FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Stable Propofol Microemulsion for parenteral delivery"
2. APPLICANT:
(a) NAME: MAC CHEM PRODUCTS INDIA PVT. LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 304, Town Centre, Andheri-kuria Road, Andheri (E),
Mumbai-400059, Maharashtra, India.


3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

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Technical Field
The present invention relates to stable microemusion composition comprising propofol for intravenous administration, which is capable of providing safe, stable and an efficient formulation obtained by simple and rapid process.
Background of the Invention
Propofol (i.e. 2,6-diisopropylpheno!) is a well-known intravenous anesthetic agent, which has been used in pharmaceutical aqueous emulsion compositions since the early 1980's. Because of the poor solubility of Propofol in water resulting from its lipophilic nature, intravenous formulations containing Propofol are optimized in order to keep the drug dissolved in a safe composition.
Many anesthetic agents commonly used in the clinical field are in a gaseous state. Propofol is useful for intravenous injection and therefore, can be very effectively used as a local analgesic adjuvant due to its hypnotic and sedative activities, an anesthetic agent for patients for whom pulmonary respiration should be cared, an anesthetic agent used under conscious state, etc., or for patients under medical treatment in intensive care unit (ICU) or patients in serious state, etc.
In spite of such clinical advantages of Propofol, the development of its injectable formulations is very difficult since Propofol exists in the non-ionized state (pKa=10.4) in blood and has physico-chemical properties including a unique high lipid solubility (octanol water partition coefficient 4.33).
Thus, since water may substantially be an essential solvent in preparing all pharmaceutical formulations including anesthetic agents, it is very difficult to formulate lipid-soluble drugs such as Propofol into pharmaceutical preparations containing water as the solvent. In order to solve such problem, lipid-soluble drugs, which are generally poorly soluble in water, have been developed into such forms as emulsions, microemulsions, micelles, etc., using a surfactant.
The first Propofol composition, which appeared on the market, was an intravenous opaque and stable macro-emulsion named "Intralipid". This composition contained triglycerides such as soybean oil, which were included at a mass fraction typically of about 10%, e.g. the "Diprivan" compositions from Astra Zeneca Pharmaceuticals, which also essentially comprise a phospholipid and glycerin.
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One major drawback of such triglycerides-containing emulsions resides in their unclear nature and in the relatively large medium particle size in the emulsions - typically greater than 150 nm (nanometers) -which may lead to the formation of clots in blood capillaries and other vessels, thus rendering these triglycerides containing compositions not totally safe through intravenous injection.
In order to minimize potential side effects due to high triglycerides content, some searchers have focused their works in developing triglycerides-free formulations with the aim to obtain clear aqueous compositions, as detailed below. Patent document US-B-6, 623,765 discloses in its examples, a clear aqueous micro-emulsion composition comprising 1% (v/v) Propofol and at least 4.05% (w/v) of a surfactant system including at least 0.05% (w/v) of sodium laurate and at least 4% of a poloxamer (i.e. a block copolymer of ethylene oxide / propylene oxide).
Zeneca Inc. formulation comprising an antiseptic activity by addition of a preservative (EDTA) in order to inhibit the microorganism growth due to lipid components (U. S. Patent No. 5,714,520) have the unsolved problems including physical unstability, pain at injection site, embolism, hyperlipidemia,
In order to improve such problems, the formulations have recently been studied using inclusion complexation of propofol with biodegradable surfactants or cyclodextrin (Giuseppe Trapani et al., J. Pharm.Sci. 1998,87,514-518), the concept of prodrugs (Sagara Y., J.Neurochem. 1999,73,2524-2530), etc. In addition, the study to reduce the pain during injection by administration in combination with such neuroblocking agents as lidocain has been actively and extensively practiced from all parts of the world (Parmar A. K., Anaesthesia, 1998,53,79-83).
The oil-in-water emulsions depended on the incorporation of preservatives to prevent the oxidation of the lipid components. The use of preservatives is also necessary to prevent microbial growth or the use of extremely aseptic techniques to avoid the contamination and development of microorganisms in the formulations.

Patent application WO 99/39696 describes the use of a sulfite, preferably sodium metabisulfite. in a non-toxic amount to delay or suppress the growth of microbial contaminants. However, such substances may cause allergic reactions.
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Patent US 5,637,625 refers to a formulation containing propofol microparticles wrapped by a fat-free and triglyceride-free phospholipid layer. Such microparticles have dimensions between 100 nm arid 200 nm. The aqueous phase of the referred formulation is constituted by glucos^phosphate buffer with pH adjusted to 7.0. Although the patent reports that the formulation does not propitiate the development of microorganisms for not containing oils as a microbial nutrient, the inclusion of glucose or another carbohydrate in the formulation accounts to favors microbial growth.
Different microemulsion formulations containing propofo disclosed in prior art are as mentioned below.
US 6623765
Composition
Propofol
Sodium Laurate
Pluronic F-77
WO2008049178
Composition
Propofol
Solutol HS-15
Glycerol
Sodium Hvdroxide
Water for Injection


3. WO2007006334

Composition
Propofol
PEG-15 hydroxy sterate
Sodium oleate
Ethanol
Polyethylene Glycol
Glycerin
Water for Injection
Therefore, the object of the present invention is to provide novel and alternative microemulasion composition comprising propofol along with pharmaceutically acceptable excipients for intravenous use.
Summary of the invention:
Accordingly, in one aspect, the present invention provides an efficient, stable microemulsion formulation comprising propofol along with pharmaceutical acceptable excipients such as surfactant, co-surfactant and water for injection suitable for intravenous delivery.
Another aspect of the present invention is to provide a simple and rapid method of preparing a microemulsion composition for intravenous injection.
The surfactant is a non-ionic polyoxyethylene-polyoxypropylene copolymer and the concentration is used upto 5%.
The co-surfactant is a non-ionic polyethylene glycol 660 hydroxystearate and the concentration is used upto 25%.


Detailed Description

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The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Generally micro emulsion system consists of oil, water and appropriate emulsifier can form spontaneously and are therefore thermodynamicaily stable. In addition, the size of the droplets in such micro emulsion remains constant and ranges from 10-]00nm.
The present invention discloses the novel pharmaceutical composition in micro emulsion form, which comprises a therapeutically effective amount of propofol with suitable excipients so as to make the formulation stable.
Therefore, according to preferred embodiment, the composition of the present invention comprises therapeutically effective amount of propofol; a surfactant; co-surfactant and water, suitable for intravenous administration
The micro emulsion of the present invention is characterized by comprising a Surfactant, lutrol,. The lutrol also known as polyoxyethylene-polyoxypropylene copolymer is preferably present in the range between 0.2%-5%.
The micro emulsion of the present invention is also characterized by containing a co-surfactant, solutol. The solutol also known as polyethylene glycol 660 hydroxystearate,. is preferably present in the range between 2%-25%. The co-surfactant is used as solubilizer.
In another preferred embodiment, the invention provides a simple process for preparation of microemulsion, which comprises the following steps:
a. adding weighed amount of surfactant and co-surfactant to a container;
b. dissolving the above mixture in water for injection by checking the pH of solution;
c. adding the solution obtained above to other container containing propofol followed by
stirring the mixture vigorously tilt clear solution obtained;
d. adjusting the pH of the solution to 6.0-7.0; and

e. finally, making up the volume with Water for injection.

The following examples, which include preferred embodiments, will serve to illustrate
the practice of this invention, it being understood that the particulars shown are by way of
example and for purpose of illustrative discussion of preferred embodiments of the
invention.
The propofol microemulsions of the present invention are presented in table 1, the best
formulations are shown in table 2 and the particle size in table 3.
Table 1

Formula Propofol Surfactant-Lutrol Co-Surfactant-SoIutolHS 15 Disodium EDTA
1 1% 0.2% 10% 0.005%
2 1% 0.3% 20% 0.005%
3 1% 0.45% 20% 0.005%
4 1% 0.4% 20% 0.005%
5 1% 0.38% 20% 0.005%
6 1% 0.3% 40% 0.005%
7 1% 0.2% 40% 0.005%
8 1% 0.1% 10% 0.005%
Table 2
Best formulations

Formula Propofol Surfactant-Lutrol Co-
Surfactant-
SolutolHS15 Disodium EDTA
10 lgm 0.425% 20% 0.005%
II Igm 0.425% 21% 0.005%
12 lgm 0.425% 22% 0.005%
13 lgm 0.425% 23% 0.005%
14 lgm 0.425% 24% 0.005%
15 lgm 0.425% 25% 0.005%
16 lgm 0.4% 20% 0.005%
17 Igm 0.4% 21% 0.005%
18 lgm 0.4% 22% 0.005%
19 lgm 0.4% 23% 0.005%
20 lgm 0.4% 24% 0.005%
21 lgm 0.4% 25% 0.005%
22 Igm 0.380% 20% 0.005%


•%■

23 lgm 0.380% 21% 0.005%
24 Igm 0.380% 22% 0.005%
25 lgm 0.380% 23% 0.005%
26 lgm 0.380% 24% 0.005%
27 lgm 0.380% 25% 0.005%
Observation
The best microemulsion obtained with combination of Lutrol and Solutol in concentration range of 0.380%-0. 425% and 19%-25% respectively.
Particle Size

Formula Propofol Surfactant-Lutrol Co-Surfactant-SolutolHS 15 Disodium EDTA Particle Size (nm)
25°C 37°C
19 lgm 0.4% 23% 0.005% 20-35 20-35
20 lgm 0.4% 24% 0.005% 20-35 20-35
21 lgm 0.4% 25% 0.005% 20-35 20-35
Stability
The stability data of the present invention was found to be stable upto 6month accelerated condition. No significant change in assay as well as in particle size observed.
Osmolality of the present formulation of Propofol microemulsion was found to be 390-415mOsm and hence suitable to administer through IV route.
Results & Discussion
1. The best microemulsion obtained with combination of Lutrol and Solutol in concentration
range of 0.380- 0. 425% and 19-25% respectively.
2. The stability data found to be stable upto 6 month accelerated condition No significant change
in assay as well as in particle size observed.
3. The present invention found to be simple, rapid, stable, and safe process.


It will be readily apparent to one skilled in the art that varying substitution and modification may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be restored to by those skilled in the art, and that such modification and variation are considered to be falling within the scope of the invention.

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We Claim,
1. Stable intravenous microemulsion comprising propofol: wherein said microemulasion is characterized by comprising a surfactant, non-ionic polyoxyethylene-polyoxypropylene copolymer; a co-surfactant, non-ionic polyethylene glycol 660 hydroxy stearate; in a range of 0.2%-5% and 2%-25% respectively along with aqueous phase.
2. Stable intravenous microemulsion comprising propofol as claimede in claim 1; wherein said microemulsion is characterized by having a pH in the range of 6 to 7.
3. The stable intravenous microemulsion as claimed in claim 1. wherein the surfactant is present in an amount of 0.380- 0. 425%.
4. The stable intravenous microemulsion as claimed in claim 1. wherein the co-surfactant is in an amount of 19-25%.
5. A process for preparation of intravenous microemulsion comprising the steps of;
a. adding weighed amount of surfactant and co-surfactant to a container;
b. dissolving the above mixture in water for injection by checking the pH of
solution;
c. adding the solution obtained above to other container containing propofol
followed by stirring the mixture vigorously till clear solution obtained;
d. adjusting the pH of the solution to 6.0-7.0; and
e. finally, making up the volume with Water for injection.
6. A composition prepared by the process as claimed in 5.
7. An intravenous microemulsion, wherein the formulation is simple and made with rapid process within 15 minutes.
Dated this 30th July, 2008 For Mac Chem Products Pvt. Ltd.



Mohan B.Jain

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