FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See Section 10 and Rule 13)
1. TITLE OF INVENTION
Process for Preparation of Propofol Emulsion
2. APPLICANT (S)
a) Name: VHB Medi Sciences Limited
b) Nationality: Indian
c) Address: 50/AB, Government Industrial Estate,
Charkop Naka, Kandivali (W), Mumbai- 400067
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of Invention
The present invention generally pertains to process for preparing a propofol emulsion. In particular, the present invention provides process for manufacturing propofol emulsion using nanonizer.
Background of Invention and Prior Art
Propofol (2, 6-Diisopropylphenol) is a well-known and widely used intravenous anesthetic agent, A significant advantage of using propofol is a rapid onset following infusion or injection and a very short recovery time. Propofol can be used both as a sedative and to induce and maintain general anesthesia.
Propofol has limited water solubility. It has to be incorporated with a solubilizing agent, surfactants or solvents to generate oil-in-water emulsions. Currently marketed propofol products are available as oil-in-water emulsions.
There are many different ways available to increase the solubility of insoluble active ingredient. Salts of the actives ingredients are synthesized to achieve the required solubility of the active component. Size reduction by grinding and milling and use of surfactants/ excipients are the most conventional methods. Using a delivery system or delivery vehicles is a modern approach.
Propofol administration causes problem of pain on injection due to higher partition of propofol in the aqueous phase. Reduction in particle size of the drug will lead to less amount of substance per dose.
Statement of the Invention
The present invention relates to process for manufacturing a propofol emulsion. In particular, the present invention provides process for manufacturing propofol emulsion using high shear force as well as ultrasonic reduction. Nanonizer assembly is used to reduce the particle size of the propofol.

Description of the Invention
Propofol formulations are available as oil-in-water emulsions. The invention relates to production of nanoparticles of propofol for oil-in-water emulsion. The reduced particle size increases available particle surface area and thus increases availability of medicament. This further reduces the amount of substance required per dose. Also, reduced particle size of the drug helps in painless administration of the formulation. The formulation with reduced drug particle size is transparent which is otherwise milky or opaque.
The process involves major steps as: sterilization of oil, mixing in high shear mixture, size reduction in sonoreducer and high pressure homogenization. The nanonizer assembly is used to carry out this process. The nanonizer assembly comprises of a storage vessel for oil, high shear mixer, ultrasonic instrument for size reduction, high pressure homogenization, transfer vessel A, transfer vessel B, transfer pump for high shear mixer and transfer pump for high pressure homogenization. Nanonizer assembly is unique design for providing nano-emulsion globules of 100-500 nm used for injectable formulation. Nanoemulsion under consideration is oil in water emulsion where drug is dissolved in oil and nano emulsion is prepared. At the end point of each unit operation, sample is tested by the instrument analyzing end point of homogenization. The instrument for analyzing end point of homogenization is developed for the determination of the homogeneity by using ultrasonic receiver and transmitter placed at various planes and angles. The output is collected in the form of frequency/ amplitude/ wavelength. The data is collected with the set of receivers and transmitters through a Programmable Logic Controller (PLC). The output is then collected in an oscilloscope that converts it into a visual expression of homogenization (Indian Patent Application 2730/MUM/2011). The complete operation of the nanonizer assembly is controlled by PLC (Programmable logic Controller), thus avoiding any manual interventions. After each batch the equipment can go for cleaning in place with purified water and subsequently with sterilization in place using pure steam. Safety measures are incorporated for power cut and for power outrages. In case of power fluctuations, step where power dropped is checked and the operation then starts from that step. All power discrepancies and other discrepancies, if any experienced, are logged in PLC history. Sonoreducer is designed

in line from high shear to high pressure equipment which reduces emulsion size as to the requirement by multiple frequency and adjustment of ultrasonic waves stepwise. Further, in line with the sonoreducer is high pressure homogenizer which will further reduce the particle size by high pressure homogenization. Sampling may be done after high pressure homogenization for checking the size reduction and homogenization using the instrument to check end point of homogenization. The emulsion may be passed repeatedly through the high pressure homogenizer till required size reduction is achieved.
Brief Description of the Drawing
1 Jacketed Storage Vessel
2 High shear mixer
3 Sonoreducer
4 Transfer vessel A
5 Transfer vessel B
6 High pressure homogenizer
Example
The process pertains to the preparation of oil-in-water emulsion propofol. Oil is sterilized at 115°C-120°C. Active ingredient propofol, sterile water and excipients are added to the sterilized oil. The mixture is then transferred to high shear mixture. High shear mixture is operated at 1000-5000, particularly at 1500 to 3000 rpm. Sampling is performed to check degree of homogenization. If homogenization is not achieved as per requirement, homogenization cycle is repeated in a high shear mixture. After achieving required degree of homogenization, the mixture is transferred to sonoreducer. Homogenization check is performed, if required the repeated cycles are performed in the sonoreducer. From sonoreducer, the mixture is then transferred to transfer vessel A, and from transfer vessel A to high pressure homogenizer. It is then transferred to transfer vessel B and from there to transfer vessel A for repeating the high pressure

homogenization cycle for achieving required size reduction. From transfer vessel B, sampling is done to carry out homogenization check. If required, the cycle in high pressure homogenizer is repeated again. On achieving required size reduction and homogenization, the mixture is collected in the collector.

We claim:
1. The process for preparation of oil-in-water emulsion of propofol wherein the process is carried out in a nanonizer assembly comprising of: storage vessel for oil, high shear mixture, sonoreducer for size reduction, transfer vessel A, high pressure homogenizer and transfer vessel B.
2. The process as claimed in claim 1 wherein oil is sterilized at 115°C-120°C
3. The process as claimed in claim 2 wherein mixture is prepared by addition of active ingredient, water and excipients to the sterilized oil
4. The process as claimed in claim 3 wherein the mixture is transferred to the high shear mixer
5. The process as claimed in claim 4 wherein high shear mixer is operated at 1000-5000 rpm, more particularly at 1200-3500 rpm
6. The process as claimed in claim 5, wherein the mixture after achieving required degree of homogenization is transferred to the sonoreducer for further reduction of size
7. The process as claimed in claim 6 wherein the mixture is further transferred to the high pressure homogenizer for further particle size reduction,
8. The process as claimed in claim 7 wherein the cycle in the high pressure homogenizer is repeated till the required size reduction is achieved
9. The process as claimed in claim 8 wherein the mixture is sampled for homogenization check, homogenization check is performed and high pressure homogenization cycle is repeated if required.
10. The process as claimed in claim 9 wherein the mixture is collected after achieving required degree of homogenization