Claims:WE CLAIM:

1. A stable oral liquid composition comprising
a) naproxen as an active ingredient;
b) xanthan gum, microcrystalline cellulose and carboxymethylcellulose sodium as suspending agents;
c) sodium benzoate as a preservative; and
d) one or more pharmaceutically acceptable excipients,
wherein the composition is free of lead and p-hydroxybenzoic acid impurities.

2. The composition as claimed in claim 1, is in the form of suspension.

3. The composition as claimed in claim 1, wherein the xanthan gum is present in an amount of 0.02% w/v to 0.4% w/v.

4. The composition as claimed in claim 1, wherein the microcrystalline cellulose and carboxymethylcellulose sodium is present in an amount of 0.1% w/v to 2.0% w/v.

5. The composition as claimed in claim 1, wherein the sodium benzoate is present in an amount of 0.04% w/v to 0.4% w/v.

6. The composition as claimed in claim 1, has a pH in the range of 2.0 to 3.7.

7. The composition as claimed in claim 1, is stable for 3 months at 40°C and 75% RH.

8. The composition as claimed in claim 1, is free of lead and p-hydroxybenzoic acid impurities.

9. A stable oral suspension comprising:
a) 1.0 % w/v to 4.0 % w/v of naproxen;
b) 0.02% w/v to 0.4% w/v of xanthan gum;
c) 0.1% w/v to 2.0% w/v of microcrystalline cellulose and carboxymethylcellulose sodium;
d) 0.04% w/v to 0.4% w/v of sodium benzoate; and
e) one or more pharmaceutically acceptable excipients;
wherein the suspension is free of lead content and p-hydroxybenzoic acid impurities.

10. The composition as claimed in claim 9, has pH in a range of 2.0 to 3.7 and is stable for 3 months at 40°C and 75% RH.
, Description:FIELD OF THE INVENTION
The present invention relates to pharmaceutical stable oral liquid compositions of naproxen and one or more pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION
Naproxen is a propionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs. Chemically it is (S)-6-methoxy-a-methyl-2-naphthaleneacetic acid, having molecular weight of 230.26. Its molecular formula is C14H14O3, with following chemical structure.

U.S. Patent 3,904,682 discloses Naproxen specifically.
In US, Naproxen suspension is available under the brand name of Naprosyn® by Atnahs Pharma US Ltd. The inactive ingredients in NAPROSYN® suspension include magnesium aluminum silicate, methylparaben, fumaric acid, sucrose, sorbitol solution, sodium chloride, flavor and purified water. The pH of the suspension ranges from 2.2 to 3.7.
Inventors of the present invention have tried to develop stable oral liquid compositions of naproxen using the inactive ingredients of NAPROSYN® suspension. The resulted suspension was having good physical properties, but it has lead content and p-Hydroxybenzoic acid (PHBA) impurities, which were unacceptable.
Therefore, in order to solve the problems described above, there is a need to develop physically and chemically stable pharmaceutical liquid compositions of naproxen. Accordingly, inventors of the present invention have developed stable oral liquid compositions of naproxen using novel excipients.

SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical stable oral liquid compositions of naproxen and one or more pharmaceutically acceptable excipients.

One embodiment of the present invention relates to a stable oral liquid composition comprising a) naproxen; b) xanthan gum; and microcrystalline cellulose and carboxymethylcellulose sodium as suspending agents; c) sodium benzoate as a preservative; and d) one or more pharmaceutically acceptable excipients; wherein the composition is free of lead and p-hydroxybenzoic acid impurities.

Another embodiment of the present invention relates to a stable oral suspension comprising: a) naproxen; b) 0.02% w/v to 0.4% w/v of xanthan gum; c) 0.1% w/v to 2.0% w/v of microcrystalline cellulose and carboxymethylcellulose sodium; d) 0.04% w/v to 0.4% w/v of sodium benzoate; and e) one or more pharmaceutically acceptable excipients; wherein the suspension is free of lead and p-hydroxybenzoic acid impurities.

In yet another embodiment of the present invention relates to use of present stable oral suspension for the relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, tendonitis, bursitis and acute gout and for the management of pain and primary dysmenorrhea.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to pharmaceutical composition comprising naproxen as active ingredient. Particularly, the present invention relates to pharmaceutical stable oral liquid compositions of naproxen and one or more pharmaceutically acceptable excipients.
The term “excipients” as used herein means a component of a pharmaceutical product that is not an active ingredient such as, for example, suspending agents, preservatives, vehicles and the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
The term “pharmaceutically acceptable” as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.
By the term “composition” as used herein refers to a liquid dosage form suitable for oral administration, such as a suspension, solution, emulsion, syrup and the like; preferably, oral suspension.
The term “active ingredient” used herein, is defined to mean active drug (e.g. naproxen), that induce a desired pharmacological or physiological effect.
The term “stable” as used herein means that the suspension composition of naproxen having good physical properties as well as free of lead content and p-Hydroxybenzoic acid (PHBA) impurities.
The present invention relates to pharmaceutical stable oral liquid compositions of naproxen and one or more pharmaceutically acceptable excipients.
The pharmaceutical liquid composition of the present invention may include a variety of excipients and purified water. Excipients of the present invention comprise a suspending agent, a preservative, a buffering agent, a stabilizer, a sweetener, a coloring agent, a flavoring agent and combinations thereof. The purified water is used in order to prepare the medicine in the form of liquid, and the excipients may be used for the excellent taste to increase the medication compliance and the stability of the pharmaceutical liquid composition.

Suspending agents according to the present invention include but are not limited to xanthan gum, microcrystalline cellulose and carboxymethylcellulose sodium, pectin, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxy propyl cellulose, gellan gum, carrageenan, propylene glycol alginate, sodium alginate, gum acacia, carbomer and the like, and combinations thereof.
Preferred suspending agents of the present invention are xanthan gum and microcrystalline cellulose and carboxymethylcellulose sodium.
Combination of Microcrystalline cellulose and carboxymethylcellulose sodium is available commercially as Avicel® RC-591NF from Dupont and FMC International Health and Nutrition.
Preservatives according to the present invention include but are not limited to sodium benzoate, benzyl alcohol, potassium sorbate, sorbic acid, benzoic acid, benzalkonium chloride, cetrimide, ethyl alcohol, propyl paraben, propyl paraben sodium, methyl paraben sodium and the like, and combinations thereof.
Preferred preservative of the present invention is sodium benzoate.
In accordance with an aspect of the present invention, there is provided a pharmaceutical liquid composition comprising naproxen.

One aspect of the present invention relates to a stable oral liquid composition comprising a) naproxen; b) xanthan gum; and microcrystalline cellulose and carboxymethylcellulose sodium as suspending agents; c) sodium benzoate as a preservative; and d) one or more pharmaceutically acceptable excipients.

Another aspect of the present invention relates to a stable oral suspension comprising: a) naproxen; b) 0.02% w/v to 0.4% w/v of xanthan gum; c) 0.1% w/v to 2.0% w/v of microcrystalline cellulose and carboxymethylcellulose sodium; d) 0.04% w/v to 0.4% w/v of sodium benzoate; and e) one or more pharmaceutically acceptable excipients; wherein the suspension is free of lead content and p-hydroxybenzoic acid impurities.

In order to have the stability described above, in one preferred embodiment, the pH of the pharmaceutical liquid preparation may range from 2.0 to 3.7.

Experiments by inventors of the present invention, have confirmed that superior stability is exhibited in the pH range from 2.0 to 3.7.

It was observed that commercially available NAPROSYN® suspension product with pH of 2.0 to 3.7 and containing parabens (like methyl paraben, propyl paraben), leads to increased p-hydroxybenzoic acid impurity. Accordingly, inventors of the present invention have developed the composition by avoiding parabens as preservative (Refer Example 1).

In yet aspect of the present invention relates to use of stable oral suspension of the present invention for the relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, polyarticular juvenile idiopathic arthritis, tendonitis, bursitis and acute gout, and for the management of pain and primary dysmenorrhea.

However, objects of the present invention are not restricted to the one set forth herein. The above and other objects of the present invention will become more apparent to one of ordinary skill in the art to which the present invention pertains by referencing the detailed description of the present invention given below.
Although the present invention may be variously changed and include several embodiments, particular embodiments shown in the drawings will be described in detail in a detailed description. However, it is to be understood that the present invention is not limited to the particular embodiments, and various changes, equivalences and substitutions may be made without departing from the scope and spirit of the invention.

An exemplary method of preparing a pharmaceutical liquid composition of the present invention will be described below.

EXAMPLES

The following examples further illustrate the invention and do not limit the scope of the invention.

COMPARATIVE EXAMPLE 1-3

Table 1: Oral suspension composition of Naproxen.

Ingredients Comparative Example 1 Comparative Example 2 Comparative Example 3
mg/ 5ml mg/ 5ml mg/ 5ml
Naproxen 125.00 125.00 125.00
Magnesium aluminium silicate (Veegum K) - - -
Xanthan gum 25.00 - 6.00
Microcrystalline cellulose &
Sodium carboxymethylcellulose (Avicel RC591) - 75.00 60.00
Methyl paraben 5.00 5.00 5.00
Sodium benzoate - - -
Fumaric acid 10.00 10.00 10.00
Sodium chloride 99.07 99.07 99.07
Sucrose 1275.00 1275.00 1275.00
Sorbitol solution 450.00 450.00 450.00
FDC Yellow No.6 0.12 0.12 0.12
Strawberry flavor 2.00 2.00 2.00
Purified water q.s. q.s. q.s.

Brief manufacturing method:
1) Methyl paraben was dissolved in a part of 90°c water under stirring,
2) fumaric acid was added to step 1, under continuous stirring,
3) sucrose was added to step 1, under continuous stirring and cooled to 25°c,
4) naproxen was added to step 3, and stirred continuously,
5) xanthan gum (Comparative Example 1 & 3) was dispersed in step 4, under continuous stirring,
6) microcrystalline cellulose & carboxymethylcellulose sodium (Comparative Example 2 & 3) was dispersed in a part of water and homogenized, added to the step 4 or 5, and homogenized,
7) sorbitol solution, FDC Yellow No.6 and flavor were added to step 6 under continuous stirring, followed by checking the pH, making-up the volume with purified water and finally homogenizing to achieve a uniform and homogenous suspension.

Table 2: Stability study:

Oral suspension compositions of Naproxen of Comparative Example 1 to 3 were tested for its stability initially and the results were shown below.

Comparative Example 1 Comparative Example 2 Comparative Example 3
Sedimentation Present Nil Nil
Cake formation Present Absent Absent
Redispersibility Not complies Not Complies Complies
Lead content Complies Complies Complies
PHBA Detected Detected Detected

Results from Table 2 showed that, Comparative Example 1 and 2 containing Xanthan gum and Microcrystalline cellulose & Sodium carboxymethylcellulose (Avicel RC591) respectively as suspending agents were failed to provide physically stable suspension. However, the Comparative Example 3, containing combination of Xanthan gum and Microcrystalline cellulose & Sodium carboxymethylcellulose (Avicel RC591) as suspending agents showed good physical properties. All of the Comparative Examples 1 to 3 were free of lead.
Composition of Comparative Example 3 has not showed any sedimentation, Cake formation and has good Redispersibility property and free of lead. However, it contains p-Hydroxybenzoic acid (PHBA) impurity.
p-Hydroxybenzoic acid (PHBA) impurity is generating from methylparaben. Accordingly, inventors of the present invention have developed the compositions without parabens.
Further, inventors of the present invention explored various possibilities and finally developed stable compositions with sodium benzoate as preservative (Refer Example 1) with comfortable results.

EXAMPLE 1
Table 3: Stable Oral suspension composition of Naproxen.
Ingredients mg/ 5ml % w/v
Naproxen 125.00 2.50
Xanthan gum 6.00 0.12
Microcrystalline cellulose &
Sodium carboxymethylcellulose (Avicel RC591) 60.00 1.20
Sodium Benzoate 10.00 0.20
Fumaric acid 10.00 0.20
Sodium Chloride 93.85 1.87
Sucrose 1275.00 25.50
Sorbitol solution 450.00 9.00
FDC Yellow No.6 0.12 0.002
Strawberry flavor 3.00 0.06
Purified water q.s. q.s.

Brief manufacturing method:
1) Fumaric acid was dissolved in a part of 90°c water under stirring,
2) sucrose was added to step 1, under continuous stirring and cooled to 25°c,
3) naproxen was added to step 2, and stirred continuously,
4) sodium benzoate was added to step 3, under stirring,
5) xanthan gum was dispersed in step 4, under continuous stirring,
6) microcrystalline cellulose & carboxymethylcellulose sodium was dispersed in a part of water and homogenized, added to the step 5, and homogenized,
7) sorbitol solution, FDC Yellow No.6 and flavors were added to step 6, under continuous stirring, followed by checking the pH, making-up the volume with purified water and finally homogenizing to achieve a uniform and homogenous suspension.

Table 4: Stability study:
Oral suspension composition of Naproxen of Example 1 was tested for its stability initially and after 3 months at 25°C/ 60%RH, 30°C/ 65%RH and 40°C/ 75%RH and the results were shown below.
Example 1
Initial 25°C/ 60%RH
3 Months 30°C/ 65%RH
3 Months 40°C/ 75%RH
3 Months
Sedimentation Nil Nil Nil Nil
Cake formation Absent Absent Absent Absent
Redispersibility Complies Complies Complies Complies
Lead content Complies Complies Complies Complies
PHBA Not Detected Not Detected Not Detected Not Detected

From the results above Table 4, it was observed that Naproxen oral suspension composition of the present invention containing sodium benzoate as preservative is stable (i.e.., free of lead and p-Hydroxybenzoic acid (PHBA) impurity) up to 3 months at 40°C/ 75%RH.

Although the embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.