Field of the Invention
This invention relates to a dry powder pharmaceutical suspension composition of 6-Mercap top urine (6-MP) comprising of 6- Mercapto purine and pharmaceutical])/ acceptable excipients for the treatment for acute lymphoblastic leukaemia (ALL), the present invention is designed to provide flexible and accurate dose administration, thereby minimizing the potential side-effects and improving patient compliance especially in paediatric population as well as patients who suffer from 'patients on nasogastric tube'.
Background of the Invention
Pediatric acute lymphoblastic leukaemia or acute lymphocytic leukaemia (ALL) is the most common malignancy diagnosed in children and represents more than a quarter of all paediatric cancers. ALL is a cancer of the bone marrow which leads to uncontrolled production of immature lymphocytes. It may affect red blood cells, white blood cells, and platelets. The risk factors include exposure to radiations, past treatment of cancers and certain genetic conditions.
In India, cancer is the ninth common cause of death among children in the age group of 0-14 years. As per the National Cancer Registry Program (NCRP) report, the proportion of childhood cancers relative to cancers in all age groups varied from 0.7% to 5.4% in boys, and from 0.5% to 3.5% in girls for the year 2012-2014. Many anti-cancer drugs are available as solid oral dosage forms such as tablets and capsules which makes it difficult to modify the dose for the pediatric population. This often leads to inaccuracy in dosing resulting in either toxicity or underdosing, both of which are undesirable. So there is a need to come up with customized dosage forms for paediatric population.

6-Mercaptopurine (6-MP), chemically known as 1,7-dihydro-6H-purine-6-thione monohydrate, is an analogue of the purine bases adenine and hypoxanthine. It is available as a tablet and contains 50 mg of the active ingredient for oral administration. 6-MP is indicated for maintenance therapy of ALL as part of a combination regimen. The response to this agent depends upon the particular sub-classification of ALL and the age of the patient (paediatric or adult).
Dose of 6-Mercaptopurine for the treatment of ALL varies according to the age and weight/surface area of the paediatric population. Currently available 50 mg tablet dosage form is unsuitable for delivering an accurate dose of 6-MP in patients who experience difficulty in swallowing the tablet, particularly the pediatric population. Generally, the practice of splitting and crushing the tablet to attain a correct dose based on age and weight/surface area of children is not recommended as this will result in inaccuracy in dosing and exposing the person crushing the tablet to cytotoxic and mutagenic dust. Hence, there is a long term need for a suitable dosage form for the treatment of pediatric population (less than 18 years of age) suffering from cancer which provides flexibility in administering the required dose.
The present invention provides a solid oral powder for suspension dosage form comprising 6-Mercaptopurine which fulfils the need of an accurate and flexible dosage form in addition to improving patient compliance especially among the pediatric population and other patient populations with "patients on nasogastric tube".
Oral liquid dosage forms are homogeneous preparations containing one or more active
ingredients dissolved or suspended in a suitable vehicle or carrier. These include solutions,
syrups, suspensions, elixirs, or concentrates in addition to powders for oral solution or
N ^usp^n5i(FnT(p^5S).tl)FO^ite6'm^ositionsi:^are designed TtovfenhanceltKe stability and thereby

shelf life of the pharmaceutical composition and are to be reconstituted with a suitable solvent before administration. Oral liquid dosage forms offer unique advantages over the solid dosage forms like tablets and capsules. These dosage forms provide rapid absorption of drug from the gastrointestinal tract. Additionally, liquid dosage forms allow the use of flavouring and/or palatability agents, which further promotes patient acceptance and compliance. Further, liquid formulations provide the option of a flexible dosing regime based on body weight or body surface area. Object/Summary of the Invention
The present invention is directed to a stable pharmaceutical composition for use in the treatment of acute lymphoblastic leukaemia comprising 6-mercaptopurine or a salt, hydrate or solvate thereof, and pharmaceutically acceptable excipients.
In one embodiment, the invention relates to a pharmaceutical composition for use in the treatment of acute lymphoblastic leukaemia comprising 6-mercaptopurine or a salt, hydrate or solvate thereof, wherein the drug ingredient has a particle size less than 120|im.
In one embodiment, the invention relates to a pharmaceutical composition for use in the treatment of acute lymphoblastic leukaemia comprising 6-mercaptopurine or a salt, hydrate or solvate thereof, wherein the composition is a solid powder dosage form for oral administration.
In one embodiment, the invention relates to a pharmaceutical composition for use in the treatment of acute lymphoblastic leukaemia comprising 6-mercaptopurine or a salt, hydrate or solvate thereof, wherein the composition is a powder for suspension for oral administration.
In another embodiment, the invention relates to a pharmaceutical composition comprising 6-F F-N. mercaptopufirie For £ kart, Ktiydfetb or Solvate 1 thereof &rfcl pharmaceutically acceptable

excipients wherein pharmaceutically acceptable excipients are selected from diluents, buffering agents, suspending agents, sweetening agents, preservatives, flavoring agents, and anticaking agents.
Detailed Description of the invention
The present invention is directed to a pharmaceutical composition for oral suspension including 6-MP used in the treatment of ALL.
Embodiments of the invention include a composition comprising of (a) about l%w/w to about 20%w/w of 6- MP and (b) pharmaceutically acceptable excipients which comprise of one or more diluents or bulk sweetners, buffering agents, suspending agents, high intensity sweetening agents, flavouring agents, anti-caking agents and preservatives.
The bulk sweeteners used in the composition of the present invention includes sugars such as sucrose, glucose, fructose, lactose and maltose) and polyols (which include mannitol, sorbitol, lactitol and xylitol) Sugars and polyols endow the pharmaceutical product with a pleasant taste which is very important in paediatric use. Polyols have gained popularity because they have fewer calories than sugar, prevent tooth decay and are a safe option for diabetics.
Preferable concentration of bulk sweeteners present in the composition is from about from about 55% w/w to about 95% w/w of total composition.
The suspending agents used in the embodied composition include gums, xanthan gum, guar gum; cellulose derivatives, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, sodium carboxymethylcellulose; polysaccharides, starch, pregelatinised starch, alginates, sodium alginate; acrylic acid copolymers, carbopols, polyvinylpyrrolidone, and ft j combinations thereof,j-pr^efj^ajjlv &om about O.L%^v/,w^to^about 10% w/w^of^the composition.

Examples of high intensity sugars used in the composition of the present invention include sucralose, saccharin, aspartame, neotame and acesulfame potassium. The specific sweetener considered for use in this invention include such as aspartame, sucralose, which can be used alone or in combinations with another non-caloric or low caloric sweetener known to have synergistic sweetening properties with aspartame, e.g. saccharin, acesulfame, advantame, thaumatin, chalcone, cyclamate, stevioside and and combinations thereof, preferably concentration of high intensity sweeteners present in the composition is from about 0.1% w/w to about 5% w/w of the composition, preferably from about 0.1 % w/w to about 2 % w/w.
The Buffering agents employed in the compositions of the present invention may include
inorganic water soluble acids such as monosodium citrate, citric acid, tartaric acid, malic
acid, trisodium citrate dihydrate /anhydrous and combinations thereof. Preferable
concentration of buffering agents for compositions of the present invention is from about
0.1% w/w to about 5% w/w of total composition, preferably from about 0.1 % w/w to about 2
% w/w and more preferably from about 0.1 % w/w to about 1 % w/w.
The preservatives employed in the compositions of the present invention may include sodium
benzoate, benzyl alcohol, methyl paraben and propyl paraben or a combination thereof. The
preferable concentration of preservative is about 0.1% w/w to about 5% w/w of total
composition.
The flavouring agents may be selected from raspberry, chocolate, vanilla, strawberry. The
preferable concentration of flavouring agents is about 0.1% w/w to about 5% w/w of total
composition.
Examples of anti-caking agents found useful for the present invention include, but are not
limited to colloidal silicon dioxide and Syloid 244 FP.
Colouring agents may be selected from miy FB)'A/ap'pR)vedicol6ur:s fofjopal use.

The composition of the present invention may be prepared in accordance with methods well known to the person skilled in the field of pharmacy. The powder pharmaceutical suspension composition is stable on storage and when constituted with an ingestible liquid, such as purified water, for administration, the corresponding liquid suspension is stable for the duration in which the therapy is required.
The pharmaceutical composition according to the present invention is a dry powder pharmaceutical suspension wherein the active ingredient i.e. 6-Mercaptopurine (6-MP) may be present in an amount of about 5 mg/mL to about 25mg/mL upon reconstitution of powder blend in the bottle.
According to another embodiment of the invention, the composition may be prepared in the form of a powder dosage form for extended stability, which may be reconstituted with an ingestible liquid at the time of administration to form a suspension, wherein the pH of the reconstituted suspension ranges from 3.0 to 6.0.
According to another embodiment, the composition is recommended for paediatric population in the age group of 2 to 18 years in addition to patient population suffering from 'patients on nasogastric tube'.
The 6-MP embodied in the present invention is finely ground drug with a mean particle size
preferably within a range of 120-100um3 more preferably within a range of less than 100
micron. Fine particles of the drug can be obtained by known means, such as use of jet mill,
ball mill, vibrating mill, hammer mill, colloid mill and the like.
The composition of the present invention may have viscosity in the range of 200 cps to 4000
Cps.
According to another embodiment: A the pharmaceutical composition comprising 6-MP and
a pharmaceutically-acceptable excipient is packed,,in.bottles-JTiade ofiglass or suitable plastic
F N.-T OFFTCF C. Y\ F N N- K\ ft 4 M H t / TJ 1 ■ * i* > - * > v
material, which is inert and can store 6-MP throughout its shelf life. The liner material of

closures coming in contact with the product may be made of expanded polyethylene, thin aluminium strip or other non-reactive and non-shedding material for pharmaceutically acceptable stability of composition.
In another embodiment, the packaging also includes a bottle adaptor and a 6mL graduated syringe for accuracy and ease of administration of the pharmaceutical composition of 6-MP. The following examples are provided to further illustrate the present invention. Formulations were manufactured using different buffer components, different sweetening agents and using different suspending agents. The details of formulations are given below,
Example 1:
A batch of powder for oral suspension using Aspartame as sweetening agent, having the
composition given in Table 1 was prepared,

Example 2:
A batch of powder for oral suspension using citric acid as buffering agent, having the composition given in Table 2 was prepared,
Example - 3: A batch of powder for oral suspension using Tartaric acid as buffering agent, having the composition given in Table 3 was prepared

Example - 4: A batch of powder for oral suspension using Tartaric acid as buffering agent, having the composition given in Table 4 was prepared,
Example - 5: A batch of powder for oral suspension using Tartaric acid as buffering agent, having the composition given in Table 5 was prepared,

As per one of the embodiments of the process, the pharmaceutical composition of 6-MP may be prepared as follows
6-Mercaptopurine is blended with milled sucrose, xanthan gum, sodium benzoate (#60 ASTM passed), citric acid anhydrous/ tartaric Acid (#60ASTM passed), sucralose, raspberry flavour and Syloid 244FP in a suitable blender and mixed for 15 minutes at a suitable RPM. The blend after mixing is unloaded and sifted twice through cone/multi mill and mixed for 30 minutes at suitable RPM in suitable blender.

Claims
1. A dry powder pharmaceutical suspension composition of 6- Mercaptopurine or a salt, hydrate, solvate thereof, which upon reconstination will provide a liquid suspension for oral use where in 6- Mercaptopurine is present at about 5 to 25 mg/mL.
2. The dry powder composition of claim 1, where in the composition comprises of about 1 to 20% w/w of 6- Mercaptopurine or a salt, hydrate, solvate thereof and pharmaceutically acceptable excipients.
3. The composition of claim 1, where in the composition is used in the treatment of acute lymphoblastic leukemia.
4. The composition of claim 1, wherein the composition is an accurate and flexible dosage form for patient population suffering from acute lymphoblastic leukemia, preferably pediatric population and patients suffering from 'patients on nasogastric tube'.
5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical excipients are selected from the group consisting of diluents, buffering agents, suspending agents, sweetening agents, preservatives, flavouring agents and anticaking agents.
6. The pharmaceutical composition according to claim 2, wherein the composition comprises
a) Pharmaceutically acceptable bulk sweetener from about 55% w/w to about 95% w/w of the composition L. ^. ... ,_ Jb) Pharmaceutically acceptable suspending agent from about 0.1% w/w to about 10% w/w or the composition

c) Pharmaceutically acceptable buffering agent from about 0.1% w/w to about 5% w/w of the composition
d) Pharmaceutically acceptable preservative is in the amount of from about 0.1% w/w to about 5% w/w of the composition
e) Pharmaceutically acceptable high intensity sweetener from about 0.1% w/w to about 5% w/w of the composition
e) Pharmaceutically acceptable flavouring agent from about 0.1% w/w to about 5%
w/w of the composition and
f) Pharmaceutically acceptable anti-caking agent from about 0.1% w/w to about 5%
w/w of the composition
6. The pharmaceutical composition according to claim 2, wherein the diluents are selected
from the group consisting of lactose, sucrose, mannitol, xylitol, lactitol, sorbitol, maltitol and combinations thereof
7. The pharmaceutical composition according to claim 2, wherein the buffering agents
are selected from the group consisting of inorganic water-soluble acids, monosodium
citrate, citric acid, tartaric acid, malic acid, trisodium citrate dihydrate and/or
anhydrous and combinations thereof
8. The pharmaceutical compositions according to claim 2, wherein the suspending agents
are selected from the group consisting of xanthan gum, guar gum, hydroxypropyl cellulose, sodium carboxymethylcellulose, hydroxy propyl methylcellulose, methyl cellulose; polysaccharides, starch, pregelatinised starch, alginates, sodium alginate; acrylic acid copolymers, carbopols, polyvinylpyrrolidone, and combinations thereof.
9. The pharmaceutical composition according to claim 2, wherein the sweetening agents
are selected from the group consisting of sucralose, aspartame, neotame, advantame, acesulfame potassium and combinations thereof.
10. The pharmaceutical composition according to claim 2, wherein the preservatives are
selected from the group consisting of sodium benzoate, methyl paraben, propyl paraben and combinations thereof
11. The pharmaceutical composition according to claim 2, wherein the flavouring agents
are selected from the group consisting of raspberry, chocolate, vanilla and strawberry.
12. The pharmaceutical composition according to claim 2, wherein the anticaking agents
are selected from the group consisting of colloidal silicon dioxide and syloid 244 FP.
l^fhl'rlh&iEiace&rc'af composition for'iiie'according TO any one^ or claims 1, wherein the particle diameter distribution of the 6-MP particles in suspension is greater than about 5

\i (D(v,0.1 )) to less than 100 \i (D(v,0.9))5 with median diameter (D(v,4,3)) less than 50