FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
Stabilized formulation of an Iron chelator
2. APPLICANT (S):
(a) NAME: FDC Ltd.
(b)NATIONALITY: Indian company incorporated under the Companies Act 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (W), Mumbai - 400 102, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention:.

Technical field:
The present invention relates to novel stable pharmaceutical formulation and a process of preparing the same.
Background and prior art:
Thalassemia treatment has been blessed due to the improved technology and medical
advances. Thalassemia involves a heterogeneous group of molecular defects with a wide
spectrum of clinical expressions.
The Management of Thalassemia has progressed steadily in major steps, which can be
summarized by decades:
1960's -Transfusion treatment corrects hypoxia;
1970's - chelation therapy reduces iron overload ;
1980's - Marrow transplantation cures the disease and prenatal diagnosis achieves near
zero Thalassemia births in Greece , Sardinia and Cyprus;
1990's - Hopefully will see the success of Oral chelators and maybe cure by genetic
engineering in all patients.
The most common treatment for all major forms of thalassemia is red blood cell transfusions. Because there is no natural way for the body to eliminate iron, the iron in the transfused blood cells builds up in a condition known as "iron overload" and becomes toxic to tissues and organs, particularly the liver and heart. Iron overload typically results in the patient's early death from organ failure. To help remove excess iron, patients undergo "iron chelation therapy," in which a drug is introduced into the body which binds with excess iron and removes it through the urine or stool.
For many years, the only FDA-approved iron chelator was Desferal, which has to be administered through a painful and difficult infusion process. When using Desferal, a needle is attached to a small battery-operated infusion pump and worn under the skin of the stomach or legs five to seven times a week for up to twelve hours. In November 2005, the FDA approved an oral chelator, Exjade. This is a pill which is dissolved in water or juice and drunk, once a day. Many patients now have an option in terms of chelators, and it is hoped that more options will become available in the coming years.
2

Compliance with chelation therapy is vital to the thalassemia patient's long term survival. However, many patients find the administration of Desferal so difficult that they do not keep up with it or abandon treatment altogether. If they do have access to another chelating option, this is extremely dangerous and lack of compliance with chelation therapy leads to accelerated health problems and early death.
Early comprehensive treatment has changed thalassemia from a fatal pediatric disease to one in which patients live productive lives throughout adulthood. Advances in treatment are exciting, resulting in the potential for cure and improved quality of life.
Recently Gene therapy has been directed at replacing or compensating for the defective P-globin alleles, especially in view of the comparative ease of obtaining hematopoietic stem cells. Although this approach remains theoretically attractive, methodologic and logistic hurdles remain.
Iron chelating therapy with Desferal (deferoxamine) in patients with thalassemia major has dramatically altered the prognosis of this previously fatal disease. The successes achieved with deferoxamine, as well as the limitations of this treatment, have stimulated the design of alternative strategies of iron - chelating therapy, including orally active iron treatment.
Alternative medications and cheap and easy treatments is the call of the hour. As disclosed in US 5665392 (Sarkar et al , Nov.07 ,1995), a pharmaceutical formulation useful for treating patients suffering from thalassemia, which comprises powder of Anemonin Pretensis in an amount in the range of 0.02 to 0.12 wt % of the formulation, quinine sulphate in an amount in the range of 0.0005 to 0.003 wt % of the formulation, distilled or demineralised water in an amount in the range of 0 to 40 wt % of the formulation and, ethanol in an amount in the range of 99.88 to 60 wt % of the formulation; and a process for preparing the formulation by mixing the above ingredients. This invention relates to a formulation for iron-chelation and as disclosed Anemonin has been a promising candidate for treating thalassemia and to take the call of the hour.
3

The United States Patent applications 20030064117 and 2006062860 discloses a medicament useful for treating aseptic inflammations, containing anemonin as an effective ingredient, and use of the anemonin compound in treating aseptic inflammations. This application further discloses a method for preparing anemonin extract and the pharmaceutical preparations for oral administration, injection and topical application, especially liquid extract, plaster, suppository, liniment, and paint etc .which can be transdermally absorbed.
Here Anemonin has been used to treat aseptic inflammations. Accordingly there are disclosures in prior art which have disclosed Anemonin as an analgesic in the form of a gel, formulations containing Anemonin for the treatment of Inflammation and for the treatment of Aseptic inflammations.
Many novel formulation have been designed and trials worked out which comprise Anemonin and aid in the Iron chelation therapy. Sarkar et al in their invention as disclosed earlier use a solvent in their formulation and this formulation may be formulated in the form of tablets, powder or suspension. The formulation disclosed by Sarkar et al comprises of ethanol which is reported and known for its toxicity. The main victims of Thalassemia are mainly belonging to the lower age group.
Although Sarkar et al have tried to approach the solution of orally active iron treatment it has to be noted that the use of high percentage of ethanol has been used in the formulation as much in the range of 99.88 to 60 % weight of formulation, also there is certain percentage of water present in the formulation . It is known from literature that Anemonin degrades to Anemonic acid by reacting with water.
Therefore, the main aim was to design an alternative strategy of iron - chelating therapy which includes orally active iron treatment being free of the aqueous environment. Normally, an active administrated in a solid dosage form will have a lesser bioavailability than when in a solution. Being in a solution the active agent will be readily available for absorption and hence have a better bioavailability. Constraints encountered in formulating a solution would be the solubility of the active ingredient and the excipients in the respective vehicles.
4

The above constraints have been overcome in our present invention. Accordingly, the present invention relates to an Oral formulation for Iron chelation comprising Anemonin and the process of preparing the same.
Anemonin used in the formulations disclosed in prior art made the use of natural Anemonin obtained from Anemonin pretensis. This being a rare species and because of the danger of the species getting extinct we have synthesized Anemonin by a synthetic process in our laboratory which forms the basis of our invention.
Disclosure of the invention:
According to the present invention there is disclosed a novel stable pharmaceutical formulation and a process of preparing the same using a vehicle containing glyceride (s) for stabilizing the formulation. The formulation also includes other excipients like sweeteners, antioxidants and non-aqueous vehicle.
According to this invention, stabilized pharmaceutical compositions are produced by dissolving the active ingredient in some quantity of glyceride and then sonicating this solution. The Sweetener is then added to the non aqueous vehicle and mixed with the solution of the active ingredient. The antioxidant is dissolved in small quantity of glyceride and added to the solution of the active ingredient and the sweetener. The volume is finally made up with glyceride and sonicated the above mixture. The final solution is then subjected to final filtration through membrane filter.
The preferred active ingredient in the formulations of this invention is Anemonin prepared through a synthetic process. The therapeutically effective dosage amounts of this drug generally range from about 0.01 %w/v to about 0.3 % w/v.
The preferred dosage forms prepared according to the present invention contain the following ingredients : Anemonin (active drug substance); Sucralose (sweetener) generally ranging from 0.03 %w/v to 0.25% w/v; Butylated Hydroxylanisole (antioxidant) added in the range of 0.01 %w/v to 0.03% w/v; Ethyl alcohol (vehicle) in the range of 0%w/v to 10% w/v as a cosolvent and MCT oil (vehicle) which is a major contributor to the formulation in the range of 5 % w/v to 95 % w/v.
5

The formulations of the present invention are made according the above process. The preferred dosage forms such as dry syrups, mouth dissolving tablets etc. are also included in the invention.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.


6