, eligible subjects will begin investigational treatment (ruxolitinib) on day 1 of cycle 1 and will be treated for a maximum of 3 years (39 cycles / 156 weeks) or until early discontinuation. Subjects who discontinue ruxolitinib for any reason before 39 cycles will be followed up every 6 months until 3 years have passed since the first dose of ruxolitinib. All subjects who continue to benefit from ruxolitinib treatment after 3 years of treatment will be given the possibility of continuing ruxolitinib outside of the study from another source, if permitted in accordance with local regulations.

[0096] The dosage of ruxolitinib is based on preliminary efficacy and safety data generated at this dose in patients with steroid-resistant graft-versus-host disease (SR-GvHD) (Zeiser et al 2015), and is based on PK / safety data generated from the Phase III clinical trials CRUXOLITINIBC2301 and CRUXOLITINIBD2301. Since patients aged 12 to under 18 years have already been treated with 10 mg BID in CRUXOLITINIBD2301, this dose is the recommended Phase II dose (RP2D) and will be used to treat all patients in this age group.

[0097] Pediatric subjects enrolled in the pediatric aGvHD study of Example 3 will provide PK data to be used to confirm the validity of the above doses, and therefore patients under 12 years of age will be enrolled only in groups 2-4 of this study once the dose has been confirmed in the appropriate age group. If a different dose is confirmed in the pediatric aGvHD study of Example 3, the dose must be adjusted accordingly in this study. Subjects enrolled in the adult aGvHD study and cGvHD study may also provide PK data to be used as additional information to confirm the validity of this dose.

[0098] The research design is shown in Figure 2.

[0099] Inclusion criteria To participate in this study, you must meet all of the following criteria: 1. Applicable to males or females aged 28 or older but under 18 years of age at the time of informed consent. 2. Subjects who have undergone successful alloSCT using bone marrow, peripheral blood stem cells, or umbilical cord blood from any donor source (compatible unrelated donor, sibling, haploidentical). Recipients of myeloablative or reduced-strength habituation are eligible. 3. Subjects diagnosed with moderate to severe cGvHD on day 1 of cycle 1, according to the NIH 2014 consensus criteria. Other possible diagnoses of clinical symptoms supporting the cGvHD diagnosis (e.g., infection, drug side effects, malignancy) must be excluded. Subjects must meet one of the following criteria: ● Untreated cGvHD patients who have not received prior systemic treatment for cGvHD, except for systemic methylprednisolone or equivalent corticosteroid therapy for up to 72 hours after the onset of chronic GvHD. Patients who have received prior systemic treatment for cGvHD prevention are acceptable (as long as the prophylactic treatment was initiated before the diagnosis of cGvHD). or ● Patients with moderate to severe cGvHD who are steroid-resistant according to facility standards and who have still been receiving systemic corticosteroids for the treatment of cGvHD during a period of less than 18 months prior to day 1 of cycle 1. If corticosteroids were discontinued due to a response, the period of less than 18 months applies to the last period of corticosteroid use. 4. The patient can swallow the investigational drug. 5. Written informed consent (and, where appropriate, approval) of the research from the subject and / or parent / legal guardian.

[0100] Exclusion criteria Individuals who meet any of the following criteria are ineligible to participate in this study. 1. SR-cGvHD subjects who have previously received cGvHD treatment with JAK1, JAK2, or JAK1 / 2 inhibitors are not accepted unless the subject has achieved complete or partial remission and has discontinued JAK inhibitor treatment at least four weeks prior to day 1 of cycle 1, or up to five times the half-life of the previous JAK inhibitor, whichever is longer. 2. Patients who initiated a systemic calcineurin inhibitor (CNI; cyclosporine or tacrolimus) within three weeks prior to initiating ruxolitinib on day 1 of cycle 1. Note: If initiated more than three weeks after ruxolitinib initiation, a systemic CNI is acceptable. 3. Patients who have experienced allo-SCT failure within the past six months; patients with recurrent primary malignant tumors, or who have received treatment for recurrence after allo-SCT, or who require discontinuation of immunosuppression as prior treatment for early malignant tumor recurrence. 4. Patients using mechanical ventilation, or those with serious respiratory diseases, including patients with resting oxygen saturation levels below 90% as measured by pulse oximetry of indoor air. 5. Gastrointestinal (GI) dysfunction (unrelated to GvHD) or gastrointestinal disorders (unrelated to GvHD) that may significantly alter the absorption of oral ruxolitinib (e.g., ulcerative disease, poorly controlled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). 6. Biliary stasis disorder, or unresolved sinusoidal obstruction syndrome / venous obstruction of the liver (defined as persistent bilirubin abnormalities and progressive organ dysfunction not attributable to cGvHD). 7. The presence of a clinically active, poorly managed infection, including a significant bacterial, fungal, viral, or parasitic infection requiring treatment. An infection is considered controlled if appropriate treatment is initiated and there are no signs of progression at the time of screening. Progression of an infection is defined as sepsis attributable to the infection, new symptoms, worsening of physical signs, or hemodynamic instability attributable to radiographic findings. Persistent fever without other signs or symptoms is not interpreted as an ongoing infection. 8. Known human immunodeficiency virus (HIV) infection. 9. Evidence of poorly controlled hepatitis B virus (HBV) or hepatitis C virus (HCV), based on an assessment conducted by the principal investigator or their representative. 10. cGvHD occurring after unplanned donor lymphocyte infusion (DLI) administered for preemptive treatment of recurrent malignant tumor. Subjects who received DLI as part of a transplant procedure, rather than for the management of recurrent malignant tumor, are eligible. 11. Any condition that, at the discretion of the principal investigator, prevents full participation in the study, including but not limited to, the management of the investigational drug and participation in necessary clinical trial sessions; posing a significant risk to the subject; or interfering with the interpretation of research data. 12. Known allergies, hypersensitivity, or intolerance to the investigational drug, excipient, or similar compound. 13. A history of bone disorders such as osteogenesis imperfecta, rickets, renal osteodystrophy, osteomyelitis, osteopenia, fibrous dysplasia, or osteomalacia, preceding the underlying diagnosis that led to allo-SCT. 14. A history of endocrine or renal-related growth retardation prior to the underlying diagnosis that led to alloSCT. 15. For adolescent women who are pregnant or breastfeeding. 16. For women who do not agree to abstinence, or who, if sexually active, do not agree to the use of highly effective contraception, and who may become pregnant (e.g., during menstruation). 17. Clinical evidence of active tuberculosis (clinical diagnosis by a local clinic) 18. Corticosteroid hormone therapy at doses exceeding 1 mg / kg / day of methylprednisolone (or equivalent prednisone at 1.25 mg / kg / day) for indications other than cGvHD, within 7 days of screening. 19. Current treatment with drugs that interfere with coagulation or platelet function, including but not limited to aspirin and related drugs, heparin, and warfarin (to minimize the risk of bleeding). Note: Heparin or low molecular weight heparin (LMWH) is acceptable when used at or below therapeutic doses, for example, for the prevention of sinusoidal obstructive syndrome / hepatic venous obstructive disease. 20. Patients receiving fluconazole at a dose of 200 mg or more daily. 21. Subjects currently receiving herbal preparations / herbal medicines and who have not consented to discontinuing them. These herbal medicines include, but are not limited to, St. John's wort, birch, ephedra, ginkgo, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and Korean ginseng. Subjects must discontinue the use of herbal medicines at least 7 days before the first dose of the research treatment. 22. History of progressive multifocal leukoencephalopathy (PML). 23. Investigational treatment within 30 days prior to the start of treatment or within 5 half-lives of the investigational drug, whichever is longer. 24. Presence of severe renal impairment (confirmed within 72 hours prior to initiating ruxolitinib): ●Glomerular filtration rate (GFR) of less than 30 mL / min / 1.73m2, using estimated creatinine clearance calculated at the bedside using the Schwartz or Cockroft-Gault formula. or ● The necessity of kidney dialysis 25. Severe comorbidities as determined by the principal investigator. 26. Average life expectancy of less than one month, as determined by the principal investigator. 27. Clinically significant or poorly managed cardiac conditions, including any of the following: ● Acute myocardial infarction within 6 months of ruxolitinib administration on day 1 of cycle 1 ● Poorly managed hypertension ● New York Heart Association Class III or IV congestive heart failure ● Unstable angina within the past 6 months from the screening ● Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third-degree atrioventricular block without a pacemaker, circulatory collapse requiring support from vasopressors or inotropic agents, or arrhythmias requiring treatment).

[0101] treatment Clinical trial treatments include the following: ● Clinical trial treatment ● Regarding ruxolitinib (investigational drug) ●Other clinical trial treatments: ● Regarding the concomitant use of corticosteroids for the treatment of untreated cGvHD or SR-cGvHD Ruxolitinib is administered twice daily as 5 mg ruxolitinib tablets or as an oral pediatric formulation of ruxolitinib. ●Untreated cGvHD: In addition to ruxolitinib, treatment must include methylprednisolone (or equivalent prednisone). ●SR-cGvHD: In addition to ruxolitinib, the concomitant use of corticosteroids is permitted.

[0102] In addition to the investigational treatment, participants may receive standard allo-SCT supportive care, including anti-infective drugs and fluid support.

[0103] If initiated before a diagnosis of cGvHD, systemic immunosuppressants used to prevent cGvHD may be continued beyond day 1 of cycle 1. Systemic CNI may be continued beyond day 1 of cycle 1 if initiated at least three weeks before ruxolitinib initiation, i.e., on day 1 of cycle 1. CNI should be used at standard doses and adjusted to therapeutic trough levels. Continued use of topical corticosteroid therapy for cGvHD is permitted according to institutional guidelines. In patients with SR-cGvHD, discontinuation of other systemic treatments for cGvHD, other than corticosteroid + / - CNI, is required before initiating ruxolitinib.

[0104] [Table 11]

[0105] The principal investigator instructs the subjects to receive the investigational treatment according to the protocol.

[0106] All prescribed and dispensed doses to subjects, as well as all dose changes during the study, must be recorded in the Electronic Medication Management Record (CRF).

[0107] Ruxolitinib is administered orally twice daily in age-group-assigned doses, given as an equivalent dose in the form of 5 mg tablets or an oral pediatric formulation. Ruxolitinib (tablets or oral pediatric formulation) must be taken approximately 12 hours apart (morning and evening), regardless of meals. Ruxolitinib is administered by the principal investigator or representative, or self-administered by the subject or parent / guardian in an outpatient setting.

[0108] Patients must be instructed not to take ruxolitinib at home on days when pre-administration blood collection for PK and biomarker samples is scheduled. Administration will be performed after pre-administration blood collection during these visits.

[0109] The age-based dose of ruxolitinib assigned on day 1 of cycle 1 must not be changed until the subject completes the visit assessment on day 1 of cycle 7. After day 1 of cycle 7, the principal investigator must re-evaluate the assigned dose of ruxolitinib based on the subject's age and / or growth. If the newly calculated dose changes by more than 10% from the previously calculated dose, the growth-based dose must be adjusted. All dose changes must be recorded in the electronic case report form (eCRF) of the medication management record.

[0110] Example 5: Stable pediatric oral solution formulation at a concentration of 1 mg / mL

[0111] [Table 12]

[0112] Example 6: Stability Results A.Purpose This example includes the following stability data: Technical batch variant 001 of ruxolitinib 1 mg / mL and 5 mg / mL solutions covers a shelf life of up to 6 months, while technical batch variant 002 of ruxolitinib 5 mg / mL (891147, 891148) covers stability data up to 24 months.

[0113] The stability data for clinical variant 002 of ruxolitinib 5 mg / mL solution (891147) covers data up to 12 months of storage, 42 days of use testing, and up to 28 days of freeze-thaw testing.

[0114] The technical batches studied are listed in Table 14, and the clinical batch studies are listed in Table 28. Ruxolitinib is a BCS class I compound. This solution formulation is a water-based solution of ruxolitinib containing / without sucrose and containing common preservatives and flavors.

[0115] Development stability report DSR2810(5.0) applies to the technical and clinical batches of ruxolitinib 1 mg / mL and 5 mg / mL solution formulations.

[0116] [Table 13]

[0117] [Table 14]

[0118] [Table 15]

[0119] B. Specifications of pharmaceuticals The analytical standards are specified in this clinical development standard AS2810.

[0120] C. Stability Test Packaging description

[0121] [Table 16]

[0122] Tested batches and stability programs

[0123] [Table 17]

[0124] [Table 18]

[0125] Table 19

[0126] Table 20

[0127] Table 21

[0128] Table 22

[0129] Table 23

[0130] Table 24

[0131] Table 25

[0132] Table 26

[0133] Table 27

[0134] Table 28

[0135] [Table 29]

[0136] [Table 30]

[0137] [Table 31]

[0138] [Table 32]

[0139] [Table 33]

[0140] [Table 34]

[0141] [Table 35]

[0142] [Table 36]

[0143] [Table 37]

[0144] [Table 38]

[0145] Special Test Freeze-thaw cycle test This test was performed with one clinical batch (5 mg / mL, batch: 2034827) packaged in a BO_300_AMBER_CR_CLOSURE container. Stability samples were stored for four complete freeze-thaw cycles (6 days at -20°C / ambient RH, followed by 1 day at 25°C / 60% RH). Samples were collected and analyzed after 28 days. The results of the freeze-thaw cycle test for the 5 mg / mL (140 mL) BO_300_AMBER_CR_CLOSURE container are considered to represent the worst-case scenario (large headspace) and apply to the 5 mg / mL (60 mL) BO_125_AMBER_CR_CLOSURE container as well.

[0146] Test during use This study was conducted using one technical batch (5 mg / mL, batch H0004) packaged in a BO_125_AMBER_CR_CLOSURE container and one clinical batch (5 mg / mL, batch 2034827) packaged in a BO_300_AMBER_CR_CLOSURE container.

[0147] Both the technical and clinical batches were stored at 25°C / 60%RH for 42 days and then analyzed.

[0148] D. Results, Discussion, and Interpretation Technical batch Testing at 5°C / ambient RH BO-125 AMBER CR CLOSURE and BO-300 AMBER CR CLOSURE (5 mg / mL dose) All results obtained for technical batch numbers H0004 (60 mL) / (5 mg / mL) and H0004 (140 mL) / (5 mg / mL) BO_125_AMBER_CR_CLOSURE and BO_300_AMBER_CR_CLOSURE, respectively, were well within specifications. For formulations (5 mg / mL) at 5°C / ambient RH, there were no significant changes in pH values, enantiomer content, degradation products, or assay values ​​for ruxolitinib, methylparaben, and propylparaben.

[0149] No significant changes were observed in any of the physical and chemical properties tests, including assays of active ingredients and preservatives, degradation products, enantiomers, pH, and appearance up to 24 months.

[0150] Long-term conditions at 25°C / 60%RH BO-125 AMBER CR CLOSURE and BO-300 AMBER CR CLOSURE (5 mg / mL dose) All results obtained for technical batch numbers H0004 (60 mL) / (5 mg / mL) and H0004 (140 mL) / (5 mg / mL) BO_125_AMBER_CR_CLOSURE and BO_300_AMBER_CR_CLOSURE, respectively, were well within specifications. Under long-term conditions of 25°C / 60%RH, there were no significant changes in pH values, enantiomer content, degradation products, or assay values ​​for the formulations (5 mg / mL) of ruxolitinib, methylparaben, and propylparaben.

[0151] No significant changes were observed in any of the physical and chemical properties tests, including assays of active ingredients and preservatives, degradation products, enantiomers, pH, and appearance up to 24 months.

[0152] Testing at 40℃ / 75%RH BO-125 AMBER CR CLOSURE and BO-300 AMBER CR CLOSURE (5 mg / mL dose) For all results obtained for technical batch numbers H0004(60mL) / (5mg / mL) and H0004(140mL) / (5mg / mL)BO_125_AMBER_CR_CLOSURE and BO_300_AMBER_CR_CLOSURE respectively, there were no significant changes in pH values, enantiomer content, and assay values ​​of ruxolitinib, methylparaben, and propylparaben for the formulation (5mg / mL) under accelerated conditions of 40°C / 75%RH.

[0153] In both batches H0004 (60 mL) and H0004 (140 mL), out-of-situation (OOS) results for degradation products were observed after 6 months of analysis. Unidentified impurity RRT0.33 was observed at levels of 0.6% and 0.7% in batches H0004 (60 mL) and H0004 (140 mL), respectively. During the root cause investigation, it was determined to be preservative-related degradation. See AQWA#2184230 for details. Additionally, degradation products 536-11 were observed at levels of 0.4% in both H0004 (60 mL) and H0004 (140 mL) after 6 months of analysis. While these do not exceed the initial stage limits set forth in this standard, their increase should be monitored.

[0154] All other results (physical and chemical) remained within the specification limits for these batches.

[0155] Test during use BO_125_AMBER_CR_CLOSURE(5mg / mL dose) This test was conducted with one technical batch H0004 (60 ml) packaged in a BO_125_AMBER_CR_CLOSURE container. Samples were stored in open bottles at 25°C / 60%RH for up to 42 days and then analyzed.

[0156] No significant changes were observed in any of the physical and chemical property tests, including assays of active ingredients and preservatives, degradation products, enantiomers, pH, and appearance on day 42.

[0157] Clinical batch Testing at 5°C / ambient RH BO_300_AMBER_CR_CLOSURE_Upright_(5mg / mL dose) All results obtained for clinical batch number 2034827 (140 mL) / (5 mg / mL) BO_300_AMBER_CR_CLOSURE_Upright were well within specifications. For the formulation (5 mg / mL) at 5°C / ambient RH, there were no significant changes in pH, enantiomer content, degradation products, or assay values ​​for ruxolitinib, methylparaben, and propylparaben.

[0158] No significant changes were observed in any of the physical and chemical properties tests, including assays of active ingredients and preservatives, degradation products, enantiomers, pH, and appearance up to 12 months.

[0159] Long-term conditions at 25°C / 60%RH BO_300_AMBER_CR_CLOSURE_Upright(5mg / mL dose) All results obtained for clinical batch number 2034827 (140 mL) / (5 mg / mL) BO_300_AMBER_CR_CLOSURE_Upright were well within specifications. No significant changes were observed in the pH values, enantiomer content, degradation products, or assay values ​​of ruxolitinib, methylparaben, and propylparaben at 25°C / 60%RH.

[0160] No significant changes were observed in any of the physical and chemical properties tests, including assays of active ingredients and preservatives, degradation products, enantiomers, pH, and appearance up to 12 months.

[0161] Testing at 30℃ / 75%RH BO_300_AMBER_CR_CLOSURE_Upright_(5mg / mL dose) All results obtained for clinical batch number 2034827 (140 mL) / (5 mg / mL) BO_300_AMBER_CR_CLOSURE_Upright were well within specifications. No significant changes were observed in the pH values, enantiomer content, degradation products, or assay values ​​of ruxolitinib, methylparaben, and propylparaben at 30°C / 75%RH.

[0162] No significant changes were observed in any of the physical and chemical properties tests, including assays of active ingredients and preservatives, degradation products, enantiomers, pH, and appearance up to 12 months.

[0163] Testing at 40℃ / 75%RH BO_300_AMBER_CR_CLOSURE_Upright(5mg / mL dose) In all results obtained for clinical batch number 2034827 (140 mL) / (5 mg / mL) BO_300_AMBER_CR_CLOSURE_Upright, there were no significant changes in pH values, enantiomer content, or assay values ​​for the formulation (5 mg / mL) under accelerated conditions of 40°C / 75% RH for ruxolitinib, methylparaben, and propylparaben.

[0164] Analysis of degradation products over a 6-month period revealed OOS results, with an unidentified impurity RRT0.33 observed at minimum levels of 0.3% and 0.7%. During the investigation of the root cause, it was determined to be preservative-related degradation. See AQWA#2338758 for details. Additionally, degradation product 536-11 was observed at a level of 0.5%.

[0165] All other results (physical and chemical) remained within the specification limits for these batches.

[0166] Testing at 5°C / ambient RH BO_300_AMBER_CR_CLOSURE_Inverted_(5mg / mL dose) All results obtained for clinical batch number 2034827 (140 mL) / (5 mg / mL) BO_300_AMBER_CR_CLOSURE_Inverted were well within specifications. For the formulation (5 mg / mL) at 5°C / ambient RH, there were no significant changes in pH, enantiomer content, degradation products, or assay values ​​for ruxolitinib, methylparaben, and propylparaben.

[0167] No significant changes were observed in any of the physical and chemical properties tests, including assays of active ingredients and preservatives, degradation products, enantiomers, pH, and appearance up to 12 months.

[0168] Long-term conditions at 25°C / 60%RH BO_300_AMBER_CR_CLOSURE_Inverted(5mg / mL dose) All results obtained for clinical batch number 2034827 (140 mL) / (5 mg / mL) BO_300_AMBER_CR_CLOSURE_Inverted were well within specifications. No significant changes were observed in the pH values, enantiomer content, degradation products, or assay values ​​of ruxolitinib, methylparaben, and propylparaben at 25°C / 60% RH.

[0169] No significant changes were observed in any of the physical and chemical properties tests, including assays of active ingredients and preservatives, degradation products, enantiomers, pH, and appearance up to 12 months.

[0170] Testing at 30℃ / 75%RH BO_300_AMBER_CR_CLOSURE_Inverted(5mg / mL dose) All results obtained for clinical batch number 2034827 (140 mL) / (5 mg / mL) BO_300_AMBER_CR_CLOSURE_Inverted were well within specifications. No significant changes were observed in the pH values, enantiomer content, degradation products, or assay values ​​of ruxolitinib, methylparaben, and propylparaben at 30°C / 75%RH.

[0171] No significant changes were observed in any of the physical and chemical properties tests, including assays of active ingredients and preservatives, degradation products, enantiomers, pH, and appearance up to 12 months.

[0172] Testing at 40℃ / 75%RH BO_300_AMBER_CR_CLOSURE_Inverted(5mg / mL dose) All results obtained for clinical batch number 2034827 (140 mL) / (5 mg / mL) BO_300_AMBER_CR_CLOSURE_Inverted were well within specifications. No significant changes were observed in the pH, enantiomer content, or assay values ​​of ruxolitinib, methylparaben, and propylparaben at 40°C / 75%RH.

[0173] Regarding degradation products in the analysis at 3 and 6 months, the results for 536-11 were observed at levels of 0.2% and 0.5%, respectively. While these do not exceed the initial limits set forth in this standard, increases should be monitored.

[0174] All other results (physical and chemical) remained within the specification limits for these batches.

[0175] Testing at 5°C / ambient RH BO_125_AMBER_CR_CLOSURE (Placebo, 1 mg / mL and 5 mg / mL doses) In the stability tests, only the assays for methylparaben and potassium sorbate were tested; all other physical and chemical parameters were not tested in the placebo sample.

[0176] When samples were stored at 5°C / ambient RH, the assay values ​​for methylparaben and API in the samples did not change significantly. The assay value of potassium sorbate remained unchanged in the 5 mg / mL sugar-containing sample (T112 1215), decreased slightly from 99.3% (at time 0) to 93.5% (at 6 months) in the 5 mg / mL non-sugar-containing sample (T110 1215), and decreased significantly from 94.8% (at time 0) to 83.3% (at 6 months) in the 1 mg / mL non-sugar-containing sample. In the 1 mg / mL sugar-containing sample (T111 1215), the measured value of potassium sorbate decreased and is not an indicator of stability. However, the analytical value of potassium sorbate decreased significantly. At 6 months, the potassium sorbate content was 25% in the 1 mg / mL non-sugar placebo and 48% in the 5 mg / mL sugar placebo. In comparison, the decrease in potassium sorbate was slower in the sugar-containing formulation than in the sugar-free formulation. Three degradation products with RRTs of 0.42, 0.43, and 0.48 were observed at 0.1% levels in the 1 mg / mL sugar-free sample at 1 month, except for the peak with RRT 0.42, which was observed at 0.1% throughout the stabilization period. The degradation peak with RRT 0.59 was observed at 0.1% levels in the 1 mg / mL sugar-containing formulation at 1 month and increased to 0.2% at 3 months. In both sugar-containing and sugar-free samples, there were no degradation peaks exceeding 0.1% at 5 mg / mL.

[0177] No changes in appearance or pH were observed in any of the samples up to 6 months.

[0178] All results (physical and chemical) remained within the specification limits for these batches.

[0179] BO_300BR (1 mg / mL and 5 mg / mL doses) Except for the assay value of potassium sorbate in the 1 mg / mL sugar formulation at 6 months, there were no significant changes in any of the physical and chemical characterization tests, including assays of active ingredients and preservatives, impurity profiles, enantiomers, pH, and appearance. The potassium sorbate content in the 1 mg / mL sugar formulation remained unchanged until 3 months, but decreased sharply to 79.5% at 6 months. No degradation products exceeding the reporting threshold (0.1%) were observed.

[0180] All results (physical and chemical) remained within the specification limits for these batches.

[0181] Accelerated testing (25℃ / 60%RH) BO_125_AMBER_CR_CLOSURE (Placebo, 1 mg / mL and 5 mg / mL doses) In the placebo samples, only the methylparaben assay and the potassium sorbate assay were tested; all other physical and chemical parameters were not tested during the stability test.

[0182] No significant changes were observed in the pH values, enantiomer content, or assay values ​​of ruxolitinib and methylparaben. Potassium sorbate decreased significantly during storage, particularly in the placebo. At 6 months, the potassium sorbate content was 12% in the 1 mg / mL non-sugar placebo and 24% in the 5 mg / mL sugar placebo. Potassium sorbate also decreased in all sample batches, but not as rapidly as in the placebo. The assay for potassium sorbate is for "reference information" only.

[0183] In the 3-month sample of T109 1215 (1 mg / mL non-sugar formulation), an impurity with an RRT of 0.43 was observed at a level of 0.1%. In the same batch, an impurity with an RRT of 0.48 was observed in the 1-month sample, but not in the 3-month and 6-month samples. In the 1-month sample of T111 1215 (1 mg / mL sugar formulation), an impurity with an RRT of 0.59 was observed at a level of 0.2%, but not in the 3-month sample, and at a level of 0.3% in the 6-month sample. No degradation products exceeding 0.1% were observed in either 5 mg / mL formulation. The appearance of T1091 1215 and T111 1215 remained transparent and colorless up to 3 months. However, at 6 months, batch number T109 1215 was transparent and its color matched "Y5" (pale yellow), while batch number T111 1215 was transparent and its color matched opacity criterion IV (according to the European Pharmacopoeia), remaining colorless. The color of T110 1215 (5 mg / mL non-sugar formulation) matched "Y4" (yellow) at 3 and 6 months, and its transparency remained transparent up to 6 months. The color of T112 1215 (5 mg / mL sugar formulation) matched "Y5" (pale yellow) at 3 and 6 months, and its transparency remained transparent up to 6 months. However, no degradation products exceeding the reporting threshold (0.1%) were detected in these samples.

[0184] All results (physical and chemical) remained within the specification limits for these batches.

[0185] BO_300BR (1 mg / mL and 5 mg / mL doses) All results obtained with BO_300BR are very similar to, or slightly better than, those obtained with BO_125_AMBER_CR_CLOSURE. There were no significant changes in pH values, enantiomer content, and assay values ​​for ruxolitinib and methylparaben, nor in the assay values ​​for potassium sorbate in both non-sugar formulations (1 mg / mL and 5 mg / mL). Potassium sorbate decreased significantly during storage in the sugar formulation batches. However, the assay values ​​for potassium sorbate are for "reference information" only.

[0186] The appearances of T109 1215, T111 1215, and T110 1215 remained colorless until 3 months, but the color changed to "Y5" (light yellow) for batch number T111 1215 at the 6th month, and the transparency remained transparent for all three batches until 6 months. For batch number T112 1215, the transparency remained transparent until 6 months, but the color was colorless until 1 month, the color matched "Y5" (light yellow) at the 3rd month, and the color matched "Y4" (yellow) at the 6th month. No decomposition products exceeding RT(0.1%) were observed. All results remained within the specification limits.

[0187] Test at 40°C / 75%RH BO_125_AMBER_CR_CLOSURE (placebo, 1mg / mL and 5mg / mL dosages) For the placebo samples, only the assays of methylparaben and potassium sorbate were tested, and all other physical and chemical parameters were not tested during the stability test. Except for color change and degradation profiles, all other physical and chemical test results of the samples stored at 40°C / 75%RH were very similar to those of the samples stored at 25°C / 60%RH. As expected, the decrease of potassium sorbate in the samples stored at 40°C / 75%RH was faster than that stored at 25°C / 60%RH. However, the assay of the potassium sorbate specification is "reference information".

[0188] The degradation profiles of most samples stored at 40°C / 75%RH were the same as those stored at 25°C / 60%RH. The only difference was that impurities 536-11 and 537-11 were detected in the 1-month sample of T110 1215. T110 1215 and T112 1215 showed a yellowish tint at 1 month. For T109 1215 and T111 1215, no color change was observed until 3 months, and a change to yellow was observed at 6 months.

[0189] All results (physical and chemical) remained within the specification limits of these batches.

[0190] BO_300BR (1 mg / mL and 5 mg / mL doses) Aside from color change, all other physical and chemical test results for samples stored at 40°C / 75%RH were very similar to those for samples stored at 25°C / 60%RH. T111 1215 showed yellowing after 3 and 6 months. All results remained within specification limits.

[0191] Clinical batch Test during use BO_300_AMBER_CR_CLOSURE(5mg / mL dose) This study was conducted using one clinical batch 2034827 (140 mL) packaged in a BO_300_AMBER_CR_CLOSURE container. Samples were stored in open bottles at 25°C / 60%RH for up to 42 days and then analyzed.

[0192] No significant changes were observed in any of the physical and chemical property tests, including assays of active ingredients and preservatives, degradation products, enantiomers, pH, and appearance on day 42.

[0193] Freeze-thaw cycle test (20°C / ambient RH / 25°C / 60%RH for 28 days) (5 mg / mL dose) BO_300_AMBER_CR_CLOSURE(5mg / mL dose) This study was conducted using one clinical batch 2034827 (140 mL) packaged in a BO_300_AMBER_CR_CLOSURE container. Samples were circulated at 20°C / ambient RH / 25°C / 60% RH for 28 days before analysis.

[0194] No significant changes were observed in any of the physical and chemical properties tests, including assays of active ingredients and preservatives, degradation products, enantiomers, pH, and appearance on day 28.

[0195] E. Conclusion Ruxolitinib solution formulations (891147, 891148), packaged in BO_125_AMBER_CR_CLOSURE and BO_300_AMBER_CR_CLOSURE respectively, exhibited generally good stability in 5 mg / mL technical batches H0004 (60 mL) and H0004 (140 mL) when stored for up to 24 months under long-term conditions of 25°C / 60%RH, up to 3 months under accelerated conditions of 40°C / 75%RH, and up to 24 months at 5°C / RH. All parameters tested remained within the proposed specifications under all tested conditions.

[0196] Under 40°C / 75%RH conditions for 6 months, both batches H0004 (60mL) and H0004 (140mL) showed out-of-situation (OOS) results for degradation products. Unidentified impurity RRT0.33 was observed at levels of 0.6% and 0.7% in batches H0004 (60mL) and H0004 (140mL), respectively. During the root cause investigation, it was determined to be preservative-related degradation. See AQWA#2184230 for details. Additionally, degradation product 536-11 was observed at a level of 0.4% and requires monitoring.

[0197] Ruxolitinib solution formulation (891147), packaged in BO_300_AMBER_CR_CLOSURE_Upright, exhibits overall good stability at 5 mg / mL clinical batch number 2034827 (140 mL) when stored for up to 12 months under long-term conditions of 25°C / 60%RH, up to 3 months under accelerated conditions of 40°C / 75%RH, up to 12 months at 30°C / 75%RH, and up to 12 months at 5°C / RH. All parameters tested remained within the proposed specifications under all tested conditions.

[0198] Batch 2034827 (140 mL)_Upright showed OOS results for degradation products after 6 months under 40°C / 75%RH conditions. Batch number 2034827 (140 mL)_Upright also showed 0.7% unspecified impurities with a RRT of 0.33. During the root cause investigation, it was determined to be preservative-related degradation. See AQWA#2338758 for details. Additionally, 536-11 degradation products were observed at a 0.5% level and should be monitored.

[0199] Ruxolitinib solution formulation (891147), packaged in BO_300_AMBER_CR_CLOSURE_Inverted, exhibits generally good stability behavior at 5 mg / mL clinical batch number 2034827 (140 mL) when stored for up to 12 months under long-term conditions of 25°C / 60%RH, up to 12 months at 30°C / 75%RH, and up to 12 months at 5°C / RH. All parameters tested remained within the proposed specifications under all tested conditions.

[0200] Analysis of batch 2034827 (140 mL)_Inverted under 3-month and 6-month conditions at 40°C / 75%RH showed that 536-11 degradation products were observed at levels of 0.2% and 0.5%, respectively. While these do not exceed the initial stage limits set forth in this standard, their increase should be monitored.

[0201] The ruxolitinib solution formulations (891147, 891148), technical batch H0004 (60 ml) and clinical batch 2034827 (140 ml), have been confirmed to be chemically and physically stable for up to 42 days, which supports a 42-day shelf life when stored in BO_125_AMBER_CR_CLOSURE and BO_300_AMBER_CR_CLOSURE containers, respectively.

[0202] Based on the available stability data for technical batches H0004 (60 mL) and H0004 (140 mL) variant 002 of 5 mg / mL at 25°C / 60%RH for 24 months and 40°C / 75%RH for 3 months, the storage of the drug is proposed to be "not to be stored at temperatures above 25°C," and the shelf life is proposed to be "24" months. Furthermore, the stability data for clinical batch 2034827_Upright (140 mL) at 12 months at 25°C / 60%RH, 12 months at 30°C / 75%RH, and 3 months at 40°C / 75%RH, as well as the stability data for clinical batch 2034827_Inverted (140 mL) at 12 months at 25°C / 60%RH, 12 months at 30°C / 75%RH, and 3 months at 40°C / 75%RH, also support the proposed shelf life of "24" months. Based on stability data for 3 months at 40℃ / 75%RH (variant 002), the transport category is assigned to "TEMPCONTROL".

[0203] Except for the appearance and assay values ​​of potassium sorbate, all other chemical and physical test results obtained from the technical batch (variant 001) demonstrate that ruxolitinib 1 mg / mL and 5 mg / mL solution formulations remain stable for up to 6 months when packaged in BO_125_AMBER_CR_CLOSURE or BO_300BR and stored at 40°C / 75%RH (accelerated conditions), 25°C / 60%RH (long-term storage conditions), and 5°C / ambient RH (refrigerated conditions). The appearance of the test samples remained unchanged for up to 6 months at 5°C / ambient RH (refrigerated conditions). Color changes were observed when stored at 25°C / 60%RH and 40°C / 75%RH. At the same formulation and sample dose intensity, samples in BO_300BR were found to have superior results compared to those in BO_125_AMBER_CR_CLOSURE. The color change of the sugar-containing formulation was faster than that of the non-sugar-containing formulation, and the dose intensity of 5 mg / mL was faster than that of 1 mg / mL. The physical and chemical properties of all tests, including enantiomers, active ingredient assays, and degradation products, remained within specification limits up to 6 months.

[0204] [Table 39]

[0205]

Table 40

[0206]

Table 41

[0207] F. Technical Stability Results Tests at 5°C / Ambient RH, 25°C / 60%RH, and 40°C / 75%RH Chemical and Physical Data: H0004 (60mL)

[0208]

Table 42

[0209]

Table 43

[0210]

Table 44

[0211]

Table 45

[0212]

Table 46

[0213]

Table 47

[0214]

Table 48

[0215] [Table 49]

[0216] [Table 50]

[0217] G. Special Tests Freeze-thaw cycle test

[0218] [Table 51]

[0219] [Table 52]

[0220] Test during use

[0221] [Table 53]

[0222] [Table 54]

[0223] [Table 55]

[0224] [Table 56]

[0225] H. Clinical stability results Tests were conducted at 5°C / ambient RH, 25°C / 60%RH, 30°C / 75%RH, and 40°C / 75%RH. Chemical and physical data: 2034827 (140 mL) _Upright

[0226] [Table 57]

[0227] [Table 58]

[0228] [Table 59]

[0229] [Table 60]

[0230] [Table 61]

[0231] Chemical and physical data: 2034827 (140 mL) _Inverted

[0232] [Table 62]

[0233] [Table 63]

[0234] [Table 64]

[0235] [Table 65]

[0236] [Table 66]

[0237] Stability results Tests were conducted at 5°C / ambient RH, 25°C / 60%RH, and 40°C / 75%RH. Placebo solution 1. Chemical and physical data: T0100216

[0238] [Table 67]

[0239] [Table 68]

[0240] [Table 69]

[0241] [Table 70]

[0242] [Table 71]

[0243] BO_125AMBER_CR_CLOSURE Chemical and physical data

[0244] [Table 72]

[0245] [Table 73]

[0246] Table 74

[0247] Table 75

[0248] Table 76

[0249] Table 77

[0250] Table 78

[0251] Table 79

[0252] Table 80

[0253] BO_300BR Chemistry and Physics

[0254] Table 81

[0255] Table 82

[0256] Table 83

[0257] Table 84

[0258] Table 85

[0259] Table 86

[0260] Table 87

[0261] Table 88

[0262] Table 89

[0263] Table 90

[0264] データ of microbiology

[0265] Table 91

[0266] Table 92

[0267] Table 93 The invention described in the original claims of this application is listed below. [1] (i) Ruxolitinib or a pharmaceutically acceptable salt thereof, (ii) solvent, and (iii) Preservatives An oral formulation containing [the specified ingredient]. [2] The oral formulation according to [1], wherein the solvent is water. [3] The oral formulation according to [1], wherein the preservative is a mixture of methylparaben and propylparaben. [4] The oral formulation according to [1], further comprising a cosolvent. [5] The oral preparation according to [1], further comprising a seasoning. [6] The oral preparation according to [1], further comprising a seasoning. [7] The oral formulation according to [1], further comprising a pH adjuster. [8] The oral formulation according to [4], wherein the cosolvent is propylene glycol. [9] The oral preparation according to [5], wherein the sweetener is sucralose.

[10] The oral preparation according to [6], wherein the flavoring agent is strawberry flavor.

[11] The oral preparation according to [7], wherein the pH adjusting agent is citric acid.

[12] The oral formulation according to [1], wherein the ruxolitinib (free base) concentration is approximately 1 mg / mL to 5 mg / mL.

[13] Table 1 An oral formulation containing ruxolitinib at a concentration of 5 mg / mL.

[14] Table 2 An oral formulation containing ruxolitinib at a concentration of 1 mg / mL.

[15] A method for treating a Janus kinase (JAK)-related disease, comprising the step of administering the oral dosage form described in [1], comprising approximately 5 mg to approximately 65 mg of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis.

[16] The method according to

[15] , wherein the JAK-related disease is myelofibrosis (MF), polycythemia vera (PV), or graft-versus-host disease (GvHD).

Claims

1. (i) Ruxolitinib or a pharmaceutically acceptable salt thereof (ii) water; (iii) pH adjusters, and (iv) Preservatives An oral formulation containing, The concentration of ruxolitinib in the oral formulation is approximately 0.1 mg / mL to approximately 10 mg / mL on a free base basis, and the pH of the oral formulation is 2.7 ± 0.

5. Oral formulation.

2. The oral formulation according to claim 1, wherein the preservative is a mixture of methylparaben and propylparaben.

3. The oral formulation according to claim 1, further comprising a cosolvent.

4. The oral formulation according to claim 1, further comprising a sweetener.

5. The oral formulation according to claim 1, further comprising a flavoring agent.

6. The oral formulation according to claim 3, wherein the cosolvent is propylene glycol.

7. The oral formulation according to claim 4, wherein the sweetener is sucralose.

8. The oral formulation according to claim 5, wherein the flavoring is strawberry flavor.

9. The oral formulation according to claim 1, wherein the pH adjusting agent is citric acid.

10. The oral formulation according to claim 1, wherein the ruxolitinib (free base) concentration is approximately 1 mg / mL to 5 mg / mL. 【Request Item 11】 【Table 1】 An oral formulation containing ruxolitinib at a concentration of 5 mg / mL. 【Request Item 12】 【Table 2】 An oral formulation containing ruxolitinib at a concentration of 1 mg / mL.

13. An oral formulation according to claim 1 for the treatment of Janus kinase (JAK)-related disorders, comprising approximately 5 mg to approximately 65 mg of ruxolitinib or a pharmaceutically acceptable salt thereof on a free base basis.

14. The oral formulation according to claim 13, wherein the JAK-related disease is myelofibrosis (MF), polycythemia vera (PV), or graft-versus-host disease (GvHD).

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