Room temperature stable hydroxyurea oral suspension

Abstract

The present invention provides a liquid composition for oral administration comprising an effective amount of hydroxyurea. The present invention also discloses a liquid formulation in the form of a ready-to-use oral suspension which remains stable at room temperature when dispensed, stored, even after the container containing the suspension is reopened. Also provided is a method of preparing the formulation and treating sickle cell anemia in a child patient.

Description

Technical Field

[0001] The present invention relates to an oral liquid preparation, in particular a liquid suspension containing an effective amount of hydroxyurea that is stable at room temperature, and provides a method for preparing the same. Background Art

[0002] Hydroxyurea, also known as hydroxycarbamide, is an antineoplastic agent used in the treatment of chronic myelogenous leukemia and sickle cell disease. The exact mechanism of hydroxyurea is not precisely known, but it is believed to inhibit DNA synthesis by inhibiting ribonucleotide diphosphate reductase, thereby causing cell death in the S phase. It also inhibits the repair of DNA damaged by chemicals or radiation.

[0003] Pediatric sickle cell disease occurs when a child's healthy red blood cell level is lower than expected, and it is a condition in which a child is born with genes from their parents and inherits them through the parents' genes. Hydroxyurea is the primary pharmaceutical method for treating pediatric sickle cell anemia. The FDA has only approved hydroxyurea in tablet and capsule forms. However, the challenge in the case of these solid dosage forms is the acceptability of this drug delivery to children. Children who have difficulty swallowing tablets or capsules or have gastric instability limit compliance in the case of these solid dosage forms. Poor compliance with solid dosage forms leads to inadequate disease management. However, this problem has been solved by a compounding method. In this method, an oral solution (100 mg / ml) is prepared by pouring out the contents of a 500 mg capsule (20 capsules) and mixing it in 50 ml of sterile water. The resulting solution is stirred for several hours, mixed in a flavored syrup base, and stored in an amber plastic container. The solution is stable at room temperature for up to 90 days.

[0004] However, this liquid solution is compounded without pharmaceutical permission, which limits its availability to users. In addition, poor compounding practices can lead to a high risk of dosing errors, insufficient efficacy, a high risk of adverse reactions, contamination of the final preparation, and the need for multiple steps for reconstitution.

[0005] To overcome the problems associated with compounding practices, a child-friendly, multi-dose, ready-to-use (no reconstitution required) 100 mg / ml strawberry-flavored oral solution with a 2-year stable shelf life has been developed and is commercially available as Xromi.

[0006] Xromi is a patented composition disclosed in patent number EP3644967A1, which comprises a stable aqueous solution of hydroxyurea, preservatives (including methyl hydroxybenzoate and / or ethyl hydroxybenzoate), sweeteners, viscosity modifiers, flavoring agents, pH regulators (one of sodium hydroxide, potassium hydroxide, sodium bicarbonate and sodium carbonate) or a mixture of one or more of these substances, wherein the aqueous solution of hydroxyurea is controlled to have a pH between 6.5 and 6.7. The prior art claims that it can be safely stored at ambient temperature for a long time without significant deterioration. However, the preparation was found to be stable for at least two months at 25°C / 60% RH (at room temperature). Therefore, the commercially available preparation Xromi needs to be stored in a refrigerator (2°C - 8°C), and after the bottle is first opened, the unused content is discarded after 12 weeks. The need for refrigeration imposes an additional burden on manufacturers, suppliers and distributors: to ensure that the product is carefully transported, handled and stored at the appropriate temperature and to reduce the risk of exposure to temperatures outside the marked storage conditions; at the same time, it also increases the additional cost of the preparation.

[0007] Therefore, there is still a need in the art to develop a room-temperature stable liquid oral preparation for pediatric patients that overcomes the above limitations of the prior art, namely the need for compounded drugs and refrigerated ready-to-use liquid solutions. Summary of the Invention

[0008] The present invention provides an oral dosage form, such as a liquid preparation, and a method for preparing such a preparation. The liquid preparation of the present invention comprises an effective amount of hydroxyurea or a pharmaceutically acceptable salt thereof, wherein the preparation is stable when maintained at room temperature for more than 3 months.

[0009] Another aspect of the present invention provides a ready-to-use liquid preparation comprising at least 10% hydroxyurea and one or more pharmaceutically acceptable excipients, wherein the selected excipients provide extended shelf-life stability at room temperature when compared to existing commercially available preparations.

[0010] In yet another aspect, the ready-to-use liquid preparation is selected from solutions, suspensions, syrups, emulsions or elixirs, and more particularly, the present invention provides an oral liquid suspension comprising an effective amount of hydroxyurea suspended in a non-aqueous carrier agent.

[0011] The liquid suspension of the present invention also provides a method for its preparation, wherein the ready-to-use liquid is used for the treatment of sickle cell anemia in pediatric patients who have difficulty swallowing capsule or tablet dosage forms. Brief Description of the Drawings

[0012] Figure A A linear graph showing the mean plasma concentration of hydroxyurea in the test product (T) and the reference product (R) relative to time (N = 28)

[0013] Figure B Represents the log average of the mean plasma concentration of hydroxyurea for the test product (T) and the reference product (R) relative to time (N = 28). Detailed Description

[0014] The following paragraphs detail various embodiments of the present invention. For the avoidance of doubt, it is specifically intended that any particular feature described individually in any one of these paragraphs (or part thereof) may be combined with one or more other features described in one or more of the remaining paragraphs (or part thereof). In other words, it is expressly intended that the features described individually in each of the following paragraphs (or part thereof) represent important aspects of the present invention, which may be adopted individually and combined with other important aspects of the present invention described elsewhere in this specification as a whole, including the examples. Those skilled in the art will understand that the present invention extends to such combinations of features, and for the sake of brevity, these combinations are not detailed herein.

[0015] Unless otherwise indicated herein or clearly contradicted by the context, the terms "a", "an", and "the" and similar referents used in the context of describing the present invention (particularly in the context of the following claims) shall be construed to cover both the singular and the plural.

[0016] The term "hydroxyurea or a pharmaceutically acceptable salt thereof" refers to hydroxyurea in the free base form, or includes its salts, including but not limited to inorganic or organic salts, hydrates, and solvates known to those skilled in the art.

[0017] The term pharmaceutically acceptable excipient refers to a pharmacologically inactive component of a pharmaceutical product, such as wetting agents, dispersants, co-solvents, sweeteners, flavoring agents, preservatives, pH regulators, stabilizers, buffers, solubilizers, and other ingredients. Excipients that can be used to prepare pharmaceutical compositions are generally safe, non-toxic, and can be used for veterinary and human pharmaceutical uses.

[0018] The term "antioxidant" is used herein to describe any compound or combination of compounds that prevents or slows the oxidation of hydroxyurea.

[0019] The term "liquid formulation" refers to a drug delivery intended for oral administration, typically in the form of a solution, suspension, syrup, emulsion, or elixir.

[0020] The term "room temperature stability" refers to the chemical and physical stability of hydroxyurea when stored at room temperature for a period of at least one month, particularly for a period of two months, and more particularly for a period of more than three months.

[0021] The term "ready-to-use" refers to a liquid preparation that can be administered without formulation or reconstitution at the time of or prior to administration of the preparation (e.g., 1 hour, 12 hours, 24 hours, 1 day, 3 days or 7 days).

[0022] The present invention relates to a pharmaceutical composition for oral administration, which comprises hydroxyurea or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in a ready-to-use formulation, i.e., wherein the final composition does not require dilution or compounding or reconstitution prior to administration and is suitable for administration at the time of production without a pharmacist having to compound the formulation.

[0023] It is well known that hydroxyurea cannot be stable in water for a long period of time when stored at room temperature, which is why commercially available liquid oral solutions need to be stored in a refrigerator (2°C - 8°C) and remain stable for 2 or 3 months when stored at room temperature. Unfortunately, none of the currently available liquid dosage forms remain stable at room temperature for longer than 3 months. Therefore, there is a need for a liquid dosage form of hydroxyurea that retains the efficacy of the active ingredient, is easy to administer to pediatric patients who have difficulty swallowing solid dosage forms, and remains stable at room temperature for a longer period of time.

[0024] The present invention provides a ready-to-use liquid preparation comprising an effective amount of hydroxyurea or a pharmaceutically acceptable salt thereof, which is suitable for oral administration and remains stable at room temperature for at least 3 months.

[0025] In one embodiment, the liquid preparation can be formulated in the form of a solution, suspension, emulsion, syrup or elixir, more preferably in the form of a ready-to-use liquid suspension.

[0026] In another embodiment, the present invention provides a ready-to-use oral suspension that remains stable at room temperature during dispensing, storage and even after reopening the container containing the suspension.

[0027] In another embodiment, the present invention provides a ready-to-use oral liquid suspension comprising hydroxyurea or a pharmaceutically acceptable salt thereof, wherein the hydroxyurea is present as the free base and is included in an amount of 5 - 15% (w / v) based on the total volume of the suspension.

[0028] In one embodiment, the present invention provides an oral liquid suspension comprising 10% hydroxyurea suspended in a non-aqueous carrier, more preferably suspended in an edible non-aqueous medium, wherein the edible non-aqueous medium is vegetable oil, partially hydrogenated vegetable oil, medium-chain triglycerides, free fatty acids, etc.

[0029] In one embodiment, hydroxyurea is micronized to ensure uniform dispersion of hydroxyurea in the vehicle and easy redispersion with simple shaking.

[0030] Micronization also ensures that hydroxyurea remains uniform for a sufficient time to ensure uniform extraction of the dose and thus ensure the accuracy of the dose.

[0031] In another embodiment, the liquid suspension further comprises at least one excipient selected from the group consisting of wetting agents, suspending agents, co-solvents, sweeteners, flavoring agents, wetting agents, and antioxidants.

[0032] Sweeteners provide the desired sweetness and palatability to the dosage form and include, but are not limited to, sorbitol, dextrose, sodium saccharin, saccharin, glucose, sucralose, trehalose, fructose, xylose, dextrose, maltitol, xylitol, mannitol, aspartame, alitame, neotame, or mixtures thereof. Preferred sweeteners are sodium saccharin, saccharin, or sucralose.

[0033] In a preferred embodiment, the sweetener is sucralose, which is present in an amount of 0.05 - 2% w / v, more preferably 0.2% w / v.

[0034] Flavoring agents enhance and modify the taste and aroma of the dosage form, which include masking taste and improving palatability. Flavoring agents used in a particular embodiment include, but are not limited to, mint, lemon oil, vanilla, citrus oils, including lemon, orange, grape, lime, and grapefruit, or mixtures thereof.

[0035] In a preferred embodiment, the flavoring agents are strawberry and vanilla, wherein the strawberry flavoring agent is present in an amount in the range of 0.05 - 1% w / v and the vanilla flavoring agent is present in an amount in the range of 0.05 - 0.5% w / w.

[0036] In one embodiment, the wetting agent can be selected from any suitable water-miscible ionic or non-ionic surfactant, such as polysorbate, sodium dodecyl sulfate, poloxamer 188, etc., and more preferably is polysorbate.

[0037] In a preferred embodiment, polysorbate is present in an amount of 0.05 - 1% w / v, more preferably 0.1% w / v.

[0038] In one embodiment, the formulation contains an effective amount of one or more stabilizers to promote the stability of hydroxyurea and prevent unacceptable deterioration. Stabilizers can include one or more antioxidants, such as soluble agents, like vitamin E, vitamin E acetate, TPGS, propyl gallate, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, and mixtures thereof.

[0039] The antioxidant acts as a stabilizing agent to prevent oxidative deterioration, thereby obtaining a stable suspension with a desired shelf life, and is present in an amount effective to stabilize the hydroxyurea contained therein such that the hydroxyurea does not deteriorate to an unacceptable extent, and the suspension is considered to be stable for at least 3 months when stored at room temperature.

[0040] In a preferred embodiment, the antioxidant is vitamin E acetate present in an amount in the range of 0.005 - 0.5% w / v, more preferably 0.05% w / v.

[0041] In another embodiment, the dispersing / suspending agent is selected from, but not limited to, calcium phosphate, calcium silicate, colloidal silica, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate, and talc, and most preferably is colloidal silica.

[0042] In a preferred embodiment, the colloidal silica is present in an amount of 1 - 5% w / v, more preferably 1.5% w / v.

[0043] In another embodiment, the present invention provides a ready-to-use stable oral suspension comprising:

[0044] i. 5 - 15% w / v of hydroxyurea or a pharmaceutically acceptable salt thereof as the active ingredient;

[0045] ii. 0.05 - 2% w / v of a sweetening agent;

[0046] iii. 0.05 - 1% w / v of a flavoring agent;

[0047] iv. 0.05 - 1% w / v of a wetting agent;

[0048] v. 0.005 - 0.5% w / v of an antioxidant; and

[0049] vi. 1 - 5% w / v of a dispersing / suspending agent,

[0050] wherein the suspension is obtained by dispersing the active agent and other excipients in an oily vehicle, most preferably a vegetable oil.

[0051] In a preferred embodiment, the present invention provides a ready-to-use oral suspension comprising:

[0052] a. 10% w / v of hydroxyurea or a pharmaceutically acceptable salt thereof as the active ingredient;

[0053] b. 0.2% w / w of sucralose as the sweetening agent;

[0054] c. 0.26% w / v of dried strawberries as the flavoring agent;

[0055] d. 0.5% v / v of strawberries as a flavoring agent;

[0056] e. 0.32% w / v of dried vanilla as a flavoring agent;

[0057] f. 0.1% w / v of polysorbate as a wetting agent / surfactant;

[0058] g. 0.05% w / v of vitamin E acetate as an antioxidant / stabilizer; and

[0059] h. 1.5% w / v of colloidal silica as a dispersing / suspending agent.

[0060] The present invention provides a ready-to-use pharmaceutical liquid suspension which has a shelf stability of more than 3 months when stored at room temperature, while hydroxyurea in the suspension is generally more chemically and physically stable than commercially available liquid solutions.

[0061] In another embodiment, the present invention provides a ready-to-use liquid suspension which can be easily administered to pediatric patients for the treatment of sickle cell anemia.

[0062] In one embodiment, the room temperature stability formulation contains no more than 6% total impurities formed during the storage period. In one embodiment, the formulation contains no more than 5% total impurities formed during the storage period, and more particularly no more than 2% total impurities formed during the storage period. In one embodiment, the storage period of the formulation of the present invention can be a reasonable period during which the formulation has sufficient chemical and physical stability. The storage period can be selected to be, for example, at least about one month, at least about three months.

[0063] In another embodiment, the present invention provides a method for preparing a ready-to-use oral liquid suspension containing hydroxyurea. The method for preparing the liquid suspension includes mixing hydroxyurea with one or more excipients, wherein the method includes: dispersing the drug and silica in vegetable oil containing dissolved antioxidant and wetting agent under stirring, incorporating flavoring agent, sweetener and bulking sweetener under stirring, and packaging the suspension into a suitable container.

[0064] In another embodiment, the present invention provides a method for preparing a room temperature stability suspension, which includes the following steps:

[0065] · Preparing a bulk suspension phase by mixing vegetable oil (medium-chain triglyceride) with polysorbate, colloidal silica, sucralose and vitamin E acetate under continuous stirring for 1 hour to obtain a lump-free suspension;

[0066] · Add micronized hydroxycarbamide to the bulk suspension obtained from step (a) with continuous stirring to form a lump-free dispersion, and mix for 1 - 2 hours;

[0067] · Add the flavoring agent to the above solution obtained in step (b) with continuous stirring until a lump-free dispersion is obtained;

[0068] · Filter the suspension through a suitable filter, and then fill and seal it in a suitable package.

[0069] The following examples illustrate the present invention, which do not limit the scope of the present invention in any way. Those skilled in the art will readily modify the method for manufacturing the pharmaceutical composition, or may modify the composition with similar materials, and finally those skilled in the art may modify the method of administering the composition of the present invention.

[0070] Examples

[0071] Example 1: Hydroxycarbamide Oral Liquid Suspension

[0072] Table 1: Hydroxycarbamide Oral Suspension for Room Temperature Stability

[0073] Ingredient Function in the Preparation Amount (% w / v) Hydroxycarbamide Active Pharmaceutical Ingredient 10.0 Colloidal Silicon Dioxide Dispersant 1.5 Sucralose Artificial Sweetener 0.2 Polysorbate 80 Wetting Agent 0.1 Strawberry Flavor Mixture Flavoring Agent 1.1 Vitamin E Acetate Antioxidant 0.05 Vegetable Oil Vehicle To 100.0 in Sufficient Quantity

[0074] Disperse hydroxycarbamide and colloidal silicon dioxide in vegetable oil to obtain a uniform suspension.

[0075] Example 2: Hydroxycarbamide Oral Liquid Suspension

[0076] Table 2: Hydroxycarbamide Oral Suspension for Room Temperature Stability

[0077]

[0078]

[0079] Example 3

[0080] Table 3: Hydroxycarbamide Oral Suspension for Room Temperature Stability

[0081] Ingredient Function in the Preparation Amount (% w / v) Hydroxycarbamide API 10％ Colloidal Silicon Dioxide Suspending Agent / Dispersant 1.5％ Sucralose Sweetener 0.2％ Polysorbate 80 Surfactant 0.1％ Dried Strawberries Flavoring Agent 0.26％ Strawberries Flavoring Agent 0.526％ Vitamin E Acetate Stabilizer / Antioxidant 0.05％ Dried Vanilla Flavoring Agent 0.327％ Medium Chain Triglycerides Vehicle To 100.0 in Sufficient Quantity

[0082] Manufacturing process for preparing a ready-to-use suspension of hydroxycarbamide:

[0083] 1. Mix medium-chain triglycerides with colloidal silicon dioxide, sucralose, and vitamin E acetate in a container with continuous stirring to obtain a bulk suspension phase.

[0084] 2. Add micronized hydroxycarbamide with continuous stirring and mix it with the bulk suspension obtained in step 1 of the above method until a lump-free dispersion is obtained.

[0085] 3. With continuous stirring, add a suitable flavoring agent to the suspension obtained in step 2 until a lump-free suspension is obtained. Allow to soak and mix for 2 hours.

[0086] 4. Filter the entire suspension through a nylon cloth and mix again for 15 minutes.

[0087] 5. Transfer the filtered suspension into an amber bottle and seal the bottle.

[0088] Example - 4 Stability Test

[0089] Expose the sealed bottle of the hydroxyurea suspension prepared in Example 3 to 25 °C ± 2 °C and RH 60% ± 5% and test for physical stability such as description, weight, and chemical stability such as shelf life and impurities.

[0090] Table 4: Stability at 25°C ± 2°C and Relative Humidity 60% ± 5%

[0091]

[0092] Conclusion: In a 3-month long-term stability study (temperature 25 °C ± 2 °C & RH 60% ± 5%), the claimed product meets the stability requirements.

[0093] Expose the sealed bottle of the hydroxyurea suspension prepared in Example 3 to 30 °C ± 2 °C and RH 75% ± 5% and test for physical stability such as description, weight, and chemical stability such as shelf life and impurities.

[0094] Table 5: Stability at Temperature 30°C ± 2°C and RH 75% ± 5%

[0095]

[0096] Conclusion: In a 3-month long-term stability study (temperature 30 °C ± 2 °C & RH 75% ± 5%), the claimed product meets the stability requirements.

[0097] Example - 5 Bioequivalence Study

[0098] This study evaluated the pharmacokinetic parameters in healthy adult subjects under fasting conditions and compared the bioequivalence of hydroxyurea suspension (100 mg / ml) with XROMI (hydroxyurea oral solution 100 mg / ml) manufactured by Nova Laboratories Ltd. at room temperature stability.

[0099] Study:Open-label, balanced, randomized, two-treatment, two-sequence, two-period, single-dose, two-way crossover, oral bioequivalence study comparing two formulations of hydroxyurea oral suspension (100 mg / ml) of the present invention and XROMI (hydroxyamine oral solution 100 mg / ml) manufactured by Novartis Laboratories Limited in healthy adult subjects under fasting conditions.

[0100] Test Product (T): Hydroxyurea Oral Suspension 100 mg / ml (of the present invention)

[0101] Each ml contains: Hydroxyurea IP……………100 mg

[0102] Reference Product (R): (Hydroxyurea Oral Solution 100 mg / ml)

[0103] Each ml contains: Hydroxyurea………………………100 mg

[0104] Manufacturer: Novartis Laboratories Limited

[0105] Dose: Test Product (T) Hydroxyurea Oral Suspension 500 mg / 5 ml

[0106] Reference Product (R) Oral Suspension IP 100 mg / ml of XROMI or Oral Solution 500 mg / ml.

[0107] Method:

[0108] During the informed consent procedure, the clinical staff clearly explained to the subjects all the study-related procedures, duration, dates and time schedules, information on study treatments, and the confidentiality of the subjects' data. Subjects who signed the consent form and expressed their willingness to participate in the study were enrolled. Subjects who met the eligibility criteria during the assessment of inclusion and exclusion criteria, and who were found to be healthy and had laboratory investigation values within the reference limits during the physical examination were considered eligible to enter the study. Subjects with pre-study laboratory values outside the reference range were also considered for participation, provided that the investigator considered these values to be clinically insignificant. Treatment was assigned to the subjects according to a randomization schedule generated by using software version 9.4 or higher. Blood samples were drawn before dosing (00.00 hours) and 24.00 hours after dosing in each period.

[0109] Using software version 9.4 for statistical analysis to evaluate the bioequivalence between the pharmacokinetic parameters of the test formulation and the reference formulation. The plasma concentration of hydroxyurea was quantified by using validated LC-MS / MS.

[0110] Number of Subjects:

[0111] · Subjects planned: 32 subjects

[0112] · Subjects enrolled: 30 subjects

[0113] · Number of subjects who completed the study: 28 subjects

[0114] · Number of subjects who withdrew from the study: 2 subjects (Subject No. 27 in Period I and Subject No. 12 in Period II)

[0115] · Number of subjects who dropped out: None

[0116] · Number of subject samples bioanalyzed: 30 subjects

[0117] · Number of subjects included in pharmacokinetic analysis: 28 subjects

[0118] · Number of subjects included in statistical analysis: 28 subjects

[0119] · Number of subjects included in safety assessment: 30 subjects

[0120] Main Criteria for Diagnosis and Inclusion:

[0121] Healthy adult human subjects aged 18 to 45 years (including both 18 and 45 years) and with a body mass index of 18.50 to 30.00 kg / m 2 (including 18.50 kg / m 2 and 30.00 kg / m 2 both), as determined by clinical history / medical history, physical examination, vital sign measurement, clinical laboratory assessment, and 12-lead ECG, were enrolled in this study.

[0122] Administration Method:

[0123] According to the randomization schedule, after an overnight fast of at least 10.00 hours, the IMP was administered to the subjects in the sitting position at each period. The oral suspension dose was administered by trained personnel in 240 mL ± 2 mL of water at ambient temperature under the supervision of the principal investigator / authorized trained person according to the current version of the SOP for dosing. The doses were administered in a staggered manner to maintain the subsequent blood sampling schedule.

[0124] Administration of the Pharmaceutical Product:

[0125] Subjects receiving the test product or reference product received a single oral suspension dose. The researchers inverted the syringe three times to ensure homogeneous mixing of the suspension that was to be directly administered into the subjects' mouths. Subjects were instructed to swallow with approximately 50 mL of water in approximately 240 ± 2 mL at ambient temperature. The dispensed syringe was carefully rinsed twice with a portion of this water (approximately 2 x 5 mL). The rinsate and the remainder of the 240 ± 2 mL of water were then given to the subjects, thus ensuring complete administration of the dispensed study product.

[0126] Duration of the Study:

[0127] The total duration of the study was 6 days, starting from the date of registration in the first period until after the study samples in the second period.

[0128] Evaluation Criteria:

[0129] Based on the 90% confidence interval of the geometric mean ratio of C max and AUC 0-t obtained after single-dose administration under fasting conditions, the comparative bioavailability of the test product versus the reference product was evaluated.

[0130] The acceptance criterion for bioequivalence was that the entire confidence interval of the difference in the means of the Ln-transformed C max and AUC 0-t should be between 80.00 - 125.00%.

[0131] Pharmacokinetic Parameters:

[0132] Using the estimated plasma concentration-time curve of hydroxyurea, the following pharmacokinetic parameters were calculated using software version 8.4.

[0133] Main Pharmacokinetic Parameters : C max 、AUC 0-t and AUC 0-inf

[0134] Secondary Pharmacokinetic Parameters : t max 、t 1 / 2 、K el and AUC%Extra_obs

[0135] Statistical Analysis:

[0136] Using software version 9.4 for statistical analysis. For C max 、AUC 0-t and AUC 0-inf, estimate the geometric mean and coefficient of variation. For AUC%Extrap, t max , t 1 / 2 , K el , estimate the arithmetic mean and standard deviation. For log-transformed C max , AUC 0-t and AUC 0-inf , estimate ANOVA at α 0.05. The ANOVA model includes sequence, treatment, and period as fixed effects, and includes subjects (sequence) as random effects. For log-transformed C max , AUC 0-t and AUC 0-inf , calculate the 90% confidence interval for the difference in treatment least-squares geometric means.

[0137] The confidence interval is expressed as a percentage of the least-squares geometric mean (LSM) relative to the reference treatment. Calculate the variability within subjects using log-transformed pharmacokinetic parameters.

[0138] For log-transformed C max , AUC 0-t and AUC 0-inf , calculate the ratio of the least-squares geometric means of the test product and the reference product.

[0139] For hydroxyurea, the 90% confidence interval for the difference in the least-squares geometric means of the log-transformed values of C max , AUC 0-t and AUC 0-inf (T relative to R) should be between 80.0 - 125.00%.

[0140] Safety Evaluation:

[0141] Include all subjects who received at least one dose of the study product in the safety evaluation.

[0142] Include all subjects who received at least one dose of the study product in the safety evaluation. The safety assessment is based on clinical laboratory evaluations, ECG recordings, clinical examinations, and measurements of vital signs (body temperature, radial artery pulse rate, sitting blood pressure, and respiratory rate) and post-study clinical laboratory safety evaluations. Laboratory evaluations (hematology, biochemistry, serology, and urine analysis) and ECG recordings are performed at screening. Clinical examinations along with vital signs (body temperature, radial artery pulse rate, sitting blood pressure, respiratory rate) are performed at screening during each cycle during the in-patient and check-out periods. Vital signs (body temperature, radial artery pulse rate, and sitting blood pressure) are recorded within 2.00 hours before dosing in each cycle, and the health status is inquired about.

[0143] Vital after administration: At the following times: before drug administration and at 2.00, 4.00, 6.00, 12.00 and 24.00 hours after drug administration, measure health assessment, pulse rate & SBP and DBP in the sitting position.

[0144] Results:

[0145] A) Pharmacokinetics and statistical evaluation:

[0146] Table 6: Descriptive statistics of pharmacokinetic parameters for hydroxycarbamide, test product (T) and reference (R) (N = 28)

[0147]

[0148]

[0149] Table B: Geometric least squares means, ratios, 90% confidence intervals, powers and ISCV of pharmacokinetic parameters (Cmax, AUC 0-t and AUC 0-inf ) of hydroxycarbamide (N = 28)

[0150]

[0151] A. Curve of mean plasma concentration versus time

[0152] Figure A Linear plot of mean plasma concentration of hydroxycarbamide for test product (T) and reference product (R) versus time (N = 28)

[0153] Figure B Plot of log mean plasma concentration of hydroxycarbamide for test product (T) and reference product (R) versus time (N = 28)

[0154] Conclusion:

[0155] The 90% confidence interval for the difference in least squares means of the Ln-transformed pharmacokinetic parameters C max , AUC 0-t and AUC 0-inf of hydroxycarbamide is within the acceptable limits of bioequivalence of 80.00 - 125.00%.

[0156] Therefore, it is concluded that the test product (T) hydroxycarbamide oral suspension IP 100 mg / ml of the present invention and the reference product (R) (hydroxycarbamide oral solution 100 mg / ml) produced by Novartis Laboratories Limited are bioequivalent in terms of rate and extent of absorption.

Claims

1. A stable liquid formulation comprising hydroxyurea or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the liquid drug formulation is stable when stored at room temperature for more than 3 months.

2. The stable liquid formulation according to claim 1, wherein the stable liquid formulation is a ready-to-use oral liquid suspension.

3. The stable liquid formulation according to claim 1, comprising hydroxyurea in an amount of 5-15% (w / v) based on the total volume of the suspension.

4. The stable liquid formulation of claim 1, comprising hydroxyurea in micronized form.

5. The stable liquid formulation according to claim 1, comprising at least one excipient selected from the group consisting of a wetting agent, a suspending agent, a co-solvent, a sweetener, a flavoring agent, a wetting agent and an antioxidant.

6. A ready-to-use oral suspension according to any one of the preceding claims, comprising: a. 5-15% w / v of hydroxyurea or a pharmaceutically acceptable salt thereof as an active ingredient; b. 0.05-2% w / v sweetener; c. 0.05-1% w / v flavoring agent; d. 0.05-1% w / v wetting agent; e. 0.005-0.5% w / v antioxidant; and f. 1-5% w / v dispersant / suspending agent The suspension is obtained by dispersing the active agent and other excipients in an oily vehicle, most preferably a vegetable oil.

7. The ready-to-use oral suspension according to claim 5, comprising: a. 10% w / v of hydroxyurea or a pharmaceutically acceptable salt thereof as an active ingredient; b. 0.2% w / w sucralose as a sweetener; c. 0.26% w / v dried strawberries as flavoring; d. 0.5% v / v strawberry as flavoring; e. 0.32% w / v dried vanilla as flavoring; f. 0.1% w / v polysorbate as a wetting agent / surfactant; g. 0.05% w / v vitamin E acetate as an antioxidant / stabilizer; and h. 1.5% w / v colloidal silicon dioxide as a dispersing / suspending agent.

8. A method for preparing a stable liquid formulation of hydroxyurea, wherein the method comprises the following steps: a) preparing a bulk suspension phase by mixing vegetable oil (medium chain triglycerides) with polysorbate, colloidal silicon dioxide, sucralose and vitamin E acetate under continuous stirring for 1 hour to obtain a lump-free suspension; b) adding micronized hydroxyurea to the bulk suspension obtained from step (a) under continuous stirring to form a lump-free dispersion and mixing for 1-2 hours; c) adding a flavoring agent to the above solution obtained in step (b) under continuous stirring until a lump-free dispersion is obtained; d) Filter the suspension through a suitable filter and then fill and seal in suitable packaging.

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