U.S. patent application number 13/557611 was filed with the patent office on 2013-01-31 for two part formulation system for opthalmic delivery.
This patent application is currently assigned to ALLERGAN, INC.. The applicant listed for this patent is Anuradha V. GORE, Sukhon LIKITLERSUANG, Sesha NEERVANNAN, Chetan P. PUJARA, Sai M. SHANKAR. Invention is credited to Anuradha V. GORE, Sukhon LIKITLERSUANG, Sesha NEERVANNAN, Chetan P. PUJARA, Sai M. SHANKAR.
Application Number | 20130029919 13/557611 |
Document ID | / |
Family ID | 46889414 |
Filed Date | 2013-01-31 |
United States Patent
Application |
20130029919 |
Kind Code |
A1 |
GORE; Anuradha V. ; et
al. |
January 31, 2013 |
TWO PART FORMULATION SYSTEM FOR OPTHALMIC DELIVERY
Abstract
Ophthalmic products and related methods are described herein.
These methods include a stabilizing composition comprising a
therapeutically active agent which is separated from a liquid
vehicle composition by a barrier. The barrier may be removed to
allow the two compositions to mix to provide an ophthalmically
acceptable liquid comprising the therapeutically active agent.
Inventors: |
GORE; Anuradha V.; (Irvine,
CA) ; SHANKAR; Sai M.; (Irvine, CA) ;
LIKITLERSUANG; Sukhon; (Irvine, CA) ; PUJARA; Chetan
P.; (Irvine, CA) ; NEERVANNAN; Sesha; (Irvine,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GORE; Anuradha V.
SHANKAR; Sai M.
LIKITLERSUANG; Sukhon
PUJARA; Chetan P.
NEERVANNAN; Sesha |
Irvine
Irvine
Irvine
Irvine
Irvine |
CA
CA
CA
CA
CA |
US
US
US
US
US |
|
|
Assignee: |
ALLERGAN, INC.
Irvine
CA
|
Family ID: |
46889414 |
Appl. No.: |
13/557611 |
Filed: |
July 25, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61511753 |
Jul 26, 2011 |
|
|
|
Current U.S.
Class: |
514/20.5 ;
514/178; 514/401; 514/424 |
Current CPC
Class: |
A61K 47/34 20130101;
A61K 9/0048 20130101; A61K 38/13 20130101; A61K 47/26 20130101;
A61K 9/08 20130101; A61K 31/417 20130101; A61K 31/559 20130101;
A61K 47/12 20130101; A61K 31/568 20130101; A61K 47/40 20130101;
A61P 27/02 20180101; A61K 31/4025 20130101; A61K 47/18 20130101;
A61K 47/02 20130101 |
Class at
Publication: |
514/20.5 ;
514/401; 514/178; 514/424 |
International
Class: |
A61K 31/4025 20060101
A61K031/4025; A61P 27/02 20060101 A61P027/02; A61K 31/568 20060101
A61K031/568; A61K 31/4164 20060101 A61K031/4164; A61K 38/13
20060101 A61K038/13 |
Claims
1. An ophthalmic pharmaceutical product comprising: a stabilizing
composition comprising a therapeutically active agent; a liquid
vehicle composition; a removable barrier; wherein the barrier is
configured to prevent contact between the stabilizing composition
and the liquid vehicle composition; and wherein the product is
configured to allow removal of the barrier; wherein the product is
configured so that removal of the barrier allows mixing of the
stabilizing composition and the vehicle composition to provide a
sterile ophthalmically acceptable liquid; wherein the
ophthalmically acceptable liquid comprises a therapeutic amount of
the therapeutically active agent.
2. The product of claim 1, wherein the therapeutically active agent
comprises phentolamine or a salt thereof.
3. The product of claim 1, wherein the therapeutically active agent
comprises a cyclosporine.
4. The product of claim 1, wherein the therapeutically active agent
testosterone or a derivative thereof.
5. The product of claim 1, wherein the therapeutically active agent
comprises: ##STR00005##
6. The product of claim 1, wherein the therapeutically active agent
comprises: ##STR00006##
7. The product of claim 1, wherein the stabilizing composition
comprises polyethylene glycol (15)-hydroxystearate,
polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene
40 stearate, polysorbate 80, sorbitan monostearate,
polyoxyethylenglyceroltriricinoleate 35, a cyclodextrin, or a
combination thereof.
8. The product of claim 1, wherein the stabilizing composition
comprises potassium chloride, mannitol, sodium chloride, or a
combination thereof.
9. The product of claim 1, wherein the stabilizing composition
comprises a phosphate buffer, a phosphate citrate buffer, NaOH
trolamine, a lactate buffer, a borate buffer, a borate citrate
buffer, or a combination thereof.
10. The product of claim 1, wherein the stabilizing composition
comprises BAK or is non-preserved.
11. The product of claim 1, wherein the stabilizing composition
comprises mannitol, lactose, trehalose, or a combination
thereof.
12. The product of claim 1, wherein the liquid vehicle composition
comprises polyethylene glycol (15)-hydroxystearate,
polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene
40 stearate, polysorbate 80, sorbitan monostearate,
polyoxyethylenglyceroltriricinoleate 35, a cyclodextrin, or a
combination thereof.
13. The product of claim 1, wherein the liquid vehicle composition
comprises polyethylene glycol (15)-hydroxystearate,
polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene
40 stearate, polysorbate 80, sorbitan monostearate,
polyoxyethylenglyceroltriricinoleate 35, a cyclodextrin, or a
combination thereof.
14. The product of claim 1, wherein the liquid vehicle composition
is non-preserved, or comprises benzalkonium chloride or a
stabilized oxychloro complex.
15. The product of claim 1, wherein the liquid vehicle composition
is an aqueous liquid with a pH of about 5 to about 8.
16. A method of stabilizing a therapeutically active agent for use
in an ophthalmically acceptable liquid comprising: providing a
stabilizing system comprising: a stabilizing composition comprising
the therapeutically active agent; a vehicle composition comprising
at least one of: a solublilizer, a surfactant, an osmolality agent,
a buffer, and a preservative; and a removable barrier separating
the stabilizing composition from the vehicle composition; wherein
the system is configured so that removal of the barrier allows
mixing between the stabilizing system and the vehicle to provide a
sterile ophthalmically acceptable liquid; and wherein the
ophthalmically acceptable liquid comprises about 0.0001% to about
5% therapeutically active agent by weight.
17. The method of claim 16, wherein the therapeutically active
agent comprises phentolamine or a salt thereof.
18. The method of claim 16, wherein the therapeutically active
agent comprises a cyclosporine.
19. The method of claim 16, wherein the therapeutically active
agent comprises: ##STR00007##
20. The method of claim 16, wherein the therapeutically active
agent comprises: ##STR00008##
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims benefit of U.S. provisional
application Ser. No. 61/511,753, filed Jul. 26, 2011, which is
hereby incorporated by reference in its entirety.
FIELD
[0002] Embodiments include ophthalmic, otic and intranasal products
and methods.
BACKGROUND OF THE INVENTION
[0003] For labile therapeutically active agents, traditional
formulation development would include use of stabilizers and/or
selection of pH range to optimize stability of the therapeutically
active agents. However, high concentrations of stabilizers or
selection of product pH that is outside physiological range may
lead to safety and tolerability concerns for the product.
SUMMARY OF THE INVENTION
[0004] Some pharmaceutical products intended for ophthalmic, otic
and intranasal delivery may be stabilized by making an
ophthalmically acceptable liquid by reconstitution prior to dose
delivery. This may be an advantage for chemically labile
therapeutically active agents which may have a limited shelf life
in a formulation suitable for ophthalmic delivery due to their
rapid degradation rates.
[0005] Some embodiments include an ophthalmic pharmaceutical
product comprising: a stabilizing composition comprising a
therapeutically active agent; a liquid vehicle composition; a
removable barrier; wherein the barrier is configured to prevent
contact between the stabilizing composition and the liquid vehicle
composition; and wherein the product is configured to allow removal
of the barrier; wherein the product is configured so that removal
of the barrier allows mixing of the stabilizing composition and the
vehicle composition to provide a sterile ophthalmically acceptable
liquid; wherein the ophthalmically acceptable liquid comprises a
therapeutic amount of the therapeutically active agent.
[0006] Some embodiments include a method of stabilizing a
therapeutically active agent for use in an ophthalmically
acceptable liquid comprising: providing a stabilizing system
comprising: a stabilizing composition comprising the
therapeutically active agent; a vehicle composition comprising at
least one of: a solublilizer, a surfactant, an osmolality agent, a
buffer, and a preservative; and a removable barrier separating the
stabilizing composition from the vehicle composition; wherein the
system is configured so that removal of the barrier allows mixing
between the stabilizing system and the vehicle to provide a sterile
ophthalmically acceptable liquid; and wherein the ophthalmically
acceptable liquid comprises about 0.0001% to about 5%
therapeutically active agent by weight.
DETAILED DESCRIPTION OF THE INVENTION
[0007] Some embodiments may include a two part formulation product,
which can be reconstituted by mixing the two parts. In this system,
a stabilizing composition contains a therapeutically active agent
in a formulation matrix that may improve the stability or
shelf-life of the therapeutically active agent in the formulation
matrix. The product also comprises a liquid vehicle composition.
The stabilizing composition is separated from the liquid vehicle
composition by a removable barrier. Removal of the barrier may
allow the two parts to be mixed, so that they may form an
ophthalmically acceptable liquid. This may allow the ophthalmically
acceptable liquid to have a long enough shelf-life.
[0008] The removable barrier may have any of a variety of
structural features as long as it can separate a stabilizing
composition from a liquid vehicle composition and be removed so as
to allow mixing of the two compositions. For example, the removable
barrier may be two separate containers for the two compositions
having removable openings such as caps or lids. Alternatively, the
removable barrier may be a feature of a single container having two
compartments separated by the removable barrier. Removal of the
barrier may damage or destroy the barrier so that it may not be
used again. Alternatively, the removable barrier may be
reusable.
[0009] Some advantages of these ophthalmic pharmaceutical products
may include: longer product shelf life, reduced degradation of the
therapeutically active agent, lower levels of degradants in
product, and/or improved safety and/or tolerability of the
product.
[0010] A stabilizing composition comprises a therapeutically active
agent and other components that may increase stability or are
compatible with storage of the therapeutically active agent, such
as a solubilizer or dispersing agent, an osmolality agent, a
buffer, a preservative, a diluent or bulking agent, and the like.
Alternatively, a stabilizing composition may be a solid, containing
the therapeutically active agent substantially alone.
[0011] The solid may be prepared by lyophilization, blending,
milling, granulation or other pharmaceutical processing.
[0012] A stabilizing composition may also be a liquid, which
contains the therapeutically active agent in solution or suspension
in an appropriate stabilizing vehicle. A stabilizing vehicle may be
aqueous or non-aqueous, with appropriate stabilizers or excipients
included as appropriate. In some embodiments, a liquid stabilizing
composition may comprise a solubilizer or dispersing agent, a
stabilizer, a buffer, a vehicle, etc.
[0013] Any therapeutically active agent may be used in the
stabilizing composition. In some embodiments, the therapeutically
active agent is unstable to the extent that it cannot be stored for
a sufficient time, such as for at least about 3 months, at least
about 6 months, or at least about 1 year, in an ophthalmically
acceptable liquid. Some non-limiting examples of the
therapeutically active agent may include: Phentolamine, Compound 1,
Compound 2, DHA, EPA, ALA, cyclosporine, ketorolac, testosterone or
a derivative thereof, or pharmaceutically acceptable salts
thereof.
##STR00001##
Omega-3 Oil
[0014] Flax seed oil, also known as linseed oil, is a clear to
yellowish oil obtained from the dried ripe seeds of the flax plant
(Linum usitatissimum, Linaceae). [0015] Fatty acid components of
flaxseed oils: [0016] 57% alpha-linolenic acid (or ALA)
all-cis-9,12,15-octadecatrienoic acid, (18:3n-3).
[0016] ##STR00002## [0017] 16% Linoleic acid
cis,cis,-9,12-octadecadienoic acid, (18:2n-6)
[0017] ##STR00003## [0018] 18% Monosaturated fatty acid [0019] 9%
Saturated fatty acid
EPA vs DHA
[0019] [0020] ALA is the precursor for the long-chian PUFA (EPA and
DHA)
##STR00004##
[0021] A solubilizer or a dispersing agent may be any compound or
substance that can help to solubilize or disperse a therapeutically
active agent or another dispersant in a liquid. If a surfactant is
used, the surfactant used may vary, and may include any compound or
salt that is surface active or can form micelles. A surfactant may
be used for assisting in dissolving an excipient or an active
agent, dispersing a solid or liquid in a composition, enhancing
wetting, modifying drop size, stabilizing an emulsion, or a number
of other purposes. Useful surfactants include, but are not limited
to, surfactants of the following classes: alcohols; amine oxides;
block polymers; carboxylated alcohol or alkylphenol ethoxylates;
carboxylic acids/fatty acids; ethoxylated alcohols; ethoxylated
alkylphenols; ethoxylated aryl phenols; ethoxylated fatty acids;
ethoxylated; fatty esters or oils (animal & vegetable); fatty
esters; fatty acid methyl ester ethoxylates; glycerol esters;
glycol esters; lanolin-based derivatives; lecithin and lecithin
derivatives; lignin and lignin derivatives; methyl esters;
monoglycerides and derivatives; polyethylene glycols; polymeric
surfactants; propoxylated and ethoxylated fatty acids, alcohols, or
alkyl phenols; protein-based surfactants; sarcosine derivatives;
sorbitan derivatives; sucrose and glucose esters and derivatives.
In some embodiments, the surfactant may include polyethylene glycol
(15)-hydroxystearate (CAS Number 70142-34-6, available as SOLUTOL
HS 15.RTM. from BASF), polyoxyethylene-polyoxypropylene block
copolymer (CAS No. 9003-11-6, available as PLURONIC.RTM. F-68 from
BASF), polyoxyethylene 40 stearate (P0E40 stearate), polysorbate 80
or polyoxyethylene (80) sorbitan monooleate (CAS No. 9005-65-6),
sorbitan monostearate (CAS No. 1338-41-6, available as SPAN.TM. 60
from Croda International PLC), polyoxyethylenglyceroltriricinoleate
35 (CAS No. 61791-12-6, available as CREMOPHOR EL.RTM. from BASF).
The amount of surfactant may vary. In some embodiments, the amount
of any surfactant such as those listed above may be about 0.001% to
about 5%, about 0.1% to about 2%, or about 0.1% to about 1%.
[0022] In some embodiments, the solubilizer or dispersing agent may
comprise: polyethylene glycol (15)-hydroxystearate,
polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene
40 stearate, polysorbate, sorbitane,
polyoxyethylenglyceroltriricinoleate 35, or a cyclodextrin.
[0023] Other solubilizing or dispersing agents may be used that are
not surface active, but may be useful in solubilizing or dispersing
a solid without substantial surface activity. Some non-limiting
examples of other solubilizing or dispersing agents that may have
mimimal surface activity include cyclodextrins, polyvinyl alcohol,
povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl
cellulose, hydroxyethyl cellulose, acrylates (e.g. PEMULEN.RTM.),
etc. In some embodiments, the amount of a solubilizing or
dispersing agent without substantial surface activity may be about
0.001% to about 20%.
[0024] The osmolality agent may vary, and may include any compound
or substance useful for adjusting the osmolality of an ophthalmic
liquid. Examples include, but are not limited to, salts,
particularly sodium chloride or potassium chloride, mannitol
glycerin, etc. The amount of osmolality agent may vary depending
upon whether an isosmotic, hyperosmotic, or a hyposmotic liquid is
desired. In some embodiments, the amount of an osmolality agent
such as those listed above may be at least about 0.0001% up to
about 1%, about 2%, or about 5%.
[0025] The buffer may vary, and may include any weak conjugate
acid-base pair suitable for maintaining a desirable pH range.
Examples include, but are not limited to, acetate buffers, citrate
buffers, phosphate buffers, borate buffers, lactate buffers, NaOH
trolamine buffers, or a combination thereof. Acids or bases may be
used to adjust the pH of these formulations as needed. The amount
of buffer used may vary. In some embodiments, the amount of buffer
used may be sufficient so that the buffer has a concentration in a
range of about 1 nM to about 100 mM in the ophthalmically
acceptable liquid.
[0026] The preservative may vary, and may include any compound or
substance suitable for prevent microbial contamination in an
ophthalmic liquid subject to multiple uses from the same container.
Preservatives that may be used in the pharmaceutical compositions
disclosed herein include, but are not limited to, cationic
preservatives such as quaternary ammonium compounds including
benzalkonium chloride, polyquad, and the like; guanidine-based
preservatives including PHMB, chlorhexidine, and the like;
chlorobutanol; mercury preservatives such as thimerosal,
phenylmercuric acetate and phenylmercuric nitrate; and oxidizing
preservatives such as stabilized oxychloro complexes (e.g.
PURITE.RTM. for liquid stabilizing compositions). Combinations of
preservatives are also included such as of benzalkonium ion and an
oxy-chlorite moiety wherein the benzalkonium ion is benzalkonium
chloride and the oxy-chlorite moiety is Purite.RTM.. Other
preservatives include polyhexamethylene biguanide alone and in
combination with benzalkonium chloride and Purite.RTM..
[0027] The diluent or bulking agent may vary, and may include any
compound or substance to add bulk to a stabilizing composition for
ease of handling, or for adjusting a solid stabilizing composition
so that it has a desirable solid properties for handling.
Non-limiting examples may include mannitol, lactose, trehalose, and
the like.
[0028] For liquid stabilizing compositions, a vehicle may be used.
The vehicle may be any compound or substance that can dissolve or
disperse any solids in a stabilizing composition so that the
stabilizing composition is in a liquid form or comprises a solid
dispersed in a liquid. Some non-limiting examples of vehicles may
include silicones, oils, or water. Suitable oils include, but are
not limited to anise oil, castor oil, clove oil, cassia oil,
cinnamon oil, almond oil, corn oil, arachis oil, cottonseed oil,
safflower oil, maize oil, linseed oil, rapeseed oil, soybean oil,
olive oil, caraway oil, rosemary oil, peanut oil, peppermint oil,
sunflower oil, eucalyptus oil, sesame oil, and the like.
[0029] A stabilizer may include any compound that is useful in
stabilizing a composition, such as an antioxidant or a
chelating/complexing agent.
[0030] If the stabilizer includes an antioxidant, the antioxidant
may vary, and may include any compound or substance that is useful
in reducing oxidation of any compound present in an ophthalmically
acceptable liquid. Examples, but are not limited to, ascorbic acid,
sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated
hydroxyanisole, and butylated hydroxytoluene.
[0031] If the stabilizer includes a chelating/complexing agent, the
chelating/complexing agent may vary, and may include any compound
or substance that is capable of chelating or complexing a metal or
another chemical species. Examples may include, but are not limited
to, edetate disodium (EDTA), citrate, phosphate, malonate, maleate,
acetate, edetate, ethanol diglycinate, diethanolglycinate,
polystyrene sulfonate, etc.
[0032] In some embodiments, a stabilizing composition comprises
polyethylene glycol (15)-hydroxystearate,
polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene
40 stearate, polysorbate 80, sorbitan monostearate,
polyoxyethylenglyceroltriricinoleate 35, a cyclodextrin, or a
combination thereof.
[0033] In some embodiments, a stabilizing composition comprises
potassium chloride, mannitol, sodium chloride, or a combination
thereof.
[0034] In some embodiments, a stabilizing composition comprises a
phosphate buffer, a phosphate citrate buffer, NaOH trolamine, a
lactate buffer, a borate buffer, a borate citrate buffer, or a
combination thereof.
[0035] In some embodiments, a stabilizing composition comprises
BAK, Purite, other preservatives or preservative combinations such
as combinations of preservatives including benzalkonium ion and an
oxy-chlorite moiety wherein the benzalkonium ion is benzalkonium
chloride and the oxy-chlorite moiety is Purite.RTM.. Other
preservatives include polyhexamethylene biguanide alone and in
combination with benzalkonium chloride and Purite.RTM..
[0036] In some embodiments, the stabilized composition is
non-preserved.
[0037] In some embodiments, a stabilizing composition comprises
mannitol, lactose, trehalose, or a combination thereof.
[0038] In some embodiments, a stabilizing composition comprises
sodium metabisulfite, ascorbic acid, EDTA, a complexing agent, or a
combination thereof.
[0039] In some embodiments, a stabilizing composition is an aqueous
liquid that may have a pH of about 1 to about 13.
[0040] In some embodiments, a stabilizing composition is a solid
comprising phentolamine or a salt thereof in an amount of about
0.001% wt/wt to about 10% wt/wt and polyethylene glycol
(15)-hydroxystearate in amount of about 0.001% wt/wt to about 5%
wt/wt.
[0041] In some embodiments, a stabilizing composition is a solid
comprising phentolamine or a salt thereof in an amount of about
0.001% wt/wt to about 10% wt/wt and
polyoxyethylene-polyoxypropylene block copolymer in amount of about
0.001% wt/wt to about 5% wt/wt.
[0042] In some embodiments, a stabilizing composition is a solid
comprising phentolamine or a salt thereof in an amount of about
0.001% wt/wt to about 10% wt/wt and polyoxyethylene 40 stearate in
amount of about 0.001% wt/wt to about 1% wt/wt.
[0043] In some embodiments, a stabilizing composition is a solid
comprising phentolamine or a salt thereof in an amount of about
0.001% wt/wt to about 10% wt/wt and
polyoxyethylenglyceroltriricinoleate 35 in amount of about 0.001%
wt/wt to about 1% wt/wt.
[0044] In some embodiments, a stabilizing composition is a solid
comprising phentolamine or a salt thereof in an amount of about
0.001% wt/wt to about 10% wt/wt and a cyclodextrin in amount of
about 0.001% wt/wt to about 20% wt/wt.
[0045] Some embodiments of solid stabilizing compositions are
listed in Tables 1 and 2.
TABLE-US-00001 TABLE 1 Examples of stabilizing composition as
therapeutically active agent alone in powder form Examples of
typical Ingredient type Ingredient conc. range % (w/w)
Therapeutically Any one of the below active agent drug substances
Phentolamine and its salts 100% At least one of the Cyclosporine
100% drug substances Testosterone, and its 100% listed derivatives
Ketorolac, and its salts 100% DHA, and its salts 100% EPA, and its
salts 100% ALA, and its salts 100%
TABLE-US-00002 TABLE 2 Examples of stabilizing compositions as
therapeutically active agent with other excipients powder form
Examples of typical conc. range Ingredient type Ingredient % (w/w)
Therapeutically active agent Any one of the below drug At least one
of the drug substances substances listed and mixtures thereof are
Phentolamine and about 0.001-10% contemplated its salts
Cyclosporine about 0.001-10% Testosterone, and about 0.001-10% its
derivatives Ketorolac, and its about 0.001-10% salts DHA, and its
salts about 0.001-10% EPA, and its salts about 0.001-10% ALA, and
its salts about 0.001-10% COMPOUND 1 about 0.001-10% COMPOUND 2
about 0.0002-10% Following ingredients may or may not be included
in the formulation Part 1 Solubilizer/dispersing agents Solutol HS
15 about 0.001-5% (may or may not be required) Pluronic F68 about
0-5% POE40Stearate about 0-10/0 Cyclodextrins about 0-10%
Osmolality agents (any one or two or Potassium chloride about 0-2%
more in combinations) Mannitol about 0-5% Sodium chloride about
0-1% Buffers (Any one of the buffers listed) Phosphate buffer *q.s.
for about 1-100 mM Phosphate citrate *q.s. for about 1-100 mM
buffer NaOH/ *q.s. for about 1-100 mM Trolamine Lactate buffer
*q.s. for about 1-100 mM Borate buffer *q.s. for about 1-100 mM
Borate citrate *q.s. for about 1-100 mM Water soluble Antioxidants
EDTA 0-1% Pyruvate 0-1% Trehalose 0-10% Oil Soluble Antioxidants
Alpha-Tocopherol 0-1% Ascorbyl Palmitate BHA BHT Preservatives (Any
one or in None - Non NA combination) preserved BAK *q.s. for about
10-200 ppm Purite 20-150 ppm BAK + Purite combo 0.1 to 2000 ppm of
Purite and from 1 to 100 ppm of benzalkonium ion PHMB + BAK 0.1 to
10 ppm PHMB and 0.1 combo to 30 ppm benzalkonium ion.
Diluent/bulking agent/cake formers Mannitol q.s. to 100% Lactose
q.s. to 100% Trehalose q.s. to 100% *q.s to achieve listed
concentration in final formulation after reconstitution
[0046] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2 and a
solubilizer/dispersing agent listed in Table 2.
[0047] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2 and an osmolality
agent listed in Table 2.
[0048] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2 and a buffer listed
in Table 2.
[0049] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2 and a preservative
listed in Table 2.
[0050] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2 and a diluent listed
in Table 2.
[0051] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a
solubilizer/dispersing agent listed in Table 2, and a osmolality
agent listed in Table 2.
[0052] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a
solubilizer/dispersing agent listed in Table 2, and a buffer listed
in Table 2.
[0053] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a
solubilizer/dispersing agent listed in Table 2, and a preservative
listed in Table 2.
[0054] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a
solubilizer/dispersing agent listed in Table 2, and a diluent
listed in Table 2.
[0055] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, an osmolality agent
listed in Table 2, and a buffer listed in Table 2.
[0056] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, an osmolality agent
listed in Table 2, and a preservative listed in Table 2.
[0057] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, an osmolality agent
listed in Table 2, and a diluent listed in Table 2.
[0058] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a buffer listed in
Table 2, and a preservative listed in Table 2.
[0059] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a buffer listed in
Table 2, and a diluent listed in Table 2.
[0060] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a preservative
listed in Table 2, and a diluent listed in Table 2.
[0061] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a
solubilizer/dispersing agent listed in Table 2, a osmolality agent
listed in Table 2, and a buffer listed in Table 2.
[0062] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a
solubilizer/dispersing agent listed in Table 2, a osmolality agent
listed in Table 2, and a preservative listed in Table 2.
[0063] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a
solubilizer/dispersing agent listed in Table 2, a osmolality agent
listed in Table 2, and a diluent listed in Table 2.
[0064] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a
solubilizer/dispersing agent listed in Table 2, a buffer listed in
Table 2, and a preservative listed in Table 2.
[0065] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a
solubilizer/dispersing agent listed in Table 2, a buffer listed in
Table 2, and a diluent listed in Table 2.
[0066] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a
solubilizer/dispersing agent listed in Table 2, a preservative
listed in Table 2, and a diluent listed in Table 2.
[0067] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, an osmolality agent
listed in Table 2, a buffer listed in Table 2, and a preservative
listed in Table 2.
[0068] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, an osmolality agent
listed in Table 2, a buffer listed in Table 2, and a diluent listed
in Table 2.
[0069] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, an osmolality agent
listed in Table 2, a preservative listed in Table 2, and a diluent
listed in Table 2.
[0070] In some embodiments, a stabilizing composition includes a
therapeutically active agent listed in Table 2, a buffer listed in
Table 2, a preservative listed in Table 2, and a diluent listed in
Table 2.
[0071] Some embodiments of liquid stabilizing compositions are
listed in Table 3.
TABLE-US-00003 TABLE 3 Examples of stabilizing compositions as
liquid containing therapeutically active agent Examples of typical
conc. range Ingredient type Ingredient % (w/w) Active Ingredients
Any one of the below Any one of the drug drug substances substances
listed Phentolamine and its salts about 0.001-10% Cyclosporine
about 0.001-10% Testosterone, and its about 0.001-10% derivatives
Ketorolac, and its salts about 0.001-10% COMPOUND 1 about 0.001-10%
COMPOUND 2 about 0.0002-10% Following ingredients may or may not be
included in the formulation Part 1 Solubilizer/ Solutol HS 15 about
0-10% Co- Polysorbate 80 about 0-10% solubilizer/ Span 60 about
0-10% dispersing agents Pluronic F68 about 0-10% (may or may not be
POE40Stearate about 0-10% required) Cremophor EL about 0-10%
Cyclodextrins about 0-20% Stabilizers Sodium Metabisulfate about
0-1% (may or may not be Ascorbic acid about 0-1% required) EDTA
about 0-1% Complexing agents about 0-40% Buffers (may or Phosphate
buffer about 0-100 mM may not be Phosphate citrate buffer about
0-100 mM required) NaOH/ about 0-100 mM Trolamine Lactate buffer
about 0-100 mM Borate buffer about 0-100 mM Borate citrate about
0-100 mM NaOH or HCl for pH Q.S adjustment pH range (for aqueous
formulations) pH 1 to 13 Vehicle Silicones QS Oil QS Water QS
[0072] In some embodiments, the stabilizing composition includes a
therapeutically active agent listed in Table 3 and a
solubilizer/dispersing agent listed in Table 3.
[0073] In some embodiments, the stabilizing composition includes a
therapeutically active agent listed in Table 3 and a stabilizer
listed in Table 3.
[0074] In some embodiments, the stabilizing composition includes a
therapeutically active agent listed in Table 3 and a buffer listed
in Table 3.
[0075] In some embodiments, the stabilizing composition includes a
therapeutically active agent listed in Table 3, a
solubilizer/dispersing agent listed in Table 3 and a stabilizer
listed in Table 3.
[0076] In some embodiments, the stabilizing composition includes a
therapeutically active agent listed in Table 3, a
solubilizer/dispersing agent listed in Table 3, and a buffer listed
in Table 3.
[0077] In some embodiments, the stabilizing composition includes a
therapeutically active agent listed in Table 3, a stabilizer listed
in Table 3, and a buffer listed in Table 3.
[0078] In some embodiments, the stabilizing composition includes a
therapeutically active agent listed in Table 3, a
solubilizer/dispersing agent listed in Table 3, a stabilizer listed
in Table 3, and a buffer listed in Table 3.
[0079] A liquid vehicle composition may be any liquid comprising a
silicone or water that may be mixed with a stabilizing composition
to provide a sterile ophthalmically acceptable liquid. An
ophthalmically acceptable liquid includes a liquid that is
tolerable to a patient for topical ophthalmic use. A liquid vehicle
composition may also comprise any of a solubilizer or dispersing
agent, a stabilizer, a buffer, and/or a preservative, as described
above. Furthermore, a liquid vehicle composition may have a pH in
the range of about 5 to about 8.
[0080] The relative amounts of a stabilizing composition and a
liquid vehicle composition may vary. In some embodiments a
stabilizing composition may be about 0.001% to about 10%, or about
0.01% to about 10% of the ophthalmically acceptable liquid.
[0081] In some embodiments, a liquid vehicle composition comprises
polyethylene glycol (15)-hydroxystearate,
polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene
40 stearate, polysorbate 80, sorbitan monostearate,
polyoxyethylenglyceroltriricinoleate 35, a cyclodextrin, or a
combination thereof.
[0082] In some embodiments, a liquid vehicle composition comprises
sodium metabisulfite, ascorbic acid, EDTA, a complexing agent, or a
combination thereof.
[0083] In some embodiments, a liquid vehicle composition comprises
a phosphate buffer, a phosphate citrate buffer, a NaOH/trolamine
buffer, a lactate buffer, a borate buffer, a borate citrate buffer,
or a combination thereof.
[0084] In some embodiments, a liquid vehicle composition is
non-preserved, or comprises benzalkonium chloride or a stabilized
oxychloro complex.
[0085] In some embodiments, a liquid vehicle composition is an
aqueous liquid with a pH of about 5 to about 8.
[0086] In some embodiments, a liquid vehicle composition comprises
a silicone.
TABLE-US-00004 TABLE 4 Examples of liquid vehicle compositions
Examples of typical conc. range Ingredient type Ingredient % (w/w)
Following ingredients may or may not be included in the formulation
Part 2 Solubilizer/ Solutol HS 15 about 0-10% Co- Polysorbate 80
about 0-10% solubilizer/dispersing Span 60 about 0-10% agents
Pluronic F68 about 0-10% (may or may not be POE40Stearate about
0-10% required) Cremophor EL about 0-10% Cyclodextrins about 0-20%
Stabilizers Sodium Metabisulfate about 0-1% (may or may not be
Ascorbic acid about 0-1% required) EDTA about 0-1% Complexing
agents about 0-40% Buffers (may or may Phosphate buffer about 0-100
mM not be required) Phosphate citrate buffer about 0-100 mM NaOH/
about 0-100 mM Trolamine Lactate buffer about 0-100 mM Borate
buffer about 0-100 mM Borate citrate about 0-100 mM NaOH or HCl for
pH Q.S adjustment Preservatives and None - Non preserved NA
combinations BAK about 10-200 ppm Purite about 10-300 ppm Vehicle
(one of these Silicones (non-aqueous QS required) formulas) Water
(aqueous formulas) QS pH range (for aqueous formulations) pH about
5 to 8
[0087] In some embodiments, a liquid vehicle composition comprises
a solubilizer/dispersing agent listed in Table 4.
[0088] In some embodiments, a liquid vehicle composition comprises
a stabilizer listed in Table 4.
[0089] In some embodiments, a liquid vehicle composition comprises
a buffer listed in Table 4.
[0090] In some embodiments, a liquid vehicle composition comprises
a preservative listed in Table 4.
[0091] In some embodiments, a liquid vehicle composition comprises
a solubilizer/dispersing agent listed in Table 4 and a stabilizer
listed in Table 4.
[0092] In some embodiments, a liquid vehicle composition comprises
a solubilizer/dispersing agent listed in Table 4 and a buffer
listed in Table 4.
[0093] In some embodiments, a liquid vehicle composition comprises
a solubilizer/dispersing agent listed in Table 4 and a preservative
listed in Table 4.
[0094] In some embodiments, a liquid vehicle composition comprises
a stabilizer listed in Table 4 and a buffer listed in Table 4.
[0095] In some embodiments, a liquid vehicle composition comprises
a stabilizer listed in Table 4 and a preservative listed in Table
4.
[0096] In some embodiments, a liquid vehicle composition comprises
a buffer listed in Table 4 and a preservative listed in Table
4.
[0097] In some embodiments, a liquid vehicle composition comprises
a solubilizer/dispersing agent listed in Table 4, a stabilizer
listed in Table 4, and a buffer listed in Table 4.
[0098] In some embodiments, a liquid vehicle composition comprises
a solubilizer/dispersing agent listed in Table 4, a stabilizer
listed in Table 4, and a preservative listed in Table 4.
[0099] In some embodiments, a liquid vehicle composition comprises
a solubilizer/dispersing agent listed in Table 4, a buffer listed
in Table 4, and a preservative listed in Table 4.
[0100] In some embodiments, a liquid vehicle composition comprises
a stabilizer listed in Table 4, a buffer listed in Table 4, and a
preservative listed in Table 4.
[0101] In some embodiments, a liquid vehicle composition comprises
a solubilizer/dispersing agent listed in Table 4, a stabilizer
listed in Table 4, a buffer listed in Table 4, and a preservative
listed in Table 4.
EXAMPLE 1
[0102] Unless otherwise indicated, all numbers expressing
quantities of ingredients, properties such as molecular weight,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the specification and
attached claims are approximations that may vary depending upon the
desired properties sought to be obtained. At the very least, and
not as an attempt to limit the application of the doctrine of
equivalents to the scope of the claims, each numerical parameter
should at least be construed in light of the number of reported
significant digits and by applying ordinary rounding
techniques.
[0103] The terms "a," "an," "the" and similar referents used in the
context of describing the invention (especially in the context of
the following claims) are to be construed to cover both the
singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. Recitation of ranges of values
herein is merely intended to serve as a shorthand method of
referring individually to each separate value falling within the
range. Unless otherwise indicated herein, each individual value is
incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g., "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of any claim. No language in the
specification should be construed as indicating any non-claimed
element essential to the practice of the invention.
[0104] Groupings of alternative elements or embodiments disclosed
herein are not to be construed as limitations. Each group member
may be referred to and claimed individually or in any combination
with other members of the group or other elements found herein. It
is anticipated that one or more members of a group may be included
in, or deleted from, a group for reasons of convenience and/or
patentability. When any such inclusion or deletion occurs, the
specification is deemed to contain the group as modified thus
fulfilling the written description of all Markush groups used in
the appended claims.
[0105] Certain embodiments are described herein, including the best
mode known to the inventors for carrying out the invention. Of
course, variations on these described embodiments will become
apparent to those of ordinary skill in the art upon reading the
foregoing description. The inventor expects skilled artisans to
employ such variations as appropriate, and the inventors intend for
the invention to be practiced otherwise than specifically described
herein. Accordingly, this invention includes all modifications and
equivalents of the subject matter recited in the claims appended
hereto as permitted by applicable law. Moreover, any combination of
the above-described elements in all possible variations thereof is
encompassed by the invention unless otherwise indicated herein or
otherwise clearly contradicted by context.
[0106] In closing, it is to be understood that the embodiments
disclosed herein are illustrative of the principles of the claims.
Other modifications that may be employed are within the scope of
the claims. Thus, by way of example, but not of limitation,
alternative embodiments may be utilized in accordance with the
teachings herein. Accordingly, the claims are not limited to
embodiments precisely as shown and described.
* * * * *