FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
Novel Silicone Oil/Water Emulsions - Formulation, Production and Use
2. APPLICANT (S)
(a) NAME: Wockhardt Limited
(b) NATIONALITY: Indian
(c) ADDRESS:
Wockhardt Towers,
Bandra-Kurla Complex,
Bandra (East),
Mumbai- 400051,
India
3. PREAMBLE TO THE DESCRIPTION
PROVISIONAL
The following specification describes the invention.

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4. DESCRIPTION
Field of the Invention
This invention relates to a process for the preparation of stable silicone oil-in-water
emulsions wherein the emulsion is substantially free of any additives.
Background of the Invention
Siliconization of glass containers is often a necessary step prior to the packaging of
pharmaceutical and cosmetic preparations. A concern when packaging preparations in
glass containers, including bottles, injection cartridges, IV infusions, syringes, vials, etc.,
is that leaching of alkali from the glass components can occur. Sometimes described as
"water attack", leaching can be a concern even for glass recommended for
pharmaceutical preparations, viz., glass types I, II, and III. One of the most common
causes of leaching is the extreme sterilization conditions that glass containers are
generally subjected to prior to filling. Such conditions, for example autoclaving, that
requires heating the containers to about 121 °C using high steam pressure, and "baking"
and/or oven sterilization, where glass containers can be subjected to temperatures
exceeding 200 °C, can result in considerable leaching of components from the glass. In
addition, certain preparations, such as, for example, acidic drugs/cosmetics, can also
promote leaching from glass. Thus, a common practice is to coat the surface of glass
containers with silicone prior to their sterilization and filling. Silicone coating of glass
containers, in addition to reducing the leaching of glass components, can also function as
lubricants. Thus, a silicone coating can improve the drainage of fluids, and suspensions,
especially viscous ones. The use of silicone coatings in containers is common for
suspensions of steroids and combinations of penicillin and dihydrosterptomycin. Silicone
can also be used in preparations in containers where the contents have high solid content,
and formulation modifications cannot improve the drainage of the preparation from the
containers. In addition, the inner surfaces of cartridges and syringes can be siliconized to
allow free movement of the plunger through the cartridge or syringe. The outside of
cartridges and syringes and other glass containers can also be siliconized to ease their
transport through the steps in an assembly line, for example, through a sterilization setup.
Siliconization typically involves application of, for example, by spraying, the silicone
emulsion onto the surface of containers, usually as the last step of the cleaning protocol.
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After spraying with the emulsion, the containers are heat sterilized, which bakes the
silicone oil onto the glass surface.
Several silicone oil-in-water emulsions are commercially available for the purposes of
lubrication and siliconization of containers and delivery systems. However, the
commercially available silicone oil-in-water emulsions usually contain several additives
that may be of concern. The concerns arise because, a) these materials can degrade
during heat sterilization, that often use temperatures in excess of 300 °C, in the case of
baking, and 121 °C with high steam pressure during autoclaving and b) the additives and
the degraded components, could effect the stability of the preparation to be filled, and
may also be incompatible with the preparations. For example, it is recommended that the
baking conditions for the commonly used 35% Dimethicone NF emulsion not exceed
200 °C to avoid the possibility of oxidation and formation of formaldehyde. Over-baking
an article treated with 35% Dimethicone NF emulsion can result in a cloudy appearance
on the surface of the treated article.
U.S. Patent No. 5,443,760 discloses an oil-in-water emulsion having a low HLB value.
The compositions are prepared with silicone-oxyalkylene copolymeric surfactants.
U.S. Patent No. 6,248,855 discloses a silicone oil-in-water emulsion containing a linear
non-cross linked silicone copolymer prepared by polymerizing an OH endblocked
polydimethylsiloxane monomer with an amine functional trialkoxysilane monomer in the
presence of a metal catalyst. In the process the polymerization is interrupted by phase
inversion emulsification of the copolymer, and addition of a carboxylic anhydride to
avoid reverse depolymerization.
U.S. Patent No. 6,300,442 discloses a process for making a cosmetically or
pharmaceutically-acceptable emulsion or gel composition in which a reaction mixture
comprising a vinyl monomer is heated in an oil solvent, such as silicone oil, in presence
of a cross linking agent and an oil soluble surfactant, with agitation, in the presence of an
inert gas, at about 40-150 °C, followed by addition of water to form an form an oil-in-
water, a water-in-oil or a water-in-oil-in-water emulsion or gel.
U.S. Patent No. 6,784,144 describes a silicone oil emulsion stabilized with soap. The
soap includes: one or more carboxylates of a fatty acid having from 8 to 18 carbon atoms;
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and a cation of a base, the soap being formed in situ from the fatty acid and the base
during formation of the emulsion.
Published International Patent Application No. WO 2004/100862 discloses oil and water
emulsions comprising silicone oil an electrosteric stabilizer and a polyol and/or hydroxy
acid. The electrosteric stabilizer can be a copolymer of polyacrylate and alkylated
polyacrylate.
Published International Patent Application No. WO 2005/105024 discloses silicone oil-
in-water emulsions that are stabilized by a combination of silicone polyether and anionic
surfactants. The resulting oil phase is dispersed in the emulsion as particles having an
average size of less than 5 micrometers (µM).
Published Internationa] Patent Application No. WO 2003/011948 discloses emulsions of
water, a volatile siloxane, long chain or high molecular weight silicone polyether, an
optional co-surfactant such as, a monohydroxy alcohol, organic diol, an organic triol, an
organic tetraol, a silicone diol, a silicone triol, a silicone tetraol and a nonionic organic
surfactant.
Published International Patent Application No. WO 2003/064500 discloses compositions
of silicone oil-in-water emulsions, having silicone polyethers that are stable in the
presence of salts, alcohols and organic solvents. The silicone polyether can be the only
emulsifier or in can be used in combination with other organic type surfactants.
Thus, there is a need for stable silicone oil-in-water emulsions wherein the emulsion is
substantially free of any additives. In particular, there is a need for silicone oil-in-water
emulsions, substantially free of any additives that are stable for an extended period of
time.
Summary
The present invention provides a stable silicone oil-in-water emulsion substantially free
of any additives. The emulsions of the invention can be stable for at least about fifteen
(15) and preferably for at least about thirty (30) minutes. The emulsions of the invention
are useful for the siliconization of glass container surfaces.
In another embodiment, the invention provides a method for preparing a siliconized glass
container (having a silicone coating) wherein the silicone coating is substantially free of
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any additives. In another embodiment, the invention provides a method for providing
sterile siliconized glass containers wherein the silicone coating is substantially free of any
additives,
The vessel for the production of the silicone oil-in-water emulsion and the emulsion
spraying assembly are depicted in the accompanying Figures 1-2.
Detailed Description
Coating of surfaces of glass containers with silicone oil is necessary to reduce the
leaching of glass components that can occur as a result of either extreme sterilization
conditions or due to the action of certain preparations that can promote leaching. In
addition, the silicone emulsion coating can also function as a lubricant. Thus, the silicone
coating can improve the drainage of fluids and suspensions from the container, the
siliconized surfaces of cartridges and syringes can also aid the free movement of the
plunger through the cartridge or syringe.
Commercially available silicone emulsions typically have one or more additives that can
be of concern, because the additives can degrade at the high temperatures of sterilization
that are commonly employed. The additives.as well as the degraded products can also be
incompatible with the container preparations.
Thus, it would be highly advantageous to have silicone oil-in-water emulsions that are
substantially free of any additives and that are stable, viz. there is no separation of the
silicone oil phase from the aqueous phase for at least about 15 minutes, preferably for
about 20 minutes, and more preferably for about 30 minutes. The present invention
provides a homogenous silicone oil-in-water emulsion that is substantially free of any
additives and that is stable for at least about 15 minutes, a process for its production, and
the use of such emulsions for the siliconization of containers.
As used herein the term "substantially free" term "substantially free of added of
additives" means that the emulsions of the invention contain less than 0.01 weight % of
additives such as, emulsifiers or stabilizers based on the weight of the silicon oil and
water. Preferably, the emulsions of the invention contain less than 0.001 weight % of any
additives. Thus, this invention provides a substantially pure homogenous silicone oil-in-
water emulsion that is stable for at least about 15 minutes.
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In another embodiment, of the present invention provides a homogenous stable silicone
oil-in-water emulsion substantially free of any additives where the amount of silicone oil
in the emulsion is from about 0.1 % to about 6 % by weight. Preferably, the amount of
silicone oil in the emulsion is from about 0.5% to about 3% by weight. More preferably,
the amount of silicone oil in the emulsion is from about 0.5% to about 2% by weight. In
another embodiment, the invention provides a homogenous stable silicone oil-in-water
emulsion substantially free of any additives, wherein the amount of silicone oil in the
emulsion is about 1% by weight. Preferably, the amount of silicone oil in the emulsion is
about 0.8% by weight.
In another embodiment, the present invention provides a process for the preparation of a
homogenous stable silicone oil-in-water emulsion, substantially free of any additives. The
process comprises the addition of silicone oil to water that is maintained at a low
temperature, to reduce the tendency of the silicone oil droplets to coalesce and form an
oil layer on the surface, and homogenization of the mixture, in the same or a different
vessel, wherein said homogenization is carried out at a low temperature. Another
embodiment of the process is that the emulsion is continually homogenized prior, to ,
application to the surface of the glass container. The homogenization carried out, at a
temperature of less than about 20 °C. Preferably, the homogenization temperature is less
than about 15 °C. More preferably, the homogenization temperature is less than about 12
°C. Even more preferably, the homogenization temperature is less than about 10 °C. Still
even more preferably, the homogenization temperature is less than about 8 °C.
In another embodiment, the present invention provides a vessel for producing a stable
homogenous silicone oil-in-water emulsion, substantially free of any additives, having a
built in homogenizer-stirrer, and which may be maintained at a low temperature. (See
Figure 1.) The silicone oil-in-water emulsion of the instant invention may be prepared or
maintained in a vessel, preferably of steel, that is enclosed by a cooling jacket, also
preferably of steel. The vessel contents may be maintained at a fixed temperature by
continually circulating a coolant, such as glycol, through the jacket. Along the vertical
axis of the vessel is a time-regulated homogenizer-stirrer, for carrying out optimum
emulsification of the emulsion. The components of the homogenizer-stirrer include the
homogenizer motor with a timer, the rotor, and present at the lower end of the rotor,
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rotor-blades. The rotor blades are enclosed by the homogenizer screen comprising
orifices of sizes from about 0.5 mm to about 2.00 mm. When the homogenizer stirrer is
switched on, the rotating rotor blades drive the emulsion through the orifices. This
results in "breaking" the silicone oil into minute particles (oil droplets), which are easily
dispersed in the emulsion. The minute particle size of the of the silicone oil droplets
enhances the stability of the emulsion. The size oil droplets (minute particles) of the
emulsions of the invention may be from about 5 microns to about 100 microns in
diameter. Preferably, the oil droplets of the emulsion may be from about 10 microns to
about 50 microns. The lid of the vessel comprises a port for addition of more silicone oil-
in-water emulsion if necessary, and a viewing port. Also present on the surface of the
vessel are handles and a product outlet. The amount of silicone oil in the oil-in-water
emulsions is from about 0.1 % to about 6% by weight. Preferably the amount of silicone
oil in the emulsion is from about 0.5 % to about 3% by weight. More preferably the
amount of silicone oil in the emulsion is about 1 % by weight. Even more preferably the
amount of silicone oil in the emulsion is about 0.8 % by weight. .
In another embodiment, the present invention provides a method for siliconization of
containers with a stable homogenous silicone oil-in-water emulsion substantially free of
any additives. In this embodiment of the invention, the homogenous stable silicone oil-
in-water emulsion, which is substantially free of additives, is sprayed onto the surfaces of
containers. The setup is illustrated in Figure 2. The preparation of the silicone oil-in-
water emulsion from the homogenizer vessel (Figure 1) followed by spraying into or onto
the containers may be part of an assembly in which the preparation of the emulsion
occurs in tandem with the spraying of the containers. Thus, as the emulsion is prepared,
it is sprayed onto the surfaces of containers that approach it from the previous station of
the assembly. The containers may be dried and baked as they pass on to the next station,
which is usually the sterilization setup, hi one embodiment, the silicone emulsion may be
prepared and added to a vessel that sprays the emulsion onto or into the incoming
container line, while additional batches of the emulsion are prepared.
Non-limiting examples of glass containers that may be siliconized include bottles,
injection cartridges, IV infusions, syringes, vials and the like. Preferably, the containers
are syringes, syringe cartridges and vials.
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The invention is further illustrated in the following illustrative examples, in which all
parts, percentages and ratios are by weight unless otherwise indicated.
The homogenizer vessel (Figure 1) for preparing the silicone oil-in-water emulsions of
the present invention has a built in homogenizer-stirrer and may be maintained at low
temperatures. The vessel (1), preferably of steel, is enclosed by a cooling jacket (2) also
preferably of steel. The vessel contents are maintained at a fixed temperature by
continually circulating a coolant, such as glycol, through the jacket. The coolant enters
the jacket by means of inlet (3) and leaves by means of outlet (4). Along the vertical axis
of the vessel is the time-regulated homogenizer-stirrer (5) for carrying out optimum
emulsification of the emulsion. The components of the homogenizer-stirrer (5) include
the homogenizer motor with tinier (5a), the rotor (5b), and present at the lower end of the
rotor (5b), rotor-blades (not seen in the figure). The rotor blades are enclosed by the
homogenizer screen (5c) comprising orifices (5d) of aboutl.5 mm. When the
homogenizer stirrer is switched on, the rotating rotor blades drive the emulsion through
the orifices (5d). The droplets (particles) of silicone oil formed are dispersed in the
emulsion. The lid (6) of the vessel (1) includes an inlet port (7) for addition of more
silicone oil-in-water emulsion, and a viewing port (8), Product outlet valve (10) and
optional vessel handles (9) are also provided.
The examples that follow and the accompanying figures merely merely illustrate the
invention in greater detail, but in no way restrict the scope of the same.
Example 1
Preparation of silicone oil-in-water emulsion - 0.8% w/v
A silicone oil-in-water emulsion concentrate (10% w/v) is prepared by homogenizing
silicone oi] in water (at a water temperature of about 2-5 °C) for 5 minutes.
The silicone oil concentrate (10% w/v) is added to water at 2 - 5 °C to provide a final
silicone oil-in-water emulsion with a concentration of 0.8% w/v. Care is taken to rinse
all silicone oil residues into the final vessel. This mixture is homogenized for 10
minutes.
The 0.8% silicone oil-in-water emulsion is transferred into the homogenizer vessel
(Figure 1) and maintained at a temperature of 6 - 10 °C.
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As the vessel has an inlet port (7), multiple lots of silicone oil-in-water emulsion (0.8%
w/v.) can prepared as described. The silicone oil-in-water emulsion is homogenized in
the vessel for at least about 10 minutes prior to being used. During use the rotor (5b) is
turned on for 3 minutes every 10 minutes using a built in timer in the homogenizer-
stirrer.
Example 2
Application of 0.8% silicone oil-in-water emulsion to glass cartridges (Figure 2)
The emulsified silicone oil prepared in example 1 is transported through the product
outlet valve (10) of the homogenizer vessel, which is connected to the spraying station at
the cartridge washing machine. The connecting tubing is purged to prevent air locks.
Referring to Figure 2, a length of (~64 cm) wide bore (inside diameter (ID.) 6.3 mm)
silicone tubing (11) is connected from the product outlet valve (10) of the homogenizer
vessel to a "Y" adaptor (12). A length (-34 cm) of narrow bore (I.D. 3.2 mm) silicone
tubing (13) is connected from one arm (12a) of the "Y" adaptor to the internal
siliconizing needle assembly (14). A length (-40 cm) of narrow bore (I.D. 3.2 mm in
diameter) silicone tubing (15) is connected from the other arm (12b) of the "Y" adaptor
to the external siliconizing needle assembly (16). The 0.8% silicone oil-in-water oil

emulsion can be sprayed into and onto the cartridges (17):
a) Inside - to provide lubrication for the plunger that is inserted later in the
process; and
b) Outside - to reduce friction of glass cartridges as they rub against each other
during processing.
Baking of Silicone Oil onto the Glass cartridge
The cartridges are passed through a sterilizing tunnel at 310 °C into a Class 100 area
where final assembly occurs. This sterilizing tunnel has two functions:
a) to remove any microbiological or endotoxin residues from the cartridges.
b) to remove water from the emulsion and dry the silicone oil onto the glass
surface.
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Final Assembly
The glass cartridges are fed from the sterilizing tunnel onto a cartridge filling line where
the following operations take place.
a. A rubber plunger is inserted into the bottom of the cartridge.
b. The product is filled into the cartridge.
c. A cap, including a rubber seal is crimped onto the cartridge.
d. In-process controls are used to assess the functionality of the cartridge.
Example 2
a) Silicone Emulsion Stability
This experiment determines the stability of the silicone oil-in-water emulsion when
prepared in accordance to the present invention. A 0.8% (w/v) silicone oil emulsion was
prepared (10L) and added to the jacketed homogenizer vessel, maintained at 10±2 °C and
stirred for 3 minutes every 10 minutes. The emulsion is assayed for silicone content in
the formulation at the start of the homogenization and then at hourly interval up to 5
hours.

Sample (hours) Silicone oil concentration (%w/w)
0 0.704
1 0.690
2 0.693
3 0.680
4 0.709
5 0.662
[0001] This illustrates that the silicone emulsions are stable for an extended period of
time.
b) Effect of Stirring
This experiment establishes that there results a rapid reduction in the concentration of
silicone oil in the formulation when the emulsion is left without stirring. A 10L batch of
0.8% (w/v) silicone oil emulsion was prepared and added to the jacketed homogenizer
vessel that was maintained at 10±2 °C, but was left without stirring. The amount of
silicone oil in the emulsion was assayed every hour up to 5 hours.

Sample (hours) Silicone oil concentration (%w/w)
0 0.756
1 0.383
10

2 0.252
3 0.217
4 *
5 0.185
* data point unavailable as the evaporating dish contained residual water when the
weighing was made. final
Comparing experiments a and b, it is clear that when the silicone oil-in-water emulsion is
prepared in accordance with the present invention, the emulsion remains stable for at
least 5 hours, viz. the concentration of silicone oil is maintained for at least 5 hours. On
the other hand, when the emulsion is prepared in accordance to experiment b, viz.
without stirring, the silicone oil concentration falls by about 50% within an hour.
The vessel for the production of the silicone oil-in-water emulsion and the emulsion
spraying assembly are depicted in the accompanying Figures 1-2 wherein:
Figure 1: Schematic presentation of the jacketed vessel with the inbuilt homogenizer-
stirrer for production of the emulsion.
Figure 2: Schematic presentation of the tubing assembly for silicone dosing.
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We claim:
1. A homogenous stable silicone oil-in-water emulsion substantially free of any
additives; wherein the emulsion is stable for at least about fifteen (15)
minutes.
2. The silicone oil-in-water emulsion of claim 1 wherein the emulsion is stable
for at least about thirty (30) minutes.
3. The silicone oil-in-water emulsion of claim 2 wherein the amount of silicone
oil in the emulsion is from about 0.1 % to about 6% by weight.
4. The silicone oil-in-water emulsion of claim 3 wherein the amount of silicone
oil in the emulsion is from about 0.5 % to about 3% by weight.
5. The silicone oil-in-water emulsion of claim 4 wherein the amount of silicone
oil in the emulsion is about 1 % by weight.
6. The silicone oil-in-water emulsion of claim 4 wherein the amount of silicone
oil in the emulsion is about 0.8 % by weight.
7. A silicone coated glass container wherein the container has been siliconized
using a silicone oil-in-water emulsion substantially free of any additives of
claim 1.
8. The silicone coated glass container of claim 7 wherein the container is a
bottle, injection cartridge, IV infusion, syringe, or vial.
9. The silicone coated glass container of claim 7 wherein the container is a
syringe, syringe cartridge or vial.
10. The silicone coated glass container of any of claims 7-9 wherein the container
is sterile.
11. A process for the preparation of a homogenous stable silicone oil-in-water
emulsion of claim 1 comprising, homogenization of a mixture of silicone oil
in water at a low temperature.
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12. The process of claim 11 wherein the homogenization is conducted in a time-
regulated manner.
13. The process of claim 12 wherein the homogenization is carried out for at least
10 minutes.
14. The process of claim 13 wherein the homogenization is conducted in cycles of
about 3 minutes of homogenization at 10 minute intervals.
15. The process of claim 14 wherein the homogenization temperature is less than
about 20 °C.
16. The process of claim 15 wherein the homogenization temperature is less than
about 15°C.
17. The process of claim 16 wherein the homogenization temperature is less than
about 12°C.
18. The process of claim 17 wherein the homogenization temperature is about 8
°C.
19. A vessel for the preparation of a homogenous stable silicone oil-in-water
emulsion of claim 1, comprising a cooling jacket, a time-regulated
homogenizer-stirrer, a port for the addition of silicone oil-in-water mixture,
and a product outlet port.
20. The vessel of claim 19 wherein said homogenizer includes a motor with a
timer, a rotor, and rotor blades; wherein the rotor blades are enclosed within a
homogenizer screen; and wherein the screen comprising orifices.
21. The vessel of claim 20 wherein said homogenizer screen comprises orifices
having sizes of from about 0.5 mm to about 2.00 mm.
22. An apparatus for the siliconization of containers, comprising a silicone oil-in-
water emulsion homogenizer vessel of claim 17 and a container spraying
station.

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23. The apparatus of claim 22, wherein the silicone oil-in-water emulsion
homogenizer vessel and the container spraying station are part of an assembly,
so that the preparation of the emulsion occurs in tandem with spraying of the
emulsion onto containers.
24. The apparatus of claim 23, wherein the spraying station comprises silicone
tubing, that at one end is connected to the outlet valve, and at the other end, by
means of a Y-shaped piece, to two pieces of tubing, wherein the latter pieces
of tubing are connected to needle assemblies.
25. Use of a homogenous stable silicone oil-in-water emulsion substantially free
of any additives of claim 1 for the siliconization of containers.
26. Use of a homogenous stable silicone oil-in-water emulsion substantially free
of any additives for the siliconization of containers according to claim 25
wherein the amount of silicone oil in the emulsion is from about 0.1 % to
about 6% by weight.
27. Use of a homogenous stable silicone oil-in-water emulsion substantially free
of any additives for the siliconization of containers according to claim 26
wherein the amount of silicone oil in the emulsion is from about 0,5 % to
about 3 % by weight.
28. Use of a homogenous stable silicone oil-in-water emulsion substantially free
of any additives for the siliconization of containers according to claim 27
wherein the amount of silicone oil in the emulsion is about 0.8 % by weight.


Dated this 19th Day of June 2006

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