DESC:FIELD OF INVENTION:
The present invention relates to a pharmaceutical composition comprising
Hydroxyurea and pharmaceutically acceptable excipients more particularly a dry syrup
formulation having sufficient shelf life.
BACKGROUND:
Hydroxyurea also known as Hydroxycarbamide is an antineoplastic agent which is
used in the treatment of chronic myeloid leukemia as well as for sickle-cell disease.
The exact mechanism of Hydroxyurea is not exactly known yet but it is believed that
it acts by inhibiting DNA synthesis through the inhibition of ribonucleoside
diphosphate reductase resulting cell death in S Phase. It also inhibits repairing of
damaged DNA by chemicals or irradiation.
Sickle-cell disease in children occurs when children has low level of healthy red blood
than expected and is a condition which a child is born with and passed down through
parent’s genes and Hydroxyurea is a major pharmacological approach for the treatment
of sickle cell anemia in children. FDA have approved hydroxyurea only in tablet and
capsule form. However, the challenge with these solid dosage forms were children’s
acceptance towards this drug delivery. Children who have difficulty in swallowing
tablet or capsules or with gastric instability limit the adherence with these solid dosage
form. The poor adherence of solid dosage form results in inadequate disease
management. This problem however was solved by Compounding method. In this
method, the oral solution (100 mg/Ml) was prepared by emptying the content of 500
3
mg capsule (20 capsule) and mixing the same in 50 ml sterile water the resulting
solution was stirred for several hours and was mixed in flavoured syrup base and stored
in amber plastic container. This solution was stable till 90 days at room temperature.
However, this liquid solution was compounded unlicensed in pharmacies which limits
its availability to the users. Further poor compounding practice leads to high risk of
dosing errors, inadequate efficacy, high risk of adverse reaction, contamination of final
formulation and required multiple steps for reconstitution.
To overcome the problem associated with compounding practice, a children friendly,
multidose, ready-to-use (no requirement for reconstitution) 100 mg/mL strawberryflavored oral solution with a stable 2-year shelf life has been developed and marketed
as Xromi.
Xromi is a patented composition disclosed in patent number EP3644967A1 which
covers a stable aqueous hydroxycarbamide solution, a preservative comprising a
methyl hydroxybenzoate and/or an ethyl hydroxybenzoate, a sweetener, a viscosity
modifying agent, a flavouring a pH adjuster being one of sodium hydroxide, potassium
hydroxide, sodium bicarbonate, and sodium carbonate, or a mixture of one or more of
these substances, wherein the aqueous hydroxycarbamide solution is controlled to have
a pH of between 6.5 and 6.7. The prior art claims stated that that it can be safely stored
at ambient temperature for prolonged periods of time without significant degradation
however, the formulation was found to be stable at 25 °C /60% RH (at room
temperature) for only at least two months. Therefore, the marketed formulation Xromi
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needs to be stored in a refrigerator (2 °C – 8 °C) and after its first opening of bottle the
unused contents were discarded after 12 weeks. The need of refrigeration causes
additional burden to manufacturer, supplier and distributors to ensure that the product
is carefully transported, handled and stored in a suitable temperature and to reduce the
risk of exposure to temperature outside the labelled storage conditions and also added
extra cost to the formulation.
Juma A. Mohamedi et. al. (Formulation Development and Evaluation of Hydroxyurea
Dry Syrup for the Management of Pediatric Patients with Sickle Cell Disease in
Tanzania) discloses formulation of dry syrup for the treatment of sickle cell disease for
pediatrics. The study further discloses that there was no significant change in the pH
was observed in all the developed dry syrups upon reconstitution and storage for 14
days.
It is initially recommended that the dose of 20 mg/kg/day should be administered orally
in children. As the dosing change with respective to the weight of children so the total
dosage per day is changed. Therefore, it is generally recommended the shelf life of the
final should be at least more than 15 days.
Thus there still remain need in art to develop a formulation which remains stable at
room temperature and doesn’t requires Extemporaneous compounding of Hydroxyurea
and the final liquid formulation should have shelf life of more than 15 days. The present
invention provides an alternative dosage of Hydroxyurea in form of reconstituted oral
System with improved shelf storage life of more than 15 days. The reconstituted oral
5
system will overcome the stability of Hydroxyurea in aqueous solution and remain
stable at room temperature and doesn’t require refrigeration
Therefore, the main objective of the present invention is to prepare a dry syrup
composition which is stable at room temperature and should have reconstituted storage
shelf life of more than 15 days at room temperature, have higher patient compliance,
easy to manufacture and hence economical and useful for oral administration.
SUMMARY OF THE INVENTION:
The present invention provides a pharmaceutical formulation comprising effective
amount of Hydroxyurea and combinations of excipients which extended the stability
of pharmaceutical formulation when in a liquid dosage form. The pharmaceutical
formulation may be in a dry form for reconstitution or in a liquid dosage form.
In accordance with the above objective the present invention provides a dry syrup
composition comprising Hydroxyurea which is reconstituted with water or suitable
diluent prior to administration to form an ingestible formulation which have extended
shelf life of more than 15 days when stored at room temperature.
The invention also provides a method of forming a liquid dosage form of
pharmaceutical formulation by adding suitable solvent which have extended storage
shelf life when in liquid dosage form.
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In an 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 referents 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, 'dry syrup' is in the form of dry powder or dry granules, which is taken
in combination with water or with any other suitable solvent when administered.
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As used herein “room temperature 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 “reconstitution” or “reconstituted” refers to ingestible liquid syrup
which is prepared by reconstituting the dry syrup with water or other suitable diluent
before administration.
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 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 reconstituted with a diluent just before use.
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In an embodiment the present invention provides dry powder formulation for
reconstitution comprising Hydroxyurea in an amount of 50% to 80% and one or more
pharmaceutically acceptable excipients.
In an embodiment the present invention provides a powder or granule for reconstitution
product in form of dry syrup comprising effective amount of Hydroxyurea and one or
more pharmaceutically acceptable excipients.
In an another one or more pharmaceutically acceptable excipients are selected from the
group comprising filler, binder, disintegrants, lubricant, antioxidant, surfactant,
solubility enhancing agent, pH modifier, viscosity agent/viscosity modifier/viscosity
imparter, preservative, sweetening agent, dispersing agent, flavoring agent, coloring
agent and coating agent.
In an another embodiment the present invention comprises:
i. 50 to 80 % of Hydroxyurea and;
ii. 0.05 to 5 % of preservative and;
iii. 1 to 5% of viscosity agent and;
iv. 1 to 30%. Sweetening agent and;
v. 0.5 to 5% dispersing agent and;
vi. 0.5 to 5%. pH modifier
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In an another embodiment preservative is selected from but not limited to Methyl
parahydroxybenzoate, ethyl para hydroxybenzoate, propyl parahydroxybenzoate,
Sodium Benzoate, Benzoic acid, Potassium Nitrate and Calcium Sorbate.
In an embodiment preferred preservative is sodium benzoate present in an amount of
about 0.05 to 5 %.
In an another embodiment the composition further comprises viscosity agent selected
from but not limited to carageenans, powdered cellulose, methylcellulose, hydroxyl
ethyl cellulose, hydroxyl propyl cellulose, carboxymethylcellulose, sodium
carboxymethylcellulose/microcrystalline cellulose mixtures, ion-exchange crosslinked polyacrylic polymers, polysaccharides, starches, carbomers, or a mixture
thereof.
In an another embodiment the preferred viscosity agent is sodium carboxymethyl
cellulose present in an amount ranging from 1% to 5%.
In an another embodiment the preferred sweetening agent is sucralose, aspartame,
xylitol, sorbitol, mannitol, cyclamate, saccharin, saccharin sodium, molasses, stevia
and erythritol.
In a preferred embodiment sweetening agents are sucralose and mannitol present in an
amount ranging from 1% to 30%.
In an another embodiment the present invention further comprises dispersing agent
selected from but not limited tolactose, microcrystalline cellulose, colloidal silicon
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dioxide, poloxamer, polyoxyethylene sorbitan fatty acid esters (polysorbates) and
sorbitan fatty acid esters or combinations thereof.
In a preferred embodiment dispersing agent is colloidal silicon dioxide present in an
amount of in an amount of 0.5 to 5%.
In an another embodiment the dry syrup further comprises one or more flavouring agent
present in an amount ranging from 2 to 10%.
In an another embodiment the present invention provides dry syrup composition
comprising
i. 63.50% of Hydroxyurea as active ingredient and;
ii. 1.04% of sodium benzoate as preservative and;
iii. 2.50% of sodium carboxymethyl cellulose as viscosity agent and;
iv. 1.67% of sucralose as artificial sweetening agent and;
v. 2.08% of colloidal silicon dioxide as dispersing agent and;
vi. 24.00% of mannitol as bulk sweetener and;
vii. 1.04% of sodium bicarbonate as pH modifier
In an another embodiment the present invention provides a dry syrup composition for
reconstitution with a suitable diluent, wherein the dry syrup composition comprises of:
i. 63.50% of Hydroxyurea as active ingredient and;
ii. 1.04% of sodium benzoate as preservative and;
iii. 2.50% of sodium carboxymethyl cellulose as viscosity agent and;
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iv. 1.67% of sucralose as artificial sweetening agent and;
v. 2.08% of colloidal silicon dioxide as dispersing agent and;
vi. 24.00% of mannitol as bulk sweetener and;
vii. 1.04% of sodium bicarbonate as pH modifier
A method of reconstituting a dry syrup formulation, the method comprising:
Providing a dry syrup formulation comprising:
i. 63.50% of Hydroxyurea as active ingredient and;
ii. 1.04% of sodium benzoate as preservative and;
iii. 2.50% of sodium carboxymethyl cellulose as viscosity agent and;
iv. 1.67% of sucralose as artificial sweetening agent and;
v. 2.08% of colloidal silicon dioxide as dispersing agent and;
vi. 24.00% of mannitol as bulk sweetener and;
vii. 1.04% of sodium bicarbonate as pH modifier
Combing the dry syrup formulation with a solvent to reconstitute the dry powder
hydroxyurea formulation into a liquid hydroxyurea formulation wherein the
reconstituted solution has shelf life of more than 15 days when stored at room
temperature.
In an embodiment the present invention provides a pharmaceutical formulation
comprising Hydroxyurea in amount ranging from 5-20 mg more preferably 10 mg.
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The present invention provides a stable solid dosage form in form of dry syrup that
increases patient compliance to the treatment, that can be easily used and does not cause
difficulty in swallowing compared to the other dosage forms marketed as capsule and
tablet dosage form. The pharmaceutical invention of present invention also provides
an extended shelf life of the reconstituted syrup which is prepared by diluting the dry
syrup with a suitable diluent.
The pharmaceutical formulations of the invention may be in a dry powder form or dry
granules form for reconstitution such as dry syrup or dry suspension more preferably
dry syrup.
In an embodiment the present invention provides an oral dosage form in dry powder or
granules for reconstitution wherein the dry formulation when reconstituted with a
suitable diluent before use form a liquid syrup as final dosage forms.
In an embodiment the reconstituted formulation has extended shelf storage of more
than 15 days when stored at room temperature.
In an another embodiment the dry powder or granules can be stored in suitable solid
container such as HDPE bottles, glass bottle, PET bottle, packed in a sachet or dual
chamber bottle that holds powder and vehicle in separate compartments.
The present invention is further described in the following comparative, experiments
and examples, which are not intended to limit the scope of the invention
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Example-1
Table 1: Composition details of Hydroxyurea dry syrup
S.No. Excipients Role of ingredient %
1 Hydroxyurea Active ingredient 63.50
2 Sodium Benzoate Preservative 1.04
3 Sodium C.M.C. Viscosity imparter/agenr 2.50
4 Sucralose Artificial sweetener 1.67
5
Colloidal Silicon
Dioxide Dispersing agent 2.08
6 Flv. Vanilla Dry Flavuring agent 4.17
7 Mannitol Bulk sweetener 24.00
8 Sodium Bicarbonate pH modifier 1.04
Example 2-
The present invention prepared from example-1 undergoes stability study at
temperature 25°C ± 2°C & RH 60% ± 5% for 6 months.
Table 2: Stability study data summary report:
Test Acceptance
criteria
Initial testing After 3 months After 6 months
Description White to off
white coloured
granular powder
filled in HDPE
bottle which
White to off
white coloured
granular
powder filled in
HDPE bottle
White to off
white coloured
granular
powder filled in
HDPE bottle
White to off
white coloured
granular powder
filled in HDPE
bottle which
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gives light
yellowish clear
solution after
reconstitution
with water
which gives
light yellowish
clear solution
after
reconstitution
with water
which gives
light yellowish
clear solution
after
reconstitution
with water
gives light
yellowish clear
solution after
reconstitution
with water
Ph Between 5.50 to
8.50
7.34 7.335 7.628
pH 7 day Between 5.50 to
8.50
7.25 7.482 7.672
Weight per ml 1.00 gm/ml to
1.30 gm/ml
1.049 gm/ml 1.0475 gm/ml 1.0584 gm/ml
Related
substance
As below As below As below As below
Single
maximum
unknown
impurities
Not more than
0.5%
Not detected Not detected 0.247%
Total
impurities
Not more than
2.0%
Not detected Not detected 0.247%
Assay: (by HPLC) Each ml of constituted solution contains:
Hydroxyurea
IP 100 mg
NLT 90% and
NMT 110%
98.07 mg
98.07%
103.20 mg
103.20%
105.23 mg
105.23%
After 7 days
Hydroxyurea
IP 100 mg
NLT 90% and
NMT 110%
98.25 mg
98.25 %
100.70 mg
100.70%
104.20 mg
104.20 %
From table 2, it is clearly observed that dry syrup was found to be stable when stored
at temperature 25°C ± 2°C & RH 60% ± 5% for 6 months.
,CLAIMS:A dry syrup formulation for reconstitution comprising Hydroxyurea in an
amount of 50 to 80% and one or more pharmaceutically acceptable excipients.
2. The dry syrup formulation as claimed in claim 1 wherein one or more
pharmaceutically acceptable excipients are preservative, viscosity agent,
sweetening agents, dispersing agent, pH modifier and flavouring agent.
3. The dry syrup formulation as claimed in claim 1 wherein preservative is
Sodium Benzoate in an amount of 0.05% to 5%.
4. The dry syrup formulation as claimed in claim 1 wherein viscosity agent is
sodium carboxymethyl cellulose in an amount of 1% to 5%.
5. The dry syrup formulation as claimed in claim 1 wherein one or more
sweetening agents are sucralose and mannitol in an amount of 1% to 30%.
6. The dry syrup formulation as claimed in claim 1 wherein dispersing agent is
colloidal silicon dioxide in an amount of 0.5% to 5%
7. The dry syrup formulation as claimed in claim 1 wherein pH modifier is sodium
bicarbonate in an amount of 0.5% to 5%.
8. The dry syrup formulation as claimed in claim 1 comprises:
i. 50% to 80 % of Hydroxyurea and;
ii. 0.05% to 5 % of preservative and;
iii. 1% to 5% of viscosity agent and;
iv. 1% to 30%. Sweetening agent and;
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v. 0.5% to 5% dispersing agent and;
vi. 0.5% to 5%. pH modifier
9. The dry syrup formulation as claimed in claim 1-8 comprises:
i. 63.50% of Hydroxyurea as active ingredient and;
ii. 1.04% of sodium benzoate as preservative and;
iii. 2.50% of sodium carboxymethyl cellulose as viscosity agent and;
iv. 1.67% of sucralose as artificial sweetening agent and;
v. 2.08% of colloidal silicon dioxide as dispersing agent and;
vi. 24.00% of mannitol as bulk sweetener and;
vii. 1.04% of sodium bicarbonate as pH modifier
10. A method of reconstituting a dry powder formulation, the method comprising:
Providing a dry syrup formulation comprising:
i. 63.50% of Hydroxyurea as active ingredient and;
ii. 1.04% of sodium benzoate as preservative and;
iii. 2.50% of sodium carboxymethyl cellulose as viscosity agent and;
iv. 1.67% of sucralose as artificial sweetening agent and;
v. 2.08% of colloidal silicon dioxide as dispersing agent and;
vi. 24.00% of mannitol as bulk sweetener and;
vii. 1.04% of sodium bicarbonate as pH modifier
Combing the dry powder formulation with a solvent to reconstitute the dry powder
hydroxyurea formulation into a liquid hydroxyurea formulation wherein the reconstituted solution has shelf life of more than 15 days when stored at room
temperature.