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 America, 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. US patent 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. CN 1650854 (A) discloses formulation that comprises artemether, arteether or artesunate, emulsifier, emulsifying aid and plant oil which can be used in the form of intravenous injection, oral taking, percutaneous absorption, and spray.

Neither of these inventions give 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 pain and muscle stiffness. 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 an anti-malarial drug 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.

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 concentrations reduces the viscosity and the volume to be injected. Embodiment of the invention relates to the process for preparation of pharmaceutical injection formulation which involves the following steps:

(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.)

(f) The final volume is adjusted with ethyl oleate. (g) Filling of 1 ml ampoule is carried out by adjusting fill volume at 1.2 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 gall ate 5 mg

Ethyl oleate Q.S

Example-2

For 100ml

Ingredients Quantity

Arteether 15000 mg

Benzyl alcohol 6 ml

Ethyl alcohol 10 ml

Butylated hydroxy toluene 5 mg

Butylated hydroxy anisol 3.3 mg

Propyl gallate 5 mg

Ethyl oleate Q.S

Sub-Acute Toxicity Study Report:

Sub-acute intravenous toxicity study of arteether (150 mg/ml) was conducted on Sprage Dawley Rats at B. V. Patel PERD Centre, Sarkhej-Gandhinagar Highway, Thaltej, Ahmedabad-380054 (Study Number: BVPPERD/TOX/090609). The study was conducted for 14 days from 24 ^th July 2009 to 7 ^th August 2009. Toxicity was evaluated in male and female Sprague Dawley rats at an intravenous dose of 0 (control), 2.5 (low), 12.5 (mid) and 25.0 (high) mg/kg body weight once a day for 14 days. The rats were observed for changes in body weight, food consumption and clinical signs every day and haematology, clinical chemistry, organ weight and gross necroscopy at the end of the treatment. Results:

Survival Data: Negligible mortality was observed in control, low, mid and high dose groups in both males and females except in low group male, the 6 ^th rat died on the 8 ^th day of the study and in mid group female, the 5 ^th rat died on the 4 ^th day of the study. Summary of Clinical Signs: No clinical signs including appearance, respiration, motor activity, Prostrations, Tremors, Convulsions, Reflexes (corneal, primodial, etc.), Ocular changes (lacrimation, ptosis, mydriasis/miosis), Salivation, Diarrhoea, other discharges etc. of intoxication were detected in all males and females. Summary of Body Weight: Gradual increase in the body weight of all animals, both males and females was observed.

Summary of Absolute Organ Weight: Absolute organ weight (of lungs, heart, liver, spleen, kidney, adrenal, testis/ovaries, epididy/uterus) of all animals, both males and females, which have undergone necroscopy, showed similar pattern in all the groups. No significant change was seen in any of the groups. Summary of Relative Organ Weight: Relative organ weight (of lungs, heart, liver, spleen, kidney, adrenal, testis/ovaries, epididy/uterus) of all animals, both males and females, which have undergone necroscopy showed similar pattern in all the groups. No significant change was seen in any of the groups. Summary of Haematology Data: All the haematological data (including the RBC count, WBC count, Differential Count, Haemoglobin, PCV, MCV, MCH, MCHC) obtained from animals of all groups, both males and females, were within the normal range. Summary of Clinical Chemistry data: All the clinical biochemistry data (including total protein, albumin, cholesterol, SGPT, SGOT, S. Creatinin, Glucose, S. Urea and Triglycerides) obtained from animals of all groups, both males and females, were within the normal range.

Summary of Necroscopy findings: Gross necroscopy (of heart, lung, spleen, kidney, liver and adrenals) did not show any abnormality in any of the surviving male and female animals. Summary of Histopathology Data: No abnormality was detected in spleen, liver and kidney of both male and female rats. Conclusion:

It is concluded that intravenous dosage of arteether (150 mg/ml) up to and inclusive of 25.0 mg/kg body weight per day was tolerated by the Sprague Dawley rat upto 14 days.