U.S. patent application number 13/715972 was filed with the patent office on 2013-06-20 for ophthalmic compositions comprising polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymers.
This patent application is currently assigned to ALLERGAN, INC.. The applicant listed for this patent is ALLERGAN, INC.. Invention is credited to Anuradha V. Gore, Richard S. Graham, Melissa Gulmezian, Kristin Prinn, Chetan P. Pujara, Ramakrishnan Srikumar.
Application Number | 20130157963 13/715972 |
Document ID | / |
Family ID | 47459182 |
Filed Date | 2013-06-20 |
United States Patent
Application |
20130157963 |
Kind Code |
A1 |
Gore; Anuradha V. ; et
al. |
June 20, 2013 |
OPHTHALMIC COMPOSITIONS COMPRISING POLYVINYL CAPRALACTAM-POLYVINYL
ACETATE-POLYETHYLENE GLYCOL GRAFT COPOLYMERS
Abstract
Compositions and methods related to ophthalmic use of polyvinyl
capralactam-polyvinyl acetate-polyethylene glycol graft copolymers
and therapeutic uses are described herein.
Inventors: |
Gore; Anuradha V.; (Irvine,
CA) ; Pujara; Chetan P.; (Irvine, CA) ;
Graham; Richard S.; (Irvine, CA) ; Gulmezian;
Melissa; (Irvine, CA) ; Prinn; Kristin; (Costa
Mesa, CA) ; Srikumar; Ramakrishnan; (Aliso Viejo,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALLERGAN, INC.; |
IRVINE |
CA |
US |
|
|
Assignee: |
ALLERGAN, INC.
IRVINE
CA
|
Family ID: |
47459182 |
Appl. No.: |
13/715972 |
Filed: |
December 14, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61576453 |
Dec 16, 2011 |
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Current U.S.
Class: |
514/20.8 ;
514/169; 514/180; 514/236.2; 514/249; 514/253.08; 514/397; 514/413;
514/622; 514/772.1; 525/419 |
Current CPC
Class: |
A61K 9/0048 20130101;
A61K 31/407 20130101; A61K 31/5575 20130101; A61K 31/498 20130101;
A61K 47/02 20130101; A61K 9/08 20130101; A61K 31/5377 20130101;
A61P 27/02 20180101; A61K 31/417 20130101; A61K 31/4985 20130101;
A61K 31/573 20130101; A61K 47/32 20130101; A61K 31/4178 20130101;
A61K 47/34 20130101; A61K 38/13 20130101; A61P 27/06 20180101; A61K
31/496 20130101; A61K 31/568 20130101; A61K 31/498 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/20.8 ;
514/249; 514/622; 514/772.1; 514/169; 514/236.2; 514/397;
514/253.08; 514/413; 514/180; 525/419 |
International
Class: |
A61K 47/32 20060101
A61K047/32 |
Claims
1. A topical ophthalmic composition comprising a polyvinyl
capralactam-polyvinyl acetate-polyethylene glycol graft
copolymer.
2. The composition of claim 1, wherein the polyvinyl
capralactam-polyvinyl acetate-polyethylene glycol graft copolymer
has an average molecular weight of about 10,000 g/mol to about
500,000 g/mol.
3. The composition of claim 1 or 2, further comprising a
therapeutically active agent.
4. The composition of claim 3, wherein the therapeutically active
agent comprises an immunosuppressant, an alpha-adrenergic
antagonist, a steroid, a prostaglandin EP2 agonist, a muscarinic, a
prostaglandin, an alpha agonist, an antibiotic, an anti-infective
agent, an anti-inflammatory, a beta blocker, or a combination
thereof.
5. The composition of claim 3, wherein the therapeutically active
agent comprises one selected from the group consisting of
cyclosporine A, a cyclosporine analog, phentolamine, testosterone,
dexamethasone, prednisolone, bimatoprost, latanoprost, Compounds A.
B, C, D, E, F, G, or H of Table 8, pilocarpine, brimonidine,
gatifloxacin, ketorolac, a steroid, timolol, or a combination
thereof.
6. The composition of claim 5, wherein the composition is a
solution.
7. The composition of claim 6, further comprising a
co-solubilizer.
8. The composition of claim 7, wherein the co-solubilizer comprises
sorbitan monostearate, a polyoxyethylene-polyoxypropylene block
copolymer, polyoxyethyleneglyceroltriricinoleate 35, a
cyclodextrin, or a combination thereof.
9. The composition of claim 6, further comprising an osmolality
agent.
10. The composition of claim 9, wherein the osmolality agent
comprises propylene glycol, glycerin, mannitol, sodium chloride, or
a combination thereof.
11. The composition of claim 10, further comprising a buffer.
12. The composition of claim 11, wherein the buffer comprises
phosphate, phosphate and citrate, trolamine, lactate, borate,
borate and citrate, or a combination thereof.
13. The composition of claim 10 further comprising a
preservative.
14. The composition of claim 13, wherein the preservative comprises
benzalkonium chloride, a stabilized oxychloro complex, or a
combination thereof.
15. A method of solubilizing a therapeutically active agent
comprising providing a composition comprising the therapeutically
active agent and a polyvinyl capralactam-polyvinyl
acetate-polyethylene glycol graft copolymer, wherein the
therapeutically active agent is not completely soluble in the
composition at room temperature without the polyvinyl
capralactam-polyvinyl acetate-polyethylene glycol graft
copolymer.
16. A method of solubilizing a therapeutically active agent
comprising mixing the therapeutically active agent and a polyvinyl
capralactam-polyvinyl acetate-polyethylene glycol graft copolymer
so that a composition according to claims 5 is formed.
17. A method of stabilizing a therapeutically active agent
comprising combining the therapeutically active agent with a
polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft
copolymer to thereby improve stability of the therapeutically
active agent.
18. A method of stabilizing a therapeutically active agent
comprising combining the therapeutically active agent and a
polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft
copolymer so that a composition according to claim 5 is formed.
19. A method of treating a disease affecting an eye comprising
administering a composition according to claim 11 to an eye in need
thereof wherein one of the active agents is bimatoprost.
20. The method of claim 19 further comprising the active agent
brimonidine.
Description
RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 61/576,453, filed Dec. 16, 2011, which is
incorporated herein by reference in its entirety.
BACKGROUND
[0002] Topically applied formulations, such as those applied to the
cornea, conjunctiva, eyelid margin, etc., are frequently used in
ophthalmology to treat acute and chronic conditions because they
may be safer than systemically delivered formulations. However,
some therapeutically active agents may have poor solubility in
aqueous solutions, which may limit topical ophthalmic use.
Solubility may be improved for some therapeutically active agents
by using a nonionic surfactant, but further improvement may be
needed.
SUMMARY
[0003] Some embodiments include a topical ophthalmic composition
comprising a polyvinyl capralactam-polyvinyl acetate-polyethylene
glycol graft copolymer (PCA-PVA-PEG).
[0004] Some embodiments include a method of solubilizing a
therapeutically active agent comprising providing a composition
including the therapeutically active agent and a PCA-PVA-PEG. In
some embodiments, the therapeutically active agent may not be
completely soluble in the composition at room temperature without
the PCA-PVA-PEG.
[0005] Some embodiments include a method of stabilizing a
therapeutically active agent comprising combining the
therapeutically active agent with a PCA-PVA-PEG to thereby improve
stability of the therapeutically active agent.
[0006] Some embodiments include a method of solubilizing a
therapeutically active agent comprising mixing the therapeutically
active agent and a polyvinyl capralactam-polyvinyl
acetate-polyethylene glycol graft copolymer so that a composition
described herein is formed.
[0007] Some embodiments include a method of stabilizing a
therapeutically active agent comprising combining the
therapeutically active agent and a polyvinyl capralactam-polyvinyl
acetate-polyethylene glycol graft copolymer so that a composition
described herein is formed.
[0008] Some embodiments include a method of treating a disease
affecting an eye comprising administering a composition described
herein to an eye in need thereof.
[0009] Other embodiments of the invention include: [0010] 1) A
topical ophthalmic composition comprising a polyvinyl
capralactam-polyvinyl acetate-polyethylene glycol graft copolymer.
[0011] 2) The composition of paragraph 1, wherein the polyvinyl
capralactam-polyvinyl acetate-polyethylene glycol graft copolymer
has an average molecular weight of about 10,000 g/mol to about
500,000 g/mol. [0012] 3) The composition of paragraphs 1 or 2,
further comprising a therapeutically active agent. [0013] 4) The
composition of paragraph 3, wherein the therapeutically active
agent comprises an immunosuppressant, an alpha-adrenergic
antagonist, a steroid, a prostaglandin EP2 agonist, a muscarinic, a
prostaglandin, an alpha agonist, an antibiotic, an anti-infective
agent, an anti-inflammatory, a beta blocker, or a combination
thereof. [0014] 5) The composition of paragraph 3, wherein the
therapeutically active agent comprises cyclosporine A, a
cyclosporine analog, phentolamine, testosterone, dexamethasone,
prednisolone, bimatoprost, latanoprost, Compounds A, B, C, D, E, F,
G and H of Table 8, pilocarpine, brimonidine, gatifloxacin,
ketorolac, a steroid, timolol, or a combination thereof. [0015] 6)
The composition of paragraph 5, wherein the composition is a
solution. [0016] 7) The composition of paragraph 6, further
comprising a co-solubilizer. [0017] 8) The composition of paragraph
7, wherein the co-solubilizer comprises sorbitan monostearate, a
polyoxyethylene-polyoxypropylene block copolymer,
polyoxyethyleneglyceroltriricinoleate 35, a cyclodextrin, or a
combination thereof. [0018] 9) The composition of paragraph 6,
further comprising an osmolality agent. [0019] 10) The composition
of paragraph 9, wherein the osmolality agent comprises propylene
glycol, glycerin, mannitol, sodium chloride, or a combination
thereof. [0020] 11) The composition of paragraph 10, further
comprising a buffer. [0021] 12) The composition of paragraph 11,
wherein the buffer comprises phosphate, phosphate and citrate,
trolamine, lactate, borate, borate and citrate, or a combination
thereof. [0022] 13) The composition of paragraph 10 further
comprising a preservative. [0023] 14) The composition of paragraph
13, wherein the preservative comprises benzalkonium chloride, a
stabilized oxychloro complex, or a combination thereof. [0024] 15)
A method of solubilizing a therapeutically active agent comprising
providing a composition comprising the therapeutically active agent
and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol
graft copolymer, wherein the therapeutically active agent is not
completely soluble in the composition at room temperature without
the polyvinyl capralactam-polyvinyl acetate-polyethylene glycol
graft copolymer. [0025] 16) A method of solubilizing a
therapeutically active agent comprising mixing the therapeutically
active agent and a polyvinyl capralactam-polyvinyl
acetate-polyethylene glycol graft copolymer so that a composition
according to claim 5 is formed. [0026] 17) A method of stabilizing
a therapeutically active agent comprising combining the
therapeutically active agent with a polyvinyl capralactam-polyvinyl
acetate-polyethylene glycol graft copolymer to thereby improve
stability of the therapeutically active agent. [0027] 18) A method
of stabilizing a therapeutically active agent comprising combining
the therapeutically active agent and a polyvinyl
capralactam-polyvinyl acetate-polyethylene glycol graft copolymer
so that a composition according to claim 5 is formed. [0028] 19) A
method of treating a disease affecting an eye comprising
administering a composition according to paragraph11 to an eye in
need thereof wherein one of the active agents is bimatoprost.
[0029] 20) The method of paragraph19 further comprising the active
agent brimonidine.
DETAILED DESCRIPTION
[0030] Polyoxyethylated surfactants such as polysorbate 80,
polysorbate 20, and polyoxyl stearate 40 may suffer from
disadvantages such as oxidative degradation of therapeutically
active agents in a composition, degradation of the surfactant,
reduced preservative effectiveness, and reduced permeability of
bioavailability of the therapeutically active agent through
biological membranes. Use of a PCA-PVA-PEG may help to reduce or
prevent these undesirable results.
[0031] A polyvinyl capralactam-polyvinyl acetate-polyethylene
glycol graft copolymer (PCA-PVA-PEG) includes a polymer comprising
at least one capralactam block, at least one polyvinyl acetate
block, and at least one polyethylene glycol block, wherein at least
one block branches from another of the type of blocks. For example,
some PCA-PVA-PEGs may be represented by the structure below.
##STR00001##
[0032] In the structure above, a may be about 10 to about 10,000,
about 100 to about 900, about 100 to about 500, or about 500 to
about 900.
[0033] In the structure above, b may be about 20 to about 20,000,
about 150 to about 1500, about 200 to about 800, or about 800 to
about 1500.
[0034] In the structure above, c may be about 30 to about 30,000,
about 300 to about 3000, about 300 to about 1000, about 1000 to
about 2000, or about 2000 to about 3000. In some embodiments, a
PCA-PVA-PEG may have an average molecular weight of about 1,000
g/mol to about 5,000,000 g/mol, about 10,000 g/mol to about 500,000
g/mol, or about 90,000 g/mol to about 140,000 g/mmol.
[0035] In some embodiments, a PCA-PVA-PEG may be a polymer
represented by CAS No. 402932-23-4, such as SOLUPLUS.RTM.,
available from BASF.
[0036] Use of a PCA-PVA-PEG may improve the solubility and/or
stability of a therapeutically active agent, including any of those
listed below. A PCA-PVA-PEG may also have minimal interference with
preservatives, and thus in some compositions may allow less
preservative to be used. Furthermore, a PCA-PVA-PEG may have
antimicrobial properties in some compositions, and may thus be
included in a self-preserved composition that may not need a
traditional preservative. A PCA-PVA-PEG may also be synergistic
with some preservatives such as stabilized oxychloro complexes.
[0037] A therapeutically active agent includes any compound or
substance recognized in the official United States Pharmacopoeia,
official Homoeopathic Pharmacopoeia of the United States, or
official National Formulary, or any supplement to any of them; and
any compound or substance intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease in humans or other
animals; and any substance other than food or water intended to
affect the structure or any function of the body of humans or other
animals.
[0038] Some therapeutically active agents may include
antihistamines, antibiotics, beta blockers, steroids,
antineoplastic agents, immunosuppressive agents, antiviral agents,
and mixtures thereof.
[0039] Examples of antihistamines may include, but are not limited
to, loradatine, hydroxyzine, diphenhydramine, chlorpheniramine,
brompheniramine, cyproheptadine, terfenadine, clemastine,
triprolidine, carbinoxamine, diphenylpyraline, phenindamine,
azatadine, tripelennamine, dexchlorpheniramine, dexbrompheniramine,
methdilazine, and trimprazine doxylamine, pheniramine, pyrilamine,
chiorcyclizine, thonzylamine, and derivatives thereof.
[0040] Examples of antibiotics may include without limitation,
cefazolin, cephradine, cefaclor, cephapirin, ceftizoxime,
cefoperazone, cefotetan, cefutoxime, cefotaxime, cefadroxil,
ceftazidime, cephalexin, cephalothin, cefamandole, cefoxitin,
cefonicid, ceforanide, ceftriaxone, cefadroxil, cephradine,
cefuroxime, cyclosporine, ampicillin, amoxicillin, cyclacillin,
ampicillin, penicillin G, penicillin V potassium, piperacillin,
oxacillin, bacampicillin, cloxacillin, ticarcillin, azlocillin,
carbenicillin, methicillin, nafcillin, erythromycin, tetracycline,
doxycycline, minocycline, aztreonam, chloramphenicol, ciprofloxacin
hydrochloride, clindamycin, metronidazole, gentamicin, lincomycin,
tobramycin, vancomycin, polymyxin B sulfate, colistimethate,
colistin, azithromycin, augmentin, sulfamethoxazole, trimethoprim,
gatifloxacin, ofloxacin, and derivatives thereof.
[0041] Examples of beta blockers may include acebutolol, atenolol,
labetalol, metoprolol, propranolol, timolol, and derivatives
thereof.
[0042] Examples of steroids may include corticosteroids, such as
cortisone, prednisolone, fluorometholone, dexamethasone, medrysone,
loteprednol, fluazacort, hydrocortisone, prednisone, betamethasone,
prednisone, methylprednisolone, riamcinolone hexacatonide,
paramethasone acetate, diflorasone, fluocinonide, fluocinolone,
triamcinolone, derivatives thereof, and mixtures thereof.
[0043] Examples of antineoplastic agents may include adriamycin,
cyclophosphamide, actinomycin, bleomycin, duanorubicin,
doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil,
carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide,
interferons, camptothecin and derivatives thereof, phenesterine,
taxol and derivatives thereof, taxotere and derivatives thereof,
vinblastine, vincristine, tamoxifen, etoposide, piposulfan,
cyclophosphamide, and flutamide, and derivatives thereof.
[0044] Examples of immunosuppressive agents may include
cyclosporine, azathioprine, tacrolimus, and derivatives
thereof.
[0045] Examples of antiviral agents may include interferon gamma,
zidovudine, amantadine hydrochloride, ribavirin, acyclovir,
valciclovir, dideoxycytidine, phosphonoformic acid, ganciclovir and
derivatives thereof.
[0046] In some embodiments, a therapeutically active agent may
comprise an immunosuppressant, an alpha-adrenergic antagonist, a
steroid, a prostaglandin EP2 agonist, a muscarinic, a
prostaglandin, an alpha agonist, an antibiotic, an anti-infective
agent, an anti-inflammatory, a beta blocker, or a combination
thereof. In some embodiments, a therapeutically active agent may
comprise cyclosporine A, a cyclosporine analog, phentolamine,
testosterone, dexamethasone, prednisolone, bimatoprost,
latanoprost, Compounds A, B, C, D, E, F, G and H of Table 8,
pilocarpine, brimonidine, gatifloxacin, ketorolac, a steroid,
timolol, or a combination thereof.
[0047] An ophthalmically acceptable liquid or solution should be
tolerable to a patient for topical ophthalmic use. Additionally, an
ophthalmically acceptable liquid may be packaged for single use, or
contain a preservative to prevent contamination over multiple
uses.
[0048] For ophthalmic application, solutions or medicaments may be
prepared using a physiological saline solution as a major vehicle.
Ophthalmic solutions may be maintained at a comfortable pH with an
appropriate buffer system. The formulations may also contain
conventional, pharmaceutically acceptable preservatives,
stabilizers and surfactants.
[0049] An ophthalmically acceptable liquid may include a buffer.
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, such as phosphate and citrate or
borate and citrate. Acids or bases, such as HCl and NaOH, may be
used to adjust the pH of these formulations as needed. The amount
of buffer used may vary. In some embodiments, the buffer may have a
concentration in a range of about 1 nM to about 100 mM.
[0050] An ophthalmically acceptable liquid may include a
preservative. The preservative may vary, and may include any
compound or substance suitable for reducing or preventing 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; oxidizing
preservatives such as stabilized oxychloro complexes (e.g.
PURITE.RTM.); and other preservatives such as benzyl alcohol. In
some embodiments, a preservative may comprise benzalkonium
chloride, a stabilized oxychloro complex, or a combination thereof.
In some embodiments, a preservative may have a concentration of
about 10 ppm to about 200 ppm, about 10 ppm to about 300 ppm, or
about 50 ppm to about 150 ppm.
[0051] An ophthalmically acceptable liquid may include a
co-solubilizer such as a surfactant. The surfactant may vary, and
may include any compound 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. Examples of surfactants
may 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 & veg.); 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 &
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),
a polyoxyethylene-polyoxypropylene block copolymer (CAS No.
9003-11-6, available as PLURONIC.RTM. F-68 from BASF),
polyoxyethylene 40 stearate (POE40 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), or
polyoxyethyleneglyceroltriricinoleate 35 (CAS No. 61791-12-6,
available as CREMOPHOR EL.RTM. from BASF), ethoxylated castor oil,
such as Cremophor EL (CAS Number 61791-12-6). 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%.
[0052] Other compounds, such as a cyclodextrin, may be used as a
co-solubilizer. Examples of cyclodextrins may include
.alpha.-cyclodextrin; .beta.-cyclodextrin; .gamma.-cyclodextrin;
cyclodextrin derivatives such as ether and mixed ether derivatives
and those derivatives bearing sugar residues such as hydroxyethyl,
hydroxypropyl (including 2- and 3-hydroxypropyl) and
dihydroxypropyl ethers, their corresponding mixed ethers and
further mixed ethers with methyl or ethyl groups, such as
methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl
ethers of .alpha.-, .beta.- and .gamma.-cyclodextrin; maltosyl,
glucosyl and maltotriosyl derivatives of .beta.- and
.gamma.-cyclodextrin, which may contain one or more sugar residues,
e.g. glucosyl or diglucosyl, maltosyl or dimaltosyl, as well as
various mixtures thereof, e.g. a mixture of maltosyl and dimaltosyl
derivatives; cyclodextrin derivatives comprising anionic functional
groups such as sulfobutylether derivatives, sulfonates, phosphates,
and the like, such as hydroxypropyl-.beta.-cyclodextrin,
hydroxypropyl-.gamma.-cyclodextrin,
sulfobutylether-.beta.-cyclodextrin, and
sulfobutylether-.gamma.-cyclodextrin, as well as
hydroxyethyl-.beta.-cyclodextrin,
hydroxyethyl-.gamma.-cyclodextrin,
dihydroxypropyl-.beta.-cyclodextrin, glucosyl-.beta.-cyclodextrin,
diglucosyl-.beta.-cyclodextrin, maltosyl-.beta.-cyclodextrin,
maltosyl-.gamma.-cyclodextrin, maltotriosyl-.beta.-cyclodextrin,
maltotriosyl-.gamma.-cyclodextrin and
dimaltosyl-.beta.-cyclodextrin, and mixtures thereof such as
maltosyl-.beta.-cyclodextrin/dimaltosyl-.beta.-cyclodextrin.
Cyclodextrins may be present at a concentration of about 0.01% to
about 30%, about 0.01% to about 10%, or about 1% to about 10%.
[0053] In some embodiments, a co-solubilizer may comprise sorbitan
monostearate, a polyoxyethylene-polyoxypropylene block copolymer,
polyoxyethyleneglyceroltriricinoleate 35, a cyclodextrin, or a
combination thereof. An ophthalmically acceptable liquid may
include a vehicle. Examples of suitable vehicles include, but are
not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl
cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl
cellulose, and acrylates (e.g. PEMULEN.RTM.).
[0054] An ophthalmically acceptable liquid may include an
osmolality agent. 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, organic
compounds such as propylene glycol, mannitol, or glycerin, or any
other suitable ophthalmically acceptable osmolality adjustor. In
some embodiments, an osmolality agent may comprise propylene
glycol, glycerin, mannitol, sodium chloride, or a combination
thereof.
[0055] The amount of osmolality agent may vary depending upon
whether an isotonic, hypertonic, or hypotonic 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%.
[0056] An ophthalmically acceptable liquid may include 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, sodium metabisulfite, sodium thiosulfate,
acetylcysteine, butylated hydroxyanisole, and butylated
hydroxytoluene.
[0057] An ophthalmically acceptable liquid may include a chelating
agent. The chelating agent may vary, and may include any compound
or substance that is capable of chelating a metal. A useful
chelating agent is edetate disodium, although other chelating
agents may also be used in place or in conjunction with it.
[0058] Compositions may be aqueous solutions or emulsions, or some
other acceptable liquid form. For an emulsion, one or more oils may
be used to form the emulsion. 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.
[0059] Some ophthalmically acceptable compositions may comprise an
ointment or a cream vehicle that may include a polymer thickener,
water, preservatives, active surfactants or emulsifiers,
antioxidants, and a solvent or mixed solvent system.
[0060] Any polymer thickeners suitable for ophthalmic application
may be used, such as hydrophilic thickeners frequently used in the
pharmaceutical industries. For example, a hydrophilic thickener may
comprise an acrylic acid or acrylate polymer, either cross-linked
or non cross-linked such as a CARBOPOL.RTM. (B.F. Goodrich,
Cleveland, Ohio), including CARBOPOL 980.RTM.. These polymers may
dissolve in water and may form a clear or slightly hazy gel upon
neutralization with a base such as sodium hydroxide, potassium
hydroxide, triethanolamine, or other amine bases. Other
commercially available thickeners may include HYPAN.RTM. (Kingston
Technologies, Dayton, N.J.), NATROSOL.RTM. (Aqualon, Wilmington,
Del.), KLUCEL.RTM. (Aqualon, Wilmington, Del.), or STABILEZE.RTM.
(ISP Technologies, Wayne, N.J.). KLUCEL.RTM. is a cellulose polymer
that may be dispersed in water and may form a uniform gel upon
complete hydration. Other useful gelling polymers may include
hydroxyethylcellulose, hydroxypropylcellulose, cellulose gum,
MVA/MA copolymers, MVE/MA decadiene crosspolymer, PVM/MA copolymer,
etc.
[0061] Any effective amount of polymer thickener may be used, such
as about 0.2% to about 4% weight/weight of the composition. A
useful weight/weight percent range for CARBOPOL.RTM. may be about
0.1% to about 5%, about 0.1% to about 2%, or about 0.5% to about
2%, a useful weight/weight percent range for NATROSOL.RTM. and
KLUCEL.RTM. may be about 0.5% to about 4%, and a useful
weight/weight percent range for HYPAN.RTM. or STABILEZE.RTM. may be
about 0.5% to about 4%.
[0062] Preservatives used in an ophthalmic ointment or cream and
may comprise about 0.1 to about 10%, about 1% to about 5%, about
0.05% to 0.5%, or about 0.05% to about 0.1% weight/weight of the
total composition. The use of preservatives may help to reduce or
prevent microorganism growth. Some useful preservatives may include
benzyl alcohol, methylparaben, propylparaben, butylparaben,
chloroxylenol, sodium benzoate, DMDM Hydantoin,
3-Iodo-2-Propylbutyl carbamate, potassium sorbate, chlorhexidine
digluconate, etc.
[0063] An ophthalmic composition may be applied in a topical cream.
Topical creams may be oil-in-water emulsions or water-in-oil
emulsions. An oil phase may include but is not limited to fatty
alcohols, acids, or esters such as isopropyl myristate, cetyl
palmitate, cetyl alcohol, stearyl alcohol, stearic acid, isopropyl
stearate, glycerol stearate, mineral oil, white petrolatum, or
other oils alone or in combination. An oil phase may be about 1% to
about 50%, about 1% to about 3%, about 10% to about 30%, about 10%
to about 25%, about 10% to about 20%, about 20% to about 30%, or
about 10% to about 15% weight/weight.
[0064] An ophthalmic composition such as those described herein may
be useful to treat or prevent ophthalmic diseases or conditions,
such as one of the following: MACULOPATHIES/RETINAL DEGENERATION:
Non-exudative age related macular degeneration (ARMD), exudative
age related macular degeneration (ARMD), choroidal
neovascularization, diabetic retinopathy, acute macular
neuroretinopathy, central serous chorioretinopathy, cystoid macular
edema, diabetic macular edema.
[0065] UVEITIS/RETINITIS/CHOROIDITIS: Acute multifocal placoid
pigment epitheliopathy, Behcet's disease, birdshot
retinochoroidopathy, infectious (syphilis, lyme, tuberculosis,
toxoplasmosis), intermediate uveitis (pars planitis), multifocal
choroiditis, multiple evanescent white dot syndrome (MEWDS), ocular
sarcoidosis, posterior scleritis, serpignous choroiditis,
subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-Harada
syndrome.
[0066] VASUCLAR DISEASES/EXUDATIVE DISEASES: Retinal arterial
occlusive disease, central retinal vein occlusion, disseminated
intravascular coagulopathy, branch retinal vein occlusion,
hypertensive fundus changes, ocular ischemic syndrome, retinal
arterial microaneurysms, Coat's disease, parafoveal telangiectasis,
hemi-retinal vein occlusion, papillophlebitis, central retinal
artery occlusion, branch retinal artery occlusion, carotid artery
disease (CAD), frosted branch angiitis, sickle cell retinopathy and
other hemoglobinopathies, angioid streaks, familial exudative
vitreoretinopathy, Eales disease.
[0067] TRAUMATIC/SURGICAL: Sympathetic ophthalmia, uveitic retinal
disease, retinal detachment, trauma, laser, PDT, photocoagulation,
hypoperfusion during surgery, radiation retinopathy, bone marrow
transplant retinopathy.
[0068] PROLIFERATIVE DISORDERS: Proliferative vitreal retinopathy
and epiretinal membranes, proliferative diabetic retinopathy,
retinopathy of prematurity (retrolental fibroplastic).
[0069] INFECTIOUS DISORDERS: Ocular histoplasmosis, ocular
toxocariasis, presumed ocular histoplasmosis syndrome (PONS),
endophthalmitis, toxoplasmosis, retinal diseases associated with
HIV infection, choroidal disease associated with HIV infection,
uveitic disease associated with HIV infection, viral retinitis,
acute retinal necrosis, progressive outer retinal necrosis, fungal
retinal diseases, ocular syphilis, ocular tuberculosis, diffuse
unilateral subacute neuroretinitis, myiasis.
[0070] GENETIC DISORDERS: Retinitis pigmentosa, systemic disorders
with associated retinal dystrophies, congenital stationary night
blindness, cone dystrophies, fundus flavimaculatus, Best's disease,
pattern dystrophy of the retinal pigmented epithelium, X-linked
retinoschisis, Sorsby's fundus dystrophy, benign concentric
maculopathy, Bietti's crystalline dystrophy, pseudoxanthoma
elasticum, Osler Weber syndrome.
[0071] RETINAL TEARS/HOLES: Retinal detachment, macular hole, giant
retinal tear.
[0072] TUMORS: Retinal disease associated with tumors, solid
tumors, tumor metastasis, benign tumors, for example, hemangiomas,
neurofibromas, trachomas, and pyogenic granulomas, congenital
hypertrophy of the RPE, posterior uveal melanoma, choroidal
hemangioma, choroidal osteoma, choroidal metastasis, combined
hamartoma of the retina and retinal pigmented epithelium,
retinoblastoma, vasoproliferative tumors of the ocular fundus,
retinal astrocytoma, intraocular lymphoid tumors.
[0073] MISCELLANEOUS: Punctate inner choroidopathy, acute posterior
multifocal placoid pigment epitheliopathy, myopic retinal
degeneration, acute retinal pigment epithelitis, ocular
inflammatory and immune disorders, ocular vascular malfunctions,
corneal graft rejection, neovascular glaucoma and the like.
Example 1
[0074] Table 1 summarizes solubility of bimatoprost in vehicles
with 5 different solubilizers over a range of temperatures.
Solubility of bimatoprost in vehicle containing PCA-PVA-PEG is
higher than other solubilizers at room temperature (RT) and
elevated temperatures.
TABLE-US-00001 TABLE 1 Bimatoprost Solubility in five different
formulation vehicles at different temperatures. At room temperature
and elevated temperatures, PCA-PVA-PEG shows the highest
solubilization for bimatoprost Solubilizer used (conc. Temperature
Solubility of solubilizer is 1%) (.degree. C.) (mg/ml) SOLUPLUS
.RTM. 5 0.427* (PCA-PVA-PEG) 25 3.513* 40 4.751* SOLUTOL .RTM. HS
15 5 1.502** 25 1.320** 40 1.237** Polysorbate 20 5 1.242** 25
1.178** 40 1.050** POE 40 Stearate 5 1.268** 25 1.213** 40 1.149**
Polysorbate 80 5 1.678** 25 1.524** 40 1.457** *Measured at 1 week
only; **Measured at 8 weeks
Example 2
Data in Support of Improved BAK Efficacy
[0075] Preservative titration studies were performed to compare the
efficacy of BAK in formulations using different solubilizers.
Typically, it is seen that in the presence of surfactants, the
preservative efficacy of BAK is significantly reduced. As a result,
higher levels of BAK may be required to meet the preservative
criteria for ophthalmic products as defined in USP <51> and
European Pharmacopeial 5.1.3 chapters. It was seen that when
PCA-PVA-PEG was used as a solubilizer, the preservative criteria
were met at lower levels of BAK as compared to all other
surfactants tested as summarized in Table 2. In fact, formulations
containing PCA-PVA-PEG met PhEurA criteria with as low as 50 ppm
BAK, which is similar to formulations containing no
solubilizers.
TABLE-US-00002 TABLE 2 Summary of Preservative Titration to Failure
results for formulations containing different solubilizers. APET
Criteria Met.sup.1 1% PS80 1% SOLUTOL .RTM. 1% PS20 1% POE40 BAK 1%
F1 Solution F2 Solution F3 Solution F4 Solution (ppm) SOLUPLUS
.RTM. Series Series Series Series 50 Ph Eur-A USP Ph Eur-B USP USP
75 Not tested Ph Eur-B Ph Eur-B Ph Eur-B USP 100 Ph Eur-A Ph Eur-B
Ph Eur-A Ph Eur-B Ph Eur-B 120 Ph Eur-A Ph Eur-B Ph Eur-A Ph Eur-B
Ph Eur-B 140 Ph Eur-A Ph Eur-A Ph Eur-A Ph Eur-A Ph Eur-B 160 Ph
Eur-A Ph Eur-A Ph Eur-A Ph Eur-A Ph Eur-B Expt # 22955 22358 22839
22861 22861 .sup.1APET criteria as defined in USP <51> and
European Pharmacopeia (Ph Eur) 5.1.3.
Example 3
Use of PCA-PVA-PEG in a Self-Preserved System
[0076] Formulations containing PCA-PVA-PEG demonstrate
antimicrobial activity even without use of any preservative.
Formulations evaluated are listed in Table 3 along with the APET
testing results. It was found that formulations containing 1%
PCA-PVA-PEG and phosphate-citrate buffer (formulation 1) met USP
criteria for all organisms. Replacing phosphate buffer with borate
buffer and removing EDTA allows the formulations to meet PhEurB
criteria for all organisms at PCA-PVA-PEG concentrations of 0.5%-1%
(formulations 3-5).
TABLE-US-00003 TABLE 3 Effect of PCA-PVA-PEG Level and Boric Acid
Buffer in APET testing Concentration (% w/v) Formulation 1 2 3 4 5
6 7 SOLUPLUS .RTM. 1.0 1.0 1.0 0.75 0.5 0.25 0.1 (PCA-PVA-PEG)
Edetate Disodium 0.01 0.01 0 0 0 0 0 Boric Acid 0 0.6 0.6 0.6 0.6
0.6 0.6 Sodium Phosphate 0.268 0 0 0 0 0 0 Dibasic Heptahydrate
Citric Acid 0.014 0 0 0 0 0 0 Monohydrate Glycerin 1.2 1.2 1.2 1.2
1.2 1.2 1.2 Mannitol 2.0 0 0 0 0 0 0 1N NaOH/1N HCl 7.4 7.4 7.4 7.4
7.4 7.4 7.4 Purified Water QS QS QS QS QS QS QS APET results (Expt
# 22994) PhEurA Fail Fail Fail Fail Fail Fail Fail PhEurB Fail Fail
Pass Pass Pass Fail Fail USP Pass Pass Pass Pass Pass Pass Pass
Example 4
Synergistic Effect of PCA-PVA-PEG on Antimicrobial Efficacy of
Purite as Preservative
[0077] Purite preserved formulations typically meet PhEurB criteria
for APET due to lack of sufficient kill for bacteria at the 6 hour
time point and mold at the 7 day time point. Combination of Purite
with PCA-PVA-PEG (SOLUPLUS.RTM.), it was seen that these
formulations meet PhEurA criteria (Table 4). It was observed that a
combination of 0.5% SOLUPLUS.RTM. with 100 ppm Purite was
sufficient to meet PhEurA criteria for APET (Table 5). More
importantly, excellent log-kill ratios were observed for all
organisms tested at the 6 hour time point (for bacteria) and 7 day
time point (for fungi).
[0078] The combination of Purite, Boric acid and PCA-PVA-PEG would
be of utility in over-the-counter (OTC) products. Addition of 0.5%
PCA-PVA-PEG in Allergan products such as REFRESH.RTM., REFRESH
PLUS.RTM., REFRESH DRYEYE.RTM., OPTIVE.RTM. and Next Generation
Emulsion would allow these products to meet PhEurA criteria for
APET testing. Similarly, for drug products such as ALPHAGAN P.RTM.,
addition of PCA-PVA-PEG and meeting PhEurA criteria would make this
product suitable for filing in the EU.
TABLE-US-00004 TABLE 4 Effect of PCA-PVA-PEG and boric acid in
combination with Purite on APET Concentration (% w/v) Formulation
Control 1 2 3 4 5 SOLUPLUS .RTM..RTM. 1.0 1.0 1.0 1.0 1.0 1.0
(Polyvinyl caprolactam- polyvinyl acetate- polyethylene glycol
graft copolymer) Purite 0 0.002 0.004 0.006 0.008 0.010 Boric Acid
0.6 0.6 0.6 0.6 0.6 0.6 Glycerin 1.2 1.2 1.2 1.2 1.2 1.2 1N NaOH/1N
HCl 7.4 7.4 7.4 7.4 7.4 7.4 Purified Water QS QS QS QS QS QS APET
results (Expt # 22994) PhEurA Fail Pass Pass Pass Pass Pass PhEurB
Pass Pass Pass Pass Pass Pass USP Pass Pass Pass Pass Pass Pass
TABLE-US-00005 TABLE 5 Effect of different levels of PCA-PVA-PEG
with Purite on APET Concentration (% w/v) Formulation 1 2 3 4 5 6
SOLUPLUS .RTM..RTM. 1.0 0.75 0.5 0.25 0.1 0 (Polyvinyl caprolactam-
polyvinyl acetate- polyethylene glycol graft copolymer) Purite 0.01
0.01 0.01 0.01 0.01 0.01 Boric Acid 0.6 0.6 0.6 0.6 0.6 0.6
Glycerin 1.5 1.5 1.5 1.5 1.5 1.5 1N NaOH/1N HCl 7.4 7.4 7.4 7.4 7.4
7.4 Purified Water QS QS QS QS QS QS APET 14 day results (Expt
#23017) PhEurA Pass Pass Pass Fail Fail Fail PhEurB Pass Pass Pass
Pass Pass Pass USP Pass Pass Pass Pass Pass Pass
Example 5
Cytotoxicity Testing of PCA-PVA-PEG Formulations
[0079] Formulations containing PCA-PVA-PEG ranging from a
concentration of 0.25% to 2% were evaluated in Human Corneal
Epithelial Cells in-vitro. The cells were incubated with the
formulations for 16 hours at 37.degree. C. and the cell viability
was measured. It was found that all the PCA-PVA-PEG formulations
were non-cytotoxic. Viability of cells treated with PCA-PVA-PEG
containing formulations was comparable to those without PCA-PVA-PEG
or with Polysorbate 80.
TABLE-US-00006 TABLE 6 Cytotoxicity testing of Formulations
containing PCA-PVA-PEG Concentration (% w/v) Formulation 1 2 3 4 5
6 7 Solubilizer: SOLUPLUS .RTM. 1.0 0.75 0.5 0.25 0.1 0.0 0.0
Polyvinyl caprolactam- polyvinyl acetate- polyethylene glycol graft
copolymer Polysorbate 80 0.0 0.0 0.0 0.0 0.0 0.0 1.0 Boric Acid 0.6
0.6 0.6 0.6 0.6 0.6 0.6 Glycerin 1.5 1.5 1.5 1.5 1.5 1.5 1.5
Mannitol 0 0 0 0 0 0 0 1N NaOH/1N HCl 7.4 7.4 7.4 7.4 7.4 7.4 7.4
Purified Water QS QS QS QS QS QS QS Results for in-vitro
cytotoxicity % Viability compared to 84 .+-. 3 83 .+-. 3 92 .+-. 3
89 .+-. 6 90 .+-. 2 92 .+-. 1 90 .+-. 4 normal saline
Example 6
Data Showing Improved Stability of Drug Substances in Formulations
Containing PCA-PVA-PEG
[0080] Stability of cyclosporine analogs was evaluated in
formulations using Polysorbate 80 (PS80) or PCA-PVA-PEG as
solubilizer. Improved stability of the compounds was observed when
either PCA-PVA-PEG or SOLUTOL.RTM. was used as the solubilizer. An
example for Compound H is shown in Table 8. The formulations were
prepared in a vehicle containing a citrate-phosphate buffer at pH
7.2 and using PS80, SOLUTOL.RTM. or PCA-PVA-PEG at 1% concentration
as the solubilizer. Samples were stored at 40.degree. C. conditions
and analyzed after 4 weeks. With either SOLUTOL.RTM. or
PCA-PVA-PEG, the recovery of the drug was two-fold higher than that
compared with PS80. Compound H is susceptible to degradation by
oxidation. It is believed that both SOLUTOL.RTM. and PCA-PVA-PEG
may improve stability for these types of compounds by reducing
oxidation.
TABLE-US-00007 TABLE 7 Stability of Compound H at 0.01% in MP500
bottles at 40.degree. C. Vehicle % Recovery at 4-weeks at
40.degree. C. 1% PS80 33.9 1% SOLUTOL .RTM. 72.3 1% SOLUPLUS .RTM.
69.6 Other components of the vehicle: citrate/phosphate buffer and
NaCl at pH~7.2
Example 7
Examples of Classes of APIs and Formulations that May be Formulated
with PCA-PVA-PEG for Ophthalmic Use
[0081] PCA-PVA-PEG may be used as a solubilizer or an additive to
formulations with a large variety of actives. These include, but
are not limited to, examples listed in Table 8. Table 9 lists
examples of solution formulations that may be prepared with
PCA-PVA-PEG. It may be used in formulations other than aqueous
solution as well. These include, but are not limited to, examples
listed in Table 10.
TABLE-US-00008 TABLE 8 Examples of APIs that may be formulated
using PCA-PVA-PEG Typical concentration range in Ophthalmic Drug
class Examples products Immuno- Cyclosporine A, Cyclosporine
analogs 0.001-0.4% suppressant Alpha- Phentolamine 0.001-2%
adrenergic antagonist Steroids Testosterone, Dexamethasone,
0.001-5% Prednisolone EP-2 agonists Compound A (below) 0.001-0.1%
Compound B (below) 0.0002-0.05% Compound E (below) 0.001-0.1%
Muscarinics Pilocarpine 0.1-6.0% Prostaglandins Bimatoprost,
Latanoprost 0.001-0.1 Alpha-agonists Brimonidine, Compounds C, D, E
and F 0.001-1% (below) Antibiotics/anti- Gatifloxicin 0.1-1%
infectives Anti- Ketorolac 0.01-1% inflammatory Steroids Beta
Blockers Timolol 0.05-0.5% Compound A ##STR00002## IUPAC Name:
isopropyl 5-((((R)-1- (4-((S)-1- hydroxyhexyl)phenyl)-
5-oxopyrrolidin-2- yl)methoxy)methyl) thiophene-2- carboxylate
Compound B ##STR00003## IUPAC Name: isopropyl 5-(3-((S)-1-
(4-((S)-1- hydroxyhexyl)phenyl)- 5-oxopyrrolidin-2-
yl)propyl)thiophene-2- carboxylate Compound C ##STR00004## IUPAC
Name: 3-[(1S)-1-(1H- imidazol- 4-yl)ethyl]-2- methylbenzyl 2-
methylpropanoate Compound D ##STR00005## IUPAC Name: 3-[(1S)-
1-(1H-imidazol-4- yl)ethyl]-2- methylbenzyl pivalate Compound E
##STR00006## IUPAC Name: 4- bromo-N-imidazolidin- 2-ylidene-1H-
benzimidazol-5-amine Compound F ##STR00007## IUPAC Name:
(S)-(+)-7-(1H- Imidazol- 4-ylmethyl)-5,6,7,8- tetrahydro-quinoline
Compound G ##STR00008## IUPAC Name: 2-hydroxyethyl 5-(3-
{(2S)-1-[4-(1- hydroxyhexyl)phenyl]- 5-oxopyrrolidin-2-
yl}propyl)thiophene-2- carboxylate Compound H ##STR00009##
Cyclosporine Analog ##STR00010##
TABLE-US-00009 TABLE 9 Examples of Solution Formulations using
PCA-PVA-PEG Examples of typical Ingredient conc. range type
Ingredient % (w/w) Active Any one or more of the drug Any
concentration Ingredients substances listed in Table 8 of drug
substances in ranges listed in Table 8 Solubilizer/ PCA-PVA-PEG
0.001-5% Preservative/ Co-preservative Secondary SPAN .TM. 60 0-1%
solubilizer/ Pluronic F68 0-5% Co-solubilizer POE40Stearate 0-1%
(may or may not CREMOPHOR EL .RTM. 0-1% be required) Cyclodextrins
0-10% Osmolality Propylene glycol 0-2% agents (any one Glycerin
0-2.5% or two or more in Mannitol 0-5% combinations) Sodium
chloride 0-1% Buffers (Any one Phosphate buffer 1-100 mM of the
buffers Phosphate citrate buffer 1-100 mM listed) NaOH/Trolamine
1-100 mM Lactate buffer 1-100 mM Borate buffer 1-100 mM Borate
citrate 1-100 mM NaOH or HCl for pH adjustment Q.S Preservatives
None--Non preserved NA (Any one or in BAK 10-200 ppm combination)
Purite 10-300 ppm Water QS
TABLE-US-00010 TABLE 10 Examples of formulations containing
PCA-PVA-PEG with non- aqueous components Ointment Micro- Examples
Cream Examples emulsion Active Ingredients % (w/w) Any one or more
of the drug Any concentration of drug substances substances listed
in Table 8 in ranges listed in Table 8 Excipients % (w/w) SOLUPLUS
.RTM. 0.1-5 0.1-3 0.1-3 0.67 Water QSAD QSAD QSAD qs 100% Propylene
glycol 10-15 5-20 -- 2 Glycerin -- -- 8-12 Benzyl alcohol
(preservative) 1-5 -- -- Isopropyl myristate -- 10-25 -- Carbopol
980 -- 0.1-2% 0.1-2 NaOH/ -- QS pH QS pH Trolamine 5.5-6.0 5.5-6.0
SPAN .TM. 60 1-5 -- -- Petrolatum 20-30 -- -- Stearyl alcohol 10-30
-- 1-3 Pluronic F68 -- 0.1-2 -- Stearic Acid -- -- 10-15 Cetyl
Alcohol -- -- 1-3 Methyl/Propylparabens -- -- PP 0.05 MP 0.1 Capmul
0.67 CREMOPHOR EL .RTM. 0.67 Lipid Nanoparticle Emulsion
Ingredients % (w/w) Active Ingredients Any concentration of drug
substances in Any one or more of the drug ranges listed in
substances listed in Table 8 Table 8 Excipients % (w/w) Medium
chain triglyceride 10-40 -- Oleic acid 0-0.5% -- Water QS -- Castor
Oil -- 1.25 SOLUPLUS .RTM. 0.01-5 0.01-2 Glycerin -- 2 Carbopol 980
0.1-1% 0.1-1 Trolamine Qs ad Qs ad
[0082] Examples of formulation vehicle compositions with
Soluplus.RTM. in Tables 11-17. All of the formulations disclosed in
Tables 11-17 may include an active agent from Table 8.
TABLE-US-00011 TABLE 11 Soluplus .RTM. containing formulation
vehicles with Boric acid buffer (Preservative-free) Concentration
(% w/v) Ingredients Range Examples Soluplus .RTM. 0.1-10 10.0 2.0
1.0 1.0 0.75 0.5 0.25 0.1 (Polyvinyl caprolactame- polyvinyl
acetate- polyethylene glycol graft copolymer) Boric Acid 0.1-1 0.6
0.6 0.6 0.6 0.6 0.6 0.6 0.6 Glycerin 1.2 1.2 1.2 1.2 1.2 1.2 1.2
1.2 1.2 1N NaOH/1N 5.0-8.2 7.4 7.4 7.4 7.4 7.4 7.4 7.4 7.4 HCl Qs
to pH Water QS QS QS QS QS QS QS QS QS
TABLE-US-00012 TABLE 12 Soluplus .RTM. containing formulation
vehicles with Boric acid buffer and Purite .RTM. as preservative
Concentration (% w/v) Ingredients Range Examples Soluplus .RTM.
0.1-10 10.0 2.0 1.0 1.0 0.75 0.5 0.25 0.1 (Polyvinyl caprolactame-
polyvinyl acetate- polyethylene glycol graft copolymer) Boric Acid
0.1-1 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 Glycerin 1.2 1.2 1.2 1.2 1.2
1.2 1.2 1.2 1.2 Purite .RTM. 0.002-0.02 50 50 100 100 100 100 100
100 1N NaOH/1N HCl pH 5.0-8.2 7.4 7.4 7.4 7.4 7.4 7.4 7.4 7.4 Qs to
pH Water QS QS QS QS QS QS QS QS QS
TABLE-US-00013 TABLE 13 Soluplus .RTM. containing formulation
vehicles with citrate-phosphate buffer (preservative-free)
Concentration (% w/v) Ingredients Range Examples Soluplus .RTM.
0.1-10 1.0 1.0 1.0 2.0 2.0 5.0 0.5 0.5 (Polyvinyl caprolactame-
polyvinyl acetate- polyethylene glycol graft copolymer) Sodium
Phosphate 0.03-3 0.268 0.268 0.268 0.268 0.268 0.268 0.268 0.268
Dibasic Heptahydrate Citric Acid 0.001-0.15 0.014 0.014 0.014 0.014
0.014 0.014 0.014 0.014 Monohydrate Glycerin 0-3 1.2 1.2 1.2 1.2
1.2 1.2 1.2 1.2 Mannitol 0-5 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 1N
NaOH/1N HCl 5.0-8.2 7.3 7.4 7.4 7.4 7.4 7.4 7.4 7.4 Qs to pH Water
QS QS QS QS QS QS QS QS
TABLE-US-00014 TABLE 14 Soluplus .RTM. containing formulation
vehicles with citrate-phosphate buffer and Benzalkonium chloride
(BAK) as preservative Concentration (% w/v) Ingredients Range
Examples Soluplus .RTM. 0.1-10 1.0 1.0 1.0 2.0 2.0 5.0 0.5 0.5
(Polyvinyl caprolactame- polyvinyl acetate- polyethylene glycol
graft copolymer) Benzalkonium Chloride 0.003-0.02 0.005 0.010 0.020
0.012 0.014 0.016 0.01 0.020 Sodium Phosphate 0.03-3 0.268 0.268
0.268 0.268 0.268 0.268 0.268 0.268 Dibasic Heptahydrate Citric
Acid 0.001-0.15 0.014 0.014 0.014 0.014 0.014 0.014 0.014 0.014
Monohydrate Glycerin 0-3 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 Mannitol
0-5 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 1N NaOH/1N HCl 5.0-8.2 7.3 7.4
7.4 7.4 7.4 7.4 7.4 7.4 Qs to pH Water QS QS QS QS QS QS QS QS
TABLE-US-00015 TABLE 15 Soluplus .RTM. containing formulation
vehicles with citrate-phosphate buffer, Benzalkonium chloride (BAK)
as preservative and EDTA Concentration (% w/v) Ingredients Range
Examples Soluplus .RTM. 0.1-10 1.0 1.0 1.0 2.0 2.0 5.0 0.5 0.5
(Polyvinyl caprolactame- polyvinyl acetate- polyethylene glycol
graft copolymer) Benzalkonium Chloride 0.003-0.02 0.005 0.010 0.020
0.012 0.014 0.016 0.01 0.020 Edetate Disodium 0-0.05 0.01 0.01 0.01
0.01 0.01 0.01 0.005 0.005 Sodium Phosphate 0.03-3 0.268 0.268
0.268 0.268 0.268 0.268 0.268 0.268 Dibasic Heptahydrate Citric
Acid 0.001-0.15 0.014 0.014 0.014 0.014 0.014 0.014 0.014 0.014
Monohydrate Glycerin 0-3 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 Mannitol
0-5 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 1N NaOH/1N HCl 5.0-8.2 7.3 7.4
7.4 7.4 7.4 7.4 7.4 7.4 Qs to pH Water QS QS QS QS QS QS QS QS
TABLE-US-00016 TABLE 16 Examples of Emulsion Vehicles with Soluplus
(Preservative-Free) Concentration (% w/v or % w/w) Ingredients
Range Examples Castor Oil 0.1-10 0.25 0.5 1.25 1.25 0.25 0.5 1.25
0.25 0.5 1.25 Polysorbate 80 0-2 0 0 0 0 0.25 0.5 0.5 0 0 0 Solutol
.RTM. 0-5 0 0.5 0.5 1 0.25 0.5 0.5 0 0 0 Polyoxyethylene 0-5 0.25
0.5 0.5 1 0 0 0 0.5 1 2 40 Stearate Soluplus .RTM. 0.01-2 0.25 0.5
2 2 0.5 0.5 1.0 1 2 2 (Polyvinyl caprolactame- polyvinyl acetate-
polyethylene glycol graft copolymer) Glycerin 0.5-3 2.5 2.5 2.5 2.5
2.5 2.5 2.5 2.5 2.5 2.5 Carbopol 980 0.1-1 0.1 0.1 0.1 0.1 0.1 0.1
0.1 0.1 0.1 0.1 Trolamine or QS QS to pH 6 to 8 NaOH Water QS to QS
QS QS QS QS QS QS QS QS QS 100%
TABLE-US-00017 TABLE 17 Examples of Emulsion Vehicles with Soluplus
(Preserved with Purite, Benzalkonium chloride or combination). Any
of the vehicles in Table 6 with the following ingredients as
preservatives Concentration Ingredients Range Examples Purite
50-200 ppm 50 100 200 50 50 100 100 0 0 0 Benzalkonium 10-200 ppm 0
0 0 20 50 20 200 50 100 200 chloride Any of the QS to 100% w/v or %
w/w vehicles from Table 6
Example 8
[0083] Some topical ophthalmic compositions comprise a polyvinyl
capralactam-polyvinyl acetate-polyethylene glycol graft
copolymer.
Example 9
[0084] In some compositions of Example 8, the polyvinyl
capralactam-polyvinyl acetate-polyethylene glycol graft copolymer
has an average molecular weight of about 10,000 g/mol to about
500,000 g/mol.
Example 10
[0085] Some compositions of Example 8 or 9 further comprise a
therapeutically active agent.
Example 11
[0086] In some compositions of Example 10, the therapeutically
active agent comprises an immunosuppressant.
Example 12
[0087] In some compositions of Example 10, the therapeutically
active agent comprises an alpha-adrenergic antagonist.
Example 13
[0088] In some compositions of Example 10, the therapeutically
active agent comprises a prostaglandin EP2 agonist.
Example 14
[0089] In some compositions of Example 10, the therapeutically
active agent comprises a muscarinic.
Example 15
[0090] In some compositions of Example 10, the therapeutically
active agent comprises a prostaglandin.
Example 16
[0091] In some compositions of Example 10, the therapeutically
active agent comprises an alpha agonist.
Example 17
[0092] In some compositions of Example 10, the therapeutically
active agent comprises an antibiotic.
Example 18
[0093] In some compositions of Example 10, the therapeutically
active agent comprises an anti-infective agent.
Example 19
[0094] In some compositions of Example 10, the therapeutically
active agent comprises an anti-inflammatory.
Example 20
[0095] In some compositions of Example 10, the therapeutically
active agent comprises a beta blocker.
Example 21
[0096] In some compositions of Example 10, the therapeutically
active agent comprises cyclosporine A.
Example 22
[0097] In some compositions of Example 10, the therapeutically
active agent comprises a cyclosporine analog.
Example 23
[0098] In some compositions of Example 10, the therapeutically
active agent comprises phentolamine.
Example 24
[0099] In some compositions of Example 10, the therapeutically
active agent comprises testosterone.
Example 25
[0100] In some compositions of Example 10, the therapeutically
active agent comprises dexamethasone.
Example 26
[0101] In some compositions of Example 10, the therapeutically
active agent comprises prednisolone.
Example 27
[0102] In some compositions of Example 10, the therapeutically
active agent comprises bimatoprost.
Example 28
[0103] In some compositions of Example 10, the therapeutically
active agent comprises latanoprost.
Example 29
[0104] In some compositions of Example 10, the therapeutically
active agent comprises Compounds A or B of Table 8.
Example 30
[0105] In some compositions of Example 10, the therapeutically
active agent comprises pilocarpine.
Example 31
[0106] In some compositions of Example 10, the therapeutically
active agent comprises brimonidine.
Example 32
[0107] In some compositions of Example 10, the therapeutically
active agent comprises Compound C of Table 8.
Example 33
[0108] In some compositions of Example 10, the therapeutically
active agent comprises Compound D of Table 8.
Example 34
[0109] In some compositions of Example 10, the therapeutically
active agent comprises Compound E of Table 8.
Example 35
[0110] In some compositions of Example 10, the therapeutically
active agent comprises Compound F or G of Table 8.
Example 36
[0111] In some compositions of Example 10, the therapeutically
active agent comprises gatifloxacin.
Example 37
[0112] In some compositions of Example 10, the therapeutically
active agent comprises ketorolac.
Example 38
[0113] In some compositions of Example 10, the therapeutically
active agent comprises a steroid.
Example 39
[0114] In some compositions of Example 10, the therapeutically
active agent comprises timolol.
Example 40
[0115] In some compositions of Example 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,
32, 33, 34, 35, 36, 37, 38, or 39, the composition is a
solution.
Example 41
[0116] Some compositions of Example 40 further comprise a
co-solubilizer.
Example 42
[0117] In some compositions of Example 41, the co-solubilizer
comprises sorbitan monostearate.
Example 43
[0118] In some compositions of Example 41, the co-solubilizer
comprises a polyoxyethylene-polyoxypropylene block copolymer.
Example 44
[0119] In some compositions of Example 41, the co-solubilizer
comprises polyoxyethyleneglyceroltriricinoleate 35.
Example 45
[0120] In some compositions of Example 41, the co-solubilizer
comprises a cyclodextrin.
Example 46
[0121] Some compositions of Example 40, 41, 42, 43, 44, or 45
further comprise an osmolality agent.
Example 47
[0122] In some compositions of Example 46, the osmolality agent
comprises propylene glycol.
Example 48
[0123] In some compositions of Example 46, the osmolality agent
comprises glycerin.
Example 49
[0124] In some compositions of Example 46, the osmolality agent
comprises mannitol.
Example 50
[0125] In some compositions of Example 46, the osmolality agent
comprises sodium chloride.
Example 51
[0126] Some compositions of Example, 40, 41, 42, 43, 44, 45, 46,
47, 48, 49, or 50 further comprise a buffer.
Example 52
[0127] In some compositions of Example 51, the buffer comprises
phosphate.
Example 53
[0128] In some compositions of Example 51, the buffer comprises
phosphate and citrate.
Example 54
[0129] In some compositions of Example 51, the buffer comprises
trolamine.
Example 55
[0130] In some compositions of Example 51, the buffer comprises
lactate.
Example 56
[0131] In some compositions of Example 51, the buffer comprises
borate.
Example 57
[0132] In some compositions of Example 51, the buffer comprises
borate and citrate.
Example 58
[0133] Some compositions of Example, 40, 41, 42, 43, 44, 45, 46,
47, 48, 49, 50, 51, 52, 53, 54, 55, 56, or 57 further comprise a
preservative.
Example 59
[0134] In some compositions of Example 58, the preservative
comprises benzalkonium chloride.
Example 60
[0135] In some compositions of Example 58, the preservative
comprises a stabilized oxychloro complex.
Example 61
[0136] A method of solubilizing a therapeutically active agent
comprising mixing the therapeutically active agent and a polyvinyl
capralactam-polyvinyl acetate-polyethylene glycol graft copolymer
so that a composition according to any of Examples 10-60 is
formed.
Example 62
[0137] A method of stabilizing a therapeutically active agent
comprising combining the therapeutically active agent with a
polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft
copolymer to thereby improve stability of the therapeutically
active agent.
Example 63
[0138] A method of stabilizing a therapeutically active agent
comprising combining the therapeutically active agent and a
polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft
copolymer so that a composition according to any of Examples 10-60
is formed.
Example 64
[0139] A method of treating a disease affecting an eye comprising
administering a composition according to any Examples 8-60 to an
eye in need thereof.
Example 65
[0140] A 65 year old Caucasian male suffering from elevated
intraocular pressure applies one drop per day of Formula 2 of Table
18 in each eye for a period of 60 days. The patient experiences a
significant drop in IOP almost immediately which persists for the
entire 60 days of treatment wherein his intraocular pressure levels
drop to acceptable levels.
TABLE-US-00018 TABLE 18 Formulation # 1 2 8 Ingredient (% w/v)
Bimatoprost 0.01 0.01 0.01 Brimonidine (190342-LF) 0.1 0.1 0.1
Soluplus 1 1 1 Sodium phosphate 0.268 0.268 dibasic heptahydrate
Citric acid monohydrate 0.014 0.014 Sodium borate 0.095 decahydrate
Boric acid 0.229 NaCl 0.8 Glycerin 2.3 2.3 BAK 0.005 0.01 Purite
0.01 Target pH pH 7.7 .+-. 0.3 Purified Water Q.S. to 100 APET
Criteria Met USP Pass Pass Pass Ph Eur B Pass Pass Pass Ph Eur A
Pass Fail Pass
Example 66
[0141] A 71 year old African American woman suffering from elevated
intraocular pressure and open-angle glaucoma applies one drop daily
in each eye of Formula 4 from Table 19. After 30 days, her symptoms
of glaucoma improve significantly and her intraocular pressure
falls to normal levels and without significant side effects so long
as she continued daily application of Formula 4 of Table 19.
TABLE-US-00019 TABLE 19 Active Formulation # 1 2 3 4 5 6 Ingredient
(% w/v) Compound D Of Table 8 0.4 0.4 0.4 0.4 0.4 0.4 Soluplus 1 1
1 1 1 2 BAK 0 0.005 0.010 0.015 0.020 0.020 Edetate Disodium 0.01
0.01 0.01 0.01 0.01 0.01 Citric Acid Monohydrate 0.13 0.13 0.13
0.13 0.13 0.13 Sodium Phosphate Dibasic 0.2 0.2 0.2 0.2 0.2 0.2
Heptahydrate Glycerin 2.2 2.2 2.2 2.2 2.2 2.2 Target pH pH 5.4
Purified Water Q.S. to 100 APET Criteria Met USP Pass Pass Pass
Pass Pass Pass Ph Eur B Pass Pass Pass Pass Pass Pass Ph Eur A Fail
Fail Fail Fail Pass Pass
[0142] A 41 year old Caucasian female is suffering from symptoms of
dry eye, applies twice daily Formulation 2 in Table 20 in each eye.
After two days of application, the symptoms of dry eye improve
significantly.
TABLE-US-00020 TABLE 20 Formulation # 1 2 Ingredient (% w/v)
Soluplus 2 5 Boric Acid 0.6 0.6 Glycerin 2 2 Target pH pH 7.4
Purified Water Q.S. to 100 APET Criteria Met USP Pass Pass Ph Eur B
Pass Pass Ph Eur A Fail Fail
[0143] 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.
[0144] 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. 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.
[0145] 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.
[0146] 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, the claims include all modifications and
equivalents of the subject matter recited in the claims as
permitted by applicable law. Moreover, any combination of the
above-described elements in all possible variations thereof is
contemplated unless otherwise indicated herein or otherwise clearly
contradicted by context.
[0147] 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.
* * * * *