DESC:FIELD OF INVENTION
The present invention relates to a pharmaceutical composition comprising Hydroxyurea and pharmaceutically acceptable excipients, more particularly, a dispersible tablet having sufficient shelf-life.
BACKGROUND
Hydroxyurea, also known as hydroxycarbamide, is an antineoplastic agent widely utilized in the treatment of chronic myeloid leukemia and sickle cell disease. Although its exact mechanism of action remains incompletely understood, it is believed to inhibit DNA synthesis by targeting ribonucleoside diphosphate reductase, an enzyme crucial for DNA replication. This inhibition prevents cells from progressing through the S phase, ultimately leading to cell death. Additionally, hydroxyurea is known to impair the repair of DNA damaged by chemical agents or radiation.
Sickle cell disease is a genetic blood disorder that predominantly affects children, characterized by lower levels of healthy red blood cells. It is an inherited condition, passed down through parental genes. In pediatric patients, hydroxyurea is the primary pharmacological intervention to manage sickle cell anemia. The U.S. Food and Drug Administration (FDA) has approved hydroxyurea in tablet and capsule forms; however, these solid dosage forms present significant challenges for children, particularly due to difficulties in swallowing and issues related to gastrointestinal stability. These factors contribute to poor adherence, leading to suboptimal disease management.
To address these challenges, pharmacists have often resorted to compounding an oral solution of hydroxyurea. Typically, this involves creating a 100 mg/mL solution by mixing the contents of twenty 500 mg capsules with 50 mL of sterile water, followed by stirring for several hours and blending with a flavored syrup base. The resulting solution is then stored in an amber plastic container. However, this compounding approach is not standardized and remains unlicensed in many pharmacies, limiting its accessibility. Furthermore, inconsistencies in compounding practices increase the risk of dosing errors, reduced efficacy, adverse reactions, contamination, and variability in the final formulation due to the multiple steps required for preparation.
To overcome the drawbacks of compounded formulations, a ready-to-use, child-friendly hydroxyurea solution known as Xromi was developed. Xromi is a strawberry-flavored, multidose oral solution with a concentration of 100 mg/mL, designed for ease of use without the need for reconstitution. Xromi, disclosed in patent EP3644967A1, comprises a stable aqueous hydroxycarbamide solution. Its composition includes a preservative (methyl hydroxybenzoate and/or ethyl hydroxybenzoate), a sweetener, a viscosity-modifying agent, a flavoring agent, and a pH adjuster, such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, or sodium carbonate. The pH of the solution is controlled between 6.5 and 6.7, purportedly allowing for safe ambient storage without significant degradation.

Despite its innovative formulation, Xromi has limitations. The marketed product demonstrates stability at room temperature (25°C / 60% RH) for only about two months, necessitating refrigerated storage (2°C – 8°C) to ensure product integrity. Once the bottle is opened, any unused contents must be discarded after 12 weeks. This need for refrigeration adds logistical and financial burdens across the supply chain, including additional costs for manufacturers, suppliers, and distributors to maintain strict temperature-controlled environments.
Alternative formulations have been explored, such as the dry syrup for pediatric sickle cell disease treatment disclosed by Juma A. Mohamedi et al. The study demonstrated that upon reconstitution, the dry syrup exhibited no significant pH changes over a 14-day storage period. However, this approach still requires reconstitution and does not fully address stability concerns at room temperature over extended periods.
Pediatric dosing of hydroxyurea is typically initiated at 20 mg/kg/day, with adjustments based on the child's weight. Given this dosing variability, a liquid formulation with a shelf life exceeding 15 days is essential to accommodate changes in daily dosage requirements without frequent re-preparation.
Thus, there remains a significant need to develop a stable, room-temperature formulation of hydroxyurea that eliminates the need for extemporaneous compounding while offering a shelf life of more than 15 days. The present invention aims to address these requirements by introducing a novel dosage form: a dispersible tablet. This formulation is designed to provide a hydroxyurea formulation that remains stable at room temperature after reconstitution, thus eliminating the need for refrigeration.
This novel dosage form represents a significant advancement in the treatment of pediatric sickle cell disease, offering improved stability, ease of use, and cost-effectiveness, ultimately enhancing therapeutic outcomes for children.
SUMMARY OF THE INVENTION
The present invention provides a pharmaceutical formulation comprising effective amount of Hydroxyurea and combinations of excipients which extends the stability of pharmaceutical formulation when in a liquid dosage form. The pharmaceutical formulation is a unit dose dispersible tablet intended for dispersion using spoonful of water prior to oral administration.
In accordance with the above objective the present invention provides a dispersible tablet comprising Hydroxyurea which is reconstituted into a suspension with a spoonful of water or suitable aqueous diluent prior to administration to form an ingestible formulation which have extended shelf-life of more than 15 days.
In another aspect the present invention provides a suitable dosage form for treating sickle cell disease in pediatric patients who has difficulty in swallowing tablet and capsule.

DETAILED DESCRIPTION OF THE INVENTION
The embodiments of the invention described below are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art can appreciate and understand the principles and practices of the invention.
The use of the terms "a" and "an" and "the" and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
The term “excipients” are substances other than the pharmacologically active drug or prodrug which are included in the manufacturing process.
The term “patient” as in treatment of “a patient” refers to a mammalian individual afflicted with or prone to a condition, disease, or disorder as specified herein, and includes both humans and animals.
As used herein, dispersible tablet is formulated preferably by direct compression which is suitable for rapid dispersion in water or any other suitable solvent for oral administration.
As used herein “shelf-stable” refers to liquid formulation chemically and physically stable at room temperature or under normal atmospheric conditions or duration of time in which the reconstituted liquid remain stable.
As used herein “effective amount” or “therapeutically effective amount” of an active agent; the terms “effective amount” or “therapeutically effective amount” mean an amount of an active agent that is nontoxic, but sufficient to provide the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on the age, weight, and general condition of the subject, the severity of the condition being treated, the judgment of the clinician, and the like. Thus, it is not always possible to specify an exact “effective amount”; however, an appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
The present invention provides a stable unit dose pharmaceutical formulation comprising effective amount of Hydroxyurea in a solid dosage form.
In an embodiment a stable pharmaceutical formulation comprising Hydroxyurea in a solid dosage form which is dispersed with a diluent just before use.
In an embodiment the present invention provides a pharmaceutical formulation comprising Hydroxyurea in amount ranging from 50 to 1000 mg.
The present invention provides a stable solid dosage form in form of dispersible tablet that increases patient compliance to the treatment that can be easily used and does not cause difficulty in swallowing compared to other dosage forms marketed as capsule and tablet dosage form. The pharmaceutical invention of present invention also provides an extended shelf-life of the dispersible tablet which at the time of oral administration can be dispersed in suitable amount of water or a suitable vehicle.
The pharmaceutical formulations of the invention may be in dispersible tablet or dispersible tablet packed in unit dose.
Sickle cell anemia is a genetic disorder characterized by the presence of abnormal hemoglobin, leading to the deformation of red blood cells into a sickle shape. This condition often results in chronic pain, organ damage, and a reduced lifespan. Hydroxyurea has demonstrated effectiveness in the treatment of sickle cell anemia by increasing fetal hemoglobin levels, reducing the frequency of painful crises, and alleviating other associated symptoms. However, the conventional formulations of hydroxyurea tablets may pose challenges in achieving precise dosage control, especially for pediatric patients or individuals requiring tailored dosages.
The need for a dispersible tablet formulation of hydroxyurea arises from the desire to provide a more flexible and patient-friendly dosage form. Pediatric patients, in particular, may face difficulties in swallowing conventional tablets or capsules. Additionally, the ability to easily break the tablet into smaller portions ensures accurate dosing, allowing healthcare providers to titrate the medication according to individual patient requirements. This adaptability is crucial, as sickle cell anemia varies widely in its clinical presentation and severity among patients.
Thus, in an embodiment the present invention provides an oral dosage form in a dispersible tablet form which can be dispersed with a suitable vehicle for oral administration or in the form of a dispersible tablet which can be put into mouth and allowed to disperse and dissolved in the oral cavity.
In another embodiment the present invention provides a dispersible tablet containing hydroxyurea in a range from 50mg to 1000mg, wherein the tablets comprise of break lines. The incorporation of break lines into the tablet design facilitates easy division into smaller, more manageable doses, ensuring precise administration in alignment with the recommended maximum dosage strength of 15mg/kg/day dosage for hydroxyurea therapy. This present invention aims to enhance patient compliance, particularly among pediatric populations, by offering a user-friendly and customizable treatment option for sickle cell anemia management. The dispersible tablet's design not only addresses challenges associated with conventional tablets but also opens avenues for personalized medicine in the context of sickle cell anemia treatment.
In an embodiment the dispersible tablet or orodispersible tablet has extended shelf storage of more than 15 days.
In another embodiment the dispersible or orodispersible tablet can be packed in unit dose alu-alu blister or alu strip.
In an embodiment the present invention provides a unit dose dispersible or orodispersible tablet comprising effective amount of Hydroxyurea and one or more pharmaceutically acceptable excipients.
Oral dosage forms of the invention comprise at least one pharmaceutically acceptable excipient selected from the group comprising filler, binder, lubricant, disintegrant, solubility enhancing agent, pH-modulating agent, sweetener/sweetening agent, flavoring agent, coloring agent and coating agent.
In an another embodiment the present invention provides one or more sweetening agents selected from aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, sucralose, fructose and other such materials known to those of ordinary skill in the art.
In an another embodiment sweetening agent is present in an amount ranging from 2 to 1000 mg.
In a preferred embodiment sweetening agent is mannitol present in an amount of 400 mg.
In an another embodiment sweetening agent is sucralose present in an amount of 5 mg.
In an embodiment the present invention comprises one or more disintegrant selected from group consisting of starch and modified starches, microcrystalline cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, CMC-Ca, CMC-Na, microcrystalline cellulose, cross-linked PV or combinations thereof.
In an embodiment disintengrant is present in an amount ranging from 20 to 50 mg.
In an another embodiment the preferred disintegrant is croscarmellose sodium or crospovidone present in an amount of 36 mg.
In an another embodiment the present invention further comprises glidant selected from colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc or combinations thereof.
In an embodiment the glidant is present in an amount of 1 to 10 mg.
In an embodiment the present invention further comprises lubricant selected from calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate or combinations thereof.
In an another embodiment lubricant is present in an amount of 0.5 to 10 mg.
In a preferred embodiment lubricant is magnesium stearate present in an amount of 2 mg.
In a preferred embodiment glidant is colloidal silicon dioxide present in an amount of 2 mg.
The present invention provides a dispersible tablet comprising:
i. 50 to 1000 mg of Hydroxyurea or pharmaceutically acceptable salts and;
ii. 2 to 1000 mg of sweetening agent and;
iii. 20 to 50 mg of disintegrant and;
iv. 1 to 10 mg of glidant and;
v. 0.5 to 10 mg of lubricant
In an another embodiment the present invention provides dispersible tablets comprising
i. 100 mg of Hydroxyurea as an active ingredient and;
ii. 400 mg of Mannitol as bulk sweetener and;
iii. 36 mg of Crospovidone/ Croscarmellose sodium as disintegrant and;
iv. 2 mg of colloidal silicon dioxide and;
v. 2 mg of sodium stearyl fumarate as lubricant
The dispersible tablet or orodispersible tablet is preferably manufactured by direct compression or dry granulation.
The present invention is further described in the following comparative, experiments and examples, which are not intended to limit the scope of the invention.
Example-1
S.no Ingredients Role of ingredients Amount
1 Hydroxyurea Active ingredient 100 mg
2 Mannitol SD Bulk sweetener 400 mg
3 Crospovidone Disintegrant 36 mg
4 Sucralose Artificial sweetener 5 mg
5 Orange flavor Flavouring agent 5 mg
6 Colloidal silicon dioxide Dispersing agent, glidant 2 mg
7 Magnesium stearate Lubricant 2 mg
Hydroxyurea, mannitol, crospovidone, sucralose orange flavor and colloidal silicon dioxide are mixed in a suitable blender followed by lubrication with magnesium stearate and compression into tablet.
Example-2
S.no Ingredients Role of ingredients Amount
1 Hydroxyurea Active ingredient 100 mg
2 Mannitol SDF Bulk sweetener 400 mg
3 Croscarmellose sodium Disintegrant 36 mg
4 Sucralose Artificial sweetener 5 mg
5 Vanilla flavor Flavouring agent 5 mg
6 Colloidal silicon dioxide Dispersing agent, glidant 2 mg
7 Sodium stearyl fumarate Lubricant 2 mg

Hydroxyurea, mannitol, croscarmellose sodium, sucralose, vanilla and colloidal silicon dioxide are mixed in a suitable blender followed by lubrication with sodium stearyl fumarate and compression into tablet.
,CLAIMS:1. A dispersible tablet formulation comprising hydroxyurea or pharmaceutically acceptable salts thereof, wherein said hydroxyurea is present in an amount ranging from 50mg to 1000mg, and the said dispersible tablet further comprises of break lines configured to enable division of the tablet into desired dosage strengths, wherein the said tablet is designed to deliver a maximum therapeutic dose of 15mg/kg/day of hydroxyurea to a patient suffering from sickle cell anaemia.
2. The dispersible tablet as claimed in claim 1 comprises one or more pharmaceutically acceptable excipients which are sweetening agent, disintegrant, glidant and lubricant.
3. The dispersible tablet as claimed in claim 1-2 further comprises:
i. 50 to 1000 mg of Hydroxyurea or pharmaceutically acceptable salts and;
ii. 2 to 1000 mg of sweetening agent and;
iii. 20 to 50 mg of disintegrant and;
iv. 1 to 10 mg of glidant and;
v. 0.5 to 10 mg of lubricant
4. The dispersible tablet as claimed in claim 3 further comprises sweetening agent selected from aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, sucralose, fructose
5. The dispersible tablet as claimed in claim 3 further comprises disintegrant selected from starch and modified starches, microcrystalline cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, CMC-Ca, CMC-Na, microcrystalline cellulose, cross-linked PV or combinations thereof.
6. The dispersible tablet as claimed in claim 3 further comprises glidant selected from colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc or combinations thereof.
7. The dispersible tablet as claimed in claim 3 further comprsises lubricant selected from calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate or combinations thereof.
8. The dispersible tablet as claimed in claim 1-7 comprises:
i. 100 mg of Hydroxyurea as an active ingredient and;
ii. 400 mg of Mannitol as bulk sweetener and;
iii. 36 mg of Crospovidone/ Croscarmellose sodium as disintegrant and;
iv. 2 mg of colloidal silicon dioxide and;
v. 2 mg of sodium stearyl fumarate as lubricant