An ophthalmic composition
The present invention relates to ophthalmic compositions,
and in particular to a topical ophthalmic composition
comprising a polyaphron dispersion. The invention also
relates to methods of making ophthalmic compositions,
ophthalmic compositions for use in the treatment of the
human and/or animal eye by topical application. The
invention further relates to a device for dropwise
dispensing the ophthalmic composition.
Ophthalmic compositions for use in the treatment of eyes are
known in the art. Such compositions may, for example,
contain pharmaceutically active agents and be used for the
treatment of specific diseases of the eye. Alternatively,
or additionally the compositions may be used as tear
replacement solutions.
When the ophthalmic compositions comprise pharmaceutically
active agents and/or excipients side effects are sometimes
observed upon topical application of the compositions to the
eye. Such side effects may be related to the dosage and/or
duration of the treatment and/or the potency of the active
agent. Moreover, the efficacy of the treatment may be
reduced if sufficient (for example, a therapeutically active
amount) of active agent cannot penetrate the eye upon
treatment. For example, if the composition is not
sufficiently viscous upon application to the eye, it may run
off the eye before a therapeutically effective amount of
active agent has penetrated the surface of the eye.
Alternatively and/or additionally the effectiveness of the
treatment may be reduced if the concentration of the
pharmaceutically active agent is low in the composition so
that in order to provide a therapeutically effective amount
of the agent to the patient, repeated doses of treatment
must be applied. In such cases, the efficacy of the
treatment will depend on the end users compliance with a
specific treatment regime. This may not be desirable as the
end users compliance with such a regime may be less than
adequate .
It is one object of the present invention to overcome or
address the problems of prior art ophthalmic compositions or
to at least provide a commercially useful alternative
thereto. It is an alternative and/or additional object to
provide an ophthalmic composition which is cheaper to make
and/or more effective than known ophthalmic compositions.
In the first aspect of the present invention there is
provided an ophthalmic composition comprising a polyaphron
dispersion. Preferably the ophthalmic composition is for
topical application to the human and/or animal eye.
Preferably it is a topical ophthalmic composition.
The present invention will now be further described. In the
following passages different aspects of the invention are
defined in more detail. Each aspect so defined may be
combined with any other aspect or aspects unless clearly
indicated to the contrary. In particular any feature
indicated as being preferred or advantageous may be combined
with any other feature or features indicated as being
preferred or advantageous.
In a further aspect of the present invention there is
provided an ophthalmic composition according to any of the
preceding claims for use in the treatment of the human
and/or animal eye by topical application.
In a further aspect of the present invention there is
provided a method of making the ophthalmic composition as
described herein comprising the following steps:
(i) providing a hydrophilic solvent;
(ii) providing a hydrophobic solvent;
(iii) mixing the hydrophilic solvent with the
hydrophobic solvent under suitable conditions to
form the composition comprising a polyaphron
dispersion;
wherein the hydrophilic solvent and/or the hydrophobic
solvent comprises a surfactant;
and wherein the hydrophilic solvent and/or the
hydrophobic solvent optionally comprises a
pharmaceutically active agent.
In a further aspect of the present invention there is
provided a device for dropwise dispensing of a composition,
the device comprising a container holding the composition as
described herein.
It is one object of the present invention to provide an
ophthalmic composition which has improved patient compliance
and/or reduced side effects upon application compared to
known compositions. It is also desirable to provide an
ophthalmic composition comprising a pharmaceutically active
agent wherein upon treatment of a patient with the
ophthalmic composition, the permeation of the
pharmaceutically active agent from the ophthalmic
composition is greater than the permeation of
pharmaceutically active agents from known ophthalmic
compositions .
Some of the advantages of the use of a polyaphron dispersion
in ophthalmic compositions as described herein, over known
ophthalmic compositions, in particular over those comprising
emulsions, may be summarized below:
· Lower surfactant levels
• Improved safety
• Higher oil levels
• Easier, more controllable manufacture
• More consistent form - easy to characterize to the
required standard
• Controllable and consistent droplet size
• Wider choice of oils
• Multiple pharmaceutically active agents each in its own
oil
· Improved stability of vulnerable pharmaceutically
active agents
• Controllable rheology, independent of dispersion
formulation .
• Lower preservative levels
· Droplet size consistent upon substantial dilution
The present inventors have found that one of the advantages
of using polyaphron dispersions in ophthalmic compositions
is that it is possible to consistently control the droplet
size (and for example the size of the discontinuous phases),
the rheology, the surfactant levels and the components which
make up the compositions. This makes it possible to provide
a composition with improved or suitable tolerability to the
end user. The compositions may be tailored to exclude
irritants, such as high levels of surfactants, low
preservatives, and/or include beneficial components. They
also provide the possibility of forming compositions having
high concentrations of pharmaceutically active agents and/or
additives. This is because the pharmaceutically active
agents and/or additives may be present in either or both of
the hydrophobic phase and/or hydrophilic phase, the
discontinuous phase and/or continuous phase of the
polyaphron dispersion depending for example on their
solubility. This is of particular use, when the amount of
pharmaceutically active agent can be increased in the
composition such that with each application of the
composition to the eye, an increased level of
pharmaceutically active agent is administered. This means
that it is possible to reduce the frequency of application
of the composition, which may help with patient compliance
and/or improved efficacy of the treatment of the eye
condition .
The ophthalmic compositions described herein also have an
advantage of potentially allowing higher levels of
pharmaceutically active agent into the compositions compared
to known ophthalmic compositions. This may be possible for
example if the active is soluble (or at least partially
soluble) in the discontinuous (preferably oil) phase of the
polyaphron dispersion. Polyaphron dispersion may have
higher levels of oil and still remain stable compared to
other compositions, for example though comprising emulsions.
The ophthalmic compositions described herein also permit
efficient and preferably improved delivery of
pharmaceutically active agents and/or additives to the eye.
This may be achieved by improved permeation.
Preferably the ophthalmic compositions are stable and/or
have an improved stability over known products.
Advantageously the compositions are stable over an extended
period of time, for example over 3 months, 6 months or 9
months or 12 to 24 months. Preferably, the compositions
are stable, for example, when they are stored under air
tight conditions in the final packaging for at least 3
months, more preferably at least 6 months at from 3 to 5°C,
or from 20°C to 25°C. Where a pharmaceutically active agent
is present in the compositions preferably each active shall
not have diminished by more than 5% by weight of the
original content at the date of commencement of the storage
test after 3 months of storage. Known decomposition products
of the actives, if any such are present, collectively
constitute no more than 5% of the original active based upon
area under the curve measurements for example by HPLC
analysis or other suitable analytical technique known in the
art .
Preferably the ophthalmic composition as described herein
has at least one or more of the following advantages over
known ophthalmic compositions, which may, for example,
assist in improving patient compliance:
a ) convenience (e.g. reduced dosing frequency by formulating
combinations of pharmaceutically active agent (s);
b ) efficacy (e.g. improved penetration to increase effect at
unchanged concentration or maintain effect at lower
concentration) ; and
c ) safety (better tolerability , e.g. by reducing irritating
excipients and/or pharmaceutically active agent (s) in
formulation) .
Moreover, the ophthalmic compositions described herein
achieve the described benefits whilst having low levels of
surfactants. This is advantageous as surfactants may be
irritants .
In the following description, the meaning of the terms used
are as follows: by hydrophilic phase or solvent is meant a
liquid phase comprising water, comprising water together
with other water-miscible liquids, or comprising a nonaqueous
liquid which is miscible with water. By hydrophobic
phase or solvent is meant a phase comprising
pharmaceutically acceptable liquids such as oils that are
immiscible or substantially immiscible with the hydrophilic
phase. By immiscible liquids is meant that when mixed
together, they separate to form two distinctly separate
liquid phases sharing a well-defined interface. By
substantially immiscible is meant that two liquids mixed as
above having a well defined interface between two phases
where each phase may nevertheless contain small quantities
of dissolved molecules of the other phase.
A polyaphron dispersion comprises a continuous phase, a
discontinuous phase and a surfactant. It will be understood
that typically a polyaphron dispersion comprises one
continuous phase and a plurality of discontinuous phases.
The polyaphron dispersion may comprise a hydrophobic
discontinuous phase, and a hydrophilic continuous phase.
Alternatively, the polyaphron dispersion may comprise a
hydrophilic discontinuous phase and a hydrophobic continuous
phase.
By polyaphron dispersion as used herein is meant a
particular kind of hydrophilic liquid-in-hydrophobic liquid
or hydrophobic liquid-in-hydrophilic liquid dispersion
comprising (a) a hydrophilic liquid miscible phase, (b) a
second hydrophobic phase being immiscible or substantially
immiscible with the first phase and (c) one or more
surfactants, wherein the dispersed or discontinuous phase is
in the form of small (e.g. micron to sub-micron diameter,
but more usually at least 1 micron diameter) droplets, and
the whole having the following characteristics, which
distinguish polyaphron dispersions from conventional or
common emulsions and other dispersion types:
1 . They are capable of existing in a stable form wherein
the volume fraction of the dispersed phase ( r ) is
greater than 0.7 and can be as high as 0.97 (f r is the
volume ratio of discontinuous to continuous phase
expressed as a fraction) .
2 . The microscopic appearance of polyaphron dispersions
where r is greater than 0.7 is that of an aggregate
of individual droplets, pushed closely together into
polyhedral shapes, resembling the appearance of a gas
foam. In this form, the dispersion has gel-like
properties and is referred to as a Gel Polyaphron
Dispersion (GPD) .
3 . Stable polyaphron dispersions can be formed with a
surfactant concentration less than 3% and more
typically less than 2% by weight of the total
composition .
4 . Gel Polyaphron Dispersions (as described in 2 above)
can be diluted to any extent by the addition of more
continuous phase without the addition of more
surfactant, when the gel-like properties disappear.
Once r has been reduced to below 0.7, the individual
droplets of internal phase become separated to take the
form of spherical droplets, which remain stable and
intact but which may nevertheless join together in
loose associations and float to the top or sink to the
bottom of the diluted dispersion (depending on the
relative densities of the two phases) . In this diluted
form each droplet is referred to as a Colloidal Liquid
Aphron (CLA) . Simple shaking of the diluted dispersion
instantly causes a homogeneous, stable dispersion of
Colloidal Liquid Aphrons to re-form.
Each of the above characteristics and a combination of them
clearly differentiate the polyaphron dispersions of the
present invention from conventional emulsions and other
dispersion types which do not have all of those
characteristics. Polyaphron dispersions are disclosed in the
following literature references by Sebba: "Biliquid Foams",
J . Colloid and Interface Science, 0 (1972) 468-474 and "The
Behaviour of Minute Oil Droplets Encapsulated in a Water
Film", Colloid Polymer Sciences, 257 (1979) 392-396, Hicks
"Investigating the Generation, Characterisation, and
Structure of Biliquid Foams", PhD Thesis, University of
Bristol, 2005, Crutchley "The Encapsulation of Oils and Oil
Soluble Substances Within Polymer Films", PhD Thesis, The
University of Leeds, 2006 and Lye and Stuckey, Colloid and
Surfaces, 131 (1998) 119-136. Aphrons are also disclosed in
US-A-4, 486, 333 and WO 97/32559.
Polyaphron dispersions are sometimes referred to as
'Biliquid Foams', 'High Internal Phase Emulsions (HIPEs) ' ,
'High Internal Phase Ratio Emulsions (HIPREs) ' and 'Gel
Emulsions'. In US 5,573,757 a composition comprising a
polyaphron dispersion is described as "a viscoelastic gel".
All descriptions that refer to dispersions having the
characteristics described above are polyaphron dispersions
as used in the present invention.
The term "topical composition" and "topical formulation" are
used herein interchangeably. When the topical composition
comprises an active ingredient (s), it refers to a
composition formulated such that the active ingredient (s)
of the composition may be applied by direct administration
to the surface of the eye and from which an amount of the
active ingredient (s) is released. Examples of topical
formulations include, but are not limited to, lotions,
sprays, hydrogels, aerosols, foams, ointments, creams, gels,
pastes, and the like. The term "topical", when used herein
to characterize the delivery, administration or application
of a composition of the present invention, is meant to
specify that the composition is delivered, administered or
applied directly to the site of interest (i.e., to the eye)
for a localized effect. Preferably, topical administration
is effected without any significant absorption of components
of the composition into the subject's blood stream (to avoid
a systemic effect) . In certain preferred embodiments of the
present invention, topical administration of a composition
is effected without any significant absorption of components
of the composition into the subject's eye tissues, such as
the aqueous humor, and corneal and conjunctival tissues.
Preferably the composition is administered directly to the
cornea and/or instilled into the anterior portion of the
eye. The composition may be administered to effect
therapeutic benefit to other parts of the eye, for example
to goblet cells, lacrimal glands, oil secreting glands
and/or nasolacrimal ducts.
The term "non-invasive", when used herein refers to a method
or mode of administration that does not rupture or puncture
(e.g., by a mechanical means) of a biological membrane to
which a composition, optionally comprising a
pharmaceutically active agent, is being delivered.
Preferably, the ophthalmic composition as described herein
is administered by non-invasive routes or procedures.
The term "ophthalmic", as used herein in connection with a
composition, refers to a composition intended to be
administered to the eye and which preferably provides a
pharmaceutical effect, preferably to the eye.
The terms "therapeutic agent", "drug", and "pharmaceutically
active agent" are used herein interchangeably. They refer to
a substance, molecule, compound, agent, factor or
composition effective in the treatment of a disease or
condition .
The ophthalmic compositions as described herein may be
formulated using any pharmaceutically acceptable carriers
and/or excipients suitable for topical administration to the
eye surface.
In one embodiment the ophthalmic composition as described
herein is not for use in tear replacement therapy, nor for
use as a tear substitute, nor is it for use in a tear
replacement solution. In one embodiment, the ophthalmic
- D
composition as described herein is for use in treating
diseases of the eye with the proviso that it is not for use
in treating "dry-eye". Preferably the ophthalmic composition
as described herein comprises a pharmaceutically active
agent and is for use in the treatment of diseases of the
human and/or animal eye, which are treatable by topical
application of said pharmaceutically active agent.
As described above, a polyaphron dispersion comprises a
continuous phase, at least one discontinuous phase and a
surfactant. The polyaphron dispersion may comprise a
hydrophobic discontinuous phase (typically a plurality of
hydrophobic discontinuous phases), and a hydrophilic
continuous phase. Alternatively, the polyaphron dispersion
may comprise a hydrophilic discontinuous phase (typically a
plurality of hydrophilic discontinuous phases), and a
hydrophobic continuous phase.
Preferably, the discontinuous phase comprises a hydrophobic
solvent and the continuous phase comprises a hydrophilic
solvent. Preferably the discontinuous phase is a
hydrophobic discontinuous phase comprising one or more
hydrophobic solvents and substantially no hydrophilic
solvents. Preferably the continuous phase is a hydrophilic
continuous phase comprising one or more hydrophilic solvents
and substantially no hydrophobic solvents. Typically a
plurality of discontinuous phases are present in the
composition .
In another embodiment of the present invention the
continuous phase comprises a hydrophobic solvent and the
discontinuous phase comprises a hydrophilic solvent.
Preferably the continuous phase is a hydrophobic continuous
phase comprising one or more hydrophobic solvents and
substantially no hydrophilic solvents. Preferably the
discontinuous phase is a hydrophilic discontinuous phase
comprising one or more hydrophilic solvents and
substantially no hydrophobic solvents. Typically a
plurality of discontinuous phases are present in the
composition .
The discontinuous phase is preferably a substantially
hydrophobic internal phase, commonly known as an oil
internal phase. Preferably, the hydrophobic phase, which is
preferably the discontinuous phase, comprises a
pharmaceutically acceptable oil phase.
Examples of oils which may be used in the present invention
include almond oil, babassu oil, blackcurrant seed oil,
borage oil, canola oil, castor oil, coconut oil, cod liver
oil, corn oil, cottonseed oil, evening primrose oil, fish
oil, grapeseed oil, mustard seed oil, oat oil, olive oil,
palm kernel oil, palm oil, peanut oil, rapeseed oil,
safflower oil, sesame oil, shark liver oil, squalane,
soybean oil, sunflower oil, walnut oil, wheat germ oil,
hydrogenated castor oil, hydrogenated coconut oil,
hydrogenated cottonseed oil, hydrogenated palm oil,
hydrogenated soybean oil, partially hydrogenated soybean
oil, hydrogenated vegetable oil, isopropyl myristate,
isopropyl isostearate, isopropyl palmitate, modified
triglycerides, caprylic/capric glycerides, caprylic/capric
triglyceride, fractionated triglycerides, glyceryl
tricaprate, glyceryl tricaproate, glyceryl tricaprylate ,
glyceryl tricaprylate/caprate, glyceryl
tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate,
glyceryl tricaprylate/caprate/linoleate, glyceryl
tricaprylate/caprate/stearate, glyceryl trilaurate, glyceryl
trilinoleate, glyceryl trilinolenate, glyceryl trioleate,
glyceryl triundecanoate , linoleic glycerides, saturated
polyglycolized glycerides, synthetic medium chain
triglyceride containing primarily Cs-Ci2 fatty acid chains,
medium chain triglycerides, long chain triglycerides,
modified triglycerides, fractionated triglycerides,
silicones, phospholipids and mixtures thereof.
Long chain triglycerides as used herein includes a glycol
triester where the acid moieties are saturated,
monounsaturated or polyunsaturated fatty acids with a chain
of 14 to 20 carbon atoms. Typical fatty acid moieties are
oleic acid, stearic acid and linoleic acid.
Suitably the hydrophobic phase comprises one or more
monoglycer ides , diglycerides , triglycerides or mixtures
thereof. Preferably the one or more monoglycerides ,
diglycerides, triglycerides are glycol esters of fatty acids
containing from 6 to 22 carbon atoms.
In a preferred embodiment the hydrophobic phase is selected
from the group consisting of castor oil, long chain
triglycerides, medium chain triglycerides, mineral oil,
silicones, phospholipids, mono- and diglycerides and
mixtures of two or more thereof.
Preferably the composition comprises one or more fatty acids
containing from 6 to 22 carbon atoms. More preferably, the
composition comprises omega-3 fatty acids. Omega-3 fatty
acids are long-chain polyunsaturated fatty acids (18-22
carbon atoms in chain length) with the first of the double
bonds ("unsaturat ions ") beginning with the third carbon atom
from the methyl end of the molecule. They are called
"polyunsaturated" because their molecules have two or more
double bonds "unsaturat ions " in their carbohydrate chain.
They are termed "long-chain" fatty acids since their carbon
backbone has at least 18 carbon atoms. In addition to
stearidonic acid "SDA" the omega-3 family of fatty acids
includes alpha-linolenic acid ("ALA"), eicosatetraenoic acid
(ETA), eicosapent aenoic acid ("EPA"), docosapent aenoic acid
(DPA), and docosahexaenoic acid ("DHA") .
Preferably the ophthalmic composition does not comprise a
fluorocarbon and/or silicone oil.
The discontinuous phase may, for example, confer an
emollient, occlusive, moisturising, conditioning or other
cosmetic or pharmaceutical benefit to the eye. It may also
increase the viscosity of the composition and may confer
solvency to the active or actives. It may contain materials
providing a heating or cooling effect when applied to the
eye (for example capsaicin or menthol) .
The composition may comprise at least 5 % by weight of the
discontinuous phase, more preferably at least 2% by weight,
the discontinuous phase based on the weight of the total
composition .
The composition may comprise less then 15% by weight of the
discontinuous phase, more preferably less than 5%, less than
4%, less than 2%, less than 1%, less than 0.5% by weight of
discontinuous phase based on the weight of the total
composition. Unlike topical compositions for use of the
skin where it is advantageous to have high levels of
discontinuous phase, (preferably oil phases), in the
described ophthalmic compositions, in some embodiments it is
advantageous to comprise much lower levels. A s the eye is
very sensitive, when an active agent is present in the
composition, low levels of active agents are typically
sufficient to treat the eye condition. One advantage of
using polyaphron dispersions is that unlike emulsions a low
percentage (such as those outlined above) of discontinuous
phases may be present in the composition and it can still be
stable. Polyaphron dispersions tolerant high levels of
dilution. Preferably the discontinuous phase comprises a
pharmaceutically acceptable oil.
The hydrophilic phase (which may be the continuous phase)
may comprise or consist essentially of a pharmaceutically
acceptable liquid that is miscible or substantially miscible
with water, preferably a compound of formula Ri-OH where R i
is Ci-Cio alkyl and/or a compound of formula HO-R 2-H where R2
is -(C 2H4) or -(C 3H ) where n is 1 to 100, preferably 1 to
25. R i and R2 may be linear or branched. Preferably R i is
C1-C4 alkyl. n is preferably 1 to 25. Preferably the
hydrophilic phase comprises propylene glycol, polyethylene
glycol, glycerol, ethanol, isopropyl alcohol, or a mixture
thereof. Where the hydrophilic phase comprises polyethylene
glycol or polypropylene glycol, the polyethylene or
polypropylene glycol is preferably a polyethylene glycol
which is liquid at room temperature (20°C) . The
polyethylene glycol may, for example, contain from 1 to 12
ethylene or propylene oxide units and/or have a molecular
weight of up to 600.
It will be understood that other suitable hydrophilic
solvents may be used.
The composition may comprise at least 95 % by weight of the
continuous phase, more preferably at least 98% by weight,
the continuous phase based on the weight of the total
composition.
Preferably the ophthalmic composition comprises water.
Preferably, the hydrophilic phase is or comprises water.
The compositions of the present invention may be nonaqueous,
substantially non-aqueous or aqueous.
By the term "non-aqueous" as used herein is meant a
composition which is effectively free of water and does not
contain water that has been deliberately added. Preferably,
a "non-aqueous" composition as used herein has less than
0.5% by weight of water based on the total weight of the
composition, more preferably less than 0.2% by weight of
water, most preferably less than 0.1% by weight of water
based on the total weight of the composition.
By the term "substantially non-aqueous" as used herein is
meant a composition comprising less than 5% by weight, more
preferably less than 4.5% by weight, of water based on the
total weight of the composition.
By the term "aqueous" is meant a composition comprising at
least 5%, at least 10%, or at least 15% by weight of water
based on the total weight of the composition.
In one embodiment the composition comprises at least 85% by
weight of water, at least 90% by weight of water, at least
95% by weight of water or at least 98% by weight of water
based on the total weight of the composition. It may be
advantageous for the composition to comprise high levels of
water if the composition is to be administered to the eye
without further dilution. Additionally, having high levels
of water decreases the potential risk of irritation to the
eye caused by other components present in the composition.
Suitable pharmaceutically acceptable excipients may be
present in the composition.
The pH of the composition and preferably the pH of the
hydrophilic phase (which is preferably the continuous phase)
is preferably from 3.5 to 9 , or from 5 to 8 , more preferably
still to a pH of from 6 to 7.5. It will be understood that
any suitable acid or base may be used to adjust the pH to
the appropriate value or pH range. Preferably, the pH of
the hydrophilic phase is adjusted as required after addition
of the hydrophobic phase (s) . The pH of the composition may
be adjusted after addition of the polyaphron dispersion.
Typically the pH of the composition will need to be raised
by the addition of a base, which suitably may sodium
hydroxide. Advantageously and preferably, the pH of the
composition may be stabilized by the incorporation of a
suitable buffer into the aqueous phase. Suitable buffer
systems having a pH within the specified range will be
familiar to those skilled in the art, and include for
example sodium citrate buffer.
The surf actant (s) used in the present invention may be
incorporated into either or both phases of the polyaphron
dispersion. The surfactant may be selected from the group
consisting of non-ionic surfactants, cationic surfactants,
anionic surfactants, zwitterionic surfactants and mixtures
of two or more thereof.
In one embodiment, preferably, the polyaphron dispersion
comprises at least one non-ionic surfactant. Preferably at
least one non-ionic surfactant is present in the hydrophilic
and/or hydrophobic phase of the present invention. The
polyaphron dispersion may comprise further non-ionic and or
ionic surfactants.
Suitable surfactants include an alkyl polyglycol ether, an
alkyl polyglycol ester, an ethoxylated alcohol, a
polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene
fatty acid ester, an ionic or non-ionic surfactant, a
hydrogenated castor oil/polyoxyethylene glycol adduct
containing from 25 to 60 ethoxy groups a castor
oil/polyoxyethylene glycol adduct containing from 25 to 45
ethoxy groups, a sorbitan fatty acid ester (for example Span
20 or Span 80), a block copolymer of ethylene oxide and
propylene oxide (for example Pluronic L121 or Pluronic F68),
or a mixture thereof.
Suitable non-ionic surfactants include poloxamers,
tyloxapol, polysorbates polyoxyethylene castor oil
derivatives, sorbitan esters, and mixtures of two or more
thereof .
Suitable cationic surfactants include hexadecyl trimethyl
ammonium bromide, CTAB and mixtures of two or more thereof.
Suitable anionic surfactants include sodium lauryl ether
sulphate (SLES), sodium lauryl sulphate and mixtures of two
or more thereof.
Suitable zwitterionic surfactants include such as
phospholipids, for example lecithin,
dipalmit oylphosphat idylcholine (DpPC) and mixtures of two or
more thereof.
Preferably, the composition of the present invention does
not comprise a fluorinated surfactant. Preferably the
composition does not comprise a surfactant which comprises a
fluorine atom. More preferably still, the composition as
described herein does not comprise a fluorinated surfactant
prepared according to the general formula: RF-Rpoi where RF
represents a linear or branched perf luoroalkyl group having
more than 5 carbon atoms and Rpoi represents a polar
hydrocarbond residue which comprises at least one functional
group chosen from the series: CO-NH(R), CO-NH(R) 2, COO-,
COOR, S03- , S02-N(R) 2, CH2 -O-, R , P02H , P03H2, where R
represents an alkyl .
Preferred surfactants are non-ionic, non-halogenated
surfactants. It is has been found that polyaphron
dispersions comprising non-ionic halogenated surfactants
(and in particular those mentioned above) may break down
under the shear stress (leading to irreversible
decomposition of the polyaphron) caused by blinking of the
eyelid when the composition is in place in the eye. This may
particularly be the case when the polyaphron dispersions
have been formed via a gas-foam intermediate. In contrast
to this the present inventors have surprisingly found that
non-ionic, non-halogenated surfactants and/or polyaphrons
made using methods described below which do not require the
formation of a gas-foam intermediate, typically do not break
down under the shear stress caused by blinking of the eyelid
when the composition is in place in the eye. This is shown
in Figure 1 . In some cases it is advantageous for the
composition and the surfactant to remain intact under the
shear stress conditions experienced in the eye. This is
particularly so when the composition comprises a
pharmaceutically active agent. When the composition
comprises a pharmaceutically active agent, one advantage of
the present invention is that the active agent may be
released from the ophthalmic composition in a controlled
manner, for example by diffusion from the polyaphron
dispersion (and typically by diffusion from the hydrophobic,
preferably the oil phase) . If the polyaphron dispersion
breaks down under the shear conditions experienced in the
eye the pharmaceutically active agent is not delivered in a
controlled manner over time. Instead, the active is suddenly
released into the eye as the polyaphron dispersion
irreversibly breaks down. In contrast to this, it is
preferable if the active is released in a controlled manner
over time. Another advantage of the polyaphron not breaking
down under shear is that the risk of damage to the
composition during transport and storage is reduced.
A further advantage of the polyaphron dispersion not
breaking down (or substantially not breaking down) under the
conditions experienced in the eye is that the risk of any
pharmaceutically active agent dissolved and/or dispersed
therein precipitating is reduced. If, for example, a
pharmaceutically active agent is dissolved and/or dispersed
in the discontinuous phase (preferably the hydrophobic
(preferably the oil)) phase of the composition and the
polyaphron breaks down under the shear conditions
experienced in the eye, the pharmaceutically active agent
may precipitate as it is expelled rapidly from the
polyaphron dispersion into the eye. The risk of
precipitation is reduced by the controlled release of the
pharmaceutically active agent from the polyaphron dispersion
where it remains in tact in the eye.
Examples of classes of surfactants which are particularly
useful in this invention include: polyethylene glycol
sorbitan fatty acid esters (Tweens, for example Tween 20
(polyoxyethylene (20) monolaurate) , Tween 60
(polyoxyethylene (20) monostearate) , Tween 80
(polyoxyethylene (20) monooleate) ); sorbitan fatty acid
esters (Spans, for example Span 20 (sorbitan monolaurate),
Span 40 (sorbitan monopalmitate) , Span 80 (sorbitan
monooleate)); polyethylene glycol fatty acid ethers (Brijs,
for example Brij 35 (polyoxyethylene (20) lauryl ether),
Brij 58 (polyoxyethylene (20) cetyl ether)); polyethylene
glycol stearate esters (Mryjs, for example Myrj S40
polyoxyethylene (40) stearate, Myrj S50 polyoxyethylene (50)
stearate, ); polyoxyethylene glycol - block- polypropylene
glycol - block - polyoxyethylene glycol - block (Poloxamers,
such as polyoxyethylene glycol (80) - polypropylene glycol
(27) - polyoxyethylene glycol (80) (Poloxamer 188) and
polyoxyethylene glycol (101) - polypropylene glycol (56) -
polyoxyethylene glycol (101) (poloxamer 407)) polyethylene
glycol lauryl esters (Laureths, for example polyethylene
glycol (4) lauryl ester (Laureth 4 ) and polyethylene glycol
(23) lauryl ester (Laureth 23)) and mixtures of two or more
thereof. One or more of each type of surfactant may be
present in the composition. Additionally or alternatively
mixtures of different types of surfactant may be present in
the composition. One of the reasons these surfactants are
particularly preferred is because of their low irritation
potential. The present inventors have also surprisingly
found that the above surfactants provide good shear
stability over other known surfactants.
It will be understood that other suitable surfactants may be
used .
Preferably the compositions of the present invention
comprise less than 0.5% by weight of surfactant, more
preferably less than 0.25%, more preferably still less than
0.1% by weight of the total composition. The compositions
described herein may comprise less than 0.075% by weight or
less than 0.05% by weight or 0.01% by weight of surfactant
based on the weight of the total composition.
Preferably, the polyaphron dispersion used in the described
composition comprises less than 5% by weight of surfactant
based on the total weight of the polyaphron dispersion. More
preferably, the polyaphron dispersion comprises less than
3%, less than 2%, or less than 1% by weight of surfactant
based on the total weight of the polyaphron disperion.
Typically in order to form the described composition the
polyaphron dispersion is diluted by for example from
approximately 80%, 90% or 95% by weight discontinuous phase
(preferably oil phase) based on the total composition (which
is then the polyaphron dispersion) to approximately 1%, 2%
or 5% by weight discontinuous phase (preferably oil phase)
based on the total composition. Thus, the surfactant level
in the final composition is typically low.
As outlined above, it is desirable for low levels of
surfactant to be present in the composition as surfactants
may act as irritants to the end user upon application to the
eye .
Preferably, the weight ratio of discontinuous phases (which
preferably are the hydrophobic phases) in the composition to
total surfactant in the composition is 40 to 180. More
preferably, the weight ratio of discontinuous phases (which
preferably are the hydrophobic phases) in the composition to
total surfactant in the composition is 50 to 120. More
preferably still, the weight ratio of discontinuous phases
(which preferably are the hydrophobic phases) in the
composition to total surfactant in the composition is 60 to
90 .
Using low levels of surfactant is advantageous for at least
the following reasons:
1 . Less potential to cause eye irritation to the eye
itself as well as to the surrounding areas of the eye
that contact the formulation in the course of
application;
2 . More efficient use of any preservative present in the
composition as it is not locked away in micelles formed
from excess surfactant. This in turn leads to less eye
irritation (preservatives have significant potential
irritants); and/or
3 . Less potential to cause partitioning and transport of
oil soluble pharmaceutically active agents into
surfactant micelles, avoiding issues with solubility
and also stability with vulnerable pharmaceutically
active agents.
Preferably the ophthalmic composition comprises a
pharmaceutically active agent. Preferably, the
pharmaceutically active agent is selected from
antihistamines, betablockers , corticosteroids,
prostaglandins, non-steroidal anti-inflammatory drugs
(NSAIDs), immune modulators, anaesthetics, antibiotics,
carbonic anhydrase inhibitors, vasoconstrictors and mixtures
of two or more thereof. One or more of each type of
pharmaceutically active agent may be present in the
composition. Additionally or alternatively mixtures of
different types of pharmaceutically active agents may be
present in the composition.
As well as the pharmaceutically active agents listed above,
the pharmaceutically active agent may additionally and/or
alternatively be selected from the group consisting of an
antifungal, an opthalmological , an anti-infective, an anti
inflammatory agent, an antiglaucoma agent, an antiglaucoma
miotic, a mydriatic, a cycloplegic, a decongestant, an anti
allergic, a local anesthetic, a diagnostic agent, a surgical
aid, an ocular vascular disorder agent and mixtures of two
or more thereof. One or more of each type of
pharmaceutically active agent may be present in the
composition. Additionally or alternatively mixtures of
different types of pharmaceutically active agents may be
present in the composition.
Compositions of the present invention may optionally further
comprise at least one additional pharmaceutically active
substance or agent.
The composition may comprise two or more distinct
discontinuous phases made up from different components, for
example from different oils. The composition may comprise
one or more pharmaceutically active substances or agents in
distinct discontinuous phases.
The pharmaceutically active agent may be present in the
hydrophilic and/or hydrophobic phase of the polyaphron
dispersion. In one embodiment at least 50%, at least 80% or
at least 90% by weight of the pharmaceutically active agent
present in the composition is in the hydrophilic phase. In
another embodiment at least 50%, at least 80% or at least
90% by weight of the pharmaceutically active agent present
in the composition is in the hydrophobic phase.
Preferably the ophthalmic composition comprises
cyclospor ine . Such a composition may be advantageous because
it may be formulated to be non-irritating. Such a
composition is suitable for use in the treatment of
conditions associated with keratocon uctivit is sicca (severe
dry eye) .
Cyclosporins are a group of nonpolar cyclic oligopeptides
with known immunosuppressant activity. Cyclosporin A , along
with several other minor metabolites, as well as cyclosporin
B , C , D , E , F , G , H , I , J , K , L, M , N , 0 , P , Q , R , S , T , U ,
V , W , X , Y and Z , have been identified. In addition,
derivatives, salts and the like of such cyclosporins and a
number of synthetic analogs have been prepared and may be
useful in the present invention.
In general, commercially available cyclosporins may contain
a mixture of several individual cyclosporins which all share
a cyclic peptide structure consisting of eleven amino acid
residues with a total molecular weight of about 1,200, but
with different substituents or configurations of some of the
amino acids .
As used here, a "cyclosporin" includes any individual member
of the cyclosporin group, salts thereof, derivatives
thereof, analogs thereof and mixtures thereof, as well as
mixtures of two or more individual cyclosporins salts
thereof, derivatives thereof, analogs thereof and mixtures
thereof .
In one embodiment, the cyclosporin comprises cyclosporin A ,
a derivative of cyclosporin A , a salt of cyclosporin A ,
and/or mixtures thereof.
Cyclosporin A has the chemical name cyclo [[(E) - (2S, 3R, R )-3-
hydroxy-4-methyl-2- (methylamino )-6-octenoyl] -L-2-
aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-Nmethyl-
L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-Nmethyl-
L-leucyl-N-methyl-L-valyl ]. The chemical structure
for cyclosporin A is represented by Formula 1 .
As used here, the term "derivatives" of a cyclosporin refer
to compounds having structures sufficiently similar to the
cyclosporin so as to function in a manner substantially
similar to or substantially identical to cyclosporin A .
Included, without limitation, within the useful cyclosporin
A derivatives are those selected from ((R) -methylthio-Sar ) -
( '-hydroxy-MeLeu ) cyclosporin A , ( (R )- (Cyclo )alkylthio-
Sar ) - ( '-hydroxy-MeLeu )4-cyclospor in A , and ((R)-
(Cyclo )alkylthio-Sar ) -cyclospor in A derivatives described
below .
These cyclosporin derivatives are represented by
following general formulas (II), (III), and (IV)
respectively :
Formula III
Formula IV
wherein Me is methyl; Al is 2-6C alkylene or 3-6C
cycloalkylene; R is OH, COOH, alkoxycarbonyl ,-NRiR2 or N(R 3)-
(CH2)-NRiR2; wherein R2 is H , alkyl, 3-6C cycloalkyl,
phenyl (optionally substituted by halo, alkoxy,
alkoxycarbonyl, amino, alkylamino or dialkylamino) , benzyl
or saturated or unsaturated heterocyclyl having 5 or 6
members and 1-3 heteroatoms ; or NRiR is a 5 or 6 membered
heterocycle which may contain a further N , 0 or S heteroatom
and may be alkylated; R 3 is H or alkyl and n is 2-4; and the
alkyl moieties contain 1-4C.
In one embodiment of the present invention the composition
does not comprise cyclosporine (for example, cyclosporine A
or a cyclosporine derivative or a cyclosporine salt) .
In one embodiment of the present invention the composition
does not comprise a vitamin D and/or a vitamin D analogue
and/or a corticosteroid.
Preferably the ophthalmic composition comprises hyaluronic
acid and/or pharmaceutically acceptable salts and/or
derivatives thereof.
In one embodiment the ophthalmic composition comprises
cyclosporine and hyaluronic acid and/or pharmaceutically
acceptable salts and/or derivatives thereof.
Preferably the ophthalmic composition comprises Flurbiprofen
and/or pharmaceutically acceptable salts and/or derivatives
thereof .
The ophthalmic composition may comprise Vancomycin,
Fluticasone, Lat anoprost , Cyclosporin, Ketotifen,
propanolol, flurbiprofen, Clotrimazole, pharmaceutically
acceptable salts of any of the above, derivatives of any of
the above and mixtures of two or more thereof.
Examples of suitable actives for use in the compositions
described herein for treating specific conditions are given
below .
Class of active Example active condition
Beta-adrenergic ketotifen glaucoma
receptor
blocker
Immune cyclosporine dry eye
suppressant
Prostaglandin latanoprost glaucoma
Antihistamine propranolol allergic
conjunctivitis
Antibiotic vancomycin bacterial
infections ,
chalazion, stye
Corticosteroid fluticasone ocular
inflammation,
blepharitis ,
Behcet 's
disease,
uveitis
Pharmaceutically acceptable salts, isomers, esters and
derivatives thereof and bases may be substituted for any of
the pharmaceutically active agents or drugs described
herein. Mixtures of pharmaceutically active agents may be
used where therapeutically effective.
The ophthalmic composition of the present invention is
preferably presented in a unit dosage form. Each unit dosage
may comprise from 0.0025mg to 500mg, and in particular from
lmg to lOOmg, of the pharmaceutically active agent. It will
be understood that the preferred unit dosage will depend on
the particular pharmaceutically active agent used, or the
particular combination of pharmaceutically active agents
used, and the method of application of the dosage.
When the composition as described herein comprises a
pharmaceutically active agent, the pharmaceutically active
agent is preferably present in an effective amount. As
used herein, the term "effective amount", refers to any
amount of a compound, agent or composition that is
sufficient to fulfill its intended purpose (s), e.g., a
desired biological or medicinal response in a tissue, system
or subject. For example, in certain embodiments of the
present invention, the purpose (s) may be: to slow down or
stop the progression, aggravation, or deterioration of the
symptoms of an eye disease or condition, to bring about
amelioration of the symptoms of the disease or condition,
and/or to cure the disease or condition. Determination of an
effective amount is well within the ordinary skill in the
art of pharmaceutical sciences and medicine, in that it may
depend on various biological factors or individual
variations and response to treatments.
The term "pharmaceutically acceptable carrier or excipient"
refers to a carrier medium which does not interfere with the
effectiveness of the biological (or pharmaceutical) activity
of the active ingredient (s) and which is preferably not
excessively toxic to the host at a concentration at which it
is administered.
The composition may comprise additives such as inert
diluents, buffering agents, dispersing or wetting agents,
preservatives, chelating agents, anti-foaming agents,
antioxidants, permeation enhancers, gelling agents,
rheology modifying agent, such as viscosity modifier(s),
tonicity agents and combinations of one or more thereof.
These additives may be included in the continuous and/or the
discontinuous phase of the polyaphron dispersion and/or they
may be added to the composition after polyaphron formation.
Inert diluents may be sucrose, sorbitol, sugar, mannitol,
microcrystalline cellulose, starches, calcium carbonate,
sodium chloride, lactose, calcium phosphate, calcium
sulfate, or sodium phosphate.
Examples of buffering agents include citric acid, acetic
acid, lactic acid, hydrogenophosphoric acid, diethylamine,
sodium hydroxide and tromethane (i.e., tris- (hydroxymethyl )
aminomethane hydrochloride) .
Examples of dispersing or wetting agents are naturally
occurring phosphatides (e.g., lecithin or soybean lecithin),
condensation products of ethylene oxide with fatty acids or
with long chain aliphatic alcohols
(e.g., polyoxyethylene stearate, polyoxyethylene sorbitol
monooleate, and polyoxyethylene sorbitan monooleate) .
Preservatives may be added to a composition of the invention
to prevent microbial contamination that can affect the
stability of the formulation and/or cause infection in the
patient. Suitable examples of preservatives include parabens
(such as methyl, ethyl, propyl, p-hydroxybenzoate, butyl,
isobutyl, and isopropyiparaben) , potassium sorbate, sorbic
acid, benzoic acid, methyl benzoate, phenoxyethanol ,
bronopol, bronidox, MDM hydantoin, iodopropynyl
butylcarbamate , benzalconium chloride, cetrimide, and
benzylalcohol . Preferred preservatives include benzalkonium
chloride, benzododecinium bromide, 'Purite' (stabilised
oxychloro complex) , methyl-, butyl-, propyl- parabens and
mixtures of two or more thereof.
Preferably the composition comprises less than 0.05% by
weight of preservative based on the total weight the
composition. More preferably the composition comprises less
than 0.02%, less than 0.01% or less than 0.005% by weight of
preservative based on the total weight the composition.
Examples of chelating agents include sodium EDTA and citric
acid.
Anti- foaming agents usually facilitate manufacture of
pharmaceutical compositions, they dissipate foam by
destabilizing the air-liquid interface and allow liquid to
drain away from air pockets. Examples of anti- foaming
agents include simethicone, dimethicone, ethanol, and ether.
Suitable antioxidants include, but are not limited to
butylated hydroxyanisole (BHA) , butylated hydroxytoluene,
ascorbic acid, sodium metabisulphite, propyl gallate, sodium
thiosulphate , alpha- tocopherol, ascorbic acid, retinoic
acid, lutein, derivatives, precursors or prodrugs thereof,
and mixtures of two or more thereof. Preferred antioxidants
are butylated hydroxyanisole (BHA) and butylated
hydroxytoluene. Addition of antioxidants may be
advantageous in extending the shelf-life of the
compositions .
One or more permeation enhancers may be added to the
composition to improve delivery, for example to the
posterior section, of the eye.
Suitable permeation enhancers include propylene glycol.
Other suitable ocular permeation enhancers may be selected
from one or more and mixtures of the following nonexhaustive
list:
Surfactants: Sorbitan glycerides (Span 20, 40, 85);
polyoxyethylene sorbitan glycerides (Tween 20,
40, 81); polyethylene glycol 1000 stearate
(Aptet 100); G 1045; polyoxyethylene stearyl
ethers (Brij 23, 35, 48, 58, 78, 98);
polyoxyethylene stearate (Myrj S40, S50);
polyoxyethylene castor oil (Cremophor EL); BL-
9 ; polyoxyethylene p- (tetramethylbutyl ) phenyl
ether (Triton X-100); saponin
Bile acids and bile salts: Deoxycholic acid;
taurocholic acid; taurodeoxycholic acid;
urodeoxycholic acid; tauroursodeoxycholic
acid; sodium cholate; sodium glycocholate
Fatty acids: capric acid
Preservatives: benzalkonium chloride; benzododecinium
bromide; chlorhexidine digluconate; benzyl
alcohol; chlorbutanol ; 2-phenylethanol ;
paraben; propyl paraben
Chelating agents: EDTA
Others: l-dodecylazacycloheptan-2-one (Azone);
hexamethylene lauramide; hexamethylene
octanamide; decylmethylsulf oxide ; Pharmasolve
(N-methyl pyrollidone ); Gelucire 44/14
(Lauroyl macrogol-32 glycerides); borneol;
dimethyl sulphoxide; sodium fusidate;
decamethonium bromate; cetyl pyridinium
chloride; a-amino acids; cyclodextrins ; medium
chain monoglycerides ; cetrimide; cytochalasins
Particularly preferred permeation enhancers are Brij 58,
Azone, b-cyclodextrin, cetrimide and mixtures of two or more
thereof .
The ophthalmic composition may comprise one or more tonicity
agents. Suitable tonicity agents include one or more of
sorbitol, glycerine, sodium chloride and dextrose.
The tonicity agent may be selected from the group consisting
of a salt, a sugar, a sugar alcohol, a glycol, a carbamide
and mixtures of two or more thereof. Suitable salts include
sodium chloride, potassium chloride, magnesium chloride,
calcium chloride, sodium lactate, sodium pyruvate, sodium
ascorbate and mixtures of two or more thereof. Suitable
sugars include dextrose, sucrose, fructose, xylose, mannose
and mixtures of two or more thereof. Suitable sugar alcohols
include sorbitol, mannitol, xylitol, maltitol, sorbitan and
mixtures of two or more thereof. Suitable glycols include
glycerol, propylene glycol and mixtures thereof. Suitable
carbamides include urea. One or more of each type of
tonicity agent may be present in the composition.
Additionally or alternatively mixtures of different types of
tonicity agents may be present in the composition.
In some embodiments the tonicity agent will be present in an
amount to make the composition (preferably a solution or
liquid) hypertonic. A hypertonic solution has an osmotic
pressure greater than that of an isotonic solution.
Typically when an hypertonic composition is added to the eye
water is drawn from it. This may cause stinging, which is
some cases should be avoided.
A hypotonic composition, preferably a solution, has an
osmotic pressure lower that than of an isotonic composition
(preferably a solution or liquid) . Typically hypotonic
ophthalmic compositions (preferably solutions or liquids)
cause less irritation than hypertonic ones.
The composition may be chosen to be substantially isotonic,
for example with human and/or animal tears. An isotonic
composition (preferably solution or liquid) has an osmotic
pressure substantially equal, (preferably equal) to that on
the other side of a semipermeable membrane. For example,
sodium chloride 0.9% is typically considered to be
approximately isotonic with human tears. The osmolality of
0.9% w/w NaCl is 290 mOsm/kg. This is isotonic with blood
and most cells in the human body.
Preferably, the compositions described herein are
approximately isotonic.
Preferably, the composition (preferably in the form of a
solution or liquid) has an osmolality of from 200 to 600
mOsm/kg, more preferably in the range 240 to 400 mOsm/kg,
even more preferably in the range 280 to 320 mOsm/kg.
The osmolality of the composition may be varied by adjusting
the amount tonicity agents present in the composition.
Osmolality may be determined by freezing point depression
using a suitable automated device such as Advanced
Instruments Inc Model 3320 Osmometer.
As outlined above, the composition of the present invention
may further comprise one or more gelling agent (s) and/or a
rheology modifying agent (s), such as viscosity modifier (s),
and mixtures of two or more thereof.
The gelling agent may be pH sensitive (such as Carbomers) or
thermally sensitive (such as polyethylene glycols or poly(
N-isopropylacrylamide ). The gelling agent may comprise one
or more polysaccharides (such as carrageenans ,
glycosaminoglycans or starches) . The gelling agent may
comprise one or more cellulose or water soluble cellulose
derivatives. The gelling agent may comprise one or more
clays .
The gelling agent may, for example, be selected from guar
gum, locust bean gum, xanthan gum, gum acacia, cellulose or
water soluble cellulose derivatives (such as hydroxymethylcellulose
hydroxyethylcellulose, hydroxypropyl-cellulose,
carboxymethylcellulose or their salts), glycosaminoglycans
(such as hyaluronic acid), clays (such as bentonites),
magnesium aluminium silicates, "Carbomers" (salts of crosslinked
polymers of acrylic acid) , or glyceryl
polymethacrylates or their dispersions in glycols. It will
be understood that other suitable gelling agents may be
used. Additionally, the inventors have discovered that some
of the gelling agents (for example, carbomers) may also
function as a chemical buffering agents thus preventing
unwanted variation in the pH of the composition during
storage and use.
Preferably, the composition of the present invention
comprises from 0.01 to 1.0% by weight of a gelling agent,
preferably from 0.02 to 0.5% by weight and more preferably
from 0.05 to 0.25% by weight of the total composition.
It will be understood that the inclusion of these additives
will be at the levels and with the type of materials which
are found to be effective and useful.
In another aspect, the present invention provides methods
for the treatment of eye diseases and conditions, in
particular eye diseases and conditions that affect the
surface of the eye, such as inflammatory conditions. Such
methods generally comprise a step of: topically
administering to a subject's eye surface, an effective
amount of a composition of the invention.
According to an embodiment, the ophthalmic composition
described herein is preserved. According to another
embodiment, the ophthalmic composition described herein of
the invention is unpreserved.
According to an embodiment, the ophthalmic composition of
the present invention is presented in single use units.
According to another embodiment, the ophthalmic composition
of the present invention is marketed in multidose
containers .
This invention also relates to a medicament comprising the
ophthalmic composition as described herein.
The ophthalmic composition may be a cosmetic composition
and/or it may be for cosmetic use.
Preferably the ophthalmic composition as described herein
has a viscosity of from 1 to 50 Pas, more preferably from 10
to 40Pas. The viscosity may be determined using a cone-andplate
Rheometer at a shear rate of 1 /s at a temperature of
37°C. An example of a suitable cone-and-plate Rheometer for
measuring the viscosity of the composition is the Bohlin CVO
120. Preferably, the viscosity of the composition is such
that it can easily be administered by topical application
(for example via a dropper) to the eye.
Preferably the mean diameter of the droplets of aphrons are
from 0.5 to 50 pm, more preferably in the range of from 1 to
20 pm, more preferably in the range of from 2 to 10 pm. The
mean diameter of the droplets (or aphrons) may be determined
using Fraunhofer diffraction laser light scattering (for
example Malvern Mastersizer 2000) or by optical microscopy.
The volume mean droplet size of the discontinuous phase
droplets (preferably oil droplets) is preferably less than
60 pm, more preferably below 50 pm and most preferably below
40 pm. The volume mean droplet (or aphrons) size may be
determined using Fraunhofer diffraction laser light
scattering (for example Malvern Mastersizer 2000) or by
optical microscopy.
Structural integrity of a polyaphron dispersion and/or of a
polyaphron dispersion in a composition or product may be
assessed using a droplet size distribution analyser, such as
a Malvern Mastersizer Analyser, which determines particle
size distribution via small angle laser diffraction.
In one aspect of the present invention there is provided an
ophthalmic composition as described herein for use in the
treatment of the human and/or animal eye by topical
application .
In one embodiment, the ophthalmic composition as described
herein may be for use in the treatment of glaucoma, dry eye,
allergic conjunctivitis, bacterial infections, chalazion,
styes, ocular inflammation, blepharitis, Behcet's disease,
uveitis and mixtures of two or more thereof, for example by
topical application.
In another embodiment, the ophthalmic composition as
described herein may be for the manufacture of a medicament
for the treatment of glaucoma, dry eye, allergic
conjunctivitis, bacterial infections, chalazion, styes,
ocular inflammation, blepharitis, Behcet's disease, uveitis
and mixtures of two or more thereof, for example by topical
application .
The ophthalmic composition as described herein may be in the
form of an eye drop and/or gel for application to the eye.
The ophthalmic composition may be a liquid or a solution.
Preferably the viscosity of the liquid is less than 1 Pa.s
measured at 25°C, preferably at a shear rate of greater than
300s_ . Preferably the liquid is able to flow and take the
shape of a container.
The ophthalmic composition may be used as an eye bath
solution or liquid. The ophthalmic composition may be in
the form of a dilutable solution or liquid.
In one embodiment the composition is in the form of a gel,
which after application to the eye and during the blinking
of the eyelid, at least a portion of the gel is liquefied.
The liquefied composition may then be distributed,
preferably evenly across the eye.
The composition as described herein preferably does not
comprise a moulded body of a polymer matrix, such as those
described in WO 2009/001099. Preferably, the ophthalmic
composition as described herein is not capable of being
moulded, preferably by sol-gel transition, into a desired
shape. Instead, preferably the composition is in the form of
a liquid, preferably a free-flowing liquid. Preferably it
is not capable of undergoing a sol-gel transition.
Preferably the composition as described herein is not in the
form, or for use, in an eye patch. As will be understood by
the person skilled in the art, an eye patch is a small patch
that is worn in front of an eye. The composition as
described herein is preferably for use in direct contact
with one or more components of the eye, it is not designed
for use on the eyelid, as an eye patch is designed. The
compositions described in WO 2009/001099 behave as
viscoelastic solids with a high degree of viscoelast icity ,
fracturing rather than flowing when deformed by applied
stresses. Therefore the formulations described in WO
2009/001099 would not flow and spread on the eye. Thus, the
formulations described in WO 2009/001099 are not suitable
for application into the eye. Instead, they would only be
suitable for use in eye patches over the eye, preformed and
not flowing in use.
In contrast to this, in the present invention, the
composition is preferably designed such that upon
application of the composition to the eye the polyaphron
droplets flow and spread across the eye at the shear stress
experienced in the eye (such as through blinking) . This is
because these formulations are preferably highly shear
thinning, preferably viscoelastic liquids. The shear rate in
the eye during blinking is estimated to be approximately
between 300 and 500s _ . Preferably the viscosity of the
composition is less than 1 Pa.s measured at 25°C, preferably
at a shear rate of greater than 300s _ .
In one embodiment of present invention there is provided
ophthalmic composition as described herein for use in the
manufacture of a medicament for the treatment of an eye
condition, for example of dry eye or severe dry eye.
It will be understood that the ophthalmic composition as
described herein is suitable for application to the human
and/or animal eye. Preferably the composition is sterile
and/or aseptic.
According to one aspect of the present invention there is
provided a method of making the ophthalmic composition as
described herein comprising the following steps:
(i) providing a hydrophilic solvent;
(ii) providing a hydrophobic solvent;
(iii) mixing the hydrophilic solvent with the
hydrophobic solvent under suitable conditions to
form the composition comprising a polyaphron
dispersion;
wherein the hydrophilic solvent and/or the hydrophobic
solvent comprises a surfactant.
The ophthalmic composition may be prepared under sterile
and/or aseptic conditions. The ophthalmic composition may
be autoclaved to sterilise it. The ophthalmic composition
may be exposed to gamma radiation to sterilise it.
Typically to autoclave a composition it will be subjected to
high pressure saturated steam (for example at a pressure of
approximately 100 kPa) at approximately 110 to 140°C, or
from 120 to 135°C for approximately 10 to 20 minutes.
Suitable conditions may be sterilizing the composition after
manufacture in autoclaves for approximately 15 minutes at
121°C. Suitable conditions will depend on the loading and
the contents. An example of a suitable autoclaving machine
is Prestige Model 21004 Portable Autoclave or Prestige
Optima B Class Autoclave.
The present inventors have surprisingly found that
polyaphron dispersions are substantially robust to
autoclaving. In other words, the polyaphrons dispersions
substantially maintain their physical integrity during and
after autoclaving. In contrast to this, it has been found
that emulsions are typically adversely affected by
autoclaving. Without wishing to be bound by any particular
theory, it is thought that this difference is a result of
the different interactions of surfactants in emulsions and
polyaphron dispersions with respect to the continuous and
discontinuous phases. It is thought that in emulsions the
nature of the surfactant interaction with the continuous and
discontinuous phases is much more sensitive to changes (and
in particular increases) in temperature. Autoclaving may be
carried out at high temperatures, for example at
temperatures above 110°C, above 120°C, or above 130°C.
Typically autoclaving is carried out at 121°C or 126°C.
Under these conditions emulsions are likely to become
unstable and the emulsion may separate (or start to
separate) into hydrophobic and hydrophilic layers. In
contrast to this, in polyaphron dispersions the surfactants
are more closely and robustly associated with the
discontinuous phases of the dispersions. It is thought for
this reason that typically polyaphrons dispersions are much
more physically stable, and less likely to separate into
distinct phases than emulsions. It is particularly
advantageous to be able to autoclave the compositions as it
will be understood that compositions for administration to
the eye should be sterile to avoid infection. One
advantageous of autoclaving the composition is that
preservatives may be omitted from the composition and/or the
amount of preservative required may be reduced.
Advantageously, it has also surprisingly been found that
after autoclaving the mean diameter of the droplets of
aphrons has varied by less than 10%, preferably less than
5%, more preferably less than 2%.
As outlined above, preservatives may be added to the
composition. It is particularly advantageous to add
preservatives if autoclaving is not used. The
preservative (s) is (are) added to keep the composition,
which is typically prepared under sterile conditions, in
suitable state for use and prevent, for example, bacterial
growth. The inventors have surprisingly found that using
polyaphron dispersions rather than emulsions enables lower
levels of preservatives to be used. In order for emulsions
to remain stable it is necessary for higher levels of
surfactants to be present than in an equivalent polyaphron
dispersion. The inventors have found that when higher
levels of surfactant are required, higher levels of
preservatives are required to maintain the same
antibacterial effect. It is advantageous to use lower levels
of preservatives, whilst still preserving the composition,
for a number of reasons: For example, to reduce cost of
preparing the composition; to reduce risks of irritation
caused by the preservatives upon application of the
composition to the eye; and/or to reduce the risk of
undesirable interaction of the preservative with any active
agents or components of the composition.
Optionally the hydrophilic solvent and/or the hydrophobic
solvent comprises one or more pharmaceutically active
agents .
Suitable methods for preparing polyaphron dispersions are
described in US-A-4486333 and EP 1469940. It will be
understood by those skilled in the art that other
manufacturing methods may be used, as appropriate.
Surprisingly, the present inventors have found that by using
the method of preparing polyaphron dispersions as described
herein and as outlined in EP 1469940 is advantageous over
methods of making polyaphrons dispersions by foaming
methods, such as those previously described by Sebba (for
example those described in US-A-4486333) . Using foaming
methods such as those described in Sebba can generate
unstable formulations. Without wishing to be bound by any
particular theory, it is believed that this is related to
the droplet size distribution prepared using the foaming
methods. Preferably, the polyaphron dispersion is formed
without forming a gas-foam intermediate.
Accordingly to another aspect of the present invention,
there is provided a method of making the ophthalmic
composition as described herein comprising the following
steps:
preparing a first polyaphron dispersion optionally
comprising a pharmaceutically active agent;
preparing a second polyaphron dispersion optionally
comprising a pharmaceutically active agent;
and mixing together said first and second polyaphron
dispersions to form the composition.
The method may further comprise:
preparing a third or further polyaphron dispersion
optionally comprising additives such as inert diluents,
buffering agents, dispersing or wetting agents,
preservatives, chelating agents, anti-foaming agents,
antioxidants, gelling agents, permeation enhancers, tonicity
agents and combinations of one or more thereof;
and mixing said third or further polyaphron with said
first and second polyaphron dispersions to form the
composition .
Additives such as inert diluents, buffering agents,
dispersing or wetting agents, gelling agents, preservatives,
chelating agents, anti-foaming agents, antioxidants, gelling
agents, permeation enhancers, tonicity agents and
combinations of one or more thereof may be added to either
or both of the hydrophilic solvent and/or the hydrophobic
solvent before the polyaphron dispersion is formed.
Additionally, and/or alternatively additives such as inert
diluents, buffering agents, dispersing or wetting agents,
gelling agents, preservatives, chelating agents, antifoaming
agents, antioxidants, permeation enhancers, gelling
agents, tonicity agents and combinations of one or more
thereof may be added to the composition after polyaphron
formation.
The ophthalmic composition may comprise more than one
polyaphron dispersion. Each polyaphron dispersion may be
composed of one or more different materials to the other
polyaphron dispersions in the ophthalmic composition. Each
of the polyaphron dispersions may comprise the same or a
different pharmaceutically active agent (preferably in the
discontinuous phase of the polyaphron dispersion) .
According to one embodiment of the present invention there
is provided a method of making the ophthalmic composition as
described herein comprising the following steps: (i)
providing a polyaphron dispersion and (i) mixing said
polyaphron dispersion with a pharmaceutically active agent.
Preferably the pharmaceutically active agent is dissolved
and/or at least partially solubilised in a solvent.
Preferably the pharmaceutically active agent is dissolved
and/or at least partially solubilised in a hydrophilic
solvent .
According to another embodiment of the present invention
there is provided a method of making the ophthalmic
composition as described herein comprising the following
steps: (i) at least partially dispersing and/or dissolving a
pharmaceutically active agent in a hydrophobic solvent; (ii)
mixing said hydrophobic solvent comprising said
pharmaceutically active agent with at least one hydrophilic
solvent and at least one surfactant under suitable
conditions to form a polyaphron dispersion.
As outlined above, it will be understood that the ophthalmic
composition as described herein is suitable for application
to the human and/or animal eye. Typically this means that
the composition is sterile and/or aseptic.
The ophthalmic composition as described herein may be
prepared under sterile and/or aseptic conditions so that the
ophthalmic composition produced is sterile and/or aseptic.
Additionally and/or alternatively, the ophthalmic
composition may be formed in sterile and/or aseptic and/or
non-sterile and/or non-aseptic conditions and then
subsequently treated to produce a sterile and/or aseptic
product. Preferably the method of making ophthalmic
composition as described herein further comprises
autoclaving the ophthalmic composition. In particular, the
present inventors have found that the ophthalmic composition
as described herein comprising the polyaphron dispersion (s)
may be autoclaved under suitable conditions to form a
composition suitable for administration to the human and/or
animal eye. Suitable autoclaving conditions are known to
the person skilled in the art. Typically, autoclaving is
carried out at approximately 121°C.
In one aspect of the present invention there is provided the
ophthalmic composition as described herein for use as a
medicament. In particular there is provided the ophthalmic
composition as described herein for use in the prophylactic
or therapeutic treatment of a human and/or animal eye.
In one aspect of the present invention there is provided a
device for dropwise dispensing of a composition, the device
comprising a container holding the composition as described
herein.
In one embodiment of the present invention there is provided
the method of treating the eye of a human and/or animal, the
method comprising administering the ophthalmic composition
described herein to the eye. The ophthalmic composition may
be administered dropwise to the eye. It may be administered
using a dropper or it may be poured into the eye.
In a preferred embodiment, the ophthalmic composition
comprises a polyaphron dispersion, a pharmaceutically active
agent and cationic surfactant. Preferably, it also contains
a buffering agent and/or an inert diluent.
In another preferred embodiment, the ophthalmic composition
comprises a polyaphron dispersion, a pharmaceutically active
agent and non-ionic surfactant. Preferably, it also
contains a buffering agent and/or an inert diluent.
When introducing elements of the present disclosure or the
preferred embodiment s (s) thereof, the articles "a", "an",
"the" and "said" are intended to mean that there are one or
more of the elements. The terms "comprising", "including"
and "having" are intended to be inclusive and mean that
there may be additional elements other than the listed
elements .
The terms "approximately" and "about", as used herein in
reference to a number, generally includes numbers that fall
within a range of 10% in either direction of the number
(greater than or less than the number) unless otherwise
stated or otherwise evident from the context (except where
such a number would exceed a possible value)
The foregoing detailed description has been provided by way
of explanation and illustration, and is not intended to
limit the scope of the appended claims. Many variations in
the presently preferred embodiments illustrated herein will
be apparent to one of ordinary skill in the art, and remain
within the scope of the appended claims and their
equivalents .
The present invention will now be described further, by way
of example only, with reference to the following figures, in
which :
Figure 1 is a graph showing apparent viscosity (Pa.s)
against shear rate (s _ ) of the composition described in
Example 3 .
The following non-limiting examples further illustrate the
present invention.
EXAMPLES
EXAMPLE 1
Gel polyaphron dispersion of the following composition was
prepared by the following method.
*The cyclosporin A content in the final formulation is
500 g/g. The osmolality of the final product is in the range
250 - 320 mOsm/kg.
Manufacturing Method
The polyaphron dispersion was made by the following method:
A low form, 250ml laboratory beaker (internal diameter
6.5cm) was charged with sufficient aqueous (continuous)
phase to make 3 0 g of gel polyaphron. This was stirred at
200 rpm with a four-bladed impeller having a diameter of 6.0
cm whilst adding the oil (discontinuous) phase drop wise
from a Pasteur pipette. The rate of addition at the start
of the process was slow (approximately one drop every 7
seconds) but was speeded up once 10% of the oil phase had
been added so that the total time to make the gel polyaphron
was approximately 20 minutes.
Prior to the manufacture of the gel polyaphron dispersion,
active was dissolved in the appropriate phase by gentle
stirring overnight with a magnetic stirrer at room
temperature in a covered beaker.
To form the final product, the polyaphron was mixed with the
Carbomer gel and glycerine and the pH adjusted by the
addition of NaOH solution (20% w/w) to the required pH .
Formulations were loaded into suitable vessels and
sterilised by autoclave (121°C, 15 minutes) .
Stability Measurements
Stability measurements made using the method outlined below.
The cyclosporin was extracted from the composition of
Example 1 into acetonitrile and assayed by HPLC under the
conditions given below.
HPLC conditions:
Column: NovaPak C8, 4 m particle size, 3.9 x 150mm column
(Waters )
Mobile phase: 75% v/v acetronitrile, 25% v/v 5 mM P04
buffer, pH 5.1.
Flow rate: 1 ml/minute.
Column Temperature: 50 °C.
Injection volume: 1 m ΐ .
Detector wavelength: 205 nm.
Retention time for cyclosporin was 3.0 minutes
The inventors observed that after 3 months storage at 40°C,
the levels of cyclosporin was 102% ±3% of the original
level .
Permeation of cyclosporine through cornea
In order to determine the permeation of cyclosporine
(CsA) formulations into and through the cornea, ex vivo
studies were conducted. In brief, the corneas from rabbits
were taken and mounted onto Ussing diffusion cells incubated
at 37°C and perfused with carbogen (95/5 oxygen/ carbonic
acid) . Approximately 3 ml sample was placed in the donor
side of the chamber, 3 ml Ringers solution (6.5g NaCl, 0.42g
KC1, 0.25g CaCl 2 and 1 mole of Sodium bicarbonate per litre;
isotonic solution pH 7.2) was placed in the receptor side of
the chamber .
Permeation across the cornea was determined by collecting
200 mΐ receptor phase at the appropriate time points. At
time zero and at 8 hours (termination of the experiment) 100
mΐ of sample from the donor phase was taken for analysis.
Corneas were collected and split into the stomal and
epithelial parts. The cyclosporine in the cornea sections
were analysed after extraction into 50/50 methanol/ water.
Levels of CsA in the receptor chamber, the cornea and in the
donor chamber were determined by HPLC analysis.
Formulations used were based on Example 1 . The table below
summarises the changes made to this formulation.
FN# Summary
1 As Example 1
2 As example 1 with the addition of 1% w/w Tween 20
(polyoxyethylene (20) sorbitan monolaurate)
3 No Carbomer, 0.01% benzalkonium chloride (BAC)
4 Castor oil replaces medium chain triglyceride
5 As example 1 with the addition of 1% Brij 58
(polyoxyethylene (20) cetyl ether)
Alternative representation of formulae:
* benzalkonium chloride
Results
Total amount of CsA (cyclospor ine A ) found in the cornea and
passed through the cornea into the receptor chamber are
summarised below.
FN CsA total amount percent of initial
level after 8 h ^g) after 8h
( q /q )
Cornea Receptor Donor Cornea Receptor
1 421 45 .6 0 .004 3 1 .2% 3.6% 0.0003%
2 531 37 .4 0 .004 49 .6% 2.3% 0.0003%
3 445 43 .1 0 .011 26 .9% 3.2% 0.0008%
4 530 25 .5 ** 15 .1% 1 .6% —
5 536 100 .0 0 .012 80 .7% 6.2% 0.0007%
** Flux could not be correlated with time so no data
presented
From these data the following conclusions may be made:
1 . The presence of Brij 58 at 1% had a significant
positive effect on the permeation of CsA into the
cornea .
2 . Less good permeation results from the use of castor oil
as the vehicle for the lipophilic CsA were observed.
3 . The use of Tween 20 has a slight detrimental effect on
the permeation of CsA into and through the cornea.
4 . The presence of benzalkonium chloride has no
significant effect on permeation of CsA.
Example 2
Gel polyaphron dispersion of the following composition was
prepared by the following method.
*The flurbiprofen content in the final formulation is
300 g/g. The osmolality of the final product is in the range
250 - 320 mOsm/kg.
Manufacturing Method
The method used was precisely as described for Example 1 .
Stability Measurements
Stability measurements made using the method outlined below.
The flurbiprofen was extracted from the composition of
Example 1 into acetonitrile and assayed by HPLC under
conditions given below.
HPLC conditions:
Column: NovaPak C18, 5 m particle size, 3.9 x 100mm column
(Waters )
Mobile phase: 65% v/v acetronitrile, 35% v/v 0 .1M sodium
acetate, pH 6.3.
Flow rate: 1 ml/minute.
Column Temperature: 25°C.
Injection volume: 25 m ΐ .
Detector wavelength: 248 nm.
Retention time for flurbiprofen was 4.5 minutes
The inventors observed that after 3 months storage at 40°C,
the levels of flurbiprofen were 98% ±2% of the original
level .
EXAMPLE 3
Gel polyaphron dispersion of the following composit
prepared by the following method.
Gel POLYAPHRON DISPERSION
Oil Phase %
Latanoprost solution* (0.28%) in Caprylic/Capric 89 .10
Triglyceride (Mygliol 812 - Condea)
Laureth-4 (Volpo L4 - Croda) 0.90
Aqueous Phase
Poloxamer 188 (Pluronic F68 - BASF) 0.50
Demineralised Water 9.50
FINAL PRODUCT % w/w
GEL POLYAPHRON DISPERSION 2 .00
0.1% Polyacrylic acid (Carbomer 980) 93 .10
Sorbitol (CxPharmsorboidex P , S Black) 4 .90
NaOH, to pH 6.7 qs
*The latanoprost content in the final formulation is 50.0
g/g. The osmolality of the final product is in the range
250 - 320 mOsm/kg.
Manufacturing Method
The polyaphron dispersion was made by the following method:
A low form, 250ml laboratory beaker (internal diameter
6.5cm) was charged with sufficient aqueous (continuous)
phase to make 3 0 g of gel polyaphron. This was stirred at
200 rpm with a four-bladed impeller having a diameter of 6.0
cm whilst adding the oil (discontinuous) phase drop wise
from a Pasteur pipette. The rate of addition at the start
of the process was slow (approximately one drop every 7
seconds) but was speeded up once 10% of the oil phase had
been added so that the total time to make the gel polyaphron
was approximately 20 minutes.
Prior to the manufacture of the gel polyaphron dispersion,
the active, a liquid at room temperature, was mixed with the
appropriate phase by gentle stirring with a magnetic stirrer
at room temperature in a covered beaker. Dispersion of the
active into the oil phase took less than 3 0 minutes.
To form the final product, the polyaphron was mixed with the
Carbomer gel and glycerine and the pH adjusted by the
addition of NaOH solution (20% w/w) to the required pH .
Stability Measurements
Stability measurements made using the method outlined below.
The latanoprost was extracted from the composition of
Example 3 into acetonitrile and assayed by HPLC under the
conditions given below.
HPLC conditions:
Instrument: Acquity H Class (Waters)
Column: BEH C18, 1.7 m particle size, 2.1 x 50mm column
(Waters) with VanGuard C18 guard column (Waters)
Mobile phase: 70% v/v acetronitrile, 30% v/v water.
Flow rate: 0.5 ml/minute.
Column Temperature: 40 °C.
Injection volume: 10 m ΐ .
Detector wavelength: 210 nm.
Retention time for latanoprost was 0.4 minutes
Formulation was dispensed into autoclavable eyedropper
bottles and sterilised using a standard run in a Prestige
Autoclave, holding samples at 121°C for 15 minutes.
Autoclavat ion cycle was confirmed using indicator tape.
The inventors observed that after autoclaving the
formulation, the levels of latanoprost was 99.4% ± 0.1% of
the level in the untreated sample.
Shear Experiment
Comparison of apparent viscosity against shear rate for a
carbomer-stabilised eyedrop formulation (using Example 3 ) .
The shear rate range covered was from 0.1 to 500 /s. The
same sample was subjected to the same shear rate regime
after 5 minutes rest. The results are shown in Figure 1 .
There is no significant difference between the two viscosity
profiles, indicating that high shear does not permanently
affect the structure of this formulation.
Method
Rheology measurements were carried out using the Bohlin CVO
120 rheometer. Controlled shear rates were applied to a
sample (approx 2 g ) via a 40 mm diameter stainless steel
cone and plate geometry. Cone angle = 4°, temperature
maintained at 25°C. The shear stress required to reach the
required shear rate was controlled directly by the
instrument. Apparent viscosity (h ) is related to shear rate
(g ) and shear stress ( ) by the equation h = t/g .
EXAMPLE 4
Gel polyaphron dispersion of the following composit
prepared by the following method.
*The latanoprost content in the final formulation is 50.0
g/g. The osmolality of the final product is in the range
250 - 320 mOsm/kg.
Manufacturing Method
The polyaphron dispersion was made as in Example 3 .
Stability Measurements
Stability measurements made using the method outlined below.
The latanoprost was extracted from the composition of
Example 4 into acetonitrile and assayed by HPLC under the
conditions given for Example 3 .
Formulation was dispensed into autoclavable eyedropper
bottles and sterilised using a standard run in a Prestige
Autoclave, holding samples at 121°C for 15 minutes.
Autoclavat ion cycle was confirmed using indicator tape.
The inventors observed that after autoclaving the
formulation, the levels of latanoprost was 83.7% ± 0.4% of
the level in the untreated sample.
In this example the use of dextrose to adjust the osmolality
of the formulation resulted in an unstable formulation, in
contrast to Example 3 .
EXAMPLE 5
Gel polyaphron dispersion of the following composit
prepared by the following method.
Gel POLYAPHRON DISPERSION
Oil Phase %
Fluticasone solution* (0.28%) in Caprylic/Capric 89 .10
Triglyceride (Mygliol 812 - Condea)
Laureth-4 (Volpo L4 - Croda) 0.90
Aqueous Phase
Poloxamer 188 (Pluronic F68 - BASF) 0.50
Demineralised Water 9.50
FINAL PRODUCT % w/w
GEL POLYAPHRON DISPERSION 2 .00
0.1% Polyacrylic acid (Carbomer 980) 93 .05
Polyoxyethylene (20) stearyl ether (Acros) 0.05
Sorbitol (CxPharmsorboidex P , S Black) 4.90
NaOH, to pH 6.7 qs
*The fluticasone content in the final formulation is 50
g/g. The osmolality of the final product is in the range
250 - 320 mOsm/kg.
Manufacturing Method
The polyaphron dispersion was made by the following method:
A low form, 250ml laboratory beaker (internal diameter
6.5cm) was charged with sufficient aqueous (continuous)
phase to make 3 0 g of gel polyaphron. This was stirred at
200 rpm with a four-bladed impeller having a diameter of 6.0
cm whilst adding the oil (discontinuous) phase drop wise
from a Pasteur pipette. The rate of addition at the start
of the process was slow (approximately one drop every 7
seconds) but was speeded up once 10% of the oil phase had
been added so that the total time to make the gel polyaphron
was approximately 20 minutes.
Prior to the manufacture of the gel polyaphron dispersion,
the active was dissolved in the appropriate phase by gentle
stirring with a magnetic stirrer at room temperature in a
covered beaker. Dissolution of the active into the oil phase
took approximately 2 hours.
To form the final product, the polyaphron was mixed with
Carbomer gel and glycerine and the pH adjusted by the
addition of NaOH solution (20% w/w) to the required pH .
Formulation was dispensed into autoclavable eyedropper
bottles and sterilised using a standard run in a Prestige
Autoclave, holding samples at 121°C for 15 minutes.
Autoclavat ion cycle was confirmed using indicator tape.
EXAMPLE 6
Gel polyaphron dispersion of the following composit
prepared by the following method.
*The vancomycin content in the final formulation is 3 0 g/g.
The osmolality of the final product is in the range 250 -
320 mOsm/kg.
Manufacturing Method
The polyaphron dispersion was made as in Example 3 .
Example 7
Gel polyaphron dispersion of the following composition was
prepared by the following method.
*The cyclosporin A content in the final formulation is
500 g/g. The osmolality of the final product is in the range
250 - 320 mOsm/kg.
Manufacturing Method
The polyaphron dispersion was made by the following method:
A low form, 250ml laboratory beaker (internal diameter
6.5cm) was charged with sufficient aqueous (continuous)
phase to make 3 0 g of gel polyaphron. This was stirred at
200 rpm with a four-bladed impeller having a diameter of 6.0
cm whilst adding the oil (discontinuous) phase drop wise
from a Pasteur pipette. The rate of addition at the start
of the process was slow (approximately one drop every 7
seconds) but was speeded up once 10% of the oil phase had
been added so that the total time to make the gel polyaphron
was approximately 20 minutes.
Prior to the manufacture of the gel polyaphron dispersion,
active was dissolved in the appropriate phase by gentle
stirring overnight with a magnetic stirrer at room
temperature in a covered beaker.
To form the final product, the polyaphron was dispersed in
the water. Sodium Chloride was added as a solution. The
required amount of xanthan gum was dispersed in the glycerol
before adding to the diluted polyaphon. The pH of the
formulation was adjusted with either NaOH or HC1 to ph 6.50
to 7.00.
Formulations were loaded into suitable vessels and
sterilised by autoclave (121°C, 15 minutes) .
EXAMPLE 8
Gel polyaphron dispersion of the following composition was
prepared by the following method.
Gel POLYAPHRON DISPERSION
Oil Phase %
Ketotifen solution* (0.255 % ) in soybean oil 89 .10
(Aldrich)
Laureth-4 (Volpo L4 - Croda) 0.90
Aqueous Phase
Polysorbate 80 (Tween 80, Sigma) 0.50
Demineralised Water 9.50
FINAL PRODUCT % w/w
GEL POLYAPHRON DISPERSION 1.10
0.1% Polyacrylic acid (Carbomer 980) 93 .05
Polyoxyethylene (20) stearyl ether (Acros) 0.05
Sorbitol (CxPharmsorboidex P , S Black) 4 .90
NaOH, to pH 6.7 qs
*The ketotifen content in the final formulation is 250 g/g.
The osmolality of the final product is in the range 250 -
320 mOsm/kg.
Manufacturing Method
The polyaphron dispersion was made by the method described
in Example 1 .
To form the final product, the polyaphron was mixed with the
Carbomer gel and glycerine and the pH adjusted by the
addition of NaOH solution (20% w/w) to the required pH .
Formulations were loaded into suitable vessels and
sterilised by autoclave (121°C, 15 minutes) .
EXAMPLE 9
Gel polyaphron dispersion of the following composition was
prepared by the following method.
Gel POLYAPHRON DISPERSION
Oil Phase %
Propranolol solution* (5.10%) in Caprylic/Capric 89 .10
Triglyceride (Mygliol 812 - Condea)
Laureth-4 (Volpo L4 - Croda) 0.90
Aqueous Phase
Poloxamer 188 (Pluronic F68 - BASF) 0.50
Demineralised Water 9.50
FINAL PRODUCT % w/w
GEL POLYAPHRON DISPERSION 5 .50
0.1% xanthan gum, 0.1% locust bean gum (both 92 .00
Aldrich)
Glycerol (Fisher) 2.50
NaOH, to pH 6.7 qs
*The propranolol content in the final formulation is 2.5
mg/g. The osmolality of the final product is in the range
250 - 320 mOsm/kg.
Manufacturing Method
The polyaphron dispersion was made as in Example 1 .
The polyaphron was dispersed into water by stirring at 260
rpm prior to the addition of the xanthan and locust bean
gum. The gums were added as a slurry, predispersed in
glycerol. Stirring was continued until the gel structure had
formed, approximately 10 minutes.
Formulations were loaded into suitable vessels and
sterilised by autoclave (121°C, 15 minutes) .
Example 10
Gel polyaphron dispersion of the following composition was
prepared by the following method.
Gel POLYAPHRON DISPERSION
Oil Phase %
Clotrimazole solution* (2.5%) in Caprylic/Capric 89 .10
Triglyceride (Mygliol 812 - Condea)
Sorbitan monooleate (Span 80 , Sigma) 0.90
Aqueous Phase
Poloxamer 188 (Pluronic F68 - BASF) 0.50
Demineralised Water 9.50
FINAL PRODUCT % w/w
GEL POLYAPHRON DISPERSION 4 .50
0.2% Polyacrylic acid (Carbomer 980) 90.60
Sorbitol (CxPharmsorboidex P , S Black) 4 .90
NaOH, to pH 7.0 to 7.4 qs
*The clotrimazole content in the final formulation is
1000 g/g. The osmolarity of the final product is in the
range 250 - 320 mOsm/kg.
Manufacturing Method
The polyaphron dispersion was made by the method described
in Eaxample 1.
Formulations were loaded into suitable vessels and
sterilised by autoclave (121°C, 15 minutes) .
The present invention will now be described in relation to
the following non-limiting clauses:
1 . An ophthalmic composition comprising a polyaphron
dispersion .
2 . The ophthalmic composition according to clause 1
comprising a pharmaceutically active agent.
3 . The ophthalmic composition according to clause 2
wherein the pharmaceutically active agent is selected
from antihistamines, bet ablocker s, corticosteroids,
prostaglandins, non-steroidal anti-inflammatory drugs
(NSAIDs), immune modulators, anaesthetics, antibiotics,
carbonic anhydrase inhibitors, vasoconstrictors, and
mixtures of two or more thereof.
4 . The ophthalmic composition according to any of the
preceding clauses wherein the pharmaceutically active
agent comprises cyclosporine .
5 . The ophthalmic composition according to any of the
preceding clauses comprising an omega-3 fatty acid.
. The ophthalmic composition according to any of the
preceding clauses wherein the composition has a pH of
from 3.5 to 9 , preferably from 5 to 8 , more preferably
from 6 to 7.5.
The ophthalmic composition according to any of the
preceding clauses comprising a gelling agent.
The ophthalmic composition according to any one of the
preceding clauses having a viscosity of 1 to 50 Pas.
The ophthalmic composition according to any of the
preceding clauses comprising a surfactant selected from
the group consisting of non-ionic surfactants, cationic
surfactants, anionic surfactants, zwitterionic
surfactants and mixtures of two or more thereof.
The ophthalmic composition according to any one of the
preceding clauses comprising a pharmaceutically
acceptable oil selected from the group consisting of
castor oil, long chain triglycerides, medium chain
triglycerides, mineral oil, silicones, phospholipids,
mono- and diglycerides and mixtures of two or more
thereof .
The ophthalmic composition according to any of the
preceding clauses for use in the treatment of the human
and/or animal eye by topical application.
The ophthalmic composition according to any of the
preceding clauses in the form of an eye drop and/or gel
for application to the eye.
The ophthalmic composition according any one of the
preceding clauses wherein the mean diameter of the
droplets of aphrons are from 0.5 to 50 m .
A method of making the ophthalmic composition according
to any of the preceding clauses comprising the
following steps:
(i) providing a hydrophilic solvent;
(ii) providing a hydrophobic solvent;
(iii)mixing the hydrophilic solvent with the
hydrophobic solvent under suitable conditions to
form the composition comprising a polyaphron
dispersion;
wherein the hydrophilic solvent and/or the hydrophobic
solvent comprises a surfactant;
and wherein the hydrophilic solvent and/or the
hydrophobic solvent optionally comprises a
pharmaceutically active agent.
The method according to clause 14 which is carried out
under sterile and/or aseptic conditions.
The method according to clause 14 or 15 which further
comprises autoclaving the ophthalmic composition.
A device for dropwise dispensing of a composition, the
device comprising a container holding the composition
as defined in any of the preceding clauses.

CLAIMS
An ophthalmic composition comprising a polyaphron
dispersion .
The ophthalmic composition according to claim 1 in the
form of a liquid.
The ophthalmic composition according to claim 1 or 2 in
the form of an eye drop.
The ophthalmic composition according to any of the
preceding claims comprising a pharmaceutically active
agent .
The ophthalmic composition according to claim 4 wherein
the pharmaceutically active agent is selected from the
group consisting of an antihistamine, a betablocker, a
corticosteroid, a prostaglandin, a non-steroidal anti
inflammatory drugs (NSAID) , an immune modulator, an
anaesthetic, an antibiotic, a carbonic anhydrase
inhibitor, a vasoconstrictor, and mixtures of two or
more thereof.
The ophthalmic composition according to any of the
preceding claims wherein the pharmaceutically active
agent comprises cyclosporine .
The ophthalmic composition according to any of the
preceding claims wherein the composition has an
osmolality of from 200 to 600 mOsm/kg.
The ophthalmic composition according to any of the
preceding comprising a tonicity agent, preferably
selected from a sugar, a sugar alcohol, a glycol, a
carbamide and mixtures of two or more thereof.
The ophthalmic composition according to any of the
preceding claims comprising an omega-3 fatty acid.
The ophthalmic composition according to any of the
preceding claims wherein the composition has a pH of
from 3.5 to 9 , preferably from 5 to 8 , more preferably
from 6 to 7.5.
The ophthalmic composition according to any of the
preceding claims comprising a gelling agent.
The ophthalmic composition according to any one of the
preceding claims having a viscosity of 1 to 50 Pas at
shear rate of Is- 1 .
The ophthalmic composition according to any of the
preceding claims wherein the surfactant is selected
from one or more non-ionic surf actant (s), cationic
surf actant (s), anionic surf actant (s), zwitterionic
surf actant (s) and mixtures of two or more thereof.
The ophthalmic composition according to any one of the
preceding claims comprising a pharmaceutically
acceptable oil selected from the group consisting of
castor oil, long chain triglycerides, medium chain
triglycerides, mineral oil, silicones, phospholipids,
mono- and diglycerides and mixtures of two or more
thereof .
The ophthalmic composition according to any one of the
preceding claims comprising a surfactant selected from
the group consisting of a polyethylene glycol sorbitan
fatty acid ester, a sorbitan fatty acid ester, a
polyethylene glycol fatty acid ester, a polyethylene
glycol stearate ester, a polyoxyethylene glycol -
block- polypropylene glycol - block - polyoxyethylene
glycol - block, a polyethylene glycol lauryl ester and
mixtures of two or more thereof.
The ophthalmic composition according to any of the
preceding claims in the form of a gel for application
to the eye.
The ophthalmic composition according any one of the
preceding claims wherein the mean diameter of the
droplets of aphrons are from 0.5 to 50 m .
The ophthalmic composition according to any of the
preceding claims for use in the treatment of the human
and/or animal eye by topical application.
The ophthalmic composition according to any of the
claims 1 to 17 for use in the treatment of the human
and/or animal eye by topical application, wherein the
composition is directly administered to the surface of
the eye .
A method of making the ophthalmic composition according
to any of the preceding claims comprising the following
steps :
(i) providing a hydrophilic solvent;
(ii) providing a hydrophobic solvent;
(iii) mixing the hydrophilic solvent with the
hydrophobic solvent under suitable conditions to
form the composition comprising a polyaphron
dispersion;
wherein the hydrophilic solvent and/or the hydrophobic
solvent comprises a surfactant;
and wherein the hydrophilic solvent and/or the
hydrophobic solvent optionally comprises a
pharmaceutically active agent.
The method according to claim 20 which is carried out
under sterile and/or aseptic conditions.
The method according to claim 20 or 21 which further
comprises autoclaving the ophthalmic composition.
A device for dropwise dispensing of a composition, the
device comprising a container holding the composition
as defined in any of the preceding claims.