U.S. patent application number 10/800992 was filed with the patent office on 2004-09-09 for preserved cyclodextrin-containing compositions.
This patent application is currently assigned to Allergan Sales, Inc.. Invention is credited to Beck, Gary J., Kerslake, Edward D.S., Olejnik, Orest.
Application Number | 20040175435 10/800992 |
Document ID | / |
Family ID | 22271266 |
Filed Date | 2004-09-09 |
United States Patent
Application |
20040175435 |
Kind Code |
A1 |
Beck, Gary J. ; et
al. |
September 9, 2004 |
Preserved cyclodextrin-containing compositions
Abstract
Compositions including a liquid medium, a cyclodextrin component
and a preservative component which has a reduced tendency to being
complexed with the cyclodextrin component. In one embodiment, the
preservative component is a chlorite component. Active components,
such as pharmaceutically active components or drugs, preferably are
included in the compositions.
Inventors: |
Beck, Gary J.; (Fullerton,
CA) ; Kerslake, Edward D.S.; (Charlestown, MA)
; Olejnik, Orest; (Coto De Caza, CA) |
Correspondence
Address: |
Frank J. Uxa
Stout, Uxa, Buyan & Mullins, LLP
Suite 300
4 Venture
Irvine
CA
92618
US
|
Assignee: |
Allergan Sales, Inc.
Irvine
CA
|
Family ID: |
22271266 |
Appl. No.: |
10/800992 |
Filed: |
March 15, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10800992 |
Mar 15, 2004 |
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09989295 |
Nov 20, 2001 |
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6723353 |
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09989295 |
Nov 20, 2001 |
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09388968 |
Sep 2, 1999 |
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6358935 |
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60098854 |
Sep 2, 1998 |
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Current U.S.
Class: |
424/661 ;
514/58 |
Current CPC
Class: |
A61K 47/40 20130101;
A61K 47/02 20130101; A61K 9/0048 20130101 |
Class at
Publication: |
424/661 ;
514/058 |
International
Class: |
A61K 031/724; A61K
033/14 |
Claims
What is claimed is:
1. A composition comprising: a liquid medium; a cyclodextrin
component in an amount in a range of about 0.1% to about 30% (w/v);
and a chlorite component in an effective preserving amount.
2. The composition of claim 1 wherein the liquid medium is an
aqueous liquid medium.
3. The composition of claim 1 wherein the cyclodextrin component is
selected from the group consisting of .beta.-cyclodextrin,
derivatives of .beta.-cyclodextrin and mixtures thereof.
4. The composition of claim 1 wherein the chlorite component is
present in an amount of about 500 ppm (w/v) or less.
5. The composition of claim 1 wherein the chlorite component is
present in an amount in a range of about 10 ppm(w/v) to about 200
ppm(w/v).
6. The composition of claim 1 wherein the chlorite component is
stabilized chlorine dioxide.
7. The composition of claim 1 which further comprises an active
component in an amount effective in providing a desired effect to a
human or an animal after the composition is administered to the
human or animal.
8. The composition of claim 7 wherein the active component is a
pharmaceutically active component effective in providing a desired
therapeutic effect to the human or animal after the composition is
administered to the human or animal.
9. A composition comprising: a liquid medium; a cyclodextrin
component in an amount in a range of about 0.1% to about 30% (w/v);
and a preservative component in an effective preserving amount, the
preservative component having a greater preservative efficacy in
the composition relative to an identical amount of benzalkonium
chloride.
10. The composition of claim 9 wherein the preservative component
forms a complex with the cyclodextrin component to a lesser degree
than benzalkonium chloride.
11. The composition of claim 9 wherein the liquid medium is an
aqueous liquid medium, and the preservative component is present in
an amount of less than about 0.8% (w/v).
12. The composition of claim 9 wherein the preservative component
is present in an amount in a range of about 10 ppm(w/v) to about
200 ppm(w/v).
13. The composition of claim 10 wherein the cyclodextrin component
is selected from the group consisting of .beta.-cyclodextrin,
derivatives of .beta.-cyclodextrin and mixtures thereof.
14. The composition of claim 9 wherein the preservative component
is selected from the group consisting of chlorite components,
sorbic acid components and mixtures thereof.
15. The composition of claim 9 wherein the preservative component
is stabilized chlorine dioxide.
16. The composition of claim 9 wherein the preservative component
is selected from the group consisting of sorbic acid, sorbates and
mixtures thereof.
17. The composition of claim 9 which further comprises an active
component in an amount effective in providing a desired effect to a
human or an animal after the composition is administered to the
human or animal.
18. The composition of claim 17 wherein the active component is a
pharmaceutically active component effective in providing a desired
therapeutic effect to the human or animal after the composition is
administered to the human or animal.
19. The composition of claim 9 which is substantially free of
inclusion complexes of the cyclodextrin component and the
preservative component.
20. A composition comprising: a liquid medium; an active component
in an amount effective in providing a desired effect to a human or
an animal after the composition is administered to the human or
animal; a cyclodextrin component in an amount effective to increase
the apparent solubility of the active component in the liquid
medium or to enhance the stability of the active component in the
composition or to reduce unwanted side effects of the active
component; and a preservative component in an effective preserving
amount, the preservative component having greater preservative
efficacy in the composition relative to an identical amount of
benzalkonium chloride.
21. The composition of claim 20 wherein the liquid medium is an
aqueous liquid medium.
22. The composition of claim 20 wherein the active component is a
pharmaceutically active component effective in providing a desired
therapeutic effect to the human or animal after the composition is
administered to the human or animal.
23. The composition of claim 21 wherein the active component is a
pharmaceutically active component effective in providing a desired
therapeutic effect to the human or animal after the composition is
administered to the human or animal.
24. The composition of claim 20 wherein the cyclodextrin component
is selected from the group consisting of .beta.-cyclodextrin,
derivatives of .beta.-cyclodextrin and mixtures thereof.
25. The composition of claim 20 wherein the cyclodextrin component
is present in an amount in a range of about 0.1% to about 30%
(w/v).
26. The composition of claim 20 wherein the preservative component
forms a complex with the cyclodextrin component to a lesser degree
than does benzalkonium chloride.
27. The composition of claim 20 wherein the preservative component
is present in an amount of about 1% (w/v) or less.
28. The composition of claim 20 wherein the preservative component
is present in an amount in a range of about 10 ppm(w/v) to about
200 ppm(w/v).
29. The composition of claim 20 wherein the preservative component
is selected from the group consisting of chlorite components,
sorbic acid components and mixtures thereof.
30. The composition of claim 29 wherein the preservative component
is stabilized chlorine dioxide.
Description
RELATED APPLICATION
[0001] This application claims benefit of Provisional Application
Serial No. 60/098,854 filed Sep. 2, 1998.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to preserved
cyclodextrin-containing compositions. More particularly, the
invention relates to cyclodextrin-containing compositions, for
example, such compositions containing one or more pharmaceutically
active components, including preservatives which have substantial
preserving efficacy in the presence of cyclodextrin components.
[0003] Cyclodextrins are widely known in the literature to increase
the solubility of poorly water soluble pharmaceuticals or drugs
and/or enhance pharmaceutical/drug stability and/or reduce unwanted
side effects of pharmaceuticals/drugs. For example, steroids, which
are hydrophobic, often exhibit an increase in water solubility of
one order of magnitude or more in the presence of cyclodextrins.
However, one substantial problem with pharmaceutical compositions
including cyclodextrins, particularly such compositions in
multi-dose formats, has to do with preserving such compositions.
Typical preservatives are relatively ineffective at normal
concentrations in such compositions, that is the compositions
including such preservatives are unable to meet or pass standard
preservative efficacy tests. It is believed that the preservative
becomes complexed with the cyclodextrin and is rendered ineffective
or has reduced effectiveness as a preservative.
[0004] It would be advantageous to provide cyclodextrin-containing
compositions which are effectively preserved.
SUMMARY OF THE INVENTION
[0005] New cyclodextrin-containing compositions have been
discovered. Such compositions include preservatives which are
effective and efficacious in the presence of cyclodextrins.
Preferably, the preservatives are present in the compositions in
amounts to provide acceptable preservative efficacy and, in
addition, are sufficiently innocuous or non-toxic so that the
compositions can be administered to humans or animals to obtain
desired therapeutic effects without significant detriment resulting
from the presence of the preservatives. For example, the present
compositions may include a pharmaceutical effective in providing a
therapeutic effect when administered to the eyes of a human or
animal. The preservative employed is preferably ophthalmically
acceptable at the concentration employed so that the human or
animal is effectively treated without significant harm caused by
the presence of the preservative.
[0006] In short, the present compositions effectively take
advantage of cyclodextrin components, e.g., in increasing the
apparent water solubility of pharmaceuticals, and are effectively
preserved and preferably substantially non-toxic in use.
[0007] In one broad aspect of the present invention, compositions
are provided which comprise a liquid medium, a cyclodextrin
component, for example, in an amount in the range of about 0.1% to
about 30% (w/v), and a preservative component in an effective
preserving amount, preferably of less than about 1% (w/v) or about
0.8% (w/v) and may be in the range of about 10 ppm(w/v) or less to
about 200 ppm(w/v). In one embodiment, the preservative component
has sufficient preservative efficacy so that the composition
including such preservative component passes one or more standard
preservative efficacy tests, such as in the United States
Preservative Efficacy Test (USPET), the European Preservative
Efficacy Test-A (EP-A), the European Preservative Efficacy Test-B
(EP-B), and the like standard tests.
[0008] Preferably, the preservative component has an increased or
greater preservative efficacy in the present composition relative
to an identical amount (w/v) of benzalkonium chloride. Benzalkonium
chloride, which is a preservative that is often used in
pharmaceutical compositions, is relatively ineffective at typical
concentrations in compositions including cyclodextrin component. It
is believed that the benzalkonium chloride complexes with the
cyclodextrin component. This complex renders the benzalkonium
chloride antimicrobially ineffective. Thus, benzalkonium chloride
has a reduced preservative efficacy in the presence of cyclodextrin
component. More preferably, the present preservative component
forms a complex with the cyclodextrin component, if at all, to a
lesser extent than does benzalkonium chloride.
[0009] The present compositions preferably are substantially free
of inclusion complexes of the cyclodextrin component and the
preservative component.
[0010] Using a preservative component in accordance with the
present invention which is substantially not affected by the
cyclodextrin component allows the preservative component to be more
efficacious as a preservative. Alternately, reduced amounts of the
preservative component can be used to achieve acceptable
preservative results. Such reduced amounts of preservative
components reduce the toxicity or sensitivity for the composition
as it is being administered to a human or animal.
[0011] Any suitable preservative component which functions as
described herein is included within the scope of the present
invention. The preservative efficacy tests identified herein are
standard tests which can be easily and routinely conducted on any
prospective preservative component to determine if such
preservative component meets the criteria. Of course, the present
preservative components should have no substantial detrimental
effect on the composition or the active component or components of
the composition or the use of the composition or the human or
animal to whom the composition is administered. Tests to determine
whether a prospective preservative component meets these criteria
are well known and can be routinely conducted. In other words, one
of ordinary skill in the art can determine, without undue
experimentation, whether or not any prospective preservative
component is within the scope of the preservative components of the
present invention.
[0012] In one particularly useful embodiment, the present
preservative component is selected from chlorite components, sorbic
acid components and mixtures thereof present in an effective
preserving amount. More preferably, the preservative component is
selected from stabilized chlorine dioxide, alkali metal chlorites,
sorbic acid, alkali metal sorbates and mixtures thereof. Chlorite
components are very effective in the present compositions since
they achieve preservative effectiveness at a relatively reduced
concentration. Both the chlorite components and sorbic acid
components are effective preservatives in the presence of
cyclodextrin. Without wishing to limit the invention to any
particular theory of operation, it is believed that the chlorite
components and the sorbic acid components are substantially free in
the presence of the cyclodextrin component or are substantially not
complexed with the chlorodextrin component.
[0013] In another broad aspect of the present invention,
compositions are provided which comprise a liquid medium, an active
component, a cyclodextrin component and a preservative component.
The active component is present in an amount effective in providing
a desired effect to a human or an animal after the composition is
administered to the human or animal. The cyclodextrin component
preferably is present in an amount effective to increase the
apparent solubility of the active component in the liquid medium
and/or enhance the stability of the active component in the
composition and/or reduce unwanted side effects of the acting
component in the composition. The preservative component is present
in an effective preserving amount, preferably less than about 1%
(w/v) or about 0.8% (w/v) and may be in the range of about 10
ppm(w/v) or less to about 200 ppm(w/v). The preservative component
is as identified elsewhere herein.
[0014] The present compositions which include active components,
preferably pharmaceutically active components, as described herein,
are particularly useful in multi-dose formats in which preservative
efficacy is particularly important. Thus, such compositions obtain
the advantages of cyclodextrin components, for example, in
enhancing the solubility of the active components and, in addition,
include effective preservative components, preferably at
concentrations which reduce the risk of causing any substantial or
significant harm or detriment to the humans or animals to whom the
compositions are administered as a result of the presence of the
preservative components.
[0015] Any feature or combination of features described herein are
included within the scope of the present invention provided that
the features included in any such combination are not mutually
inconsistent.
[0016] Additional advantages and aspects of the present invention
are apparent in the following detailed description and claims.
DETAILED DESCRIPTION
[0017] The present compositions include liquid media, cyclodextrin
components, and preservative components. Preferably, the present
compositions further include active components, more preferably
pharmaceutically active components. The present compositions can
have the characteristics of simple liquid, for example, aqueous
liquid, solutions.
[0018] Any suitable cyclodextrin component may be employed in
accordance with the present invention. The useful cyclodextrin
components include, but are not limited to, those materials which
are effective in increasing the apparent solubility, preferably
water solubility, of poorly soluble active components and/or
enhance the stability of the active components and/or reduce
unwanted side effects of the active components. Examples of useful
cyclodextrin components include, but are not limited to:
.alpha.-cyclodextrin, derivatives of .alpha.-cyclodextrin,
.beta.-cyclodextrin, derivatives of .beta.-cyclodextrin,
.gamma.-cyclodextrin, derivatives of .gamma.-cyclodextrin,
carboxymethyl-.beta.-cyclodextrin,
carboxymethyl-ethyl-.beta.-cyclodextri- n,
diethyl-.beta.-cyclodextrin, dimethyl-.beta.-cyclodextrin,
methyl-.beta.-cyclodextrin, random methyl-.beta.-cyclodextrin,
glucosyl-.beta.-cyclodextrin, maltosyl-.beta.-cyclodextrin,
hydroxyethyl-.beta.-cyclodextrin,
hydroxypropyl-.beta.-cyclodextrin,
sulfobutylether-.beta.-cyclodextrin, and the like and mixtures
thereof. As used herein, the term "derivatives" as it relates to a
cyclodextrin means any substituted or otherwise modified compound
which has the characteristic chemical structure of a cyclodextrin
sufficiently to function as a cyclodextrin component, for example,
to enhance the solubility and/or stability of active components
and/or reduce unwanted side effects of the active components and/or
to form inclusive complexes with active components, as described
herein.
[0019] The specific cyclodextrin component selected should have
properties acceptable for the desired application. The present
compositions, and therefore the cyclodextrin component, may be
applied topically and/or systemically. Topical application is
preferred. In certain situations, the cyclodextrin component should
have or exhibit reduced toxicity, particularly if the composition
is to be exposed to sensitive body tissue, for example, eye tissue,
etc. Very useful cyclodextrin components include
.beta.-cyclodextrin, derivatives of .beta.-cyclodextrin and
mixtures thereof. Particularly useful cyclodextrin components
include sulfobutylether .beta.-cyclodextrin, hydroxypropyl
.beta.-cyclodextrin and mixtures thereof. Sulfobutylether
.beta.-cyclodextrin is especially useful, for example, because of
its substantially reduced toxicity.
[0020] The amount of cyclodextrin component in the present
compositions is not of critical importance. Such amount should be
effective to perform the desired function or functions in the
present composition and/or after administration to the human or
animal. The amount of cyclodextrin component preferably is
sufficient to complex at least in major amount, and more preferably
substantially all, of the active component in the present
composition. In one useful embodiment, the amount of cyclodextrin
component in the present composition is in the range of about 0.1
to about 30% (w/v) or more of the composition.
[0021] The present preservative components are selected so as to be
effective and efficacious as preservatives in the present
compositions, that is in the presence of cyclodextrin components,
and preferably have reduced toxicity and more preferably
substantially no toxicity when the compositions are administered to
a human or animal.
[0022] As stated above, preservatives which are commonly used in
pharmaceutical compositions are often less effective when used in
the presence of cyclodextrins. In certain instances, this reduced
preservative efficacy can be compensated for by using increased
amounts of the preservative. However, where sensitive or delicate
body tissue is involved, this approach may not be available since
the preservative itself may cause some adverse reaction or
sensitivity in the human or animal, to whom the composition is
administered.
[0023] Preferably, the present preservative components are
effective in concentrations of less than about 1% (w/v) or about
0.8% (w/v) and may be 500 ppm (w/v) or less, for example, in the
range of about 10 ppm(w/v) or less to about 200 ppm(w/v). In one
embodiment, the present preservative components have greater
preservative efficacy in the composition relative to an identical
amount (w/v) of benzalkonium chloride in the presence of the
cyclodextrin component. Testing to determine comparative
preservative efficacy is well known and can be routinely conducted.
Preservative components in accordance with the present invention
preferably include, but are not limited to, those which form
complexes with the cyclodextrin component to a lesser extent than
does benzalkonium chloride.
[0024] Very useful examples of the present preservative components
include, but are not limited to, chlorite components, sorbic acid
components and mixtures thereof.
[0025] Specific examples of chlorite components useful as
preservatives in accordance with the present invention include
stabilized chlorine dioxide (SCD), metal chlorites, such as alkali
metal and alkaline earth metal chlorites, and the like and mixtures
therefor. Technical grade (or USP grade) sodium chlorite is a very
useful preservative component. The exact chemical composition of
many chlorite components, for example, SCD, is not completely
understood. The manufacture or production of certain chlorite
components is described in McNicholas U.S. Pat. No. 3,278,447,
which is incorporated in its entirety herein by reference. Specific
examples of useful SCD products include that sold under the
trademark Dura Klor by Rio Linda Chemical Company, Inc., and that
sold under the trademark Anthium Dioxide by International Dioxide,
Inc. An especially useful SCD is a product sold under the trademark
Purogene.RTM. by Bio-Cide International, Inc.
[0026] Specific examples of sorbic acid components useful as
preservatives in accordance with the present invention include
sorbic acid itself, as well as pharmaceutically and/or
ophthalmically acceptable sorbic acid derivatives and mixture
thereof. Useful sorbic acid components include, but are not limited
to, metal sorbates, such as alkali metal and alkaline earth metal
sorbates, and the like and mixtures thereof. If a sorbic acid
component is employed as a preservative in accordance with the
present invention, the composition advantageously has a pH of less
than about 7, for example in the range of about 3 or about 4 to
less than 7. Such pH conditions increase the antimicrobial
effectiveness of the sorbic acid component so that somewhat reduced
concentrations of the sorbic acid component may be effectively
employed. Of course, it is not essential that the composition have
a pH of less than 7.
[0027] The preservative component may be included in the
composition at a predetermined concentration, e.g., to provide an
effective preserving amount of preservative component in the
composition. For example, if a chlorite component is employed as a
preservative in accordance with the present invention, the
concentration of the chlorite component preferably is less than
about 500 ppm (w/v), and more preferably is in the range of about
10 ppm (w/v) or less to about 200 ppm (w/v). If a sorbic acid
component is employed as a preservative, the concentration of the
sorbic acid component preferably is in the range of less than about
1% (w/v) or about 0.8% (w/v), and more preferably is in a range of
about 0.05% (w/v) or less to about 0.8% (w/v).
[0028] The presently useful active components preferably are chosen
to benefit from the presence of the cyclodextrin components. In
general, the active components are provided with increased apparent
solubility, preferably increased apparent water solubility, by the
presence of the cyclodextrin components. Without wishing to limit
the invention to any particular theory of operation, it is believed
that the active components form inclusion or clathrate complexes
with the cyclodextrin components.
[0029] Examples of the pharmaceutically active component which may
be benefitted by the presence of cyclodextrin components in the
present invention include, but are not limited to, diphenyl
hydantoin, adiphenine, allobarbital, aminobenzoic acid,
amobarbital, ampicillin, anethole, aspirin, azopropazone, azulene
barbituric acid, beclomethasone, beciomethasone dipropronate,
bencyclane, benzaldehyde, benzocaine, benzodiazepines,
benzodiazepines, benzothiazide, betamethasone, betamethasone
17-valerate, bromobenzoic acid bromoisovalerylurea,
butyl-p-aminobenzoate, chloralhydrate, chlorambucil,
chloramphenicol, chlorobenzoic acid, chlorpromazine, cinnamic acid,
clofibrate, coenzyme A, cortisone, cortisone acetate,
cyclobarbital, cyclohexyl anthranilate, deoxycholic acid,
dexamethasone, dexamethasone acetate, diazepam, digitoxin, digoxin,
estradiol, flufenamic acid, fluocinolone acetonide, 5-fluorouracil,
flurbiprogen, griseofulvin, guaiazulene, hydrocortisone,
hydrocortisone acetate, ibuprofen, indican, indomethacin, iodine,
ketoprofen, lankacidin-group antibiotics, mefenamic acid,
menadione, mephobarbital, methbarbital, methicillin, metronidazole,
mitomycin, nitrazepam, nitroglycerin, nitrosureas, paramethasone,
penicillin, pentobarbital, phenobarbital, phenobarbitone,
phenyl-butyric acid, phenyl-valeric acid, phenytoin, prednisolone,
prednisolone acetate, prednisone, progesterone, propylparaben,
proscillaridin, prostaglandin A series, prostaglandin B series,
prostaglandin E series, prostaglandin F series, quinoline
anti-microbials reserpine, spironolactone, sulfacetamide sodium,
sulfonamide, androgens, including but not limited to testosterone,
thalidomide, thiamine dilaurylsulphate, thiamphenicolpalmitate,
thiopental, triamcinolone, vitamin A, vitamin D3, vitamin E,
vitamin K3, and warfarin.
[0030] The complexes may be prepared by any method known in the art
for the preparation of complexes of cyclodextrin components. For
example, the active component and cyclodextrin component may be
dissolved in water or an organic solvent (either miscible or
immiscible with water). Convenient solvents include for example
diethylether, tetrahydrofuran, dioxane, acetone, dimethylsulfoxide,
dimethylformamide and lower aliphatic alcohols. Preferably the
active component is dissolved in either water or a mixture of water
and a water-miscible solvent such as methanol or ethanol. The
active component may also be suspended in water.
[0031] After equilibrium is reached, the complex may be isolated by
any suitable technique for example, lyophilization, evaporation of
the solvent, precipitation, low temperature crystallization, or
spray-drying. Cyclodextrin inclusion complexes may also be produced
by physically grinding or kneading the cyclodextrin component and
the active component with or without a small amount of solvent. The
ratio of cyclodextrin component to active component used to prepare
the complexes may be any convenient ratio but the cyclodextrin
component preferably is used in a molar excess.
[0032] Benefits may be obtained by having the molar ratio of
cyclodextrin component to active component in the range of about
10:1 to about 1:1 or less, preferably about 5:1 or about 3:1 or
about 2:1 to about 1:1 or less and by using the methods and ratios
described above. Complexes are conveniently obtained containing up
to 20% w/w of the active component. However, in view of the low
doses of the drug normally administered and the difficulty of
preparing homogenous mixtures of active ingredient and excipients
it may be desirable to prepare the complex with an excess of the
cyclodextrin component present, for example, complexes containing
in the order of about 0.001% to about 10% by weight of the active
component.
[0033] The liquid media useful in the present invention are
selected to have no substantial detrimental effect on the present
compositions, on the use of the compositions or on the human or
animal to whom the compositions are administered. The liquid media
are preferably aqueous-ingredients which are conventionally
employed in compositions of the same general type.
[0034] The present compositions in the form of aqueous suspensions
may include excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example,
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gun tragacanth and gun acacia; dispersing or
wetting agents may be a naturally occurring phosphatide, for
example, lecithin, or condensation products of ethylene oxide with
long chain aliphatic alcohols, for example,
heptadecaethyleneoxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol mono-oleate, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and hexitol anhydrides, for example, polyoxyethylene sorbitan
mono-oleate, and the like and mixtures thereof. Such aqueous
suspensions may also contain one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose, saccharin, and the like and mixtures thereof.
[0035] The present compositions in the form of oily suspensions may
be formulated in a vegetable oil, for example, olive oil, sesame
oil or coconut oil, or in a mineral oil such as liquid paraffin.
Such suspensions may contain a thickening agent, for example
beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as
those set forth above, and flavoring agents may be added to provide
a palatable oral preparation.
[0036] The present compositions may also be in the form of
oil-in-water emulsions. The oily phase may be a vegetable oil, for
example, olive oil or arachis oil, or a mineral oil, for example,
liquid paraffin, and the like and mixtures thereof. Suitable
emulsifying agents may be naturally-occurring gums, for example,
gum acacia or gun tragacanth, naturally-occurring phosphatides, for
example, soya bean lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example, sorbitan
mono-oleate, and condensation products of the said partial esters
with ethylene oxide, for example, polyoxyethylene sorbitan
mono-oleate. The emulsions may also contain sweetening and
flavoring agents.
[0037] The present compositions in the form of syrups and elixirs
may be formulated with sweetening agents, for example, as described
elsewhere herein. Such formulations may also contain a demulcent,
and flavoring and coloring agents.
[0038] The specific dose level for any particular human or animal
depends upon a variety of factors including the activity of the
active component employed, the age, body weight, general health,
sex, diet, time of administration, route of administration, rate of
excretion, drug combination and the severity of the particular
condition undergoing therapy.
[0039] The active component in the present compositions may be
administered at dosage levels and dosage intervals required to
achieve the desired therapeutic effect normally associated with the
active component and the disease or condition state in absence of
the cyclodextrin component.
[0040] The following non-limiting examples illustrate certain
aspects of the present invention.
EXAMPLES 1 AND 2
[0041] Two (2) aqueous compositions were prepared by blending
together the following components:
1 Components Composition 1 Composition 2 Sodium chloride 0.62%
(w/v) 0.62% (w/v) Potassium chloride 0.14% (w/v) 0.14% (w/v)
Calcium chloride 0.02% (w/v) 0.02% (w/v) (dihydrate) Magnesium
chloride 0.006% (w/v) 0.006% (w/v) (hexahydrate) Sodium
carboxymethyl- 0.5% (w/v) 0.5% (w/v) cellulose Boric acid 0.2%
(w/v) 0.2% (w/v) Sodium borate 0.14% (w/v) 0.14% (w/v)
(decahydrate) Brimodine tartarate.sup.(1) 0.2% (w/v) 0.2% (w/v)
Stabilized chlorine 50 ppm (w/v) 50 ppm (w/v) dioxide.sup.(2)
Sulfobutylether .beta. -- 1% (w/v) cyclodextrin Water, USP Q.S. to
volume Q.S. to volume pH 7.4 7.4 .sup.(1)Tartarate of
5-bromo-6-(2-imidozolin-2-ylamino) quinoxaline .sup.(2)Product sold
by Bio-Cide International Inc., under the trademark PUROGENE
.RTM.
[0042] Each of these compositions was tested for preservative
efficacy in accordance with (1) United States Preservative Efficacy
Test (USPET) test criteria; (2) European Preservative Efficacy-A
(EP-A) test criteria; and (3) European Preservative-B (EP-B) test
criteria. These test criteria are well known and conventionally
utilized to determine the preservative efficacy of any given
preservative or preserved composition.
[0043] The test results for each of these compositions is set forth
in the following table.
2 Composition USPET EP-A EP-B 1 Pass Fail Fail 2 Pass Fail Pass
[0044] These test results show that Composition 1 passes the USPET
test criteria, and fails the EP-A and EP-B test criteria. The EP-B
criteria were failed marginally by Composition 1 against C.
Albicans. It is believed that composition 1 may pass the EP-B test
criteria upon retest.
[0045] Composition 2 passes both the USPET and the EP-B test
criteria and fails only the more strict EP-A test criteria.
[0046] These results demonstrate that the presence of a
cyclodextrin component (Composition 2) does not have any
detrimental effect on the preservative efficacy of stabilized
chlorine dioxide, a chlorite component. These results indicate that
the stabilized chlorine dioxide remains free and effective as a
preservative in Composition 2, rather than being complexed by the
cyclodextrin component and thus inhibited in providing preservative
efficacy.
[0047] Composition 2, in accordance with the present invention, is
ophthalmically acceptable and effective in providing therapeutic
effects resulting from the presence of the brimonidine tartarate.
The presence of the cyclodextrin component in Composition 2
enhances the effective or apparent water solubility of the
brimonidine tartarate, substantially without detrimentally causing
increased toxicity, for example, when administered to a patient in
need of the therapeutic effects provided by brimonidine
tartarate.
EXAMPLES 3 TO 9 (COMPARATIVE)
[0048] A series of seven (7) aqueous compositions were prepared by
blending together the following components:
3 Compo- Benzalkonium Hydroxybutyl sition Chloride .beta.
cyclodextrin Water pH 3 50 ppm (w/v) 20% (w/v) Q.S. to vol. 8.0 4
100 ppm (w/v) 20% (w/v) Q.S. to vol. 8.0 5 50 ppm (w/v) 10% (w/v)
Q.S to vol. 7.2 6 50 ppm (w/v) 10% (w/v) Q.S. to vol. 8.0 7 50 ppm
(w/v) 10% (w/v) Q.S. to vol. 8.0 8 50 ppm (w/v) -- Q.S. to vol. 7.2
9 50 ppm (w/v) -- Q.S. to vol. 8.0
[0049] Each of these aqueous compositions was tested for
preservative efficacy in accordance with the USPET test criteria.
Results of these tests are summarized in the following table.
4 USPET Composition Results 3 Fail 4 Fail 5 Fail 6 Fail 7 Fail 8
Pass 9 Pass
[0050] These test results indicate that benzalkonium chloride is
ineffective as a preservative when used in compositions including
cyclodextrin components. Without wishing to limit the invention to
any particular theory of operation, it is believed that the
cyclodextrin component complexes the benzalkonium chloride
sufficiently to inhibit or even prevent the benzalkonium chloride
from being an effective preservative.
[0051] These results are in substantial contrast to the results set
forth in Examples 1 and 2 in which stabilized chlorine dioxide is
shown to be an effective preservative with or without a
cyclodextrin component.
EXAMPLES 10 TO 21
[0052] A series of twelve (12) aqueous compositions were prepared
by blending together the following components:
5 Composition .sup.(1) 10 11 12 13 14 15 Prednisolone -- -- -- --
0.1 0.1 Acetate, w/v % Sulfobutylether -- -- 8.0 8.0 8.0 8.0
.beta.-cyclodextrin, w/v % Benzalkonium 0.15 .0075 0.15 .0075 0.15
.0075 chloride, w/v % Stabilized chlorine -- -- -- -- -- --
dioxide.sup.(2), w/v % Composition .sup.(1) 16 17 18 19 20 21
Prednisolone -- -- -- -- 0.1 0.1 Acetate, w/v % Sulfobutylether --
-- 8.0 8.0 8.0 8.0 .beta.-cyclodextrin, w/v % Benzalkonium -- -- --
-- -- -- chloride, w/v % Stabilized chlorine 0.15 .0075 0.15 .0075
0.15 .0075 dioxide.sup.(2), w/v % .sup.(1) Each of the compositions
includes USP water in a quantity sufficient to equal 100% w/v.
.sup.(2)Product sold by Bio-Cide International Inc., under the
trademark PUROGENE .RTM.
[0053] Each of these compositions was tested for preservative
efficacy in accordance with (1) United States Preservative Efficacy
Test (USPET) test criteria; (2) European Preservative Efficacy-A
(EP-A) test criteria; and (3) European Preservative-B (EP-B) test
criteria.
[0054] The test results for each of these compositions is set forth
in the following table.
6 Composition USPET EP-A EP-B 10 Pass Pass Pass 11 Pass Pass Pass
12 Fail Fail Fail 13 Fail Fail Fail 14 Fail Fail Fail 15 Fail Fail
Fail 16 Pass Fail Fail 17 Pass Fail Fail 18 Pass Fail Fail 19 Pass
Fail Fail 20 Pass Fail Fail 21 Pass Fail Fail
[0055] Compositions 10 and 11, which include only benzalkonium
chloride, pass all of the preservative efficacy criteria. On the
other hand, compositions 12 to 15, which include benzalkonium
chloride and the cyclodextrin fail all preservative efficacy
criteria. The addition of prednisolone acetate does not help to
increase the antimicrobial activity, except for the activity
against S. Aureus. All of the solutions, that is Compositions 16 to
21, containing stabilized chlorine dioxide pass the USPET.
Compositions containing only stabilized chlorine dioxide, that is
Compositions 16 and 17, fail the EP-A and EP-B tests on fungi only.
When the cyclodextrin is added to the compositions including
stabilized chlorine dioxide, Compositions 18 to 21, the
antimicrobial activity is decreased. Compositions containing
stabilized chlorine dioxide, the cyclodextrin, and prednisolone
acetate, Compositions 20 and 21, fail the EP-A and EP-B criteria
for the fungi only. The compositions including stabilized chlorine
dioxide only fail the EP-B test only for A. Niger.
[0056] Although the presence of the cyclodextrin component does
result in a decrease in the antimicrobial activity of the
compositions, the combination of the cyclodextrin component and
stabilized chlorine dioxide, a chlorite component, passes the
preservative efficacy tests passed by compositions including only
stabilized chlorine dioxide. These results indicate that a
substantial portion of the stabilized chlorine dioxide remains free
or not complexed by the cyclodextrin and effective as a
preservative rather than being complexed by the cyclodextrin
component and thus inhibited in providing preservative
efficacy.
EXAMPLES 22 TO 29
[0057] A series of eight (8) aqueous compositions were prepared by
blending together the following components:
7 Composition.sup.(1) 22 23 24 25 Prednisolone 0.1 0.1 0.1 0.1
Acetate, w/v % Sulfobutylether 8.0 8.0 8.0 8.0 .beta.-cyclodextrin,
w/v % Benzalkonium 0.15 0.15 0.15 0.15 chloride, w/v % Stabilized
chlorine -- -- -- -- dioxide.sup.(2), w/v % Potassium .05 .5 -- --
sorbate, w/v % Glycerin, w/v % -- -- 2.0 -- Propyl glycol, w/v % --
-- -- 2.0 Composition.sup.(1) 26 27 28 29 Prednisolone 0.1 0.1 0.1
0.1 Acetate, w/v % Sulfobutylether 8.0 8.0 8.0 8.0
.beta.-cyclodextrin, w/v % Benzalkonium -- -- -- -- chloride, w/v %
Stabilized chlorine .0075 .0075 .0075 .0075 dioxide.sup.(2), w/v %
Potassium .05 .5 -- -- sorbate, w/v % Glycerin, w/v % -- -- 2.0 --
Propyl glycol, w/v % -- -- -- 2.0 .sup.(1)Each of the compositions
includes USP water in a quantity sufficient to equal 100% w/v.
.sup.(2)Product sold by Bio-Cide International Inc., under the
trademark PUROGENE .RTM.
[0058] Each of these compositions was tested for preservative
efficacy in accordance with (1) United States Preservative Efficacy
Test (USPET) test criteria; (2) European Preservative Efficacy-A
(EP-A) test criteria; and (3) European Preservative-B (EP-B) test
criteria.
[0059] The test results for each of these compositions is set forth
in the following table.
8 Composition USPET EP-A EP-B 22 Fail Fail Fail 23 Fail Fail Fail
24 Fail Fail Fail 25 Fail Fail Fail 26 Pass Fail Fail 27 Pass Fail
Pass 28 Pass Fail Fail 29 Pass Fail Fail
[0060] These results indicate that all benzylkonium
chloride-containing compositions fail all of the USPET, EP-A and
EP-B criteria.
[0061] With regard to compositions including stabilized chlorine
dioxide, Compositions 26, 28 and 29 fail the EP-A and EP-B criteria
because of either or both C. albicans and A. niger or just a niger.
Each of these compositions pass the USPET criteria. Composition 27
shows interesting results. This composition fails the EP-A criteria
for C. albicans and A. niger, but passes both USPET and EP-B
criteria. Upon repeat of the test, the composition passes the EP-A
criteria.
[0062] The potassium sorbate even has an effect on the benzalkonium
chloride-containing composition, that is Composition 23.
Composition 23 still fails the USPET criteria, but only because of
E. coli and A. niger. Other samples fail because of P. aerogenosa.
Thus, the potassium sorbate is providing enhanced preservative
efficacy in compositions including benzalkonium chloride.
EXAMPLES 30 TO 33
[0063] A series of four (4) aqueous compositions were prepared by
blending together the following components:
9 Composition.sup.(1) 30 31 32 33 Prednisolone -- 0.1 0.1 0.1
Acetate, w/v % Sulfobutylether -- 8.0 8.0 8.0 .beta.-cyclodextrin,
w/v % Stabilized chlorine .0075 -- -- -- dioxide.sup.(2), w/v %
Potassium -- 0.5 0.5 0.5 sorbate, w/v % PH 7.4 6.5 5.5 4.5
.sup.(1)Each of the compositions includes USP water in a quantity
sufficient to equal 100% w/v. .sup.(2)Product sold by Bio-Cide
International Inc., under the trademark PUROGENE .RTM.
[0064] Each of these compositions was tested for preservative
efficacy in accordance with (1) United States Preservative Efficacy
Test (USPET) test criteria; (2) European Preservative Efficacy-A
(EP-A) test criteria; and (3) European Preservative-B (EP-B) test
criteria.
[0065] The test results for each of these compositions is set forth
in the following table.
10 Composition USPET EP-A EP-B 30 Pass Fail Fail 31 Pass Fail Fail
32 Pass Fail Pass 33 Pass Pass Pass
[0066] These results indicate that cyclodextrin compositions
including either stabilized chlorine dioxide or potassium sorbate
pass the USPET criteria. In particular, Compositions 31, 32 an 33
include both potassium sorbate and the cyclodextrin and pass the
USPET criteria. At somewhat reduced pHs, as shown in Compositions
32 and 33, compositions including potassium sorbate and
cyclodextrin pass the EP-B criteria (Composition 32) and even the
EP-B and EP-A criteria (Composition 33).
[0067] Without wishing to limit the invention to any particular
theory of operation, it is believed that the cyclodextrin component
does not complex the sorbate component sufficiently to inhibit the
sorbate from acting as an effective preservative. Also, the sorbate
at more acidic conditions is a more effective preservative
component.
[0068] While this invention has been described with respect to
various specific examples and embodiments, it is to be understood
that the invention is not limited thereto and that it can be
variously practiced with the scope of the following claims.
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