FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
TITLE OF THE INVENTION:
Stable Solid Oral Pharmaceutical Composition of Thyroxine Active Drug APPLICANT(S):
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad 380 009,
Gujarat, India
The following specification particularly describes the invention and the manner in which it is to be performed:

Stable solid oral pharmaceutical composition of thyroxine active drug
FIELD OF THE INVENTION
Present invention relates to a stable solid oral pharmaceutical composition prepared by a process comprising granulation of the mixture comprising sugar alcohol and colorant by a granulating solution comprising thyroxine active drug, alkalizer and alcoholic solvent.
BACKGROUND OF THE INVENTION
Thyroxine is used in the treatment and/or prophylaxis of thyroid hormone disorders. Thyroxine active drug such as levothyroxine sodium or thyroxine sodium is prescribed for hypothyroidism and thyroid hormone replacement therapy.
Levothyroxine sodium is approved as SYNTHROID and UNITHROID, which comprises lactose as one of the excipients.
It is well known that the stability of thyroid hormone drugs is quite poor. They are hygroscopic and degrade in the presence of moisture or light, and under conditions of high temperature. The instability is especially notable in the presence of pharmaceutical excipients, such as carbohydrates, including lactose, sucrose, dextrose and starch, as well as certain dyes.
Therefore, it is desirable to select the excipients to prepare a stabilized dosage form of thyroxine active drug which will have a longer shelf life with required dissolution profile.
Another problem associated with thyroxine active drug is to achieve a satisfactory "content uniformity" of thyroxine active drug in the formulation matrix.

Conventional powder mixing technology is not normally sufficiently refined to achieve a satisfactory uniform mix under these circumstances, particularly since the dose amount of levothyroxine sodium or thyroxine sodium is very small ranging from about 12.5 micrograms to about 300 micrograms per tablet dosage formulation.
Many attempts have been made to stabilize thyroxine formulations such as US 5225204, which describes a stable formulation comprising a complex of levothyroxine sodium and a water soluble polymer adsorbed on a cellulose compound. US 5955105, describes thyroid hormone preparations stabilized by an inorganic salt, a carbohydrate having a molecular weight of greater than 500 such as microcrystalline cellulose, maltodextrin, starch and hydroxypropyl cellulose, and glycine.
Similarly, US 5635209 is directed to stabilized composition of levothyroxine sodium medication containing potassium iodide and a microcrystalline cellulose.
US 6646007 discloses process for a pharmaceutical preparation comprising levothyroxine sodium suspended in aqueous gelatin solution, where in gelatin is used as binder.
In additions to above, different approaches to prepare a stable and uniform preparation of levothyroxine disclosed in US 6555581, US 7067148, US 7101569, WO 199716178 and US 7052717.
Each of these patents attempts to remedy one or the other problem associated with formulating thyroxine active drug products either by using various excipients besides the standard lactose or by using various manufacturing techniques to achieve content uniformity.
Problems like stability and content uniformity have been so widespread that some

drug companies marketing levothyroxine sodium have been forced to recall various batches due to lack of stability or content uniformity.
Thus, there is still a need in the art for stable formulation of thyroxine active drug having appropriate content uniformity and which is substantially free of the disadvantages, defects and limitations of the formulations disclosed in the art.
Present invention provides a stable pharmaceutical composition of thyroxine active drug having desired content uniformity and dissolution profile.
SUMMARY OF THE INVENTION
One object of the present invention is to provide a stable solid oral pharmaceutical composition comprising thyroxine active drug prepared by a process comprising steps of:
(a) preparing a solution comprising thyroxine active drug, alkalizer and solvent;
(b) granulating the mixture comprising one or more diluent and colorant with solution prepared in step (a);
(c) optionally, drying the granules prepared in step (b);
(d) mixing granules prepared in step (b) or (c) with disintegrant and lubricant;
(e) preparing a pharmaceutical composition from the mixture or blend of step (d).
Another object of the invention is to provide a stable solid oral pharmaceutical composition consisting of thyroxine active drug, sugar alcohol, alkalizer, colorant, disintegrant and lubricant.
Another object of the invention is to provide a process for the preparation of a stable solid oral pharmaceutical composition of thyroxine active drug comprising steps of:
(a) preparing a solution comprising thyroxine active drug, alkalizer and solvent;
(b) granulating the mixture comprising one or more diluent and colorant with solution prepared in step (a);

(c) optionally, drying the granules prepared in step (b);
(d) mixing granules prepared in step (b) or (c) with disintegrant and lubricant;
(e) preparing a pharmaceutical composition from the mixture or blend of step (d).
DETAILED DESCRIPTION OF THE INVENTION
Present invention relates to a novel approach of providing the stable pharmaceutical composition of thyroxine active drug having required content uniformity wherein said composition provides desired dissolution profile and stability. Present invention also relates to the process of preparation of said stable solid oral pharmaceutical composition.
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 "Thyroxine active drug" or "Active ingredient" as used herein includes thyroxine or its isomers, its enantiomers, its racemates, its pharmaceutically acceptable salt or its polymorphs, or mixtures thereof. Preferably, thyroxine active drug present in the composition according to present invention is thyroxine sodium, most preferably, levothyroxine sodium.
First embodiment of the invention provides a stable solid oral pharmaceutical composition comprising thyroxine active drug prepared by a process comprising steps of:
(a) preparing a solution comprising thyroxine active drug, alkalizer and solvent;
(b) granulating the mixture comprising one or more diluent and colorant with solution prepared in step (a);
(c) optionally, drying the granules prepared in step (b);
(d) mixing granules prepared in step (b) or (c) with disintegrant and lubricant;

(e) preparing a pharmaceutical composition from the mixture or blend of step (d).
A preferred embodiment of the invention provides a uniform solid oral pharmaceutical composition comprising granulation of the mixture comprising sugar alcohol such as mannitol and colorant such as lake of quinoline yellow by a granulating, solution comprising thyroxine active drug, alkalizer such as sodium hydroxide or meglumine and alcoholic solvent.
It is surprisingly found that solution of thyroxine active drug with alkalizer such as sodium hydroxide or meglumine not only provide alkaline medium to enhance stability of active ingredient but also facilitates it to adsorb uniformly over solid carrier such as mannitol in the form of a thin film which ensures uniform drug distribution. Moreover, addition of colorant such as lake of quinoline yellow further aids into stability of the product.
Thus, another embodiment of the invention provides a stable solid oral pharmaceutical composition of thyroxine active drug prepared by a process comprising steps of:
(a) preparing a solution comprising thyroxine active drug, alkalizer and alcoholic solvent;
(b) granulating the mixture comprising sugar alcohol and lake of quinoline yellow with solution prepared in step (a);
(c) optionally, drying the granules prepared in step (b);
(d) mixing granules prepared in step (b) or (c) with disintegrant and lubricant;
(e) preparing a pharmaceutical composition from the mixture or blend of step (d).
Solution of step (a) comprising thyroxine active drug, alkalizer and alcoholic solvent can be prepared by adding components in any order, preferably, solution of alkalizer and alcoholic solvent is prepared first and then thyroxine active drug is dissolved in the said solution. Optionally, solution of step (a) further comprises one or more pharmaceutical excipients.

The alcoholic solvent used for preparation of solution according to step (a) is anhydrous alcoholic solvent, most preferably anhydrous ethanol. The term "anhydrous" as used herein means the alcoholic solvent comprising less than 10% of water, preferably less than 5% of water, most preferably less than 2% of water.
Mixture of step (b) comprising diluent such as sugar alcohol and colorant such as lake of quinoline yellow can be in dry form or semi solid form. Said mixture may further comprise one or more other pharmaceutical excipient.
Another embodiment of the invention provides a stable solid oral pharmaceutical composition consisting of thyroxine active drug, sugar alcohol, alkalizer, colorant, disintegrant and lubricant.
A preferred embodiment of the invention provides a stable solid oral pharmaceutical composition consisting of 0.01% to 0.2% w/w of thyroxine active drug, 90% to 93% w/w of sugar alcohol, 0.001% to 0.010% w/w of alkalizer, 0.10% to 0.30%) w/w of colorant, 3% to 6% w/w of disintegrant and 2% to 5% w/w of lubricant.
Another embodiment of the invention provides a stable solid oral pharmaceutical composition consisting of 0.01% to 0.2% w/w of thyroxine active drug, 90% to 93% w/w of mannitol, 0.001%) to 0.010 % w/w of sodium hydroxide, 0.10% to 0.30%) w/w of lake of quinoline yellow, 3% to 6% w/w of sodium starch glycolate and 2%> to 5% w/w of sodium stearyl fumarate.
Another embodiment of the invention provides a composition consisting of 0.07 %> w/w of thyroxine active drug, 91.93 % w/w of mannitol, 0.006 % w/w of sodium hydroxide, 0.20 % w/w of lake of quinoline yellow, 4.28 % w/w of sodium starch glycolate and 3.5 % w/w of sodium stearyl fumarate.

Another embodiment of the invention provides a process for the preparation of a stable solid oral pharmaceutical composition of thyroxine active drug comprising steps of:
(a) preparing a solution comprising thyroxine active drug, alkalizer and solvent;
(b) granulating the mixture comprising one or more diluent and colorant with solution prepared in step (a);
(c) optionally, drying the granules prepared in step (b);
(d) mixing granules prepared in step (b) or (c) with disintegrant and lubricant;
(e) preparing a pharmaceutical composition from the mixture or blend of step (d).
Another embodiment of the invention provides a process for the preparation of a stable solid oral pharmaceutical composition of thyroxine active drug comprising steps of:
(a) preparing a solution comprising thyroxine active drug, sodium hydroxide and anhydrous ethanol;
(b) granulating the mixture comprising mannitol and lake of quinoline yellow with solution prepared in step (a);
(c) optionally, drying the granules prepared in step (b);
(d) mixing granules prepared in step (b) or (c) with sodium starch glycolate and sodium stearyl fumarate;
(e) preparing a pharmaceutical composition from the mixture or blend of step (d).
The order of steps in the process of preparation of pharmaceutical compositions according to present invention is for the purpose of representation only and should not limit the scope of the embodiments with respect to performance of steps in the mentioned sequence.
Pharmaceutical excipient according to present invention comprises diluent, disintegrant, lubricant, colorant and the like.

Compositions according to present invention may optionally further comprises one or more glidant, binder, surfactant, flavoring agent, preservatives, antioxidants and the like. Example and suitable amount of said optional excipient is known to a skilled person or as given in Handbook of pharmaceutical excipients (sixth edition, 2009).
A diluent according to present invention includes, but not limited to sugar alcohols, microcrystalline cellulose, dibasic calcium phosphate, silicon dioxide and mixtures thereof. Preferably, diluent is sugar alcohol such as mannitol, xylitol or sorbitol, most preferably, diluent is mannitol. Pharmaceutical composition comprises diluent in the amount of 90% to 93% w/w of the total composition.
A disintegrant according to present invention includes, but not limited to sodium starch glycolate, crospovidone, croscarmellose sodium and low substituted hydroxypropyl cellulose. Preferably, alkaline disintegrant is used which improves stability of the formulation. Most preferably, disintegrant is sodium starch glycolate. Pharmaceutical composition comprises disintegrant in the amount of 3% to 6% w/w of the total composition.
A solvent according to present invention includes, but not limited to water and alcoholic solvents such as ethanol, methanol. Preferably, solvent is ethanol, most preferably anhydrous ethanol.
An alkalizer according to present invention includes, but is not limited to sodium hydroxide, sodium Citrate, meglumine and ammonium hydroxide. Preferably, alkalizer is sodium hydroxide. Pharmaceutical composition comprises alkalizer in the amount of 0.001 to 0.010% w/w of the total composition.
A lubricant according to present invention includes, but not limited to sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, talc and glyceryl behenate. Preferably, alkaline lubricant is used which improves

the stability of the formulation. Most preferably, lubricant is sodium stearyl fumarate. Pharmaceutical composition comprises lubricant in the amount of 2% to 5% w/w of the total composition.
A colorant according to present invention includes, but not limited to lake of quinoline yellow, FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake. Preferably, colorant is Lake of quinoline yellow. Pharmaceutical composition comprises colorant in the amount of 0.10% to 0.30% w/w of the total composition.
A pharmaceutical composition according to present invention is a solid composition for immediate release for oral administration and it can be in the form of tablet or capsule. Preferably, said composition is in the form of tablet for oral administration.
Invention illustrated by following example, which do not limit the scope of the invention. It will be appreciated that various modification are within the spirit or the scope of the invention.
Example 1

No Ingredient % w/w Quantity / Unit (In mg)
1. Mannitol 91.937 128.712
2. Lake of Quinoline yellow 0.200 0.280
3. Ethanol Anhydrous — Q.S
4. Sodium Hydroxide 0.006 0.008
5. Levothyroxine Sodium 0.071 0.100
6. Sodium starch Glycolate 4.286 6.000
7. Sodium Stearyl Fumarate 3.500 4.900
Total 140.00

(a) dry mixture of 128.71 mg of mannitol and 0.28 mg of lake of quinoline yellow was prepared in rapid mixer granulator.
(b) 100 μg of levothyroxine sodium was dissolved in the mixture of 0.008 mg of sodium hydroxide and anhydrous ethanol;
(c) The solution prepared in step (b) was added in the dry mixture prepared in
step (a) by peristaltic pump to obtain granules;
(d) The granules prepared in step (c) were dried in fluidized bed dryer.
(e) The granules prepared in step (d) were mixed with 6 mg of sodium starch glycolate and 4.9 mg of sodium stearyl fumarate.
(f) The above mixture prepared in step (e) was compressed to obtain tablet.
Composition of Example 1 was packed in HDPE bottle with 1 g silica canister & LDPE plug and kept for 3 months under the conditions 30°C/75% RH and 25°C/60% RH. Assay and dissolution results of composition are summarized in table 1.
Table 1: Stability data of compositions of example 1

S.N Month Assay Dissolution* Assay Dissolution*
30°C/75% R H 25°C/60% RH
1 Initial 99.4 100.8 99.4 100.8
2 1M 99.2 100.8 — -
3 2M 97.3 99.9 — -
4 3M 97.4 97.6 97.9 100.1
5 6M - - 106.4 102.1
6 9M - - 104.8 100.0
* : 0.0IN HCl+0.2%SLS/500 ml/Paddle/50 rpm/45 min.
It was observed that compositions prepared according to present invention shows good stability and dissolution, even after storage at various conditions.

Dissolution of compositions of Example 1 was also checked in a media without surfactant comprising 0.01N HC1/500 ml, at Paddle/75 rpm. Data represented in table 2 shows more than 80% drug releases in said dissolution media.
Table 2: Dissolution data of compositions of example 1

Dissolution without Surfactant
0.0IN HC1/500 ml/Paddle/75 rpm
Time in Mins % Drug Dissolved
0 0.0
5 15.5
10 42.8
15 65.4
30 73.8
45 84.6
Uniformity content of composition prepared according to Example 1 was determined by performing an HPLC assay wherein amount of active ingredient in each of compositions of example 1 was compared to the labeled amount of active ingredient. Table 3 represents data of uniformity of content indicates uniformity of content is high despite the small amount of active ingredient.
Table 3: Data of uniformity of content of example 1

Unit No. % Assay
1 104.6
2 106.2
3 104.9
4 104.7
5 105.6
6 105.5
7 105.3
8 104.5
9 109.9
10 107.8
Mean 105.9
Minimum 104.5
Maximum 109.9
RSD 1.61
AV 8.5
RSD - Relative standard deviation. AV - Acceptance value.

Example 2
Example 1 is repeated using 128.71 mg of mannitol, 0.28 mg of lake of sunset
yellow, 100 ug of levothyroxine sodium, 0.08 mg of sodium hydroxide,
anhydrous ethanol, 6 mg of sodium starch glycolate and 4.9 mg of sodium stearyl
fumarate.
Example 3
Example 1 is repeated using 128.71 mg of mannitol, 0.28 mg of ferric Oxide Red, 100 ug of levothyroxine sodium, 0.08 mg of sodium hydroxide, anhydrous ethanol, 6 mg of sodium starch glycolate and 4.9 mg of sodium stearyl fumarate.
Example 4
Example 1 is repeated using 128.71 mg of mannitol, 100 ug of levothyroxine sodium, 0.08 mg of sodium hydroxide, anhydrous ethanol, 6 mg of sodium starch glycolate and 4.9 mg of sodium stearyl fumarate.
Compositions of Example 1 to 4 were packed in HDPE bottle with 1 g silica canister & LDPE plug and kept for 1 month at 30°C/75% RH to determine impact of colorant on the stability of the product. Results are summarized in Table 4.
Table 4: Stability data with different colorants.

Example Colorant Initial Assay 1 M 30°C/75% RH Delta Value
Example 1 Lake of Quinoline Yellow 99.4 98.9 0.5
Example 2 Lake of Sunset yellow 100.7 94.8 5.9
Example 3 Ferric Oxide Red 104.8 94.9 9.9
Example 4 No Colorant 98.6 88.7 9.9
It was observed that Lake of Quinoline yellow shows good stability as compared to other colorants.

We Claim:
1. A stable solid oral pharmaceutical composition comprising thyroxine active
drug prepared by a process comprising steps of:
(a) preparing a solution comprising thyroxine active drug, alkalizer and solvent;
(b) granulating the mixture comprising one or more diluent and colorant with solution prepared in step (a);
(c) optionally, drying the granules prepared in step (b);
(d) mixing granules prepared .in step (b) or (c) with disintegrant and lubricant;
(e) preparing a pharmaceutical composition from the mixture or blend of step (d).

2. The composition as claimed in claim 1, wherein alkalizer is selected from sodium hydroxide and meglumine.
3. The composition as claimed in claim 1, wherein colorant is lake of quinoline yellow.
4. A composition consisting of 0.01% to 0.2% w/w of thyroxine active drug, 90% to 93% w/w of sugar alcohol, 0.001% to 0.010% w/w of alkalizer, 0.10% to 0.30%) w/w of colorant, 3% to 6% w/w of disintegrant and 2% to 5% w/w of lubricant.
5. The composition as claimed in claim 4, wherein sugar alcohol is mannitol, alkalizer is sodium hydroxide, colorant is lake of quinoline yellow, disintegrant is sodium starch glycolate and lubricant is sodium stearyl fumarate.
6. A composition consisting of 0.07 % w/w of thyroxine active drug, 91.93 % w/w of mannitol, 0.006 % w/w of sodium hydroxide, 0.20 % w/w of lake of quinoline yellow, 4.28 % w/w of sodium starch glycolate and 3.5 % w/w of sodium stearyl fumarate.

7. A process for the preparation of a stable solid oral pharmaceutical composition
of thyroxine active drug comprising steps of:
(a) preparing a solution comprising thyroxine active drug, alkalizer and solvent;
(b) granulating the mixture comprising one or more diluent and colorant with solution prepared in step (a);
(c) optionally, drying the granules prepared in step (b);
(d) mixing granules prepared in step (b) or (c) with disintegrant and lubricant;
(e) preparing a pharmaceutical composition from the mixture or blend of step (d).
8. The process for the preparation of the solid oral pharmaceutical composition as
claimed in claim 7, wherein the process comprising steps of:
(a) preparing a solution comprising thyroxine active drug, sodium hydroxide and anhydrous ethanol;
(b) granulating the mixture comprising mannitol and lake of quinoline yellow with solution prepared in step (a);
(c) optionally, drying the granules prepared in step (b);
(d) mixing granules prepared in step (b) or (c) with sodium starch glycolate and sodium stearyl fumarate;
(e) preparing a pharmaceutical composition from the mixture or blend of step (d).
9. The composition or process as claimed in any of the preceding claims, wherein
the thyroxine active drug is levothyroxine sodium.
10. A stable solid oral pharmaceutical composition comprising thyroxine active
drug and process of its preparation as herein described with reference to the
examples accompanying the specification.