DESC:

FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention – A METHOD FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITION OF LEVOTHYROXINE ORAL SOLUTION
2. Applicant(s)
NAME: TITAN LABORATORIES PVT. LTD
NATIONALITY: INDIAN
ADDRESS: A/01 – GF & A/101, Plot NO. 120, Anand Bhavan, Spectrum building, R.B. Mehta Marg, Ghatkopar-East, Mumbai – 400077, Maharashtra, INDIA

3. PREAMBLE TO THE DESCRIPTION

The following specification particularly describes the invention and the manner in which it is to be performed.

A METHOD FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITION OF LEVOTHYROXINE ORAL SOLUTION

FIELD OF THE INVENTION
The present invention is all about method for the preparation of pharmaceutical composition of levothyroxine oral solution. More particularly the present invention is about the method of preparing stable pharmaceutical composition of levothyroxine.

BACKGROUND OF THE INVENTION
Hormone plays a vital role in the human body to maintain the balance of many organs and system to work properly. Thyroid hormones regulate multiple metabolic processes and play an essential role in normal growth and development, and normal maturation of the central nervous system and bone.

Thyroid hormones comprise one or more of the following: L-3,5,3',5'-tetraiodothyronine (levothyroxine or LT4); L-3,5,3'-triiodothyronine (liothyronine or LT3); L-3,3',5'-triiodothyronine (LrT3); L-3,5-diiodothyronine (LT2); or any mixtures thereof. The concentrations of T4 and T3 in the blood are regulated by the hypothalamic/pituitary/thyroid (HPT) axis.

The hypothalamus secrets thyrotropin-releasing hormone (TRH) which is transported via the hypothalamic-hypophyseal portal system to the anterior pituitary gland where it binds to TRH receptors which lead to thyroid-stimulating hormone (TSH) release from pituitary thyrotroph cells. TSH is then get connected to TSH receptors located primarily in the thyroid gland which activates thyrocyte proliferation, thyroglobulin and sodium-iodide symporter gene transcription, and stimulation of TH synthesis and secretion. Thyroid gland is the main source of secretion of T4.

TH synthesis in the thyroid gland requires several steps which includes the uptake of iodide by active transport, thyroglobulin (Tg) biosynthesis, oxidation and binding of iodide to Tg, and oxidative coupling of two iodotyrosines into iodothyronines. The synthesis of TH in thyroid gland is unilateral as evidenced by the iodide uptake, which leads to a 30-fold increase in intracellular iodide concentration in thyrocyte vs. serum. The release of TH from the thyroid gland is stimulated by TSH and followed by intracellular proteolysis and hydrolysis.

TH activity is an important determinant of development and growth, and in adults plays a critical role in the regulation of the function and metabolism of virtually every organ system. Hypothyroid patients are deficient in endogenously produced THs. There are many causes to hypothyroidism, including but not limited to, autoimmune disease, e.g. Hashimoto's thyroiditis and atrophic thyroiditis; surgical removal of part or all of the thyroid gland; radiation treatment; congenital hypothyroidism; and antithyroid medicines. Synthetic levothyroxine is a recommended replacement therapy for acute and chronic cases of hypothyroidism, providing patients long term control of their symptoms with a favourable side effect profile and a long serum half-life.

Levothyroxine, also known as L-thyroxine, synthetic T4, or 3,5,3’,5’-tetraiodo-L-thyronine, CAS number 51-48-9, is a synthetic form of thyroxine, used as a hormone substitute for patients with thyroid conditions, such as hypothyroidism, as well as conditions in which the thyroid gland becomes enlarged, causing swelling of the neck. Hypothyroidism is a medical term that refers to any state in which a person's thyroid hormone production is below normal. This medication replaces or provides thyroid hormone support, which is normally produced by the thyroid gland. Low thyroid hormone levels can occur naturally or when the thyroid gland is injured by radiation/medications or removed by surgery. Having enough thyroid hormone is important for maintaining normal mental health and physical activity. In children, having enough thyroid hormone is important for normal mental and physical development.

Levothyroxine sodium was initially manufactured as synthetic T4 in 1958 and it was first introduced into the market as early as before 1962 without an approved NDA, apparently in the belief that it was not a new drug.

Orally administered levothyroxine sodium is used as replacement therapy in conditions characterized by diminished or absent thyroid function such as cretinism, myxedema, non-toxic goiter, or hypothyroidism

Oral levothyroxine solutions have certain advantages over solid dosage forms. For instance, levothyroxine solutions possess greater potency uniformity than tablets. Tablets often have very low levothyroxine content, which leads to difficulties in achieving drug content uniformity in the manufacturing process. Such that the actual levothyroxine dose that a patient receives with tablet therapy can deviate from label amounts by 20%. Whereas it is much more facile to manufacture homogeneous levothyroxine solutions. In addition, many patients have greater difficulty swallowing tablets than solutions, especially children and the elderly.

Oral levothyroxine solutions also have certain disadvantages compared to solid dosage forms, such as decreased storage stability. But even levothyroxine tablets are known to have storage stability problems. And several regulatory agency approved brands have been subjected to recall due to failure to maintain potency through the expiration date.

WO2018069805 and EP2683361 discloses processes for the preparation of a stable liquid pharmaceutical composition comprising levothyroxine or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

WO2018007466 discloses preparation of an oral levothyroxine composition, comprising the steps of combining levothyroxine or a salt thereof, a water-miscible organic solvent or a sugar alcohol and water, adjusting the pH to at least 8 providing a basic aqueous medium, dissolving the levothyroxine in the basic aqueous medium to yield a levothyroxine solution, and lowering the pH of the levothyroxine solution to between 3.5-4.9.

The present inventors have arrived to the method for the preparation of pharmaceutical composition of levothyroxine oral solution to prepare a stable oral solution composition of levothyroxine as described herein.

Therefore, here in the present invention the inventors have found that the present invention can overcome the above stated problems associated with the existing treatment.

OBJECTIVES OF THE INVENTION

The main object of the present invention is to provide method for the preparation of pharmaceutical composition of levothyroxine oral solution.

The other main object of the present invention is to provide easy and simple method for preparing stable levothyroxine oral solution.

Another object of the present invention is to provide stable levothyroxine oral solution.

One more object of the present invention is to provide stable levothyroxine oral solution as an alternative dosage form to solid tablet formulation.

Yet another objective of this invention is to overcome problems of patient non-compliance to children and geriatric patients.

Yet another objective of the present invention is to provide a levothyroxine oral solution which exhibits bio equivalent against marketed levothyroxine formulations.

SUMMARY OF THE INVENTION
The present invention is all about to provide method for the preparation of pharmaceutical composition of levothyroxine oral solution.

The main aspect of the present invention is to provide a method for the preparation of an oral levothyroxine composition, comprising the steps of:
a) taking glycerol in vessel,
b) adjusting the pH of step a) to 5.0 to 5.5 with 5% citric acid anhydrous solution,
c) adding the purified water to step b),
d) adding the levothyroxine salt to step c) and stirring without heating,
e) mixing glycerol with sodium methyl hydroxy benzoate and adjusting pH to 5.0 to 5.5 with 5% citric acid anhydrous solution,
f) adding solution of step e) to step d) and stirring to get final solution.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

As used in this document, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

Nothing in this disclosure is to be construed as an admission that the embodiments described in this disclosure are not entitled to antedate such disclosure by virtue of prior invention. As used in this document, the term "comprising" means "including, but not limited to."

As used herein term “formulation” or “composition” or “dosage” conveys the same meaning and can be used interchangeably.

As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is being used.

By "pharmaceutically acceptable", it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

As used herein, the term "therapeutic" means an agent utilized to treat, combat, inhibit, ameliorate, prevent or improve an unwanted condition or disease of a patient.

A 'therapeutically effective amount" or "effective amount" of a composition is a predetermined amount calculated to achieve the desired effect, i.e., to induce a favorable therapeutic response.

As used herein "Optional" or "optionally' means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
As used herein the term thyroid hormone should be understood to include pharmaceutically acceptable salts thereof, preferably sodium salts. (Food and Drug Administration 1997; Wertheimer and Santella 2005).

As per one embodiment of the present invention is mainly focused on method for the preparation of an oral levothyroxine composition.

The main embodiment of the present invention is to provide a method for the preparation of an oral levothyroxine composition, comprising the steps of:

a) taking glycerol in vessel,
b) adjusting the pH of step a) to 5.0 to 5.5 with 5% citric acid anhydrous solution,
c) adding the purified water to step b),
d) adding the levothyroxine salt to step c) and stirring without heating,
e) mixing glycerol with sodium methyl hydroxy benzoate and adjusting pH to 5.0 to 5.5 with 5% citric acid anhydrous solution,
f) adding solution of step e) to step d) and stirring to get final solution.

As per one embodiment of the present invention is to provide a method for the preparation of an oral levothyroxine composition which is simple and less complex and have minimal step to achieve a stable composition of levothyroxine in solution form can result in stable composition of levothyroxine in solution form.

As per one embodiment, the levothyroxine as used herein is preferably in salt form. In a preferred embodiment, the levothyroxine is in the form of sodium salt.

As per one embodiment, the levothyroxine is present in the range from 0.1 mcg/ml to 1000 mcg/ml, preferably in the range from 0.1 mcg/ml to 900 mcg/ml, preferably in the range from 0.1 mcg/ml to 800 mcg/ml, preferably in the range from 0.1 mcg/ml to 500 mcg/ml, preferably in the range from 1 mcg/ml to 500 mcg/ml, preferably in the range from 1 mcg/ml to 400 mcg/ml, preferably in the range from 1 mcg/ml to 300 mcg/ml, preferably in the range from 1 mcg/ml to 200 mcg/ml. As per more preferred embodiment, the levothyroxine is present in the range from 5 mcg/ml to 20 mcg/ml.

As per one embodiment of the present invention is to provide a method for the preparation of an oral levothyroxine composition which requires pH adjustment is achieved at one stage and so the final pH adjustment step is nullified.

As per one embodiment of the present invention is to provide a method for the preparation of an oral levothyroxine composition in which the pH adjustment is achieved in a single step) which does not require 2 stage pH adjustment.

As per main embodiment, the aqueous solvent is selected from water or water miscible organic solvent.

As per one embodiment, Water miscible organic solvent can be selected from alkane triols, alkane diols, polyethylene glycol, glycerol, ethanol, isopropyl alcohol, benzyl alcohol, acetone, benzyl benzoate, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, glycofurol, isopropyl myristate, isopropyl palmitate, propylene carbonate, pyrrolidine, glycerine triacetate, triethyl citrate, triolein, or a combination of two or more thereof.

As per one embodiment, the aqueous solvent is water. As per preferred embodiment, the aqueous solvent is mixture of water and water miscible solvent. As per more preferred embodiment, the solvent is water miscible solvent, preferably glycerol.

As per one embodiment, the pH of the final formulation is in the range from 4 to 8, preferably 5 to 8, more preferably 5 to 7, more preferably 5 to 6 and most preferably 5 to 5.5.

As per one embodiment, “Buffering agent” or “pH modifying” as used in the present invention is the buffer is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. The pH of the liquid suspension of the present invention can be adjusted to a pH in the range from 4 to 8. The buffer can include an organic acid, inorganic acid, or salts thereof. Examples of suitable acids include, but are not limited to, malic acid, citric acid, ascorbic acid, tartaric acid, adipic acid, lactic acid, furmaric acid, maleic acid, acetic acid, phosphoric acid, or salts thereof, singly or in combination. Examples of suitable bases include, but are not limited to, calcium and sodium carbonate, calcium and sodium bicarbonate, and salts of the organic or inorganic acids listed above. The above listed compatible acids can be used for pH reduction; however, the increase in pH can be obtained through the use of small amounts of food grade inorganic bases including, but not limited to, metal hydroxides or basic salts thereof including sodium hydroxide solution, potassium hydroxide solution, ammonium hydroxide solution, ammonium chloride solution, sodium citrate, sodium dihydrogen phosphate, etc. Such pH modifying or buffering agents are well known in the art and can be applied as needed.

As per one embodiment, the pH adjusting step in the method for the preparation of an oral levothyroxine composition of present invention is to be done by using carboxylic acid. Carboxylic acid for the present invention is selected from citric acid, lauric acid, tartaric acid, acetic acid, glacial acetic acid, maleic acid and sorbic acid. In a preferred embodiment, citric acid is used for the present invention.

As per one embodiment, Preservatives for present invention of solution are included to prevent the growth of microorganisms during the product manufacturing and shelf life. Preservatives can be selected from but not limited to benzoic acid, potassium sorbate, sodium benzoate, Sodium Methylhydroxy benzoate, chlorobutanol, ethanol, butyl paraben, propyl paraben and methyl paraben.

As per one embodiment, Vehicle for present invention can be used as a base for present invention. Vehicle can be considered as any inert substance, or mixture of substances, added to increase the volume of the liquid composition of present invention in order to make the liquid suspension of the present invention suitable form. The vehicle used in the suspension of the invention is preferably water.

As per one embodiment, the one or more inactive excipients can be selected from flavoring agent, sweetening agent, anti-oxidant or combinations thereof will be well-known to those of skill in the art.

As per one embodiment, non-limiting examples of flavoring agents are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plums pineapple, apricot, peppermint, Tutti Frutti flavor and so forth and the like or any combinations thereof. Solid forms, such as spray dried forms of flavoring agents, may also be useful in the liquid dosage forms disclosed herein.

As per one embodiment, non-limiting examples of sweetening agents are Glucose, Sucralose, Trehalose, Fructose, Xylose, Dextrose, Galactose, Tagatose, Maltose, Sucrose, Glycerol, Dulcitol, Mannitol, Lactitol, Sorbitol, Xylitol, Saccharine or the corresponding sodium, potassium or calcium salt, Cyclamate or the corresponding sodium or calcium salt, Aspartame, or Acesulfame or the potassium salt thereof, Dulcin or Ammonium glycyrrhizinate, Alitame, Inulin, Isomalt, Neohesperidin dihydrochalcone, Thaumatin and the like or any combinations thereof.

As per one embodiment, non-limiting examples of the anti-oxidant vitamins A, C and E, selenium, and carotenoids, such as beta-carotene, lycopene, lutein, and zeaxanthin. Beta-carotene, Selenium, BHA, BHT and salicylic acid.

As per one embodiment, the main aim of the present invention is to achieve a stable oral levothyroxine composition and so therein it is achieved by providing a method for the preparation of pharmaceutical composition of levothyroxine oral solution.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. 20 While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLE 1: FORMULATION OF LEVOTHYROXINE ORAL SOLUTION AND PROCESS OF PREPARATION
Sr. No Ingredients For 100 mcg/ 5ml in
(%w/v) For 50 mcg/ 5ml in
(%w/v) For 25 mcg/ 5ml in
(%w/v)
1 Levothyroxine Sodium 0.002 0.001 0.0005
2 Glycerol 75.60 75.60 75.60
3 Sodium Methylhydroxy
benzoate 0.18 0.18 0.18
4 Citric Acid Anhydrous q.s. to pH 5.5 q.s. to pH 5.5 q.s. to pH 5.5
5 Purified Water q.s. to 100 % q.s. to 100 % q.s. to 100 %
Table 1: Formulation of levothyroxine oral solution

Procedure:
a) glycerol was provided in vessel,
b) the pH of step a) was adjusted to 5.0 to 5.5 with 5% citric acid anhydrous solution,
c) the purified water was added to step b),
d) the levothyroxine salt added to step c) and stirred without heating,
e) the glycerol was mixed with sodium methyl hydroxy benzoate and pH was adjusted to 5.0 to 5.5 with 5% citric acid anhydrous solution,
f) solution of step e) was added to step d) and stirred to get final solution.
,CLAIMS:CLAIMS
We claim;
1. A method for the preparation of pharmaceutical composition of levothyroxine oral solution comprising the steps of;
a) taking glycerol in vessel,
b) adjusting the pH of step a) to 5.0 to 5.5 with 5% citric acid anhydrous solution,
c) adding the purified water to step b),
d) adding the levothyroxine salt to step c) and stirring without heating,
e) mixing glycerol with sodium methyl hydroxy benzoate and adjusting pH to 5.0 to 5.5 with 5% citric acid anhydrous solution,
f) adding solution of step e) to step d) and stirring to get final solution.
2. The method for the preparation of pharmaceutical composition of levothyroxine oral solution as claimed in claim 1, wherein the composition is an oral solution.
3. The method for the preparation of pharmaceutical composition of levothyroxine oral solution as claimed in claim 1, wherein the levothyroxine present is in the range from 5 to 20 mcg/ml.
4. The method for the preparation of pharmaceutical composition of levothyroxine oral solution as claimed in claim 1, wherein the pH of the composition is 4 to 8.
5. The method for the preparation of pharmaceutical composition of levothyroxine oral solution as claimed in claim 1, wherein the salt of levothyroxine is the sodium salt.