FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10 and rale 13]
1. Title: PROPOFOL BASED ANESTHETIC WITH PRESERVATEVE.
2. Applicant: Claris Lifesciences Limited,
Claris Corporate Headquarters, Nr.Parimal Crossing, Ellisbridge, Ahmedabad - 380 006, Gujarat, India.

The following specification particularly describes the invention and the manner in which it is to be performed.


DESCRIPTION
Field of Invention
This invention relates to processes and compositions and methods of 5 use of formulations containing propofoi (2,6-diisopropylphenol) and one or more preservative. The present invention relates to a novel sterile pharmaceutical composition for parenteral administration containing propofoi and preservative preferably, lipophilic organic compound (butylated hydroxytoluene, butylated hydroxyanisole) or
10 its pharmaceutically acceptable salts thereof. The composition comprises an oil-in-water emulsion of propofoi additionally comprising an amount of lipophilic organic compound (butylated hydroxytoluene, butylated hydroxyanisole) or its pharmaceutically acceptable salts thereof sufficient to prevent significant growth of
15 microorganisms for at least 24 hours after, adventitious contamination. The present invention also relates to the use of the composition to induce anesthesia in mammals, including sedation, and the induction and maintenance of general anesthesia.
20 Background of the Invention
Propofoi (2,6-diisopropylphenol) is an injectable anesthetic, which has hypnotic properties and can be used to induce and maintain general anesthesia and sedation. Injectable anesthetics such as propofoi are administered directly into the bloodstream. This results 25 in a rapid onset of anesthesia influenced almost entirely by the rate

at which the anesthetic agent crosses the blood-brain barrier. Therefore, the anesthetic agent must have sufficient lipid solubility to be able to cross this barrier and depress the relevant mechanisms of the brain. Propofol is poorly water-soluble and therefore is 5 generally formulated as an emulsion. However, propofol containing emulsions have been shown to support microbial growth. Therefore it is desirable to formulate propofol emulsions in a manner in which microbial growth is prevented. Without a preservative in the formulation, any excess formulation must be thrown away within a 10 few hours of its first use.
To overcome the contamination deficiencies found with propofol formulations, preservatives often added in the oil-in-water formulation to preserve its sterility and delay and retard the
15 microorganism growth. U.S. Pat. Nos. 5,714,520, 5,731,355 and 5,731,356 disclose the use of EDTA in an amount sufficient to prevent no more than a 10-fold increase in microbial growth over 24 hours after adventitious extrinsic contamination with the microorganisms Staphylococcus aureus (ATCC 6538), Escherichia
20 coli (ATCC 8739). Pseudoinonas aeruginosa (ATCC 9027) and Candida albicans (ATCC 10231). Disodium EDTA (ethylenediamine tetraacetate) has been shown to delay, but not prevent, the onset of microbial growth in propofol emulsions. A propofol preparation for clinical use is commercially available as D1PRIVAN 1% Injection. In
25 this formulation, a chelating or sequestering agent (i.e., ethylene

diaminetetraacetic acid (EDTA)) is included in the propofol preparation. Unfortunately, formulations containing EDTA is not truly an antimicrobial preserved product under USP standards.
5 U.S. Pat. No. 6,150,423 discloses using benzyl alcohol as preservative against microbial growth. U.S. Pat. No. 6,140,373 and 6,140,374 discloses the use of a number of antimicrobial agents in propofol containing oil-in- water emulsions including combinations of EDTA and benzyl alcohol. However, addition of benzyl alcohol JO destroys the oil-in-water emulsion and therefore its use is restricted to formulation having a substantially phospholipid-free emulsifying agent.
U.S. Pat. No. 6,147,122 discloses a sterile oil-in-water emulsion of 15 propofol and an amount of sodium metabisulfite. The amount of sodium metabisulfite in propofol administrated to patients requires careful monitoring not to exceed the limit set by the World Health Organization (WHO) (7.0 mg/kg as S02) and the amount infused in total-parenteral- nutrition amino acid formulations, as well as during 20 peritoneal dialysis. In addition, sodium metabisulfite is known for its potential allergy and hypersensitivity in some patients.
U.S. Pat. No. 6,028,108 discloses a sterile oil-in-water emulsion of
propofol and an amount of pentetate sufficient to prevent significant
25 growth of microorganisms for at least 24 hours after adventitious

. extrinsic contamination. U.S. Pat. No. 6,177,477 discloses a sterile oil- in-water emulsion of propofol and an amount of tromethamine (T1US) sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious extrinsic contamination. 5
There is a continuing need to find a suitable preservative for use in the oil-in- water emulsion containing propofol. We surprisingly discovered inclusion of an amount of lipophilic organic compound (butylated hydroxy toluene, butylated hydroxyanisole) or its
10 pharmaceutically acceptable salts thereof in a propofol oil-in-water emulsion is highly effective in preventing significant growth of a wide range of different microorganisms, including Gram (+) and Gram (-) bacteria as well as yeast and fungi, for at least 24 hours after adventitious contamination.
15
Many compounds varying dramatically in structure are known to serve as conventional preservatives. Depending upon the intended application or use of a product, a particular preservative is generally preferred. For example, conventional preservatives for food use are
20 generally different than preservatives for cosmetic use, which in turn are generally different than preservatives for pharmaceutical use. Exemplary conventional preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, chlorobutanol, chlorocresol, methyl, ethyl and phenol, phenoxyethanol, propyl
25 gallate, sorbic acid, benzyl alcohol, EDTA, pentetate, abide, organic

solvent (such as glycol, propylene glycol, or polyethylene glycol), peroxide, ozone, chlorite, sodium bisulfite, potassium metabisulfite, potassium sulfite, sodium sulfite, and others known to those of ordinary skill in the art. 5
Description of the invention
Summary of Invention:
10 The present invention is directed to a sterile pharmaceutical composition comprising oil-in-water emulsion formulation having as preservative preferably, lipophilic organic compound (butylated hydroxytoluene, butylated hydroxyanisole) or its pharmaceutically acceptable salts thereof. The term "preservative" means an agent
15 which delays onset or retards rate of growth to less than 1 logarithmic increase over a 24hour period as compared to an unpreserved formulation.
The invention is a sterile pharmaceutical composition for parenteral 20 administration comprised of an oil-in-water emulsion, in which Propofol is dissolved in a water-immiscible lipophilic agents, preferably soybean oil, and surface stabilizing amphiphilic agent, preferably egg lecithin and tonicity modifying water-soluble hydroxy group preferably glycerol and preservative preferably, lipophilic

organic compound (butylated hydroxytoluene, butylated hydroxyanisole) or its pharmaceutical^ acceptable salts thereof.
Detail description of the invention
5
The compound 2,6-diisopropylphenol (propofol) is a well-known anesthetic agent. The onset of anesthesia is largely controlled by a drug's diffusion rate through the blood-brain barrier. Propofol is lipophilic and this helps the compound to provide rapid anesthetic
10 action. However, this lipophilicity renders propofol, a liquid at room temperature, relatively insoluble in water. As a result, propofol is commonly administered (directly into the bloodstream either by infusion or by bolus injection) as an oil-in- water emulsion, containing a lipid component. Lipids, however, are good substrates
15 for bacterial growth and, bacterial growth can be delay and retard with preservatives preferably, lipophilic organic compound (butylated hydroxytoluene, butylated hydroxyanisole) or its pharmaceutically acceptable salts thereof.
20 An oil-in-water emulsion is meant to be a distinct, two-phase system that is in equilibrium and in effect, as a whole, is kinetically stable and thermodynamically unstable. Typically the lipophilic agent is oil such as soybean oil, sunflower oil, castor oil, cottonseed oil, corn oil, coconut oil, arachis oil, marine oils or olive oil and mixture
25 thereof. Preferably the oil is soybean oil. Suitable tonicity modifying

water-soluble hydroxy group is selected from a monosaccharide, a
disaccharide, a trisaccharide, sucrose, dextrose, trehalose, mannitol,
lactose, glycerol, glycerin, sorbitol, and mixtures thereof. Propofol
dissolved in the water immiscible lipophilic agents, is emulsified in
5 aqueous medium with the aid of a surface stabilizing amphiphilic
agent. Suitable surface stabilizing amphiphilic agent include for
example egg lecithin, egg phosphatidylcholine, soy lecithin, soy
phosphatidylcholine, l,2-dimyristoyl-sn~glycero-3-
phosphotidlycholine (DMPC), l,2-dimyristoyl-sn-glycero-3-
10 [phospho-rac-(l-glycerol)] (DMPG), L-alpha-phosphatidylcholine,
palmitoyl-linoleoyl phosphatidylcholine, stearoyl-linoleoyl
phosphatidylcholine, lysolecithin, phosphatidic acid, phosphatidyl-
DL-glycerol, phosphatidylethanolamine, palmitoyl-oleoyl
phosphatidylcholine, phosphatidylinositol, phosphatidylserine, 1,3-
15 bis(sn-3-phosphatidyl)-sn-glycerol, l,3_di(3-sn-phosphatidyl)-sn-glycerol, and mixtures thereof. Preferably, the surface stabilizing amphiphilic agent is egg lecithin. The formulation of the present invention typically comprises from 0.1% to 10% by weight of Propofol.
20
Propofol is a liquid that is very poorly soluble in water. To manufacture stable injectable propofol formulations with the desired anti-microbial properties, lipid content and with little or no phase separation of the propofol during mixing or storage, it was found
25 necessary to not only select an appropriate composition of the

formulation but also use appropriate processing conditions. Examples of suitable processing conditions are those, which provide intense mechanical agitation or high sheer. The formulation is conveniently prepared by the initial preparation of a aqueous phase, 5 oil phase, which are then mixed and homogenization.
AQUEOUS PHASE PREPARATION
Water for injection, tonicity modifying water-soluble hydroxy group, and ampiphilic agents were mixed to prepare the aqueous Phase.
10 The dissolution process was accelerated by heating the mixture while mixing with a high-speed mixture vessel to 4000rpm and maintain the flow rate of 3000L/Hr. The aqueous phase was usually a mixture of polyhydroxy compounds in water and in some cases also contained well-dispersed phospholipid prepared using a high-
15 speed mixture vessel.
OIL PHASE PREPARATION
Propofol, lipophilic agents, and preservative preferably, lipophilic organic compound (butylated hydroxytoluene, butyiated 20 hydroxyanisole) or its pharmaceutically acceptable salts thereof are mixed to prepare the Oil phase. Adding of Propofol to lipophilic agent with caution, and mix it for 30-40 minutes.
The mixing was prepared by adding the Oil phase to the aqueous 25 phase under agitation with a high-speed mixture vessel. Maintain

the speed of mixture vessel to 4200rpm. after the completion of oil phase addition to aqueous phase keep re-circulation of formed emulsion till the globule size of emulsion reduces.
5 HOMOGENIZATION
The dispersions of the water insoluble matrix in aqueous medium were prepared by either of several homogenization methods. For example, dispersions were prepared by high-pressure homogenization of the mixed emulsion. The temperature of the
10 process-fluid rises rapidly because of homogenization at a high pressure. In some cases high-pressure homogenization at high temperatures resulted in dispersion with a tendency to suffer from phase separation. Therefore, the effluent of the homogenizer was cooled by heat exchanger, to maintain an acceptable temperature at
15 the inlet of the homogenizer. After the homogenization phase is over adjust the pH about 8.9 to 9.2 with sodium hydroxide solution and start the final stage of homogenization.
Packaging And Sterilization
20 The aqueous dispersion prepared by one of the above processes was filled into glass vials to about 70~90% volume capacity, purged with a generally inert atmosphere, for example nitrogen, and sealed with compatible stoppers and seals. The packaged novel propofol formulations were found generally to be stable pharmaceutically
25 acceptable steam sterilization cycles.

In the preferred embodiment lipophilic agents is an oil such as soybean oil, sunflower oil, castor oil, cottonseed oil, corn oil, coconut oil, arachis oil, marine oils or olive oil alternatively the 5 lipophilic agents can be an ester of a medium or long chain fatty acid, for example triglyceride or a compound such as glycerol ester or polyoxyl hydrogenated castor oil, isopropyl myristate, ethyl oleate, capriccaprylic triglyceride and mixture thereof.
10 In the preferred embodiment amphiphilic agent is selected from the
group consisting of egg lecithin, egg phosphatidylcholine, soy
lecithin, soy phosphatidylcholine, l,2-dimyristoyl-sn-glycero-3-
phosphotidlycholine (DMPC), l,2-dimyristoyl-sn-glycero-3-
[phospho-rac-(l-glycerol)] (DMPG), L-alpha-phosphatidylcholine,
15 palmitoyl-linoleoyl phosphatidylcholine, stearoyl-Hnoleoyl
phosphatidylcholine, lysolecithin, phosphatide acid, phosphatidyl -
DL-glycerol, phosphatidylethanolamine, palmitoyl-oleoyl
phosphatidylcholine, phosphatidylinositol, phosphatidylserine, 1,3-bis(sn-3-phosphatidyl)-sn-glycerol, l,3-di(3-sn-phosphatidyl)-sn-
20 glycerol, and mixtures thereof.
In the preferred embodiment tonicity modifying water-soluble hydroxy group excipient is selected from the group consisting of a monosaccharide, a disaccharide, a trisaccharide, sucrose, dextrose,

trehalose, mannitol, lactose, glycerol, glycerin, sorbitol, and mixtures thereof.
Preferred composition of the present invention is as below-
5 Table 1

Component Range
(Weight %) Preferred Amount
(Weight %)
Propofol 1.0-10.0 1
Soybean oil 5.0-20.0 10
Egg Lecithin 0.5-2.0 1.2
Glycerol 2.0-3.0 2.25
Butylated Hydroxy anisole 0.00001-0.00 lj 0.0001
Butylated hydroxytoluene 0.00001-0MI 0.0001
Sodium Hydroxide q.s to 100 q.s to 100
Water for Injection

The following examples are intended to be illustrative for the present invention and should not be construed as limiting the scope of this invention defined by the appended example
10
Example 1
Weigh accurately required quantity of lO.OOgm Propofol, 96.00gm Refined Soya Oil, O.OOlgm BHA (O.OOlmg/ml) and O.OOlgm BHT (O.OOlmg/ml) solution and 12.00gm Egg lecithin, in a clean dry
15 beaker and mix it on magnetic stirrer at 60°C until all ingredients gets dissolved. In parallel to above aqueous phase is prepared take 22.50gm Glycerol and 600ml Water for Injection in clean dry beaker, with constant stirring on magnetic stirrer at 55°C. After complete

dissolving oil phase add this solution in aqueous phase. Slowly with
continuous stirring temperature maintain 60°C. (Stirring lhr.) make
up the volume of the batch size 1000ml with water for injection.
Homogenize the solution until required globule size is achieved.
5 After homogenization check the globule size and pH of the solution.
Adjust the pH of the solution to 8.90-9.20 with 0.1N sodium
hydroxide. Then fill the solution in previously washed, dried USP
type-I glass vials. Purge the solution with Nitrogen gas Seal it
with gray-colored rubber closure and flip off seal. Sterilized the 10 sample by Autoclave.
Example 2
Weigh accurately required quantity of lO.OOgm Propofol, 98.00gm Refined Soya Oil, O.OOlgm BHA (O.OOlmg/ml) solution and 12.00gm
15 Egg lecithin, in a clean dry beaker and mix it on magnetic stirrer at 60°C until all ingredients gets dissolved. In parallel to above aqueous phase is prepared take 22.50gm Glycerol and 600ml Water for Injection in clean dry beaker, with constant stirring on magnetic stirrer at 55°C. After complete dissolving oil phase add this solution
20 in aqueous phase. Slowly with continuous stirring temperature maintain 60°C. (Stirring lhr.) make up the volume of the batch size 1000ml with water for injection. Homogenize the solution until required globule size is achieved. After homogenization check the globule size and pH of the solution. Adjust the pH of the solution to
25 8.90-9.20 with 0.1N sodium hydroxide. Then fill the solution in

previously washed, dried USP type-I glass vials. Purge the solution with Nitrogen gas. Seal it with gray-colored rubber closure and flip off seal. Sterilized the sample by Autoclave.
5 Example 3
Weigh accurately required quantity of lO.OOgm Propofol, 98.00gm Refined Soya Oil, O.OOlgm BHT (0.001 mg/ml) solution and 12.00gm Egg lecithin, in a clean dry beaker and mix it on magnetic stirrer at 60°C until all ingredients gets dissolved. In parallel to above aqueous
10 phase is prepared take 22.50gm Glycerol and 600ml Water for Injection in clean dry beaker, with constant stirring on magnetic stirrer at 55°C. After complete dissolving oil phase add this solution in aqueous phase. Slowly with continuous stirring temperature maintain 60°C. (Stirring lhr.). make up the volume of the batch size
15 1000ml with water for injection. Homogenize the solution until required globule size is achieved. After homogenization check the globule size and pH of the solution. Adjust the pH of the solution to 8.90-9.20 with 0.1N sodium hydroxide. Then fill the solution in previously washed, dried USP type-I glass vials. Purge the solution
20 with Nitrogen gas. Seal it with gray-colored rubber closure and flip off seal. Sterilized the sample by Autoclave.
In the preferred embodiment propofol oil-in-water emulsions
containing 0.00002%BHT, 0.00002%BHT/0.000005%BHA,
25 0.00001%BHT/0.0000025BHA, 0.000006%BHT/0.0000015%BHA

and 0.00001 %BHA were tested by the USP preservative efficacy test as described in United States Pharmacopoeia. Briefly, this involves inoculating the test solution with 105 to 106 test organisms per milliliter and then determining the number of surviving 5 organisms after 6, 12, 18, and 24hrs incubation at 20-25°C. using standard microbiological methods. The USP test organisms include the bacteria Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, yeast (Candida albicans), and mold (Aspergillums niger). In order to meet the criteria of the USP
10 preservative efficacy test, the bacteria must demonstrate not less than 1.0 log reduction from initial count and no increase of Yeast and Molds from the initial calculated count. The initial inoculums level can either be calculated knowing the stock culture concentration or by using a buffer control instead of the test solution. The results,
15 using formulations, which are Propofol 1% fat emulsions, are given below in Tables 2 -6.
Table-2

PROPOFOL WITHBHT Preservative : BHT: 0.00002%,
Initial Strength l(f
Time E.Coli S. Aureus P. Aeruginosa A.Niger C.Albicans
Initial 2.7X105 2.6X105 2.5X105 2.4X105 3.3X105
6hrs 2.9X103 2.6X104 2.8X103 2.6X10" 2.9X104
12hrs 3.1X102 3.2X103 2.9X102 2.5X103 3.5X103
18hrs 2.6X102 2.9X103 2.6X102 2.0X103 2.7X103
24-hrs 2.4X102 2.6X103 2.1X102 1.8X103 2.4X103
Log reduction 3 2 3 2 2

5

Table-3

PROPOFOL WITHBHT-BHA
Preservative :BHT •' 0.00002%, BHA -' 0.000005%
Initial Strength l(f
Time E.Coli S.Aureus P.Aeruginosa A.Niger C. Albicans
Initial 2.7X105 2.6X105 2.5X10° 2.4X105 3.3X105
6hrs 2.3X102 3.3X104 6.3X103 4.1X104 6.9X104
12hrs 2.9X101 4.1X103 7.9X102 3.3X103 1.9X103
18hrs 2.3X101 2.0X103 6.6X102 2.6X103 L2X103
24hrs 1.0X101 1.9X103 4.0X102 2.2X103 0.6X103
Log reduction 4 3 3 2 3
Table-4

PROPOFOL WITHBHT-BHA
Preservative : BHT -' 0.00001%, BHA : 0.0000025%
Initial Strength l(f
Time E.Coli S.Aureus P.Aeruginosa A.Niger C. Albicans
Initial 2.7X105 2.6X105 2.5X105 2.4X105 3.3X105
6hrs 5.0X103 8.0X101 3.9X103 7.0X104 4.9X103
12hrs 6.1X102 9.0X101 5.2X102 8.0X103 7.2X102
18hrs 4.9X102 8.3X101 4.4X102 6.4X103 6.1X102
24hrs 3.3X102 6.6X101 3.2X102 4.0X103 5.3X102
Log reduction 3 4 3 2 3
Table-5

PROPOFOL WITHBHT-BHA
Preservative : BHT: 0.000006%, BHA : 0.0000015%
Initial Strength l(f
Time E.Coli S.Aureus P.Aeruginosa A.Niger C. Albicans
Initial 2.7X105 2.6X105 2.5X105 2.4X105 3.3X10°
6hrs 2.8X103 2.7X103 2.8X103 2.7X104 2.9X104
12hrs 3.1X102 2.9X102 2.5X102 3.0X103 3.4X103
18hrs 2.8X102 2.4X102 2.1X102 2.8X103 3.0X103
24hrs 2.6X102 1.9X102 1.6X102 2.4X103 2.6X103
Log reduction 3 3 3 2 2

Table-6

PROPOFOL WITH BHA Preservative : BHA : 0.0001%
Initial Strength l(f
Time E.Coli S.Aureus P.Aeruginosa A.Niger C.Albicans
6hrs 3.0X105 4.3X105 3.0X104 3.0X105 3.0X105
12hrs 2.9X105 3.3X105 3.3X103 2.6X105 3.1X104
18hrs 3.9X10' 3.9X104 2.6X103 2.2X105 2.3X104
24hrs 3.0X104 2.5X104 1.4X103 1.7X105 1.0X104
Log reduction 2 2 3 1 2

We claim,
1. A sterile pharmaceutical anesthetic composition of propofol
oil-in-water emulsion comprises mixture of- propofol;
lipophilic agents; tonicity modifying water-soluble hydroxy
5 group; surface stabilizing amphiphilic agent; preservative
selected from the group consisting of; butylated hydroxytoluene, butylated hydroxyanisole or mixture thereof; and water.
10 2. A sterile pharmaceutical anesthetic composition of claim 1,
wherein said lipophilic agent is ester of a medium or long chain fatty acid, is selected from the group consisting of triglyceride derivatives, glycerol ester or polyoxyl hydrogenated castor oil, isopropyl myristate, ethyl oleate, capriccaprylic triglyceride
15 and mixture thereof.
3. A sterile pharmaceutical anesthetic composition of claim 2,
wherein said lipophilic agent is oil is selected from the group
consisting of soybean oil, sunflower oil, castor off, cottonseed
20 oil, corn oil, coconut oil, arachis oil, marine oils or olive oil and
mixture thereof.
4. A sterile pharmaceutical anesthetic comp'osition of claim 3,
wherein said lipophilic agent is Soybean oil.
25

5. A sterile pharmaceutical anesthetic composition of claim 1,
wherein tonicity modifying water-soluble hydroxy group is
selected from the group consisting of a monosaccharide, a
disaccharide, a trisaccharide, sucrose, dextrose, trehalose,
5 mannitol, lactose, glycerol, glycerin, sorbitol, and mixtures
thereof.
6. A sterile pharmaceutical anesthetic composition of claim 5,
wherein tonicity modifying water-soluble hydroxy is glycerol.
10
7. A sterile pharmaceutical anesthetic composition of claim 1,
wherein surface stabilizing amphiphilic agent is selected from
egg lecithin, egg phosphatidylcholine, soy lecithin, soy
phosphatidylcholine, l,2-dimyristoyl-sn-glycero-3-
15 phosphotidlycholine (DMPC), l,2-dimyristoyl-sn-glycero-3-
[phospho-rac-(l-glycerol)] (DMPG), L-alpha-
phosphatidylcholine, palmitoyl-linoleoyl phosphatidylcholine,
stearoyl-Iinoleoyl phosphatidylcholine, lysolecithin,
phosphatidic acid, phosphatidyl-DL-glycerol,
20 phosphatidylethanolamine, palmitoyl-oleoyl
phosphatidylcholine, phosphatidylinositol, phosphatidylserine,
l,3-bis(sn~3-phosphatidyl)-sn-glycerol, l,3~di(3-sn-
phosphatidyl)-sn-glycerol, and mixtures thereof.

8. A sterile pharmaceutical anesthetic composition of claim 7,
wherein surface stabilizing amphophilic agent is egg lecithin.
9. A sterile pharmaceutical anesthetic composition of propofol
5 oil-in-water emulsion comprising: from 1 to 10 weight percent
propofol; from 5 to 20 weight % lipophilic agent; from 0.5 to
2.0 weight % surface stabilizing amphophilic agent; from 2.0 to
3.0 weight % tonicity modifying water-soluble hydroxy group;
from 0.00001 to 0.001 Weight % preservative selected from
10 the group consisting of: butylated hydroxytoluene, butylated
hydroxyanisole or mixture thereof.
15