Pediatric formulations of tyrosine kinase inhibitors

Abstract

This invention provides an ultra-low-dose dosage form of tyrosine kinase inhibitor for pediatric treatment. [Solution] A pediatric dosage form for administering an ultra-low dose of an active drug component, comprising a plurality of pellets, each pellet essentially consisting of a coating of a tyrosine kinase inhibitor on a nonpareil seed. The nonpareil coated with the tyrosine kinase inhibitor has its surface coated with a coating essentially consisting of hydroxypropyl methylcellulose. The active coated beads according to the invention enable administration to human subjects in mg / kg units. The entirety of such pellets contained within a capsule forms a single-dose unit of the ultra-low dose of the tyrosine kinase inhibitor.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the priority and benefits of U.S. Provisional Patent Application No. 63 / 001,824, filed on March 30, 2020, entitled "Pediatric Formulation of Tyrosine Kinase Inhibitor", the content of which is incorporated herein by reference in its entirety as if fully set forth herein.

Background Art

[0002] Background of the Invention Congenital heart disease (CHD) is the most common defect seen in newborns, occurring in approximately 1% of live births. In the United States, over one million people suffer from some form of CHD, most of whom require continuous monitoring and treatment to prevent deterioration of heart function. Atrioventricular canal defect (AVCD) includes various abnormalities of the atrioventricular valves and the atrial and ventricular septa. In the complete form, a single common atrioventricular valve and an atrial septal defect (primum type) combined with a posterior septal defect at the inlet portion of the ventricular septum are seen. In the partial form, there are two separate left and right atrioventricular valves with a cleft in the mitral valve, and there is an atrial septal defect (primum type) but no communication in the ventricular septum. The cleft mitral valve is considered a low - severity form of AVCD. AVCD is also the most common CHD seen in children with Down syndrome and is one of the structural heart defects most frequently associated with extracardiac abnormalities in the context of chromosomal and Mendelian disorders. Anatomical features are clearly seen in AVCD associated with Noonan syndrome (NS). Generally, this defect is of the partial type and is ultimately associated with subaortic stenosis due to accessory fibrous tissue and / or abnormal papillary muscles in the left ventricle resulting in abnormal insertion of the mitral valve.

[0003] Congenital heart defects (CHDs) occur in approximately 60–86% of patients affected by RAS disease, a group of disorders involving abnormalities in the RAS-MAPK pathway. Pulmonary valve stenosis (PVS) and hypertrophic cardiomyopathy are the most common defects that show a clear association with RAS disease. Many NS patients are born with some form of cardiac defect (congenital heart defect) that causes some of the main signs and symptoms of the disorder. Some cardiac problems may develop later in life. Some forms of congenital heart defects associated with this disorder include valvular disorders. Pulmonary valve stenosis is narrowing of the pulmonary valve, which is a flap of tissue separating the artery that supplies blood to the lungs (pulmonary artery) from the right lower ventricle (ventricle) of the heart. This is the most common cardiac problem seen in NS and can occur alone or in conjunction with other cardiac defects. Further cardiac defects include myocardial thickening (hypertrophic cardiomyopathy), which is an abnormal growth or thickening of the myocardium that affects some NS patients. Structural defects of the heart may be present in NS patients. The defect may involve a hole in the wall separating the two lower ventricles of the heart (ventricular septal defect), narrowing of the artery that carries oxygen to the lungs (pulmonary artery stenosis), or narrowing of the major blood vessel that carries blood from the heart to the body (aorta) (aortic coarctation). Arrhythmias also occur in the majority of NS patients. The scope of CHD is broader in NS with multiple lentigo (NSML), and the atrioventricular ductal defect (AVCD) family is the third most common cardiac defect. Most patients with cardiovascular disease and RAS disease-related congenital heart defects require treatment for many years. In particular, the mortality rate associated with RAS disease-related congenital heart defects is usually low.

[0004] Unfortunately, there is no cure for NS. Current treatments aim to manage the signs and symptoms of the disorder. NS is a lifelong disorder, and the severity of the cardiac defect affects an individual's life expectancy. Therefore, there is a need to treat this cardiovascular disease in patients with NS using low-risk therapies that have the greatest effect on the heart disease present in NS. [Overview of the Initiative]

[0005] As described below, the present invention includes compositions and pharmaceutical formulations for inhibiting abnormal protein tyrosine phosphorylation, such as the phosphorylation of Src family tyrosine kinases and their substrates.

[0006] In one aspect, the invention includes a pediatric formulation for treating a cardiovascular disease or condition involving abnormal protein tyrosine phosphorylation in a subject, which comprises administering an ultra-low dose of a tyrosine kinase inhibitor (TKI) to a subject in need, wherein the TKI reduces abnormal levels of tyrosine phosphorylation and improves at least one cardiac function in the subject.

[0007] In another aspect, the invention includes a pharmaceutical formulation comprising an ultra-low dose TKI as described herein and a pharmaceutically acceptable carrier. In various aspects of the above aspect or any other aspect described herein, congenital heart disease is associated with RAS diseases, selected from the group consisting of neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with lentigo polycarcinoma (Leopard syndrome), capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardiac-facial-cutaneous syndrome, and Regius syndrome.

[0008] In one exemplary embodiment, the ultra-low dose of the TKI is in the range of approximately 1 / 175 to 1 / 250 of the chemotherapy dose of the TKI.

[0009] In another embodiment, the TKI is selected from the group consisting of afatinib, axitinib, bosutinib, cabozantinib, cejiranib, ceritinib, crizotinib, dabrafenib, dasatinib, erlotinib, everolimus, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, restaurtinib, nilotinib, nintedanib, palbociclib, pazopanib, and ponatinib.

[0010] In a further embodiment, a low-dose coated dastinib formulation is disclosed for use in pediatric patients. The manufacturing process for the pediatric formulation allows for administration to the target population on a mg / kg basis. The manufacturing process is a Worster coating process for nonpareils, which are small beads made of various substrates. Nonpareils are typically sugar seeds with a mesh size of about 20 to about 50.

[0011] In another exemplary embodiment, the nonpareil is coated with an equal or greater amount by weight of a TKI compound, which in one exemplary embodiment is anhydrous dastinib.

[0012] In a further exemplary embodiment, nonpareil seeds are placed in a coating pan and moistened with a 30% sucrose solution using a sprayer. Anhydrous dasatinib is sprinkled over the thus treated pellets, and the material is distributed by hand as needed.

[0013] In another exemplary embodiment, both sugar nonpareils (mesh size 35–45) and MCC spheres (Vivapure MCC spheres 200) were used. For coating purposes, spheres of comparable starting particle sizes were selected.

[0014] In an exemplary embodiment, low-dose coated nonpareils for use in pediatric patients are placed in capsules containing a total effective therapeutic dose, which can be opened by a healthcare professional and sprinkled over food or suspended in a solution or suspension, allowing for oral administration of a solid or liquid suspension to a pediatric population on a mg / kg basis.

[0015] In a further exemplary embodiment, encapsulated low-dose coated nonpareils for use in pediatric patients may be placed in a card-shaped dose pack having multiple capsules with a single total dose or multiple capsules with a total dose for multiple doses, so that a healthcare professional can administer them to a pediatric patient to enable oral administration of a solid or liquid suspension to a pediatric population on a mg / kg basis. [Brief explanation of the drawing]

[0016] [Figure 1] This graph shows the difference between plasma dasatinib concentration and time, comparing the drug delivery composition according to the invention with reference formulations of dasatinib (20 mg IG-100 and Sprycel®). [Modes for carrying out the invention]

[0017] Details of the invention Dasatinib was originally developed by Bristol-Myers Squibb (approved in June 2006) for the treatment of chronic, accelerated, or blast-phase chronic myeloid leukemia (CML) that is resistant to or intolerant to imatinib, and for Ph-positive acute lymphoblastic leukemia in adults that is resistant to or intolerant to prior treatment. More recently, the FDA approved dasatinib for the treatment of newly diagnosed pediatric patients aged 1 year or older with Ph-positive acute lymphoblastic leukemia (approved in November 2017).

[0018] Non-clinical studies were conducted in mice to determine the pharmacokinetic (PK) and pharmacokinetic (PD) characteristics of low-dose dasatinib therapy in NS and NSML mice for the treatment of hypertrophic cardiomyopathy (HCM). The objective was to construct common PK data across identical mouse models and to correlate these data with HCM endpoints using qPCR and immunoblotting. The PK characteristics obtained from these mice were determined by Kana Mizuno and Alexander A. Vinks at Cincinnati Children's Hospital Medical Center. The PK profile and exposure (area under the concentration-time curve; AUC) of dasatinib in the dose range of 0.05 mg / kg to 0.5 mg / kg were estimated in NS and NSML mice. Based on the exposure-response relationship, target exposure levels for protecting cardiac function were identified. Considering efficacy and safety, a recommended target AUC value of 12–24 ng·h / mL was identified for cardiac protection.

[0019] The invention discloses a pediatric dasatinib formulation (IG-100) that can be administered in ultra-low doses on a mg / kg basis. In one aspect of the invention, the pediatric formulation is manufactured by using a Worster coating process on sugar nonpareils, and then coating them with a seal coat of water and HPMC. The final coated spheres exhibit excellent uniformity and enable oral administration of solid or liquid suspensions in pediatric populations on a mg / kg basis.

[0020] The pediatric formulation according to the invention was tested in a single-dose, open-label, randomized, two-period, two-treatment, crossover relative bioavailability study in 28 healthy adults. Participants received a single dose of IG-100 (20 mg suspension) during one period and a single dose of Sprycel® (20 mg tablet) under fasting conditions during another period. Human plasma samples were analyzed for dasatinib using efficacy-validated assays, and plasma concentration data were provided. As shown in Figure 1, the formulation according to the present invention exhibits an expected exposure profile demonstrating bioequivalence to the reference drug described.

[0021] The preparation process for the ultra-low-dose dosage form aims to produce a suspension system to which approximately 1% of the API (dasatinib) can be added to the nonpareil. The suspension system is an aqueous substrate containing hydroxypropyl cellulose as a binder, along with other excipients to improve spray properties. The API is charged into the suspension and continuously mixed during the spraying process. The nonpareil is packed into a fluidized bed using a Worster column (bottom spray); the beads are fluidized and heated to approximately 60°C. Spraying is started with the goal of an approximate weight increase to which approximately 1% of the active ingredient is sprayed onto the nonpareil. The coating is sprayed at approximately 20 g / min. Once the weight increase is achieved, the nonpareil is allowed to dry for approximately 15 minutes. The beads are then sieved through a 20-mesh screen to ensure that no large aggregates have formed.

[0022] Next, the activated coated beads are refilled into the fluidized bed by a Wurster coater insert and a seal coat is applied. The seal coat is a combination of water and hydroxypropyl methylcellulose (HPMC) with a few excipients to facilitate coating. The seal coating process follows the same process except that the solids content increases by 3 - 5% for the activated coated beads. Sugar has no effect on the MCC spheres. The final coated spheres have an RSD of 3.7 and a uniformity of the desired analyte of 95% - 104%. According to one exemplary embodiment, the seal-coated activated beads contain about 7.6 mg of dasatinib per 1 g of the coated activated beads.

[0023] The coated particles according to the invention comprise a suitable carrier surrounded by a coating layer. The suitable carrier according to the invention is preferably based on an inert excipient customarily used as a carrier in formulation technology.

[0024] Excipients that may preferably be used include, without limitation: mannitol, saccharose, lactose (e.g., lactose monohydrate), glucose, erythritol, xylitol, cellulose, microcrystalline cellulose, starch, croscarmellose sodium, crospovidone and mixtures thereof. It is contemplated that other excipients known in the art may be used within the scope of the invention. It is further contemplated that within the scope of the invention, the carrier according to the invention may be based on a suitable size of powder, granule, small bead, particle, pellet, starter pellet, nonpareil composed of the above excipients or mixtures thereof. If coated particles of a defined shape (e.g., round shape) are desired, it is advantageous to use a carrier of a defined shape and size such as a starter pellet made of microcrystalline cellulose or saccharose (nonpareil).

[0025] The exemplary embodiments above utilize dasatinib anhydrous, but one of ordinary skill in the art will recognize that methods and compositions used in the manufacture of pediatric formulations can be used with other TKIs. Within the scope of the invention, other TKIs are contemplated to include, without limitation, the following TKIs: afatinib, axitinib, bosutinib, cabozantinib, cediranib, ceritinib, crizotinib, dabrafenib, dasatinib, erlotinib, everolimus, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, lestaurtinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib. It is further contemplated that within the scope of the invention, these TKIs may be used alone, or in combination with each other, or in combination with another API that may be beneficial to the desired therapeutic effect. Similarly, one of ordinary skill in the art should recognize that TKIs may be utilized in their various salt forms, analogs, and prodrugs.

[0026] It will be recognized that the actual dosage of the agent used in the compositions of the present invention will vary depending on the particular complex used, the particular composition formulated, the mode of administration, and the particular site, host, and disease and / or condition being treated. The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can vary to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration and thereby provide a therapeutically effective amount without causing toxicity in a human subject.

[0027] The selected dose level varies depending on various pharmacokinetic factors, including the activity of the particular therapeutic agent, the route of administration, the timing of administration, the excretion rate of the specific compound being employed, the severity of the condition, other health considerations affecting the subject, and the status of the subject's liver and kidney function. It also varies depending on factors such as the duration of treatment, other drugs, compounds, and / or materials used in combination with the specific therapeutic agent being employed, and the age, weight, condition, overall health status, and medical history of the subject receiving treatment. Methods for determining the optimal dose are described in the Art of this, for example, in Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000.

[0028] The optimal dose for a given set of conditions can be determined by those skilled in the art using conventional dose determination tests, taking into account experimental data for each drug. For oral administration of the formulations according to the invention, the generally adopted exemplary daily dose is about 0.001 to about 3000 mg per kg of body weight, and the treatment course is repeated at appropriate intervals. In some embodiments, the daily dose is about 1 to 3000 mg per kg of body weight. The methods and compositions according to the present invention are suitable for use in treating diseases and conditions of both humans and non-humans, including the treatment of socially and economically important animals such as dogs, cats, cows, horses, sheep, pigs, goats, and other species. Unless otherwise specified, the methods and compositions according to the present invention are not limited to the treatment of humans.

[0029] The typical daily dose in a patient may be approximately 0.04 mg / kg to approximately 0.22 mg / kg, administered once daily or in divided doses. In one embodiment, the dose is approximately 0.14 mg to approximately 1.1 mg. In another embodiment, the dose is approximately 0.2 mg to approximately 1.7 mg. In yet another embodiment, the dose is approximately 0.24 mg to approximately 2.4 mg.

[0030] In particular, for dasatinib or its derivatives or analogues, the preferred dose is typically about 0.04 mg / kg to about 0.22 mg / kg, as shown in Table 1 below.

[0031] (Table I) Optimal IG-100 doses based on PK models in pediatric NS or NSML patients to achieve different exposure targets. TIFF2026094419000002.tif65156 1 The dosage of IG-100 is based on the median infant weight for each child age range, derived from the World Health Organization (WHO) growth chart for the first two years of life (0-2 years).

[0032] Pharmaceutical preparations for oral use can be obtained by combining a pharmacological agent with a solid excipient, as described in this disclosure. Preferred excipients are fillers, in particular, that include, but are not limited to, sugars including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP).

[0033] If desired, disintegration regulators such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, may be added. Other components such as stabilizers, such as sodium citrate, ascorbyl palmitate, propyl gallate, reducing agents, ascorbic acid, vitamin E, sodium bisulfite, butylated hydroxytoluene, BHA, acetylcysteine, monothioglycerol, phenyl-α-naphthylamine, or antioxidants such as lecithin may be used.

[0034] Furthermore, other components conventionally used in the field of pharmaceutical compositions and formulations, such as lubricants, colorants, or fragrances, may be used. Conventional pharmaceutical excipients or carriers may also be used. Pharmaceutical excipients may include, but are not limited to, calcium carbonate, calcium phosphate, various sugars or starches, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol, and physiologically compatible solvents. Other pharmaceutical excipients well known in the art are intended within the scope of the invention. Exemplary pharmaceutically acceptable carriers include, but are not limited to, all kinds of solvents, including aqueous and non-aqueous solvents, dispersions, coatings, antimicrobial and / or antifungal agents, isotonic and / or absorption retarders, etc. The use of such media and / or agents for pharmaceutically active substances is well known in the art. Unless any conventional media, carrier, or agent is incompatible with the active ingredient, its use in the compositions according to the present invention is intended. In particular, as described above, auxiliary active ingredients may also be incorporated into the compositions. For any administration of any of the compounds used in this invention, the preparation should meet the sterility, pyrogenicity, general safety, and purity standards required by the FDA and other regulatory agencies.

[0035] The pharmaceutical compositions according to the present invention can be prepared according to methods that are well known and routinely practiced in the art. For example, see Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000. The pharmaceutical compositions are preferably manufactured under GMP conditions. The pharmaceutical compositions according to the present invention are usually administered to the subject multiple times. The interval between each administration may be once daily, once weekly, once monthly, or once year. The interval may also be irregular, as indicated by the therapeutic response or other parameters well known in the art.

[0036] Alternatively, the pharmaceutical composition can be administered as a sustained-release formulation, in which case the required frequency of administration is reduced. The dose and frequency vary depending on the half-life of the pharmacologically active agent contained in the pharmaceutical composition in the target patient. The dose and frequency of administration may also vary depending on whether the treatment is prophylactic or therapeutic. For prophylactic use, relatively low doses are administered over a long period of time at relatively low frequency. Some patients may continue treatment for life.

[0037] Within the scope of the present invention, sustained-release or controlled-release formulations well known in the art may be used to deliver the active ingredients described above. The pharmacokinetic principles of controlled drug delivery are described, for example, in BM Silber et al., "Pharmacokinetic / Pharmacodynamic Basis of Controlled Drug Delivery" in Controlled Drug Delivery: Fundamentals and Applications (JR Robinson & VHL Lee, eds, 2d ed., Marcel Dekker, New York, 1987), ch. 5, pp. 213-251, which is incorporated herein by reference.

[0038] Those skilled in the art can easily prepare controlled-release or sustained-release formulations containing the pharmacological agent according to the present invention by modifying the formulation described above, for example, in accordance with the principles disclosed in VHK Li et al, "Influence of Drug Properties and Routes of Drug Administration on the Design of Sustained and Controlled Release Systems" in Controlled Drug Delivery: Fundamentals and Applications (JR Robinson & VHL Lee, eds, 2d ed., Marcel Dekker, New York, 1987), ch. 1, pp. 3-94, which is incorporated herein by reference. This preparation process typically takes into account the physicochemical properties of the pharmacological agent, such as water solubility, partition coefficient, molecular size, stability, and nonspecific binding to proteins and other biomolecules. This preparation process also takes into account biological factors such as the absorption, distribution, metabolism, duration of action, potential for side effects, and safety margin of the pharmacological agent. Thus, those skilled in the art can modify the formulation for specific applications to have the desired properties described above. [Examples]

[0039] The following examples are provided to illustrate certain features of the present invention. These examples should not be construed as limiting the present invention to the specific features described in these examples.

[0040] Example I: Manufacturing Process List of main equipment TIFF2026094419000003.tif26128

[0041] Material composition TIFF2026094419000004.tif10128

[0042] Theoretical final weight TIFF2026094419000005.tif70147 5 Evaporation during the coating process

[0043] coating TIFF2026094419000006.tif65128

[0044] Theoretical final weight TIFF2026094419000007.tif66170

[0045] Manufacturing Description 1. Mix the water at approximately 450 RPM. 2. Add hypromellose and stir for about 45 minutes or until the solution becomes clear. 3. Add strong ammonia water and mix for about 10 minutes. 4. Add talcum and mix for about 10 minutes. 5. Increase the speed to approximately 850 RPM and slowly add the dasatinib. Mix for about 15 minutes. 6. Reduce the speed to approximately 300 RPM and mix for at least 2 hours. 7. Coat dasatinib with a Worster coating in an approximately 75% coating suspension.

[0046] List of main equipment TIFF2026094419000008.tif29128

[0047] List of main equipment TIFF2026094419000009.tif26128

[0048] Material composition TIFF2026094419000010.tif10128

[0049] Theoretical final weight TIFF2026094419000011.tif48147 6 Evaporation during the coating process

[0050] coating TIFF2026094419000012.tif55128

[0051] Theoretical final weight TIFF2026094419000013.tif40170

[0052] Manufacturing Description 1. Mix the water at approximately 450 RPM. 2. Add hypromellose and stir for about 45 minutes or until the solution becomes clear. 3. Add talcum and mix for about 10 minutes. 4. Reduce the speed to 300 RPM and mix for at least one hour. 5. Apply a Worster coating with a coating suspension of approximately 70%.

[0053] List of main equipment TIFF2026094419000014.tif29128TIFF2026094419000015.tif62150

[0054] Example II: Bioavailability study comparing 20 mg tablets of dasatinib and 20 mg suspension of IG-100 under fasting conditions. Research information Samples were collected to support the "Pilot single-dose, two-stage, two-treatment, bidirectional crossover relative bioavailability study comparing 20 mg tablets of dasatinib with a 20 mg suspension of IG-100 under fasting conditions." Samples were analyzed according to Worldwide-SOP-BSC-006, Revision 4 and processed according to Worldwide-SOP-BSC-011, Revision 6. Study data were collected using Analyst® (Version 1.6.1, Applied Biosystems / Sciex) and Watson Laboratory Information Management System® (LIMS; Version 7.5, Thermo Fisher Scientific) software.

[0055] Method Overview Human plasma samples were analyzed for dasatinib according to the Worldwide procedure ATM-2572, Original, which came into effect on October 23, 2020. Assay validation was finalized and reported under Worldwide DCN 1004600. The method used in this study was validated in the range of 0.200–200 ng / mL based on the analysis of 0.0500 mL of plasma by LC-MS-MS. Quantification was performed using a weighted 1 / x calculated from a calibration standard. 2 Linear least squares regression analysis was used.

[0056] Solution preparation The stock solution was prepared and stored according to the analytical test method described in Table II.

[0057] (Table II) TIFF2026094419000016.tif32164

[0058] Solutions, calibration standards, and quality control samples were prepared using the following reference substances. Certificates of analysis are provided in the reference substance certificate section of this report, and may contain only text. TIFF2026094419000017.tif40156

[0059] The solutions, calibration standards, quality control, and matrix control blanks were prepared using the following matrices, as shown in Table III.

[0060] (Table III) TIFF2026094419000018.tif65128

[0061] standard curve The peak area ratio of dasatinib to the internal standard (y) and the concentration of the calibration standard (x) were fitted by weighted linear least-squares regression analysis to the equation y = a + bx, where "a" is the y-intercept and "b" is the slope of the calibration curve. The calibration standard used for each sample set was entered as an unknown variable in the derived equation of the least-squares regression line to obtain an "inverse" value.

[0062] On each extraction day, calibration standards for dasatinib in human K2-EDTA plasma were prepared at 0.200, 0.400, 2.00, 10.0, 20.0, 100, 180, and 200 ng / mL and divided into 0.0500 mL portions. (See Individual Run Report, Table IV).

[0063] (Table IV) Selection of Individual Run Reports for Research - 4009179 TIFF2026094419000019.tif66170

[0064] Quality control samples Qualified quality control (QC) samples were prepared as shown in the table below and processed with each study run. A sample run was considered valid if at least two-thirds of the qualified QC samples were within 15% of their theoretical values ​​and at least 50% of the QC at each level met this criterion. Furthermore, if a sample run exceeded the volume of a single 96-well block, each block was evaluated individually and considered valid if at least two-thirds of the qualified QC samples were within 15% of their theoretical values ​​(after QC inactivation, if applicable) and at least 50% of the QC samples at each level met this criterion. If an individual block in a run did not meet the acceptance criteria, all samples within that block were repeated as an analytical repeat. The calculated QC values ​​were recorded for monitoring the accuracy and precision of the assay.

[0065] Sample analysis Samples were received worldwide between October 21, 2020 and November 19, 2020 (including duplicate samples processed at clinics and sent to bioanalysis facilities). Samples were recorded and stored at approximately -20°C in boxes clearly marked with the Worldwide shipment ID, as shown in Table V.

[0066] (Table V) TIFF2026094419000020.tif47140

[0067] Sample collection date and storage period For dasatinib, sample storage exceeded the established long-term stability of 15 days at -20°C. Further long-term stability of dasatinib in human K2-EDTA at -20°C for at least 48 days is under investigation. TIFF2026094419000021.tif18160

[0068] Reproducibility of actual samples The reproducibility (ISR) of real-world samples for dasatinib was evaluated for each clinical sample using ATM-2572, Original. Selected real-world samples, representing at least 10% of the samples across the entire study, were reanalyzed once, focusing on those near Cmax and within the efflux phase of the IGIA Pharmaceuticals, Inc. Protocol 4009179 Bioanalytical Study Report. ISR is demonstrated if at least two-thirds of the total concentrations obtained from the original and reanalyses are within ±20.0% of their mean concentration. The column showing the calculation of this % variability is labeled "% bias." Due to Watson's limitations, the naming convention cannot be revised to "% variability." Samples that fall outside the individual ISR acceptance criteria are reported with ">20.0" in the flag column, where applicable. If the re-assay result is marked as not reportable (NR), the sample result is excluded from the ISR evaluation. In such cases, the percentage variability cannot be determined and is reported as an asterisk in the % bias column.

[0069] ISR data is provided in Table VI, which reports on the reproducibility of actual samples.

[0070] (Table VI) TIFF2026094419000022.tif15160

[0071] Restarting and reinjecting the run No runs in this study required a restart. One out of a total of 10 runs in this study required at least one reinjection. The following runs were reinjected for the indicated reasons. Appropriate corrective actions were taken before each reinjection to resolve the issue.

[0072] (Table VII) TIFF2026094419000023.tif29160

[0073] Re-imported Run No orchids were re-imported within the study.

[0074] Rejected Ran All data from the studies reported in this specification were within acceptable limits.

[0075] Deviation No methodological deviations affecting data integrity occurred during the study. All protocol and SOP deviations that occurred were documented during the study and did not affect data integrity. In run 1, the scientist mistakenly failed to start the run with QC low after the carryover blank and failed to start the second block with QC low. All standards, curves, and QC were within range, and the run met the acceptable criteria. The data were unaffected.

[0076] In runs 5 and 6, the validation revision of ATM-2572 was incorrectly used. This validation revision was compared to the original revision to confirm that it did not contain any changes that could affect sample analysis. The data were unaffected.

[0077] For dasatinib, the established LTS at -20°C was only 15 days, but the QC medium-high batch was eligible at day 24 in ATM257204. The QC validation run met the acceptance criteria, and a sufficient LTS (104 days) was established to cover all study and prepared QC samples. According to the study protocol, only subjects that completed at least one period were to be analyzed. Samples from subject 115 were mistakenly analyzed despite not completing Period 1, Treatment A, Day 1, 18 hours, and Period 1, Treatment A, Day 2, 24 hours, resulting in a deviation from the protocol. All analyzed samples from subject 115 were marked NR and are not included in the table.

[0078] conclusion In an open-label, randomized, two-stage, two-treatment, crossover relative bioavailability study involving 28 healthy adults, the pediatric formulation of the invention exhibits an expected exposure profile that demonstrates bioequivalence to the reference drug described, as shown in Figure 1.

[0079] The inventions described exemplary herein can be suitably implemented in the absence of any element or group of elements, limitations or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be read broadly and non-restrictively. Furthermore, the terms and expressions used herein are descriptive rather than restrictive, and in using such terms and expressions, there is no intention to exclude any equivalents of the indicated and described features or any part thereof, and it should be recognized that various modifications are possible within the scope of the claimed invention. Therefore, while the invention is specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the invention disclosed herein may be made by those skilled in the art, and that such modifications and variations are considered to be within the scope of the invention disclosed herein. The invention is described broadly and comprehensively herein. Each of the narrower species and less comprehensive groups included within the scope of the comprehensive disclosure also forms part of these inventions. This excludes any personal subject matter from the comprehensive description of each invention by adding a proviso or negative limitation, regardless of whether the excluded items are specifically listed herein.

[0080] In addition, if the features or aspects of the invention are described by a Markush group, a person skilled in the art will recognize that the invention is also described in terms of any individual member or subgroup of a member of the Markush group. It should also be understood that the above descriptions are intended to be illustrative, not restrictive. Many aspects will become apparent to a person skilled in the art upon consideration of the above descriptions. The scope of the invention should therefore not be determined by reference to the above descriptions, but by reference to the entire range of equivalents that such claims have, together with the appended claims. All disclosures of articles and references, including patent publications, are incorporated herein by reference. While preferred aspects of our invention have been described and illustrated, it will be apparent to a person skilled in the art that in broader aspects thereof changes and modifications can be made without departing from our invention. Accordingly, we intend that the appended claims encompass all such changes and modifications that fall within the true spirit and scope of disclosure of our invention.

Claims

1. Each pellet essentially consists of a coating of tyrosine kinase inhibitors on nonpareil seeds. Nonpareil coated with a tyrosine kinase inhibitor has its surface coated with a coating essentially made of hydroxypropyl methylcellulose. The entirety of such pellets forms a single-dose unit of ultra-low dose tyrosine kinase inhibitor. Multiple pellets A pediatric dosage form for administering ultra-low doses of active drug components, including [specific ingredient].

2. The ultra-low-dose dosage form according to claim 1, wherein the tyrosine kinase inhibitor is selected from the group consisting of afatinib, axitinib, bosutinib, cabozantinib, cejilanib, ceritinib, crizotinib, dabrafenib, dasatinib, erlotinib, everolimus, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, restaurtinib, nilotinib, nintedanib, palbociclib, pazopanib, and ponatinib.

3. The ultra-low-dose dosage form according to claim 1, wherein the tyrosine kinase inhibitor is a combination of one or more tyrosine kinase inhibitors selected from the group consisting of afatinib, axitinib, bosutinib, cabozantinib, cedilanib, ceritinib, crizotinib, dabrafenib, dasatinib, erlotinib, everolimus, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, restaurtinib, nilotinib, nintedanib, palbociclib, pazopanib, and ponatinib.

4. The ultra-low-dose dosage form according to claim 1, wherein the tyrosine kinase inhibitor is dastinib.

5. The ultra-low-dose dosage form according to claim 3, wherein the dastinib is in an anhydrous form.

6. The ultra-low-dose dosage form according to claim 1, wherein the nonpareil seeds are coated with an amount equal to or greater than the weight of a tyrosine kinase inhibitor.

7. The ultra-low-dose dosage form according to claim 1, wherein approximately 1% of the tyrosine kinase inhibitor coats the nonpareil.

8. The ultra-low-dose dosage form according to claim 1, wherein the pellet contains approximately 7.6 mg of dasatinib per gram of coated sphere.

9. The ultra-low dose dosage form according to claim 1, wherein the entirety of such pellets is enclosed in a capsule having a desired therapeutic dose.

10. The ultra-low-dose dosage form according to claim 9, wherein the capsule is contained in a card-shaped dose pack containing a single therapeutic dose.

11. The ultra-low-dose dosage form according to claim 9, wherein the capsules are contained in a card-shaped dose pack containing multiple therapeutic doses.

12. A method for formulating an ultra-low-dose dosage form for pediatric treatment, comprising the following steps: A process of filling a fluidized bed with nonpareil using a Worster column, comprising the steps of fluidizing the nonpareil and heating it to approximately 60°C; A step of spraying a coating of the active drug component in the suspension onto the nonpareil to enable the desired weight increase of the nonpareil; The process involves drying nonpareils coated with an active drug component to form activated coated beads; A process for screening activated coated beads; A step of filling a fluid bed with activated coated beads using a Worster coater insert; and A step of applying a seal coat to the activated coated beads in order to achieve the desired weight increase.

13. A method for formulating an ultra-low-dose dosage form for pediatric treatment according to claim 12, wherein the nonpareil is a sugar nonpareil having a mesh size of 35 to 45.

14. A method for formulating an ultra-low-dose dosage form for pediatric treatment according to claim 12, wherein the active drug component is a tyrosine kinase inhibitor.

15. A method for formulating an ultra-low-dose dosage form for pediatric treatment according to claim 14, wherein the tyrosine kinase inhibitor is selected from the group consisting of afatinib, axitinib, bosutinib, cabozantinib, cejilanib, ceritinib, crizotinib, dabrafenib, dasatinib, erlotinib, everolimus, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, restaurtinib, nilotinib, nintedanib, palbociclib, pazopanib, and ponatinib.

16. A method for formulating an ultra-low-dose dosage form for pediatric treatment according to claim 14, wherein the tyrosine kinase inhibitor is dasatinib.

17. A method for formulating an ultra-low-dose dosage form for pediatric treatment according to claim 12, wherein the nonpareil is microcrystalline cellulose.

18. A method for formulating an ultra-low-dose dosage form for pediatric treatment according to claim 12, wherein the active drug component in the suspension is approximately 1 percent dasatinib.

19. A method for formulating an ultra-low-dose dosage form for pediatric treatment according to claim 12, wherein the seal coat is water, hydroxypropyl methylcellulose, and an excipient.

20. A method for formulating an ultra-low-dose dosage form for pediatric treatment according to claim 12, wherein the seal-coated active-coated beads enable administration to human subjects in mg / kg units.

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