Title of Invention

AN ARTEETHER INJECTION FOR TREATMENT OF MALARIA

Abstract

Malaria is a vector borne infectious disease caused by protozoan parasites. Oil based arteether injections are used as anti-malarial drugs, specifically for the treatment of chloroquine resistant Plasmodium falciparum malaria and cerebral malaria cases. Arteether is a fast acting blood schizontocide. The injectable formulation of arteether contains a mixture of ethyl oleate and ethyl alcohol in specific concentrations to reduce the viscosity and the filling volume of the product. This creates minimum muscle pain and muscle stiffness because a higher concentration of "arteether (150 mg) is present in a small volume of injectable solution (1ml). Other pharmaceutical excipients like antioxidants and preservatives are also used in the formulation.

Full Text

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 AN ARTEETHER INJECTION FOR TREATMENT OF MALARIA 2. APPLICANT (S) (a) NAME : Lincoln Pharmaceuticals Limited. (b) NATIONALITY: an Indian Company (c) ADDRESS : Nirav Complex, Opp. Navrang High School Naranpura, Ahmedabad-380014 Gujarat, India. 3. PREMABLE TO THE DESCRIPTION PROVISIONAL COMPLETE The following specification describes the invention. The following specification particularly describes the invention and the manner in which it is to be performed. The present invention relates to a novel pharmaceutical injectable formulation of Arteether for treatment of malaria. More preferably, composition of ethyl oleate and ethyl alcohol reduces the viscosity and filling volume of the product. Background of the Invention: Malaria is a vector-borne infectious disease caused by protozoan parasites. It is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. Each year, there are approximately 515 million cases of malaria, killing between one and three million people, the majority of whom are young children in Sub-Saharan Africa. Active malaria infection with P. falciparum is a medical emergency requiring hospitalization, (www.wikipedia.org vistited on 12/1/2008) Treatment of malaria involves supportive measures as well as specific antimalarial drugs like Quinine, Chloroquine, Sulfadoxine/Pyrimethamine, Mefloquine,* Artemisinin. Many efforts have been done to prepare injectable formulation of arteether. The US 6326023 discloses a synergistic formulation comprising pharmaceutically effective amount of alpha/beta arteether and a neutralized refined vegetable oil suitable for administration by rectal route, a method for the treatment of cerebral and comatose malaria and process for the preparation of the said formulation. 2 I CN 1650854 (A) discloses formuation that comprises artemether, arteether or artesunate, emulsifier, emulsifying aid and plant oilwhich can be used in the form of intravenous injection, oral taking, percutaneous absorption, and spray. Neither of these inventions gives higher dissolution of arteether in less volume of solvent. Objects of the Invention: The main object of the invention is to prepare a novel injectable formulation of Arteether which would reduce the viscosity of the product by 4 to 8 times compared to market products. Another object of the invention is to produce a less viscous product compared to other oil base injections due to which it will create minimum muscle pain on IM injection and less muscle stiffness after injection. Another object of the invention is to reduce the filling volume of the product. Maximum patient compliance is achieved in sense of the reduced pain on injection and the after effects of the painful injection. Yet another object of the invention is to produce a much safer product compared to the products existing in the market Summary of the Invention: The present invention provides a novel injectable formulation of arteether with a mixture of ethyl oleate and ethyl alcohol in a specific concentration to reduce the viscosity and the filling volume of the product that creates minimum 3 pain and muscle stifihess. In this preparation 150 mg arteether is present in 1 ml of injectable solution. Thus, in accordance of this invention, the formulation is containing 150 mg of arteether in a medium of oil base and ethyl alcohol. Detailed Description of Invention: In the present invention arteether is used as an active ingredient. Arteether is widely used as anti-malarial drugs and is available as injectables in oily vehicles. Arteether is a fast acting blood schizontocide specifically indicated for the treatment of chloroquine-resistant Plasmodium falciparum malaria and cerebral malaria cases. It is a semi-synthetic derivative of artemisinin, a natural product of the Chinese plant Artemisia annua. It is currently only used as a second line drug in severe cases of malaria. Artemisinin and its derivatives have become essential components of antimalarial treatment. These plant-derived peroxides are unique among antimalarial drugs in killing the young intra-erythrocytic malaria parasites, thereby preventing their development to more pathological mature stages. This results in rapid clinical and parasitological responses to treatment and life-saving benefit in severe malaria. Artemisinin combination treatments (ACTs) are now first-line drugs for uncomplicated falciparum malaria. Solvents used in the present invention are ethyl alcohol and ethyl oleate. Ethyl oleate is the ester formed by the condensation of the fatty acid oleic acid and ethanol. It is a colorless to light yellow liquid. Ethyl oleate is produced by the body during ethanol intoxication. 4 Ethyl oleate is used as a solvent for pharmaceutical drug preparations involving lipophilic substances such as steroids. It also finds use as a lubricant and a plasticizer. Ethyl oleate is one of the fatty acid ethyl esters (FAEE) that is formed in the body after ingestion of ethanol. Ethyl alcohol is easily miscible in water and is a good solvent. Other pharmaceutical excipients like, antioxidants, preservatives are also used. In the present invention arteether 150 mg, benzyl alcohol 0.04-0.06 ml, ethyl alcohol 0.1-0.15 ml, butylated hydroxy toluene?0.05 mg, butylated hydroxy anisol 0.033 mg, propyl gallate 0.05 mg and ethyl oleate quantity sufficient to make 1 ml are used. This unique mixture of ethyl oleate and solvent ethyl alcohol in safe concentration reduces the viscosity and the volume to be injection Embodiment of the invention relates to process for preparation of pharmaceutical injection formulation which involves following steps of: (a) Arteether is dissolved into half the quantity of ethyl oleate. (b) Benzyl Alcohol is added to the mixture prepared in step (a) and stirred well. (c) Butylated hydroxy toluene (BHT), butylated hydroxy anisol (BHA) and propyl gallate are dissolved in ethyl oleate. (d) The mixture in Step (c) is added into the mixture in Step (a). (e) Ethyl alcohol is added in the mixture prepared in Step-(a). (This step should be done in closed container.) 5 (f) The final volume is adjusted with ethyl oleate. (g) Filling of 1 ml ampoule is carried out by adjusting fill volume at 12 ml. Important Note: Nitrogen flushing is carried out during solution preparation, sterile filtration and ampoule filling (pre and post filling). The invention is illustrated more in detail in the following examples. The examples describe and demonstrate embodiments within the scope of the present invention. These examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope. Example-1 For 100ml Ingredients Quantity Arteether 15000 mg Benzyl alcohol 4 ml Ethyl alcohol 15 ml Butylated hydroxy toluene 5 mg Butylated hydroxy anisol 3.3 mg Propyl gallate 5 mg Ethyl oleate Q.S 6 Example-2 For 100ml Ingredients Arteether Benzyl alcohol Ethyl alcohol Butylated hydroxy toluene Butylated hydroxy anisol Propyl gallate Ethyl oleate Dated this 13th day of January 2009 Quantity 15000 mg 6 ml 10 ml 5mg 3.3 mg 5mg Q.S 7

Documents:

97-MUM-2009-ABSTRACT(1-10-2009).pdf

97-MUM-2009-ABSTRACT(5-10-2009).pdf

97-MUM-2009-ANNEXURE 1-4(7-1-2014).pdf

97-MUM-2009-CLAIMS(5-10-2009).pdf

97-MUM-2009-CLAIMS(AMENDED)-(1-10-2012).pdf

97-MUM-2009-CLAIMS(AMENDED)-(7-1-2014).pdf

97-MUM-2009-CLAIMS(COMPLETE)-(1-10-2009).pdf

97-MUM-2009-CLAIMS(MARKED COPY)-(1-10-2012).pdf

97-MUM-2009-CLAIMS(MARKED COPY)-(7-1-2014).pdf

97-MUM-2009-CORRESPONDENCE(10-11-2009).pdf

97-MUM-2009-CORRESPONDENCE(13-1-2009).pdf

97-MUM-2009-CORRESPONDENCE(19-4-2010).pdf

97-MUM-2009-CORRESPONDENCE(5-10-2009).pdf

97-mum-2009-correspondence.pdf

97-MUM-2009-DESCRIPTION(COMPLETE)-(1-10-2009).pdf

97-MUM-2009-DESCRIPTION(COMPLETE)-(5-10-2009).pdf

97-mum-2009-description(provisional).doc

97-mum-2009-description(provisional).pdf

97-MUM-2009-FORM 1 (5-10-2009).pdf

97-MUM-2009-FORM 1(1-10-2009).pdf

97-MUM-2009-FORM 1(14-1-2009).pdf

97-mum-2009-form 1.pdf

97-MUM-2009-FORM 18(19-4-2010).pdf

97-mum-2009-form 2(5-10-2009).pdf

97-MUM-2009-FORM 2(COMPLETE)-(1-10-2009).pdf

97-MUM-2009-FORM 2(TITLE PAGE)-(5-10-2009).pdf

97-MUM-2009-FORM 2(TITLE PAGE)-(COMPLETE)-(1-10-2009).pdf

97-MUM-2009-FORM 2(TITLE PAGE)-(PROVISIONAL)-(14-1-2009).pdf

97-mum-2009-form 2(title page).pdf

97-mum-2009-form 2.doc

97-mum-2009-form 2.pdf

97-mum-2009-form 26.pdf

97-MUM-2009-FORM 3(7-1-2014).pdf

97-mum-2009-form 3.pdf

97-mum-2009-form 5.pdf

97-MUM-2009-FORM 9(10-11-2009).pdf

97-MUM-2009-PETITON UNDER RULE-137(7-1-2014).pdf

97-MUM-2009-REPLY TO EXAMINATION REPORT(1-10-2012).pdf

97-MUM-2009-REPLY TO HEARING(7-1-2014).pdf