Note: Descriptions are shown in the official language in which they were submitted.
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Pharmaceutical Compositions
The invention relates to pharmaceutical, in particular ophthalmic
compositions, e.g. gels and
a method for treating ocular disorders/diseases by administration of said
compositions.
Ophthalmic compositions have often to be applied several, typically two to
four times a day,
like, for instance, ophthalmic compositions comprising ketotifen which are
known, e.g. from .
WO 01/07049 and commercially available, e.g. under the trademark Zaditen~ or
Zaditor~.
Such repeated administration is not optimal in practice because the patient
has, for instance,
to have the medicament always available and is disrupted several times a day
by the need of
administering the composition. Therefore such multiple administration of a
drug, in particular
of an ophthalmic composition, generally leads to the problem of overdosing
and/or
underdosing. Overdosing, however, may typically generate ocular irritation,
whereas
underdosing may typically lead to re-occurrence of the symptoms.
There is thus a need for a so-called once-a-day administration of ophthalmic
drugs. It has
now been found that pharmaceutical compositions, in particular ophthalmic
compositions,
can be formulated for once-a-day administration. Said compositions provide the
therapeutic
effect the drug they comprise, for instance of an ophthalmic drug like
ketotifen, at the eye
over about 24 hours. Such compositions are surprisingly well tolerated, and
produce a highly
reliable and strongly reproducible clinical result in a patient treated
therewith.
Therefore, in one aspect the present invention provides an ophthalmic
composition,
particularly for topical once-a-day administration, which comprises an
ophthalmic drug and a
linear polysaccharide compound, preferably a hyaluronic acid compound
(hereinafter
compositions of the present invention).
Suitable ophthalmic drugs include anti-inflammatory drugs such as
indomethacin, diclofenac,
tenoxicam, piroxicam, hydrocortisone, medrysone, prednisolone,
methylprednisolone,
betamethasone, triamcinolone acetonide, dexamethasone, fluorometholone; drugs
against
allergy such as ketotifen, antazoline, cromoglycate; drugs for treatment of
glaucoma such as
timoloi, betaxolol, carteoloi, befunolol, tevobunoiol, pilocarpine,
unoprostone, latanoprost,
valsartan; miotics such as pilocarpine, aceclidine, carbachol, acetycholine;
mydriatics such
as tropicamide, atropine, phenylephrine, cyclopentolate, scopolamine,
homatropine, napha-
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zoline; antibiotics such as lomefloxacine, pefloxacine, gentamicine,
sulfacetamide, sulfadi-
cramide, sulfadiazine, neomycine, framycitine, polymixine B, kanamycine,
tobramycine,
amikacine, tetracycline, oxytetracycline, bacitracine, chloramphenicol,
doxycicline,
minocycline, erythromycine, rifamycine, streptomycine; antiviral drugs such as
idoxuridine,
5-iodo-2'-deoxycytidine, vidarabine, trifluridine, acyclovir, foscarnet,
interferon; anaesthetics
such as tetracaine, oxybuprocaine, lidocaine; antimycotics such as
amphotericine B,
nystatine, fluorocytosine, griseofulvine; antiseptics such as chlorhexidine,
picloxidine; and
trophic agents such as ascorbic acid, retinol. Preferably the ophthalmic drug
is selected from
diclofenac, prednisolone, ketotifen, timolol, valsartan, griseofulvine,
ascorbic acid and retinal,
or is, very particularly, ketotifen.
Suitable ophthalmic drugs may be e.g. in their free base or acid form, or in
form of a
pharmaceutically acceptable salt thereof and may be used in combination of two
or more
than two.
The concentration of ophthalmic drug is preferably from about 0.005 - 5%,
preferably 0.01 -
2%, even more preferably from 0.01 - 1 %, e.g. 0.01 to 0.2%, e.g. 0.01 to 0.1
% and in
particular from 0.01 to 0.05, preferably 0.02 - 0.04%, in each case by weight
based on the
total weight of the composition.
A drug is preferably in solution. If desired, however, the compositions of the
present
invention may be in the form of a suspension, e.g. containing particles of
ophthalmic drug
e.g. with a mean particle diameter of 200 to 25000 nm.
The compositions of the present invention may comprise pharmaceutically
acceptable
excipients, which are suitable for ophthalmic compositions. The excipients of
the
compositions of the present invention and the compositions themselves should,
in general,
not detrimentally affect the lacrimal system nor the ocular tear film.
Information on the properties, specifications and characteristics are
described e.g in
standard texts such as Fiedler, H.P.; 1996; Lexikon der Hilfsstoffe fur
Pharmazie. Kosmetik
and angrenzende Gebiete; Editio Cantor Verlag Aulendort (Germany), and Kibbe,
A.H.;
2000; Handbook of Pharmaceutical Excipients, a joint publication of
Pharmaceutical Press,
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London (UK), and American Pharmaceutical Association, Washington (US) as well
as
manufacturers' brochures, the contents of which are incorporated herein by
reference.
The linear polysaccharide compound of the compositions of the instant
invention preferably
comprises a hyaluronic acid compound (hyaluronan; Fiedler, loc. cit., p. 763)
such as known
and commercially available from Vitrolife AB, Sweden, or from Pentapharm AG,
Switzerland,
e.g. under the names hyaluronic acid Pentapharm or hyaluronic acid BT. Even
more
preferably the linear polysaccharide compound of the compositions is a
hyaluronic acid
compound. Preferably, the hyaluronic acid compound is an alkali salt of
hyaluronic acids,
e.g. sodium hyaluronate. The hyaluronic acid may be obtained in a way known
per se, e.g.
from cocks combs or biotechnically. The molecular weight is e.g. from about
0.4*10s to about
3*106 g/mol or to about 4*106 g/mol. Preferred molecular weights are above
about 0.75*10g
g/mol, even more preferably about 2.6*106 g/moi.
The exact amounts of polysaccharide compound, in particular of hyaluronic
compound may
vary within wide limits, e.g. in order to produce a composition according to
the present
invention which has a viscosity within the preferred range indicated below.
For example, the
amount may be from 0.05 to 10%, e.g. 0.1 to 10%, preferably from 0.1 to 2% by
weight of
the total composition.
Furthermore, the compositions of the present invention may comprise (2.) an
usual tonicity
enhancing agent. Suitable tonicity enhancing agents are, e.g.
2.1 ionic compounds, such as alkali metal or alkaline earth metal halides,
such as CaCh,
KBr, KCI, LiCI, Nal, NaBr or NaCI, or boric acid, and/or
2.2 non-ionic compounds such as urea, glycerol, sorbitol, mannitol, propylene
glycol, or
dextrose.
Conveniently, sufficient tonicity enhancing agent is added to impart to the
ready-for-use
ophthalmic composition an osmolality of approximately from 50 to 1000 mOsmol,
preferred
from 100 to 400 mOsmol, more preferred from 200 to 400 mOsmol and even more
preferred
from 280 to 350 mOsmol.
For the adjustment of the pH, preferably to a physiological pH, addition of
(3.) pH modifying
agents or a pharmaceutically acceptable buffer system. A suitable pH-modifying
agent
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includes e.g. sodium hydroxide e.g. in form of a one molar solution. Examples
of buffer
substances are acetate, ascorbate, borate, hydrogen carbonatelcarbonate,
citrate,
gluconate, lactate, phosphate, propionate and tromethamine (tris-
(hydroxymethyl)-amino-
methane, TRIS) buffers. Tromethamine buffer is preferred. The buffer substance
added is
typically of an amount to ensure and maintain a physiologically tolerable pH
range. The pH
range is generally in the range of from 4 to 9, preferably from 4.5 to 8.5 and
more preferably
fromS.Oto8.2.
The compositions of the present invention may further comprise (4.) a
preservative, e.g. on
storage or to inhibit microbial growth after opening a closed container
holding such a
composition and exposing such a composition to the air. A preservative may
typically be
selected from e.g.
4.1 a quaternary ammonium compound such as e.g. benzalkonium chloride (N-
benzyl-
N-(C$-C~$-alkyl)-N,N-dimethylammonium chloride), benzoxonium chloride,
cetrimide
(hexadecyl-trimethylammonium bromide) or the like.
4.2 alkyl-mercury salts of thiosalicylic acid, such as e.g. thiomersal,
phenylmercuric nitrate,
phenylmercuric acetate or phenylmercuric borate,
4.3 parabens, such as e.g. methylparaben or propylparaben,
4.4 alcohols, such as e.g. chlorobutanol, benzyl alcohol or phenyl ethanol,
4.5 biguanide derivatives, such as e.g. chlorohexidine or polyhexamethylene
biguanide,
4.6 sodium perborate,
4.7 imidazolidinyl urea as known and commercially available under the trade
name
Germal~ll,
4.8 sorbic acid,
4.9 stabilized oxychloro complexes such as known and commercially available
under the
trade name Purite~,
4.10 polyglycol-polyamine condensation resins, such as known and commercially
available
e.g. under the trade name Polyquart~ from Henkel KGaA, and/or
4.11 a mixture of any components 4,1 to 4.10.
Preferred preservatives are quaternary ammonium compounds, in particular
benzalkonium
chloride and cetrimide. Where appropriate, a sufficient amount of preservative
is added to
the ophthalmic composition to ensure protection against secondary
contaminations during
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use caused by bacteria and fungi, e.g. the preferred preservatives are present
in an amount
of about 0.001-0.02%.
The compositions according to the instant invention may additionally require
the presence of
(5.) a solubilizer, in particular if the active or the inactive ingredients
tends to form a
suspension or an emulsion. A solubilizer suitable for an above concerned
composition is e.g.
5.1 octylphenoxy-poly(ethylenoxy)-ethanol (tyloxapol) known and commercially
available
under the trade name Triton, e.g. Triton ~ WR 1339, (Fiedler, loc. cit., p
1609),
5.2 polyethylene glycol glyceryl fatty acid ester. The fatty acid ester may
include mono
and/or di and/or tri fatty acid ester. The fatty acid constituent may include
both
saturated and unsaturated fatty acids having a chain length of from e.g. C$-
Czo. The
polyethylene glycols may have e.g. from 5 to 40 [CH2-CH2-O] units, e.g. 5 or
30 units.
Particularly suitable is polyethylene glycol (15) glyceryl monostearate or
polyethylene
glycol (15) glyceryl monooleate which is commercially available, e.g. under
the trade
name TGMS~-15 or TGMO~-15, respectively, e.g. from Nikko Chemicals Co., Ltd.
Further suitable is polyethylene glycol (30) glyceryl monooleate which is
commercially
available, e.g. under the trade name Tagat~ O, e.g. from Goldschmidt (H.
Fiedler, loc
cit, vol. 2, p. 1502-1503). Further suitable are polyethylene glycol glyceryl
C8-Coo fatty
acid ester with from 5 to 10 (CH2-CH2-Ol units, e.g. 7 units, e.g. Cetiol~ HE,
or
Labrasol~
5.3 polyoxyethylene C8_2o fatty acid esters, e.g. polyoxyethylene stearic acid
esters of the
type known and commercially available under the trade name Myrj~ (Fiedler,
loc. cit.,
2, p. 1042) or Brij~ (Fiedler, loc. cit., p. 259; Handbook of Pharmaceutical
Excipients,
loc. cit., p. 367). An especially preferred product of this class is Myrj~ 52
having a D~5
of about 1.1, a melting point of about 40 to 44°C, an HLB value of
about 16.9, an acid
value of about 0 to 1 and a saponification value of about 25 to 35,
5.4 glycerol ethers (Fiedler, loc. cit., p.701 ),
5.5 cyclodextrins, e.g. a-, (3- or y-cyclodextrin, e.g. alkylated,
hydroxyalkylated, carboxy-
alkylated or alkyloxycarbonyl-alkylated derivatives, or mono- or digiycosyl-a-
, (i- or y-
cyclodextrin, mono- or dimaltosyl-a-, (3- or y- cyclodextrin or panosyl-
cyclodextrin, e.g.
such as known and commercially available under the trade name CavamaxC~ or
Cavasol~ from Wacker Chemie. An especially preferred product of this class is
hydroxypropyl-x-cyclodextrin, e.g. as known and commercially available under
the
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trade name Cavasol~ W7 HP or Cavasol~ W8 HP. A mixture of cyclodextrins may
also be used.
5.6 polyoxyethylene-sorbitan- C8_2o fatty acid esters (polysorbates) e.g.
produced by co-
polymerising ethylene oxide with fatty acid esters of a sorbitol and its
anhydrides of
e.g. mono- and tri- lauryl, palmityl, stearyl and oleyl esters e.g. of the
type known and
commercially available under the trade name Tween~ (Fiedler, loc.cit., p.1615)
including the products Tween~
20 [polyoxyethylene(20)sorbitanmonolaurate],
21 [polyoxyethylene(4)sorbitanmonolaurate],
40 [polyoxyethylene(20)sorbitanmonopalmitate],
60 [polyoxyethylene(20)sorbitanmonostearate],
65 [polyoxyethylene(20)sorbitantristearate],
80 [polyoxyethylene(20)sorbitanmonooleate],
81 [polyoxyethylene(5)sorbitanmonooleate],
85 [polyoxyethylene(20)sorbitantrioleate].
Especially preferred products of this class are Tween~20 and Tween~80.
5.7 reaction products of natural or hydrogenated vegetable oils and ethylene
glycol, i.e.
polyoxyethylene glycolated natural or hydrogenated vegetable oils, for example
poly-
oxyethylene glycolated natural or hydrogenated castor oils. Such products may
be
obtained in known manner, e.g. by reaction of a natural or hydrogenated castor
oil or
fractions thereof with ethylene oxide, e.g. in a molar ratio of from about
1:35 to about
1:60, with optional removal of free polyethylene glycol components from the
product,
e.g. in accordance with the methods disclosed in German Auslegeschriften
1,182,388
and 1,518,819. Especially suitable are the various tensides available under
the trade
name Cremophor. Particularly suitable are the products Cremophor RH 40 having
a
saponification no. ca. 50-60, an acid no.=<1, an iodine no.=<1, a water
content
(Fischer)=<2%, an nDSO =ca.1,453-1,457 and an HLB=ca. 14-16; Cremophor RH 60
having a saponification no.=ca. 40-50, an acid no. =<1, an iodine no.=<1, a
water
content (Fischer)=ca. 4.5-5.5%, an np~s=ca.1.453-1,457 and an HLB=ca.15-17;
and
Cremophor EL having a molecular weight (by steam osmometry)=ca. 1630, a
saponification no.=ca. 65-70, an acid no.=ca. 2, an iodine no.=ca. 28-32 and
an noes
=ca.1.471 (c.f. Fiedler loc. cit. p. 326-327). Also suitable for use in this
category are the
various tensides available under the trade name Nikkol, e.g. Nikkol HCO-60.
The said
product NIKKOL HCO-60 is a reaction product of hydrogenated castor oil and
ethylene
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oxide exhibiting the following characteristics: acid no.=ca. 0.3;
saponification no.=ca.
47.4; hydroxy value=ca. 42.5. pH (5%)=ca. 4.6; Color APHA=ca. 40; m.p.=ca.
36.0°C.;
Freezing point=ca. 32.4°C.; H20 content (%, KF)=ca. 0.03, and/or
5.8 mixtures of the components 5.1 to 5.7.
Especially preferred solubilizers are Cremophor EL, Cremophor RH 40, tyloxapol
and
cyclodextrins. The concentration used depends especially on the concentration
of the active
ingredient. The amount added is typically sufficient to solubilize the active
ingredient. For
example, the concentration of the solubilizer is from 0.1 to 5000 times the
concentration of
the active ingredient, preferably 0.5 to 1000, e.g. 1 to 500.
It has furthermore been found that the well-known incompatibility of
benzalkonium chloride
and hyaluronic acid compounds, in particular sodium hyaluronate, which leads
to the
irreversible formation of a colourless precipitate within a few seconds after
contact of said
compounds which has widely been exploited even for titrating
glucosaminoglycans (Harris et
al. J. Lab. Clin. Med., Vol. 74(1969), p. 527-535) can be overcome by addition
of solubilizers
like those mentioned, in particular a solubilizers selected from reaction
products of natural or
hydrogenated oils and ethylene glycol, for example Chremophor~EL, and
octylphenoxy-
poly(ethylenoxy)ethanol (tyloxapol) which is preferred.
Further excipients may be comprised in the compositions of the present
invention, which
may in particular function as a combined stabilizer/solubilizer. Such a
combined additional
stabilizer/soiubilizer is for example a cyclodextrin or a mixture of
cyclodextrins. A preferred
cyclodextrin is in particular selected from the group of a-cyclodextrin, (3-
cyclodextrin, y-cyclo-
dextrin, hydroxypropyl-~i-cyclodextrin, hydroxypropyl-y-cyclodextrin, dimethyl-
(3-cyclodextrin,
randomly methylated (3-cyclodextrin and dimethyl-y-cyclodextrin. The amount is
generally in
the range of from approximately 0.01 to approximately 90% by weight, more
preferably in the
range of from 0.1 - 20% by weight.
The ophthalmic compositions may comprise further pharmaceutically acceptable
excipients,
such as (6.) emulsifiers, (7.) wetting agents or (8.) fillers, such as, e.g.
the polyethylene
glycols (Fiedler, loc. cit., p. 2108, Handbook of Pharmaceutical Excipients,
loc. cit., p 392)
such as PEG 200, 300, 400 and 600, or Carbowax~ 1000, 1500, 4000, 6000 and
10000.
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Other excipients that may be used if desired are listed below but they are not
intended to
limit in any way the scope of the possible excipients. They are especially
(9.) complexing
agents, such as disodium-ethylenediamine tetraacetate, ethylenediamine
tetraacetic acid
(EDTA), (10.) antioxidants, such as ascorbic acid, acetylcysteine, cysteine,
sodium hydrogen
sulfite, butylated hydroxyanisole, butylated hydroxytoluene or alpha-
tocopherol acetate; (11.)
stabilizers, such thiourea, thiosorbitol, sodium dioctyl sulfosuccinate or
monothioglycerol; or
(12.) other excipients, such as, for example, lauric acid sorbitol ester,
triethanol amine oleate
or palmitic acid ester. Preferred exipients are complexing agents, such as
disodium-EDTA.
The amount and type of excipient added is in accordance with the particular
requirements
and is generally in the range of from about 0.0001 to about 90% by weight.
In another embodiment, the present invention provides for compositions further
comprising
(13.) an ophthalmic carrier. Such carriers are typically adapted for topical
administration, and
are for example
13.1 water,
13.2 mixtures of water and water-miscible solvents, such as C~- to C~-
alkanols,
13.3 vegetable oils or mineral oils comprising from 0.5 to 5% by weight
hydroxyethyl-
cellulose, ethyl oleate, carboxymethyl-cellulose, polyvinyl-pyrrolidone,
13.4 water-soluble polymers for ophthalmic uses, such as, for example,
cellulose
derivatives, such as methylcellulose, alkali metal salts of carboxy-
methylcellulose,
hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropyl-cellulose
and
hydroxypropylcellulose,
13.5 acrylates or methacrylates, such as salts of polyacrylic acid or ethyl
acrylate, poly-
acrylamides,
13.6 natural products, such as gelatin, alginates, pectins, tragacanth, karaya
gum, gellan
gum such as Gelrite~, xanthan gum, carrageenin, agar and acacia,
13.7 starch derivatives, such as starch acetate and hydroxypropyl starch,
13.3 synthetic products, such as polyvinyl alcohol, polyvinylpyrrolidone,
polyvinyl methyl
ether, polyethylene oxide, or
13.9 mixtures of those polymers.
Preferred carriers are water, cellulose derivatives, such as methylcellulose,
alkali metal salts
of carboxymethylcellulose, hydroxymethylce!lulose, hydroxyethylcellulose,
methylhydroxy-
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propylcellulose and hydroxypropylcellulose, or mixtures thereof. The
concentration of the
carrier is, for example, from 1 to 100 000 times the concentration of the
active ingredient.
It will be appreciated that although the excipients have been described above
by reference to
a particular function any particular excipient may have alternative or
multiple functions, e.g.
cyclodextrin or a mixture of cyclodextrins may act as e.g. stabilizer,
complexing agent and/or
solubilizer.
Applicants have found that compositions of the present invention with moderate
viscosity,
e.g. from 500 to 2000, e.g. about 1000 to 2000, mPa s at 20-25°C are
particularly
comfortable to apply. Upon instillation into the eye, the viscosity of the
compositions of the
present invention generally decreases, due to dilution with tear liquid.
Nevertheless, and
particularly surprising, the compositions of the present invention still have
a good or even
excellent retention after instillation into the eye.
If desired, the excipients of the compositions of the present invention and
the amounts
thereof may be chosen such, that the viscosity of the compositions increases
from storage
temperatures, e.g. 20°C, to the temperatures at the surface of the
eyes, e.g. 32-34°C, so
that the compositions are of relatively low viscosity when in the container,
for instance a drop
bottle, and have a viscosity in the range indicated above on the eye. This can
e. g. be
achieved by incorporation of thermo-reversible polymers.
The compositions of the present invention are stable, as indicated by
conventional tests, e.g.
under stressed conditions, such as 15h at 80°C or 1 month at
40°C. The compositions of the
present invention are stable over 2, even 3, years showing less than 5 %
degradation of the
ophthalmic drug at 20 to 30°C.
An expressly preferred embodiment of the compositions according to the instant
invention
comprises ketotifen or a pharmaceutically acceptable salt thereof as the
ophthalmic drug, in
particular, ketotifen hydrogen fumarate, preferably in a concentration from
0.005 to 0.2%,
even more preferably from 0.01 - 0.1 %, e.g. 0.01 to 0.05%, e.g. 0.01 to 0.04%
and in
particular from 0.02 - 0.04%, even more preferably about O.Q25%, by weight
based on the
total weight of the composition.
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These composition comprise the hyaluronic acid compound, preferably sodium
hya(uronate,
for instance in a concentration of 0.05 to 10%, preferably from 0.1 to 2%,
based on the total
weight of the composition.
A specific type of the aforementioned compositions furthermore comprises
benzalkonium
chloride as preservative, and a solubilizer, in particular selected from a
reaction product of
natural or hydrogenated oils and ethylene glycol and octylphenoxy-
poly(ethylenoxy)ethanol.
The ophthalmic compositions of the present invention may be prepared in
conventional
manner e.g. by mixing the ophthalmic drug and appropriate excipients.
The compositions of the present invention are preferably clear, preferably in
form of clear
solution or gel, e.g. clear gel.
Filling may be effected before or after sterilization of the resulting
mixture. Sterilization of the
composition of the present invention and the primary package can be effected
e.g. by
gamma irradiation, by ethylene oxide treatment, by electron beam, by
autoclaving, by
microwave treatment, by filtration through a sterile filter, or by steam
sterilization.
The compositions of the present invention may be packaged in conventional
manner. The
compositions of the present invention may be stored in single or multiple unit
dosage form,
e.g. closed bottles, tubes or other containers made from glass, plastic such
as e.g. poly-
ethylene, polyethylene terephthalate, or polypropylene, or metal or
combinations thereof. For
example bottles may contain about 1 to 5 ml of the compositions of the present
invention.
The container may be fitted with a dropper to facilitate administration.
The compositions of the present invention may be formulated in conventional
manner e.g. to
be particularly adapted for topical ophthalmic use. In so far as the
procedures for formulation
are not particularly described herein such formulation procedures may for
example be known
in the art, or analogous to those known in the art or to procedures described
herein.
Representative procedures are disclosed in for example, Remington's
Pharmaceutical
Sciences, 19th Ed., Mack Publ., Co., 1995, H. Sucker et al, Pharmazeutische
Technologie,
2nd Edition, Thieme, 1991, R: H. Mueller et al, Pharmazeutische Technologies
Moderne
Arzneimittelformen, 2nd Edition, Wissenschaftliche Verlagsgesellschaft,
Stuttgart, 1998, L.
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Lachman et al. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986,
and Halters
Handbuch der pharmazeutischen Praxis, 4th Ed. Vol. 7, (Springer Verlag, 1971 )
as well as
later editions, the contents of all of which are incorporated herein by
reference.
The excipients used may e.g. be those known in the art e.g in the Lexikon der
Hilfsstoffe fur
Pharmazie. Kosmetik and angrenzende Gebiete; and Handbook of Pharmaceutical
Excipients, references referred to above, or analogous to those known in the
art or new
excipients having analogous function to those described in the art or herein.
The compositions of the present invention are useful for the treatment of
ophthalmic
diseases/disorders, dependent on the drug comprised in the compositions for
the treatment
e.g. of inflammation, allergy, glaucoma, miosis, anaesthesia, viruses, fungi
or microorganism
as indicated e.g. in standard animal trials and clinical trials. The
compositions of the present
invention comprising ketotifen as drug are useful for the temporary prevention
of itching of
the eye due to allergic conjunctivitis, and in particular of seasonal allergic
conjunctivitis, and
may be used for the treatment and prevention of signs and symptoms of seasonal
allergic
conjunctivitis as also indicated in standard animal trials and clinical
trials.
One animal test comprises a modified Draize test on three albino rabbits
wherein the ocular
tolerability after a single dose instillation of 50 microlitres of
compositions of the present
invention on the ocular surface is shown for the 15 minutes after instillation
then after 1, 2
and 7 days. The tolerability was based on visual examination considering the
following
parameters: discomfort as judged by blinking or partial/complete closure of
the eye, duration
of discomfort, discharge, redness of conjunctiva (palpebral and bulbar
conjunctiva),
chemosis of conjunctiva (swelling), degree of opacity of cornea and area of
cornea involved,
and pathological modification of the iris.
A clinical trig! may be effected to test the effrcacy and tolerability of
about 30 to 40 microlitre
of compositions of the present invention containing 0.025% of drug
administered once a day
by instillation onto the ocular surface, e.g. to the inside lower lid, to
groups of, e.g. 10 to 25,
healthy volunteers, or patients suffering from ophthalmic disease/disorder to
be treated. The
trial lasts e.g. 8 days.
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The subjects are examined to determine the effect against conjunctivitis, e.g.
fast onset of
action and long duration of action and good tolerability, e.g. lack of
significant irritation or
reddening.
Additionally the bioavailability of the compositions of the present invention
in the above trials
as determined by absorption in the conjunctiva or surrounding tissues are
comparable with
commercially available forms which are administered twice a day.
The bioavailability of an addressed once-a-day ophthalmic composition was
assessed with
the pharmacokinetic assay described infra:
A fixed volume, e.g. 50 microliters, of the ophthalmic formulation was
instilled onto the upper
part of the conjunctiva of rabbits. Bulbar conjunctiva, cornea and sclera were
sampled after
either 5, 15, 30 minutes, or, 1, 8, 16, or 20 h. Samples were extracted for
drug determination
related to the wet weight amount of tissue. Content of drug was determined
using a liquid
chromatography linked to mass spectrography (LC-MS) validated method.
The exact amount of drug, for instance ketotifen, to be administered will
naturally depend on
a variety of factors, e.g. choice of salt, excipients, formulation properties,
and severity of the
condition. Conveniently, the composition of the present invention is
administered to the
cornea once a day, e.g. after breakfast. Preferably from about 25 to about 75
microlitres,
e.g. from about 50 to about 75 microlitres, is administered, e.g. using a
dropper.
The daily dose of the drug depends on the kind of drug and on the indication.
Ketotifen, for
example, is to be administered in doses from about 1 microgramslkg to about 5
micrograms/kg. For larger mammals, e.g. a 70 kg mammal such as a human, a dose
of from
about 100 to about 300 micrograms, is indicated.
Therefore, in a further aspect the present invention provides:
~ a composition as described above for use in the treatment of ophthalmic
diseases/disorders, for instance, treatment of inflammation, allergy,
glaucoma, miosis,
anaesthesia or infections caused by viruses, fungi or microorganisms,
~ a composition as described above comprising ketotifen for use in the
treatment of
allergic conjunctivitis and, in particular, of treatment and prevention of
seasonal allergic
conjunctivitis, or a condition treatable by ketotifen therapy,
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~ a method for treating ophthalmic diseases/disorders, for instance, treatment
of
inflammation, allergy, glaucoma, miosis, anaesthesia or infections caused by
viruses,
fungi or microorganism, including a topics! once-a-day administration of a
composition
as described above, thereby providing the therapeutic effect of the drug in
said
composition at the eye over about 24 hours,
~ a method for treating allergic conjunctivitis, in particular for treating
and preventing
seasonal allergic conjunctivitis or a condition treatable by ketotifen
therapy, including a
once-a-day administration of a composition as described above comprising
ketotifen to
the eye of a patient in need thereof,
~ the use of a composition as described above in the preparation of a
medicament for
the treatment of ophthalmic diseases/disorders, for instance, the treatment of
inflammation, allergy, glaucoma, miosis, anaesthesia or infections caused by
viruses,
fungi or microorganisms, and
~ the use of a composition as described above comprising ketotifen in the
preparation of
a medicament for the treatment of allergic conjunctivitis, in particular, for
treatment and
prevention of seasonal allergic conjunctivitis or a condition treatable by
ketotifen
therapy.
All percentages referred to herein are weight/weight except where otherwise
indicated.
Following is a description by way of example only of compositions of the
present invention.
Examples 1 - 4:
The excipients (amounts given in % weight/ weight as described in table below)
are added in
turn to the water and the mixture stirred.
Ex.1 Ex.2 Ex.3 Ex.4
ketotifen hydrogen fumarate0.03450.03450.03450.0345
sodium hyaluronate 0.10 0.50 1.00 0.10
D-sorbitol (2.2) 5,40 5.08 4.50 4.50
cetrimide (4.1 ) 0.005 0.005 0.005-
benzalkonium chloride - - - 0.01
(10%; 4.1)
tyloxapol (5.1 ) - - - 0.1
EDTA (9.) - - - 0.05
water (13.) ad ad ad ad
100 100 100 100
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The compositions of examples 1 to 4 are stable clear, colourless solutions.
They show a
good to moderate tolerability in rabbit eye and are effective against seasonal
allergic
conjunctivitis as administered as described above.
The compositions of Example 3 and 4 demonstrate an improvement of the
bioavailabi(ity in
conjunctiva, cornea and sclera as compared to Zaditen~ after single dose
application. The
improvement of ketotifen bioavai(ability (AUCo.os-aon [N~g~g'v]) after 50p1
single topical
application of the formulations according to Ex. 3 and 4 to the ocular surface
are shown in
the following table.
Example Conjunctiva Cornea Sclera
Tolerability
Ex.3 9.71 31.39 11.14 Moderate
Ex.4 8.70 25.14 13.47 Moderate
Zaditen~ 5.74 14.27 8.76 Good
(Comparison)
